FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Doyle, SM Kravats, AN Hoskins, JR Shih, YH Stan, G Wickner, S AF Doyle, Shannon M. Kravats, Andrea N. Hoskins, Joel R. Shih, Yu-Hsuan Stan, George Wickner, Sue TI Interaction and collaboration between DnaK and ClpB during protein disaggregation SO JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS LA English DT Meeting Abstract C1 [Doyle, Shannon M.; Kravats, Andrea N.; Hoskins, Joel R.; Wickner, Sue] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Shih, Yu-Hsuan; Stan, George] Univ Cincinnati, Dept Chem, Cincinnati, OH USA. EM doyles@mail.nih.gov NR 3 TC 1 Z9 1 U1 1 U2 3 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0739-1102 EI 1538-0254 J9 J BIOMOL STRUCT DYN JI J. Biomol. Struct. Dyn. PD MAY 18 PY 2015 VL 33 SU 1 MA 50 BP 34 EP 35 DI 10.1080/07391102.2015.1032599 PG 2 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA CL1FR UT WOS:000356688600050 PM 26103261 ER PT J AU Kravats, AN Genest, O Hoskins, JR Doyle, SM Wickner, S AF Kravats, Andrea N. Genest, Olivier Hoskins, Joel R. Doyle, Shannon M. Wickner, Sue TI A region in the middle domain of E. coli Hsp90 is important for collaboration with DnaK SO JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS LA English DT Meeting Abstract C1 [Kravats, Andrea N.; Genest, Olivier; Hoskins, Joel R.; Doyle, Shannon M.; Wickner, Sue] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM andrea.kravats@nih.gov NR 1 TC 0 Z9 0 U1 1 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0739-1102 EI 1538-0254 J9 J BIOMOL STRUCT DYN JI J. Biomol. Struct. Dyn. PD MAY 18 PY 2015 VL 33 SU 1 MA 51 BP 35 EP 35 DI 10.1080/07391102.2015.1032600 PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA CL1FR UT WOS:000356688600051 PM 26103262 ER PT J AU Koonin, EV AF Koonin, Eugene V. TI Origin and evolution of adaptive immunity systems SO JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS LA English DT Meeting Abstract C1 [Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov NR 4 TC 0 Z9 0 U1 1 U2 12 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0739-1102 EI 1538-0254 J9 J BIOMOL STRUCT DYN JI J. Biomol. Struct. Dyn. PD MAY 18 PY 2015 VL 33 SU 1 MA 94 BP 61 EP 61 DI 10.1080/07391102.2015.1032708 PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA CL1FR UT WOS:000356688600091 PM 26103305 ER PT J AU Williams, RS AF Williams, R. Scott TI Aprataxin and the threat of RNA contamination in DNA SO JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS LA English DT Meeting Abstract ID X-CHROMOSOME; INACTIVATION; MAINTENANCE C1 [Williams, R. Scott] NIEHS, Genome Integr & Struct Biol Lab, US Dept HHS, NIH, Res Triangle Pk, NC 27709 USA. EM williamsrs@niehs.nih.gov NR 7 TC 1 Z9 1 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0739-1102 EI 1538-0254 J9 J BIOMOL STRUCT DYN JI J. Biomol. Struct. Dyn. PD MAY 18 PY 2015 VL 33 SU 1 MA 108 BP 68 EP 68 DI 10.1080/07391102.2015.1032666 PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA CL1FR UT WOS:000356688600104 ER PT J AU Perez-Gomez, A Bleymehl, K Stein, B Pyrski, M Birnbaumer, L Munger, SD Leinders-Zufall, T Zufall, F Chamero, P AF Perez-Gomez, Anabel Bleymehl, Katherin Stein, Benjamin Pyrski, Martina Birnbaumer, Lutz Munger, Steven D. Leinders-Zufall, Trese Zufall, Frank Chamero, Pablo TI Innate Predator Odor Aversion Driven by Parallel Olfactory Subsystems that Converge in the Ventromedial Hypothalamus SO CURRENT BIOLOGY LA English DT Article ID GRUENEBERG GANGLION NEURONS; CGMP-SIGNALING PATHWAY; DEFENSIVE BEHAVIOR; AGGRESSIVE-BEHAVIOR; SENSORY NEURONS; CAT ODOR; ANXIETY; FEAR; AMYGDALA; RAT AB The existence of innate predator aversion evoked by predator-derived chemostimuli called kairomones offers a strong selective advantage for potential prey animals. However, it is unclear how chemically diverse kairomones can elicit similar avoidance behaviors. Using a combination of behavioral analyses and single-cell Ca2+ imaging in wild-type and gene-targeted mice, we show that innate predator-evoked avoidance is driven by parallel, non-redundant processing of volatile and nonvolatile kairomones through the activation of multiple olfactory subsystems including the Grueneberg ganglion, the vomeronasal organ, and chemosensory neurons within the main olfactory epithelium. Perturbation of chemosensory responses in specific subsystems through disruption of genes encoding key sensory transduction proteins (Cnga3, Gnao1) or by surgical axotomy abolished avoidance behaviors and/or cellular Ca2+ responses to different predator odors. Stimulation of these different subsystems resulted in the activation of widely distributed target regions in the olfactory bulb, as assessed by c-Fos expression. However, in each case, this c-Fos increase was observed within thesame subnuclei of the medial amygdala and ventromedial hypothalamus, regions implicated in fear, anxiety, and defensive behaviors. Thus, the mammalian olfactory system has evolved multiple, parallel mechanisms for kairomone detection that converge in the brain to facilitate a common behavioral response. Our findings provide significant insights into the genetic substrates and circuit logic of predator-driven innate aversion and may serve as a valuable model for studying instinctive fear [1] and human emotional and panic disorders [2, 3]. C1 [Perez-Gomez, Anabel; Bleymehl, Katherin; Stein, Benjamin; Pyrski, Martina; Leinders-Zufall, Trese; Zufall, Frank; Chamero, Pablo] Univ Saarland, Sch Med, Dept Physiol, D-66421 Homburg, Germany. [Perez-Gomez, Anabel; Bleymehl, Katherin; Stein, Benjamin; Pyrski, Martina; Leinders-Zufall, Trese; Zufall, Frank; Chamero, Pablo] Univ Saarland, Sch Med, Ctr Integrat Physiol & Mol Med, D-66421 Homburg, Germany. [Birnbaumer, Lutz] NIEHS, Neurobiol Lab, Res Triangle Pk, NC 27709 USA. [Munger, Steven D.] Univ Florida, Dept Med, Dept Pharmacol & Therapeut, Div Endocrinol Diabet & Metab, Gainesville, FL 32610 USA. [Munger, Steven D.] Univ Florida, Ctr Smell & Taste, Gainesville, FL 32610 USA. RP Zufall, F (reprint author), Univ Saarland, Sch Med, Dept Physiol, D-66421 Homburg, Germany. EM frank.zufall@uks.eu RI Leinders-Zufall, Trese/B-4103-2009; OI Leinders-Zufall, Trese/0000-0002-0678-362X; Chamero, Pablo/0000-0002-4305-1073 FU Deutsche Forschungsgemeinschaft [CH 920/2-1]; International Graduate School [GK 1326]; National Institute on Deafness and Other Communication Disorders [DC005633]; University of Saarland HOMFORexzellent grant; Intramural Research Program of the NIH [Z01 ES-101643]; Volkswagen Foundation; [Sonderforschungsbereich 894] FX All animal care and experimental procedures were performed in accordance with guidelines established by the animal welfare committee of the University of Saarland. We thank Peter Mombaerts for supplying OMP-GFP and OMP-Cre mice, Martin Biel for providing Cnga3 null mice, and Lisa Stowers for the gift of the Feld4 plasmid. This work was supported by Deutsche Forschungsgemeinschaft grants CH 920/2-1 (P.C.), Sonderforschungsbereich 894 projects A16 (T.L.-Z.) and A17 (F.Z.), and International Graduate School GK 1326 (K.B.); National Institute on Deafness and Other Communication Disorders grant DC005633 (S.D.M. and F.Z.); a University of Saarland HOMFORexzellent grant (P.C.); the Intramural Research Program of the NIH to L.B. (project Z01 ES-101643); and the Volkswagen Foundation (T.L.-Z.). T.L.-Z. is also a Lichtenberg Professor of the Volkswagen Foundation. NR 46 TC 21 Z9 21 U1 1 U2 22 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 MAY 18 PY 2015 VL 25 IS 10 BP 1340 EP 1346 DI 10.1016/j.cub.2015.03.026 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CI5HN UT WOS:000354785900027 PM 25936549 ER PT J AU Guertin, KA Gu, FY Wacholder, S Freedman, ND Panagiotou, OA Reyes-Guzman, C Caporaso, NE AF Guertin, Kristin A. Gu, Fangyi Wacholder, Sholom Freedman, Neal D. Panagiotou, Orestis A. Reyes-Guzman, Carolyn Caporaso, Neil E. TI Time to First Morning Cigarette and Risk of Chronic Obstructive Pulmonary Disease: Smokers in the PLCO Cancer Screening Trial SO PLOS ONE LA English DT Article ID NICOTINE DEPENDENCE PHENOTYPE; FAGERSTROM TEST; LUNG HEALTH; SMOKING; DIAGNOSIS; COPD; QUESTIONNAIRE; PREVALENCE; PREDICTORS; SYMPTOMS AB Background Time to first cigarette (TTFC) after waking is an indicator of nicotine dependence. The association between TTFC and chronic obstructive pulmonary disease (COPD), the third leading cause of death in the United States, has not yet been reported. Methods We investigated the cross-sectional association between TTFC and prevalent COPD among 6,108 current smokers in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. COPD was defined as a self-reported diagnosis of emphysema, chronic bronchitis, or both. Current smokers in PLCO reported TTFC, the amount of time they typically waited before smoking their first cigarette of the day after waking, in four categories: <= 5, 6-30, 31-60, or >60 minutes. We used logistic regression models to investigate the association between TTFC and prevalent COPD with adjustments for age, gender, race, education, and smoking (cigarettes/day, years smoked during lifetime, pack-years, age at smoking initiation), and prior lung cancer diagnosis. Results COPD was reported by 19% of these 6,108 smokers. Individuals with the shortest TTFC had the greatest risk of COPD; compared to those with the longest TTFC (>60 minutes) the adjusted odds ratios (OR) and 95% confidence intervals (CI) for COPD were 1.48 (95% CI, 1.15-1.91), 1.64 (95% CI, 1.29-2.08), 2.18 (95% CI, 1.65-2.87) for those with TTFC 31-60 minutes, 6-30 minutes, and <= 5 minutes, respectively (P-trend <0.0001). The association between TTFC and emphysema was similar to that for bronchitis, albeit the ORs were slightly stronger for chronic bronchitis; comparing TTFC <= 5 minutes to >60 minutes, the adjusted OR (95% CI) was 2.29 (1.69-3.12) for emphysema and 2.99 (1.95-4.59) for chronic bronchitis. Conclusions Current smokers with shorter TTFC have increased risk of COPD compared to those with longer TTFC, even after comprehensive adjustment for established smoking covariates. Future epidemiologic studies, including prospective designs, should incorporate TTFC to better assess disease risk and evaluate the potential utility of TTFC as a COPD screening tool for smokers in the clinical setting. C1 [Guertin, Kristin A.; Freedman, Neal D.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Gu, Fangyi; Reyes-Guzman, Carolyn; Caporaso, Neil E.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Wacholder, Sholom; Panagiotou, Orestis A.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Guertin, KA (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM kristin.guertin@nih.gov; Caporaso@nih.gov RI Freedman, Neal/B-9741-2015; Panagiotou, Orestis/I-5934-2015 OI Freedman, Neal/0000-0003-0074-1098; Panagiotou, Orestis/0000-0001-9604-8380 FU Intramural NIH HHS NR 33 TC 2 Z9 2 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 MAY 18 PY 2015 VL 10 IS 5 AR e0125973 DI 10.1371/journal.pone.0125973 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CI7BG UT WOS:000354917300031 PM 25985429 ER PT J AU Sato, M Matsubara, T Adachi, J Hashimoto, Y Fukamizu, K Kishida, M Yang, YA Wakefield, LM Tomonaga, T AF Sato, Misako Matsubara, Tsutomu Adachi, Jun Hashimoto, Yuuki Fukamizu, Kazuna Kishida, Marina Yang, Yu-an Wakefield, Lalage M. Tomonaga, Takeshi TI Differential Proteome Analysis Identifies TGF-beta-Related Pro-Metastatic Proteins in a 4T1 Murine Breast Cancer Model SO PLOS ONE LA English DT Article ID GROWTH-FACTOR-BETA; MESENCHYMAL TRANSITION; TRANSLATION INITIATION; RECEPTOR KINASE; TISSUE SAMPLES; MAMMARY-TUMOR; SB-431542; EXPRESSION; INHIBITOR; PROLIFERATION AB Transforming growth factor-beta (TGF-beta) has a dual role in tumorigenesis, acting as either a tumor suppressor or as a pro-oncogenic factor in a context-dependent manner. Although TGF-beta antagonists have been proposed as anti-metastatic therapies for patients with advanced stage cancer, how TGF-beta mediates metastasis-promoting effects is poorly understood. Establishment of TGF-beta-related protein expression signatures at the metastatic site could provide new mechanistic information and potentially allow identification of novel biomarkers for clinical intervention to discriminate TGF-beta oncogenic effects from tumor suppressive effects. In the present study, we found that systemic administration of the TGF-beta receptor kinase inhibitor, SB-431542, significantly inhibited lung metastasis from transplanted 4T1 mammary tumors in Balb/c mice. The differentially expressed proteins in the comparison of lung metastases from SB-431542 treated and control vehicle-treated groups were analyzed by a quantitative LTQ Orbitrap Velos system coupled with stable isotope dimethyl labeling. A total of 36,239 peptides from 6,694 proteins were identified, out of which 4,531 proteins were characterized as differentially expressed. A subset of upregulated proteins in the control group was validated by western blotting and immunohistochemistry. The eukaryotic initiation factor (eIF) family members constituted the most enriched protein pathway in vehicle-treated compared with SB-43512-treated lung metastases, suggesting that increased protein expression of specific eIF family members, especially eIF4A1 and eEF2, is related to the metastatic phenotype of advanced breast cancer and can be down-regulated by TGF-beta pathway inhibitors. Thus our proteomic approach identified eIF pathway proteins as novel potential mediators of TGF-beta tumor-promoting activity. C1 [Sato, Misako; Adachi, Jun; Hashimoto, Yuuki; Fukamizu, Kazuna; Kishida, Marina; Tomonaga, Takeshi] Proteome Res Ctr, Natl Inst Biomed Innovat, Lab Proteome Res, Saito, Osaka, Japan. [Sato, Misako] Osaka City Univ, Grad Sch Med, Dept Hepatol, Osaka 558, Japan. [Matsubara, Tsutomu] Osaka City Univ, Grad Sch Med, Dept Anat & Regenerat Biol, Osaka 558, Japan. [Yang, Yu-an; Wakefield, Lalage M.] NIH, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. RP Sato, M (reprint author), Proteome Res Ctr, Natl Inst Biomed Innovat, Lab Proteome Res, Saito, Osaka, Japan. EM mmatsubara@med.osaka-cu.ac.jp; tomonaga@nibiohn.go.jp FU JSPS KAKENHI [25871241] FX MS; JSPS KAKENHI grant-in-Aid for Young Scientists (B) Grant Number 25871241 (http://www.jsps.go.jp/english/e-grants/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 4 Z9 4 U1 2 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 MAY 18 PY 2015 VL 10 IS 5 AR e0126483 DI 10.1371/journal.pone.0126483 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CI7BG UT WOS:000354917300043 PM 25993439 ER PT J AU Shi, YB AF Shi, Yun-Bo TI The 2014 Ming K Jeang Award for Excellence in Cell & Bioscience SO CELL AND BIOSCIENCE LA English DT Editorial Material AB Three research groups led by Dr. Robert Clarke of Georgetown University Medical Center, Washington, DC, USA; Dr. Lixin Wei of Shanghai Jiaotong University, Shanghai, China; and Dr. Zhiming Zhang of Xiamen University, Xiamen, Fujian, China, won the 2014 Ming K Jeang Award for Excellence in Cell & Bioscience. C1 NIH, Bethesda, MD 20892 USA. RP Shi, YB (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM shi@helix.nih.gov NR 6 TC 0 Z9 0 U1 0 U2 3 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 MAY 18 PY 2015 VL 5 AR 22 DI 10.1186/s13578-015-0014-1 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CI6BH UT WOS:000354843100001 PM 26000165 ER PT J AU Cairelli, MJ Fiszman, M Zhang, H Rindflesch, TC AF Cairelli, Michael J. Fiszman, Marcelo Zhang, Han Rindflesch, Thomas C. TI Networks of neuroinjury semantic predications to identify biomarkers for mild traumatic brain injury SO JOURNAL OF BIOMEDICAL SEMANTICS LA English DT Article DE Semantic predications; Semantic networks; Natural language processing; Degree centrality; Traumatic brain injury ID LITERATURE-BASED DISCOVERY; LANGUAGE SYSTEM UMLS; CEREBROSPINAL-FLUID; CONCUSSION; CENTRALITY; KNOWLEDGE; PATTERNS; SEQUELAE; BIOLOGY; PLAYERS AB Objective: Mild traumatic brain injury (mTBI) has high prevalence in the military, among athletes, and in the general population worldwide (largely due to falls). Consequences can include a range of neuropsychological disorders. Unfortunately, such neural injury often goes undiagnosed due to the difficulty in identifying symptoms, so the discovery of an effective biomarker would greatly assist diagnosis; however, no single biomarker has been identified. We identify several body substances as potential components of a panel of biomarkers to support the diagnosis of mild traumatic brain injury. Methods: Our approach to diagnostic biomarker discovery combines ideas and techniques from systems medicine, natural language processing, and graph theory. We create a molecular interaction network that represents neural injury and is composed of relationships automatically extracted from the literature. We retrieve citations related to neurological injury and extract relationships (semantic predications) that contain potential biomarkers. After linking all relationships together to create a network representing neural injury, we filter the network by relationship frequency and concept connectivity to reduce the set to a manageable size of higher interest substances. Results: 99,437 relevant citations yielded 26,441 unique relations. 18,085 of these contained a potential biomarker as subject or object with a total of 6246 unique concepts. After filtering by graph metrics, the set was reduced to 1021 relationships with 49 unique concepts, including 17 potential biomarkers. Conclusion: We created a network of relationships containing substances derived from 99,437 citations and filtered using graph metrics to provide a set of 17 potential biomarkers. We discuss the interaction of several of these (glutamate, glucose, and lactate) as the basis for more effective diagnosis than is currently possible. This method provides an opportunity to focus the effort of wet bench research on those substances with the highest potential as biomarkers for mTBI. C1 [Cairelli, Michael J.; Fiszman, Marcelo; Rindflesch, Thomas C.] NIH, Natl Lib Med, Bethesda, MD 20892 USA. [Zhang, Han] China Med Univ, Dept Med Informat, Shenyang 110001, Liaoning, Peoples R China. RP Cairelli, MJ (reprint author), NIH, Natl Lib Med, 38A 9N912A,8600 Rockville Pike, Bethesda, MD 20892 USA. EM mike.cairelli@nih.gov FU National Library of Medicine Research Participation Program; Intramural Research Program of the National Institutes of Health, National Library of Medicine FX This research was supported in part by an appointment to the National Library of Medicine Research Participation Program administered by the Oak Ridge Institute for Science and Education through an inter-agency agreement between the US Department of Energy and the National Library of Medicine. This study was supported in part by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 76 TC 2 Z9 2 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2041-1480 J9 J BIOMED SEMANT JI J. Biomed. Semant. PD MAY 18 PY 2015 VL 6 AR 25 DI 10.1186/s13326-015-0022-4 PG 14 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA CI7DH UT WOS:000354922600001 PM 25992264 ER PT J AU Luk, ACS Gao, HY Xiao, SZ Liao, JY Wang, DX Tu, JJ Rennert, OM Chan, WY Lee, TL AF Luk, Alfred Chun-Shui Gao, Huayan Xiao, Sizhe Liao, Jinyue Wang, Daxi Tu, Jiajie Rennert, Owen M. Chan, Wai-Yee Lee, Tin-Lap TI GermlncRNA: a unique catalogue of long non-coding RNAs and associated regulations in male germ cell development SO DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION LA English DT Article ID COMPREHENSIVE SAGE DATABASE; LARGE GENE LISTS; MOUSE SPERMATOGENESIS; TRANSCRIPT DISCOVERY; MESSENGER-RNAS; X-CHROMOSOME; EXPRESSION; DISEASE; LANDSCAPE; PROTEINS AB Spermatogenic failure is a major cause of male infertility, which affects millions of couples worldwide. Recent discovery of long non-coding RNAs (lncRNAs) as critical regulators in normal and disease development provides new clues for delineating the molecular regulation in male germ cell development. However, few functional lncRNAs have been characterized to date. A major limitation in studying lncRNA in male germ cell development is the absence of germ cell-specific lncRNA annotation. Current lncRNA annotations are assembled by transcriptome data from heterogeneous tissue sources; specific germ cell transcript information of various developmental stages is therefore under-represented, which may lead to biased prediction or fail to identity important germ cell-specific lncRNAs. GermlncRNA provides the first comprehensive web-based and open-access lncRNA catalogue for three key male germ cell stages, including type A spermatogonia, pachytene spermatocytes and round spermatids. This information has been developed by integrating male germ transcriptome resources derived from RNA-Seq, tiling microarray and GermSAGE. Characterizations on lncRNA-associated regulatory features, potential coding gene and microRNA targets are also provided. Search results from GermlncRNA can be exported to Galaxy for downstream analysis or downloaded locally. Taken together, GermlncRNA offers a new avenue to better understand the role of lncRNAs and associated targets during spermatogenesis. C1 [Luk, Alfred Chun-Shui; Gao, Huayan; Liao, Jinyue; Tu, Jiajie; Chan, Wai-Yee; Lee, Tin-Lap] Fac Med, Sch Biomed Sci, Reprod Dev & Endocrinol Program, Shatin, Hong Kong, Peoples R China. [Luk, Alfred Chun-Shui; Liao, Jinyue; Tu, Jiajie; Chan, Wai-Yee; Lee, Tin-Lap] CUHK, Shandong Univ SDU, Joint Lab Reprod Genet, Shatin, Hong Kong, Peoples R China. [Gao, Huayan; Chan, Wai-Yee; Lee, Tin-Lap] Chinese Univ Hong Kong, CUHK BGI Innovat Inst Trans Om, Shatin, Hong Kong, Peoples R China. [Xiao, Sizhe] BGI HK Res Inst, GigaScience, Tai Po Ind Estate, Hong Kong, Hong Kong, Peoples R China. [Wang, Daxi] Beijing Genom Inst Shenzhen BGI SZ, Beishan Ind Zone, Beijing, Peoples R China. [Rennert, Owen M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Lee, TL (reprint author), Fac Med, Sch Biomed Sci, Reprod Dev & Endocrinol Program, Shatin, Hong Kong, Peoples R China. EM leetl@cuhk.edu.hk RI Lee, Tin-Lap/A-7853-2009 OI Lee, Tin-Lap/0000-0002-6654-0988 FU Hong Kong Research Grant Council [469711, 468312]; CUHK [MD10783, MD11449]; Faculty of Medicine; Chinese University of Hong Kong; Division of Intramural Research of the National Institute of Child Health and Human Development FX This work was supported by funds from the General Research Fund (GRF) from Hong Kong Research Grant Council (Grant numbers 469711 and 468312) and CUHK Direct Grants (MD10783 and MD11449), Faculty of Medicine, The Chinese University of Hong Kong and the Division of Intramural Research of the National Institute of Child Health and Human Development. NR 63 TC 5 Z9 7 U1 1 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1758-0463 J9 DATABASE-OXFORD JI Database PD MAY 17 PY 2015 AR bav044 DI 10.1093/database/bav044 PG 14 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA CR0ZC UT WOS:000361051400001 ER PT J AU Fee, E AF Fee, Elizabeth TI The first American medical school: the formative years SO LANCET LA English DT Editorial Material C1 Natl Lib Med, Bethesda, MD 20894 USA. RP Fee, E (reprint author), Natl Lib Med, Bethesda, MD 20894 USA. EM feee@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 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 MAY 16 PY 2015 VL 385 IS 9981 BP 1940 EP 1941 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CI1YR UT WOS:000354541700016 PM 26090632 ER PT J AU Cai, LS Peng, YY Xie, YP Hong, JS Liow, JS Deuitch, L Hall, M Innis, R Pike, VW AF Cai, Lisheng Peng, Yiyuan Xie, Yepeng Hong, Jinsoo Liow, Jeih-San Deuitch, Lora Hall, Matthew Innis, Robert Pike, Victor W. TI Exploration of analogs of [C-11]dLop as potential probes for measuring increased P-gp function SO JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS LA English DT Meeting Abstract C1 [Cai, Lisheng; Hong, Jinsoo; Liow, Jeih-San; Deuitch, Lora; Innis, Robert; Pike, Victor W.] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. [Peng, Yiyuan; Xie, Yepeng] Jiangxi Normal Univ, Dept Chem, Nanchang, Peoples R China. [Hall, Matthew] NCI, CCR LCB MRS, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0362-4803 EI 1099-1344 J9 J LABELLED COMPD RAD JI J. Label. Compd. Radiopharm. PD MAY 15 PY 2015 VL 58 SU 1 MA 308 BP S308 EP S308 PG 1 WC Biochemical Research Methods; Chemistry, Medicinal; Chemistry, Analytical SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA DD5GH UT WOS:000369950200309 ER PT J AU Cai, LS Qu, BX Hurtle, B Dadiboyena, S Morse, C Diaz-Arrastia, R Innis, R Pike, VW AF Cai, Lisheng Qu, Baoxi Hurtle, Bryan Dadiboyena, Sureshbabu Morse, Cheryl Diaz-Arrastia, Ramon Innis, Robert Pike, Victor W. TI [F-18]Tau911, a candidate for PET imaging of the THK site in neurofibrillary tangles SO JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS LA English DT Meeting Abstract C1 [Cai, Lisheng; Hurtle, Bryan; Dadiboyena, Sureshbabu; Morse, Cheryl; Innis, Robert; Pike, Victor W.] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. [Qu, Baoxi; Diaz-Arrastia, Ramon] USUHS, Ctr Neurosci & Regenerat Med, 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 0362-4803 EI 1099-1344 J9 J LABELLED COMPD RAD JI J. Label. Compd. Radiopharm. PD MAY 15 PY 2015 VL 58 SU 1 MA 211 BP S211 EP S211 PG 1 WC Biochemical Research Methods; Chemistry, Medicinal; Chemistry, Analytical SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA DD5GH UT WOS:000369950200212 ER PT J AU Chen, XY Lang, LX Niu, G AF Chen, Xiaoyuan Lang, Lixin Niu, Gang TI In Vivo Albumin Labeling with F-18-AlF-NEB for Lymph Node Imaging SO JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS LA English DT Meeting Abstract C1 [Chen, Xiaoyuan; Lang, Lixin; Niu, Gang] NIH, NIBIB, 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 0362-4803 EI 1099-1344 J9 J LABELLED COMPD RAD JI J. Label. Compd. Radiopharm. PD MAY 15 PY 2015 VL 58 SU 1 MA 225 BP S225 EP S225 PG 1 WC Biochemical Research Methods; Chemistry, Medicinal; Chemistry, Analytical SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA DD5GH UT WOS:000369950200226 ER PT J AU Cortes, M Singh, P Morse, C Kowalski, A Jenko, K Shrestha, S Zoghbi, S Fujita, M Innis, RB Pike, VW AF Cortes, Michelle Singh, Prachi Morse, Cheryl Kowalski, Aneta Jenko, Kimberly Shrestha, Saurav Zoghbi, Sami Fujita, M. Innis, Robert B. Pike, Victor W. TI Synthesis of a candidate brain-penetrant COX-2 PET radioligand as a potential probe for neuroinflammation SO JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS LA English DT Meeting Abstract ID INHIBITORS C1 [Cortes, Michelle; Singh, Prachi; Morse, Cheryl; Kowalski, Aneta; Jenko, Kimberly; Shrestha, Saurav; Zoghbi, Sami; Fujita, M.; Innis, Robert B.; Pike, Victor W.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0362-4803 EI 1099-1344 J9 J LABELLED COMPD RAD JI J. Label. Compd. Radiopharm. PD MAY 15 PY 2015 VL 58 SU 1 MA 312 BP S312 EP S312 PG 1 WC Biochemical Research Methods; Chemistry, Medicinal; Chemistry, Analytical SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA DD5GH UT WOS:000369950200313 ER PT J AU Dadiboyena, S Simeon, FG Lu, SY Cai, LS Pike, VW AF Dadiboyena, Sureshbabu Simeon, Fabrice G. Lu, Shuiyu Cai, Lisheng Pike, Victor W. TI (Pyridinyl-phenyl)selenoxides and (pyridinyl-phenyl)selenones as precursors for preparing [F-18]fluoropyridines from [F-18]fluoride ion SO JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS LA English DT Meeting Abstract C1 [Dadiboyena, Sureshbabu; Simeon, Fabrice G.; Lu, Shuiyu; Cai, Lisheng; Pike, Victor W.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0362-4803 EI 1099-1344 J9 J LABELLED COMPD RAD JI J. Label. Compd. Radiopharm. PD MAY 15 PY 2015 VL 58 SU 1 MA 148 BP S148 EP S148 PG 1 WC Biochemical Research Methods; Chemistry, Medicinal; Chemistry, Analytical SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA DD5GH UT WOS:000369950200149 ER PT J AU Hong, JS Lu, SY Xu, R Liow, JS Zoghbi, S Woock, A Gladding, R Innis, RB Pike, VW AF Hong, Jinsoo Lu, Shuiyu Xu, Rong Liow, Jeih-San Zoghbi, Sami Woock, Alicia Gladding, Robert Innis, Robert B. Pike, Victor W. TI Preparation of [C-11]FIMX for evaluation as a PET radioligand for imaging mGluR1 in monkey brain SO JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS LA English DT Meeting Abstract C1 [Hong, Jinsoo; Lu, Shuiyu; Xu, Rong; Liow, Jeih-San; Zoghbi, Sami; Woock, Alicia; Gladding, Robert; Innis, Robert B.; Pike, Victor W.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0362-4803 EI 1099-1344 J9 J LABELLED COMPD RAD JI J. Label. Compd. Radiopharm. PD MAY 15 PY 2015 VL 58 SU 1 MA 066 BP S66 EP S66 PG 1 WC Biochemical Research Methods; Chemistry, Medicinal; Chemistry, Analytical SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA DD5GH UT WOS:000369950200067 ER PT J AU Jacobson, O Kiesewetter, DO Chen, XY AF Jacobson, Orit Kiesewetter, Dale O. Chen, Xiaoyuan TI Applications of [F-18]Hexafluorobenzene for Preparing Cyclized or Dimeric Radioligands SO JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS LA English DT Meeting Abstract C1 [Jacobson, Orit; Kiesewetter, Dale O.; Chen, Xiaoyuan] NIBIB, 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 0362-4803 EI 1099-1344 J9 J LABELLED COMPD RAD JI J. Label. Compd. Radiopharm. PD MAY 15 PY 2015 VL 58 SU 1 MA 150 BP S150 EP S150 PG 1 WC Biochemical Research Methods; Chemistry, Medicinal; Chemistry, Analytical SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA DD5GH UT WOS:000369950200151 ER PT J AU Jacobson, O Chen, XY AF Jacobson, Orit Chen, Xiaoyuan TI PET Imaging of Tenascin-C with a Radiolabeled Single-Strand DNA Aptamer SO JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS LA English DT Meeting Abstract C1 [Jacobson, Orit; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 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 0362-4803 EI 1099-1344 J9 J LABELLED COMPD RAD JI J. Label. Compd. Radiopharm. PD MAY 15 PY 2015 VL 58 SU 1 MA 086 BP S86 EP S86 PG 1 WC Biochemical Research Methods; Chemistry, Medicinal; Chemistry, Analytical SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA DD5GH UT WOS:000369950200087 ER PT J AU Jagoda, EM Elbuluk, O Williams, M Wong, KR Xu, BY Szajek, LP Choyke, P AF Jagoda, Elaine M. Elbuluk, Osama Williams, Mark Wong, Karen Xu, Biying Szajek, Lawrence P. Choyke, Peter TI [Tc-94m] labeled peptide targets Met in human gastric carcinoma (MKN-45, SNU-16) and glioblastoma (U87-MG) cells and xenografts SO JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS LA English DT Meeting Abstract C1 [Jagoda, Elaine M.; Elbuluk, Osama; Williams, Mark; Wong, Karen; Choyke, Peter] NCI, Mol Imaging Program, Bethesda, MD 20892 USA. [Xu, Biying] NHLBI, Imaging Probe Dev Ctr, Bethesda, MD 20892 USA. [Szajek, Lawrence P.] NIH, PET Dept, CC, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0362-4803 EI 1099-1344 J9 J LABELLED COMPD RAD JI J. Label. Compd. Radiopharm. PD MAY 15 PY 2015 VL 58 SU 1 MA 085 BP S85 EP S85 PG 1 WC Biochemical Research Methods; Chemistry, Medicinal; Chemistry, Analytical SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA DD5GH UT WOS:000369950200086 ER PT J AU Lee, SJ Alexoff, D Fowler, JS Kim, SW Hooker, J Ma, L Nauth, A Weber, C Qu, WC AF Lee, So Jeong Alexoff, David Fowler, Joanna S. Kim, Sung Won Hooker, Jacob Ma, Ling Nauth, Alexander Weber, Carina Qu, Wenchao TI Radiosynthesis of [2-C-11]indole via rapid nucleophilic [C-11]cyanation and reductive cyclization SO JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS LA English DT Meeting Abstract C1 [Lee, So Jeong] SUNY Stony Brook, Dept Chem, Stony Brook, NY 11794 USA. [Lee, So Jeong; Alexoff, David; Fowler, Joanna S.; Qu, Wenchao] Brookhaven Natl Lab, Upton, NY 11973 USA. [Kim, Sung Won] NIH, Bethesda, MD 20892 USA. [Hooker, Jacob; Ma, Ling] Harvard Univ, Sch Med, Dept Radiol, Charlestown, MA USA. [Nauth, Alexander; Weber, Carina] Johannes Gutenberg Univ Mainz, D-55122 Mainz, Germany. NR 2 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0362-4803 EI 1099-1344 J9 J LABELLED COMPD RAD JI J. Label. Compd. Radiopharm. PD MAY 15 PY 2015 VL 58 SU 1 MA 039 BP S39 EP S39 PG 1 WC Biochemical Research Methods; Chemistry, Medicinal; Chemistry, Analytical SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA DD5GH UT WOS:000369950200040 ER PT J AU Liu, ZB Kiesewetter, DO Chen, XY AF Liu, Zhibo (Zippo) Kiesewetter, Dale O. Chen, Xiaoyuan TI In vivo radiolabeling: a rapid targeting-excreting strategy for mapping nanoparticles with PET imaging SO JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS LA English DT Meeting Abstract C1 [Liu, Zhibo (Zippo); Kiesewetter, Dale O.; Chen, Xiaoyuan] 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 0362-4803 EI 1099-1344 J9 J LABELLED COMPD RAD JI J. Label. Compd. Radiopharm. PD MAY 15 PY 2015 VL 58 SU 1 MA 021 BP S21 EP S21 PG 1 WC Biochemical Research Methods; Chemistry, Medicinal; Chemistry, Analytical SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA DD5GH UT WOS:000369950200022 ER PT J AU Marriner, GA Kiesewetter, DO D'Hooge, F Lee, SS Boutureira, O Raj, R Khan, N Via, LE Barry, CE Davis, BG AF Marriner, Gwendolyn A. Kiesewetter, Dale O. D'Hooge, Franois Lee, Seung S. Boutureira, Omar Raj, Ritu Khan, Naseer Via, Laura E. Barry, Clifton E. Davis, Ben G. TI Evaluation of Trehalose Derivatives as Radiotracers Specific for Tuberculosis in Animal Models of Disease SO JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS LA English DT Meeting Abstract C1 [Marriner, Gwendolyn A.; Via, Laura E.; Barry, Clifton E.] NIAID, TB Res Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Kiesewetter, Dale O.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. [D'Hooge, Franois; Lee, Seung S.; Boutureira, Omar; Raj, Ritu; Khan, Naseer; Davis, Ben G.] Univ Oxford, Dept Chemstry, Oxford, England. RI Boutureira, Omar/I-9045-2014; Davis, Benjamin/C-5281-2011 OI Boutureira, Omar/0000-0002-0768-8309; Davis, Benjamin/0000-0002-5056-407X NR 2 TC 0 Z9 0 U1 3 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0362-4803 EI 1099-1344 J9 J LABELLED COMPD RAD JI J. Label. Compd. Radiopharm. PD MAY 15 PY 2015 VL 58 SU 1 MA 250 BP S250 EP S250 PG 1 WC Biochemical Research Methods; Chemistry, Medicinal; Chemistry, Analytical SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA DD5GH UT WOS:000369950200251 ER PT J AU Simeon, FG Lu, SY Pike, VW AF Simeon, Fabrice G. Lu, Shuiyu Pike, Victor W. TI Diarylselenoxides as precursors to no-carrier-added [F-18]fluoroarenes SO JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS LA English DT Meeting Abstract C1 [Simeon, Fabrice G.; Lu, Shuiyu; Pike, Victor W.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0362-4803 EI 1099-1344 J9 J LABELLED COMPD RAD JI J. Label. Compd. Radiopharm. PD MAY 15 PY 2015 VL 58 SU 1 MA 149 BP S149 EP S149 PG 1 WC Biochemical Research Methods; Chemistry, Medicinal; Chemistry, Analytical SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA DD5GH UT WOS:000369950200150 ER PT J AU Simeon, FG Lu, SY Pike, VW AF Simeon, Fabrice G. Lu, Shuiyu Pike, Victor W. TI Diarylselenones are effective precursors for the synthesis of [F-18] fluoroarenes from [F-18]fluoride ion SO JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS LA English DT Meeting Abstract C1 [Simeon, Fabrice G.; Lu, Shuiyu; Pike, Victor W.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. NR 1 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0362-4803 EI 1099-1344 J9 J LABELLED COMPD RAD JI J. Label. Compd. Radiopharm. PD MAY 15 PY 2015 VL 58 SU 1 MA 001 BP S1 EP S1 PG 1 WC Biochemical Research Methods; Chemistry, Medicinal; Chemistry, Analytical SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA DD5GH UT WOS:000369950200002 ER PT J AU Singh, P Cortes, M Morse, C Jenko, K Shrestha, S Gladding, R Fujita, M Innis, RB Pike, VW AF Singh, Prachi Cortes, Michelle Morse, Cheryl Jenko, Kimberly Shrestha, Saurav Gladding, Robert Fujita, Masahiro Innis, Robert B. Pike, Victor W. TI Radiosynthesis and evaluation of [C-11]FK881 as a PET radioligand for imaging brain COX-1 in monkey SO JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS LA English DT Meeting Abstract C1 [Singh, Prachi; Cortes, Michelle; Morse, Cheryl; Jenko, Kimberly; Shrestha, Saurav; Gladding, Robert; Fujita, Masahiro; Innis, Robert B.; Pike, Victor W.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. NR 2 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0362-4803 EI 1099-1344 J9 J LABELLED COMPD RAD JI J. Label. Compd. Radiopharm. PD MAY 15 PY 2015 VL 58 SU 1 MA 055 BP S55 EP S55 PG 1 WC Biochemical Research Methods; Chemistry, Medicinal; Chemistry, Analytical SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA DD5GH UT WOS:000369950200056 ER PT J AU Telu, S Liow, JS Zoghbi, S Woock, A Gladding, R Innis, RB Pike, VW AF Telu, Sanjay Liow, Jeih-San Zoghbi, Sami Woock, Alicia Gladding, Robert Innis, Robert B. Pike, Victor W. TI Synthesis of a candidate C-11-labeled ligand for imaging brain oxytocin receptors in rhesus monkey SO JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS LA English DT Meeting Abstract C1 [Telu, Sanjay; Liow, Jeih-San; Zoghbi, Sami; Woock, Alicia; Gladding, Robert; Innis, Robert B.; Pike, Victor W.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0362-4803 EI 1099-1344 J9 J LABELLED COMPD RAD JI J. Label. Compd. Radiopharm. PD MAY 15 PY 2015 VL 58 SU 1 MA 286 BP S286 EP S286 PG 1 WC Biochemical Research Methods; Chemistry, Medicinal; Chemistry, Analytical SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA DD5GH UT WOS:000369950200287 ER PT J AU Tworowska, I Wagh, N Thamake, S Reedy, J Ranganathan, D Brechbiel, M Delpassand, ES Schultz, MK AF Tworowska, Izabela Wagh, Nilesh Thamake, Sanjay Reedy, Jessica Ranganathan, David Brechbiel, Martin Delpassand, Ebrahim S. Schultz, Michael K. TI Pb-203-labeled radiotracer targeting metastatic melanoma. SO JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS LA English DT Meeting Abstract C1 [Tworowska, Izabela; Thamake, Sanjay; Ranganathan, David; Delpassand, Ebrahim S.] RadioMedix Inc, Houston, TX USA. [Tworowska, Izabela; Wagh, Nilesh] RITA Fdn, Houston, TX USA. [Reedy, Jessica; Schultz, Michael K.] Univ Iowa, Radiol & Radiat Oncol Free Rad & Radiat Biol Prog, Iowa City, IA USA. [Brechbiel, Martin] NCI, Rockville, MD USA. NR 1 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0362-4803 EI 1099-1344 J9 J LABELLED COMPD RAD JI J. Label. Compd. Radiopharm. PD MAY 15 PY 2015 VL 58 SU 1 MA 132 BP S132 EP S132 PG 1 WC Biochemical Research Methods; Chemistry, Medicinal; Chemistry, Analytical SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA DD5GH UT WOS:000369950200133 ER PT J AU Yong, KJ Baidoo, KE Milenic, DE Brechbiel, M AF Yong, Kwon J. Baidoo, Kwamena E. Milenic, Diane E. Brechbiel, Martin TI Comparison of Cell Killing Mechanisms of Radioimmunotherapy - Lu-177 vs. Pb-212 (Low LET vs. High LET Radiation) Targeting Disseminated Intraperitoneal Disease Tumor Xenografts SO JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS LA English DT Meeting Abstract C1 [Yong, Kwon J.; Baidoo, Kwamena E.; Milenic, Diane E.; Brechbiel, Martin] NCI, Chem Sect, ROB, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0362-4803 EI 1099-1344 J9 J LABELLED COMPD RAD JI J. Label. Compd. Radiopharm. PD MAY 15 PY 2015 VL 58 SU 1 MA 047 BP S47 EP S47 PG 1 WC Biochemical Research Methods; Chemistry, Medicinal; Chemistry, Analytical SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA DD5GH UT WOS:000369950200048 ER PT J AU Petereit, DG Coleman, CN AF Petereit, Daniel Grant Coleman, C. Norman TI Editorial: "Global Challenges in Radiation Oncology" SO FRONTIERS IN ONCOLOGY LA English DT Editorial Material DE editorial radiation oncology; global cancer disparities; LMICs ID MIDDLE-INCOME COUNTRIES; AMERICAN-INDIANS; CERVICAL-CANCER; DEVELOPING-WORLD; ALASKA NATIVES; HEALTH; RADIOTHERAPY; RESOURCES; MORTALITY; AFRICA C1 [Petereit, Daniel Grant] Rapid City Reg Canc Ctr, Walking Forward Program, Rapid City, SD 57701 USA. [Petereit, Daniel Grant; Coleman, C. Norman] Int Canc Expert Corps, New York, NY USA. [Coleman, C. Norman] NCI, Div Canc Treatment & Diag, Radiat Res Program, Rockville, MD USA. RP Petereit, DG (reprint author), Rapid City Reg Canc Ctr, Walking Forward Program, Rapid City, SD 57701 USA. EM dpetereit@regionalhealth.com NR 33 TC 1 Z9 1 U1 0 U2 0 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 2234-943X J9 FRONT ONCOL JI Front. Oncol. PD MAY 15 PY 2015 VL 5 AR 103 DI 10.3389/fonc.2015.00103 PG 4 WC Oncology SC Oncology GA CO4NS UT WOS:000359138200001 PM 26029661 ER PT J AU Bates, SE Robey, RW Piekarz, RL AF Bates, Susan E. Robey, Robert W. Piekarz, Richard L. TI CCR 20th Anniversary Commentary: Expanding the Epigenetic Therapeutic Portfolio SO CLINICAL CANCER RESEARCH LA English DT Editorial Material ID HISTONE DEACETYLASE INHIBITOR; T-CELL LYMPHOMA; PHASE-II TRIAL; DEPSIPEPTIDE FR901228; ROMIDEPSIN; CHROMATIN; CANCER; SAFETY AB Epigenetic targets have emerged as an exciting area for drug discovery. The discovery that histone deacetylase (HDAC) inhibitors had marked anticancer activity in T-cell lymphoma gave impetus to the field. In a phase I study published in Clinical Cancer Research in March 2002, romidepsin (depsipeptide), a potent HDAC inhibitor, was found to be tolerable, with a side effect profile that was later understood to be characteristic of this class of agents. Evidence of activity in this key phase I trial provided momentum for the further study of epigenetic agents. (C)2015 AACR. C1 [Bates, Susan E.; Robey, Robert W.] NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Piekarz, Richard L.] NCI, Invest Drug Branch, Canc Therapy Evaluat Program, NIH, Bethesda, MD 20892 USA. RP Bates, SE (reprint author), NCI, Bldg 10,Room 12N226, Bethesda, MD 20892 USA. EM batess@helix.nih.gov NR 21 TC 2 Z9 2 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 MAY 15 PY 2015 VL 21 IS 10 BP 2195 EP 2197 DI 10.1158/1078-0432.CCR-14-2555 PG 3 WC Oncology SC Oncology GA CL9YQ UT WOS:000357335500001 PM 25979924 ER PT J AU Bates, SE AF Bates, Susan E. TI Quit Early, Quit Often SO CLINICAL CANCER RESEARCH LA English DT Editorial Material C1 NCI, Bethesda, MD 20892 USA. RP Bates, SE (reprint author), NCI, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAY 15 PY 2015 VL 21 IS 10 BP 2212 EP 2212 DI 10.1158/1078-0432.CCR-14-2749 PG 1 WC Oncology SC Oncology GA CL9YQ UT WOS:000357335500006 PM 25979926 ER PT J AU Zhang, L Morgan, RA Beane, JD Zheng, ZL Dudley, ME Kassim, SH Nahvi, AV Ngo, LT Sherry, RM Phan, GQ Hughes, MS Kammula, US Feldman, SA Toomey, MA Kerkar, SP Restifo, NP Yang, JC Rosenberg, SA AF Zhang, Ling Morgan, Richard A. Beane, Joal D. Zheng, Zhili Dudley, Mark E. Kassim, Sadik H. Nahvi, Azam V. Ngo, Lien T. Sherry, Richard M. Phan, Giao Q. Hughes, Marybeth S. Kammula, Udai S. Feldman, Steven A. Toomey, Mary Ann Kerkar, Sid P. Restifo, Nicholas P. Yang, James C. Rosenberg, Steven A. TI Tumor-Infiltrating Lymphocytes Genetically Engineered with an Inducible Gene Encoding Interleukin-12 for the Immunotherapy of Metastatic Melanoma SO CLINICAL CANCER RESEARCH LA English DT Article ID T-CELL EXHAUSTION; CANCER REGRESSION; IL-12; EXPRESSION; THERAPY; TIM-3; ENVIRONMENT; ANTITUMOR; RESPONSES; LYMPHOMA AB Purpose: Infusion of interleukin-12 (IL12) can mediate antitumor immunity in animal models, yet its systemic administration to patients with cancer results in minimal efficacy and severe toxicity. Here, we evaluated the antitumor activity of adoptively transferred human tumor-infiltrating lymphocytes (TILs) genetically engineered to secrete single-chain IL12 selectively at the tumor site. Experimental Design: Thirty-three patients with metastatic melanoma were treated in a cell dose-escalation trial of autologous TILs transduced with a gene encoding a single-chain IL12 driven by a nuclear factor of the activated T cells promoter (NFAT. IL12). No IL2 was administered. Results: The administration of 0.001 to 0.1 x 10(9) NFAT. IL12-transduced TILs to 17 patients resulted in a single, objective response (5.9%). However, at doses between 0.3 and 3 x 10(9) cells, 10 of 16 patients (63%) exhibited objective clinical responses. The responses tended to be short, and the administered IL12-producing cells rarely persisted at 1 month. Increasing cell doses were associated with high serum levels of IL12 and IFN gamma as well as clinical toxicities, including liver dysfunction, high fevers, and sporadic life-threatening hemodynamic instability. Conclusions: In this first-in-man trial, administration of TILs transduced with an inducible IL12 gene mediated tumor responses in the absence of IL2 administration using cell doses 10- to 100-fold lower than conventional TILs. However, due to toxicities, likely attributable to the secreted IL12, further refinement will be necessary before this approach can be safely used in the treatment of cancer patients. (C)2015 AACR. C1 [Zhang, Ling; Morgan, Richard A.; Beane, Joal D.; Zheng, Zhili; Dudley, Mark E.; Kassim, Sadik H.; Nahvi, Azam V.; Ngo, Lien T.; Sherry, Richard M.; Phan, Giao Q.; Hughes, Marybeth S.; Kammula, Udai S.; Feldman, Steven A.; Toomey, Mary Ann; Kerkar, Sid P.; Restifo, Nicholas P.; Yang, James C.; Rosenberg, Steven A.] NCI, Surg Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Rosenberg, SA (reprint author), NCI, Ctr Canc Res, Bldg 10 CRC,Room 3W-3940,10 Ctr Dr, Bethesda, MD 20892 USA. EM sar@mail.nih.gov OI Restifo, Nicholas P./0000-0003-4229-4580 FU National Cancer Institute, Center for Cancer Research FX This work was supported by the intramural program of the National Cancer Institute, Center for Cancer Research. NR 28 TC 24 Z9 26 U1 4 U2 11 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 MAY 15 PY 2015 VL 21 IS 10 BP 2278 EP 2288 DI 10.1158/1078-0432.CCR-14-2085 PG 11 WC Oncology SC Oncology GA CL9YQ UT WOS:000357335500015 PM 25695689 ER PT J AU O'Brien, KM Fei, CY Sandler, DP Nichols, HB Deroo, LA Weinberg, CR AF O'Brien, Katie M. Fei, Chunyuan Sandler, Dale P. Nichols, Hazel B. Deroo, Lisa A. Weinberg, Clarice R. TI Hormone Therapy and Young-Onset Breast Cancer SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE hormone therapy; propensity score; young-onset breast cancer ID PROGESTIN-REPLACEMENT THERAPY; ESTROGEN PLUS PROGESTIN; WOMENS HEALTH; POSTMENOPAUSAL WOMEN; CONTROLLED-TRIAL; REPRODUCTIVE FACTORS; MENOPAUSAL SYMPTOMS; RISK-FACTORS; COHORT; PREMENOPAUSAL AB Estrogen plus progestin hormone therapy (HT) is associated with an increased risk of postmenopausal breast cancer, but few studies have examined the impact of HT use on the risk of breast cancer in younger women. We assessed the association between estrogen plus progestin HT or unopposed estrogen HT and young-onset breast cancer using data from the Two Sister Study (2008-2010), a sister-matched study of 1,419 cases diagnosed with breast cancer before the age of 50 years and 1,665 controls. We assessed exposures up to a family-specific index age to ensure comparable opportunities for exposures and used propensity scores to control for birth cohort effects on HT use. Ever HT use was uncommon (7% and 11% in cases and controls, respectively). Use of estrogen plus progestin was not associated with an increased risk of young-onset breast cancer (odds ratio = 0.80, 95% confidence interval: 0.41, 1.59). Unopposed estrogen use was inversely associated with the risk of young-onset breast cancer (odds ratio = 0.58, 95% confidence interval: 0.34, 0.99). Duration of use, age at first use, and recency of use did not modify these associations. C1 [O'Brien, Katie M.; Weinberg, Clarice R.] NIEHS, Biostat & Computat Biol Branch, Res Triangle Pk, NC 27709 USA. [Fei, Chunyuan] AbbVie Inc, Global Surveillance & Pharmacoepidemiol, N Chicago, IL USA. [Sandler, Dale P.; Deroo, Lisa A.] NIEHS, Div Intramural Res, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Nichols, Hazel B.] Univ N Carolina, Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Deroo, Lisa A.] Univ Bergen, Dept Global Publ Hlth & Primary Care, Bergen, Norway. RP Weinberg, CR (reprint author), NIEHS, Biostat & Computat Biol Branch, POB 12233,Mail Drop A3-03, Res Triangle Pk, NC 27709 USA. EM weinber2@niehs.nih.gov OI O'Brien, Katie/0000-0002-1931-1349; Sandler, Dale/0000-0002-6776-0018 FU Intramural Research Program of the National Institutes of Health; National Institute of Environmental Health Sciences [Z01-ES044005, Z01-ES102245]; Susan G. Komen for the Cure [FAS0703856] FX This work was supported by the Intramural Research Program of the National Institutes of Health, the National Institute of Environmental Health Sciences (project Z01-ES044005 to D.P.S. and project Z01-ES102245 to C.R.W.), and Susan G. Komen for the Cure (grant FAS0703856 to C.R.W.). NR 43 TC 4 Z9 4 U1 0 U2 2 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 MAY 15 PY 2015 VL 181 IS 10 BP 799 EP 807 DI 10.1093/aje/kwu347 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CK4FY UT WOS:000356179700009 PM 25698646 ER PT J AU Davis, D Yaveroglu, ON Malod-Dognin, N Stojmirovic, A Przulj, N AF Davis, Darren Yaveroglu, Omer Nebil Malod-Dognin, Noel Stojmirovic, Aleksandar Przulj, Natasa TI Topology-function conservation in protein-protein interaction networks SO BIOINFORMATICS LA English DT Article ID TRANSCRIPTIONAL REGULATION; FUNCTION PREDICTION; MEDIATOR SUBUNIT; RNA-POLYMERASE AB Motivation: Proteins underlay the functioning of a cell and the wiring of proteins in protein-protein interaction network (PIN) relates to their biological functions. Proteins with similar wiring in the PIN (topology around them) have been shown to have similar functions. This property has been successfully exploited for predicting protein functions. Topological similarity is also used to guide network alignment algorithms that find similarly wired proteins between PINs of different species; these similarities are used to transfer annotation across PINs, e.g. from model organisms to human. To refine these functional predictions and annotation transfers, we need to gain insight into the variability of the topology-function relationships. For example, a function may be significantly associated with specific topologies, while another function may be weakly associated with several different topologies. Also, the topology-function relationships may differ between different species. Results: To improve our understanding of topology-function relationships and of their conservation among species, we develop a statistical framework that is built upon canonical correlation analysis. Using the graphlet degrees to represent the wiring around proteins in PINs and gene ontology (GO) annotations to describe their functions, our framework: (i) characterizes statistically significant topology-function relationships in a given species, and (ii) uncovers the functions that have conserved topology in PINs of different species, which we term topologically orthologous functions. We apply our framework to PINs of yeast and human, identifying seven biological process and two cellular component GO terms to be topologically orthologous for the two organisms. C1 [Davis, Darren; Yaveroglu, Omer Nebil] Univ Calif Irvine, Calif Inst Telecommun & Technol Calit2, Irvine, CA USA. [Yaveroglu, Omer Nebil; Malod-Dognin, Noel; Przulj, Natasa] Univ London Imperial Coll Sci Technol & Med, Dept Comp, London, England. [Stojmirovic, Aleksandar] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Stojmirovic, Aleksandar] Janssen Res & Dev LLC, Spring House, PA USA. RP Przulj, N (reprint author), Univ London Imperial Coll Sci Technol & Med, Dept Comp, London, England. EM natasha@imperial.ac.uk FU European Research Council (ERC) Starting Independent Researcher Grant [278212]; National Science Foundation (NSF) Cyber-Enabled Discovery and Innovation (CDI) [OIA-1028394]; ARRS project [J1-5454]; Serbian Ministry of Education and Science Project [III44006]; intramural programme of US National Library of Medicine FX This work is supported by the European Research Council (ERC) Starting Independent Researcher Grant [278212], National Science Foundation (NSF) Cyber-Enabled Discovery and Innovation (CDI) [OIA-1028394], ARRS project [J1-5454], the Serbian Ministry of Education and Science Project [III44006] and the intramural programme of US National Library of Medicine. NR 35 TC 9 Z9 9 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD MAY 15 PY 2015 VL 31 IS 10 BP 1632 EP 1639 DI 10.1093/bioinformatics/btv026 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA CJ7JZ UT WOS:000355672500015 PM 25609797 ER PT J AU Imashimizu, M Takahashi, H Oshima, T McIntosh, C Bubunenko, M Court, DL Kashlev, M AF Imashimizu, Masahiko Takahashi, Hiroki Oshima, Taku McIntosh, Carl Bubunenko, Mikhail Court, Donald L. Kashlev, Mikhail TI Visualizing translocation dynamics and nascent transcript errors in paused RNA polymerases in vivo SO GENOME BIOLOGY LA English DT Article ID PYRIMIDINE-PURINE STEPS; ELONGATION-FACTOR GREA; ESCHERICHIA-COLI; DNA HYBRID; GENOME INSTABILITY; STRUCTURAL BASIS; II ELONGATION; TERMINATION; PROTEIN; SEQUENCES AB Background: Transcription elongation is frequently interrupted by pausing signals in DNA, with downstream effects on gene expression. Transcription errors also induce prolonged pausing, which can lead to a destabilized genome by interfering with DNA replication. Mechanisms of pausing associated with translocation blocks and misincorporation have been characterized in vitro, but not in vivo. Results: We investigate the pausing pattern of RNA polymerase (RNAP) in Escherichia coli by a novel approach, combining native elongating transcript sequencing (NET-seq) with RNase footprinting of the transcripts (RNET-seq). We reveal that the G-dC base pair at the 5' end of the RNA-DNA hybrid interferes with RNAP translocation. The distance between the 5' G-dC base pair and the 3' end of RNA fluctuates over a three-nucleotide width. Thus, the G-dC base pair can induce pausing in post-translocated, pre-translocated, and backtracked states of RNAP. Additionally, a CpG sequence of the template DNA strand spanning the active site of RNAP inhibits elongation and induces G-to-A errors, which leads to backtracking of RNAP. Gre factors efficiently proofread the errors and rescue the backtracked complexes. We also find that pausing events are enriched in the 5' untranslated region and antisense transcription of mRNA genes and are reduced in rRNA genes. Conclusions: In Escherichia coli, robust transcriptional pausing involves RNAP interaction with G-dC at the upstream end of the RNA-DNA hybrid, which interferes with translocation. CpG DNA sequences induce transcriptional pausing and G-to-A errors. C1 [Imashimizu, Masahiko; McIntosh, Carl; Bubunenko, Mikhail; Court, Donald L.; Kashlev, Mikhail] NCI, Ctr Canc Res, Frederick, MD 21702 USA. [Takahashi, Hiroki] Chiba Univ, Med Mycol Res Ctr, Chuo Ku, Chiba 2608673, Japan. [Oshima, Taku] Nara Inst Sci & Technol, Grad Sch Biol Sci, Ikoma, Nara 6300192, Japan. RP Kashlev, M (reprint author), NCI, Ctr Canc Res, Frederick, MD 21702 USA. EM kashlevm@mail.nih.gov RI Takahashi, Hiroki/M-9169-2015 FU Intramural Research Program of National Institutes of Health, National Cancer Institute, Center for Cancer Research; JSPS; MEXT KAKENHI [221S0002]; JSPS KAKENHI [26450090] FX We thank Lucyna Lubkowska for Escherichia coli RNAP and Gre proteins and Maria Kireeva for discussions. We are also grateful to Zachary Burton for discussions at the initial stage of this work and sharing his error analysis data of yeast NET-seq [35]. We also thank the NCI sequencing facility for Illumina sequencing and support. This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research to MK. MI is partially supported by a fellowship from JSPS. HT and TO are supported by MEXT KAKENHI (number 221S0002) and JSPS KAKENHI (number 26450090), respectively. NR 94 TC 10 Z9 10 U1 2 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-6906 EI 1474-760X J9 GENOME BIOL JI Genome Biol. PD MAY 15 PY 2015 VL 16 AR 98 DI 10.1186/s13059-015-0666-5 PG 17 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA CK0OA UT WOS:000355903300001 PM 25976475 ER PT J AU Madrid, FF Maroun, MC Olivero, OA Long, M Stark, A Grossman, LI Binder, W Dong, JS Burke, M Nathanson, SD Zarbo, R Chitale, D Zeballos-Chavez, R Peebles, C AF Madrid, Felix Fernandez Maroun, Marie-Claire Olivero, Ofelia A. Long, Michael Stark, Azadeh Grossman, Lawrence I. Binder, Walter Dong, Jingsheng Burke, Matthew Nathanson, S. David Zarbo, Richard Chitale, Dhananjay Zeballos-Chavez, Rocio Peebles, Carol TI Autoantibodies in breast cancer sera are not epiphenomena and may participate in carcinogenesis SO BMC CANCER LA English DT Article DE Autoantibodies; Autoimmunity; Immunogenicity; Breast cancer; Carcinogenesis; Centrosomes; Mitochondria; Centromeres; Cytoskeleton ID PRIMARY BILIARY-CIRRHOSIS; SYSTEMIC-LUPUS-ERYTHEMATOSUS; ANTINUCLEAR ANTIBODIES; BENZODIAZEPINE-RECEPTOR; RHEUMATOID-ARTHRITIS; LUNG-CANCER; DIAGNOSIS; ANTIGEN; AUTOIMMUNITY; INFLAMMATION AB Background: The objective of this work was to demonstrate that autoantibodies in breast cancer sera are not epiphenomena, and exhibit unique immunologic features resembling the rheumatic autoimmune diseases. Methods: We performed a comprehensive study of autoantibodies on a collection of sera from women with breast cancer or benign breast disease, undergoing annual screening mammography. All women in this study had suspicious mammography assessment and underwent a breast biopsy. We used indirect immunofluorescence, the crithidia assay for anti-dsDNA antibodies, and multiple ELISAs for extractable nuclear antigens. Results: Autoantibodies were detected in virtually all patients with breast cancer, predominantly of the IgG1 and IgG3 isotypes. The profile detected in breast cancer sera showed distinctive features, such as antibodies targeting mitochondria, centrosomes, centromeres, nucleoli, cytoskeleton, and multiple nuclear dots. The majority of sera showing anti-mitochondrial antibodies did not react with the M2 component of pyruvate dehydrogenase, characteristic of primary biliary cirrhosis. Anti-centromere antibodies were mainly anti-CENP-B. ELISAs for extractable nuclear antigens and the assays for dsDNA were negative. Conclusions: The distinctive autoantibody profile detected in BC sera is the expression of tumor immunogenicity. Although some of these features resemble those in the rheumatic autoimmune diseases and primary biliary cirrhosis, the data suggest the involvement of an entirely different set of epithelial antigens in breast cancer. High titer autoantibodies targeting centrosomes, centromeres, and mitochondria were detected in a small group of healthy women with suspicious mammography assessment and no cancer by biopsy; this suggests that the process triggering autoantibody formation starts in the pre-malignant phase and that future studies using validated autoantibody panels may allow detection of breast cancer risk in asymptomatic women. Autoantibodies developing in breast cancer are not epiphenomena, but likely reflect an antigen-driven autoimmune response triggered by epitopes developing in the mammary gland during breast carcinogenesis. Our results support the validity of the multiple studies reporting association of autoantibodies with breast cancer. Results further suggest significant promise for the development of panels of breast cancer-specific, premalignant-phase autoantibodies, as well as studies on the autoantibody response to tumor associated antigens in the pathogenesis of cancer. C1 [Madrid, Felix Fernandez; Maroun, Marie-Claire; Dong, Jingsheng] Wayne State Univ, Sch Med, Dept Internal Med, Div Rheumatol, Detroit, MI 48201 USA. [Madrid, Felix Fernandez] Karmanos Canc Inst, Detroit, MI 48201 USA. [Olivero, Ofelia A.] NCI, NIH, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. [Long, Michael] Childrens Hosp Michigan, Wayne State Sch Med, Dept Pathol, Detroit, MI 48201 USA. [Stark, Azadeh] Henry Ford Hlth Syst, Dept Pathol, Detroit, MI 48202 USA. [Stark, Azadeh] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Grossman, Lawrence I.] Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Binder, Walter; Peebles, Carol] INOVA Diagnost Inc, San Diego, CA 92131 USA. [Burke, Matthew] Henry Ford Hosp & Hlth Network, Dept Diagnost Radiol, Detroit, MI 48202 USA. [Nathanson, S. David] Henry Ford Hlth Syst, Dept Surg, Detroit, MI 48202 USA. [Zarbo, Richard; Chitale, Dhananjay] Henry Ford Hosp, Dept Pathol & Lab Med, Detroit, MI 48202 USA. [Zeballos-Chavez, Rocio] Childrens Hosp Michigan, Dept Pediat, Wayne State Sch Med, Detroit, MI 48201 USA. RP Madrid, FF (reprint author), Wayne State Univ, Sch Med, Dept Internal Med, Div Rheumatol, 640 Canfield, Detroit, MI 48201 USA. EM fmadrid@med.wayne.edu FU NIH [R01 CA122277] FX We thank Dr. Eric Gershwin for confirming the results of the M2 ELISA in his lab and Dr. Patrick Leung for his advice on the manuscript. We also thank Matthew Garin, Michelle Look, Amanda Oberlee-Clouse and Larry Tait for their fine art work. This study was partially supported by NIH R01 CA122277. NR 50 TC 2 Z9 2 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD MAY 15 PY 2015 VL 15 AR 407 DI 10.1186/s12885-015-1385-8 PG 15 WC Oncology SC Oncology GA CJ3RQ UT WOS:000355402000001 PM 25975273 ER PT J AU Orr, N Dudbridge, F Dryden, N Maguire, S Novo, D Perrakis, E Johnson, N Ghoussaini, M Hopper, JL Southey, MC Apicella, C Stone, J Schmidt, MK Broeks, A Van't Veer, LJ Hogervorst, FB Fasching, PA Haeberle, L Ekici, AB Beckmann, MW Gibson, L Aitken, Z Warren, H Sawyer, E Tomlinson, I Kerin, MJ Miller, N Burwinkel, B Marme, F Schneeweiss, A Sohn, C Guenel, P Truong, T Cordina-Duverger, E Sanchez, M Bojesen, SE Nordestgaard, BG Nielsen, SF Flyger, H Benitez, J Zamora, MP Perez, JIA Menendez, P Anton-Culver, H Neuhausen, SL Brenner, H Dieffenbach, AK Arndt, V Stegmaier, C Hamann, U Brauch, H Justenhoven, C Bruning, T Ko, YD Nevanlinna, H Aittomaki, K Blomqvist, C Khan, S Bogdanova, N Dork, T Lindblom, A Margolin, S Mannermaa, A Kataja, V Kosma, VM Hartikainen, JM Chenevix-Trench, G Beesley, J Lambrechts, D Moisse, M Floris, G Beuselinck, B Chang-Claude, J Rudolph, A Seibold, P Flesch-Janys, D Radice, P Peterlongo, P Peissel, B Pensotti, V Couch, FJ Olson, JE Slettedahl, S Vachon, C Giles, GG Milne, RL McLean, C Haiman, CA Henderson, BE Schumacher, F Le Marchand, L Simard, J Goldberg, MS Labreche, F Dumont, M Kristensen, V Alnaes, GG Nord, S Borresen-Dale, AL Zheng, W Deming-Halverson, S Shrubsole, M Long, JR Winqvist, R Pylkas, K Jukkola-Vuorinen, A Grip, M Andrulis, IL Knight, JA Glendon, G Tchatchou, S Devilee, P Tollenaar, RAEM Seynaeve, CM Van Asperen, CJ Garcia-Closas, M Figueroa, J Chanock, SJ Lissowska, J Czene, K Darabi, H Eriksson, M Klevebring, D Hooning, MJ Hollestelle, A van Deurzen, CHM Kriege, M Hall, P Li, JM Liu, JJ Humphreys, K Cox, A Cross, SS Reed, MWR Pharoah, PDP Dunning, AM Shah, M Perkins, BJ Jakubowska, A Lubinski, J Jaworska-Bieniek, K Durda, K Ashworth, A Swerdlow, A Jones, M Schoemaker, MJ Meindl, A Schmutzler, RK Olswold, C Slager, S Toland, AE Yannoukakos, D Muir, K Lophatananon, A Stewart-Brown, S Siriwanarangsan, P Matsuo, K Ito, H Iwata, H Ishiguro, J Wu, AH Tseng, CC Van den Berg, D Stram, DO Teo, SH Yip, CH Kang, P Ikram, MK Shu, XO Lu, W Gao, YT Cai, H Kang, D Choi, JY Park, SK Noh, DY Hartman, M Miao, H Lim, WY Lee, SC Sangrajrang, S Gaborieau, V Brennan, P McKay, J Wu, PE Hou, MF Yu, JC Shen, CY Blot, W Cai, QY Signorello, LB Luccarini, C Bayes, C Ahmed, S Maranian, M Healey, CS Gonzalez-Neira, A Pita, G Alonso, MR Alvarez, N Herrero, D Tessier, DC Vincent, D Bacot, F Hunter, DJ Lindstrom, S Dennis, J Michailidou, K Bolla, MK Easton, DF Silva, ID Fletcher, O Peto, J AF Orr, Nick Dudbridge, Frank Dryden, Nicola Maguire, Sarah Novo, Daniela Perrakis, Eleni Johnson, Nichola Ghoussaini, Maya Hopper, John L. Southey, Melissa C. Apicella, Carmel Stone, Jennifer Schmidt, Marjanka K. Broeks, Annegien Van't Veer, Laura J. Hogervorst, Frans B. Fasching, Peter A. Haeberle, Lothar Ekici, Arif B. Beckmann, Matthias W. Gibson, Lorna Aitken, Zoe Warren, Helen Sawyer, Elinor Tomlinson, Ian Kerin, Michael J. Miller, Nicola Burwinkel, Barbara Marme, Frederik Schneeweiss, Andreas Sohn, Chistof Guenel, Pascal Truong, Therese Cordina-Duverger, Emilie Sanchez, Marie Bojesen, Stig E. Nordestgaard, Borge G. Nielsen, Sune F. Flyger, Henrik Benitez, Javier Zamora, Maria Pilar Perez, Jose Ignacio Arias Menendez, Primitiva Anton-Culver, Hoda Neuhausen, Susan L. Brenner, Hermann Dieffenbach, Aida Karina Arndt, Volker Stegmaier, Christa Hamann, Ute Brauch, Hiltrud Justenhoven, Christina Bruning, Thomas Ko, Yon-Dschun Nevanlinna, Heli Aittomaki, Kristiina Blomqvist, Carl Khan, Sofia Bogdanova, Natalia Dork, Thilo Lindblom, Annika Margolin, Sara Mannermaa, Arto Kataja, Vesa Kosma, Veli-Matti Hartikainen, Jaana M. Chenevix-Trench, Georgia Beesley, Jonathan Lambrechts, Diether Moisse, Matthieu Floris, Guiseppe Beuselinck, Benoit Chang-Claude, Jenny Rudolph, Anja Seibold, Petra Flesch-Janys, Dieter Radice, Paolo Peterlongo, Paolo Peissel, Bernard Pensotti, Valeria Couch, Fergus J. Olson, Janet E. Slettedahl, Seth Vachon, Celine Giles, Graham G. Milne, Roger L. McLean, Catriona Haiman, Christopher A. Henderson, Brian E. Schumacher, Fredrick Le Marchand, Loic Simard, Jacques Goldberg, Mark S. Labreche, France Dumont, Martine Kristensen, Vessela Alnaes, Grethe Grenaker Nord, Silje Borresen-Dale, Anne-Lise Zheng, Wei Deming-Halverson, Sandra Shrubsole, Martha Long, Jirong Winqvist, Robert Pylkas, Katri Jukkola-Vuorinen, Arja Grip, Mervi Andrulis, Irene L. Knight, Julia A. Glendon, Gord Tchatchou, Sandrine Devilee, Peter Tollenaar, Robertus A. E. M. Seynaeve, Caroline M. Van Asperen, Christi J. Garcia-Closas, Montserrat Figueroa, Jonine Chanock, Stephen J. Lissowska, Jolanta Czene, Kamila Darabi, Hatef Eriksson, Mikael Klevebring, Daniel Hooning, Maartje J. Hollestelle, Antoinette van Deurzen, Carolien H. M. Kriege, Mieke Hall, Per Li, Jingmei Liu, Jianjun Humphreys, Keith Cox, Angela Cross, Simon S. Reed, Malcolm W. R. Pharoah, Paul D. P. Dunning, Alison M. Shah, Mitul Perkins, Barbara J. Jakubowska, Anna Lubinski, Jan Jaworska-Bieniek, Katarzyna Durda, Katarzyna Ashworth, Alan Swerdlow, Anthony Jones, Michael Schoemaker, Minouk J. Meindl, Alfons Schmutzler, Rita K. Olswold, Curtis Slager, Susan Toland, Amanda E. Yannoukakos, Drakoulis Muir, Kenneth Lophatananon, Artitaya Stewart-Brown, Sarah Siriwanarangsan, Pornthep Matsuo, Keitaro Ito, Hidema Iwata, Hiroji Ishiguro, Junko Wu, Anna H. Tseng, Chiu-Chen Van den Berg, David Stram, Daniel O. Teo, Soo Hwang Yip, Cheng Har Kang, Peter Ikram, Mohammad Kamran Shu, Xiao-Ou Lu, Wei Gao, Yu-Tang Cai, Hui Kang, Daehee Choi, Ji-Yeob Park, Sue K. Noh, Dong-Young Hartman, Mikael Miao, Hui Lim, Wei Yen Lee, Soo Chin Sangrajrang, Suleeporn Gaborieau, Valerie Brennan, Paul McKay, James Wu, Pei-Ei Hou, Ming-Feng Yu, Jyh-Cherng Shen, Chen-Yang Blot, William Cai, Qiuyin Signorello, Lisa B. Luccarini, Craig Bayes, Caroline Ahmed, Shahana Maranian, Mel Healey, Catherine S. Gonzalez-Neira, Anna Pita, Guillermo Alonso, M. Rosario Alvarez, Nuria Herrero, Daniel Tessier, Daniel C. Vincent, Daniel Bacot, Francois Hunter, David J. Lindstrom, Sara Dennis, Joe Michailidou, Kyriaki Bolla, Manjeet K. Easton, Douglas F. Silva, Isabel dos Santos Fletcher, Olivia Peto, Julian CA GENICA Network kConFab Investigators Australian Ovarian Canc Study Grp TI Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2 SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; ESTROGEN-RECEPTOR-ALPHA; CONFER SUSCEPTIBILITY; FUNCTIONAL VARIANTS; COMMON VARIANTS; ANALYSES REVEAL; RISK LOCUS; EXPRESSION; BINDING; FOXA1 AB We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88-0.92]; P-value = 1.58 x 10(-25)). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans 14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08-1.17]; P-value = 7.89 x 10(-09)) and rs13294895 (OR = 1.09 [1.06-1.12]; P-value = 2.97 x 10(-11)). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06-1.18]; P-value = 2.77 x 10(-05)). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-alpha, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis. C1 [Orr, Nick; Dryden, Nicola; Maguire, Sarah; Novo, Daniela; Perrakis, Eleni; Johnson, Nichola; Garcia-Closas, Montserrat; Ashworth, Alan; Fletcher, Olivia] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England. [Orr, Nick; Dryden, Nicola; Maguire, Sarah; Novo, Daniela; Perrakis, Eleni; Johnson, Nichola; Garcia-Closas, Montserrat; Ashworth, Alan; Swerdlow, Anthony; Schoemaker, Minouk J.; Fletcher, Olivia] Inst Canc Res, Div Breast Canc Res, London SW3 6JB, England. [Garcia-Closas, Montserrat; Swerdlow, Anthony; Jones, Michael; Schoemaker, Minouk J.] Inst Canc Res, Div Genet & Epidemiol, London SW3 6JB, England. [Dudbridge, Frank; Gibson, Lorna; Aitken, Zoe; Silva, Isabel dos Santos; Peto, Julian] London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London WC1, England. [Ghoussaini, Maya; Pharoah, Paul D. P.; Dunning, Alison M.; Shah, Mitul; Perkins, Barbara J.; Luccarini, Craig; Bayes, Caroline; Ahmed, Shahana; Maranian, Mel; Healey, Catherine S.; Easton, Douglas F.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. [Dennis, Joe; Michailidou, Kyriaki; Bolla, Manjeet K.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Hopper, John L.; Apicella, Carmel; Giles, Graham G.; Milne, Roger L.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic 3010, Australia. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Melbourne, Vic 3010, Australia. [Stone, Jennifer] Univ Western Australia, Ctr Genet Origins Hlth & Dis, Perth, WA 6009, Australia. [Schmidt, Marjanka K.; Broeks, Annegien; Hogervorst, Frans B.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, NL-1066 CX Amsterdam, Netherlands. [Haeberle, Lothar; Beckmann, Matthias W.] Univ Hosp Erlangen, Dept Gynecol & Obstet, Univ Breast Ctr Franconia, D-91054 Erlangen, Germany. [Ekici, Arif B.] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Inst Human Genet, Comprehens Canc Ctr Erlangen EMN, D-91054 Erlangen, Germany. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Warren, Helen] Queen Mary Univ London, Dept Clin Pharmacol, William Harvey Res Inst, Barts & London Sch Med, London, England. [Warren, Helen] Queen Mary Univ London, NIHR Barts Cardiovasc Biomed Res Unit, London, England. [Sawyer, Elinor] Guys Hosp, Kings Coll London, Div Canc Studies, London SE1 9RT, England. [Tomlinson, Ian] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX1 2JD, England. [Tomlinson, Ian] Univ Oxford, Oxford Biomed Res Ctr, Oxford OX1 2JD, England. [Kerin, Michael J.; Miller, Nicola] Univ Hosp Galway, Inst Clin Sci, Galway, Ireland. [Burwinkel, Barbara; Marme, Frederik; Schneeweiss, Andreas; Sohn, Chistof] Heidelberg Univ, Dept Obstet & Gynecol, D-69120 Heidelberg, Germany. [Marme, Frederik; Schneeweiss, Andreas] Heidelberg Univ, Natl Ctr Tumor Dis, D-69120 Heidelberg, Germany. [Burwinkel, Barbara] German Canc Res Ctr, Mol Epidemiol Grp, D-69120 Heidelberg, Germany. [Guenel, Pascal; Truong, Therese; Cordina-Duverger, Emilie; Sanchez, Marie] CESP Ctr Res Epidemiol & Populat Hlth, Inserm Natl Inst Hlth & Med Res, U1018, Environm Epidemiol Canc, Villejuif, France. [Guenel, Pascal; Truong, Therese; Cordina-Duverger, Emilie; Sanchez, Marie] Univ Paris 11, UMRS 1018, Villejuif, France. [Bojesen, Stig E.; Nordestgaard, Borge G.; Nielsen, Sune F.] Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, DK-2730 Herlev, Denmark. [Bojesen, Stig E.; Nordestgaard, Borge G.; Nielsen, Sune F.] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, DK-2730 Herlev, Denmark. [Flyger, Henrik] Copenhagen Univ Hosp, Herlev Hosp, Dept Breast Surg, DK-2730 Copenhagen, Denmark. [Benitez, Javier] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Program, Human Genet Grp, Madrid 28029, Spain. [Benitez, Javier] Ctr Invest Red Enfermedades Raras CIBERER, Valencia 46010, Spain. [Zamora, Maria Pilar] Hosp Univ La Paz, Serv Oncol Med, Madrid 28046, Spain. [Perez, Jose Ignacio Arias] Hosp Monte Naranco, Serv Cirugia Gen & Especialidades, Oviedo 33012, Spain. [Menendez, Primitiva] Hosp Monte Naranco, Serv Anat Patol, Oviedo 33012, Spain. [Anton-Culver, Hoda] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [Neuhausen, Susan L.] City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA USA. [Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. 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[Winqvist, Robert; Pylkas, Katri] Univ Oulu, Oulu Univ Hosp, Lab Canc Genet & Tumor Biol, Dept Clin Genet, Oulu, Finland. [Winqvist, Robert; Pylkas, Katri] Univ Oulu, Oulu Univ Hosp, Bioctr Oulu, Oulu, Finland. [Jukkola-Vuorinen, Arja] Univ Oulu, Oulu Univ Hosp, Dept Oncol, Oulu, Finland. [Grip, Mervi] Univ Oulu, Oulu Univ Hosp, Dept Surg, Oulu, Finland. [Andrulis, Irene L.; Glendon, Gord] Mt Sinai Hosp, Ontario Canc Genet Network, Toronto, ON M5G 1X5, Canada. [Knight, Julia A.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada. [Andrulis, Irene L.] Univ Toronto, Dalla Lana Sch Publ Hlth, Dept Mol Genet, Toronto, ON, Canada. [Knight, Julia A.] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Epidemiol, Toronto, ON, Canada. [Tchatchou, Sandrine] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Human Genet, NL-2300 RC Leiden, Netherlands. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Pathol, NL-2300 RC Leiden, Netherlands. [Tollenaar, Robertus A. E. M.] Leiden Univ, Med Ctr, Dept Surg Oncol, NL-2300 RC Leiden, Netherlands. [Seynaeve, Caroline M.; Hooning, Maartje J.; Hollestelle, Antoinette; Kriege, Mieke] Erasmus MC Canc Inst, Family Canc Clin, Dept Med Oncol, Rotterdam, Netherlands. [Van Asperen, Christi J.] Leiden Univ, Med Ctr, Dept Clin Genet, NL-2300 RC Leiden, Netherlands. [Figueroa, Jonine; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Lissowska, Jolanta; Klevebring, Daniel] M Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, Jolanta; Klevebring, Daniel] Inst Oncol, Warsaw, Poland. [Czene, Kamila; Darabi, Hatef; Eriksson, Mikael; Hall, Per; Humphreys, Keith] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. [van Deurzen, Carolien H. M.] Erasmus Univ, Dept Pathol, Med Ctr, NL-3000 DR Rotterdam, Netherlands. [Li, Jingmei; Liu, Jianjun] Genome Inst Singapore, Div Human Genet, Singapore 138672, Singapore. [Cox, Angela] Univ Sheffield, Dept Oncol, Sheffield Canc Res, Sheffield, S Yorkshire, England. [Cross, Simon S.] Univ Sheffield, Dept Neurosci, Acad Unit Pathol, Sheffield, S Yorkshire, England. [Reed, Malcolm W. R.] Univ Sussex, Brighton & Sussex Med Sch, Brighton, E Sussex, England. [Jakubowska, Anna; Lubinski, Jan; Jaworska-Bieniek, Katarzyna; Durda, Katarzyna] Pomeranian Med Univ, Dept Genet & Pathol, PL-70115 Szczecin, Poland. [Meindl, Alfons] Tech Univ Munich, Div Gynaecol & Obstet, D-81675 Munich, Germany. [Schmutzler, Rita K.] Univ Cologne, Ctr Hereditary Breast & Ovarian Canc, CIO, Fac Med, D-50931 Cologne, Germany. [Schmutzler, Rita K.] Univ Cologne, CMMC, Fac Med, D-50931 Cologne, Germany. [Schmutzler, Rita K.] Univ Hosp Cologne, Cologne, Germany. [Toland, Amanda E.] Ohio State Univ, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. [Yannoukakos, Drakoulis] Natl Ctr Sci Res Demokritos, Aghia Paraskevi Attikis, IRRP, Mol Diagnost Lab, Athens, Greece. [Muir, Kenneth; Stewart-Brown, Sarah] Univ Warwick, Warwick Med Sch, Div Hlth Sci, Coventry CV4 7AL, W Midlands, England. [Muir, Kenneth; Lophatananon, Artitaya] Univ Manchester, Instt Populat Hlth, Manchester, Lancs, England. [Siriwanarangsan, Pornthep] Minist Publ Hlth, Nonthaburi, Thailand. [Matsuo, Keitaro] Kyushu Univ, Fac Med Sci, Dept Prevent Med, Fukuoka 812, Japan. [Ito, Hidema] Aichi Canc Ctr, Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi 464, Japan. [Iwata, Hiroji; Ishiguro, Junko] Aichi Canc Ctr Hosp, Dept Breast Oncol, Nagoya, Aichi 464, Japan. [Teo, Soo Hwang; Kang, Peter] Sime Darby Med Ctr, Canc Res Initiat Fdn, Subang Jaya, Selangor, Malaysia. [Teo, Soo Hwang; Yip, Cheng Har] Univ Malaya, Canc Res Inst, Med Ctr, Breast Canc Res Unit, Kuala Lumpur, Malaysia. [Ikram, Mohammad Kamran] Natl Univ Singapore, Singapore Eye Res Inst, Singapore 168751, Singapore. [Lu, Wei] Shanghai Ctr Dis Control & Prevent, Shanghai, Peoples R China. [Gao, Yu-Tang] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Kang, Daehee; Park, Sue K.] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea. [Noh, Dong-Young] Seoul Natl Univ, Coll Med, Dept Surg, Seoul, South Korea. [Kang, Daehee; Choi, Ji-Yeob; Park, Sue K.] Seoul Natl Univ, Grad Sch, Dept Biomed Sci, Seoul, South Korea. [Kang, Daehee; Choi, Ji-Yeob; Park, Sue K.] Seoul Natl Univ, Canc Res Inst, Seoul, South Korea. [Hartman, Mikael; Miao, Hui; Lim, Wei Yen] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore. [Hartman, Mikael] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Surg, Singapore 117595, Singapore. [Hartman, Mikael; Miao, Hui] Natl Univ Hlth Syst, Singapore, Singapore. [Lee, Soo Chin] Natl Univ Hlth Syst, Dept Haematol Oncol, Singapore, Singapore. [Lee, Soo Chin] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore 117548, Singapore. [Sangrajrang, Suleeporn] Natl Canc Inst, Bangkok, Thailand. [Gaborieau, Valerie; Brennan, Paul; McKay, James] Int Agcy Res Canc, F-69372 Lyon, France. [Wu, Pei-Ei] Acad Sinica, Taiwan Biobank, Taipei 115, Taiwan. [Wu, Pei-Ei] Acad Sinica, Inst Biomed Sci, Taipei 115, Taiwan. [Hou, Ming-Feng; Shen, Chen-Yang] Kaohsiung Med Univ, Chung Ho Mem Hosp, Ctr Canc, Kaohsiung 804, Taiwan. [Hou, Ming-Feng; Shen, Chen-Yang] Kaohsiung Med Univ, Chung Ho Mem Hosp, Dept Surg, Kaohsiung 804, Taiwan. [Yu, Jyh-Cherng] Triserv Gen Hosp, Dept Surg, Taipei 114, Taiwan. [Yu, Jyh-Cherng] Natl Def Med Ctr, Taipei 114, Taiwan. [Shen, Chen-Yang] China Med Univ, Sch Publ Hlth, Taichung 404, Taiwan. [Blot, William] Int Inst Epidemiol, Rockville, MD USA. [Signorello, Lisa B.] Dana Farber Harvard Canc Ctr, Boston, MA USA. [Signorello, Lisa B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Hunter, David J.; Lindstrom, Sara] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Gonzalez-Neira, Anna; Pita, Guillermo; Alonso, M. Rosario; Alvarez, Nuria; Herrero, Daniel] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Program, Human Genotyping CEGEN Unit, Madrid, Spain. [Gonzalez-Neira, Anna; Pita, Guillermo; Tessier, Daniel C.; Vincent, Daniel; Bacot, Francois] Ctr Innovat Genome Quebec, Montreal, PQ, Canada. [Tessier, Daniel C.; Vincent, Daniel; Bacot, Francois] McGill Univ, Montreal, PQ, Canada. RP Orr, N (reprint author), Inst Canc Res, 237 Fulham Rd, London SW3 6JB, England. EM nicholas.orr@icr.ac.uk RI Shrubsole, Martha/K-5052-2015; Hartikainen, Jaana/E-6256-2015; Hartman, Mikael/B-4324-2011; Dork, Thilo/J-8620-2012; Bowtell, David/H-1007-2016; Bruning, Thomas/G-8120-2015; Andrulis, Irene/E-7267-2013; Garcia-Closas, Montserrat /F-3871-2015; Knight, Julia/A-6843-2012; Yip, Cheng-Har/B-1909-2010; Teo, Soo-hwang/H-2353-2014; Li, Jingmei/I-2904-2012; Nord, Silje/R-5212-2016; Brenner, Hermann/B-4627-2017; Peissel, Bernard/E-8187-2017; OI Dunning, Alison Margaret/0000-0001-6651-7166; Ikram, Mohammad Kamran/0000-0003-0173-9571; Giles, Graham/0000-0003-4946-9099; Shrubsole, Martha/0000-0002-5591-7575; Bowtell, David/0000-0001-9089-7525; Bruning, Thomas/0000-0001-9560-5464; Garcia-Closas, Montserrat /0000-0003-1033-2650; Li, Jingmei/0000-0001-8587-7511; Nord, Silje/0000-0002-3271-5356; Brenner, Hermann/0000-0002-6129-1572; Peissel, Bernard/0000-0001-9233-3571; dos Santos Silva, Isabel/0000-0002-6596-8798; Schoemaker, Minouk/0000-0001-8403-2234; Cross, Simon/0000-0003-2044-1754; Aitken, Zoe/0000-0002-5413-2450; Khan, Sofia/0000-0003-4185-8882; Cox, Angela/0000-0002-5138-1099; Moisse, Matthieu/0000-0001-8880-9311; Yannoukakos, Drakoulis/0000-0001-7509-3510 FU Cancer Research UK [C1287/A10118, C1287/A12014, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565]; European Community [223175 (HEALTH-F2-2009-223175)]; National Institutes of Health [CA128978, R01 CA77398]; Post-Cancer GWAS initiative (GAME-ON initiative) [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]; Department of Defence [W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR); Komen Foundation for the Cure; Breast Cancer Research Foundation; Ovarian Cancer Research Fund; National Cancer Institute (USA) [UM1 CA164920]; Dutch Cancer Society [NKI 2007-3839, 2009 4363]; BBMRI-NL - Dutch government [NWO 184.021.007]; Dutch National Genomics Initiative; ELAN-Fond of the University Hospital of Erlangen; Breakthrough Breast Cancer; NHS; National Cancer Research Network (NCRN); NIHR Comprehensive Biomedical Research Centre, Guy's & St. Thomas' NHS Foundation Trust in partnership with King's College London, UK; Oxford Biomedical Research Centre; Dietmar-Hopp Foundation; Helmholtz Society; German Cancer Research Center (DKFZ); Fondation de France; Institut National du Cancer (INCa); Ligue Nationale contre le Cancer; Ligue contre le Cancer Grand Ouest; Agence Nationale de Securite Sanitaire (ANSES) Agence Nationale de la Recherche (ANR); Chief Physician Johan Boserup and Lise Boserup Fund; Danish Medical Research Council; Herlev Hospital; Genome Spain Foundation; Red Tematica de Investigacion Cooperativa en Cancer; Asociacion Espanola Contra el Cancer; Fondo de Investigacion Sanitario [PI11/00923, PI081120]; Instituto de Salud Carlos III; California Breast Cancer Act; California Breast Cancer Research Fund [97-10500]; Lon V Smith Foundation [LVS39420]; Baden Wurttemberg Ministry of Science, Research and Arts; German Cancer Aid (Deutsche Krebshilfe); Deutsche Krebshilfe [107 352]; Federal Ministry of Education and Research (BMBF) Germany [01KW9975/5, 01KW9976/8, 01KW9977/0, 01KW0114]; Robert Bosch Foundation, Stuttgart; Deutsches Krebsforschungszentrum (DKFZ), Heidelberg; Institute for Prevention and Occupational Medicine of the German Social Accident Insurance; Institute of the Ruhr University Bochum (IPA), Bochum; Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH; Johanniter Krankenhaus, Bonn, Germany; Helsinki University Central Hospital Research Fund; Academy of Finland [266528, 250083, 122715]; Finnish Cancer Society; Nordic Cancer Union; Sigrid Juselius Foundation; Stockholm County Council; Karolinska Institutet; Swedish Cancer Society; Gustav V Jubilee foundation; Government Funding (EVO) of Kuopio University Hospital; Cancer Fund of North Savo; Finnish Cancer Organizations; University of Eastern Finland; National Breast Cancer Foundation; National Health and Medical Research Council (NHMRC); Queensland Cancer Fund; Cancer Councils of New South Wales, Victoria, Tasmania and South Australia; Cancer Foundation of Western Australia; Stichting tegen Kanker [232-2008, 196-2010]; FWO; Deutsche Krebshilfe e.V. [70-2892-BR I]; Hamburg Cancer Society; German Cancer Research Center; Federal Ministry of Education and Research (BMBF), Germany [01KH0402]; Italian Association for Cancer Research (AIRC); Fondazione IRCCS Istituto Nazionale Tumori; NIH [CA128978, CA116167, CA176785, CA63464, CA54281, CA098758, CA132839, R01CA100374, R01CA64277, R01CA148667, R37CA70867]; NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; VicHealth and Cancer Council Victoria; Australian NHMRC [209057, 251553, 504711]; Quebec Breast Cancer Foundation; Canadian Institutes of Health Research [CRN-87521]; Ministry of Economic Development, Innovation and Export Trade [PSR-SIIRI-701]; Norwegian Research council [155218/V40, 175240/S10]; FUGE-NFR [181600/V11]; Swizz Bridge Award; National Health and Medical Research Council of Australia; New South Wales Cancer Council; Victorian Health Promotion Foundation (Australia); Victorian Breast Cancer Research Consortium; Friends of Hannover Medical School; Rudolf Bartling Foundation; Finnish Cancer Foundation; Academy of Finland (Center of Excellence) [251314]; University of Oulu; University of Oulu Support Foundation; EVO funds for Oulu University Hospital; Dutch Cancer Society (RUL) [1997-1505]; Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL) [CP16]; National Cancer Institute, Department of Health and Human Services, USA; Marit and Hans Rausings Initiative Against Breast Cancer; Dutch Cancer Society (DDHK) [2004-3124, 2009-4318]; Agency for Science, Technology and Research of (A*STAR); US National Institute of Health (NIH); Susan G. Komen Breast Cancer Foundation; Yorkshire Cancer Research [S295, S299, S305PA]; UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge; DKFZ; Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; National Institutes of Health Grant [P30 CA016056]; Hellenic Cooperative Oncology Group [HR R_BG/04]; Greek General Secretary for Research and Technology (GSRT) Program, Research Excellence II; European Union (European Social Fund-ESF); Greek national funds through the Operational Program 'Education and Lifelong Learning' of the National Strategic Reference Framework (NSRF)-ARISTEIA; Institute of Cancer Research (ICR), London; Breast Cancer Research Trust, UK; Ministry of Education, Science, Sports, Culture and Technology of Japan; Ministry Health, Labour and Welfare of Japan; Health and Labour Sciences Research Grants for Research on Applying Health Technology from Ministry Health, Labour and Welfare of Japan; National Cancer Center Research and Development Fund; California Breast Cancer Research Program [1RB-0287, 3PB-0102, 5PB-0018, 10PB-0098]; California Department of Health; Malaysian Ministry of Science, Technology and Innovation (MOSTI); Malaysian Ministry of Higher Education [UM.C/HlR/MOHE/06]; Cancer Research Initiatives Foundation (CARIF); Biomedical Research Council, Singapore [BMRC08/1/35/19/550]; National Medical Research Council, Singapore (NMRC/CG/SERI); Genetic Associations and Mechanisms in Oncology (GAME-ON) Network [U19 CA148065]; BRL (Basic Research Laboratory) program through National Research Foundation of Korea - Ministry of Education, Science and Technology [2012-0000347]; National Medical Research Council; Biomedical Research Council [05/1/21/19/425]; National Cancer Institute, Thailand; Taiwan Biobank project of the Institute of Biomedical Sciences, Academia Sinica, Taiwan; National Program of Cancer Registries, Centers for Disease Control and Prevention (CDC); Charity Open Access Fund (COAF); [KULPFV/10/016-SymBioSysII]; [P30 CA68485]; [PBZ_KBN_122/P05/2004]; [N01CN25403] FX BCAC is funded by Cancer Research UK (C1287/A10118, C1287/A12014) and by the European Community's Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175). Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement no. 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692 and C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112-the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The Australian Breast Cancer Family Study (ABCFS) was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The ABCS study was supported by the Dutch Cancer Society (grants NKI 2007-3839; 2009 4363); BBMRI-NL, which is a Research Infrastructure financed by the Dutch government (NWO 184.021.007) and the Dutch National Genomics Initiative. The work of the BBCC was partly funded by ELAN-Fond of the University Hospital of Erlangen. The BBCS is funded by Cancer Research UK and Breakthrough Breast Cancer and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). E.S. is supported by NIHR Comprehensive Biomedical Research Centre, Guy's & St. Thomas' NHS Foundation Trust in partnership with King's College London, UK. I.T. is supported by the Oxford Biomedical Research Centre. The BSUCH study was supported by the Dietmar-Hopp Foundation, the Helmholtz Society and the German Cancer Research Center (DKFZ). The CECILE study was funded by Fondation de France, Institut National du Cancer (INCa), Ligue Nationale contre le Cancer, Ligue contre le Cancer Grand Ouest, Agence Nationale de Securite Sanitaire (ANSES) Agence Nationale de la Recherche (ANR). The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev Hospital. The CNIO-BCS was supported by the Genome Spain Foundation, the Red Tematica de Investigacion Cooperativa en Cancer and grants from the Asociacion Espanola Contra el Cancer and the Fondo de Investigacion Sanitario (PI11/00923 and PI081120). The Human Genotyping-CEGEN Unit (CNIO) is supported by the Instituto de Salud Carlos III. The CTS was initially supported by the California Breast Cancer Act of 1993 and the California Breast Cancer Research Fund (contract 97-10500) and is currently funded through the National Institutes of Health (R01 CA77398). Collection of cancer incidence data was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. H.A.C receives support from the Lon V Smith Foundation (LVS39420). The ESTHER study was supported by a grant from the Baden Wurttemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe). The GC-HBOC was supported by Deutsche Krebshilfe (107 352).; The GENICA was funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0 and 01KW0114, the Robert Bosch Foundation, Stuttgart, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, the Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, as well as the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany. The HEBCS was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society, and The Nordic Cancer Union and the Sigrid Juselius Foundation. Financial support for KARBAC was provided through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, The Swedish Cancer Society and the Gustav V Jubilee foundation. The KBCP was financially supported by the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, and by the strategic funding of the University of Eastern Finland. 'kConFab' is supported by a grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. LMBC is supported by the 'Stichting tegen Kanker' (232-2008 and 196-2010). Diether Lambrechts is supported by the FWO and the KULPFV/10/016-SymBioSysII. The MARIE study was supported by the Deutsche Krebshilfe e.V. [70-2892-BR I], the Hamburg Cancer Society, the German Cancer Research Center and the Federal Ministry of Education and Research (BMBF), Germany (01KH0402). MBCSG is supported by grants from the Italian Association for Cancer Research (AIRC) and by funds from the Italian citizens who allocated the 5/1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects '5 x 1000'). The MCBCS was supported by the NIH grants CA128978, CA116167 and CA176785 and NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), and the Breast Cancer Research Foundation and a generous gift from the David F. and Margaret T. Grohne Family Foundation and the Ting Tsung and Wei Fong Chao Foundation. MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. The MEC was support by NIH grants CA63464, CA54281, CA098758 and CA132839. The work of MTLGEBCS was supported by the Quebec Breast Cancer Foundation, the Canadian Institutes of Health Research for the 'CIHR Team in Familial Risks of Breast Cancer' program-grant # CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade-grant # PSR-SIIRI-701. The NBCS was supported by grants from the Norwegian Research council, 155218/V40, 175240/S10 to A.L.B.D., FUGE-NFR 181600/V11 to V.N.K. and a Swizz Bridge Award to A.L.B.D. The NBHS was supported by NIH grant R01CA100374. Biological sample preparation was conducted by the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485.; The OBCS was supported by research grants from the Finnish Cancer Foundation, the Academy of Finland (grant number 250083, 122715 and Center of Excellence grant number 251314), the Finnish Cancer Foundation, the Sigrid Juselius Foundation, the University of Oulu, the University of Oulu Support Foundation and the special Governmental EVO funds for Oulu University Hospital-based research activities. OFBCR was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The ORIGO study was supported by the Dutch Cancer Society (RUL 1997-1505) and the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL CP16). The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The pKARMA study was supported by Marit and Hans Rausings Initiative Against Breast Cancer. The RBCS was funded by the Dutch Cancer Society (DDHK 2004-3124, DDHK 2009-4318). The SASBAC study was supported by funding from the Agency for Science, Technology and Research of (A*STAR), the US National Institute of Health (NIH) and the Susan G. Komen Breast Cancer Foundation. The SBCS was supported by Yorkshire Cancer Research S295, S299, S305PA. SEARCH is funded by a programme grant from Cancer Research UK (C490/A10124) and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. The SZBCS was supported by Grant PBZ_KBN_122/P05/2004. SKKDKFZS is supported by the DKFZ. The TNBCC was supported by: a Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a grant from the Breast Cancer Research Foundation, a generous gift from the David F. and Margaret T. Grohne Family Foundation and the Ting Tsung and Wei Fong Chao Foundation, the Stefanie Spielman Breast Cancer fund and the OSU Comprehensive Cancer Center, DBBR (a CCSG Share Resource by National Institutes of Health Grant P30 CA016056), the Hellenic Cooperative Oncology Group research grant (HR R_BG/04) and the Greek General Secretary for Research and Technology (GSRT) Program, Research Excellence II, the European Union (European Social Fund-ESF), and Greek national funds through the Operational Program 'Education and Lifelong Learning' of the National Strategic Reference Framework (NSRF)-ARISTEIA. The UKBGS is funded by Breakthrough Breast Cancer and the Institute of Cancer Research (ICR), London. ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. The ACP study is funded by the Breast Cancer Research Trust, UK. The HERPACC was supported by a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Science, Sports, Culture and Technology of Japan, by a Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from Ministry Health, Labour and Welfare of Japan, by Health and Labour Sciences Research Grants for Research on Applying Health Technology from Ministry Health, Labour and Welfare of Japan and by National Cancer Center Research and Development Fund. LAABC is supported by grants (1RB-0287, 3PB-0102, 5PB-0018 and 10PB-0098) from the California Breast Cancer Research Program. Incident breast cancer cases were collected by the USC Cancer Surveillance Program (CSP) which is supported under subcontract by the California Department of Health. The CSP is also part of the National Cancer Institute's Division of Cancer Prevention and Control Surveillance, Epidemiology, and End Results Program, under contract number N01CN25403.; MYBRCA is funded by research grants from the Malaysian Ministry of Science, Technology and Innovation (MOSTI), Malaysian Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation (CARIF). Additional controls were recruited by the Singapore Eye Research Institute, which was supported by a grant from the Biomedical Research Council (BMRC08/1/35/19/550), Singapore and the National Medical Research Council, Singapore (NMRC/CG/SERI/2010). The SBCGS was supported primarily by NIH grants R01CA64277, R01CA148667 and R37CA70867. Biological sample preparation was conducted by the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The scientific development and funding of this project were, in part, supported by the Genetic Associations and Mechanisms in Oncology (GAME-ON) Network U19 CA148065. SEBCS was supported by the BRL (Basic Research Laboratory) program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2012-0000347). SGBCC is funded by the National Medical Research Council start-up Grant and Centre Grant (NMRC/CG/NCIS/2010). Additional controls were recruited by the Singapore Consortium of Cohort Studies-Multi-ethnic cohort (SCCS-MEC), which was funded by the Biomedical Research Council, grant number: 05/1/21/19/425. The TBCS was funded by The National Cancer Institute, Thailand. The TWBCS is supported by the Taiwan Biobank project of the Institute of Biomedical Sciences, Academia Sinica, Taiwan. The NBHS was supported by NIH grant R01CA100374. Biological sample preparation was conducted by the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The SCCS is supported by a grant from the National Institutes of Health (R01 CA092447). The Arkansas Central Cancer Registry is fully funded by a grant from National Program of Cancer Registries, Centers for Disease Control and Prevention (CDC). Funding to pay the Open Access publication charges for this article was provided by the Charity Open Access Fund (COAF). NR 47 TC 10 Z9 10 U1 3 U2 21 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 MAY 15 PY 2015 VL 24 IS 10 BP 2966 EP 2984 DI 10.1093/hmg/ddv035 PG 19 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CJ2PK UT WOS:000355326800022 PM 25652398 ER PT J AU Muller, YL Piaggi, P Hanson, RL Kobes, S Bhutta, S Abdussamad, M Leak-Johnson, T Kretzler, M Huang, K Weil, EJ Nelson, RG Knowler, WC Bogardus, C Baier, LJ AF Muller, Yunhua L. Piaggi, Paolo Hanson, Robert L. Kobes, Sayuko Bhutta, Shujera Abdussamad, Maryam Leak-Johnson, Tennille Kretzler, Matthias Huang, Ke Weil, E. Jennifer Nelson, Robert G. Knowler, William C. Bogardus, Clifton Baier, Leslie J. TI A cis-eQTL in PFKFB2 is associated with diabetic nephropathy, adiposity and insulin secretion in American Indians SO HUMAN MOLECULAR GENETICS LA English DT Article ID ACTIVATED PROTEIN-KINASE; GENOME-WIDE ASSOCIATION; BODY-MASS INDEX; PIMA-INDIANS; FRUCTOSE 2,6-BISPHOSPHATE; RESPIRATORY CHAMBER; ENERGY-EXPENDITURE; GLYCOGEN-SYNTHASE; GENE-EXPRESSION; GLYCOLYSIS AB A prior genome-wide association study (GWAS) in Pima Indians identified a variant within PFKFB2 (rs17258746) associated with body mass index (BMI). PFKFB2 encodes 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase isoform 2, which plays a role in glucose metabolism. To follow-up on the GWAS, tag SNPs across PFKFB2 were genotyped in American Indians (AI) who had longitudinal data on BMI (n = 6839), type 2 diabetes (T2D; n = 7710), diabetic nephropathy (DN; n = 2452), % body fat (n = 555) and insulin secretion (n = 298). Two SNPs were further genotyped in urban AI to assess replication for DN (n = 864). PFKFB2 expression was measured in 201 adipose biopsies using real-time RT-PCR and 61 kidney biopsies using the Affymetrix U133 array. Two SNPs (rs17258746 and rs11120137), which capture the same signal, were associated with maximum BMI in adulthood (beta = 1.02 per risk allele, P = 7.3 x 10(-4)), maximum BMI z-score in childhood (beta = 0.079, P = 0.03) and % body fat in adulthood (beta = 3.4%, P = 3 x 10(-7)). The adiposity-increasing allele correlated with lower PFKFB2 adipose expression (beta = 0.81, P = 9.4 x 10(-4)). Lower expression of PFKFB2 further correlated with higher % body fat (r = -0.16, P = 0.02) and BMI (r = -0.17, P = 0.02). This allele was also associated with increased risk for DN in both cohorts of AI [odds ratio = 1.64 (1.32-2.02), P = 5.8 x 10(-6)], and similarly correlated with lower PFKFB2 expression in kidney glomeruli (beta = 0.87, P = 0.03). The same allele was also associated with lower insulin secretion assessed by acute insulin response (beta = 0.78, P = 0.03) and 30-min plasma insulin concentrations (beta = 0.78, P = 1.1 x 10(-4)). Variation in PFKFB2 appears to reduce PFKFB2 expression in adipose and kidney tissues, and thereby increase risk for adiposity and DN. C1 [Muller, Yunhua L.; Piaggi, Paolo; Hanson, Robert L.; Kobes, Sayuko; Bhutta, Shujera; Abdussamad, Maryam; Huang, Ke; Weil, E. Jennifer; Nelson, Robert G.; Knowler, William C.; Bogardus, Clifton; Baier, Leslie J.] NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. [Leak-Johnson, Tennille; Kretzler, Matthias] Univ Michigan, Dept Internal Med & Computat Med, Ann Arbor, MI 48109 USA. RP Baier, LJ (reprint author), 445 North 5th St, Phoenix, AZ 85004 USA. EM lbaier@phx.niddk.nih.gov RI Hanson, Robert/O-3238-2015; OI Hanson, Robert/0000-0002-4252-7068; Piaggi, Paolo/0000-0003-2774-9161 FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; NIDDK [P30DK081943] FX This work was supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. M.K. and T.L.J. were supported by NIDDK P30DK081943 George M. O'Brien Kidney Research Core Center at the University of Michigan. NR 41 TC 2 Z9 2 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 MAY 15 PY 2015 VL 24 IS 10 BP 2985 EP 2996 DI 10.1093/hmg/ddv040 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CJ2PK UT WOS:000355326800023 PM 25662186 ER PT J AU Ho, JH Jedrych, JJ Feng, HC Natalie, AA Grandinetti, L Mirvish, E Crespo, MM Yadav, D Fasanella, KE Proksell, S Kuan, SF Pastrana, DV Buck, CB Shuda, Y Moore, PS Chang, Y AF Ho, Jonhan Jedrych, Jaroslaw J. Feng, Huichen Natalie, August A. Grandinetti, Lisa Mirvish, Ezra Crespo, Maria M. Yadav, Dhiraj Fasanella, Kenneth E. Proksell, Siobhan Kuan, Shih-Fan Pastrana, Diana V. Buck, Christopher B. Shuda, Yoko Moore, Patrick S. Chang, Yuan TI Human Polyomavirus 7-Associated Pruritic Rash and Viremia in Transplant Recipients SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE polyomavirus; HPyV7; skin viral infection; transplantation-associated disease; immunosuppression ID MERKEL CELL POLYOMAVIRUS; CARCINOMA; EXPRESSION; ANTIGENS AB Human polyomavirus 7 (HPyV7) is one of 11 HPyVs recently discovered through genomic sequencing technologies. Two lung transplant recipients receiving immunosuppressive therapy developed pruritic, brown plaques on the trunk and extremities showing a distinctive epidermal hyperplasia with virus-laden keratinocytes containing densely packed 36-45-nm icosahedral capsids. Rolling circle amplification and gradient centrifugation testing were positive for encapsidated HPyV7 DNA in skin and peripheral blood specimens from both patients, and HPyV7 early and capsid proteins were abundantly expressed in affected tissues. We describe for the first time that HPyV7 is associated with novel pathogenicity in some immunosuppressed individuals. C1 [Ho, Jonhan; Jedrych, Jaroslaw J.; Natalie, August A.; Grandinetti, Lisa; Mirvish, Ezra] Univ Pittsburgh, Sch Med, Dept Dermatol, Pittsburgh, PA 15213 USA. [Crespo, Maria M.] Univ Pittsburgh, Sch Med, Div Pulm Allergy & Crit Care, Pittsburgh, PA 15213 USA. [Yadav, Dhiraj; Fasanella, Kenneth E.; Proksell, Siobhan] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15213 USA. [Kuan, Shih-Fan] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA 15213 USA. [Feng, Huichen; Shuda, Yoko; Moore, Patrick S.; Chang, Yuan] Univ Pittsburgh, Inst Canc, Canc Virol Program, Pittsburgh, PA 15213 USA. [Pastrana, Diana V.; Buck, Christopher B.] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. RP Chang, Y (reprint author), Univ Pittsburgh, Canc Res Inst, Hillman Canc Res Pavil, Lab 1 8, 5117 Ctr Ave, Pittsburgh, PA 15213 USA. EM yc70@pitt.edu RI Moore, Patrick/F-3960-2011; Chang, Yuan/F-4146-2011 OI Moore, Patrick/0000-0002-8132-858X; FU National Institutes of Health [CA136363, CA136806, CA170354, P30CA047904]; American Cancer Society; NLM-Pittsburgh (Biomedical Informatics training grant) [5T15LM007059-27]; Pittsburgh Foundation; UPMC Foundation FX This work was supported by the National Institutes of Health (CA136363, CA136806, and CA170354 to P. S. M. and Y. C.; and P30CA047904 to the UPCI Hillman Cancer Center Core), the American Cancer Society (to P. S. M. and Y. C.), the NLM-Pittsburgh (Biomedical Informatics training grant 5T15LM007059-27 to H. F.), and the Pittsburgh and UPMC Foundations. NR 14 TC 16 Z9 16 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD MAY 15 PY 2015 VL 211 IS 10 BP 1560 EP 1565 DI 10.1093/infdis/jiu524 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CI4MG UT WOS:000354723000006 PM 25231015 ER PT J AU Eller, MA Opollo, MS Liu, M Redd, AD Eller, LA Kityo, C Kayiwa, J Laeyendecker, O Wawer, MJ Milazzo, M Kiwanuka, N Gray, RH Serwadda, D Sewankambo, NK Quinn, TC Michael, NL Wabwire-Mangen, F Sandberg, JK Robb, ML AF Eller, Michael A. Opollo, Marc S. Liu, Michelle Redd, Andrew D. Eller, Leigh Anne Kityo, Cissy Kayiwa, Joshua Laeyendecker, Oliver Wawer, Maria J. Milazzo, Mark Kiwanuka, Noah Gray, Ronald H. Serwadda, David Sewankambo, Nelson K. Quinn, Thomas C. Michael, Nelson L. Wabwire-Mangen, Fred Sandberg, Johan K. Robb, Merlin L. TI HIV Type 1 Disease Progression to AIDS and Death in a Rural Ugandan Cohort Is Primarily Dependent on Viral Load Despite Variable Subtype and T-Cell Immune Activation Levels SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE HIV-1; AIDS; subtype D; immune activation; PD-1; viral load ID HUMAN-IMMUNODEFICIENCY-VIRUS; RECEIVING ANTIRETROVIRAL THERAPY; SEX-DIFFERENCES; RAKAI DISTRICT; RNA LEVELS; INFECTION; CD4(+); MORTALITY; BURDEN; AFRICA AB Methods.aEuro integral HIV-1 seroconverters (n = 156) from rural Uganda were evaluated to assess the effects of T-cell activation, viral load, and viral subtype on disease progression during clinical follow-up. Results.aEuro integral The frequency of activated T cells was increased in HIV-1-infected Ugandans, compared with community matched uninfected individuals, but did not differ significantly between viral subtypes. Higher HIV-1 load, subtype D, older age, and high T-cell activation levels were associated with faster disease progression to AIDS or death. In a multivariate Cox regression analysis, HIV-1 load was the strongest predictor of progression, with subtype also contributing. T-cell activation did not emerge an independent predictor of disease progression from this particular cohort. Conclusions.aEuro integral These findings suggest that the independent contribution of T-cell activation on morbidity and mortality observed in European and North American cohorts may not be directly translated to the HIV epidemic in East Africa. In this setting, HIV-1 load appears to be the primary determinant of disease progression. C1 [Eller, Michael A.; Liu, Michelle; Eller, Leigh Anne; Milazzo, Mark; Michael, Nelson L.; Robb, Merlin L.] Walter Reed Army Inst Res, US Mil HIV Res Program, Silver Spring, MD 20910 USA. [Eller, Michael A.; Liu, Michelle; Eller, Leigh Anne; Milazzo, Mark; Robb, Merlin L.] Henry M Jackson Fdn Adv Mil Med, Bethesda, MD USA. [Redd, Andrew D.; Laeyendecker, Oliver; Quinn, Thomas C.] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Laeyendecker, Oliver; Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Wawer, Maria J.; Gray, Ronald H.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Opollo, Marc S.; Wabwire-Mangen, Fred] Makerere Univ, Coll Hlth Sci, Makerere Univ Walter Reed Project, Kampala, Uganda. [Kityo, Cissy; Kayiwa, Joshua] Makerere Univ, Coll Hlth Sci, Joint Clin Res Ctr, Kampala, Uganda. [Kiwanuka, Noah; Serwadda, David; Wabwire-Mangen, Fred] Makerere Univ, Coll Hlth Sci, Sch Publ Hlth, Kampala, Uganda. [Sewankambo, Nelson K.] Makerere Univ, Coll Hlth Sci, Fac Med, Kampala, Uganda. [Kiwanuka, Noah; Serwadda, David; Sewankambo, Nelson K.] Uganda Virus Res Inst, Rakai Hlth Sci Program, Entebbe, Uganda. [Sandberg, Johan K.] Karolinska Inst, Dept Med, Karolinska Univ Hosp Huddinge, Ctr Infect Med, Stockholm, Sweden. RP Eller, MA (reprint author), Walter Reed Army Inst Res, HJF, US Mil HIV Res Program, 503 Robert Grant Ave,1N11, Silver Spring, MD 20910 USA. EM meller@hivresearch.org OI Sewankambo, Nelson/0000-0001-9362-053X; Laeyendecker, Oliver/0000-0002-6429-4760 FU Henry M. Jackson Foundation for the Advancement of Military Medicine [W81XWH-11-2-0174]; US Army Medical Research and Materiel Command [W81XWH-11-2-0174]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by a cooperative agreement (W81XWH-11-2-0174) between the Henry M. Jackson Foundation for the Advancement of Military Medicine and the US Army Medical Research and Materiel Command; and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 50 TC 3 Z9 3 U1 2 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD MAY 15 PY 2015 VL 211 IS 10 BP 1574 EP 1584 DI 10.1093/infdis/jiu646 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CI4MG UT WOS:000354723000008 PM 25404522 ER PT J AU Meya, DB Okurut, S Zziwa, G Rolfes, MA Kelsey, M Cose, S Joloba, M Naluyima, P Palmer, BE Kambugu, A Mayanja-Kizza, H Bohjanen, PR Eller, MA Wahl, SM Boulware, DR Manabe, YC Janoff, EN AF Meya, David B. Okurut, Samuel Zziwa, Godfrey Rolfes, Melissa A. Kelsey, Melander Cose, Steve Joloba, Moses Naluyima, Prossy Palmer, Brent E. Kambugu, Andrew Mayanja-Kizza, Harriet Bohjanen, Paul R. Eller, Michael A. Wahl, Sharon M. Boulware, David R. Manabe, Yuka C. Janoff, Edward N. TI Cellular Immune Activation in Cerebrospinal Fluid From Ugandans With Cryptococcal Meningitis and Immune Reconstitution Inflammatory Syndrome SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE cryptococcal meningitis; cryptococcus; HIV; cerebrospinal fluid; immune responses; cell activation ID CENTRAL-NERVOUS-SYSTEM; CD4(+) T-CELLS; HIV-1-INFECTED PATIENTS; ANTIRETROVIRAL THERAPY; CLINICAL-FEATURES; INFECTED PATIENTS; HIV-INFECTION; NEOFORMANS; TUBERCULOSIS; MECHANISMS AB Methods.aEuro integral We characterized the lineage and activation status of mononuclear cells in blood and CSF of HIV-infected patients with noncryptococcal meningitis (NCM) (n = 10), those with CM at day 0 (n = 40) or day 14 (n = 21) of antifungal therapy, and those with CM-IRIS (n = 10). Results.aEuro integral At diagnosis, highly activated CD8(+) T cells predominated in CSF in both CM and NCM. CM-IRIS was associated with an increasing frequency of CSF CD4(+) T cells (increased from 2.2% to 23%; P = .06), a shift in monocyte phenotype from classic to an intermediate/proinflammatory, and increased programmed death ligand 1 expression on natural killer cells (increased from 11.9% to 61.6%, P = .03). CSF cellular responses were distinct from responses in peripheral blood. Conclusions.aEuro integral After CM, T cells in CSF tend to evolve with the development of IRIS, with increasing proportions of activated CD4(+) T cells, migration of intermediate monocytes to the CSF, and declining fungal burden. These changes provide insight into IRIS pathogenesis and could be exploited to more effectively treat CM and prevent CM-IRIS. C1 [Meya, David B.; Kambugu, Andrew; Manabe, Yuka C.] Makerere Univ, Coll Hlth Sci, Infect Dis Inst, Kampala, Uganda. [Meya, David B.; Cose, Steve; Mayanja-Kizza, Harriet] Makerere Univ, Coll Hlth Sci, Sch Med, Kampala, Uganda. [Joloba, Moses] Makerere Univ, Dept Microbiol, Sch Biomed Sci, Kampala, Uganda. [Okurut, Samuel; Zziwa, Godfrey] Makerere Univ Reed Project, Kampala, Uganda. [Cose, Steve] Uganda Virus Res Inst, Med Res Council, Uganda Res Unit AIDS, Entebbe, Uganda. [Meya, David B.; Rolfes, Melissa A.; Boulware, David R.] Univ Minnesota, Dept Med, Ctr Infect Dis & Microbiol Translat Res, Minneapolis, MN 55455 USA. [Kelsey, Melander; Janoff, Edward N.] Univ Colorado Denver, Mucosal & Vaccine Res Program Colorado, Aurora, CO USA. [Kelsey, Melander; Janoff, Edward N.] Denver Vet Affairs Med Ctr, Baltimore, MD USA. [Manabe, Yuka C.] Johns Hopkins Univ, Dept Med, Div Infect Dis, Baltimore, MD USA. [Eller, Michael A.] Walter Reed Army Inst Res, US Mil HIV Res Program, Silver Spring, MD USA. [Eller, Michael A.] Henry M Jackson Fdn Adv Mil Med, Bethesda, MD USA. [Wahl, Sharon M.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [Cose, Steve] London Sch Hyg & Trop Med, London, England. RP Meya, DB (reprint author), Makerere Univ, Coll Hlth Sci, Infect Dis Inst, POB 22418, Kampala, Uganda. EM david.meya@gmail.com OI Mayanja-Kizza, Harriet/0000-0002-9297-6208; Joloba, Moses/0000-0002-0334-9983; Boulware, David/0000-0002-4715-0060; Cose, Stephen/0000-0002-5156-037X FU National Institutes of Health [R01AI078934, U01AI089244, NS065713, R01AI108479, K24AI096925, T32AI055433, R21NS065713]; Wellcome Trust (Training Health Researchers into Vocational Excellence [THRiVE]) in East Africa [087540]; GlaxoSmithKline Collaborative Investigator Research Award; Veterans Affairs Research Service FX This work was supported by the National Institutes of Health (grants R01AI078934, U01AI089244, NS065713, R01AI108479, K24AI096925, T32AI055433, and R21NS065713); the Wellcome Trust (Training Health Researchers into Vocational Excellence [THRiVE]) in East Africa (grant 087540), the GlaxoSmithKline Collaborative Investigator Research Award, and the Veterans Affairs Research Service. NR 45 TC 9 Z9 9 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD MAY 15 PY 2015 VL 211 IS 10 BP 1597 EP 1606 DI 10.1093/infdis/jiu664 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CI4MG UT WOS:000354723000010 PM 25492918 ER PT J AU Dawadi, S Viswanatham, K Boshoff, HI Barry, CE Aldrich, CC AF Dawadi, Surendra Viswanatham, Kishore Boshoff, Helena I. Barry, Clifton E., III Aldrich, Courtney C. TI Investigation and Conformational Analysis of Fluorinated Nucleoside Antibiotics Targeting Siderophore Biosynthesis SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID ACID RELATED-COMPOUNDS; MYCOBACTERIUM-TUBERCULOSIS; ADENYLATING ENZYMES; COUPLING-CONSTANTS; 2-HYDROXYL GROUP; SUGAR RING; INHIBITORS; ADENOSINE; MECHANISM; ANALOGS AB Antibiotic resistance represents one of the greatest threats to public health. The adenylation inhibitor 5'-O-[N-(salicyl)sulfamoyl]adenosine (SAL-AMS) is the archetype for a new class of nucleoside antibiotics that target iron acquisition in pathogenic microorganisms and is especially effective against Mycobacterium tuberculosis, the causative agent of tuberculosis. Strategic incorporation of fluorine at the 2' and 3' positions of the nucleoside was performed by direct fluorination to enhance activity and improve drug disposition properties. The resulting SAL-AMS analogues were comprehensively assessed for biochemical potency, whole-cell antitubercular activity, and in vivo pharmacokinetic parameters. Conformational analysis suggested a strong preference of fluorinated sugar rings for either a 2'-endo, 3'-exo (South), or a 3'-endo,2'-exo (North) conformation. The structureactivity relationships revealed a strong conformational bias for the C3'-endo conformation to maintain potent biochemical and whole-cell activity, whereas improved pharmacokinetic properties were associated with the C2'-endo conformation. C1 [Dawadi, Surendra; Viswanatham, Kishore; Aldrich, Courtney C.] Univ Minnesota, Dept Med Chem, Minneapolis, MN 55455 USA. [Boshoff, Helena I.; Barry, Clifton E., III] NIAID, TB Res Sect, Bethesda, MD 20892 USA. RP Aldrich, CC (reprint author), Univ Minnesota, Dept Med Chem, Minneapolis, MN 55455 USA. EM aldri015@umn.edu RI Barry, III, Clifton/H-3839-2012 FU NIH [AI070219]; NIAID, NIH FX This work was supported by a grant from the NIH (AI070219 to C.C.A.) and the Intramural Research Program of the NIAID, NIH (C.E.B.). NR 54 TC 3 Z9 3 U1 3 U2 18 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD MAY 15 PY 2015 VL 80 IS 10 BP 4835 EP 4850 DI 10.1021/acs.joc.5b00550 PG 16 WC Chemistry, Organic SC Chemistry GA CI6XW UT WOS:000354908500001 PM 25916415 ER PT J AU Soliman, SE Kovac, P AF Soliman, Sameh E. Kovac, Pavol TI Stereoselective Syntheses of the Conjugation-Ready, Downstream Disaccharide and Phosphorylated Upstream, Branched Trisaccharide Fragments of the O-PS of Vibrio cholerae O139 SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID SHIGELLA-DYSENTERIAE TYPE-1; PROTECTIVE IMMUNITY; POLYSACCHARIDE; LIPOPOLYSACCHARIDE; OLIGOSACCHARIDES; OGAWA; CHAIN; GLYCOSIDATION; GALACTOSE; ANTIGEN AB N-Bromosuccinimide-mediated 4,6-O-benzylidene ring opening in 8-azido-3,6-dioxaoctyl 4,6-O-benzylidene-2-deoxy-2-trichloroacetamido-beta-d-glucopyranoside afforded the corresponding 4-O-benzoyl-6-bromo-6-deoxy analogue, which was coupled with 3,4,6-tri-O-acetyl-2-O-benzyl-alpha-D-galactopyranosyl chloride to give the 1,2-cis alpha-linked disaccharide as the major product. Conventional hydroxyl group manipulation in the latter and products of further conversions gave the desired, functionalized disaccharide alpha-d-GalpA-(1 -> 3)-beta-d-QuipNAc. The rare, foregoing sequence forms the downstream end in the O-specific polysaccharide of both Vibrio cholerae O22 and O139. Halide-assisted glycosylation at 4(I)-OH in 8-azido-3,6-dioxaoctyl 6-O-benzyl-2-deoxy-3-O-(2,3,4,6-tetra-O-acetyl-beta-d-galactopyranosyl)-2-trichloroacetamido-beta-d-glucopyranoside, obtained by regioselective reductive opening of the acetal ring in the parent 4(I),6(I)-O-benzylidene derivative, with 2,4-di-O-benzyl-alpha-colitosyl bromide, gave exclusively the alpha-linked trisaccharide. The latter was sequentially deacetylated and selectively benzylated to give 8-azido-3,6-dioxaoctyl 2,4-di-O-benzyl-3,6-dideoxy-alpha-L-xylo-hexopyranosyl-(1 -> 4)-[3-O-benzyl-beta-d-galactopyranosyl-(1 -> 3)]-6-O-benzyl-2-deoxy-2-trichloroacetamido-beta-d-glucopyranoside. Subsequent selective phosphorylation of the triol, thus obtained, with 2,2,2-trichloroethyl phosphorodichloridate afforded isomeric (R,S)-(P)-4(II),6(II)-cyclic phosphates, which were both obtained in crystalline form and fully characterized. Each of the latter was globally deprotected by catalytic (Pd/C) hydrogenation/hydrogenolysis to give the desired, amino-functionalized, spacer-equipped, phosphorylated upstream trisaccharide fragment of the O-PS of V. cholerae O139. C1 [Soliman, Sameh E.; Kovac, Pavol] NIDDK, LBC, Sect Carbohydrates, NIH, Bethesda, MD 20892 USA. [Soliman, Sameh E.] Univ Alexandria, Dept Chem, Fac Sci, Alexandria 21321, Egypt. RP Kovac, P (reprint author), NIDDK, LBC, Sect Carbohydrates, NIH, Bethesda, MD 20892 USA. EM kpn@helix.nih.gov FU National Institutes of Health (NIH); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH) and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). NR 35 TC 5 Z9 5 U1 2 U2 12 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD MAY 15 PY 2015 VL 80 IS 10 BP 4851 EP 4860 DI 10.1021/acs.joc.5b00562 PG 10 WC Chemistry, Organic SC Chemistry GA CI6XW UT WOS:000354908500002 PM 25928584 ER PT J AU Hu, H Liu, X Jin, WF Ropers, HH Wienker, TF AF Hu, Hao Liu, Xiang Jin, Wenfei Ropers, H. Hilger Wienker, Thomas F. TI Evaluating information content of SNPs for sample-tagging in re-sequencing projects SO SCIENTIFIC REPORTS LA English DT Article ID HUMAN-POPULATIONS; GENETIC-MARKERS; PANEL; SELECTION; IDENTIFICATION; ASSOCIATION; ANCESTRY; TRACKING AB Sample-tagging is designed for identification of accidental sample mix-up, which is a major issue in re-sequencing studies. In this work, we develop a model to measure the information content of SNPs, so that we can optimize a panel of SNPs that approach the maximal information for discrimination. The analysis shows that as low as 60 optimized SNPs can differentiate the individuals in a population as large as the present world, and only 30 optimized SNPs are in practice sufficient in labeling up to 100 thousand individuals. In the simulated populations of 100 thousand individuals, the average Hamming distances, generated by the optimized set of 30 SNPs are larger than 18, and the duality frequency, is lower than 1 in 10 thousand. This strategy of sample discrimination is proved robust in large sample size and different datasets. The optimized sets of SNPs are designed for Whole Exome Sequencing, and a program is provided for SNP selection, allowing for customized SNP numbers and interested genes. The sample-tagging plan based on this framework will improve re-sequencing projects in terms of reliability and cost-effectiveness. C1 [Hu, Hao; Ropers, H. Hilger; Wienker, Thomas F.] Max Planck Inst Mol Genet, Dept Human Mol Genet, D-14195 Berlin, Germany. [Liu, Xiang] BlackBerry Deutschland GmbH, D-44799 Bochum, Germany. [Jin, Wenfei] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. RP Hu, H (reprint author), Max Planck Inst Mol Genet, Dept Human Mol Genet, D-14195 Berlin, Germany. EM hu@molgen.mpg.de FU Max Planck Society; European Commission [241995] FX We are very grateful to Hossein Najmabadi and Kimia Kahrizi from Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran, for they provided the sample DNAs from the Middle East. This work was supported by the Max Planck Society and by the European Commission Framework Program 7 (FP7) project GENCODYS with grant number 241995. NR 23 TC 0 Z9 0 U1 4 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAY 15 PY 2015 VL 5 AR 10247 DI 10.1038/srep10247 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ1MZ UT WOS:000355249000001 PM 25975447 ER PT J AU Zou, TT Rao, JN Liu, L Xiao, L Chung, HK Li, YW Chen, G Gorospe, M Wang, JY AF Zou, Tongtong Rao, Jaladanki N. Liu, Lan Xiao, Lan Chung, Hee Kyoung Li, Yanwu Chen, Gang Gorospe, Myriam Wang, Jian-Ying TI JunD enhances miR-29b levels transcriptionally and posttranscriptionally to inhibit proliferation of intestinal epithelial cells SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE microRNAs; transcriptional regulation; intestinal epithelial cells; cell proliferation; transcriptional factors ID MESSENGER-RNA STABILITY; REPRESSES CDK4 TRANSCRIPTION; PROXIMAL PROMOTER REGION; CUG-BINDING PROTEIN-1; POLYAMINE DEPLETION; OXIDATIVE STRESS; C-MYC; MICRORNA MATURATION; SIGNALING PATHWAY; GENE-EXPRESSION AB Through its actions as component of the activating protein-1 (AP-1) transcription factor, JunD potently represses cell proliferation. Here we report a novel function of JunD in the regulation of microRNA expression in intestinal epithelial cells (IECs). Ectopically expressed JunD specifically increased the expression of primary and mature forms of miR-29b, whereas JunD silencing inhibited miR-29b expression. JunD directly interacted with the miR-29b1 promoter via AP-1-binding sites, whereas mutation of AP-1 sites from the miR-29b1 promoter prevented JunD-mediated transcriptional activation of the miR-29b1 gene. JunD also enhanced formation of the Drosha micro-processor complex, thus further promoting miR-29b biogenesis. Cellular polyamines were found to regulate miR-29b expression by altering JunD abundance, since the increase in miR-29b expression levels in polyamine-deficient cells was abolished by JunD silencing. In addition, miR-29b silencing prevented JunD-induced repression of IEC proliferation. Our findings indicate that JunD activates miR-29b by enhancing its transcription and processing, which contribute to the inhibitory effect of JunD on IEC growth and maintenance of gut epithelium homeostasis. C1 [Zou, Tongtong; Rao, Jaladanki N.; Liu, Lan; Xiao, Lan; Chung, Hee Kyoung; Li, Yanwu; Chen, Gang; Wang, Jian-Ying] Univ Maryland, Sch Med, Dept Surg, Cell Biol Grp, Baltimore, MD 21201 USA. [Zou, Tongtong; Rao, Jaladanki N.; Liu, Lan; Xiao, Lan; Chung, Hee Kyoung; Li, Yanwu; Chen, Gang; Wang, Jian-Ying] Baltimore Vet Affairs Med Ctr, Baltimore, MD USA. [Gorospe, Myriam] NIA, Lab Genet & Genom, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Wang, Jian-Ying] Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. RP Wang, JY (reprint author), Baltimore Vet Affairs Med Ctr 112, 10 North Greene St, Baltimore, MD 21201 USA. EM jwang@smail.umaryland.edu FU US Department of Veterans Affairs; National Institute of Diabetes and Digestive and Kidney Diseases [DK-57819, DK-61972, DK-68491]; National Institute on Aging-Intramural Research Program FX This work was supported by Merit Review Awards (to J.-Y. Wang, J. N. Rao) from the US Department of Veterans Affairs; grants from National Institute of Diabetes and Digestive and Kidney Diseases (DK-57819, DK-61972, DK-68491 to J.-Y. Wang); and funding from the National Institute on Aging-Intramural Research Program (to M. Gorospe). J.-Y. Wang is a Senior Research Career Scientist, Biomedical Laboratory Research & Development Service, US Department of Veterans Affairs. NR 54 TC 6 Z9 6 U1 1 U2 3 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 MAY 15 PY 2015 VL 308 IS 10 BP C813 EP C824 DI 10.1152/ajpcell.00027.2015 PG 12 WC Cell Biology; Physiology SC Cell Biology; Physiology GA CI4JP UT WOS:000354714800004 PM 25788572 ER PT J AU Yan, XT Chu, JH Gomez, J Koenigs, M Holm, C He, XX Perez, MF Zhao, HY Mane, S Martinez, FD Ober, C Nicolae, DL Barnes, KC London, SJ Gilliland, F Weiss, ST Raby, BA Cohn, L Chupp, GL AF Yan, Xiting Chu, Jen-Hwa Gomez, Jose Koenigs, Maria Holm, Carole He, Xiaoxuan Perez, Mario F. Zhao, Hongyu Mane, Shrikant Martinez, Fernando D. Ober, Carole Nicolae, Dan L. Barnes, Kathleen C. London, Stephanie J. Gilliland, Frank Weiss, Scott T. Raby, Benjamin A. Cohn, Lauren Chupp, Geoffrey L. TI Noninvasive Analysis of the Sputum TranScriptome Discriminates Clinical Phenotypes of Asthma SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE molecular endotyping; genomic; RNA; severe asthma; pathway analysis ID GENE-EXPRESSION; CHILDHOOD ASTHMA; RESEARCH-PROGRAM; CLUSTER-ANALYSIS; IDENTIFICATION; ASSOCIATION; MICROARRAY; REGRESSION; PROTEIN; SAFETY AB Rationale: The airway transcriptome includes genes that contribute to the pathophysiologic heterogeneity seen in individuals with asthma. Objectives: We analyzed sputum gene expression for transcriptomic endotypes of asthma (TEA), gene signatures that discriminate phenotypes of disease. Methods: Gene expression in the sputum and blood of patients with asthma was measured using Affymetrix microarrays. Unsupervised clustering analysis based on pathways from the Kyoto Encyclopedia of Genes and Genomes was used to identify TEA clusters. Logistic regression analysis of matched blood samples defined an expression profile in the circulation to determine the TEA cluster assignment in a cohort of children with asthma to replicate clinical phenotypes. Measurements and Main Results: Three TEA clusters were identified. TEA cluster 1 had the most subjects with a history of intubation (P = 0.05), a lower prebronchodilator FEV1 (P = 0.006), a higher bronchodilator response (P = 0.03), and higher exhaled nitric oxide levels (P = 0.04) compared with the other TEA clusters. TEA cluster 2, the smallest cluster, had the most subjects that were hospitalized for asthma (P = 0.04). TEA cluster 3, the largest cluster, had normal lung function, low exhaled nitric oxide levels, and lower inhaled steroid requirements. Evaluation of TEA clusters in children confirmed that TEA clusters 1 and 2 are associated with a history of intubation (P = 5.58 X 10(-6)) and hospitalization (P = 0.01), respectively. Conclusions: There are common patterns of gene expression in the sputum and blood of children and adults that are associated with near-fatal, severe, and milder asthma. C1 [Yan, Xiting; Gomez, Jose; Koenigs, Maria; Holm, Carole; He, Xiaoxuan; Perez, Mario F.; Cohn, Lauren; Chupp, Geoffrey L.] Yale Univ, Sch Med, Dept Internal Med, Sect Pulm Crit Care & Sleep Med, New Haven, CT 06510 USA. [Yan, Xiting; Zhao, Hongyu] Yale Univ, Sch Med, Keck Lab, Biostat Resource, New Haven, CT USA. [Zhao, Hongyu] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. [Zhao, Hongyu] Yale Univ, Sch Med, Program Computat Biol & Bioinformat, New Haven, CT USA. [Zhao, Hongyu; Mane, Shrikant] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA. [Chu, Jen-Hwa; Weiss, Scott T.; Raby, Benjamin A.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Chu, Jen-Hwa; Weiss, Scott T.; Raby, Benjamin A.] Harvard Univ, Sch Med, Boston, MA USA. [Martinez, Fernando D.] Univ Arizona, Arizona Resp Ctr, Tucson, AZ USA. [Martinez, Fernando D.] Univ Arizona, Inst BIO5, Tucson, AZ USA. [Ober, Carole; Nicolae, Dan L.] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Barnes, Kathleen C.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [London, Stephanie J.] NIEHS, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Gilliland, Frank] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. RP Chupp, GL (reprint author), 300 Cedar St,S441 TAG, New Haven, CT 06520 USA. EM geoffrey.chupp@yale.edu OI Gomez, Jose/0000-0002-6521-6318; Chu, Jen-hwa/0000-0001-7179-9428; London, Stephanie/0000-0003-4911-5290 FU National Institutes of Health (NIH) [R01HL095390-04, R01HL118346-01]; NIH [T32HL007778-18, T15LM007056-26]; NIH/NHLBI [K99HL114651-01A1]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences; Mary Beryl Patch Turnbull Scholar Program; NCATS grant [UL13 TR000142] FX Supported by National Institutes of Health (NIH) grants R01HL095390-04 and R01HL118346-01 (G.L.C.); NIH training grants T32HL007778-18 and T15LM007056-26 and FAMRI Young Clinical Scientist Award (J.G.); NIH/NHLBI grant K99HL114651-01A1 (J.-H.C.); Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (S.J.L.); the Mary Beryl Patch Turnbull Scholar Program (K.C.B.); and NCATS grant UL13 TR000142 (X.Y.). NR 37 TC 19 Z9 19 U1 0 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD MAY 15 PY 2015 VL 191 IS 10 BP 1116 EP 1125 DI 10.1164/rccm.201408-1440OC PG 10 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA CI8KO UT WOS:000355021400010 PM 25763605 ER PT J AU Beach, JR Hammer, JA AF Beach, Jordan R. Hammer, John A., III TI Myosin II isoform co-assembly and differential regulation in mammalian systems SO EXPERIMENTAL CELL RESEARCH LA English DT Review DE Nonmuscle myosin II; Isoform; Filament assembly ID HEAVY-CHAIN PHOSPHORYLATION; SMOOTH-MUSCLE MYOSIN; LIVE CELLS; A GENE; MIGRATING CELLS; PROTEIN-KINASE; LIVING CELLS; TAIL REGION; LIGHT-CHAIN; IN-VIVO AB Non-muscle myosin 2 (NM2) is a major force-producing, actin-based motor in mammalian nonmuscle cells, where it plays important roles in a broad range of fundamental biological processes, including cytokinesis, cell migration, and epithelial barrier function. This breadth of function at the tissue and cellular levels suggests extensive diversity and differential regulation of NM2 bipolar filaments, the major, if not sole, functional form of NM2s in vivo. Previous in vitro, cellular and animal studies indicate that some of this diversity is supported by the existence of multiple NM2 isoforms. Moreover, two recent studies have shown that these isoforms can co-assemble to form heterotypic filaments, further expanding functional diversity. In addition to isoform co-assembly, cells may differentially regulate NM2 function via isoform-specific expression, RLC phosphorylation, MHC phosphorylation or regulation via binding partners. Here, we provide a brief summary of NM2 filament assembly, summarize the recent findings regarding NM2 isoform co-assembly, consider the mechanisms cells might utilize to differentially regulate NM2 isoforms, and review the data available to support these mechanisms. Published by Elsevier Inc. C1 [Beach, Jordan R.; Hammer, John A., III] NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. RP Beach, JR (reprint author), NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. EM jordan.beach@nih.gov; hammer@nhlbi.nih.gov FU NIH DIR, United States [ZIAHL000514-31] FX The authors would like to thank Kirsten Remmert (NHLBI) for artistic contributions to the figure, Jim Sellers (NHLBI) for helpful discussions, and Tom Egelhoff (CCF) for critical reading of the manuscript. This work was supported by NIH DIR, United States (ZIAHL000514-31 to JAH). NR 81 TC 7 Z9 7 U1 0 U2 17 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 EI 1090-2422 J9 EXP CELL RES JI Exp. Cell Res. PD MAY 15 PY 2015 VL 334 IS 1 BP 2 EP 9 DI 10.1016/j.yexcr.2015.01.012 PG 8 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CI6YW UT WOS:000354911100002 PM 25655283 ER PT J AU Lin, MY Sheng, ZH AF Lin, Mei-Yao Sheng, Zu-Hang TI Regulation of mitochondrial transport in neurons SO EXPERIMENTAL CELL RESEARCH LA English DT Review DE Mitochondrial transport; Mitochondrial docking; Mitophagy; Motile mitochondria; Stationary mitochondria; Kinesin motors; Dynein motors; Syntaphilin; Synaptic activity ID KINESIN HEAVY-CHAIN; FAST AXONAL-TRANSPORT; CORTICAL-NEURONS; SYNAPTIC-TRANSMISSION; TARGETED DISRUPTION; HIPPOCAMPAL-NEURONS; MOTOR PROTEIN; MIRO GTPASE; MOTILITY; TRAFFICKING AB Mitochondria are cellular power plants that supply ATP to power various biological activities essential for neuronal growth, survival, and function. Due to unique morphological features, neurons face exceptional challenges to maintain ATP and Ca2+ homeostasis. Neurons require specialized mechanisms distributing mitochondria to distal areas where energy and Ca2+ buffering are in high demand, such as synapses and axonal branches. These distal compartments also undergo development- and activity-dependent remodeling, thereby altering mitochondrial trafficking and distribution. Mitochondria move bi-directionally, pause briefly, and move again, frequently changing direction. In mature neurons, only one-third of axonal mitochondria are motile. Stationary mitochondria serve as local energy sources and buffer intracellular Ca2+. The balance between motile and stationary mitochondria responds quickly to changes in axonal and synaptic physiology. Furthermore, neurons are postmitotic cells surviving for the lifetime of the organism; thus, mitochondria need to be removed when they become aged or dysfunction. Mitochondria also alter their motility under stress conditions or when their integrity is impaired. Therefore, regulation of mitochondrial transport is essential to meet altered metabolic requirements and to remove aged and damaged mitochondria or replenish healthy ones to distal terminals. Defects in mitochondrial transport and altered distribution are implicated in the pathogenesis of several major neurological disorders. Thus, research into the mechanisms regulating mitochondrial motility is an important emerging frontier in neurobiology. This short review provides an updated overview on motor-adaptor machineries that drive and regulate mitochondrial transport and docking receptors that anchor axonal mitochondria in response to the changes in synaptic activity, metabolic requirement, and altered mitochondrial integrity. The review focuses on microtubule (MT)-based mitochondrial trafficking and anchoring. Additional insight from different perspectives can be found in other in-depth reviews. Published by Elsevier Inc. C1 [Lin, Mei-Yao; Sheng, Zu-Hang] NINDS, Synapt Funct Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. RP Sheng, ZH (reprint author), NINDS, Synapt Funct Sect, Porter Neurosci Res Ctr, NIH, Room 2B-215,35 Convent Dr, Bethesda, MD 20892 USA. EM shengz@ninds.nih.gov FU Intramural Research Program of NINDS, NIH [NS003029-08 DIR] FX The authors thank all the colleagues in their laboratory and other laboratories who contributed to the research described in this article and D Schoenberg for proof editing. The authors' lab is supported by the Intramural Research Program of NINDS, NIH (NS003029-08 DIR, Z-H. S.). NR 74 TC 20 Z9 20 U1 3 U2 23 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 EI 1090-2422 J9 EXP CELL RES JI Exp. Cell Res. PD MAY 15 PY 2015 VL 334 IS 1 BP 35 EP 44 DI 10.1016/j.yexcr.2015.01.004 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CI6YW UT WOS:000354911100006 PM 25612908 ER PT J AU Kupferschmidt, DA Lovinger, DM AF Kupferschmidt, David A. Lovinger, David M. TI Inhibition of presynaptic calcium transients in cortical inputs to the dorsolateral striatum by metabotropic GABA(B) and mGlu2/3 receptors SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID LONG-TERM DEPRESSION; EXCITATORY SYNAPTIC-TRANSMISSION; MOSSY FIBER SYNAPSES; CYCLIC-AMP FORMATION; GLUTAMATE-RECEPTOR; CORTICOSTRIATAL SYNAPSES; CA2+ CHANNELS; TRANSMITTER RELEASE; RAT HIPPOCAMPUS; NEUROTRANSMITTER RELEASE AB Cortical inputs to the dorsolateral striatum (DLS) are dynamically regulated during skill learning and habit formation, and are dysregulated in disorders characterized by impaired action control. Therefore, a mechanistic investigation of the processes regulating corticostriatal transmission is key to understanding DLS-associated circuit function, behaviour and pathology. Presynaptic GABA(B) and group II metabotropic glutamate (mGlu2/3) receptors exert marked inhibitory control over corticostriatal glutamate release in the DLS, yet the signalling pathways through which they do so are unclear. We developed a novel approach using the genetically encoded calcium (Ca2+) indicator GCaMP6 to assess presynaptic Ca2+ in corticostriatal projections to the DLS. Using simultaneous photometric presynaptic Ca2+ and striatal field potential recordings, we report that relative to P/Q-type Ca2+ channels, N-type channels preferentially contributed to evoked presynaptic Ca2+ influx in motor cortex projections to, and excitatory transmission in, the DLS. Activation of GABA(B) or mGlu2/3 receptors inhibited both evoked presynaptic Ca2+ transients and striatal field potentials. mGlu2/3 receptor-mediated depression did not require functional N-type Ca2+ channels, but was attenuated by blockade of P/Q-type channels. These findings reveal presynaptic mechanisms of inhibitory modulation of corticostriatal function that probably contribute to the selection and shaping of behavioural repertoires. C1 [Kupferschmidt, David A.; Lovinger, David M.] US Natl Inst Hlth, Sect Synapt Pharmacol & Vivo Neural Funct, Lab Integrat Neurosci, NIH, Rockville, MD USA. RP Lovinger, DM (reprint author), NIAAA, Lab Integrat Neurosci, NIH, Rockville, MD 20892 USA. EM lovindav@mail.nih.gov FU Division of Intramural Clinical and Biological Research of the NIAAA; Natural Sciences and Engineering Research Council (NSERC) of Canada [PDF 438487-13] FX This work was supported by the Division of Intramural Clinical and Biological Research of the NIAAA, and the Natural Sciences and Engineering Research Council (NSERC) of Canada (PDF 438487-13). NR 78 TC 6 Z9 6 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3751 EI 1469-7793 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD MAY 15 PY 2015 VL 593 IS 10 BP 2295 EP 2310 DI 10.1113/JP270045 PG 16 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA CI3KH UT WOS:000354646100005 PM 25781000 ER PT J AU Zengeya, TT Kulkarni, RA Meier, JL AF Zengeya, Thomas T. Kulkarni, Rhushikesh A. Meier, Jordan L. TI Modular Synthesis of Cell-Permeating 2-Ketoglutarate Esters SO ORGANIC LETTERS LA English DT Article ID ALPHA-KETOGLUTARATE; SUCCINATE-DEHYDROGENASE; METABOLIC FLUX; MUTATIONS; CANCER; PARAGANGLIOMA; GROWTH; ACIDS; GENE; IDH1 AB Cell-permeating esters of 2-ketoglutarate (2-KG) have been synthesized through a convergent sequence from two modules in two and three steps, respectively. This route provides access to a full series of mono- and disubstituted 2-KG esters, enabling us to define the effect of regioisomeric masking on metabolite release and antihypoxic activity in cell-based assays. In addition to providing insight into the biological activity of cell permeable 2-KG esters, the straightforward and modular nature of this synthetic route may prove useful for the development of next-generation 2-KG analogues for diagnostic and therapeutic applications. C1 [Zengeya, Thomas T.; Kulkarni, Rhushikesh A.; Meier, Jordan L.] NCI, Biol Chem Lab, Frederick, MD 21702 USA. RP Meier, JL (reprint author), NCI, Biol Chem Lab, Frederick, MD 21702 USA. EM jordan.meier@nih.gov RI Meier, Jordan/N-2608-2014 FU NIH, National Cancer Institute, Center for Cancer Research [ZIA BC011488-02] FX We thank Prof. Tsui-Fen Chou (UCLA) for ODD-Luc He La cells, Dr. W. Marston Linehan (NCI) for the kind gift of a 2-KG detection kit, and Dr. Martin Schnermann (NCI) for many helpful discussions. This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (ZIA BC011488-02). NR 31 TC 1 Z9 1 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1523-7060 EI 1523-7052 J9 ORG LETT JI Org. Lett. PD MAY 15 PY 2015 VL 17 IS 10 BP 2326 EP 2329 DI 10.1021/acs.orglett.5b00737 PG 4 WC Chemistry, Organic SC Chemistry GA CI6XU UT WOS:000354908300009 PM 25915096 ER PT J AU Lieskovska, J Palenikova, J Langhansova, H Chagas, AC Calvo, E Kotsyfakis, M Kopecky, J AF Lieskovska, Jaroslava Palenikova, Jana Langhansova, Helena Chagas, Andrezza Campos Calvo, Eric Kotsyfakis, Michalis Kopecky, Jan TI Tick sialostatins L and L2 differentially influence dendritic cell responses to Borrelia spirochetes SO PARASITES & VECTORS LA English DT Article DE Dendritic cells; Borrelia burgdorferi; Tick cystatin; Signalling ID ACTIVATED PROTEIN-KINASE; NECROSIS-FACTOR-ALPHA; TOLL-LIKE RECEPTOR-2; IXODES-SCAPULARIS; LYME-DISEASE; SIGNALING PATHWAYS; BONE-MARROW; BURGDORFERI INFECTION; ARTHRITIS DEVELOPMENT; CYTOKINE INDUCTION AB Background: Transmission of pathogens by ticks is greatly supported by tick saliva released during feeding. Dendritic cells (DC) act as immunological sentinels and interconnect the innate and adaptive immune system. They control polarization of the immune response towards Th1 or Th2 phenotype. We investigated whether salivary cystatins from the hard tick Ixodes scapularis, sialostatin L (Sialo L) and sialostatin L2 (Sialo L2), influence mouse dendritic cells exposed to Borrelia burgdorferi and relevant Toll-like receptor ligands. Methods: DCs derived from bone-marrow by GM-CSF or Flt-3 ligand, were activated with Borrelia spirochetes or TLR ligands in the presence of 3 mu M Sialo L and 3 mu M Sialo L2. Produced chemokines and IFN-beta were measured by ELISA test. The activation of signalling pathways was tested by western blotting using specific antibodies. The maturation of DC was determined by measuring the surface expression of CD86 by flow cytometry. Results: We determined the effect of cystatins on the production of chemokines in Borrelia-infected bone-marrow derived DC. The production of MIP-1 alpha was severely suppressed by both cystatins, while IP-10 was selectively inhibited only by Sialo L2. As TLR-2 is a major receptor activated by Borrelia spirochetes, we tested whether cystatins influence signalling pathways activated by TLR-2 ligand, lipoteichoic acid (LTA). Sialo L2 and weakly Sialo L attenuated the extracellular matrix-regulated kinase (Erk1/2) pathway. The activation of phosphatidylinositol-3 kinase (PI3K)/Akt pathway and nuclear factor-kappa B (NF-kappa B) was decreased only by Sialo L2. In response to Borrelia burgdorferi, the activation of Erk1/2 was impaired by Sialo L2. Production of IFN-beta was analysed in plasmacytoid DC exposed to Borrelia, TLR-7, and TLR-9 ligands. Sialo L, in contrast to Sialo L2, decreased the production of IFN-beta in pDC and also impaired the maturation of these cells. Conclusions: This study shows that DC responses to Borrelia spirochetes are affected by tick cystatins. Sialo L influences the maturation of DC thus having impact on adaptive immune response. Sialo L2 affects the production of chemokines potentially engaged in the development of inflammatory response. The impact of cystatins on Borrelia growth in vivo is discussed. C1 [Lieskovska, Jaroslava; Palenikova, Jana; Langhansova, Helena; Kopecky, Jan] Univ South Bohemia, Fac Sci, CZ-37005 Ceske Budejovice, Czech Republic. [Lieskovska, Jaroslava; Palenikova, Jana; Langhansova, Helena; Kotsyfakis, Michalis; Kopecky, Jan] Acad Sci Czech Republic, Ctr Biol, Inst Parasitol, CZ-37005 Ceske Budejovice, Czech Republic. [Chagas, Andrezza Campos; Calvo, Eric] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. RP Lieskovska, J (reprint author), Univ South Bohemia, Fac Sci, Branisovska 1760, CZ-37005 Ceske Budejovice, Czech Republic. EM lieskovs@paru.cas.cz RI Kotsyfakis, Michail/G-9525-2014; Langhansova, Helena /G-9292-2014; Kopecky, Jan/G-9347-2014; Lieskovska, Jaroslava/G-9309-2014; OI Kotsyfakis, Michail/0000-0002-7526-1876; Calvo, Eric/0000-0001-7880-2730 FU Czech Science Foundation [P302/12/2208, 14-25799S] FX This work was supported by the Czech Science Foundation, grants P302/12/2208 and 14-25799S. NR 58 TC 2 Z9 4 U1 1 U2 6 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 MAY 15 PY 2015 VL 8 AR 275 DI 10.1186/s13071-015-0887-1 PG 11 WC Parasitology SC Parasitology GA CI6DM UT WOS:000354848900001 PM 25975355 ER PT J AU Liu, L Ouyang, M Rao, JN Zou, TT Xiao, L Chung, HK Wu, J Donahue, JM Gorospe, M Wang, JY AF Liu, Lan Ouyang, Miao Rao, Jaladanki N. Zou, Tongtong Xiao, Lan Chung, Hee Kyoung Wu, Jing Donahue, James M. Gorospe, Myriam Wang, Jian-Ying TI Competition between RNA-binding proteins CELF1 and HuR modulates MYC translation and intestinal epithelium renewal SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID GU-RICH ELEMENTS; MESSENGER-RNA; C-MYC; POLYAMINE DEPLETION; MYOTONIC-DYSTROPHY; POSTTRANSCRIPTIONAL REGULATION; MICRORNA BIOGENESIS; SIGNALING PATHWAY; BARRIER FUNCTION; MUCOSAL GROWTH AB The mammalian intestinal epithelium is one of the most rapidly self-renewing tissues in the body, and its integrity is preserved through strict regulation. The RNA-binding protein (RBP) ELAV-like family member 1 (CELF1), also referred to as CUG-binding protein 1 (CUGBP1), regulates the stability and translation of target mRNAs and is implicated in many aspects of cellular physiology. We show that CELF1 competes with the RBP HuR to modulate MYC translation and regulates intestinal epithelial homeostasis. Growth inhibition of the small intestinal mucosa by fasting in mice was associated with increased CELF1/Myc mRNA association and decreased MYC expression. At the molecular level, CELF1 was found to bind the 3'-untranslated region (UTR) of Myc mRNA and repressed MYC translation without affecting total Myc mRNA levels. HuR interacted with the same Myc 3'-UTR element, and increasing the levels of HuR decreased CELF1 binding to Myc mRNA. In contrast, increasing the concentrations of CELF1 inhibited formation of the [HuR/Myc mRNA] complex. Depletion of cellular polyamines also increased CELF1 and enhanced CELF1 association with Myc mRNA, thus suppressing MYC translation. Moreover, ectopic CELF1 overexpression caused G1-phase growth arrest, whereas CELF1 silencing promoted cell proliferation. These results indicate that CELF1 represses MYC translation by decreasing Myc mRNA association with HuR and provide new insight into the molecular functions of RBPs in the regulation of intestinal mucosal growth. C1 [Liu, Lan; Ouyang, Miao; Rao, Jaladanki N.; Zou, Tongtong; Xiao, Lan; Chung, Hee Kyoung; Wu, Jing; Donahue, James M.; Wang, Jian-Ying] Univ Maryland, Sch Med, Dept Surg, Cell Biol Grp, Baltimore, MD 21201 USA. [Wang, Jian-Ying] Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. [Liu, Lan; Ouyang, Miao; Rao, Jaladanki N.; Zou, Tongtong; Xiao, Lan; Chung, Hee Kyoung; Wu, Jing; Donahue, James M.; Wang, Jian-Ying] Baltimore Vet Affairs Med Ctr, Baltimore, MD 21201 USA. [Gorospe, Myriam] NIA, Lab Genet & Genom, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Wang, JY (reprint author), Univ Maryland, Sch Med, Dept Surg, Cell Biol Grp, Baltimore, MD 21201 USA. EM jwang@smail.umaryland.edu FU U.S. Department of Veterans Affairs; National Institutes of Health [DK57819, DK61972, DK68491]; National Institute on Aging-Intramural Research Program FX This work was supported by Merit Review Awards (to J.-Y.W. and J.N.R.) from the U.S. Department of Veterans Affairs; grants from the National Institutes of Health (DK57819, DK61972, and DK68491 to J.-Y.W.); and funding from the National Institute on Aging-Intramural Research Program (to M.G.). J.-Y.W. is a Senior Research Career Scientist, Biomedical Laboratory Research & Development Service, U.S. Department of Veterans Affairs. NR 62 TC 15 Z9 16 U1 1 U2 6 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 MAY 15 PY 2015 VL 26 IS 10 BP 1797 EP 1810 DI 10.1091/mbc.E14-11-1500 PG 14 WC Cell Biology SC Cell Biology GA CI0FU UT WOS:000354413000003 PM 25808495 ER PT J AU Burroughs, AM Zhang, DP Aravind, L AF Burroughs, A. Maxwell Zhang, Dapeng Aravind, L. TI The eukaryotic translation initiation regulator CDC123 defines a divergent clade of ATP-grasp enzymes with a predicted role in novel protein modifications SO BIOLOGY DIRECT LA English DT Article ID UBIQUITIN-RELATED DOMAINS; GENOME-WIDE ASSOCIATION; ESCHERICHIA-COLI; NUCLEIC-ACID; CRYSTAL-STRUCTURE; ADP-RIBOSYLATION; NATURAL-HISTORY; D123 PROTEIN; DNA VIRUSES; LIGASE AB Deciphering the origin of uniquely eukaryotic features of sub-cellular systems, such as the translation apparatus, is critical in reconstructing eukaryogenesis. One such feature is the highly conserved, but poorly understood, eukaryotic protein CDC123, which regulates the abundance of the eukaryotic translation initiation eIF2 complex and binds one of its components eIF2 gamma. We show that the eukaryotic protein CDC123 defines a novel clade of ATP-grasp enzymes distinguished from all other members of the superfamily by a RAGNYA domain with two conserved lysines (henceforth the R2K clade). Combining the available biochemical and genetic data on CDC123 with the inferred enzymatic function, we propose that the eukaryotic CDC123 proteins are likely to function as ATP-dependent protein-peptide ligases which modify proteins by ribosome-independent addition of an oligopeptide tag. We also show that the CDC123 family emerged first in bacteria where it appears to have diversified along with the two other families of the R2K clade. The bacterial CDC123 family members are of two distinct types, one found as part of type VI secretion systems which deliver polymorphic toxins and the other functioning as potential effectors delivered to amoeboid eukaryotic hosts. Representatives of the latter type have also been independently transferred to phylogenetically unrelated amoeboid eukaryotes and their nucleo-cytoplasmic large DNA viruses. Similarly, the two other prokaryotic R2K clade families are also proposed to participate in biological conflicts between bacteriophages and their hosts. These findings add further evidence to the recently proposed hypothesis that the horizontal transfer of enzymatic effectors from the bacterial endosymbionts of the stem eukaryotes played a fundamental role in the emergence of the characteristically eukaryotic regulatory systems and sub-cellular structures. C1 [Burroughs, A. Maxwell; Zhang, Dapeng; Aravind, L.] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM aravind@mail.nih.gov FU National Library of Medicine, NIH, USA FX Research by the authors is supported by the Intramural Research Program of the National Library of Medicine, NIH, USA. NR 74 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 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD MAY 15 PY 2015 VL 10 AR 21 DI 10.1186/s13062-015-0053-x PG 11 WC Biology SC Life Sciences & Biomedicine - Other Topics GA CI0KH UT WOS:000354425500001 PM 25976611 ER PT J AU Kumarasamy, N Aga, E Ribaudo, HJ Wallis, CL Katzenstein, DA Stevens, WS Norton, MR Klingman, KL Hosseinipour, MC Crump, JA Supparatpinyo, K Badal-Faesen, S Bartlett, JA AF Kumarasamy, Nagalingeswaran Aga, Evgenia Ribaudo, Heather J. Wallis, Carole L. Katzenstein, David A. Stevens, Wendy S. Norton, Michael R. Klingman, Karin L. Hosseinipour, Mina C. Crump, John A. Supparatpinyo, Khuanchai Badal-Faesen, Sharlaa Bartlett, John A. TI Lopinavir/Ritonavir Monotherapy as Second-line Antiretroviral Treatment in Resource-Limited Settings: Week 104 Analysis of AIDS Clinical Trials Group (ACTG) A5230 SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE second-line antiretroviral therapy; protease inhibitor monotherapy; intensification; ACTG 5230 ID REVERSE-TRANSCRIPTASE; VIROLOGICAL FAILURE; 1ST-LINE FAILURE; RESISTANCE; THERAPY; HIV-1; NUCLEOSIDE; MUTATIONS; DATABASE; OPTIONS AB Background. The AIDS Clinical Trials Group (ACTG) A5230 study evaluated lopinavir/ritonavir (LPV/r) monotherapy following virologic failure (VF) on first-line human immunodeficiency virus (HIV) regimens in Africa and Asia. Methods. Eligible subjects had received first-line regimens for at least 6 months and had plasma HIV-1 RNA levels 1000-200 000 copies/mL. All subjects received LPV/r 400/100 mg twice daily. VF was defined as failure to suppress to <400 copies/mL by week 24, or confirmed rebound to >400 copies/mL at or after week 16 following confirmed suppression. Subjects with VF added emtricitabine 200 mg/tenofovir 300 mg (FTC/TDF) once daily. The probability of continued HIV-1 RNA <400 copies/mL on LPV/r monotherapy through week 104 was estimated with a 95% confidence interval (CI); predictors of treatment success were evaluated with Cox proportional hazards models. Results. One hundred twenty-three subjects were enrolled. Four subjects died and 2 discontinued prematurely; 117 of 123 (95%) completed 104 weeks. Through week 104, 49 subjects met the primary endpoint; 47 had VF, and 2 intensified treatment without VF. Of the 47 subjects with VF, 41 (33%) intensified treatment, and 39 of 41 subsequently achieved levels <400 copies/mL. The probability of continued suppression <400 copies/mL over 104 weeks on LPV/r monotherapy was 60% (95% CI, 50%-68%); 80%-85% maintained levels <400 copies/mL with FTC/TDF intensification as needed. Ultrasensitive assays on specimens with HIV-1 RNA level <400 copies/mL at weeks 24, 48, and 104 revealed that 61%, 62%, and 65% were suppressed to <40 copies/mL, respectively. Conclusions. LPV/r monotherapy after first-line VF with FTC/TDF intensification when needed provides durable suppression of HIV-1 RNA over 104 weeks. C1 [Kumarasamy, Nagalingeswaran] VHS, YRG CARE Med Ctr, Chennai, Tamil Nadu, India. [Aga, Evgenia; Ribaudo, Heather J.] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Wallis, Carole L.] Lancet Labs, Johannesburg, South Africa. [Katzenstein, David A.] Stanford Univ, Palo Alto, CA 94304 USA. [Stevens, Wendy S.; Badal-Faesen, Sharlaa] Univ Witwatersrand, Johannesburg, South Africa. [Norton, Michael R.] AbbVie, N Chicago, IL USA. [Klingman, Karin L.] NIH, Div AIDS, Bethesda, MD 20892 USA. [Hosseinipour, Mina C.] Kamuzu Cent Hosp, Lilongwe, Malawi. [Crump, John A.] Kilimanjaro Christian Med Ctr, Moshi, Tanzania. [Supparatpinyo, Khuanchai] Chiang Mai Univ, Chiang Mai, Thailand. [Bartlett, John A.] Duke Univ, Med Ctr, Durham, NC USA. RP Kumarasamy, N (reprint author), VHS, YRG CARE Med Ctr, Chennai, Tamil Nadu, India. EM kumarasamy@yrgcare.org FU ACTG, National Institutes of Health [U01 AI068634, U01 AI069484, U01 AI068636, U01AI067854, U01 AI069432]; AbbVie FX This clinical trial was supported by the ACTG, National Institutes of Health (grant numbers U01 AI068634, U01 AI069484, U01 AI068636, U01AI067854, and U01 AI069432). Drug supplies were provided by AbbVie and Gilead Sciences, Inc. Viral failure samples were processed in the Mellors Laboratory, Pittsburgh, Pennsylvania. Additional funding for laboratory tests was provided by AbbVie. NR 15 TC 5 Z9 5 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAY 15 PY 2015 VL 60 IS 10 BP 1552 EP 1558 DI 10.1093/cid/civ109 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CH0ON UT WOS:000353721300018 PM 25694653 ER PT J AU Morse, CG McLaughlin, M Matthews, L Proschan, M Thomas, F Gharib, AM Abu-Asab, M Orenstein, A Engle, RE Hu, XJ Lempicki, R Hadigan, C Kleiner, DE Heller, T Kovacs, JA AF Morse, Caryn G. McLaughlin, Mary Matthews, Lindsay Proschan, Michael Thomas, Francine Gharib, Ahmed M. Abu-Asab, Mones Orenstein, Abigail Engle, Ronald E. Hu, Xiaojun Lempicki, Richard Hadigan, Colleen Kleiner, David E. Heller, Theo Kovacs, Joseph A. TI Nonalcoholic Steatohepatitis and Hepatic Fibrosis in HIV-1-Monoinfected Adults With Elevated Aminotransferase Levels on Antiretroviral Therapy SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE hepatotoxicity; liver biopsy; insulin resistance; PNPLA3 ID FATTY LIVER-DISEASE; HUMAN-IMMUNODEFICIENCY-VIRUS; SIMPLE NONINVASIVE INDEX; HIV-INFECTED PERSONS; INSULIN-RESISTANCE; HEPATOCELLULAR-CARCINOMA; NATURAL-HISTORY; RISK-FACTORS; ASSOCIATION; PREVALENCE AB Background. Persistent aminotransferase elevations are common in human immunodeficiency virus (HIV)infected patients on antiretroviral therapy (ART), including those without hepatitis B or C coinfection, but their clinical significance is unknown. Methods. HIV-infected adults with aminotransferase levels elevated above the upper limit of normal for >= 6 months while receiving ART, and without chronic viral hepatitis or other known causes of chronic liver disease, underwent a detailed metabolic assessment and liver biopsy. Results. Sixty-two HIV-infected subjects completed the study. Forty (65%) had clinically significant liver pathology, including 34 (55%) with nonalcoholic steatohepatitis (NASH) and 11 (18%) with bridging fibrosis, 10 of whom also had NASH. Nonspecific abnormalities alone were seen in 22 (35%) subjects, including mild steatosis, mild to moderate inflammation, and evidence of drug adaptation. Insulin resistance, obesity, and the presence of either of 2 minor alleles in the PNPLA3 gene were significantly associated with increased risk of NASH and fibrosis. NASH and/or fibrosis were not associated with duration of HIV infection or ART, specific antiretroviral drugs, history of opportunistic infection, immune status, or duration of aminotransferase elevation. Conclusions. HIV-infected adults with chronic aminotransferase elevations while receiving ART have a high rate of liver disease. Noninvasive testing can help identify liver disease in such patients, but liver biopsy is necessary to definitively identify those at risk for liver disease progression and complications. Longitudinal follow-up of this cohort will better characterize the natural history of aminotransferase elevations in this population and identify noninvasive biomarkers of liver disease progression. C1 [Morse, Caryn G.; Matthews, Lindsay; Kovacs, Joseph A.] NIH, Crit Care Med Dept, AIDS Sect, Ctr Clin, Bethesda, MD 20892 USA. [McLaughlin, Mary; Hadigan, Colleen] NIAID, Lab Immunoregulat, Bethesda, MD 20892 USA. [Proschan, Michael] NIAID, Biostat Res Branch, Bethesda, MD 20892 USA. [Thomas, Francine] NIDDK, Diagnost Radiol, NIH, Ctr Clin, Bethesda, MD 20892 USA. [Gharib, Ahmed M.] NIDDK, Biomed & Metab Imaging Branch, Bethesda, MD 20892 USA. [Abu-Asab, Mones] NEI, Histol Core, Bethesda, MD 20892 USA. [Orenstein, Abigail] Baystate Med Ctr, Springfield, MA USA. [Engle, Ronald E.] NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. [Hu, Xiaojun; Lempicki, Richard] Leidos Biomed Res Inc, Frederick, MD USA. [Kleiner, David E.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Heller, Theo] NIDDK, Liver Dis Branch, Bethesda, MD 20892 USA. RP Morse, CG (reprint author), NIH, Ctr Clin, Bldg 10,Rm 5A06,MSC 1403, Bethesda, MD 20892 USA. EM cmorse@cc.nih.gov RI Gharib, Ahmed/O-2629-2016; OI Gharib, Ahmed/0000-0002-2476-481X; Morse, Caryn/0000-0002-1177-4365 FU NIH; NIH Clinical Center; National Institute of Allergy and Infectious Diseases (NIAID); National Institute of Diabetes and Digestive and Kidney Diseases; National Cancer Institute (NCI); National Eye Institute; NIH Office of AIDS Research; NCI; NIAID, NIH [HHSN261200800001E] FX This work was supported by the NIH Intramural Research Program, NIH Clinical Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Diabetes and Digestive and Kidney Diseases, National Cancer Institute (NCI), and National Eye Institute and by an NIH Office of AIDS Research Bench to Bedside Award. This project has been funded in part with funds from the NCI and the NIAID, NIH, under contract No. HHSN261200800001E. NR 40 TC 19 Z9 19 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAY 15 PY 2015 VL 60 IS 10 BP 1569 EP 1578 DI 10.1093/cid/civ101 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CH0ON UT WOS:000353721300020 PM 25681381 ER PT J AU Miller, A Birnbaum, L AF Miller, Aubrey Birnbaum, Linda TI Preparing for disasters SO SCIENCE LA English DT Letter C1 [Miller, Aubrey; Birnbaum, Linda] NIEHS, Res Triangle Pk, NC 27709 USA. RP Miller, A (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM miller.aubrey@nih.gov NR 2 TC 0 Z9 0 U1 2 U2 5 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 MAY 15 PY 2015 VL 348 IS 6236 BP 766 EP 767 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CI0LN UT WOS:000354428700029 PM 25977543 ER PT J AU Peeters, RP Ng, L Ma, M Forrest, D AF Peeters, R. P. Ng, L. Ma, M. Forrest, D. TI The timecourse of apoptotic cell death during postnatal remodeling of the mouse cochlea and its premature onset by triiodothyronine (T3) SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE Thyroid hormone receptor; Thyroid hormone; Auditory system; Apoptosis; Organ of Corti ID HORMONE RECEPTOR-BETA; THYROID-HORMONE; HEARING-LOSS; CONGENITAL HYPOTHYROIDISM; GENE-EXPRESSION; AUDITORY-SYSTEM; INNER-EAR; MICE; RESISTANCE; MUTATION AB Apoptosis underlies various forms of tissue remodeling during development. Prior to the onset of hearing, thyroid hormone (T3) promotes cochlear remodeling, which involves regression of the greater epithelial ridge (GER), a transient structure of columnar cells adjacent to the mechanosensory hair cells. We investigated the timecourse of apoptosis in the GER and the influence of ectopic T3 on apoptosis. In saline-treated mice, activated caspase 3-positive cells were detected in the GER between postnatal days 7 and 13 and appeared progressively along the cochlear duct from base to apex over developmental time. T3 given on P0 and P1 advanced the overall program of apoptosis and remodeling by similar to 4 days. Thyroid hormone receptor beta was required for these actions, suggesting a receptor-mediated process of initiation of apoptosis. Finally, T3 given only at PO or P1 resulted in deafness in adult mice, thus revealing a transient period of susceptibility to long-term damage in the neonatal auditory system. Published by Elsevier Ireland Ltd. C1 [Peeters, R. P.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Peeters, R. P.] Erasmus MC, Rotterdam Thyroid Ctr, Rotterdam, Netherlands. [Peeters, R. P.; Ng, L.; Ma, M.; Forrest, D.] NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. RP Peeters, RP (reprint author), Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. EM r.peeters@erasmusmc.nl FU ZonMw [91696017]; Erasmus MC Fellowship; NIDDK at the National Institutes of Health FX This work was supported by ZonMw VENI Grant: 91696017, an Erasmus MC Fellowship (RPP), and by the intramtiral research program at NIDDK at the National Institutes of Health. NR 44 TC 2 Z9 2 U1 1 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD MAY 15 PY 2015 VL 407 IS C BP 1 EP 8 DI 10.1016/j.mce.2015.02.025 PG 8 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA CH1AH UT WOS:000353753000001 PM 25737207 ER PT J AU Calu, D Nasser, H Shaham, Y AF Calu, Donna Nasser, Helen Shaham, Yavin TI Unexpected Results on the Role of Nucleus Accumbens Dopamine in Stress-Induced Relapse SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID COCAINE; SEEKING; WITHDRAWAL; MODEL; RATS C1 [Calu, Donna; Nasser, Helen; Shaham, Yavin] NIDA, Behav Neurosci Res Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Shaham, Y (reprint author), NIDA, Behav Neurosci Res Branch, Intramural Res Program, NIH, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM yavin.shaham@nih.gov OI Calu, Donna/0000-0003-2377-9494 FU Intramural NIH HHS NR 10 TC 1 Z9 1 U1 0 U2 2 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 MAY 15 PY 2015 VL 77 IS 10 BP 848 EP 849 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CG8LP UT WOS:000353559600003 PM 25925717 ER PT J AU Bilbao, A Robinson, JE Heilig, M Malanga, CJ Spanagel, R Sommer, WH Thorsell, A AF Bilbao, Ainhoa Robinson, J. Elliott Heilig, Markus Malanga, C. J. Spanagel, Rainer Sommer, Wolfgang H. Thorsell, Annika TI A Pharmacogenetic Determinant of Mu-Opioid Receptor Antagonist Effects on Alcohol Reward and Consumption: Evidence from Humanized Mice SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Alcohol; Intracranial self-stimulation (ICSS); Mouse; Mu-opioid receptor; Pharmacogenetics; Reward ID SINGLE-NUCLEOTIDE POLYMORPHISM; INTRACRANIAL SELF-STIMULATION; GENE OPRM1; FUNCTIONAL POLYMORPHISM; SUBJECTIVE RESPONSES; NALTREXONE RESPONSE; A118G POLYMORPHISM; DEPENDENT PATIENTS; NUCLEUS-ACCUMBENS; KNOCKOUT MICE AB BACKGROUND: It has been proposed that therapeutic responses to naltrexone in alcoholism are moderated by variation at the mu-opioid receptor gene locus (OPRM1). This remains controversial because human results vary and no prospectively genotyped studies have been reported. We generated humanized mice carrying the respective human OPRM1 A118G alleles. Here, we used this model system to examine the role of OPRM1 A118G variation for opioid antagonist effects on alcohol responses. METHODS: Effects of naltrexone on alcohol reward were examined using intracranial self-stimulation. Effects of naltrexone or nalmefene on alcohol intake were examined in continuous access home cage two-bottle free-choice drinking and operant alcohol self-administration paradigms. RESULTS: Alcohol lowered brain stimulation reward thresholds in 118GG mice in a manner characteristic of rewarding drugs, and this effect was blocked by naltrexone. Brain stimulation reward thresholds were unchanged by alcohol or naltrexone in 118AA mice. In the home cage, increased alcohol intake emerged in 118GG mice with increasing alcohol concentrations and was 33% higher at 17% alcohol. At this concentration, naltrexone selectively suppressed alcohol intake in 118GG animals to a level virtually identical to that of 118AA mice. No effect of naltrexone was found in the latter group. Similarly, both naltrexone and nalmefene were more effective in suppressing operant alcohol self-administration in 118GG mice. CONCLUSIONS: In a model that allows close experimental control, OPRM1 A118G variation robustly moderates effects of opioid antagonism on alcohol reward and consumption. These findings strongly support a personalized medicine approach to alcoholism treatment that takes into account OPRM1 genotype. C1 [Bilbao, Ainhoa; Spanagel, Rainer; Sommer, Wolfgang H.] Heidelberg Univ, Cent Inst Mental Hlth, Inst Psychopharmacol, Mannheim, Germany. [Robinson, J. Elliott; Malanga, C. J.] Univ N Carolina, Sch Med, Dept Neurol, Lab Dev Neuropharmacol, Chapel Hill, NC 27599 USA. [Heilig, Markus] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD USA. [Heilig, Markus; Thorsell, Annika] Linkoping Univ, Dept Clin & Expt Med, SE-58185 Linkoping, Sweden. RP Thorsell, A (reprint author), Linkoping Univ, Dept Clin & Expt Med, Plan 12, SE-58185 Linkoping, Sweden. EM annika.thorsell@liu.se OI Heilig, Markus/0000-0003-2706-2482; Robinson, J. Elliott/0000-0001-9417-3938 FU Bundesministerium fur Bildung ind Forschung [FKZ: FKZ 01EW1112, FKZ: 01GS08152, FKZ: 01ZX1311A (40)]; Deutsche Forschungsgemeinschaft [SFB 636]; Reinhart-Koselleck Award [SP 383/5-1]; Ministerium fur Wissenschaft, Forschung und Kunst in Baden-Wurttemberg; National Institute on Alcohol Abuse and Alcoholism [AA021312, AA018335]; National Institute on Alcohol Abuse and Alcoholism; Swedish Research Council [2010-3219] FX The work presented here was supported by the Bundesministerium fur Bildung ind Forschung [ERA-Net TRANSALC, FKZ: FKZ 01EW1112; NGFN Plus, FKZ: 01GS08152; and the e:Med program, FKZ: 01ZX1311A (40)], the Deutsche Forschungsgemeinschaft (SFB 636 [B1, D7]), Reinhart-Koselleck Award SP 383/5-1, the Ministerium fur Wissenschaft, Forschung und Kunst in Baden-Wurttemberg, the National Institute on Alcohol Abuse and Alcoholism (extramural: AA018335 [CJM], AA021312 [JER]), and the intramural program of the National Institute on Alcohol Abuse and Alcoholism. Support has also been given by the Swedish Research Council (Grant #2010-3219 [MH]). NR 55 TC 8 Z9 8 U1 2 U2 4 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 MAY 15 PY 2015 VL 77 IS 10 BP 850 EP 858 DI 10.1016/j.biopsych.2014.08.021 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CG8LP UT WOS:000353559600004 PM 25442002 ER PT J AU Lucantonio, F Kambhampati, S Haney, RZ Atalayer, D Rowland, NE Shaham, Y Schoenbaum, G AF Lucantonio, Federica Kambhampati, Sarita Haney, Richard Z. Atalayer, Deniz Rowland, Neil E. Shaham, Yavin Schoenbaum, Geoffrey TI Effects of Prior Cocaine Versus Morphine or Heroin Self-Administration on Extinction Learning Driven by Overexpectation Versus Omission of Reward SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Addiction; Cocaine; Extinction; Heroin; Morphine; Orbitofrontal; Rat; Self-administration ID ORBITAL PREFRONTAL CORTEX; ORBITOFRONTAL CORTEX; DECISION-MAKING; ADMINISTERED COCAINE; EXPERIENCED RATS; IMPULSIVE CHOICE; DOPAMINE NEURONS; DENDRITIC SPINES; CUE-EXPOSURE; HUMAN BRAIN AB BACKGROUND: Addiction is characterized by an inability to stop using drugs, despite adverse consequences. One contributing factor to this compulsive drug taking could be the impact of drug use on the ability to extinguish drug seeking after changes in expected outcomes. Here, we compared effects of cocaine, morphine, and heroin self-administration on two forms of extinction learning: standard extinction driven by reward omission and extinction driven by reward overexpectation. METHODS: In experiment 1, we trained rats to self-administer cocaine, morphine, or sucrose for 3 hours per day (limited access). In experiment 2, we trained rats to self-administer heroin or sucrose for 12 hours per day (extended access). Three weeks later, we trained the rats to associate several cues with palatable food reward, after which we assessed extinction of the learned Pavlovian response, first by pairing two cues together in the overexpectation procedure and later by omitting the food reward. RESULTS: Rats trained under limited access conditions to self-administer sucrose or morphine demonstrated normal extinction in response to both overexpectation and reward omission, whereas cocaine-experienced rats or rats trained to self-administer heroin under extended access conditions exhibited normal extinction in response to reward omission but failed to show extinction in response to overexpectation. CONCLUSIONS: Here we show that cocaine and heroin can induce long-lasting deficits in the ability to extinguish reward seeking. These deficits were not observed in a standard extinction procedure but instead only affected extinction learning driven by a more complex phenomenon of overexpectation. C1 [Lucantonio, Federica; Kambhampati, Sarita; Shaham, Yavin; Schoenbaum, Geoffrey] NIDA, Intramural Res Program, Baltimore, MD 21224 USA. [Lucantonio, Federica; Haney, Richard Z.; Schoenbaum, Geoffrey] Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. [Atalayer, Deniz; Rowland, Neil E.] Univ Florida, Dept Psychol, Gainesville, FL 32611 USA. [Atalayer, Deniz] Columbia Univ, Med Ctr, New York, NY USA. RP Schoenbaum, G (reprint author), NIDA, Intramural Res Program, 251 Bayview Dr, Baltimore, MD 21224 USA. EM geoffrey.schoenbaum@nih.gov FU National Institute on Drug Abuse FX This work was supported by funding from the National Institute on Drug Abuse. This article was prepared, in part, while GS was employed at the University of Maryland, Baltimore. The opinions expressed in this article are the authors' own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government. NR 57 TC 5 Z9 5 U1 3 U2 12 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 MAY 15 PY 2015 VL 77 IS 10 BP 912 EP 920 DI 10.1016/j.biopsych.2014.11.017 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CG8LP UT WOS:000353559600011 PM 25641634 ER PT J AU Zhang, X Raghavan, S Ihnat, M Hamel, E Zammiello, C Bastian, A Mooberry, SL Gangjee, A AF Zhang, Xin Raghavan, Sudhir Ihnat, Michael Hamel, Ernest Zammiello, Cynthia Bastian, Anja Mooberry, Susan L. Gangjee, Aleem TI The design, synthesis and biological evaluation of conformationally restricted 4-substituted-2,6-dimethylfuro[2,3-d]pyrimidines as multi-targeted receptor tyrosine kinase and microtubule inhibitors as potential antitumor agents SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Conformation restriction; Synthesis; Multitargeted inhibitors; Antitubulin; Receptor tyrosine kinase inhibitors ID THYMIDYLATE SYNTHASE; ANTIMITOTIC AGENTS; BINDING AGENTS; HALICHONDRIN-B; SOLID TUMORS; TUBULIN; CANCER; ANGIOGENESIS; RESISTANCE; COMBINATION AB A series of eleven conformationally restricted, 4-substituted 2,6-dimethylfuro[ 2,3-d]pyrimidines was designed to explore the bioactive conformation required for dual inhibition of microtubule assembly and receptor tyrosine kinases (RTKs), and their biological activities are reported. All three rotatable single bonds in the lead compound 1 were sequentially restricted to address the role of each in SAR for microtubule and RTK inhibitory effects. Compounds 2, 3, 7 and 10 showed microtubule depolymerizing activity comparable to or better than the lead 1, some with nanomolar EC50 values. While compound 8 had no effect on microtubules, 8 and 10 both showed potent RTK inhibition with nanomolar IC(50)s. These compounds confirm that the bioactive conformation for RTK inhibition is different from that for tubulin inhibition. The tetrahydroquinoline analog 10 showed the most potent dual tubulin and RTK inhibitory activities (low nanomolar inhibition of EGFR, VEGFR2 and PDGFR-beta). Compound 10 has highly potent activity against many NCI cancer cell lines, including several chemo-resistant cell lines, and could serve as a lead for further preclinical studies. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Zhang, Xin; Raghavan, Sudhir; Gangjee, Aleem] Duquesne Univ, Grad Sch Pharmaceut Sci, Div Med Chem, Pittsburgh, PA 15282 USA. [Ihnat, Michael; Bastian, Anja] Univ Oklahoma, Hlth Sci Ctr, Dept Pharmaceut Sci, Coll Pharm, Oklahoma City, OK 73117 USA. [Zammiello, Cynthia; Mooberry, Susan L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA. [Hamel, Ernest] NIH, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Ft Detrick, MD 21702 USA. RP Mooberry, SL (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, Canc Therapy & Res Ctr, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM mooberry@uthscsa.edu; gangjee@duq.edu FU NCI [CA142868]; Duquesne University Adrian Van Kaam Chair in Scholarly Excellence; CTRC Cancer Center Support Grant [P30 CA054174]; NSF [NMR: CHE 0614785] FX We gratefully acknowledge the support of the NCI for grant CA142868 (A.G., S.L.M.) and for conducting the 60 cell line screen, support by the Duquesne University Adrian Van Kaam Chair in Scholarly Excellence (A.G.), the CTRC Cancer Center Support Grant, P30 CA054174 and an NSF equipment grant for NMR instrumentation (NMR: CHE 0614785). NR 40 TC 5 Z9 5 U1 2 U2 22 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 MAY 15 PY 2015 VL 23 IS 10 BP 2408 EP 2423 DI 10.1016/j.bmc.2015.03.061 PG 16 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA CG6BM UT WOS:000353380400011 PM 25882519 ER PT J AU Kim, YS Zhou, Y Bryant, H Milenic, DE Baidoo, KE Lewis, BK Frank, JA Brechbiel, MW AF Kim, Young-Seung Zhou, Yang Bryant, Henry, Jr. Milenic, Diane E. Baidoo, Kwamena E. Lewis, Bobbi K. Frank, Joseph A. Brechbiel, Martin W. TI Synthesis and characterization of gadolinium-Peptidomimetic complex as an alpha(v)beta(3) integrin targeted MR contrast agent SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Integrin alpha(v)beta(3); Gadolinium; DOTA; Peptidomimetics; Antagonist; Gd-153; MR imaging ID TUMOR; RGD; EXPRESSION; MELANOMA AB There is growing interest in small and rigid peptidomimetic alpha(v)beta(3) integrin antagonists that are readily synthesized and characterized and amenable to physiological conditions. Peptidomimetic 4-[2-(3,4,5,6-tetrahydropyrimidine-2-ylamino)ethyloxy]benzoyl-2-[N-(3-amino-neopenta-1-carbamyl)]-aminoethylsulfonyl-amino-beta-alanine (IAC) was successfully conjugated to DOTA, complexed with Gd(III) and radiolabeled with Gd-153. Radioassay results demonstrated specificity of the labeled conjugate by blocking similar to 95% binding with the addition of a 50-fold molar excess of cold IAC to the reaction solution. Relaxometry was used to support the hypothesis that the specificity of the Gd-peptidomimetic targeting alpha(v)beta(3) integrin would increase the contrast and therefore enhance the sensitivity of an MRI scan of alpha(v)beta(3) integrin positive tissues. Magnetic resonance imaging of cell pellets (M21 human melanoma) was also performed, and the images clearly show that cells reacted with Gd(III)-DOTA-IAC display a brighter image than cells without the Gd(III)-DOTA-IAC contrast agent. In addition, Gd(III)-DOTA-IAC and IAC, with IC50 of 300 nM and 230 nM, respectively, are 2.1 and 2.7 times more potent than c(RGDfK) whose IC50 is 625 nM. This promising preliminary data fuels further investigation of DOTA-IAC conjugates for targeting tumor associated angiogenesis and avb3 integrin positive tumors using magnetic resonance imaging. Published by Elsevier Ltd. C1 [Kim, Young-Seung; Zhou, Yang; Milenic, Diane E.; Baidoo, Kwamena E.; Brechbiel, Martin W.] NCI, Radioimmune & Inorgan Chem Sect, ROB, NIH, Bethesda, MD 20892 USA. [Bryant, Henry, Jr.] NIH, Lab Diagnost Radiol Res CC, Bethesda, MD 20892 USA. [Lewis, Bobbi K.; Frank, Joseph A.] NIH, Frank Lab, Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Frank, Joseph A.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. RP Brechbiel, MW (reprint author), NCI, Radioimmune & Inorgan Chem Sect, ROB, NIH, 10 Ctr Dr,Bldg 10,Rm B3B69, Bethesda, MD 20892 USA. EM martinwb@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 23 TC 2 Z9 2 U1 2 U2 20 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 MAY 15 PY 2015 VL 25 IS 10 BP 2056 EP 2059 DI 10.1016/j.bmcl.2015.03.092 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA CG7ZL UT WOS:000353526300008 PM 25870133 ER PT J AU Leyva, MJ Kim, YS Peach, ML Schneekloth, JS AF Leyva, Melissa J. Kim, Yeong Sang Peach, Megan L. Schneekloth, John S., Jr. TI Synthetic derivatives of the SUMO consensus sequence provide a basis for improved substrate recognition SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Combinatorial chemistry; Conjugation; Enzymes; Peptide mimics; SUMO ID PROTEIN-TYROSINE-PHOSPHATASE; UBIQUITIN-CONJUGATING ENZYME; SUMOYLATION; INHIBITORS; IDENTIFICATION; PATHWAY; MOTIF; UBC9; YOPH; SPECIFICITY AB Protein sumoylation is a dynamic posttranslational modification that regulates a diverse subset of the proteome. The mechanism by which sumoylation enzymes recognize their cognate substrates is unclear, and the consequences of sumoylation remain difficult to predict. While small molecule probes of the sumoylation process could be valuable for understanding SUMO biology, few small molecules that modulate this process exist. Here, we report the synthesis and evaluation of over 600 oxime-containing peptide sumoylation substrates. Our work demonstrates that higher modification efficiency can be achieved with non-natural side chains that deviate substantially from the consensus site requirement of a hydrophobic substituent. Furthermore, docking studies suggest that these improved substrates mimic binding interactions that are used by other endogenous protein sequences through tertiary interactions. The development of these high efficiency substrates provides key mechanistic insights toward specific recognition of low molecular weight species in the sumoylation pathway. (C) 2015 Published by Elsevier Ltd. C1 [Leyva, Melissa J.; Kim, Yeong Sang; Schneekloth, John S., Jr.] NCI, Biol Chem Lab, Frederick, MD 21702 USA. [Peach, Megan L.] NCI, Basic Sci Program, Biol Chem Lab, Leidos Biomed Res Inc, Frederick, MD 21702 USA. RP Schneekloth, JS (reprint author), NCI, Biol Chem Lab, 376 Boyles St, Frederick, MD 21702 USA. EM schneeklothjs@mail.nih.gov FU Intramural Research Program of the National Institutes of Health; Center for Cancer Research; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, and the National Cancer Institute, National Institutes of Health. This work was also funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. The authors thank Dr. Terrence R. Burke, Jr. (NCI, NIH) for providing the aldehydes for the oxime ligation reactions. 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 37 TC 0 Z9 0 U1 2 U2 11 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 MAY 15 PY 2015 VL 25 IS 10 BP 2146 EP 2151 DI 10.1016/j.bmcl.2015.03.069 PG 6 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA CG7ZL UT WOS:000353526300025 PM 25881829 ER PT J AU Cardone, A Bornstein, A Pant, HC Brady, M Sriram, R Hassan, SA AF Cardone, Antonio Bornstein, Aaron Pant, Harish C. Brady, Mary Sriram, Ram Hassan, Sergio A. TI Detection and Characterization of Nonspecific, Sparsely Populated Binding Modes in the Early Stages of Complexation SO JOURNAL OF COMPUTATIONAL CHEMISTRY LA English DT Article DE protein-protein association; protein aggregation; complex formation; configurational-bias Monte Carlo; nonspecific interactions; solvent effects; implicit solvent model ID PROTEIN-PROTEIN ASSOCIATION; SCREENED COULOMB POTENTIALS; CYCLIN-DEPENDENT KINASE-5; IMPLICIT SOLVENT MODELS; MONTE-CARLO SIMULATIONS; CDK5 NEURONAL ACTIVATOR; FREE-ENERGY; INDUCED-FIT; TAU HYPERPHOSPHORYLATION; SECONDARY STRUCTURE AB A method is proposed to study protein-ligand binding in a system governed by specific and nonspecific interactions. Strong associations lead to narrow distributions in the proteins configuration space; weak and ultraweak associations lead instead to broader distributions, a manifestation of nonspecific, sparsely populated binding modes with multiple interfaces. The method is based on the notion that a discrete set of preferential first-encounter modes are metastable states from which stable (prerelaxation) complexes at equilibrium evolve. The method can be used to explore alternative pathways of complexation with statistical significance and can be integrated into a general algorithm to study protein interaction networks. The method is applied to a peptide-protein complex. The peptide adopts several low-population conformers and binds in a variety of modes with a broad range of affinities. The system is thus well suited to analyze general features of binding, including conformational selection, multiplicity of binding modes, and nonspecific interactions, and to illustrate how the method can be applied to study these problems systematically. The equilibrium distributions can be used to generate biasing functions for simulations of multiprotein systems from which bulk thermodynamic quantities can be calculated. (c) 2015 Wiley Periodicals, Inc. C1 [Cardone, Antonio; Brady, Mary; Sriram, Ram] NIST, Software & Syst Div, Gaithersburg, MD 20899 USA. [Cardone, Antonio] Univ Maryland, Inst Adv Comp Studies, College Pk, MD 20742 USA. [Bornstein, Aaron] Goucher Coll, Math & Comp Sci, Baltimore, MD 21204 USA. [Pant, Harish C.] NINDS, Lab Neurochem, NIH, Bethesda, MD 20892 USA. [Hassan, Sergio A.] NIH, Div Computat Biosci, Ctr Mol Modeling, CIT, Bethesda, MD 20892 USA. RP Hassan, SA (reprint author), NIST, Software & Syst Div, Gaithersburg, MD 20899 USA. EM hassan@mail.nih.gov FU NIH Intramural Research Program through the CIT; NIH Intramural Research Program through the NINDS; internal NIST Research Fund FX Contract/grant sponsor: NIH Intramural Research Program through the CIT and NINDS and an internal NIST Research Fund NR 83 TC 2 Z9 2 U1 3 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0192-8651 EI 1096-987X J9 J COMPUT CHEM JI J. Comput. Chem. PD MAY 15 PY 2015 VL 36 IS 13 BP 983 EP 995 DI 10.1002/jcc.23883 PG 13 WC Chemistry, Multidisciplinary SC Chemistry GA CG5UF UT WOS:000353360700004 PM 25782918 ER PT J AU Olafsson, V Kundu, P Wong, EC Bandettini, PA Liu, TT AF Olafsson, Valur Kundu, Prantik Wong, Eric C. Bandettini, Peter A. Liu, Thomas T. TI Enhanced identification of BOLD-like components with multi-echo simultaneous multi-slice (MESMS) fMRI and multi-echo ICA SO NEUROIMAGE LA English DT Article ID DIFFERENTIATING BOLD; TIME-SERIES; BRAIN FMRI; SENSITIVITY; EPI; SIGNALS; TESLA; REST; MRI AB The recent introduction of simultaneous multi-slice (SMS) acquisitions has enabled the acquisition of blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) data with significantly higher temporal sampling rates. In a parallel development, the use of multi-echo fMRI acquisitions in conjunction with a multi-echo independent component analysis (ME-ICA) approach has been introduced as a means to automatically distinguish functionally-related BOLD signal components from signal artifacts, with significant gains in sensitivity, statistical power, and specificity. In this work, we examine the gains that can be achieved with a combined approach in which data obtained with a multi-echo simultaneous multi-slice (MESMS) acquisition are analyzed with ME-ICA. We find that ME-ICA identifies significantly more BOLD-like components in the MESMS data as compared to data acquired with a conventional multi-echo single-slice acquisition. We demonstrate that the improved performance of MESMS derives from both an increase in the number of temporal samples and the enhanced ability to filter out high-frequency artifacts. (C) 2015 Elsevier Inc. All rights reserved. C1 [Olafsson, Valur] Univ Pittsburgh, Neurosci Imaging Ctr, Pittsburgh, PA 15203 USA. [Kundu, Prantik] Icahn Inst Med Mt Sinai, Brain Imaging Ctr, New York, NY 10029 USA. [Kundu, Prantik] Icahn Inst Med Mt Sinai, Translat & Mol Imaging Inst, New York, NY 10029 USA. [Wong, Eric C.; Liu, Thomas T.] Univ Calif San Diego, Ctr Funct Magnet Resonance Imaging, La Jolla, CA 92093 USA. [Wong, Eric C.; Liu, Thomas T.] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA. [Wong, Eric C.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Bandettini, Peter A.] NIMH, Sect Funct Imaging Methods, Bethesda, MD 20892 USA. [Bandettini, Peter A.] NIMH, Funct MRI Core Facil, Bethesda, MD 20892 USA. [Liu, Thomas T.] Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA. RP Olafsson, V (reprint author), Univ Pittsburgh, Neurosci Imaging Ctr, 3025 E Carson St, Pittsburgh, PA 15203 USA. EM vto77@pitt.edu; prantik.kundu@mssm.edu; ttliu@ucsd.edu OI Kundu, Prantik/0000-0001-9367-3068 FU NIH [R01NS051661, R21MH096495]; ONR MURI Award [N00014-10-1-0072] FX The authors would like to thank Jia Guo, Kun Lu, Eman Ghobrial, Vinai Roopchansingh, Wen-Ming Luh, and Noah Brenowitz for helping with setting up the MESMS acquisition pipeline, Chi Wah Wong on discussions for the resting state experimental setup, and Souheil Inati for discussions on ME-ICA and MESMS implementations. This work was supported in part by NIH Grants R01NS051661 and R21MH096495, and ONR MURI Award No. N00014-10-1-0072. NR 32 TC 10 Z9 10 U1 1 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD MAY 15 PY 2015 VL 112 BP 43 EP 51 DI 10.1016/j.neuroimage.2015.02.052 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA CG3TV UT WOS:000353203400005 PM 25743045 ER PT J AU Cook, MB Rosenberg, PS McCarty, FA Wu, MX King, J Eheman, C Anderson, WF AF Cook, Michael B. Rosenberg, Philip S. McCarty, Frances A. Wu, Manxia King, Jessica Eheman, Christie Anderson, William F. TI Racial Disparities in Prostate Cancer Incidence Rates by Census Division in the United States, 1999-2008 SO PROSTATE LA English DT Article DE prostate cancer; incidence rate; census division; regional variation; epidemiology; SEER program ID OVERLAPPING REGIONS; NATIONAL PROGRAM; COMPARING TRENDS; SEER PROGRAM; WHITE MEN; BLACK-MEN; AGE; EPIDEMIOLOGY; SURVEILLANCE; COMPLETENESS AB BACKGROUNDBlack men have a higher incidence of prostate cancer than white men in the U.S., but little is known whether incidence or racial differences vary geographically. Understanding these differences may assist future studies on causes of prostate cancer. To address such, we leverage the unique resource of the National Program of Cancer Registries (NPCR) combined with Surveillance, Epidemiology and End Results (SEER). METHODSProstate cancer counts and population denominators by race (black, white), age, calendar year, and U.S. census division, for the period 1999-2008, were extracted from NPCR and SEER. We calculated age-standardized incidence rates (ASR) and estimated annual percent changes (EAPC) by race and census division. We assessed black-to-white incidence rate ratios (BWIRR) by census division and by calendar period. RESULTSThis analysis included 1,713,471 prostate cancer cases and 1,217 million person-years. Black ASRs ranged from 176 per 100,000 person-years in Mountain division to 259 in Middle Atlantic. BWIRRs ranged from 1.20 in Western divisions to 1.72 in Southeastern divisions. EAPCs indicated that prostate cancer incidence is not decreasing in East South Central, unlike all other divisions. White EAPCs displayed similar variations by census division, resulting in modest temporal changes in BWIRRs. CONCLUSIONSWithin the U.S., there exists significant geographic variability in prostate cancer incidence rates. Although there are large geographic differences in BWIRRs, temporal trends are fairly stable. This may indicate that primary factors affecting prostate cancer incidence rates vary geographically but affect both black and white men to a similar degree. Prostate 75: 758-763, 2015. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. C1 [Cook, Michael B.; Rosenberg, Philip S.; Anderson, William F.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [McCarty, Frances A.] Ctr Dis Control & Prevent, Res Data Ctr, Natl Ctr Hlth Stat, Hyattsville, MD USA. [Wu, Manxia; King, Jessica; Eheman, Christie] Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Div Canc Prevent & Control, Atlanta, GA USA. RP Cook, MB (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, 9609 Med Ctr Dr,Rm 7-E106,MSC 9774, Bethesda, MD 20892 USA. EM michael.cook@nih.gov RI Cook, Michael/A-5641-2009 OI Cook, Michael/0000-0002-0533-7302 FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services FX Grant sponsor: The Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services. NR 18 TC 6 Z9 6 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-4137 EI 1097-0045 J9 PROSTATE JI Prostate PD MAY 15 PY 2015 VL 75 IS 7 BP 758 EP 763 DI 10.1002/pros.22958 PG 6 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA CF7DL UT WOS:000352716300008 PM 25619191 ER PT J AU Beck, DE Abdelmalak, M Lv, W Reddy, PVN Tender, GS O'Neill, E Agama, K Marchand, C Pommier, Y Cushman, M AF Beck, Daniel E. Abdelmalak, Monica Lv, Wei Reddy, P. V. Narasimha Tender, Gabrielle S. O'Neill, Elizaveta Agama, Keli Marchand, Christophe Pommier, Yves Cushman, Mark TI Discovery of Potent Indenoisoquinoline Topoisomerase I Poisons Lacking the 3-Nitro Toxicophore SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID TYROSYL-DNA PHOSPHODIESTERASE; LACTAM SIDE-CHAIN; BIOLOGICAL EVALUATION; NITRATED INDENOISOQUINOLINES; CLEAVAGE COMPLEXES; ANTITUMOR-ACTIVITY; ANTICANCER AGENTS; MJ-III-65 NSC-706744; TOP1 INHIBITORS; DESIGN AB 3-Nitroindenoisoquinoline human topoisomerase IB (Top1) poisons have potent antiproliferative effects on cancer cells. The undesirable nitro toxicophore could hypothetically be replaced by other functional groups that would retain the desired biological activities and minimize potential safety risks. Eleven series of indenoisoquinolines bearing 3-nitro bioisosteres were synthesized. The molecules were evaluated in the Top1-mediated DNA cleavage assay and in the National Cancer Institute's 60 cell line cytotoxicity assay. The data reveal that fluorine and chlorine may substitute for the 3-nitro group with minimal loss of Top1 poisoning activity. The new information gained from these efforts can be used to design novel indenoisoquinolines with improved safety. C1 [Beck, Daniel E.; Lv, Wei; Reddy, P. V. Narasimha; O'Neill, Elizaveta; Cushman, Mark] Purdue Univ, Coll Pharm, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. [Beck, Daniel E.; Lv, Wei; Reddy, P. V. Narasimha; O'Neill, Elizaveta; Cushman, Mark] Purdue Univ, Purdue Ctr Canc Res, W Lafayette, IN 47907 USA. [Abdelmalak, Monica; Tender, Gabrielle S.; Agama, Keli; Marchand, Christophe; Pommier, Yves] NCI, Ctr Canc Res, Mol Pharmacol Lab, Frederick, MD 21702 USA. RP Cushman, M (reprint author), Purdue Univ, Coll Pharm, Dept Med Chem & Mol Pharmacol, 575 Stadium Mall Dr, W Lafayette, IN 47907 USA. EM cushman@purdue.edu RI Marchand, Christophe/D-8559-2016 FU National Institutes of Health (NIH) [U01CA089566, P30CACA023168]; NIH, National Cancer Institute, Center for Cancer Research; Developmental Therapeutics Program at the National Cancer Institute [NO1-CO-56000] FX This work was made possible by the National Institutes of Health (NIH) through support with Research Grants U01CA089566 and P30CACA023168. This research was also supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. In vitro cytotoxicity testing was performed by the Developmental Therapeutics Program at the National Cancer Institute, under contract NO1-CO-56000. D.E.B. thanks Stephanie Pitman, Rubayat Khan, Huaping Mo, and Karl Wood for technical assistance. NR 70 TC 14 Z9 14 U1 2 U2 14 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD MAY 14 PY 2015 VL 58 IS 9 BP 3997 EP 4015 DI 10.1021/acs.jmedchem.5b00303 PG 19 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA CI6YX UT WOS:000354911200025 PM 25909279 ER PT J AU Fowler, T Garruss, AS Ghosh, A De, S Becker, KG Wood, WH Weirauch, MT Smale, ST Aronow, B Sen, R Roy, AL AF Fowler, Trent Garruss, Alexander S. Ghosh, Amalendu De, Supriyo Becker, Kevin G. Wood, William H. Weirauch, Matthew T. Smale, Stephen T. Aronow, Bruce Sen, Ranjan Roy, Ananda L. TI Divergence of transcriptional landscape occurs early in B cell activation SO EPIGENETICS & CHROMATIN LA English DT Article ID PRIMARY RESPONSE GENES; TOLL-LIKE RECEPTORS; GERMINAL CENTER B; CPG ISLANDS; INNATE IMMUNITY; EXPRESSION; MYC; LYMPHOCYTES; ELONGATION; MECHANISMS AB Background: Signaling via B cell receptor (BCR) and Toll-like receptors (TLRs) results in activation of B cells with distinct physiological outcomes, but transcriptional regulatory mechanisms that drive activation and distinguish these pathways remain unknown. Results: Two hours after ligand exposure RNA-seq, ChIP-seq and computational methods reveal that BCR-or TLR-mediated activation of primary resting B cells proceeds via a large set of shared and a smaller subset of distinct signal-selective transcriptional responses. BCR stimulation resulted in increased global recruitment of RNA Pol II to promoters that appear to transit slowly to downstream regions. Conversely, lipopolysaccharide (LPS) stimulation involved an enhanced RNA Pol II transition from initiating to elongating mode accompanied by greater H3K4me3 activation markings compared to BCR stimulation. These rapidly diverging transcriptomic landscapes also show distinct repressing (H3K27me3) histone signatures, mutually exclusive transcription factor binding in promoters, and unique miRNA profiles. Conclusions: Upon examination of genome-wide transcription and regulatory elements, we conclude that the B cell commitment to different activation states occurs much earlier than previously thought and involves a multi-faceted receptor-specific transcriptional landscape. C1 [Fowler, Trent; Roy, Ananda L.] Tufts Univ, Sch Med, Sackler Sch Biomed Sci, Dept Dev Chem & Mol Biol, Boston, MA 02111 USA. [Garruss, Alexander S.] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA. [Garruss, Alexander S.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Ghosh, Amalendu; De, Supriyo; Becker, Kevin G.; Wood, William H.; Sen, Ranjan] NIA, Lab Mol Biol & Immunol, Baltimore, MD 21224 USA. [De, Supriyo; Becker, Kevin G.; Wood, William H.] NIA, Gene Express Unit, Genet Lab, Baltimore, MD 21224 USA. [Weirauch, Matthew T.; Aronow, Bruce] Cincinnati Childrens Hosp Med Ctr, Ctr Autoimmune Genom & Etiol, Cincinnati, OH 45229 USA. [Weirauch, Matthew T.; Aronow, Bruce] Cincinnati Childrens Hosp Med Ctr, Div Biomed Informat & Dev Biol, Cincinnati, OH 45229 USA. [Smale, Stephen T.] Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90095 USA. RP Roy, AL (reprint author), Tufts Univ, Sch Med, Sackler Sch Biomed Sci, Dept Dev Chem & Mol Biol, 150 Harrison Ave, Boston, MA 02111 USA. EM ananda.roy@tufts.edu OI De, Supriyo/0000-0002-2075-7655 FU Intramural Research Program of the NIH; National Institute on Aging; [R01 GM086372]; [AHA 12GRNT12180023] FX We are deeply indebted to Drs. Ali Shilatifard, Deqing Hu, and Xin Gao of the Stowers Institute for performing an independent RNA-seq and ChIP-seq of RNA Pol II as well as their guidance and helpful discussions throughout the course of this work. We thank Xiaoting Chen (CCHMC) for help with the motif enrichment analysis and members of Tufts' Computational Biology Initiative for analysis assistance. We also thank Dr. Dinah Singer (NCI) and Dr. Harinder Singh (CCHMC) for critically reading the manuscript and for their thoughtful suggestions. This work was supported in part by the Intramural Research Program of the NIH, the National Institute on Aging to RS, and by grants to STS (R01 GM086372) and ALR (AHA 12GRNT12180023). NR 85 TC 3 Z9 3 U1 0 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-8935 J9 EPIGENET CHROMATIN JI Epigenetics Chromatin PD MAY 14 PY 2015 VL 8 AR 20 DI 10.1186/s13072-015-0012-x PG 14 WC Genetics & Heredity SC Genetics & Heredity GA CI1PK UT WOS:000354516100001 PM 25987903 ER PT J AU Moler, FW Silverstein, FS Holubkov, R Slomine, BS Christensen, JR Nadkarni, VM Meert, KL Clark, AE Browning, B Pemberton, VL Page, K Shankaran, S Hutchison, JS Newth, CJL Bennett, KS Berger, JT Topjian, A Pineda, JA Koch, JD Schleien, CL Dalton, HJ Ofori-Amanfo, G Goodman, DM Fink, EL McQuillen, P Zimmerman, JJ Thomas, NJ van der Jagt, EW Porter, MB Meyer, MT Harrison, R Pham, N Schwarz, AJ Nowak, JE Alten, J Wheeler, DS Bhalala, US Lidsky, K Lloyd, E Mathur, M Shah, S Wu, T Theodorou, AA Sanders, RC Dean, JM AF Moler, Frank W. Silverstein, Faye S. Holubkov, Richard Slomine, Beth S. Christensen, James R. Nadkarni, Vinay M. Meert, Kathleen L. Clark, Amy E. Browning, Brittan Pemberton, Victoria L. Page, Kent Shankaran, Seetha Hutchison, Jamie S. Newth, Christopher J. L. Bennett, Kimberly S. Berger, John T. Topjian, Alexis Pineda, Jose A. Koch, Joshua D. Schleien, Charles L. Dalton, Heidi J. Ofori-Amanfo, George Goodman, Denise M. Fink, Ericka L. McQuillen, Patrick Zimmerman, Jerry J. Thomas, Neal J. van der Jagt, Elise W. Porter, Melissa B. Meyer, Michael T. Harrison, Rick Nga Pham Schwarz, Adam J. Nowak, Jeffrey E. Alten, Jeffrey Wheeler, Derek S. Bhalala, Utpal S. Lidsky, Karen Lloyd, Eric Mathur, Mudit Shah, Samir Wu, Theodore Theodorou, Andreas A. Sanders, Ronald C., Jr. Dean, J. Michael CA THAPCA Trial Investigators TI Therapeutic Hypothermia after Out-of-Hospital Cardiac Arrest in Children SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID HYPOXIC-ISCHEMIC ENCEPHALOPATHY; RANDOMIZED-CONTROLLED-TRIAL; EMERGENCY CARDIOVASCULAR CARE; AMERICAN-HEART-ASSOCIATION; TRAUMATIC BRAIN-INJURY; WHOLE-BODY HYPOTHERMIA; INTERCENTER VARIANCE; CLINICAL-TRIALS; CARDIOPULMONARY; RESUSCITATION AB BACKGROUND Therapeutic hypothermia is recommended for comatose adults after witnessed out-of-hospital cardiac arrest, but data about this intervention in children are limited. METHODS We conducted this trial of two targeted temperature interventions at 38 children's hospitals involving children who remained unconscious after out-of-hospital cardiac arrest. Within 6 hours after the return of circulation, comatose patients who were older than 2 days and younger than 18 years of age were randomly assigned to therapeutic hypothermia (target temperature, 33.0 degrees C) or therapeutic normothermia (target temperature, 36.8 degrees C). The primary efficacy outcome, survival at 12 months after cardiac arrest with a Vineland Adaptive Behavior Scales, second edition (VABS-II), score of 70 or higher (on a scale from 20 to 160, with higher scores indicating better function), was evaluated among patients with a VABS-II score of at least 70 before cardiac arrest. RESULTS A total of 295 patients underwent randomization. Among the 260 patients with data that could be evaluated and who had a VABS-II score of at least 70 before cardiac arrest, there was no significant difference in the primary outcome between the hypothermia group and the normothermia group (20% vs. 12%; relative likelihood, 1.54; 95% confidence interval [CI], 0.86 to 2.76; P=0.14). Among all the patients with data that could be evaluated, the change in the VABS-II score from baseline to 12 months was not significantly different (P=0.13) and 1-year survival was similar (38% in the hypothermia group vs. 29% in the normothermia group; relative likelihood, 1.29; 95% CI, 0.93 to 1.79; P=0.13). The groups had similar incidences of infection and serious arrhythmias, as well as similar use of blood products and 28-day mortality. CONCLUSIONS In comatose children who survived out-of-hospital cardiac arrest, therapeutic hypothermia, as compared with therapeutic normothermia, did not confer a significant benefit in survival with a good functional outcome at 1 year. C1 [Moler, Frank W.; Silverstein, Faye S.] Univ Michigan, Ann Arbor, MI 48109 USA. [Meert, Kathleen L.; Shankaran, Seetha] Wayne State Univ, Detroit, MI USA. [Holubkov, Richard; Clark, Amy E.; Browning, Brittan; Page, Kent; Bennett, Kimberly S.; Dean, J. Michael] Univ Utah, Salt Lake City, UT USA. [Slomine, Beth S.; Christensen, James R.] Kennedy Krieger Inst, Baltimore, MD USA. [Slomine, Beth S.; Christensen, James R.] Johns Hopkins Univ, Baltimore, MD USA. [Bhalala, Utpal S.] Johns Hopkins Childrens Ctr, Baltimore, MD USA. [Pemberton, Victoria L.] NHLBI, Bethesda, MD 20892 USA. [Nadkarni, Vinay M.; Topjian, Alexis] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Fink, Ericka L.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Thomas, Neal J.] Penn State Hershey Childrens Hosp, Hershey, PA USA. [Hutchison, Jamie S.] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Newth, Christopher J. L.] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Harrison, Rick] Mattel Childrens Hosp UCLA, Los Angeles, CA USA. [McQuillen, Patrick] Univ Calif San Francisco, Benioff Childrens Hosp, San Francisco, CA 94143 USA. [Schwarz, Adam J.] Childrens Hosp Orange Cty, Orange, CA 92668 USA. [Mathur, Mudit] Loma Linda Univ, Childrens Hosp, Loma Linda, CA 92350 USA. [Berger, John T.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Pineda, Jose A.] Washington Univ, St Louis, MO 63130 USA. [Koch, Joshua D.] Childrens Med Ctr Dallas, Dallas, TX USA. [Koch, Joshua D.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Wu, Theodore] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Schleien, Charles L.] Columbia Univ, Med Ctr, New York Presbyterian Morgan Stanley Childrens Ho, New York, NY USA. [van der Jagt, Elise W.] Univ Rochester, Med Ctr, Golisano Childrens Hosp, Rochester, NY 14642 USA. [Dalton, Heidi J.] Phoenix Childrens Hosp, Phoenix, AZ USA. [Theodorou, Andreas A.] Diamond Childrens Med Ctr, Tucson, AZ USA. [Ofori-Amanfo, George] Duke Childrens Hosp & Hlth Ctr, Durham, NC USA. [Goodman, Denise M.] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL 60611 USA. [Zimmerman, Jerry J.] Seattle Childrens Hosp, Seattle, WA USA. [Porter, Melissa B.] Univ Louisville, Kosair Childrens Hosp, Louisville, KY 40292 USA. [Meyer, Michael T.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Nga Pham] Childrens Healthcare Atlanta, Atlanta, GA USA. [Nowak, Jeffrey E.] Childrens Hosp & Clin Minnesota, Minneapolis, MN USA. [Alten, Jeffrey] Childrens Alabama, Birmingham, AL USA. [Wheeler, Derek S.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Lidsky, Karen] Rainbow Babies & Childrens Hosp, Cleveland, OH 44106 USA. [Lloyd, Eric] Nationwide Childrens Hosp, Columbus, OH USA. [Shah, Samir] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. [Sanders, Ronald C., Jr.] Arkansas Childrens Hosp, Little Rock, AR 72202 USA. RP Moler, FW (reprint author), Univ Michigan Hlth Syst, F-6900 UH South,SPF 5243,1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. EM fmoler@umich.edu RI Hahn, Cecil/J-3372-2016; OI Hahn, Cecil/0000-0002-0887-8761; Michelson, David/0000-0002-0600-3523; Thomas, Neal/0000-0002-7991-7510 FU National Heart, Lung, and Blood Institute FX Funded by the National Heart, Lung, and Blood Institute and others; THAPCA-OH ClinicalTrials.gov number, NCT00878644. NR 37 TC 72 Z9 73 U1 0 U2 14 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 MAY 14 PY 2015 VL 372 IS 20 BP 1898 EP 1908 DI 10.1056/NEJMoa1411480 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA CI1HB UT WOS:000354493300005 PM 25913022 ER PT J AU Jablonski, M Miller, DS Pasinelli, P Trotti, D AF Jablonski, Michael Miller, David S. Pasinelli, Piera Trotti, Davide TI ABC transporter-driven pharmacoresistance in Amyotrophic Lateral Sclerosis SO BRAIN RESEARCH LA English DT Review DE Amyotrophic Lateral Sclerosis; Drug efflux transporters; Blood-brain barrier; Pharmacoresistance; Neurodegeneration ID BLOOD-BRAIN-BARRIER; TRANSGENIC MOUSE MODEL; P-GLYCOPROTEIN EXPRESSION; PLACEBO-CONTROLLED TRIAL; PROTECTS MOTOR-NEURONS; NECROSIS-FACTOR-ALPHA; GROWTH-FACTOR-I; MICROVESSEL ENDOTHELIAL-CELLS; MEMANTINE PROLONGS SURVIVAL; DELAYS DISEASE PROGRESSION AB Amyotrophic Lateral Sclerosis (ALS) is a slowly progressing neurodegenerative disease that affects motor neurons of the nervous system. Despite the identification of many potential therapeutics targeting pathogenic mechanisms in in vitro models, there has been limited progress in translating them into a successful pharmacotherapy in the animal model of ALS. Further, efforts to translate any promising results from preclinical trials to effective pharmacotherapies for patients have been unsuccessful, with the exception of riluzole, the only FDA-approved medication, which only modestly extends survival both in the animal model and in patients. Thus, it is essential to reconsider the strategies for developing ALS pharmacotherapies. Growing evidence suggests that problems identifying highly effective ALS treatments may result from an underestimated issue of drug bioavailability and disease-driven pharmacoresistance, mediated by the ATP-binding cassette (ABC) drug efflux transporters. ABC transporters are predominately localized to the lumen of endothelial cells of the blood-brain and blood-spinal cord barriers (BBB, BSCB) where they limit the entry into the central nervous system (CNS) of a wide range of neurotoxicants and xenobiotics, but also therapeutics. In ALS, expression and function of ABC transporters is increased at the BBB/BSCB and their expression has been detected on neurons and glia in the CNS parenchyma, which may further reduce therapeutic action in target cells. Understanding and accounting for the contribution of these transporters to ALS pharmacoresistance could both improve the modest effects of riluzole and set in motion a re-evaluation of previous ALS drug disappointments. In addition, identifying pathogenic mechanisms regulating ABC transporter expression and function in ALS may lead to the development of new therapeutic strategies. It is likely that novel pharmacological approaches require counteracting pharmacoresistance to improve therapeutic efficacy. This article is part of a Special Issue entitled ALS complex pathogenesis. (C) 2014 Elsevier B.V. All rights reserved. C1 [Jablonski, Michael; Pasinelli, Piera; Trotti, Davide] Thomas Jefferson Univ, Farber Inst Neurosci, Weinberg Unit ALS Res, Dept Neurosci, Philadelphia, PA 19004 USA. [Miller, David S.] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. RP Trotti, D (reprint author), Thomas Jefferson Univ, Farber Inst Neurosci, Weinberg Unit ALS Res, Dept Neurosci, 900 Walnut St, Philadelphia, PA 19004 USA. EM Michael.jablonski@jefferson.edu; davide.trotti@jefferson.edu FU National Institute of Health [RO1-NS074886]; DoD [08019250 x 13401]; Muscular Dystrophy Association Developmental Award; National Institute of Environmental Health Sciences, National Institutes of Health; Farber Family Foundation; [F31-NS080539] FX The authors thank Warren Anderson, Nathan Henderson, and Eric Kostuk for assembly of Tables 1 and 2. This work was supported by the National Institute of Health Grant RO1-NS074886 (DT), DoD Grant 08019250 x 13401 (PP), the Muscular Dystrophy Association Developmental Award (DAJ), F31-NS080539 (MRJ) and by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health (DSM). The Weinberg Unit for ALS research is also supported by the Farber Family Foundation. NR 137 TC 7 Z9 7 U1 0 U2 8 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 MAY 14 PY 2015 VL 1607 SI SI BP 1 EP 14 DI 10.1016/j.brainres.2014.08.060 PG 14 WC Neurosciences SC Neurosciences & Neurology GA CH0XS UT WOS:000353746300001 PM 25175835 ER PT J AU Marangi, G Traynor, BJ AF Marangi, Giuseppe Traynor, Bryan J. TI Genetic causes of amyotrophic lateral sclerosis: New genetic analysis methodologies entailing new opportunities and challenges SO BRAIN RESEARCH LA English DT Review DE Amyotrophic lateral sclerosis; Gene discovery; Genetic heterogeneity; GWAS; NGS; Somatic mosaicism ID GENOME-WIDE ASSOCIATION; MOTOR-NEURON DISEASE; DE-NOVO MUTATIONS; COPY NUMBER VARIATION; FRONTOTEMPORAL LOBAR DEGENERATION; HEXANUCLEOTIDE REPEAT EXPANSION; HEAVY NEUROFILAMENT SUBUNIT; SUPEROXIDE-DISMUTASE GENE; HOMOZYGOUS SMN2 DELETION; SPORADIC ALS AB The genetic architecture of amyotrophic lateral sclerosis (ALS) is being increasingly understood. In this far-reaching review, we examine what is currently known about ALS genetics and how these genes were initially identified. We also discuss the various types of mutations that might underlie this fatal neurodegenerative condition and outline some of the strategies that might be useful in untangling them. These include expansions of short repeat sequences, common and low-frequency genetic variations, de novo mutations, epigenetic changes, somatic mutations, epistasis, oligogenic and polygenic hypotheses. This article is part of a Special Issue entitled ALS complex pathogenesis. Published by Elsevier B.V. C1 [Marangi, Giuseppe; Traynor, Bryan J.] NIA, Neuromuscular Dis Res Sect, Neurogenet Lab, Bethesda, MD 20892 USA. [Marangi, Giuseppe] Univ Cattolica Sacro Cuore, Inst Med Genet, I-00168 Rome, Italy. [Traynor, Bryan J.] Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD USA. RP Marangi, G (reprint author), Univ Cattolica Sacro Cuore, Inst Med Genet, Largo Francesco Vito 1, I-00168 Rome, Italy. EM giuseppe.marangi@rm.unicatt.it NR 198 TC 28 Z9 28 U1 5 U2 22 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 MAY 14 PY 2015 VL 1607 SI SI BP 75 EP 93 DI 10.1016/j.brainres.2014.10.009 PG 19 WC Neurosciences SC Neurosciences & Neurology GA CH0XS UT WOS:000353746300006 PM 25316630 ER PT J AU Lim, CG Vitiello, B AF Lim, Choon Guan Vitiello, Benedetto TI Child psychiatry services in Asia: evolving state of affairs? SO CHILD AND ADOLESCENT PSYCHIATRY AND MENTAL HEALTH LA English DT Editorial Material ID MENTAL-HEALTH; TRENDS C1 [Lim, Choon Guan] Inst Mental Hlth, Dept Child & Adolescent Psychiat, 10 Buangkok View, Hougang Singapore 539747, Singapore. [Vitiello, Benedetto] NIMH, Treatment & Prevent Intervent Res Branch, Bethesda, MD 20892 USA. RP Lim, CG (reprint author), Inst Mental Hlth, Dept Child & Adolescent Psychiat, 10 Buangkok View, Hougang Singapore 539747, Singapore. EM choon_guan_lim@imh.com.sg NR 6 TC 0 Z9 0 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND EI 1753-2000 J9 CHILD ADOL PSYCH MEN JI Child Adolesc. Psychiatry Ment. Health PD MAY 13 PY 2015 VL 9 AR 12 DI 10.1186/s13034-015-0044-9 PG 2 WC Pediatrics; Psychiatry SC Pediatrics; Psychiatry GA DE9EF UT WOS:000370937900001 PM 25972920 ER PT J AU Monosov, IE Leopold, DA Hikosaka, O AF Monosov, Ilya E. Leopold, David A. Hikosaka, Okihide TI Neurons in the Primate Medial Basal Forebrain Signal Combined Information about Reward Uncertainty, Value, and Punishment Anticipation SO JOURNAL OF NEUROSCIENCE LA English DT Article DE basal forebrain; electrophysiology; emotion; learning; memory; motivation ID BRAIN-STEM AFFERENTS; LONG-TERM-MEMORY; CHOLINERGIC NEURONS; DIAGONAL BAND; SEMANTIC MEMORY; IN-VIVO; PROACTIVE-INTERFERENCE; SUBSTANTIA INNOMINATA; ORBITOFRONTAL NEURONS; EFFERENT CONNECTIONS AB It has been suggested that the basal forebrain (BF) exerts strong influences on the formation of memory and behavior. However, what information is used for the memory-behavior formation is unclear. We found that a population of neurons in the medial BF (medial septum and diagonal band of Broca) of macaque monkeys encodes a unique combination of information: reward uncertainty, expected reward value, anticipation of punishment, and unexpected reward and punishment. The results were obtained while the monkeys were expecting (often with uncertainty) a rewarding or punishing outcome during a Pavlovian procedure, or unexpectedly received an outcome outside the procedure. In vivo anterograde tracing using manganese-enhanced MRI suggested that the major recipient of these signals is the intermediate hippocampal formation. Based on these findings, we hypothesize that the medial BF identifies various contexts and outcomes that are critical for memory processing in the hippocampal formation. C1 [Monosov, Ilya E.] Washington Univ, Sch Med, Dept Anat & Neurobiol, St Louis, MO 63110 USA. [Leopold, David A.] NIMH, Sect Cognit Neurophysiol & Imaging, Bethesda, MD 20892 USA. [Monosov, Ilya E.; Hikosaka, Okihide] NEI, Lab Sensorimotor Res, Bethesda, MD 20892 USA. [Leopold, David A.] NINDS, Neurophysiol Imaging Facil, NIMH, NEI, Bethesda, MD 20892 USA. RP Monosov, IE (reprint author), Washington Univ, Sch Med, Dept Anat & Neurobiol, 660 S Euclid Ave, St Louis, MO 63110 USA. EM ilya.monosov@gmail.com OI Leopold, David/0000-0002-1345-6360 FU National Eye Institute intramural research program; Department of Anatomy and Neurobiology, Washington University School of Medicine FX This work was supported by the National Eye Institute intramural research program and the Department of Anatomy and Neurobiology, Washington University School of Medicine to I.E.M. We thank E. Bromberg-Martin, B. Cumming, P. Daye, A. Ghazizadeh, J. Herman, H. Kim, R. Krauzlis, L. Optican, R. Wurtz, and M. Yasuda for valuable scientific discussions; F. Ye and C. Zhu for excellent MRI services; M. Smith for histological expertise and service; and A. Hays, J. McClurkin, B. Nagy, N. Nichols, D. Parker, and T. Ruffner for technical support. NR 104 TC 4 Z9 4 U1 5 U2 14 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 13 PY 2015 VL 35 IS 19 BP 7443 EP 7459 DI 10.1523/JNEUROSCI.0051-15.2015 PG 17 WC Neurosciences SC Neurosciences & Neurology GA CL0YK UT WOS:000356668800012 PM 25972172 ER PT J AU Zander, RA Obeng-Adjei, N Guthmiller, JJ Kulu, DI Li, J Ongoiba, A Traore, B Crompton, PD Butler, NS AF Zander, Ryan A. Obeng-Adjei, Nyamekye Guthmiller, Jenna J. Kulu, Divine I. Li, Jun Ongoiba, Aissata Traore, Boubacar Crompton, Peter D. Butler, Noah S. TI PD-1 Co-inhibitory and OX40 Co-stimulatory Crosstalk Regulates Helper T Cell Differentiation and Anti-Plasmodium Humoral Immunity SO CELL HOST & MICROBE LA English DT Article ID CHRONIC VIRAL-INFECTION; BLOOD-STAGE MALARIA; GERMINAL-CENTERS; MOLECULAR-MECHANISMS; CLONAL EXPANSION; INTERFERON-GAMMA; B-CELLS; RESPONSES; BET; FALCIPARUM AB The differentiation and protective capacity of Plasmodium-specific T cells are regulated by both positive and negative signals during malaria, but the molecular and cellular details remain poorly defined. Here we show that malaria patients and Plasmodium-infected rodents exhibit atypical expression of the co-stimulatory receptor OX40 on CD4 T cells and that therapeutic enhancement of OX40 signaling enhances helper CD4 T cell activity, humoral immunity, and parasite clearance in rodents. However, these beneficial effects of OX40 signaling are abrogated following coordinate blockade of PD-1 co-inhibitory pathways, which are also upregulated during malaria and associated with elevated parasitemia. Co-administration of biologics blocking PD-1 and promoting OX40 signaling induces excessive interferon-gamma that directly limits helper T cell-mediated support of humoral immunity and decreases parasite control. Our results show that targeting OX40 can enhance Plasmodium control and that crosstalk between co-inhibitory and co-stimulatory pathways in pathogen-specific CD4 T cells can impact pathogen clearance. C1 [Zander, Ryan A.; Guthmiller, Jenna J.; Kulu, Divine I.; Butler, Noah S.] Univ Oklahoma, Hlth Sci Ctr, Dept Microbiol & Immunol, Oklahoma City, OK 73104 USA. [Obeng-Adjei, Nyamekye; Crompton, Peter D.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Li, Jun] Univ Oklahoma, Dept Chem & Biochem, Norman, OK 73019 USA. [Ongoiba, Aissata; Traore, Boubacar] Univ Sci Tech & Technol Bamako, Mali Int Ctr Excellence Res, Bamako, Mali. RP Butler, NS (reprint author), Univ Oklahoma, Hlth Sci Ctr, Dept Microbiol & Immunol, Oklahoma City, OK 73104 USA. EM noah-butler@ouhsc.edu RI Crompton, Peter/N-1130-2016 FU NIH [T32AI007633, 1K22AI099070]; American Heart Association [13BGIA17140002]; Presbyterian Health Foundation of Oklahoma City; NIH/NIGMS [8P20GM103447]; Division of Intramural Research, NIH/NIAID FX We thank Lauren Zenewicz, Mark Lang, and Linda Thompson for critical review, Chaonan Hsu for technical assistance, and the Flow Cytometry Laboratory at OUHSC. This work was supported by grants from the NIH (T32AI007633 to R.A.Z.; 1K22AI099070 to N.S.B.), the American Heart Association (13BGIA17140002 to N.S.B.), and the Presbyterian Health Foundation of Oklahoma City (PHF Seed Grant to N.S.B.). N.S.B. is also an OK-INBRE scholar supported by a grant from the NIH/NIGMS (8P20GM103447). The study in Mali was supported by the Division of Intramural Research, NIH/NIAID. NR 45 TC 13 Z9 13 U1 1 U2 5 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 MAY 13 PY 2015 VL 17 IS 5 BP 628 EP 641 DI 10.1016/j.chom.2015.03.007 PG 14 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA CK3FH UT WOS:000356101500014 PM 25891357 ER PT J AU Bible, PW Kanno, Y Wei, L Brooks, SR O'Shea, JJ Morasso, MI Loganantharaj, R Sun, HW AF Bible, Paul W. Kanno, Yuka Wei, Lai Brooks, Stephen R. O'Shea, John J. Morasso, Maria I. Loganantharaj, Rasiah Sun, Hong-Wei TI PAPST, a User Friendly and Powerful Java Platform for ChIP-Seq Peak Co-Localization Analysis and Beyond SO PLOS ONE LA English DT Article ID READ ALIGNMENT; IDENTIFICATION; UPDATE; SITES; RNAS AB Comparative co-localization analysis of transcription factors (TFs) and epigenetic marks (EMs) in specific biological contexts is one of the most critical areas of ChIP-Seq data analysis beyond peak calling. Yet there is a significant lack of user-friendly and powerful tools geared towards co-localization analysis based exploratory research. Most tools currently used for co-localization analysis are command line only and require extensive installation procedures and Linux expertise. Online tools partially address the usability issues of command line tools, but slow response times and few customization features make them unsuitable for rapid data-driven interactive exploratory research. We have developed PAPST: Peak Assignment and Profile Search Tool, a user-friendly yet powerful platform with a unique design, which integrates both gene-centric and peak-centric co-localization analysis into a single package. Most of PAPST's functions can be completed in less than five seconds, allowing quick cycles of data-driven hypothesis generation and testing. With PAPST, a researcher with or without computational expertise can perform sophisticated co-localization pattern analysis of multiple TFs and EMs, either against all known genes or a set of genomic regions obtained from public repositories or prior analysis. PAPST is a versatile, efficient, and customizable tool for genome-wide data-driven exploratory research. Creatively used, PAPST can be quickly applied to any genomic data analysis that involves a comparison of two or more sets of genomic coordinate intervals, making it a powerful tool for a wide range of exploratory genomic research. We first present PAPST's general purpose features then apply it to several public ChIP-Seq data sets to demonstrate its rapid execution and potential for cutting-edge research with a case study in enhancer analysis. To our knowledge, PAPST is the first software of its kind to provide efficient and sophisticated post peak-calling ChIP-Seq data analysis as an easy-to-use interactive application. PAPST is available at https://github.com/paulbible/papst and is a public domain work. C1 [Bible, Paul W.; Morasso, Maria I.] NIAMSD, Skin Biol Lab, Intramural Res Program, Bethesda, MD 20892 USA. [Kanno, Yuka; O'Shea, John J.] NIAMSD, Mol Immunol & Inflammat Branch, Intramural Res Program, Bethesda, MD 20892 USA. [Wei, Lai] Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, State Key Lab Ophthalmol, Guangzhou 510275, Guangdong, Peoples R China. [Brooks, Stephen R.; Sun, Hong-Wei] NIAMSD, Biodata Min & Discovery Sect, Off Sci & Technol, Intramural Res Program, Bethesda, MD 20892 USA. [Loganantharaj, Rasiah] Univ Louisiana Lafayette, Ctr Adv Comp Studies, Lab Bioinformat, Lafayette, LA 70504 USA. RP Bible, PW (reprint author), NIAMSD, Skin Biol Lab, Intramural Res Program, Bethesda, MD 20892 USA. EM paul.bible2@nih.gov; sunh1@mail.nih.gov OI Kanno, Yuka/0000-0001-5668-9319 FU Intramural Research Program; Office of Science and Technology of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health FX This work was supported by the Intramural Research Program and the Office of Science and Technology of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. NR 26 TC 4 Z9 4 U1 1 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 13 PY 2015 VL 10 IS 5 AR e0127285 DI 10.1371/journal.pone.0127285 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CI1ZP UT WOS:000354544200156 PM 25970601 ER PT J AU Wieskopf, JS Mathur, J Limapichat, W Post, MR Al-Qazzaz, M Sorge, RE Martin, LJ Zaykin, DV Smith, SB Freitas, K Austin, JS Dai, F Zhang, J Marcovitz, J Tuttle, AH Slepian, PM Clarke, S Drenan, RM Janes, J Al Sharari, S Segall, SK Aasvang, EK Lai, WK Bittner, R Richards, CI Slade, GD Kehlet, H Walker, J Maskos, U Changeux, JP Devor, M Maixner, W Diatchenko, L Belfer, I Dougherty, DA Su, AI Lummis, SCR Damaj, MI Lester, HA Patapoutian, A Mogil, JS AF Wieskopf, Jeffrey S. Mathur, Jayanti Limapichat, Walrati Post, Michael R. Al-Qazzaz, Mona Sorge, Robert E. Martin, Loren J. Zaykin, Dmitri V. Smith, Shad B. Freitas, Kelen Austin, Jean-Sebastien Dai, Feng Zhang, Jie Marcovitz, Jaclyn Tuttle, Alexander H. Slepian, Peter M. Clarke, Sarah Drenan, Ryan M. Janes, Jeff Al Sharari, Shakir Segall, Samantha K. Aasvang, Eske K. Lai, Weike Bittner, Reinhard Richards, Christopher I. Slade, Gary D. Kehlet, Henrik Walker, John Maskos, Uwe Changeux, Jean-Pierre Devor, Marshall Maixner, William Diatchenko, Luda Belfer, Inna Dougherty, Dennis A. Su, Andrew I. Lummis, Sarah C. R. Damaj, M. Imad Lester, Henry A. Patapoutian, Ardem Mogil, Jeffrey S. TI The nicotinic alpha 6 subunit gene determines variability in chronic pain sensitivity via cross-inhibition of P2X2/3 receptors SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID SPARED NERVE INJURY; ACETYLCHOLINE-RECEPTORS; P2X(3) RECEPTORS; NEUROPATHIC PAIN; MECHANICAL HYPERALGESIA; INFLAMMATORY PAIN; TRANSGENIC MICE; P2X3 RECEPTORS; MOUSE STRAINS; EXPRESSION AB Chronic pain is a highly prevalent and poorly managed human health problem. We used microarray-based expression genomics in 25 inbred mouse strains to identify dorsal root ganglion (DRG)-expressed genetic contributors to mechanical allodynia, a prominent symptom of chronic pain. We identified expression levels of Chrna6, which encodes the alpha 6 subunit of the nicotinic acetylcholine receptor (nAChR), as highly associated with allodynia. We confirmed the importance of alpha 6* (alpha 6-containing) nAChRs by analyzing both gain-and loss-of-function mutants. We find that mechanical allodynia associated with neuropathic and inflammatory injuries is significantly altered in alpha 6* mutants, and that alpha 6* but not alpha 4* nicotinic receptors are absolutely required for peripheral and/or spinal nicotine analgesia. Furthermore, we show that Chrna6's role in analgesia is at least partially due to direct interaction and cross-inhibition of alpha 6* nAChRs with P2X2/3 receptors in DRG nociceptors. Finally, we establish the relevance of our results to humans by the observation of genetic association in patients suffering from chronic postsurgical and temporomandibular pain. C1 [Wieskopf, Jeffrey S.; Sorge, Robert E.; Martin, Loren J.; Austin, Jean-Sebastien; Marcovitz, Jaclyn; Tuttle, Alexander H.; Slepian, Peter M.; Clarke, Sarah; Mogil, Jeffrey S.] McGill Univ, Dept Psychol, Montreal, PQ H3A 1B1, Canada. [Wieskopf, Jeffrey S.; Sorge, Robert E.; Martin, Loren J.; Austin, Jean-Sebastien; Marcovitz, Jaclyn; Tuttle, Alexander H.; Slepian, Peter M.; Clarke, Sarah; Mogil, Jeffrey S.] McGill Univ, Alan Edwards Ctr Res Pain, Montreal, PQ H3A 1B1, Canada. [Mathur, Jayanti; Zhang, Jie; Janes, Jeff] Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA. [Limapichat, Walrati; Post, Michael R.; Dougherty, Dennis A.] CALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USA. [Al-Qazzaz, Mona; Lummis, Sarah C. R.] Univ Cambridge, Dept Biochem, Cambridge CB2 1QW, England. [Zaykin, Dmitri V.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Smith, Shad B.; Segall, Samantha K.; Maixner, William; Diatchenko, Luda] Univ N Carolina, Ctr Neurosensory Disorders, Chapel Hill, NC 27599 USA. [Freitas, Kelen; Damaj, M. Imad] Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Richmond, VA 23219 USA. [Dai, Feng; Lai, Weike; Belfer, Inna] Univ Pittsburgh, Dept Anesthesiol, Pittsburgh, PA 15213 USA. [Dai, Feng; Lai, Weike; Belfer, Inna] Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA 15213 USA. [Drenan, Ryan M.] Purdue Univ, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. [Al Sharari, Shakir] King Saud Univ, Dept Pharmacol, Riyadh 11451, Saudi Arabia. [Aasvang, Eske K.] Univ Copenhagen, Rigshosp, Sect Surg Pathophysiol, DK-2100 Copenhagen, Denmark. [Bittner, Reinhard] Marienhosp Stuttgart, Dept Surg, D-70199 Stuttgart, Germany. [Richards, Christopher I.] Univ Kentucky, Dept Chem, Lexington, KY 40506 USA. [Slade, Gary D.] Univ N Carolina, Sch Dent, Dept Dent Ecol, Chapel Hill, NC 27599 USA. [Maskos, Uwe; Changeux, Jean-Pierre] Inst Pasteur, Dept Neurosci, CNRS UMR 3571, Neurobiol Integrat Syst Cholinerg, F-75724 Paris, France. [Devor, Marshall] Hebrew Univ Jerusalem, Inst Life Sci, Dept Cell & Dev Biol, IL-91904 Jerusalem, Israel. [Devor, Marshall] Hebrew Univ Jerusalem, Ctr Res Pain, IL-91904 Jerusalem, Israel. [Diatchenko, Luda] McGill Univ, Fac Dent, Dept Anesthesia, Montreal, PQ H3A 1G1, Canada. [Diatchenko, Luda] McGill Univ, Alan Edwards Ctr Res Pain, Montreal, PQ H3A 1G1, Canada. [Su, Andrew I.] Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA. [Lester, Henry A.] CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA. [Patapoutian, Ardem] Scripps Res Inst, Dept Mol & Cellular Neurosci, La Jolla, CA 92037 USA. [Patapoutian, Ardem] Salk Inst Biol Studies, Howard Hughes Med Inst, La Jolla, CA 92037 USA. RP Mogil, JS (reprint author), McGill Univ, Dept Psychol, 1205 Dr Penfield Ave, Montreal, PQ H3A 1B1, Canada. EM jeffrey.mogil@mcgill.ca RI Post, Michael/E-4529-2016 OI Post, Michael/0000-0002-3214-7619 FU Canadian Institutes for Health Research; Louise and Alan Edwards Foundation; NIH FX Supported by the Canadian Institutes for Health Research and the Louise and Alan Edwards Foundation (J.S.M.) and the NIH (D.A.D., H.A.L., and A.P.). NR 81 TC 4 Z9 4 U1 1 U2 13 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 MAY 13 PY 2015 VL 7 IS 287 AR 287ra72 DI 10.1126/scitranslmed.3009986 PG 14 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA CI0NM UT WOS:000354433900013 PM 25972004 ER PT J AU Vandraas, KF Vikanes, AV Stoer, NC Troisi, R Stephansson, O Sorensen, HT Vangen, S Magnus, P Grjibovski, AM Grotmol, T AF Vandraas, Kathrine F. Vikanes, Ase V. Stoer, Nathalie C. Troisi, Rebecca Stephansson, Olof Sorensen, Henrik T. Vangen, Siri Magnus, Per Grjibovski, Andrej M. Grotmol, Tom TI Hyperemesis gravidarum and risk of cancer in offspring, a Scandinavian registry-based nested case-control study SO BMC CANCER LA English DT Article DE Hyperemesis; Cancer; Fetal programming ID MEDICAL BIRTH REGISTRY; EARLY-LIFE EXPOSURES; BREAST-CANCER; DUTCH FAMINE; PREGNANCY; CONSEQUENCES; CHILDHOOD; OUTCOMES; QUALITY; NORWAY AB Background: Hyperemesis gravidarum is a serious condition affecting 0.8-2.3 % of pregnant women and can be regarded as a restricted period of famine. Research concerning potential long-term consequences of the condition for the offspring, is limited, but lack of nutrition in-utero has been associated with chronic disease in adulthood, including some cancers. There is growing evidence that several forms of cancer may originate during fetal life. We conducted a large study linking the high-quality population-based medical birth- and cancer registries in Norway, Sweden and Denmark, to explore whether hyperemesis is associated with increased cancer risk in offspring. Methods: A registry-based nested case-control study. Twelve types of childhood cancer were selected; leukemia, lymphoma, cancer of the central nervous system, testis, bone, ovary, breast, adrenal and thyroid gland, nephroblastoma, hepatoblastoma and retinoblastoma. Conditional logistic regression models were applied to study associations between hyperemesis and risk of childhood cancer, both all types combined and separately. Cancer types with five or more exposed cases were stratified by age at diagnosis. All analysis were adjusted for maternal age, ethnicity and smoking, in addition to the offspring's Apgar score, placental weight and birth weight. Relative risks with 95 % confidence intervals were calculated. Results: In total 14,805 cases and approximately ten controls matched on time, country of birth, sex and year of birth per case (147,709) were identified. None of the cancer types, analyzed combined or separately, revealed significant association with hyperemesis. When stratified according to age at diagnosis, we observed a RR 2.13 for lymphoma among adolescents aged 11-20 years ((95 % CI 1.14-3.99), after adjustment for maternal ethnicity and maternal age, RR 2.08 (95 % CI 1.11-3.90)). The finding was not apparent when a stricter level of statistical significance was applied. Conclusions: The main finding of this paper is that hyperemesis does not seem to increase cancer risk in offspring. The positive association to lymphoma may be by chance and needs confirmation. C1 [Vandraas, Kathrine F.; Vikanes, Ase V.; Magnus, Per] Norwegian Inst Publ Hlth, Dept Genes & Environm, N-0403 Oslo, Norway. [Vandraas, Kathrine F.] Oslo Univ Hosp, Norwegian Natl Advisory Unit Womens Hlth, Oslo, Norway. [Stoer, Nathalie C.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Troisi, Rebecca] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Stephansson, Olof] Karolinska Univ Hosp & Inst, Dept Med, Clin Epidemiol Unit, SE-14186 Stockholm, Sweden. [Stephansson, Olof] Karolinska Univ Hosp & Inst, Div Obstet & Gynecol, Dept Women & Childrens Hlth, SE-14186 Stockholm, Sweden. [Sorensen, Henrik T.] Aarhus Univ Hosp, Dept Clin Epidemiol, DK-8000 Aarhus, Denmark. [Grjibovski, Andrej M.] Norwegian Inst Publ Hlth, Dept Int Publ Hlth, N-0403 Oslo, Norway. [Grjibovski, Andrej M.] Northern State Med Univ, Int Sch Publ Hlth, Arkhangelsk 163000, Russia. [Grjibovski, Andrej M.] Int Kazakh Turkish Univ, Dept Prevent Med, Turkestan, Kazakhstan. [Grotmol, Tom] Canc Registry Norway, N-0304 Oslo, Norway. [Vikanes, Ase V.] Oslo Univ Hosp, Intervent Ctr, Oslo, Norway. RP Vandraas, KF (reprint author), Norwegian Inst Publ Hlth, Dept Genes & Environm, POB 4404, N-0403 Oslo, Norway. EM kafv@fhi.no RI Grjibovski, Andrej/B-9815-2016 OI Grjibovski, Andrej/0000-0002-5464-0498 FU Norwegian National Advisory Unit on Women's Health, Rikshospitalet, Norway; Swedish Research Council FX The authors wish to thank Steinar Tretli and Mika Gissler for making this research project possible. In addition we wish to thank the MBRs and national cancer registries in Norway, Sweden and Denmark for providing us with data for this study, especially Tobias Svensson and Rikke Bech Nielsen. Finally, we thank the Norwegian National Advisory Unit on Women's Health, Rikshospitalet, Norway, for funding. Olof Stephanson was funded by the Swedish Research Council. NR 39 TC 1 Z9 1 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD MAY 13 PY 2015 VL 15 AR 398 DI 10.1186/s12885-015-1425-4 PG 8 WC Oncology SC Oncology GA CI0MB UT WOS:000354430100001 PM 25963309 ER PT J AU Jin, KX Jiang, HS Xiao, DC Zou, M Zhu, J Xiang, MQ AF Jin, Kangxin Jiang, Haisong Xiao, Dongchang Zou, Min Zhu, Jun Xiang, Mengqing TI Tfap2a and 2b act downstream of Ptf1a to promote amacrine cell differentiation during retinogenesis SO MOLECULAR BRAIN LA English DT Article DE Tfap2; Ptf1a; Foxn4; Amacrine cell; Horizontal cell; Retinal development ID AP-2 TRANSCRIPTION FACTORS; RETINAL PROGENITOR CELLS; BRANCHIOOCULOFACIAL SYNDROME; HORIZONTAL CELLS; GANGLION-CELL; VERTEBRATE DEVELOPMENT; EXPRESSION ANALYSIS; MAMMALIAN RETINA; COMBINED GOLGI; CHICK RETINA AB Retinogenesis is a precisely controlled developmental process during which different types of neurons and glial cells are generated under the influence of intrinsic and extrinsic factors. Three transcription factors, Foxn4, ROR beta 1 and their downstream effector Ptf1a, have been shown to be indispensable intrinsic regulators for the differentiation of amacrine and horizontal cells. At present, however, it is unclear how Ptf1a specifies these two cell fates from competent retinal precursors. Here, through combined bioinformatic, molecular and genetic approaches in mouse retinas, we identify the Tfap2a and Tfap2b transcription factors as two major downstream effectors of Ptf1a. RNA-seq and immunolabeling analyses show that the expression of Tfap2a and 2b transcripts and proteins is dramatically downregulated in the Ptf1a null mutant retina. Their overexpression is capable of promoting the differentiation of glycinergic and GABAergic amacrine cells at the expense of photoreceptors much as misexpressed Ptf1a is, whereas their simultaneous knockdown has the opposite effect. Given the demonstrated requirement for Tfap2a and 2b in horizontal cell differentiation, our study thus defines a Foxn4/ROR beta 1-Ptf1a-Tfap2a/2b transcriptional regulatory cascade that underlies the competence, specification and differentiation of amacrine and horizontal cells during retinal development. C1 [Jin, Kangxin; Xiao, Dongchang; Xiang, Mengqing] Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, State Key Lab Ophthalmol, Guangzhou 510060, Guangdong, Peoples R China. [Jiang, Haisong; Zou, Min; Xiang, Mengqing] Rutgers State Univ, Robert Wood Johnson Med Sch, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. [Jiang, Haisong; Zou, Min; Xiang, Mengqing] Rutgers State Univ, Robert Wood Johnson Med Sch, Dept Pediat, Piscataway, NJ 08854 USA. [Zhu, Jun] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. RP Xiang, MQ (reprint author), Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, State Key Lab Ophthalmol, 54 South Xianlie Rd, Guangzhou 510060, Guangdong, Peoples R China. EM xiang@cabm.rutgers.edu RI Zou, Min/E-1042-2013 FU Fundamental Research Funds of the State Key Laboratory of Ophthalmology, Sun Yat-sen University; National Basic Research Program (973 Program) of China [2015CB964600]; National Institutes of Health [EY020849, EY012020] FX We thank Dr. Shenguo Li for thoughtful comments on the manuscript and are grateful to Dr. Christopher Wright for generously sharing the Ptf1a knockout mouse line. This work was supported in part by the Fundamental Research Funds of the State Key Laboratory of Ophthalmology, Sun Yat-sen University (to M.X.), the National Basic Research Program (973 Program) of China (2015CB964600 to M.X.), and the National Institutes of Health (EY020849 and EY012020 to M.X.). NR 60 TC 3 Z9 3 U1 1 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-6606 J9 MOL BRAIN JI Mol. Brain PD MAY 13 PY 2015 VL 8 AR 28 DI 10.1186/s13041-015-0118-x PG 14 WC Neurosciences SC Neurosciences & Neurology GA CH9IO UT WOS:000354349400001 PM 25966682 ER PT J AU Bulea, TC Kim, J Damiano, DL Stanley, CJ Park, HS AF Bulea, Thomas C. Kim, Jonghyun Damiano, Diane L. Stanley, Christopher J. Park, Hyung-Soon TI Prefrontal, posterior parietal and sensorimotor network activity underlying speed control during walking SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE electroencephalography; source localization; motor cortex; gait; motor learning; gamma oscillations; event-related desynchronization; neurorehabilitation ID INDEPENDENT COMPONENT ANALYSIS; BODY-WEIGHT SUPPORT; TREADMILL WALKING; CORTICOMUSCULAR COHERENCE; CORTICAL ACTIVATION; BRAIN ACTIVITY; MOTOR CONTROL; EEG SIGNALS; GAIT; REHABILITATION AB Accumulating evidence suggests cortical circuits may contribute to control of human locomotion. Here, noninvasive electroencephalography (EEG) recorded from able-bodied volunteers during a novel treadmill walking paradigm was used to assess neural correlates of walking. A systematic processing method, including a recently developed subspace reconstruction algorithm, reduced movement-related EEG artifact prior to independent component analysis and dipole source localization. We quantified cortical activity while participants tracked slow and fast target speeds across two treadmill conditions: an active mode that adjusted belt speed based on user movements and a passive mode reflecting a typical treadmill. Our results reveal frequency specific, multi-focal task related changes in cortical oscillations elicited by active walking. Low gamma band power, localized to the prefrontal and posterior parietal cortices, was significantly increased during double support and early swing phases, critical points in the gait cycle since the active controller adjusted speed based on pelvis position and swing foot velocity. These phasic gamma band synchronizations provide evidence that prefrontal and posterior parietal networks, previously implicated in visuo-spatial and somotosensory integration, are engaged to enhance lower limb control during gait. Sustained mu and beta band desynchronization within sensorimotor cortex, a neural correlate for movement, was observed during walking thereby validating our methods for isolating cortical activity. Our results also demonstrate the utility of EEG recorded during locomotion for probing the multi-regional cortical networks which underpin its execution. For example, the cortical network engagement elicited by the active treadmill suggests that it may enhance neuroplasticity for more effective motor training. C1 [Bulea, Thomas C.; Damiano, Diane L.; Stanley, Christopher J.] NIH, Dept Rehabil Med, Funct & Appl Biomech Sect, Bethesda, MD 20892 USA. [Kim, Jonghyun] Daegu Gyeonbuk Inst Sci & Technol, Robot Engn Dept, Daegu, South Korea. [Park, Hyung-Soon] Korea Adv Inst Sci & Technol, Dept Mech Engn, Taejon 305701, South Korea. RP Park, HS (reprint author), Korea Adv Inst Sci & Technol, Dept Mech Engn, 291 Daehakro, Taejon 305701, South Korea. EM hyungspark@kaist.ac.kr RI Park, Hyung-Soon/B-3334-2010; Damiano, Diane/B-3338-2010 OI Park, Hyung-Soon/0000-0003-4274-7420; Damiano, Diane/0000-0002-2770-5356 FU Intramural Research Program of the NIH Clinical Center [08-CC-0205]; National Research Foundation of Korea (NRF) - Ministry of Education, Science and Technology [NRF-2013R1A1A2063097] FX This work was supported by the Intramural Research Program of the NIH Clinical Center (protocol number 08-CC-0205). This research was also supported in part by the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF-2013R1A1A2063097). NR 64 TC 4 Z9 4 U1 2 U2 15 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 MAY 12 PY 2015 VL 9 AR UNSP 247 DI 10.3389/fnhum.2015.00247 PG 13 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA CK2BL UT WOS:000356014200001 PM 26029077 ER PT J AU Villemure, C Ceko, M Cotton, VA Bushnell, MC AF Villemure, Chantal Ceko, Marta Cotton, Valerie A. Bushnell, M. Catherine TI Neuroprotective effects of yoga practice: age-, experience-, and frequency-dependent plasticity SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE yoga; age-related gray matter decline; neuroprotection; magnetic resonance imaging; voxel-based morphometry ID VOXEL-BASED-MORPHOMETRY; LONG-TERM MEDITATION; GRAY-MATTER DENSITY; STRUCTURAL PLASTICITY; MINDFULNESS MEDITATION; CORTICAL THICKNESS; ANTERIOR INSULA; BRAIN STRUCTURE; HUMAN AWARENESS; NATIONAL-SURVEY AB Yoga combines postures, breathing, and meditation. Despite reported health benefits, yoga's effects on the brain have received little study. We used magnetic resonance imaging to compare age-related gray matter (GM) decline in yogis and controls. We also examined the effect of increasing yoga experience and weekly practice on GM volume and assessed which aspects of weekly practice contributed most to brain size. Controls displayed the well documented age-related global brain GM decline while yogis did not, suggesting that yoga contributes to protect the brain against age-related decline. Years of yoga experience correlated mostly with GM volume differences in the left hemisphere (insula, frontal operculum, and orbitofrontal cortex) suggesting that yoga tunes the brain toward a parasympatically driven mode and positive states. The number of hours of weekly practice correlated with GM volume in the primary somatosensory cortex/superior parietal lobule (S1/SPL), precuneus/posterior cingulate cortex (PCC), hippocampus, and primary visual cortex (V1). Commonality analyses indicated that the combination of postures and meditation contributed the most to the size of the hippocampus, precuneus/PCC, and S1/SPL while the combination of meditation and breathing exercises contributed the most to V1 volume. Yoga's potential neuroprotective effects may provide a neural basis for some of its beneficial effects. C1 [Villemure, Chantal; Ceko, Marta; Cotton, Valerie A.; Bushnell, M. Catherine] NIH, Natl Ctr Complementary & Integrat Hlth, Bethesda, MD 20892 USA. [Villemure, Chantal; Bushnell, M. Catherine] McGill Univ, Fac Dent, Montreal, PQ, Canada. [Ceko, Marta; Cotton, Valerie A.] McGill Univ, Integrated Program Neurosci, Montreal, PQ, Canada. [Bushnell, M. Catherine] McGill Univ, Dept Anesthesia, Montreal, PQ, Canada. RP Villemure, C (reprint author), NIH, Natl Ctr Complementary & Integrat Hlth, 10 Ctr Dr,CRC Room 4-1630, Bethesda, MD 20892 USA. EM chantal.villemure@nih.gov OI CEKO, MARTA/0000-0001-8679-8145 FU Intramural Research Program of the NIH, National Center for Complementary and Alternative Medicine FX This research was supported in part by the Intramural Research Program of the NIH, National Center for Complementary and Alternative Medicine. We thank the team at the McConnell Brain Imaging Centre of the Montreal Neurological Institute for expert MRI data acquisition. NR 67 TC 4 Z9 4 U1 7 U2 30 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 MAY 12 PY 2015 VL 9 AR UNSP 281 DI 10.3389/fnhum.2015.00281 PG 12 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA CK2BS UT WOS:000356014900001 PM 26029093 ER PT J AU Lubitz, SA Yin, XY Rienstra, M Schnabel, RB Walkey, AJ Magnani, JW Rahman, F McManus, DD Tadros, TM Levy, D Vasan, RS Larson, MG Ellinor, PT Benjamin, EJ AF Lubitz, Steven A. Yin, Xiaoyan Rienstra, Michiel Schnabel, Renate B. Walkey, Allan J. Magnani, Jared W. Rahman, Faisal McManus, David D. Tadros, Thomas M. Levy, Daniel Vasan, Ramachandran S. Larson, Martin G. Ellinor, Patrick T. Benjamin, Emelia J. TI Long-Term Outcomes of Secondary Atrial Fibrillation in the Community The Framingham Heart Study SO CIRCULATION LA English DT Article DE atrial fibrillation; atrial flutter; epidemiology; heart failure; risk factors; stroke ID FOLLOW-UP; CARDIAC-SURGERY; MYOCARDIAL-INFARCTION; RISK SCORE; ONSET; POPULATION; FAILURE; STROKE; RECURRENCE; MANAGEMENT AB Background-Guidelines have proposed that atrial fibrillation (AF) can occur as an isolated event, particularly when precipitated by a secondary, or reversible, condition. However, knowledge of long-term AF outcomes after diagnosis during a secondary precipitant is limited. Methods and Results-In 1409 Framingham Heart Study participants with new-onset AF, we examined associations between first-detected AF episodes occurring with and without a secondary precipitant and both long-term AF recurrence and morbidity. We selected secondary precipitants based on guidelines (surgery, infection, acute myocardial infarction, thyrotoxicosis, acute alcohol consumption, acute pericardial disease, pulmonary embolism, or other acute pulmonary disease). Among 439 patients (31%) with AF diagnosed during a secondary precipitant, cardiothoracic surgery (n=131 [30%]), infection (n=102 [23%]), noncardiothoracic surgery (n=87 [20%]), and acute myocardial infarction (n=78 [18%]) were most common. AF recurred in 544 of 846 eligible individuals without permanent AF (5-, 10-, and 15-year recurrences of 42%, 56%, and 62% with versus 59%, 69%, and 71% without secondary precipitants; multivariable-adjusted hazard ratio, 0.65 [95% confidence interval, 0.54-0.78]). Stroke risk (n=209/1262 at risk; hazard ratio, 1.13 [95% confidence interval, 0.82-1.57]) and mortality (n=1098/1409 at risk; hazard ratio, 1.00 [95% confidence interval, 0.87-1.15]) were similar between those with and without secondary precipitants, although heart failure risk was reduced (n=294/1107 at risk; hazard ratio, 0.74 [95% confidence interval, 0.56-0.97]). Conclusions-AF recurs in most individuals, including those diagnosed with secondary precipitants. Long-term AF-related stroke and mortality risks were similar between individuals with and without secondary AF precipitants. Future studies may determine whether increased arrhythmia surveillance or adherence to general AF management principles in patients with reversible AF precipitants will reduce morbidity. C1 [Lubitz, Steven A.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Lubitz, Steven A.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Yin, Xiaoyan; Magnani, Jared W.; Levy, Daniel; Vasan, Ramachandran S.; Larson, Martin G.; Benjamin, Emelia J.] Boston Univ, Framingham, MA USA. [Yin, Xiaoyan; Magnani, Jared W.; Levy, Daniel; Vasan, Ramachandran S.; Larson, Martin G.; Benjamin, Emelia J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Rienstra, Michiel] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9700 AB Groningen, Netherlands. [Schnabel, Renate B.] Univ Med Ctr Hamburg Eppendorf, Dept Gen & Intervent Cardiol, Hamburg, Germany. [Walkey, Allan J.] Boston Univ, Sch Med, Dept Med, Ctr Pulm, Framingham, MA USA. [Walkey, Allan J.] Boston Univ, Sch Med, Dept Med, Sect Pulm & Crit Care Med, Framingham, MA USA. [Magnani, Jared W.; Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Sect Cardiovasc Med, Framingham, MA USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Sect Prevent Med, Framingham, MA USA. [Rahman, Faisal] Boston Univ, Med Ctr, Dept Med, Framingham, MA USA. [McManus, David D.] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA USA. [McManus, David D.] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Worcester, MA USA. [Tadros, Thomas M.] Sutter Med Grp, Sacramento, CA USA. [Levy, Daniel] NHLBI, Populat Sci Branch, Bethesda, MD 20892 USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Framingham, MA USA. [Larson, Martin G.] Boston Univ, Sch Publ Hlth, Dept Biostat, Framingham, MA USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Framingham, MA USA. RP Lubitz, SA (reprint author), Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, 55 Fruit St,GRB 109, Boston, MA 02114 USA. EM slubitz@mgh.harvard.edu OI Walkey, Allan/0000-0003-4685-6894; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336; Rienstra, Michiel/0000-0002-2581-070X FU National Institutes of Health [K23HL114724, N01-HC-25195, 6R01-NS17950, 2R01HL092577, 1R01 HL102214, R01HL104156, K24HL105780, 1U01HL105268-01, KL2RR031981, K01HL116768]; Doris Duke Charitable Foundation Clinical Scientist Development Award [2014105]; American Heart Association Established Investigator Award [13EIA14220013]; Netherlands Organization for Scientific Research (Veni grant) [016.136.055]; Department of Defense [W81XWH-12-FEST-IIA] FX This work was supported by National Institutes of Health grants K23HL114724 (to Dr Lubitz); N01-HC-25195, 6R01-NS17950, and 2R01HL092577 (to Drs Ellinor and Benjamin); 1R01 HL102214 (to Dr Benjamin), and R01HL104156 and K24HL105780 (to Dr Ellinor); a Doris Duke Charitable Foundation Clinical Scientist Development Award 2014105 (to Dr Lubitz); and an American Heart Association Established Investigator Award 13EIA14220013 (to Dr Ellinor). Dr Rienstra is supported by a grant from the Netherlands Organization for Scientific Research (Veni grant 016.136.055). Partial salary support is additionally provided by National Institutes of Health grants 1U01HL105268-01 and KL2RR031981 and Department of Defense grant W81XWH-12-FEST-IIA (to Dr McManus), as well as National Institutes of Health grant K01HL116768 (to Dr Walkey). NR 52 TC 8 Z9 9 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAY 12 PY 2015 VL 131 IS 19 BP 1648 EP U82 DI 10.1161/CIRCULATIONAHA.114.014058 PG 16 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CH7JT UT WOS:000354213000010 PM 25769640 ER PT J AU Rosendorff, C Lackland, DT Allison, M Aronow, WS Black, HR Blumenthal, RS Cannon, CP de Lemos, JA Elliott, WJ Findeiss, L Gersh, BJ Gore, JM Levy, D Long, JB O'Connor, CM O'Gara, PT Ogedegbe, G Oparil, S White, WB AF Rosendorff, Clive Lackland, Daniel T. Allison, Matthew Aronow, Wilbert S. Black, Henry R. Blumenthal, Roger S. Cannon, Christopher P. de Lemos, James A. Elliott, William J. Findeiss, Laura Gersh, Bernard J. Gore, Joel M. Levy, Daniel Long, Janet B. O'Connor, Christopher M. O'Gara, Patrick T. Ogedegbe, Gbenga Oparil, Suzanne White, William B. CA Amer Heart Assoc Amer Coll Cardiology Amer Soc Hypertension TI Treatment of Hypertension in Patients With Coronary Artery Disease A Scientific Statement From the American Heart Association, American College of Cardiology, and American Society of Hypertension SO CIRCULATION LA English DT Editorial Material DE AHA Scientific Statements; blood pressure; coronary artery disease; epidemiology; hypertension; secondary prevention ID ACUTE MYOCARDIAL-INFARCTION; RANDOMIZED CONTROLLED-TRIAL; CONVERTING-ENZYME-INHIBITORS; LEFT-VENTRICULAR HYPERTROPHY; HIGH BLOOD-PRESSURE; ISOLATED SYSTOLIC HYPERTENSION; LIPID-LOWERING TREATMENT; HIGH-RISK PATIENTS; ANGIOTENSIN-RECEPTOR BLOCKER; PRESERVED EJECTION FRACTION C1 [Rosendorff, Clive; Lackland, Daniel T.; Allison, Matthew; Aronow, Wilbert S.; Black, Henry R.; Blumenthal, Roger S.; Cannon, Christopher P.; de Lemos, James A.; Elliott, William J.; Findeiss, Laura; Gersh, Bernard J.; Gore, Joel M.; Levy, Daniel; Long, Janet B.; O'Connor, Christopher M.; O'Gara, Patrick T.; Ogedegbe, Gbenga; Oparil, Suzanne; White, William B.; Amer Heart Assoc; Amer Coll Cardiology; Amer Soc Hypertension] NHLBI, NIH, Bethesda, MD 20824 USA. RP Rosendorff, C (reprint author), NHLBI, NIH, Bethesda, MD 20824 USA. OI Allison, Matthew/0000-0003-0777-8272 NR 284 TC 14 Z9 16 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAY 12 PY 2015 VL 131 IS 19 BP E435 EP E470 DI 10.1161/CIR.0000000000000207 PG 36 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CH7JT UT WOS:000354213000002 PM 25829340 ER PT J AU Delis, F Rombola, C Bellezza, R Rosko, L Grandy, DK Volkow, ND Thanos, PK AF Delis, Foteini Rombola, Christina Bellezza, Robert Rosko, Lauren Grandy, David K. Volkow, Nora D. Thanos, Panayotis K. TI Regulation of ethanol intake under chronic mild stress: roles of dopamine receptors and transporters SO FRONTIERS IN BEHAVIORAL NEUROSCIENCE LA English DT Article DE dopamine transporter; D2 receptor; D1 receptor; chronic mild stress; ethanol ID REWARD DEFICIENCY SYNDROME; CONDITIONED PLACE PREFERENCE; MICE LACKING DOPAMINE-D-2; ALCOHOL-PREFERRING RATS; NUCLEUS-ACCUMBENS; D2 RECEPTOR; KNOCKOUT MICE; IN-VIVO; GENETIC INFLUENCES; NOVELTY SEEKING AB Studies have shown that exposure to chronic mild stress decreases ethanol intake and preference in dopamine D2 receptor wild-type mice (Drd2(+/+)), while it increases intake in heterozygous (Drd2(+/-)) and knockout (Drd2(-/-)) mice. Dopaminergic neurotransmission in the basal forebrain plays a major role in the reinforcing actions of ethanol as well as in brain responses to stress. In order to identify neurochemical changes associated with the regulation of ethanol intake, we used in vitro receptor autoradiography to measure the levels and distribution of dopamine D1 and D2 receptors and dopamine transporters (DAT). Receptor levels were measured in the basal forebrain of Drd2(+/+), Drd2(+/-), and Drd2(-/-) mice belonging to one of four groups: control (C), ethanol intake (E), chronic mild stress exposure (S), and ethanol intake under chronic mild stress (ES). D2 receptor levels were higher in the lateral and medial striatum of Drd2(+/+) ES mice, compared with Drd2(+/+) E mice. Ethanol intake in Drd2(+/+) mice was negatively correlated with striatal D2 receptor levels. D2 receptor levels in Drd2(+/-) mice were the same among the four treatment groups. DAT levels were lower in Drd2(+/-) C and Drd2(-/-) C mice, compared with Drd2(+/+) C mice. Among Drd2(+/-) mice, S and ES groups had higher DAT levels compared with C and E groups in most regions examined. In Drd2(-/-) mice, ethanol intake was positively correlated with DAT levels in all regions studied. D1 receptor levels were lower in Drd2(+/-) and Drd2(-/-) mice, compared with Drd2(+/+), in all regions examined and remained unaffected by all treatments. The results suggest that in normal mice, ethanol intake is associated with D2 receptor-mediated neurotransmission, which exerts a protective effect against ethanol overconsumption under stress. In mice with low Drd2 expression, where DRD2 levels are not further modulated, ethanol intake is associated with DAT function which is upregulated under stress leading to ethanol overconsumption. C1 [Delis, Foteini; Rombola, Christina; Bellezza, Robert; Rosko, Lauren; Thanos, Panayotis K.] SUNY Stony Brook, Dept Psychol, Stony Brook, NY 11794 USA. [Grandy, David K.] Oregon Hlth & Sci Univ, Sch Med, Dept Physiol & Pharmacol, Portland, OR 97201 USA. [Volkow, Nora D.] NIAAA, Lab Neuroimaging, Bethesda, MD USA. RP Thanos, PK (reprint author), SUNY Stony Brook, Dept Psychol, Psychol B 131, Stony Brook, NY 11794 USA. EM peter.thanos@stonybrook.edu FU NIAA [AA11034, AA07574, AA07611] FX (NIAA)AA11034, AA07574, AA07611. NR 81 TC 0 Z9 0 U1 0 U2 4 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5153 J9 FRONT BEHAV NEUROSCI JI Front. Behav. Neurosci. PD MAY 12 PY 2015 VL 9 AR 118 DI 10.3389/fnbeh.2015.00118 PG 11 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA CI2JH UT WOS:000354572500001 PM 26029066 ER PT J AU Dyda, F Hickman, AB AF Dyda, Fred Hickman, Alison B. TI Mechanism of spacer integration links the CRISPR/Cas system to transposition as a form of mobile DNA SO MOBILE DNA LA English DT Article DE CRISPR/Cas; Adaptive immunity; Cas1 nuclease protein; DNA transposition; Integrase ID CAS ADAPTIVE IMMUNITY; ACQUISITION; SUPERFAMILY AB It has recently become clear that many bacterial and archaeal species possess adaptive immune systems. These are typified by multiple copies of DNA sequences known as clustered regularly interspaced short palindromic repeats (CRISPRs). These CRISPR repeats are the sites at which short spacers containing sequences of previously encountered foreign DNA are integrated, and the spacers serve as the molecular memory of previous invaders. In vivo work has demonstrated that two CRISPR-associated proteins - Cas1 and Cas2 - are required for spacer integration, but the mechanism by which this is accomplished remained unclear. Here we review a recent paper describing the in vitro reconstitution of CRISPR spacer integration using purified Cas1 and Cas2 and place the results in context of similar DNA transposition reactions and the crystal structure of the Cas1/Cas2 complex. C1 [Dyda, Fred; Hickman, Alison B.] Natl Inst Diabet & Digest & Kidney Dis, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Dyda, F (reprint author), Natl Inst Diabet & Digest & Kidney Dis, Mol Biol Lab, NIH, 5 Ctr Dr, Bethesda, MD 20892 USA. EM Fred.Dyda@nih.gov FU Intramural Research Program of the NIH, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) FX This work was supported by the Intramural Research Program of the NIH, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). NR 12 TC 0 Z9 0 U1 3 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1759-8753 J9 MOBILE DNA-UK JI Mob. DNA PD MAY 12 PY 2015 VL 6 AR 9 DI 10.1186/s13100-015-0039-3 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA CI7GB UT WOS:000354929900001 PM 27408625 ER PT J AU Sico, JJ Chang, CCH So-Armah, K Justice, AC Hylek, E Skanderson, M McGinnis, K Kuller, LH Kraemer, KL Rimland, D Goetz, MB Butt, AA Rodriguez-Barradas, MC Gibert, C Leaf, D Brown, ST Samet, J Kazis, L Bryant, K Freiberg, MS AF Sico, Jason J. Chang, Chung-Chou H. So-Armah, Kaku Justice, Amy C. Hylek, Elaine Skanderson, Melissa McGinnis, Kathleen Kuller, Lewis H. Kraemer, Kevin L. Rimland, David Goetz, Matthew Bidwell Butt, Adeel A. Rodriguez-Barradas, Maria C. Gibert, Cynthia Leaf, David Brown, Sheldon T. Samet, Jeffrey Kazis, Lewis Bryant, Kendall Freiberg, Matthew S. CA Vet Aging Cohort Study TI HIV status and the risk of ischemic stroke among men SO NEUROLOGY LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; CEREBROVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; ADMINISTRATIVE DATA; INFECTED PATIENTS; HEPATITIS-C; CARE; VETERANS; AIDS; PREVENTION AB Objective:Given conflicting data regarding the association of HIV infection and ischemic stroke risk, we sought to determine whether HIV infection conferred an increased ischemic stroke risk among male veterans.Methods:The Veterans Aging Cohort Study-Virtual Cohort consists of HIV-infected and uninfected veterans in care matched (1:2) for age, sex, race/ethnicity, and clinical site. We analyzed data on 76,835 male participants in the Veterans Aging Cohort Study-Virtual Cohort who were free of baseline cardiovascular disease. We assessed demographics, ischemic stroke risk factors, comorbid diseases, substance use, HIV biomarkers, and incidence of ischemic stroke from October 1, 2003, to December 31, 2009.Results:During a median follow-up period of 5.9 (interquartile range 3.5-6.6) years, there were 910 stroke events (37.4% HIV-infected). Ischemic stroke rates per 1,000 person-years were higher for HIV-infected (2.79, 95% confidence interval 2.51-3.10) than for uninfected veterans (2.24 [2.06-2.43]) (incidence rate ratio 1.25 [1.09-1.43]; p < 0.01). After adjusting for demographics, ischemic stroke risk factors, comorbid diseases, and substance use, the risk of ischemic stroke was higher among male veterans with HIV infection compared with uninfected veterans (hazard ratio 1.17 [1.01-1.36]; p = 0.04).Conclusions:HIV infection is associated with an increased ischemic stroke risk among HIV-infected compared with demographically and behaviorally similar uninfected male veterans. C1 [Sico, Jason J.; Justice, Amy C.; Skanderson, Melissa; McGinnis, Kathleen] West Haven Vet Adm Med Ctr, VA Connecticut Hlth Care Syst, West Haven, CT 06516 USA. [Sico, Jason J.; So-Armah, Kaku; Justice, Amy C.] Yale Univ, Sch Med, New Haven, CT USA. [Chang, Chung-Chou H.; Kraemer, Kevin L.; Butt, Adeel A.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Chang, Chung-Chou H.; Kuller, Lewis H.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Hylek, Elaine] Boston Med Ctr, Boston, MA USA. [Rimland, David] Emory Univ, Sch Med, Atlanta, GA USA. [Rimland, David] Atlanta Vet Adm Med Ctr, Atlanta, GA USA. [Goetz, Matthew Bidwell; Leaf, David] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Goetz, Matthew Bidwell; Leaf, David] VA Greater Los Angeles Hlth Care Syst, Los Angeles, CA USA. [Butt, Adeel A.] VA Pittsburgh Hlth Care Syst, Pittsburgh, PA USA. [Rodriguez-Barradas, Maria C.] Michael E DeBakey Vet Adm Med Ctr, Houston, TX USA. [Rodriguez-Barradas, Maria C.] Baylor Coll Med, Houston, TX 77030 USA. [Gibert, Cynthia] Washington DC Vet Adm Med Ctr, Washington, DC USA. [Gibert, Cynthia] George Washington Univ, Sch Med, Washington, DC USA. [Brown, Sheldon T.] James J Peters VA, Bronx, NY USA. [Brown, Sheldon T.] Mt Sinai Sch Med, New York, NY USA. [Samet, Jeffrey] Boston Univ, Sch Med, Boston, MA 02215 USA. [Kazis, Lewis] Boston Univ, Ctr Assessment Pharmaceut Practices, Dept Hlth Policy & Management, Sch Publ Hlth, Boston, MA 02215 USA. [Kazis, Lewis] Vet Adm Med Ctr, Ctr Healthcare Org & Implementat Res, Bedford, MA USA. [Bryant, Kendall] NIAAA, Bethesda, MD USA. [Freiberg, Matthew S.] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Freiberg, Matthew S.] Nashville Vet Affairs Med Ctr, Nashville, TN USA. RP Sico, JJ (reprint author), West Haven Vet Adm Med Ctr, VA Connecticut Hlth Care Syst, West Haven, CT 06516 USA. EM jason.sico@va.gov OI Butt, Adeel/0000-0002-1118-1826; Goetz, Matthew/0000-0003-4542-992X; Justice, Amy/0000-0003-0139-5502 FU NIH, National Institute on Alcohol Abuse and Alcoholism [5U10AA013566-10]; NIH, National Heart Lung and Blood Institute [R01 HL095136-05]; Department of Veteran Affairs Health Services Research and Development [11-262] FX Research funding was made possible by the NIH, National Institute on Alcohol Abuse and Alcoholism (grant 5U10AA013566-10); NIH, National Heart Lung and Blood Institute (grant R01 HL095136-05); and Department of Veteran Affairs Health Services Research and Development (grant 11-262). The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veteran Affairs. No conflicts of interest are reported. NR 34 TC 24 Z9 24 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD MAY 12 PY 2015 VL 84 IS 19 BP 1933 EP 1940 DI 10.1212/WNL.0000000000001560 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA CI2BY UT WOS:000354550900009 PM 25862803 ER PT J AU Mmbando, BP Mgaya, J Cox, SE Mtatiro, SN Soka, D Rwezaula, S Meda, E Msaki, E Snow, RW Jeffries, N Geller, NL Makani, J AF Mmbando, Bruno P. Mgaya, Josephine Cox, Sharon E. Mtatiro, Siana N. Soka, Deogratias Rwezaula, Stella Meda, Elineema Msaki, Evarist Snow, Robert W. Jeffries, Neal Geller, Nancy L. Makani, Julie TI Negative Epistasis between Sickle and Foetal Haemoglobin Suggests a Reduction in Protection against Malaria SO PLOS ONE LA English DT Article ID CELL TRAIT; RISK-FACTORS; GENE; MORTALITY; EXPLAIN; GLOBIN AB Background Haemoglobin variants, Sickle (HbS) and foetal (HbF) have been associated with malaria protection. This study explores epistatic interactions between HbS and HbF on malaria infection. Methods The study was conducted between March 2004 and December 2013 within the sickle cell disease (SCD) programme at Muhimbili National Hospital, Tanzania. SCD status was categorized into HbAA, HbAS and HbSS using hemoglobin electrophoresis and High Performance Liquid Chromatography (HPLC). HbF levels were determined by HPLC. Malaria was diagnosed using rapid diagnostic test and/or blood film. Logistic regression and generalized estimating equations models were used to evaluate associations between SCD status, HbF and malaria. Findings 2,049 individuals with age range 0-70 years, HbAA 311(15.2%), HbAS 241(11.8%) and HbSS 1,497(73.1%) were analysed. At enrolment, malaria prevalence was significantly higher in HbAA 13.2% compared to HbAS 1.24% and HbSS 1.34% (p<0.001). Mean HbF was lower in those with malaria compared to those without malaria in HbAA (0.43% vs 0.82%) but was the reverse in HbSS (8.10% vs 5.59%). An increase in HbF was associated with a decrease in risk of malaria OR=0.50 (95% CI: 0.28, 0.90; p=0.021) in HbAA, whereas for HbSS the risk of malaria increased OR= 2.94 (1.44, 5.98; p=0.003). A similar pattern was seen during multiple visits; HbAA OR= 0.52 (0.34, 0.80; p=0.003) vs HbSS OR= 2.01 (1.27, 3.23; p=0.003). Conclusion Higher prevalence of malaria in HbAA compared to HbAS and HbSS confirmed the protective effect of HbS. Lower prevalence of malaria in HbAA with high HbF supports a protective effect of HbF. However, in HbSS, the higher prevalence of malaria with high levels of HbF suggests loss of malaria protection. This is the first epidemiological study to suggest a negative epistasis between HbF and HbS on malaria. C1 [Mmbando, Bruno P.; Mgaya, Josephine; Cox, Sharon E.; Mtatiro, Siana N.; Soka, Deogratias; Msaki, Evarist; Makani, Julie] Muhimbili Univ Hlth & Allied Sci, Dar Es Salaam, Tanzania. [Mmbando, Bruno P.] Natl Inst Med Res, Tanga, Tanzania. [Cox, Sharon E.] London Sch Hyg & Trop Med, London WC1, England. [Rwezaula, Stella; Meda, Elineema] Muhimbili Natl Hosp, Dar Es Salaam, Tanzania. [Snow, Robert W.] KEMRI Wellcome Trust Programme, Nairobi, Kenya. [Snow, Robert W.; Makani, Julie] Univ Oxford, Oxford, England. [Jeffries, Neal; Geller, Nancy L.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Mmbando, BP (reprint author), Muhimbili Univ Hlth & Allied Sci, Dar Es Salaam, Tanzania. EM bmmbando@muhimbili-wellcome.org OI Snow, Robert/0000-0003-3725-6088; Cox, Sharon/0000-0002-9908-2936 FU Wellcome Trust [080025, 084538, 079080, 103602]; NIH [4U41HG006941-02] FX This study was supported by Wellcome Trust (Project grant 080025; Strategic award 084538) to J. Makani (http://www.wellcome.ac.uk). B.P. Mmbando was supported by NIH through H3Africa (4U41HG006941-02, http://h3africa.org/). R.W. Snow is supported by The Wellcome Trust as a Principal Fellow (079080 & 103602, http://www.wellcome.ac.uk). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 21 TC 2 Z9 2 U1 1 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 12 PY 2015 VL 10 IS 5 AR e0125929 DI 10.1371/journal.pone.0125929 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CI1ZI UT WOS:000354543500034 PM 25965586 ER PT J AU Byrne, RT Jenkins, HT Peters, DT Whelan, F Stowell, J Aziz, N Kasatsky, P Rodnina, MV Koonin, EV Konevega, AL Antson, AA AF Byrne, Robert T. Jenkins, Huw T. Peters, Daniel T. Whelan, Fiona Stowell, James Aziz, Naveed Kasatsky, Pavel Rodnina, Marina V. Koonin, Eugene V. Konevega, Andrey L. Antson, Alfred A. TI Major reorientation of tRNA substrates defines specificity of dihydrouridine synthases SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE dihydrouridine synthase; tRNA modification; protein-RNA interaction; substrate specificity; X-ray crystallography ID CRYSTAL-STRUCTURE; PSEUDOURIDINE SYNTHASE; GUANINE TRANSGLYCOSYLASE; PROTEIN; IDENTIFICATION; RECOGNITION; SOFTWARE; COMPLEX; FAMILY; ENZYME AB The reduction of specific uridines to dihydrouridine is one of the most common modifications in tRNA. Increased levels of the dihydrouridine modification are associated with cancer. Dihydrouridine synthases (Dus) from different subfamilies selectively reduce distinct uridines, located at spatially unique positions of folded tRNA, into dihydrouridine. Because the catalytic center of all Dus enzymes is conserved, it is unclear how the same protein fold can be reprogrammed to ensure that nucleotides exposed at spatially distinct faces of tRNA can be accommodated in the same active site. We show that the Escherichia coli DusC is specific toward U16 of tRNA. Unexpectedly, crystal structures of DusC complexes with tRNA(Phe) and tRNA(Trp) show that Dus subfamilies that selectively modify U16 or U20 in tRNA adopt identical folds but bind their respective tRNA substrates in an almost reverse orientation that differs by a 160 degrees rotation. The tRNA docking orientation appears to be guided by subfamily-specific clusters of amino acids ("binding signatures") together with differences in the shape of the positively charged tRNA-binding surfaces. tRNA orientations are further constrained by positional differences between the C-terminal "recognition" domains. The exquisite substrate specificity of Dus enzymes is therefore controlled by a relatively simple mechanism involving major reorientation of the whole tRNA molecule. Such reprogramming of the enzymatic specificity appears to be a unique evolutionary solution for altering tRNA recognition by the same protein fold. C1 [Byrne, Robert T.; Jenkins, Huw T.; Peters, Daniel T.; Whelan, Fiona; Stowell, James; Antson, Alfred A.] Univ York, Dept Chem, York Struct Biol Lab, York YO10 5DD, N Yorkshire, England. [Stowell, James; Aziz, Naveed] Univ York, Dept Biol, York YO10 5DD, N Yorkshire, England. [Aziz, Naveed] Genome Canada, Ottawa, ON K2P 1P1, Canada. [Kasatsky, Pavel; Konevega, Andrey L.] Kurchatov Inst, Natl Res Ctr, BP Konstantinov Nucl Phys Inst, Mol & Radiat Biophys Dept, Gatchina 188300, Russia. [Kasatsky, Pavel; Konevega, Andrey L.] St Petersburg State Polytech Univ, St Petersburg 195251, Russia. [Rodnina, Marina V.; Konevega, Andrey L.] Max Planck Inst Biophys Chem, Dept Phys Biochem, D-37077 Gottingen, Germany. [Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Antson, AA (reprint author), Univ York, Dept Chem, York Struct Biol Lab, York YO10 5DD, N Yorkshire, England. EM fred.antson@york.ac.uk RI Jenkins, Huw/E-1094-2011; Antson, Alfred/N-2551-2016; Konevega, Andrey/B-7887-2008; OI Jenkins, Huw/0000-0002-3302-6966; Antson, Alfred/0000-0002-4533-3816; Whelan, Fiona/0000-0002-0791-6850 FU Wellcome Trust Fellowship [098230]; Biotechnology and Biological Sciences Research Council PhD studentship; Russian Science Foundation [14-34-00023]; US Department of Health and Human Services; Max Planck Society FX The authors thank Ralf Flaig (Diamond Light Source), Gideon Grogan, Sam Hart, Johan Turkenburg, Celina Whalley (University of York), Robert Nicholls (Medical Research Council Laboratory of Molecular Biology), and David Waterman (Science and Technology Facilities Council) for assistance and useful discussions. We thank Diamond Light Source for access to beamlines I02, I04, and I24 (under Proposals MX1221, MX7864, and MX9948), which contributed to the results presented here. This work was funded by Wellcome Trust Fellowship 098230 (to A.A.A.), a Biotechnology and Biological Sciences Research Council PhD studentship (to R.T.B.), and Russian Science Foundation Grant 14-34-00023 (to A.L.K.). E.V.K. is supported by intramural funds of the US Department of Health and Human Services (to the National Library of Medicine). M.V.R. is supported by funding from the Max Planck Society. NR 36 TC 5 Z9 10 U1 1 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 MAY 12 PY 2015 VL 112 IS 19 BP 6033 EP 6037 DI 10.1073/pnas.1500161112 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CH9XS UT WOS:000354390600058 PM 25902496 ER PT J AU Park, JH Kang, HJ Lee, YK Kang, H Kim, J Chung, JH Chang, JS McPherron, AC Lee, SB AF Park, Jun Hong Kang, Hong-Jun Lee, Yun Kyung Kang, Hyeog Kim, Jihyun Chung, Jay H. Chang, Ji Suk McPherron, Alexandra C. Lee, Sean Bong TI Inactivation of EWS reduces PGC-1 alpha protein stability and mitochondrial homeostasis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE EWS; PGC-1alpha; protein stability; mitochondria homeostasis; energy metabolism ID AMYOTROPHIC-LATERAL-SCLEROSIS; SARCOMA GENE EWS; GAMMA COACTIVATOR 1-ALPHA; RNA-POLYMERASE-II; TRANSCRIPTIONAL COACTIVATOR; MULTIFUNCTIONAL PROTEIN; HEPATIC GLUCONEOGENESIS; ENERGY-METABOLISM; BINDING PROTEIN; MUTATIONS AB EWS (Ewing sarcoma) encodes an RNA/ssDNA binding protein that is frequently rearranged in a number of different cancers by chromosomal translocations. Physiologically, EWS has diverse and essential roles in various organ development and cellular processes. In this study, we uncovered a new role of EWS in mitochondrial homeostasis and energy metabolism. Loss of EWS leads to a significant decrease in mitochondria abundance and activity, which is caused by a rapid degradation of Peroxisome proliferator-activated receptor. Coactivator (PGC-1 alpha), a central regulator of mitochondria biogenesis, function, and cellular energy metabolism. EWS inactivation leads to increased ubiquitination and proteolysis of PGC-1 alpha via proteasome pathway. Complementation of EWS in Ews-deficient cells restores PGC-1 alpha and mitochondrial abundance. We found that expression of E3 ubiquitin ligase, FBXW7 (F-box/WD40 domain protein 7), is increased in the absence of Ews and depletion of Fbxw7 in Ews-null cells restores PGC-1 alpha expression and mitochondrial density. Consistent with these findings, mitochondrial abundance and activity are significantly reduced in brown fat and skeletal muscles of Ews-deficient mice. Furthermore, expression of mitochondrial biogenesis, respiration and fatty acid beta-oxidation genes is significantly reduced in the liver of Ews-null mice. These results demonstrate a novel role of EWS in mitochondrial and cellular energy homeostasis by controlling PGC-1 alpha protein stability, and further implicate altered mitochondrial and energy metabolism in cancers harboring the EWS translocation. C1 [Park, Jun Hong; Kang, Hong-Jun; Lee, Sean Bong] Tulane Univ, Sch Med, Dept Pathol & Lab Med, New Orleans, LA 70112 USA. [Lee, Yun Kyung] NIDDK, Mol Endocrinol Branch, NIH, Bethesda, MD 20892 USA. [Kang, Hyeog; Chung, Jay H.] NHLBI, Lab Obes & Aging Res, NIH, Bethesda, MD 20892 USA. [Kim, Jihyun; Chang, Ji Suk] Pennington Biomed Res Ctr, Lab Gene Regulat & Metab, Baton Rouge, LA 70808 USA. [McPherron, Alexandra C.] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Lee, SB (reprint author), Tulane Univ, Sch Med, Dept Pathol & Lab Med, 1430 Tulane Ave, New Orleans, LA 70112 USA. EM slee30@tulane.edu FU Tulane Startup Fund FX We thank Jan Endlich (JFE Enterprises) for transmission electron microscopy, Yun-Ping Wu (National Institute of Diabetes and Digestive and Kidney Diseases, NIDDK) for confocal microscopy, Yihong Ye (NIDDK) for Ubiquitin antibody, Mary Price (Tulane Cancer Center) for flow cytometry, and Thomas Gettys (Pennington Biomedical Research Center) for the 4C1.3 PGC-1 alpha antibody. We thank Richard L. Proia and Elisabetta Mueller (NIDDK) for helpful comments and discussions. This work was supported by the Tulane Startup Fund (S.B.L.). NR 46 TC 3 Z9 4 U1 0 U2 2 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 MAY 12 PY 2015 VL 112 IS 19 BP 6074 EP 6079 DI 10.1073/pnas.1504391112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CH9XS UT WOS:000354390600065 PM 25918410 ER PT J AU Han, TH Dharkar, P Mayer, ML Serpe, M AF Han, Tae Hee Dharkar, Poorva Mayer, Mark L. Serpe, Mihaela TI Functional reconstitution of Drosophila melanogaster NMJ glutamate receptors SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Drosophila; NMJ; Neto; glutamate receptors; crystallography ID NEUROMUSCULAR-JUNCTION; LIGAND-BINDING; ION-CHANNEL; CRYSTAL-STRUCTURES; KAINATE RECEPTORS; CONCANAVALIN-A; AMPA; SUBUNIT; MUSCLE; BLOCK AB The Drosophila larval neuromuscular junction (NMJ), at which glutamate acts as the excitatory neurotransmitter, is a widely used model for genetic analysis of synapse function and development. Despite decades of study, the inability to reconstitute NMJ glutamate receptor function using heterologous expression systems has complicated the analysis of receptor function, such that it is difficult to resolve the molecular basis for compound phenotypes observed in mutant flies. We find that Drosophila Neto functions as an essential component required for the function of NMJ glutamate receptors, permitting analysis of glutamate receptor responses in Xenopus oocytes. In combination with a crystallographic analysis of the GluRIIB ligand binding domain, we use this system to characterize the subunit dependence of assembly, channel block, and ligand selectivity for Drosophila NMJ glutamate receptors. C1 [Han, Tae Hee; Serpe, Mihaela] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Cellular Regulat & Metab, NIH, Bethesda, MD 20892 USA. [Dharkar, Poorva; Mayer, Mark L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Cellular & Mol Neurophysiol, NIH, Bethesda, MD 20892 USA. RP Mayer, ML (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Cellular & Mol Neurophysiol, NIH, Bethesda, MD 20892 USA. EM mayerm@mail.nih.gov; mihaela.serpe@nih.gov FU US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; Intramural Research Program of The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services FX We thank Carla Glasser and Peter Nguyen for technical assistance; Aaron DiAntonio (Washington University) for the GluRIIB plasmid; Susumu Tomita (Yale University) for the HA-tagged GluK2 plasmid; and Prof. Koji Nakanishi (Columbia University) for the gift of argiotoxin. Data were collected at Southeast Regional Collaborative Access Team 22-ID beamline at the Advanced Photon Source, Argonne National Laboratory. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract W-31-109-Eng-38. This work was supported by the Intramural Research Program of The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services. NR 49 TC 4 Z9 4 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 12 PY 2015 VL 112 IS 19 BP 6182 EP 6187 DI 10.1073/pnas.1500458112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CH9XS UT WOS:000354390600083 PM 25918369 ER PT J AU Skau, CT Plotnikov, SV Doyle, AD Waterman, CM AF Skau, Colleen T. Plotnikov, Sergey V. Doyle, Andrew D. Waterman, Clare M. TI Inverted formin 2 in focal adhesions promotes dorsal stress fiber and fibrillar adhesion formation to drive extracellular matrix assembly SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE INF2; integrin; actin; fluorescence microscopy ID ACTIN POLYMERIZATION; ARP2/3 COMPLEX; CELL-MIGRATION; PAXILLIN PHOSPHORYLATION; REGULATES ACTIN; DYNAMICS; INF2; MATURATION; VINCULIN; FIBROBLASTS AB Actin filaments and integrin-based focal adhesions (FAs) form integrated systems that mediate dynamic cell interactions with their environment or other cells during migration, the immune response, and tissue morphogenesis. How adhesion-associated actin structures obtain their functional specificity is unclear. Here we show that the formin-family actin nucleator, inverted formin 2 (INF2), localizes specifically to FAs and dorsal stress fibers (SFs) in fibroblasts. High-resolution fluorescence microscopy and manipulation of INF2 levels in cells indicate that INF2 plays a critical role at the SF-FA junction by promoting actin polymerization via free barbed end generation and centripetal elongation of an FA-associated actin bundle to form dorsal SF. INF2 assembles into FAs during maturation rather than during their initial generation, and once there, acts to promote rapid FA elongation and maturation into tensin-containing fibrillar FAs in the cell center. We show that INF2 is required for fibroblasts to organize fibronectin into matrix fibers and ultimately 3D matrices. Collectively our results indicate an important role for the formin INF2 in specifying the function of fibrillar FAs through its ability to generate dorsal SFs. Thus, dorsal SFs and fibrillar FAs form a specific class of integrated adhesionassociated actin structure in fibroblasts that mediates generation and remodeling of ECM. C1 [Skau, Colleen T.; Waterman, Clare M.] NHLBI, Cell Biol & Physiol Ctr, Bethesda, MD 20892 USA. [Doyle, Andrew D.] Natl Inst Dent & Craniofacial Res, Cell Biol Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. [Plotnikov, Sergey V.] Univ Toronto, Dept Cell & Syst Biol, Toronto, ON M5S 3G5, Canada. RP Waterman, CM (reprint author), NHLBI, Cell Biol & Physiol Ctr, Bethesda, MD 20892 USA. EM watermancm@nhlbi.nih.gov OI Waterman, Clare/0000-0001-6142-6775 FU Intramural Program of the National Heart, Lung, and Blood Institute, NIH FX The authors thank Dr. Mike Davidson and Dr. Henry Higgs for fluorescent protein constructs; Dr. Benjamin Geiger for the antitensin antibody; Dr. Mary Beckerle for the antizyxin antibody; Dr. Ingo Thievessen and Dr. Robert Fischer for mouse pedagogy and helpful discussion; William Shin for work on the C.M.W. laboratory microscopes; and Schwanna Thacker for administrative assistance. This work is supported by the Intramural Program of the National Heart, Lung, and Blood Institute, NIH. NR 64 TC 11 Z9 11 U1 1 U2 16 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 MAY 12 PY 2015 VL 112 IS 19 BP E2447 EP E2456 DI 10.1073/pnas.1505035112 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CH9XS UT WOS:000354390600010 PM 25918420 ER PT J AU Rosendorff, C Lackland, DT Allison, M Aronow, WS Black, HR Blumenthal, RS Cannon, CP de Lemos, JA Elliott, WJ Findeiss, L Gersh, BJ Gore, JM Levy, D Long, JB O'Connor, CM O'Gara, PT Ogedegbe, O Oparil, S White, WB AF Rosendorff, Clive Lackland, Daniel T. Allison, Matthew Aronow, Wilbert S. Black, Henry R. Blumenthal, Roger S. Cannon, Christopher P. de Lemos, James A. Elliott, William J. Findeiss, Laura Gersh, Bernard J. Gore, Joel M. Levy, Daniel Long, Janet B. O'Connor, Christopher M. O'Gara, Patrick T. Ogedegbe, Olugbenga Oparil, Suzanne White, William B. CA Amer Heart Assoc Amer Coll Cardiology Amer Soc Hypertension TI Treatment of Hypertension in Patients With Coronary Artery Disease SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE ACC Scientific Statements; blood pressure; coronary artery disease; epidemiology; hypertension; secondary prevention ID CHRONIC HEART-FAILURE; ACUTE MYOCARDIAL-INFARCTION; RANDOMIZED CONTROLLED-TRIAL; CONVERTING-ENZYME-INHIBITORS; LEFT-VENTRICULAR HYPERTROPHY; HIGH BLOOD-PRESSURE; ISOLATED SYSTOLIC HYPERTENSION; ASSOCIATION TASK-FORCE; HIGH-RISK PATIENTS; ANGIOTENSIN-RECEPTOR BLOCKER C1 [Rosendorff, Clive] VA Med Ctr, Portland, OR 97239 USA. [Lackland, Daniel T.] Med Univ S Carolina, Charleston, SC USA. [Allison, Matthew] UCSD, La Jolla, CA USA. [Aronow, Wilbert S.] New York Med Coll, Valhalla, NY 10595 USA. [Black, Henry R.; Ogedegbe, Olugbenga] NYU, Sch Med, New York, NY 10003 USA. [Blumenthal, Roger S.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. [Cannon, Christopher P.; O'Gara, Patrick T.] Brigham & Womens Hosp, Boston, MA 02115 USA. [de Lemos, James A.] UT Southwestern, Dallas, TX USA. [Elliott, William J.] Pacific Northwest Univ Hlth Sci, Yakima, WA USA. [Findeiss, Laura] Univ Calif Irvine, Irvine, CA 92717 USA. [Gersh, Bernard J.] Mayo Clin, Rochester, MN USA. [Gore, Joel M.] Univ Massachusetts, Amherst, MA 01003 USA. [Levy, Daniel] NIH, Bethesda, MD USA. [Long, Janet B.] Rhode Isl Cardiol Ctr, Providence, RI USA. [O'Connor, Christopher M.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC 27706 USA. [Oparil, Suzanne] Univ Alabama Birmingham, Birmingham, AL USA. [White, William B.] Univ Connecticut, Sch Med, Storrs, CT USA. RP Rosendorff, C (reprint author), VA Med Ctr, Portland, OR 97239 USA. NR 283 TC 30 Z9 30 U1 1 U2 2 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 MAY 12 PY 2015 VL 65 IS 18 BP 1998 EP 2038 DI 10.1016/j.jacc.2015.02.038 PG 41 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CH4GD UT WOS:000353991000012 PM 25840655 ER PT J AU Adjemian, MK Volpe, RJ Adjemian, J AF Adjemian, Michael K. Volpe, Richard J. Adjemian, Jennifer TI Relationships between Diet, Alcohol Preference, and Heart Disease and Type 2 Diabetes among Americans SO PLOS ONE LA English DT Article ID CARDIOVASCULAR RISK-FACTORS; LIFE-STYLE; INSULIN SENSITIVITY; HEMOSTATIC FACTORS; CROSSOVER TRIAL; SOCIAL-STATUS; US ADULTS; RED WINE; CONSUMPTION; MORTALITY AB Although excessive alcohol consumption is a recognized cause of morbidity and mortality, many studies have linked moderate alcohol consumption to improved cardiovascular health and a lower risk of Type 2 Diabetes (T2D). Self-reported alcohol and diet data used to generate these results suffer from measurement error due to recall bias. We estimate the effects of diet, alcohol, and lifestyle choices on the prevalence and incidence of cardiovascular disease and T2D among U.S. adults using a nationally representative cohort of households with scanner data representing their food-at-home, alcohol, and tobacco purchases from 2007-2010, and self-reported health surveys for the same study participants from 2010-2012. Multivariate regression models were used to identify significant associations among purchase data and lifestyle/demographic factors with disease prevalence in 2010, and with incidence of new disease from 2011-2012. After controlling for important confounders, respondents who purchased moderate levels of wine were 25% less likely than non-drinkers to report heart disease in 2010. However, no alcohol-related expenditure variables significantly affected the likelihood of reporting incident heart disease from 2011-2012. In contrast, many types of alcohol-related purchases were associated with a lower prevalence of T2D, and respondents who purchased the greatest volumes of wine or beer-but not liquor-were less likely to report being diagnosed with T2D in 2011-2012 than non-drinkers. C1 [Adjemian, Michael K.] USDA, Econ Res Serv, Washington, DC 20024 USA. [Volpe, Richard J.] Calif Polytech State Univ San Luis Obispo, Coll Agr Food & Environm Sci, Agribusiness Dept, San Luis Obispo, CA 93407 USA. [Adjemian, Jennifer] NIAID, Epidemiol Unit, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Adjemian, Jennifer] US Publ Hlth Serv Commissioned Corps, Rockville, MD USA. RP Adjemian, MK (reprint author), USDA, Econ Res Serv, Washington, DC 20024 USA. EM MAdjemian@ers.usda.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This research was supported in part by the intramural research program of the 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 44 TC 2 Z9 2 U1 1 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 MAY 11 PY 2015 VL 10 IS 5 AR e0124351 DI 10.1371/journal.pone.0124351 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CI1YY UT WOS:000354542500011 PM 25961601 ER PT J AU Grassmann, F Fleckenstein, M Chew, EY Strunz, T Schmitz-Valckenberg, S Gobel, AP Klein, ML Ratnapriya, R Swaroop, A Holz, FG Weber, BHF AF Grassmann, Felix Fleckenstein, Monika Chew, Emily Y. Strunz, Tobias Schmitz-Valckenberg, Steffen Goebel, Arno P. Klein, Michael L. Ratnapriya, Rinki Swaroop, Anand Holz, Frank G. Weber, Bernhard H. F. TI Clinical and Genetic Factors Associated with Progression of Geographic Atrophy Lesions in Age-Related Macular Degeneration SO PLOS ONE LA English DT Article ID DISEASE PROGRESSION; NATURAL-HISTORY; MESSENGER-RNA; EYE DISEASE; FACTOR-H; COMPLEMENT; RISK; AMD; ARMS2; NEUROGENESIS AB Worldwide, age-related macular degeneration (AMD) is a serious threat to vision loss in individuals over 50 years of age with a pooled prevalence of approximately 9%. For 2020, the number of people afflicted with this condition is estimated to reach 200 million. While AMD lesions presenting as geographic atrophy (GA) show high inter-individual variability, only little is known about prognostic factors. Here, we aimed to elucidate the contribution of clinical, demographic and genetic factors on GA progression. Analyzing the currently largest dataset on GA lesion growth (N = 388), our findings suggest a significant and independent contribution of three factors on GA lesion growth including at least two genetic factors (ARMS2_rs10490924 [P < 0.00088] and C3_rs2230199 [P < 0.00015]) as well as one clinical component (presence of GA in the fellow eye [P < 0.00023]). These correlations jointly explain up to 7.2% of the observed inter-individual variance in GA lesion progression and should be considered in strategy planning of interventional clinical trials aimed at evaluating novel treatment options in advanced GA due to AMD. C1 [Grassmann, Felix; Strunz, Tobias; Weber, Bernhard H. F.] Univ Regensburg, Inst Human Genet, D-93053 Regensburg, Germany. [Fleckenstein, Monika; Schmitz-Valckenberg, Steffen; Goebel, Arno P.; Holz, Frank G.] Univ Bonn, Dept Ophthalmol, D-53127 Bonn, Germany. [Chew, Emily Y.; Ratnapriya, Rinki; Swaroop, Anand] NEI, NIH, Bethesda, MD 20892 USA. [Klein, Michael L.] Oregon Hlth & Sci Univ, Macular Degenerat Ctr, Casey Eye Inst, Portland, OR 97239 USA. [Klein, Michael L.] Devers Eye Inst, Portland, OR 97239 USA. RP Weber, BHF (reprint author), Univ Regensburg, Inst Human Genet, D-93053 Regensburg, Germany. EM bweb@klinik.uni-regensburg.de OI Swaroop, Anand/0000-0002-1975-1141 FU Deutsche Forschungsgemeinschaft [WE 1259/19-2]; Alcon Research Institute; Intramural Research program of the National Eye Institute; National Eye Institute, National Institutes of Health, Bethesda, MD [R01-EY021532] FX This study was supported in parts by the Deutsche Forschungsgemeinschaft (WE 1259/19-2 to BHFW), the Alcon Research Institute (to BHFW, EYC, and AS), the Intramural Research program of the National Eye Institute (EYC and AS), and by grants from the National Eye Institute, National Institutes of Health, Bethesda, MD (R01-EY021532 to MLK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 12 Z9 12 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 11 PY 2015 VL 10 IS 5 AR e0126636 DI 10.1371/journal.pone.0126636 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CI1YY UT WOS:000354542500128 PM 25962167 ER PT J AU Peters, LB Bahr, N Bodenreider, O AF Peters, Lee B. Bahr, Nathan Bodenreider, Olivier TI Evaluating drug-drug interaction information in NDF-RT and DrugBank SO JOURNAL OF BIOMEDICAL SEMANTICS LA English DT Article DE Drug-drug interactions; NDF-RT; DrugBank ID ELECTRONIC HEALTH RECORDS; CLINICAL DECISION-SUPPORT; ORDER AB Background: There is limited consensus among drug information sources on what constitutes drug-drug interactions (DDIs). We investigate DDI information in two publicly available sources, NDF-RT and DrugBank. Methods: We acquire drug-drug interactions from NDF-RT and DrugBank, and normalize the drugs to RxNorm. We compare interactions between NDF-RT and DrugBank and evaluate both sources against a reference list of 360 critical interactions. We compare the interactions detected with NDF-RT and DrugBank on a large prescription dataset. Finally, we contrast NDF-RT and DrugBank against a commercial source. Results: DrugBank drug-drug interaction information has limited overlap with NDF-RT (24-30%). The coverage of the reference set by both sources is about 60%. Applied to a prescription dataset of 35.5M pairs of co-prescribed systemic clinical drugs, NDF-RT would have identified 808,285 interactions, while DrugBank would have identified 1,170,693. Of these, 382,833 are common. The commercial source Multum provides a more systematic coverage (91%) of the reference list. Conclusions: This investigation confirms the limited overlap of DDI information between NDF-RT and DrugBank. Additional research is required to determine which source is better, if any. Usage of any of these sources in clinical decision systems should disclose these limitations. C1 [Peters, Lee B.; Bodenreider, Olivier] Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, NIH, Bethesda, MD 20894 USA. [Bahr, Nathan] Oregon Hlth & Sci Univ, Dept Med Informat & Clin Epidemiol, Portland, OR 97201 USA. RP Bodenreider, O (reprint author), Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, NIH, Bethesda, MD 20894 USA. EM obodenreider@mail.nih.gov FU Intramural Research Program of the NIH, National Library of Medicine FX This work was supported by the Intramural Research Program of the NIH, National Library of Medicine. NR 20 TC 2 Z9 2 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2041-1480 J9 J BIOMED SEMANT JI J. Biomed. Semant. PD MAY 11 PY 2015 VL 6 AR 19 DI 10.1186/s13326-015-0018-0 PG 10 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA CH6QF UT WOS:000354160400001 PM 25964850 ER PT J AU Cheng, XT Zhou, B Lin, MY Cai, Q Sheng, ZH AF Cheng, Xiu-Tang Zhou, Bing Lin, Mei-Yao Cai, Qian Sheng, Zu-Hang TI Axonal autophagosomes recruit dynein for retrograde transport through fusion with late endosomes SO JOURNAL OF CELL BIOLOGY LA English DT Article ID DEGRADATION; LYSOSOMES; NEURONS; MECHANISMS; DISEASE; MATURATION; HUNTINGTIN; VACUOLES; MOTORS; END AB Efficient degradation of autophagic vacuoles (AVs) via lysosomes is an important cellular homeostatic process. This is particularly challenging for neurons because mature acidic lysosomes are relatively enriched in the soma. Although dynein-driven retrograde transport of AVs was suggested, a fundamental question remains how autophagosomes generated at distal axons acquire dynein motors for retrograde transport toward the soma. In this paper, we demonstrate that late endosome (LE)-loaded dynein-snapin complexes drive AV retrograde transport in axons upon fusion of autophagosomes with LEs into amphisomes. Blocking the fusion with syntaxin17 knockdown reduced recruitment of dynein motors to AVs, thus immobilizing them in axons. Deficiency in dynein-snapin coupling impaired AV transport, resulting in AV accumulation in neurites and synaptic terminals. Altogether, our study provides the first evidence that autophagosomes recruit dynein through fusion with LEs and reveals a new motor-adaptor sharing mechanism by which neurons may remove distal AVs engulfing aggregated proteins and dysfunctional organelles for efficient degradation in the soma. C1 [Cheng, Xiu-Tang] Shanghai Jiao Tong Univ, Joint PhD Program, Natl Inst Hlth, Sch Med,Basic Med Fac, Shanghai 200025, Peoples R China. [Cheng, Xiu-Tang; Zhou, Bing; Lin, Mei-Yao; Sheng, Zu-Hang] NINDS, Synapt Funct Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. [Cai, Qian] Rutgers State Univ, Dept Cell Biol & Neurosci, Piscataway, NJ 08854 USA. RP Sheng, ZH (reprint author), NINDS, Synapt Funct Sect, Porter Neurosci Res Ctr, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM shengz@ninds.nih.gov FU Intramural Research Program of NINDS; NIH [ZIA HS003029, ZIA NS002946, R01NS089737]; National Institutes of Health (NIH); Shanghai Jiao Tong University FX X.-T. Cheng is a PhD student working at the National Institutes of Health (NIH) through the joint NIH PhD program with Shanghai Jiao Tong University. The work was supported by the Intramural Research Program of NINDS, NIH ZIA HS003029 and ZIA NS002946 (Z.-H. Sheng), and NIH grant R01NS089737 (Q. Cai). NR 36 TC 24 Z9 24 U1 0 U2 10 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD MAY 11 PY 2015 VL 209 IS 3 BP 377 EP 386 DI 10.1083/jcb.201412046 PG 10 WC Cell Biology SC Cell Biology GA CH8IT UT WOS:000354280600010 PM 25940348 ER PT J AU Gerber, PP Cabrini, M Jancic, C Paoletti, L Banchio, C von Bilderling, C Sigaut, L Pietrasanta, LI Duette, G Freed, EO Saint Basile, GD Moita, CF Moita, LF Amigorena, S Benaroch, P Geffner, J Ostrowski, M AF Pereyra Gerber, Pehuen Cabrini, Mercedes Jancic, Carolina Paoletti, Luciana Banchio, Claudia von Bilderling, Catalina Sigaut, Lorena Pietrasanta, Lia I. Duette, Gabriel Freed, Eric O. de Saint Basile, Genevieve Moita, Catarina Ferreira Moita, Luis Ferreira Amigorena, Sebastian Benaroch, Philippe Geffner, Jorge Ostrowski, Matias TI Rab27a controls HIV-1 assembly by regulating plasma membrane levels of phosphatidylinositol 4,5-bisphosphate SO JOURNAL OF CELL BIOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; TO-CELL TRANSMISSION; HUMAN MACROPHAGES; LENTIVIRAL VECTOR; II-ALPHA; TRAFFICKING; 4-KINASE; DOMAINS; GAG; TETRASPANINS AB During the late stages of the HIV-1 replication cycle, the viral polyprotein Pr55(Gag) is recruited to the plasma membrane (PM), where it binds phosphatidylinositol 4,5-bisphosphate (PI(4,5)P-2) and directs HIV-1 assembly. We show that Rab27a controls the trafficking of late endosomes carrying phosphatidylinositol 4-kinase type 2 alpha (PI4KII.) toward the PM of CD4(+) T cells. Hence, Rab27a promotes high levels of PM phosphatidylinositol 4-phosphate and the localized production of PI(4,5) P-2, therefore controlling Pr55(Gag) membrane association. Rab27a also controls PI(4,5)P-2 levels at the virus-containing compartments of macrophages. By screening Rab27a effectors, we identified that Slp2a, Slp3, and Slac2b are required for the association of Pr55(Gag) with the PM and that Slp2a cooperates with Rab27a in the recruitment of PI4KII. to the PM. We conclude that by directing the trafficking of PI4KII alpha-positive endosomes toward the PM, Rab27a controls PI(4,5)P-2 production and, consequently, HIV-1 replication. C1 [Pereyra Gerber, Pehuen; Cabrini, Mercedes; Duette, Gabriel; Geffner, Jorge; Ostrowski, Matias] Univ Buenos Aires, CONICET, Inst Invest Biomed Retrovirus & Sindrome Inmunode, Buenos Aires, DF, Argentina. [Jancic, Carolina] Acad Nacl Med Buenos Aires, CONICET, Inst Med Expt, Buenos Aires, DF, Argentina. [Paoletti, Luciana; Banchio, Claudia] Consejo Nacl Invest Cient & Tecn, Inst Biol Mol & Celular Rosario, Santa Fe, Argentina. [von Bilderling, Catalina] Univ Buenos Aires, CONICET, Inst Fis Buenos Aires, Dept Fis, Buenos Aires, DF, Argentina. [Sigaut, Lorena; Pietrasanta, Lia I.] Univ Buenos Aires, CONICET, Fac Ciencias Exactas & Nat, Ctr Microscopias Avanzadas, Buenos Aires, DF, Argentina. [Freed, Eric O.] NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. [de Saint Basile, Genevieve] Univ Paris 05, Sorbonne Paris Cite, Inst Natl Sante & Rech Med U768, F-75015 Paris, France. [de Saint Basile, Genevieve] Univ Paris 05, Sorbonne Paris Cite, Inst Imagine, F-75015 Paris, France. [Moita, Catarina Ferreira; Moita, Luis Ferreira] Inst Gulbenkian Ciencias, Innate Immun & Inflammat Lab, P-2780156 Oeiras, Portugal. [Amigorena, Sebastian; Benaroch, Philippe] Inst Curie, Ctr Rech, Inst Natl Sante & Rech Med U932, F-75248 Paris, France. RP Ostrowski, M (reprint author), Univ Buenos Aires, CONICET, Inst Invest Biomed Retrovirus & Sindrome Inmunode, C1121ABG, Buenos Aires, DF, Argentina. EM maostro@fmed.uba.ar OI Moita, Luis/0000-0003-0707-315X; Amigorena, Sebastian/0000-0001-8583-8416 FU Universidad de Buenos Aires; CONICET; Agencia Nacional de Promocion Cientifica y Tecnologica (Argentina) [2010-1681, 2012-00353]; Creative and Novel Ideas in HIV Research Program through a supplement to the University of Alabama at Birmingham Center for AIDS Research [P30 AI027767-24] FX This work was supported by doctoral fellowships from Universidad de Buenos Aires and CONICET to M. Cabrini and P.P. Gerber, respectively, and grants 2010-1681 and 2012-00353 from Agencia Nacional de Promocion Cientifica y Tecnologica (Argentina) and the Creative and Novel Ideas in HIV Research Program through a supplement to the University of Alabama at Birmingham Center for AIDS Research funding grant P30 AI027767-24 to M. Ostrowski. NR 71 TC 8 Z9 8 U1 3 U2 13 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD MAY 11 PY 2015 VL 209 IS 3 BP 435 EP 452 DI 10.1083/jcb.201409082 PG 18 WC Cell Biology SC Cell Biology GA CH8IT UT WOS:000354280600014 PM 25940347 ER PT J AU Li, JM Cai, Y Liu, F Yang, L Hu, X Patrylo, PR Cai, HB Luo, XG Xiao, D Yan, XX AF Li, Jian-Ming Cai, Yan Liu, Fei Yang, La Hu, Xia Patrylo, Peter R. Cai, Huaibin Luo, Xue-Gang Xiao, Dong Yan, Xiao-Xin TI Experimental microembolism induces localized neuritic pathology in guinea pig cerebrum SO ONCOTARGET LA English DT Article DE Alzheimer's disease; amyloid pathology; axonal pathology; brain aging; silent stroke ID ALZHEIMERS-DISEASE; SENILE PLAQUES; A-BETA; BETA-SECRETASE-1 ELEVATION; MICROVASCULAR PATHOLOGY; AMYLOID PLAQUES; BLOOD-VESSELS; MOUSE MODELS; RISK-FACTORS; IN-VIVO AB Microbleeds are a common finding in aged human brains. In Alzheimer's disease (AD), neuritic plaques composed of beta-amyloid (A beta) deposits and dystrophic neurites occur frequently around cerebral vasculature, raising a compelling question as to whether, and if so, how, microvascular abnormality and amyloid/neuritic pathology might be causally related. Here we used a guinea pig model of cerebral microembolism to explore a potential inductive effect of vascular injury on neuritic and amyloid pathogenesis. Brains were examined 7-30 days after experimental microvascular embolization occupying similar to 0.5% of total cortical area. Compared to sham-operated controls, glial fibrillary acidic protein immunoreactivity was increased in the embolized cerebrum, evidently around intracortical vasculature. Swollen/sprouting neurites exhibiting increased reactivity of nicotinamide adenine dinucleotide phosphate diaphorase, parvalbumin, vesicular glutamate transporter 1 and choline acetyltransferase appeared locally in the embolized brains in proximity to intracortical vasculature. The embolization-induced swollen/sprouting neurites were also robustly immunoreactive for beta-amyloid precursor protein and beta-secretase-1, the substrate and initiating enzyme for A beta genesis. These experimental data suggest that microvascular injury can induce multisystem neuritic pathology associated with an enhanced amyloidogenic potential in wild-type mammalian brain. C1 [Li, Jian-Ming; Cai, Yan; Hu, Xia; Luo, Xue-Gang; Yan, Xiao-Xin] Cent S Univ, Sch Basic Med Sci, Dept Anat & Neurobiol, Changsha, Hunan, Peoples R China. [Li, Jian-Ming; Yang, La] Changsha Med Univ, Neurosci Res Ctr, Changsha, Hunan, Peoples R China. [Liu, Fei] Cent S Univ, Xiangya Hosp 3, Dept Neurosurg, Changsha, Hunan, Peoples R China. [Patrylo, Peter R.] So Illinois Univ, Sch Med, Ctr Integrated Res Cognit & Neural Sci, Carbondale, IL 62901 USA. [Cai, Huaibin] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Xiao, Dong] China Univ Min & Technol, State Key Lab Coal Resources & Safe Min, Xuzhou, Jiangsu, Peoples R China. RP Yan, XX (reprint author), Cent S Univ, Sch Basic Med Sci, Dept Anat & Neurobiol, Changsha, Hunan, Peoples R China. EM yanxiaoxin@csu.edu.cn FU National Natural Science Foundation of China [81171091, 81200837]; Hunan Provincial Natural Science Foundation of China [2015JJ6010]; Changsha Municipal Committee for Research and Technology [K1207042-31] FX This study was supported by the National Natural Science Foundation of China (#81171091; #81200837), Hunan Provincial Natural Science Foundation of China (#2015JJ6010) and Changsha Municipal Committee for Research and Technology (#K1207042-31). NR 60 TC 1 Z9 2 U1 2 U2 6 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAY 10 PY 2015 VL 6 IS 13 BP 10772 EP 10785 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CO2SH UT WOS:000359006400010 PM 25871402 ER PT J AU Kawabata, S Hollander, MC Munasinghe, JP Brinster, LR Mercado-Matos, JR Li, J Regales, L Pao, W Janne, PA Wong, KK Butman, JA Lonser, RR Hansen, MR Gurgel, RK Vortmeyer, AO Dennis, PA AF Kawabata, Shigeru Hollander, M. Christine Munasinghe, Jeeva P. Brinster, Lauren R. Mercado-Matos, Jose R. Li, Jie Regales, Lucia Pao, William Jaenne, Pasi A. Wong, Kwok-Kin Butman, John A. Lonser, Russell R. Hansen, Marlan R. Gurgel, Richard K. Vortmeyer, Alexander O. Dennis, Phillip A. TI Epidermal growth factor receptor as a novel molecular target for aggressive papillary tumors in the middle ear and temporal bone SO ONCOTARGET LA English DT Article DE mouse model of adenomatous ear tumor; ear tumorigenesis; EGFR; EGFR-targeted therapy ID ENDOLYMPHATIC SAC TUMORS; HIPPEL-LINDAU-DISEASE; CELL LUNG-CANCER; CONDITIONAL EXPRESSION; ACQUIRED-RESISTANCE; KINASE INHIBITORS; GENE-EXPRESSION; EGFR T790M; GEFITINIB; MUTATION AB Adenomatous tumors in the middle ear and temporal bone are rare but highly morbid because they are difficult to detect prior to the development of audiovestibular dysfunction. Complete resection is often disfiguring and difficult because of location and the late stage at diagnosis, so identification of molecular targets and effective therapies is needed. Here, we describe a new mouse model of aggressive papillary ear tumor that was serendipitously discovered during the generation of a mouse model for mutant EGFR-driven lung cancer. Although these mice did not develop lung tumors, 43% developed head tilt and circling behavior. Magnetic resonance imaging (MRI) scans showed bilateral ear tumors located in the tympanic cavity. These tumors expressed mutant EGFR as well as active downstream targets such as Akt, mTOR and ERK1/2. EGFR-directed therapies were highly effective in eradicating the tumors and correcting the vestibular defects, suggesting these tumors are addicted to EGFR. EGFR activation was also observed in human ear neoplasms, which provides clinical relevance for this mouse model and rationale to test EGFR-targeted therapies in these rare neoplasms. C1 [Kawabata, Shigeru; Dennis, Phillip A.] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Hollander, M. Christine; Mercado-Matos, Jose R.] NCI, Med Oncol Branch, CCR, NIH, Bethesda, MD 20892 USA. [Munasinghe, Jeeva P.] NINDS, Mouse Imaging Facil, NIH, Bethesda, MD 20892 USA. [Brinster, Lauren R.] NIH, Div Vet Resources, Bethesda, MD 20892 USA. [Li, Jie; Vortmeyer, Alexander O.] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA. [Regales, Lucia] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Pao, William] Vanderbilt Univ, Sch Med, Div Hematol Oncol, Dept Med,Vanderbilt Ingram Canc Ctr, Nashville, TN 37212 USA. [Jaenne, Pasi A.; Wong, Kwok-Kin] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Butman, John A.] NIH, Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Lonser, Russell R.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Hansen, Marlan R.] Univ Iowa Hosp & Clin, Dept Otolaryngol Head & Neck Surg, Iowa City, IA 52242 USA. [Gurgel, Richard K.] Univ Utah, Div Otolaryngol Head & Neck Surg, Salt Lake City, UT USA. RP Kawabata, S (reprint author), Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. EM skawaba1@jhmi.edu; pdennis@jhmi.edu RI Butman, John/J-2780-2013 OI Butman, John/0000-0002-1547-9195 FU Intramural Research Program of the NIH, NCI, CCR; NIH Bench-to-Bedside Award; NIH/NCI [R01CA121210, P01CA129243, R01CA135257] FX The authors would like to thank Maiga Emmanuel (Office of the Director, NCI) for assistance with genotyping; Morales-Contreras Juan, Dumas Tarra, and Dr. John U. Dennis (Laboratory Animal Medicine, NCI) for veterinary services; Vivian Diaz and Danielle Donahue (Mouse Imaging Facility, NINDS) for assistance with mouse MRI scan and micro-CT scan, respectively; Dr. Liqiang Xi and Dr. Mark Raffeld (Laboratory of Pathology, NCI) for molecular diagnostic services; Dr. Hiroshi Furuta (Furuta clinic of Otolaryngology, Yodogawa-ku, Osaka, Japan) for advice on the analysis of mouse endolymphatic duct/sac system; and Dr. Nathanael S. Gray (Harvard Medical School, Boston, MA, USA) for providing WZ4002 compound. This research was supported by the Intramural Research Program of the NIH, NCI, CCR (PAD), the NIH Bench-to-Bedside Award (FY2010, PAD, AOV, and SK), and NIH/NCI grants R01CA121210 (WP), P01CA129243 (WP), and R01CA135257 (PAJ). NR 32 TC 1 Z9 1 U1 1 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAY 10 PY 2015 VL 6 IS 13 BP 11357 EP 11368 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CO2SH UT WOS:000359006400053 PM 26027747 ER PT J AU Thomas, A Chen, YB Steinberg, SM Luo, J Pack, S Raffeld, M Abdullaev, Z Alewine, C Rajan, A Giaccone, G Pastan, I Miettinen, M Hassan, R AF Thomas, Anish Chen, Yuanbin Steinberg, Seth M. Luo, Ji Pack, Svetlana Raffeld, Mark Abdullaev, Zied Alewine, Christine Rajan, Arun Giaccone, Giuseppe Pastan, Ira Miettinen, Markku Hassan, Raffit TI High mesothelin expression in advanced lung adenocarcinoma is associated with KRAS mutations and a poor prognosis SO ONCOTARGET LA English DT Article DE Mesothelin; Non-small cell lung cancer; KRAS; EGFR ID PANCREATIC INTRAEPITHELIAL NEOPLASIA; EPITHELIOID MESOTHELIOMAS; TISSUE MICROARRAY; OVARIAN-CANCER; RAS ONCOGENE; PHASE-I; CARCINOMAS; DIAGNOSIS; MARKER; TUMORS AB Mesothelin is a cell surface glycoprotein which is highly expressed in several epithelial cancers and may have a role in cell adhesion and metastases. In this study, we used prospectively obtained clinical and pathological data to characterize mesothelin expression in advanced lung adenocarcinoma. Tissue was obtained from patients who underwent molecular profiling of potentially actionable genes on a trial of molecular profiling and targeted therapies in advanced thoracic malignancies. We immunohistochemically evaluated the intensity, and the percentage of cells expressing mesothelin in 93 advanced lung adenocarcinomas. The evaluation was blinded for molecular data and outcome. Mutations of EGFR, KRAS, BRAF, AKT1, PIK3CA and HER2 were assessed by pyrosequencing; HER2 amplification and ALK translocation were assessed by fluorescence in situ hybridization. 53% of advanced lung adenocarcinomas expressed mesothelin to some degree; high mesothelin expression, defined as mesothelin positivity in more than 25% of cells, was found in 24% of patients. High mesothelin expression was associated with inferior survival (median 18.2 months vs. 32.9 months; P = 0.014). High mesothelin expression was strongly associated with mutant KRAS (P < 0.0001) and wild-type EGFR (P = 0.002). Our results provide strong rationale to explore anti-mesothelin targeted therapies in advanced lung adenocarcinoma especially in the KRAS-mutant subgroup. C1 [Thomas, Anish; Chen, Yuanbin; Rajan, Arun; Hassan, Raffit] NCI, Thorac & GI Oncol Branch, NIH, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NIH, Biostat & Data Management Sect, Ctr Canc Res, Bethesda, MD 20892 USA. [Luo, Ji] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Pack, Svetlana; Raffeld, Mark; Abdullaev, Zied; Miettinen, Markku] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Alewine, Christine; Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Giaccone, Giuseppe] Georgetown Univ, Lombardi Canc Ctr, Washington, DC USA. RP Hassan, R (reprint author), NCI, Thorac & GI Oncol Branch, NIH, Bethesda, MD 20892 USA. EM hassanr@mail.nih.gov RI Giaccone, Giuseppe/E-8297-2017; OI Giaccone, Giuseppe/0000-0002-5023-7562; Thomas, Anish/0000-0003-3293-3115 FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. We would like to thank the patients, research nurses and investigators of the pilot trial of molecular profiling and targeted therapies in advanced thoracic malignancies. NR 34 TC 10 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 MAY 10 PY 2015 VL 6 IS 13 BP 11694 EP 11702 PG 9 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CO2SH UT WOS:000359006400079 PM 26028668 ER PT J AU Stevanovic, S Draper, LM Langhan, MM Campbell, TE Kwong, ML Wunderlich, JR Dudley, ME Yang, JC Sherry, RM Kammula, US Restifo, NP Rosenberg, SA Hinrichs, CS AF Stevanovic, Sanja Draper, Lindsey M. Langhan, Michelle M. Campbell, Tracy E. Kwong, Mei Li Wunderlich, John R. Dudley, Mark E. Yang, James C. Sherry, Richard M. Kammula, Udai S. Restifo, Nicholas P. Rosenberg, Steven A. Hinrichs, Christian S. TI Complete Regression of Metastatic Cervical Cancer After Treatment With Human Papillomavirus-Targeted Tumor-Infiltrating T Cells SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID GYNECOLOGIC-ONCOLOGY-GROUP; PHASE-II TRIAL; COMPLETE RESPONSES; TRANSFER THERAPY; IMMUNOTHERAPY; MELANOMA; ANTIGEN; EXPRESSION; CARCINOMA; CD8(+) AB Purpose Metastatic cervical cancer is a prototypical chemotherapy-refractory epithelial malignancy for which better treatments are needed. Adoptive T-cell therapy (ACT) is emerging as a promising cancer treatment, but its study in epithelial malignancies has been limited. This study was conducted to determine if ACT could mediate regression of metastatic cervical cancer. Patients and Methods Patients enrolled onto this protocol were diagnosed with metastatic cervical cancer and had previously received platinum-based chemotherapy or chemoradiotherapy. Patients were treated with a single infusion of tumor-infiltrating T cells selected when possible for human papillomavirus (HPV) E6 and E7 reactivity (HPV-TILs). Cell infusion was preceded by lymphocyte-depleting chemotherapy and was followed by administration of aldesleukin. Results Three of nine patients experienced objective tumor responses (two complete responses and one partial response). The two complete responses were ongoing 22 and 15 months after treatment, respectively. One partial response was 3 months in duration. The HPV reactivity of T cells in the infusion product (as measured by interferon gamma production, enzyme-linked immunospot, and CD137 upregulation assays) correlated positively with clinical response (P = .0238 for all three assays). In addition, the frequency of HPV-reactive T cells in peripheral blood 1 month after treatment was positively associated with clinical response (P = .0238). Conclusion Durable, complete regression of metastatic cervical cancer can occur after a single infusion of HPV-TILs. Exploratory studies suggest a correlation between HPV reactivity of the infusion product and clinical response. Continued investigation of this therapy is warranted. Published by the American Society of Clinical Oncology C1 [Stevanovic, Sanja; Draper, Lindsey M.; Langhan, Michelle M.; Campbell, Tracy E.; Kwong, Mei Li; Wunderlich, John R.; Dudley, Mark E.; Yang, James C.; Sherry, Richard M.; Kammula, Udai S.; Restifo, Nicholas P.; Rosenberg, Steven A.; Hinrichs, Christian S.] NCI, Bethesda, MD 20892 USA. RP Hinrichs, CS (reprint author), NCI, Surg Branch, Canc Res Ctr, 10 Ctr Dr,Room 3-3888, Bethesda, MD 20892 USA. EM hinrichs@nih.gov OI Restifo, Nicholas P./0000-0003-4229-4580; Stevanovic, Sanja/0000-0002-0853-0327 FU Milstein Family Foundation FX We thank the Milstein Family Foundation for its generous support. We also thank Robert P.T. Somerville and Sadik Kassim for clinical cell manufacturing; Eric Tran, Alena Gros, Anna Pasetto, and Drew C. Deniger for technical assistance and helpful discussions; Sid Kerkar and Mark Raffeld for immunohistologic analyses; and the National Cancer Institute Surgery Branch immunotherapy clinical fellows and nurses for their care of the patients. NR 38 TC 57 Z9 59 U1 1 U2 11 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 MAY 10 PY 2015 VL 33 IS 14 BP 1543 EP + DI 10.1200/JCO.2014.58.9093 PG 10 WC Oncology SC Oncology GA CK2RR UT WOS:000356059900008 PM 25823737 ER PT J AU Hobday, TJ Qin, R Reidy-Lagunes, D Moore, MJ Strosberg, J Kaubisch, A Shah, M Kindler, HL Lenz, HJ Chen, H Erlichman, C AF Hobday, Timothy J. Qin, Rui Reidy-Lagunes, Diane Moore, Malcolm J. Strosberg, Jonathan Kaubisch, Andreas Shah, Manisha Kindler, Hedy Lee Lenz, Heinz-Josef Chen, Helen Erlichman, Charles TI Multicenter Phase II Trial of Temsirolimus and Bevacizumab in Pancreatic Neuroendocrine Tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CELL CARCINOMA; THERAPY AB Purpose There are few effective therapies for pancreatic neuroendocrine tumors (PNETs). Recent placebo-controlled phase III trials of the mammalian target of rapamycin (mTOR) inhibitor everolimus and the vascular endothelial growth factor (VEGF)/platelet-derived growth factor receptor inhibitor sunitinib have noted improved progression-free survival (PFS). Preclinical studies have suggested enhanced antitumor effects with combined mTOR and VEGF pathway-targeted therapy. We conducted a clinical trial to evaluate combination therapy against these targets in PNETs. Patients and Methods We conducted a two-stage single-arm phase II trial of the mTOR inhibitor temsirolimus 25 mg intravenously (IV) once per week and the VEGF-A monoclonal antibody bevacizumab 10 mg/kg IV once every 2 weeks in patients with well or moderately differentiated PNETs and progressive disease by RECIST within 7 months of study entry. Coprimary end points were tumor response rate and 6-month PFS. Results A total of 58 patients were enrolled, and 56 patients were eligible for response assessment. Confirmed response rate (RR) was 41% (23 of 56 patients). PFS at 6 months was 79% (44 of 56). Median PFS was 13.2 months (95% CI, 11.2 to 16.6). Median overall survival was 34 months (95% CI, 27.1 to not reached). For evaluable patients, the most common grade 3 to 4 adverse events attributed to therapy were hypertension (21%), fatigue (16%), lymphopenia (14%), and hyperglycemia (14%). Conclusion The combination of temsirolimus and bevacizumab had substantial activity and reasonable tolerability in a multicenter phase II trial, with RR of 41%, well in excess of single targeted agents in patients with progressive PNETs. Six-month PFS was a notable 79% in a population of patients with disease progression by RECIST criteria within 7 months of study entry. On the basis of this trial, continued evaluation of combination mTOR and VEGF pathway inhibitors is warranted. (C) 2014 by American Society of Clinical Oncology C1 [Hobday, Timothy J.; Qin, Rui; Erlichman, Charles] Mayo Clin, Rochester, MN 55905 USA. [Reidy-Lagunes, Diane] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Kaubisch, Andreas] Montefiore Med Ctr, Bronx, NY 10467 USA. [Moore, Malcolm J.] Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. [Strosberg, Jonathan] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Shah, Manisha] Ohio State Univ, Columbus, OH 43210 USA. [Kindler, Hedy Lee] Univ Chicago, Chicago, IL 60637 USA. [Lenz, Heinz-Josef] Univ So Calif, Los Angeles, CA USA. [Chen, Helen] NCI, Rockville, MD USA. RP Hobday, TJ (reprint author), Mayo Clin, 200 First St SW, Rochester, MN 55905 USA. EM hobday.timothy@mayo.edu FU National Cancer Institute [N01 62205, N01 62203, N01 62208, N01 62209, N01 62206, N01 62204, N01 62207, N01 62201, HHSN261201100070C, N01-CM-00080] FX Supported by National Cancer Institute Contracts No. N01 62205, N01 62203, N01 62208, N01 62209, N01 62206, N01 62204, N01 62207, N01 62201, HHSN261201100070C, and N01-CM-00080. NR 13 TC 18 Z9 18 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 10 PY 2015 VL 33 IS 14 BP 1551 EP 1556 DI 10.1200/JCO.2014.56.2082 PG 6 WC Oncology SC Oncology GA CK2RR UT WOS:000356059900009 PM 25488966 ER PT J AU Palomba, G Loi, A Porcu, E Cossu, A Zara, I Budroni, M Dei, M Lai, S Mulas, A Olmeo, N Ionta, MT Atzori, F Cuccuru, G Pitzalis, M Zoledziewska, M Olla, N Lovicu, M Pisano, M Abecasis, GR Uda, M Tanda, F Michailidou, K Easton, DF Chanock, SJ Hoover, RN Hunter, DJ Schlessinger, D Sanna, S Crisponi, L Palmieri, G AF Palomba, Grazia Loi, Angela Porcu, Eleonora Cossu, Antonio Zara, Ilenia Budroni, Mario Dei, Mariano Lai, Sandra Mulas, Antonella Olmeo, Nina Ionta, Maria Teresa Atzori, Francesco Cuccuru, Gianmauro Pitzalis, Maristella Zoledziewska, Magdalena Olla, Nazario Lovicu, Mario Pisano, Marina Abecasis, Goncalo R. Uda, Manuela Tanda, Francesco Michailidou, Kyriaki Easton, Douglas F. Chanock, Stephen J. Hoover, Robert N. Hunter, David J. Schlessinger, David Sanna, Serena Crisponi, Laura Palmieri, Giuseppe TI Genome-wide association study of susceptibility loci for breast cancer in Sardinian population SO BMC CANCER LA English DT Article DE Breast cancer risk; BRCA1/2 mutation analysis; Genome-wide association study; Sardinian population ID ANDROGEN RECEPTOR-ACTIVITY; BRCA2 GERMLINE MUTATIONS; PROSTATE-CANCER; VAV3 ONCOGENE; ESTROGEN-RECEPTOR; RHO-GTPASE; RISK; DISEASES; CELLS; VARIANTS AB Background: Despite progress in identifying genes associated with breast cancer, many more risk loci exist. Genome-wide association analyses in genetically-homogeneous populations, such as that of Sardinia (Italy), could represent an additional approach to detect low penetrance alleles. Methods: We performed a genome-wide association study comparing 1431 Sardinian patients with non-familial, BRCA1/2-mutation-negative breast cancer to 2171 healthy Sardinian blood donors. DNA was genotyped using GeneChip Human Mapping 500 K Arrays or Genome-Wide Human SNP Arrays 6.0. To increase genomic coverage, genotypes of additional SNPs were imputed using data from HapMap Phase II. After quality control filtering of genotype data, 1367 cases (9 men) and 1658 controls (1156 men) were analyzed on a total of 2,067,645 SNPs. Results: Overall, 33 genomic regions (67 candidate SNPs) were associated with breast cancer risk at the p < 10(-6) level. Twenty of these regions contained defined genes, including one already associated with breast cancer risk: TOX3. With a lower threshold for preliminary significance to p < 10(-5), we identified 11 additional SNPs in FGFR2, a well-established breast cancer-associated gene. Ten candidate SNPs were selected, excluding those already associated with breast cancer, for technical validation as well as replication in 1668 samples from the same population. Only SNP rs345299, located in intron 1 of VAV3, remained suggestively associated (p-value, 1.16x10(-5)), but it did not associate with breast cancer risk in pooled data from two large, mixed-population cohorts. Conclusions: This study indicated the role of TOX3 and FGFR2 as breast cancer susceptibility genes in BRCA1/2-wild-type breast cancer patients from Sardinian population. C1 [Palomba, Grazia; Pisano, Marina; Palmieri, Giuseppe] CNR, Ist Chim Biomol, I-07100 Sassari, Italy. [Loi, Angela; Porcu, Eleonora; Dei, Mariano; Lai, Sandra; Mulas, Antonella; Pitzalis, Maristella; Zoledziewska, Magdalena; Olla, Nazario; Lovicu, Mario; Uda, Manuela; Sanna, Serena; Crisponi, Laura] CNR, Ist Ric Genet & Biomed, I-09042 Cagliari, Italy. [Cossu, Antonio; Tanda, Francesco] Azienda Osped Univ, Ist Anat Patol, Sassari, Italy. [Zara, Ilenia; Cuccuru, Gianmauro] Res & Dev Sardina CRS4, Ctr Adv Studies, Cagliari, Italy. [Budroni, Mario] Serv Epidemiol, Sassari, Italy. [Olmeo, Nina] Serv Oncol Med, Sassari, Italy. [Ionta, Maria Teresa; Atzori, Francesco] Azienda Osped Univ, Dipartimento Oncol Med, Cagliari, Italy. [Abecasis, Goncalo R.] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Michailidou, Kyriaki; Easton, Douglas F.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Easton, Douglas F.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. [Chanock, Stephen J.; Hoover, Robert N.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Hunter, David J.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Schlessinger, David] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. [Palmieri, Giuseppe] CNR, CNR, Inst Biomol Chem ICB, Unit Canc Genet, I-07100 Sassari, Italy. RP Palomba, G (reprint author), CNR, Ist Chim Biomol, Traversa La Crucca 3, I-07100 Sassari, Italy. EM graziap68@yahoo.it; loiangela@hotmail.com; eleonoraporcu@gmail.com; cossu@uniss.it; laura.crisponi@irgb.cnr.it; gpalmieri@yahoo.com OI Mulas, Antonella/0000-0002-6856-1483; COSSU, Antonio Giuseppe Maria/0000-0002-2390-2205; sanna, serena/0000-0002-3768-1749; Pitzalis, Maristella/0000-0003-4975-6987; Palmieri, Giuseppe/0000-0002-4350-2276 FU Italian Ministry of Health "Progetto Ricerca Finalizzata"; Sardinia Regional Government (Regione Autonoma della Sardegna); Intramural Research Program of the NIH, National Institute on Aging; National Institute on Aging [NO1-AG-1-2109]; National Institute of Health (NIH) Cancer Post-Cancer GWAS [1 U19 CA 148065-01]; European Community's Seventh Framework Programme (COGS) [223175, HEALTH-F2-2009-223175]; Cancer Research UK [C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692]; National Institutes of Health [CA128978]; Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]; Department of Defence [W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure; Breast Cancer Research Foundation; Ovarian Cancer Research Fund FX Authors would like to thank patients for their important contribution to this study. Authors are grateful to all the other members of the Sardinian Translational Oncology Group (STOG) as well as to Giuseppe Mameli, for his technical assistance. This work was supported by the Italian Ministry of Health "Progetto Ricerca Finalizzata", by the Sardinia Regional Government (Regione Autonoma della Sardegna), and by the Intramural Research Program of the NIH, National Institute on Aging. The SardiNIA ("ProgeNIA") team was supported by Contract NO1-AG-1-2109 from the National Institute on Aging. Combining the GWAS data was supported in part by The National Institute of Health (NIH) Cancer Post-Cancer GWAS initiative grant: No. 1 U19 CA 148065-01 (DRIVE, part of the GAME-ON initiative). Funding for the individual GWAS is summarised in Michailidou et al. (2013). Funding for the Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The project would not have been possible without the contributions of Per Hall (COGS); Douglas F. Easton, Paul Pharoah, Kyriaki Michailidou, Manjeet K. Bolla, Qin Wang (BCAC), Andrew Berchuck (OCAC), Rosalind A. Eeles, Douglas F. Easton, Ali Amin Al Olama, Zsofia Kote-Jarai, Sara Benlloch (PRACTICAL), Georgia Chenevix-Trench, Antonis Antoniou, Lesley McGuffog, Fergus Couch and Ken Offit (CIMBA), Joe Dennis, Alison M. Dunning, Andrew Lee, and Ed Dicks, Craig Luccarini and the staff of the Centre for Genetic Epidemiology Laboratory, Javier Benitez, Anna Gonzalez-Neira and the staff of the CNIO genotyping unit, Jacques Simard and Daniel C. Tessier, Francois Bacot, Daniel Vincent, Sylvie LaBoissiere and Frederic Robidoux and the staff of the McGill University and Genome Quebec Innovation Centre, Stig E. Bojesen, Sune F. Nielsen, Borge G. Nordestgaard, and the staff of the Copenhagen DNA laboratory, and Julie M. Cunningham, Sharon A. Windebank, Christopher A. Hilker, Jeffrey Meyer and the staff of Mayo Clinic Genotyping Core Facility. Editorial advice and writing assistance on parts of this manuscript were provided by Valerie Matarese. We also thank Prof. Francesco Cucca for the critical revision of the manuscript. NR 37 TC 2 Z9 2 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD MAY 10 PY 2015 VL 15 AR 383 DI 10.1186/s12885-015-1392-9 PG 10 WC Oncology SC Oncology GA CI5ZQ UT WOS:000354838800001 PM 25956309 ER PT J AU Kellman, P Bandettini, WP Mancini, C Hammer-Hansen, S Hansen, MS Arai, AE AF Kellman, Peter Bandettini, W. Patricia Mancini, Christine Hammer-Hansen, Sophia Hansen, Michael S. Arai, Andrew E. TI Characterization of myocardial T1-mapping bias caused by intramyocardial fat in inversion recovery and saturation recovery techniques SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE T1 map; MOLLI; SASHA; Chronic myocardial infarction; Lipomatous metaplasia; Fatty metaplasia; Fat ID CARDIOVASCULAR MAGNETIC-RESONANCE; STATE FREE PRECESSION; CONTRAST T1; INFARCTION; HEART; MOLLI; SEPARATION; PRECISION; SEQUENCES; TISSUE AB Background: Quantitative measurement of T1 in the myocardium may be used to detect both focal and diffuse disease processes such as interstitial fibrosis or edema. A partial volume problem exists when a voxel in the myocardium also contains fat. Partial volume with fat occurs at tissue boundaries or within the myocardium in the case of lipomatous metaplasia of replacement fibrosis, which is commonly seen in chronic myocardial infarction. The presence of fat leads to a bias in T1 measurement. The mechanism for this artifact for widely used T1 mapping protocols using balanced steady state free precession readout and the dependence on off-resonance frequency are described in this paper. Methods: Simulations were performed to illustrate the behavior of mono-exponential fitting to bi-exponential mixtures of myocardium and fat with varying fat fractions. Both inversion recovery and saturation recovery imaging protocols using balanced steady state free precession are considered. In-vivo imaging with T1-mapping, water/fat separated imaging, and late enhancement imaging was performed on subjects with chronic myocardial infarction. Results: In n = 17 subjects with chronic myocardial infarction, lipomatous metaplasia is evident in 8 patients (47%). Fat fractions as low as 5% caused approximately 6% T1 elevation for the out-of-phase condition, and approximately 5% reduction of T1 for the in-phase condition. T1 bias in excess of 1000 ms was observed in lipomatous metaplasia with fat fraction of 38% in close agreement with simulation of the specific imaging protocols. Conclusions: Measurement of the myocardial T1 by widely used balanced steady state free precession mapping methods is subject to bias when there is a mixture of water and fat in the myocardium. Intramyocardial fat is frequently present in myocardial scar tissue due lipomatous metaplasia, a process affecting myocardial infarction and some non-ischemic cardiomyopathies. In cases of lipomatous metaplasia, the T1 biases will be additive or subtractive depending on whether the center frequency corresponds to the myocardium and fat being in-phase or out-of-phase, respectively. It is important to understand this mechanism, which may otherwise lead to erroneous interpretation. C1 [Kellman, Peter; Bandettini, W. Patricia; Mancini, Christine; Hammer-Hansen, Sophia; Hansen, Michael S.; Arai, Andrew E.] NHLBI, DHHS, NIH, Bethesda, MD 20892 USA. RP Kellman, P (reprint author), NHLBI, DHHS, NIH, 10 Ctr Dr MSC-1061, Bethesda, MD 20892 USA. EM kellman@nih.gov RI Hansen, Michael/J-5391-2015 OI Hansen, Michael/0000-0002-8087-8731 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 49 TC 8 Z9 8 U1 2 U2 3 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 MAY 10 PY 2015 VL 17 AR 33 DI 10.1186/s12968-015-0136-y PG 11 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA CH6XL UT WOS:000354179600001 PM 25958014 ER PT J AU Hu, ZH Follmann, DA Miura, K AF Hu, Zonghui Follmann, Dean A. Miura, Kazutoyo TI Vaccine design via nonnegative lasso-based variable selection SO STATISTICS IN MEDICINE LA English DT Article DE amino acid sequence; malaria vaccine; nonnegative lasso regression; seemingly independent screening ID APICAL MEMBRANE ANTIGEN-1; MALARIA VACCINE; REGRESSION; IMMUNIZATION; TRIAL AB There are many different strains of malaria parasites, each represented by a unique sequence of amino acids. A desirable vaccine would match the amino acid sequence of the parasite antigen. Because of the three-dimensional structure of protein, not all sites in the amino acid sequence participate in the binding between the vaccine-induced antibody and the parasite antigen. Nor do all sites have equal importance. In this work, we apply a nonnegative lasso-based variable selection to identify the important' amino acid sites and evaluate their relative importance. We then define a metric, the functional coverage, to measure the effective' matching in the amino acid sequence between the vaccine and the parasite. With the variable selection procedure, development of a vaccine needs only to target the important sites, and the potential effectiveness of a vaccine candidate is reflected by the functional coverage. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. C1 [Hu, Zonghui; Follmann, Dean A.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Miura, Kazutoyo] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. RP Hu, ZH (reprint author), NIAID, Biostat Res Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM huzo@niaid.nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 14 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD MAY 10 PY 2015 VL 34 IS 10 BP 1791 EP 1798 DI 10.1002/sim.6452 PG 8 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA CF5CE UT WOS:000352572200013 PM 25643693 ER PT J AU Wentzensen, N Trabert, B AF Wentzensen, Nicolas Trabert, Britton TI Hormone therapy: short-term relief, long-term consequences SO LANCET LA English DT Editorial Material ID ESTROGEN PLUS PROGESTIN; NIH-AARP DIET; OVARIAN-CANCER; UNITED-STATES; REPLACEMENT THERAPY; ENDOMETRIAL CANCER; BREAST-CANCER; HEALTH; RISK; WOMEN C1 [Wentzensen, Nicolas; Trabert, Britton] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Wentzensen, N (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM wentzenn@mail.nih.gov RI Trabert, Britton/F-8051-2015 NR 12 TC 3 Z9 4 U1 0 U2 5 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 MAY 9 PY 2015 VL 385 IS 9980 BP 1806 EP 1808 DI 10.1016/S0140-6736(14)62458-2 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA CH6ZE UT WOS:000354184500005 PM 25684588 ER PT J AU Gapstur, SM Patel, AV Banks, E Dal Maso, L Talamini, R Chetrit, A Hirsh-Yechezkel, G Lubin, F Sadetzki, S Beral, V Bull, D Cairns, B Crossley, B Gaitskell, K Goodill, A Green, J Hermon, C Key, T Moser, K Reeves, G Sitas, F Collins, R Peto, R Gonzalez, CA Lee, N Marchbanks, P Ory, HW Peterson, HB Wingo, PA Martin, N Silpisornkosol, S Theetranont, C Boosiri, B Chutivongse, S Jimakorn, P Virutamasen, P Wongsrichanalai, C Goodman, MT Lidegaard, O Kjaer, SK Morch, LS Kjaer, SK Tjonneland, A Byers, T Rohan, T Mosgaard, B Vessey, M Yeates, D Freudenheim, JL Titus, LJ Chang-Claude, J Kaaks, R Anderson, KE Lazovich, D Robien, K Hampton, J Newcomb, PA Rossing, MA Thomas, DB Weiss, NS Lokkegaard, E Riboli, E Clavel-Chapelon, F Cramer, D Hankinson, SE Tamimi, RM Tworoger, SS Franceschi, S La Vecchia, C Negri, E Adami, HO Magnusson, C Riman, T Weiderpass, E Wolk, A Schouten, LJ van den Brandt, PA Chantarakul, N Koetsawang, S Rachawat, D Palli, D Black, A Brinton, LA Freedman, DM Hartge, P Hsing, AW Jnr, JVL Lissowska, J Hoover, RN Schairer, C Babb, C Urban, M Graff-Iversen, S Selmer, R Bain, CJ Green, AC Purdie, DM Siskind, V Webb, PM Moysich, K McCann, SE Hannaford, P Kay, C Binns, CW Lee, AH Zhang, M Ness, RB Nasca, P Coogan, PF Palmer, JR Rosenberg, L Whittemore, A Katsouyanni, K Trichopoulou, A Trichopoulos, D Tzonou, A Dabancens, A Martinez, L Molina, R Salas, O Lurie, G Carney, ME Wilkens, LR Hartman, L Manjer, J Olsson, H Kumle, M Grisso, JA Morgan, M Wheeler, JE Edwards, RP Kelley, JL Modugno, F Onland-Moret, NC Peeters, PHM Casagrande, J Pike, MC Wu, AH Canfell, K Miller, AB Gram, IT Lund, E McGowan, L Shu, XO Zheng, W Farley, TMM Holck, S Meirik, O Risch, HA AF Gapstur, S. M. Patel, A. V. Banks, E. Dal Maso, L. Talamini, R. Chetrit, A. Hirsh-Yechezkel, G. Lubin, F. Sadetzki, S. Beral, V. Bull, D. Cairns, B. Crossley, B. Gaitskell, K. Goodill, A. Green, J. Hermon, C. Key, T. Moser, K. Reeves, G. Sitas, F. Collins, R. Peto, R. Gonzalez, C. A. Lee, N. Marchbanks, P. Ory, H. W. Peterson, H. B. Wingo, P. A. Martin, N. Silpisornkosol, S. Theetranont, C. Boosiri, B. Chutivongse, S. Jimakorn, P. Virutamasen, P. Wongsrichanalai, C. Goodman, M. T. Lidegaard, O. Kjaer, S. K. Morch, L. S. Kjaer, S. K. Tjonneland, A. Byers, T. Rohan, T. Mosgaard, B. Vessey, M. Yeates, D. Freudenheim, J. L. Titus, L. J. Chang-Claude, J. Kaaks, R. Anderson, K. E. Lazovich, D. Robien, K. Hampton, J. Newcomb, P. A. Rossing, M. A. Thomas, D. B. Weiss, N. S. Lokkegaard, E. Riboli, E. Clavel-Chapelon, F. Cramer, D. Hankinson, S. E. Tamimi, R. M. Tworoger, S. S. Franceschi, S. La Vecchia, C. Negri, E. Adami, H. O. Magnusson, C. Riman, T. Weiderpass, E. Wolk, A. Schouten, L. J. van den Brandt, P. A. Chantarakul, N. Koetsawang, S. Rachawat, D. Palli, D. Black, A. Brinton, L. A. Freedman, D. M. Hartge, P. Hsing, A. W. Jnr, J. V. Lacey Lissowska, J. Hoover, R. N. Schairer, C. Babb, C. Urban, M. Graff-Iversen, S. Selmer, R. Bain, C. J. Green, A. C. Purdie, D. M. Siskind, V. Webb, P. M. Moysich, K. McCann, S. E. Hannaford, P. Kay, C. Binns, C. W. Lee, A. H. Zhang, M. Ness, R. B. Nasca, P. Coogan, P. F. Palmer, J. R. Rosenberg, L. Whittemore, A. Katsouyanni, K. Trichopoulou, A. Trichopoulos, D. Tzonou, A. Dabancens, A. Martinez, L. Molina, R. Salas, O. Lurie, G. Carney, M. E. Wilkens, L. R. Hartman, L. Manjer, J. Olsson, H. Kumle, M. Grisso, J. A. Morgan, M. Wheeler, J. E. Edwards, R. P. Kelley, J. L. Modugno, F. Onland-Moret, N. C. Peeters, P. H. M. Casagrande, J. Pike, M. C. Wu, A. H. Canfell, K. Miller, A. B. Gram, I. T. Lund, E. McGowan, L. Shu, X. O. Zheng, W. Farley, T. M. M. Holck, S. Meirik, O. Risch, H. A. CA Collaborative Grp Epidemiological TI Menopausal hormone use and ovarian cancer risk: individual participant meta-analysis of 52 epidemiological studies SO LANCET LA English DT Article ID WOMEN; THERAPY; HEALTH AB Background Half the epidemiological studies with information about menopausal hormone therapy and ovarian cancer risk remain unpublished, and some retrospective studies could have been biased by selective participation or recall. We aimed to assess with minimal bias the effects of hormone therapy on ovarian cancer risk. Methods Individual participant datasets from 52 epidemiological studies were analysed centrally. The principal analyses involved the prospective studies (with last hormone therapy use extrapolated forwards for up to 4 years). Sensitivity analyses included the retrospective studies. Adjusted Poisson regressions yielded relative risks (RRs) versus never-use. Findings During prospective follow-up, 12 110 postmenopausal women, 55% (6601) of whom had used hormone therapy, developed ovarian cancer. Among women last recorded as current users, risk was increased even with <5 years of use (RR 1.43, 95% CI 1.31-1.56; p<0.0001). Combining current-or-recent use (any duration, but stopped <5 years before diagnosis) resulted in an RR of 1.37 (95% CI 1.29-1.46; p<0.0001); this risk was similar in European and American prospective studies and for oestrogen-only and oestrogen-progestagen preparations, but differed across the four main tumour types (heterogeneity p<0.0001), being definitely increased only for the two most common types, serous (RR 1.53, 95% CI 1.40-1.66; p<0.0001) and endometrioid (1.42, 1.20-1.67; p<0.0001). Risk declined the longer ago use had ceased, although about 10 years after stopping long-duration hormone therapy use there was still an excess of serous or endometrioid tumours (RR 1.25, 95% CI 1.07-1.46, p=0.005). Interpretation The increased risk may well be largely or wholly causal; if it is, women who use hormone therapy for 5 years from around age 50 years have about one extra ovarian cancer per 1000 users and, if its prognosis is typical, about one extra ovarian cancer death per 1700 users. C1 [Gapstur, S. M.; Patel, A. V.] Amer Canc Soc, Atlanta, GA 30329 USA. [Banks, E.] Australian Natl Univ, Caberra, ACT, Australia. [Dal Maso, L.; Talamini, R.] Aviano Canc Ctr, I-33081 Aviano, Italy. [Chetrit, A.; Hirsh-Yechezkel, G.; Lubin, F.; Sadetzki, S.] Gertner Inst, Tel Hashomer, Israel. [Beral, V.; Bull, D.; Cairns, B.; Crossley, B.; Gaitskell, K.; Goodill, A.; Green, J.; Hermon, C.; Key, T.; Moser, K.; Reeves, G.] Canc Epidemiol Unit, Oxford, England. [Sitas, F.] NSW Canc Council, Woolloomooloo, NSW, Australia. [Collins, R.; Peto, R.] Radcliffe Infirm, Clin Trial Serv Unit, Oxford OX2 6HE, England. [Collins, R.; Peto, R.] Epidemiol Studies Unit CTSU, Oxford, England. [Gonzalez, C. A.] Catalan Inst Oncol, Barcelona, Spain. [Lee, N.; Marchbanks, P.; Ory, H. W.; Peterson, H. B.; Wingo, P. A.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Martin, N.; Silpisornkosol, S.; Theetranont, C.] Chiang Mai Univ, Chiang Mai, Thailand. [Boosiri, B.; Chutivongse, S.; Jimakorn, P.; Virutamasen, P.; Wongsrichanalai, C.] Chulalongkorn Univ, Bangkok, Thailand. [Goodman, M. T.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Lidegaard, O.; Kjaer, S. K.; Morch, L. S.] Copenhagen Univ Hosp, Copenhagen, Denmark. [Kjaer, S. K.; Tjonneland, A.] Danish Canc Soc Res Ctr, Copenhagen, Denmark. [Byers, T.] Colorado Sch Publ Hlth, Denver, CO USA. [Rohan, T.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Mosgaard, B.] Herlev Univ Hosp, Copenhagen, Denmark. [Vessey, M.; Yeates, D.] Dept Publ Hlth, Oxford, England. [Freudenheim, J. L.] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. [Titus, L. J.] Geisel Sch Med Dartmouth, Hanover, NH USA. [Chang-Claude, J.; Kaaks, R.] German Canc Res Ctr, Heidelberg, Germany. [Anderson, K. E.; Lazovich, D.; Robien, K.] Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA. [Hampton, J.; Newcomb, P. A.; Rossing, M. A.; Thomas, D. B.; Weiss, N. S.] Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA. [Lokkegaard, E.] Univ Copenhagen, Hillerod Hosp, DK-1168 Copenhagen, Denmark. [Riboli, E.] Univ London Imperial Coll Sci Technol & Med, London SW7 2AZ, England. [Clavel-Chapelon, F.] INSERM, U1018, Villejuif, France. [Clavel-Chapelon, F.] Paris South Univ, Inst Gustave Roussy, Villejuif, France. [Cramer, D.; Hankinson, S. E.; Tamimi, R. M.; Tworoger, S. S.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Franceschi, S.] Int Agcy Res Canc, F-69372 Lyon, France. [La Vecchia, C.; Negri, E.] Univ Milan, Ist Ric Farmacol Mario Negri, I-20122 Milan, Italy. [Adami, H. O.; Magnusson, C.; Riman, T.; Weiderpass, E.; Wolk, A.] Karolinska Inst, Stockholm, Sweden. [Schouten, L. J.; van den Brandt, P. A.] Maastricht Univ, NL-6200 MD Maastricht, Netherlands. [Chantarakul, N.; Koetsawang, S.; Rachawat, D.] Mahidol Univ, Bangkok 10700, Thailand. [Palli, D.] Canc Res & Prevent Inst, Florence, Italy. [Black, A.; Brinton, L. A.; Freedman, D. M.; Hartge, P.; Hsing, A. W.; Jnr, J. V. Lacey; Lissowska, J.; Hoover, R. N.; Schairer, C.] NCI, Bethesda, MD 20892 USA. [Babb, C.; Urban, M.] MRC, Canc Epidemiol Res Grp, Natl Hlth Lab Serv, Johannesburg, South Africa. [Graff-Iversen, S.; Selmer, R.] Norwegian Inst Publ Hlth, Oslo, Norway. [Bain, C. J.; Green, A. C.; Purdie, D. M.; Siskind, V.; Webb, P. M.] QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia. [Bain, C. J.; Green, A. C.; Purdie, D. M.; Siskind, V.; Webb, P. M.] Univ Queensland, Brisbane, Qld, Australia. [Moysich, K.; McCann, S. E.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Hannaford, P.; Kay, C.] Royal Coll Gen Practitioners Oral Contracept Stud, London, England. [Binns, C. W.; Lee, A. H.; Zhang, M.] Curtin Univ, Sch Publ Hlth, Perth, WA 6845, Australia. [Ness, R. B.] Univ Texas Houston, Sch Publ Hlth, Houston, TX USA. [Nasca, P.] Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Boston, MA 02125 USA. [Coogan, P. F.; Palmer, J. R.; Rosenberg, L.] Boston Univ, Slone Epidemiol Ctr, Boston, MA 02215 USA. [Whittemore, A.] Stanford Univ, Stanford, CA 94305 USA. [Katsouyanni, K.; Trichopoulou, A.; Trichopoulos, D.; Tzonou, A.] Univ Athens, Sch Med, GR-11527 Athens, Greece. [Dabancens, A.; Martinez, L.; Molina, R.; Salas, O.] Univ Chile, Santiago, Chile. [Lurie, G.; Carney, M. E.; Wilkens, L. R.] Univ Hawaii, Honolulu, HI 96822 USA. [Hartman, L.; Manjer, J.; Olsson, H.] Univ Lund Hosp, S-22185 Lund, Sweden. [Kumle, M.] Univ Hosp North Norway, Tromso, Norway. [Grisso, J. A.; Morgan, M.; Wheeler, J. E.] Univ Penn, Philadelphia, PA 19104 USA. [Edwards, R. P.; Kelley, J. L.; Modugno, F.] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Onland-Moret, N. C.; Peeters, P. H. M.] Univ Med Ctr, Utrecht, Netherlands. [Casagrande, J.; Pike, M. C.; Wu, A. H.] Univ So Calif, Los Angeles, CA USA. [Canfell, K.] Univ New S Wales, Sydney, NSW 2052, Australia. [Miller, A. B.] Univ Toronto, Toronto, ON M5S 1A1, Canada. [Gram, I. T.; Lund, E.] Arctic Univ Tromso, Tromso, Norway. [McGowan, L.] George Washington Univ, Washington, DC USA. [Shu, X. O.; Zheng, W.] Vanderbilt Univ, Nashville, TN 37235 USA. [Farley, T. M. M.; Holck, S.; Meirik, O.] WHO, CH-1211 Geneva, Switzerland. [Risch, H. A.] Yale Univ, Sch Publ Hlth, New Haven, CT 06520 USA. RP Gapstur, SM (reprint author), NDPH, Canc Epidemiol Unit, Richard Doll Bldg, Oxford OX3 7LF, England. EM collaborations@ceu.ox.ac.uk RI Brinton, Louise/G-7486-2015; Onland-Moret, N. Charlotte/G-9185-2011; Weiderpass, Elisabete/M-4029-2016; OI Brinton, Louise/0000-0003-3853-8562; Weiderpass, Elisabete/0000-0003-2237-0128; Lokkegaard, Ellen/0000-0003-4149-5663; Babb de Villiers, Chantal/0000-0003-1334-1819; Kjaer, Susanne/0000-0002-8347-1398; dal maso, luigino/0000-0001-6163-200X; La Vecchia, Carlo/0000-0003-1441-897X FU Medical Research Council, Cancer Research UK; Cancer Research UK; UK Medical Research Council FX Medical Research Council, Cancer Research UK.; The chief acknowledgment is to the participants and to the investigators in these studies. Data checking and analysis in the Oxford Cancer Epidemiology Unit was supported by Cancer Research UK and the UK Medical Research Council. Adrian Goodill drew the graphs. NR 16 TC 49 Z9 51 U1 3 U2 21 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 MAY 9 PY 2015 VL 385 IS 9980 BP 1835 EP 1842 DI 10.1016/S0140-6736(14)61687-1 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA CH6ZE UT WOS:000354184500027 ER PT J AU Nakashima, S Kakugawa, T Yura, H Tomonaga, M Harada, T Hara, A Hara, S Nakano, M Yamasaki, E Sakamoto, N Ishimatsu, Y Isomoto, H Gochuico, BR Suffredini, AF Mukae, H Kurazono, H Hirayama, T Moss, J Kohno, S AF Nakashima, Shota Kakugawa, Tomoyuki Yura, Hirokazu Tomonaga, Masaomi Harada, Tatsuhiko Hara, Atsuko Hara, Shintaro Nakano, Masayuki Yamasaki, Eiki Sakamoto, Noriho Ishimatsu, Yuji Isomoto, Hajime Gochuico, Bernadette R. Suffredini, Anthony F. Mukae, Hiroshi Kurazono, Hisao Hirayama, Toshiya Moss, Joel Kohno, Shigeru TI Identification of Helicobacter pylori VacA in human lung and its effects on lung cells SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Helicobacter pylori; VacA; A549 cells; Normal human bronchial epithelial cells; Interleukin-8; Interleukin-6 ID IDIOPATHIC PULMONARY-FIBROSIS; BRONCHOALVEOLAR LAVAGE FLUID; TYROSINE-PHOSPHATASE-BETA; GASTROESOPHAGEAL-REFLUX; INTERSTITIAL PNEUMONIA; VACUOLATING CYTOTOXIN; DISEASE; PEPSIN; BRONCHIECTASIS; ASPIRATION AB Objective: Prior reports suggested that infection with Helicobacter pylori was associated with respiratory diseases; pathogenetic mechanisms however, were not defined. We tested the hypothesis that VacA, an exotoxin of H. pylori, a gastric pathogen, was aspirated into the lung and could stimulate secretion of inflammatory cytokines by lung epithelial cells. Methods: The presence of VacA was determined by immunohistochemistry in surgical lung biopsy tissue samples from 72 patients with interstitial pneumonia. The effects of VacA on A549 human alveolar epithelial adenocarcinoma cells and normal human bronchial epithelial cells were determined. After incubation with VacA, the secretions of cytokines were measured by Multiplex Luminex (R) Assays. Results: VacA was detected with anti-VacA antibodies in bronchial epithelial cells and alveolar epithelial cells from 10 of 72 patients with interstitial pneumonia. VacA was more prevalent in lungs of patients with collagen vascular disease-associated interstitial pneumonia than in those of patients with idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia and cryptogenic organizing pneumonia. Incubation of A549 cells and normal human bronchial epithelial cells with VacA for 24 h was cytotoxic, and resulted in vacuolation. VacA induced interleukin-8 production by A549 cells and normal human bronchial epithelial cells and interleukin-6 production by A549 cells. Based on multiplex screening, interleukin-8 and interleukin-6 were the primary secretory products induced by VacA. Conclusions: H. pylori VacA is present in human lung and can induce interleukin-8 and interleukin-6 production by human lung cells. VacA could have a role in the pathogenesis of respiratory diseases by its cytotoxic effects and by inducing the secretion of interleukin-8 and interleukin-6 by targeted airway epithelial cells. (C) 2015 Elsevier Inc. All rights reserved. C1 [Nakashima, Shota; Kakugawa, Tomoyuki; Yura, Hirokazu; Tomonaga, Masaomi; Harada, Tatsuhiko; Hara, Atsuko; Hara, Shintaro; Sakamoto, Noriho; Ishimatsu, Yuji; Kohno, Shigeru] Nagasaki Univ, Dept Internal Med 2, Sch Med, Nagasaki 8528501, Japan. [Nakano, Masayuki; Hirayama, Toshiya] Nagasaki Univ, Inst Trop Med, Dept Bacteriol, Nagasaki 8528523, Japan. [Yamasaki, Eiki; Kurazono, Hisao] Obihiro Univ Agr & Vet Med, Dept Anim & Food Hyg, Obihiro, Hokkaido 0808555, Japan. [Isomoto, Hajime] Nagasaki Univ Hosp, Dept Gastroenterol & Hepatol, Nagasaki 8528501, Japan. [Gochuico, Bernadette R.] NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Suffredini, Anthony F.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Mukae, Hiroshi] Univ Occupat & Environm Hlth, Dept Resp Med, Kitakyushu, Fukuoka 8078555, Japan. [Moss, Joel] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. RP Kakugawa, T (reprint author), Nagasaki Univ, Dept Internal Med 2, Sch Med, 1-7-1 Sakamoto, Nagasaki 8528501, Japan. EM kakugawa@nagasaki-u.ac.jp FU National Institutes of Health; NHLBI; NHGRI, CC FX B.G., A.S. and J.M. were supported by the Intramural Research Program, National Institutes of Health, NHGRI, CC and NHLBI, respectively. NR 36 TC 7 Z9 7 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAY 8 PY 2015 VL 460 IS 3 BP 721 EP 726 DI 10.1016/j.bbrc.2015.03.096 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA CP4XG UT WOS:000359885300038 PM 25817795 ER PT J AU Kuo, CL Vsevolozhskaya, OA Zaykin, DV AF Kuo, Chia-Ling Vsevolozhskaya, Olga A. Zaykin, Dmitri V. TI Assessing the Probability that a Finding Is Genuine for Large-Scale Genetic Association Studies SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; COMBINING P-VALUES; FALSE DISCOVERY; QUANTITATIVE TRAIT; TRUNCATED PRODUCT; POSITIVE REPORT; MICROARRAY; EPIDEMIOLOGY; METAANALYSIS; REPLICATION AB Genetic association studies routinely involve massive numbers of statistical tests accompanied by P-values. Whole genome sequencing technologies increased the potential number of tested variants to tens of millions. The more tests are performed, the smaller P-value is required to be deemed significant. However, a small P-value is not equivalent to small chances of a spurious finding and significance thresholds may fail to serve as efficient filters against false results. While the Bayesian approach can provide a direct assessment of the probability that a finding is spurious, its adoption in association studies has been slow, due in part to the ubiquity of P-values and the automated way they are, as a rule, produced by software packages. Attempts to design simple ways to convert an association P-value into the probability that a finding is spurious have been met with difficulties. The False Positive Report Probability (FPRP) method has gained increasing popularity. However, FPRP is not designed to estimate the probability for a particular finding, because it is defined for an entire region of hypothetical findings with P-values at least as small as the one observed for that finding. Here we propose a method that lets researchers extract probability that a finding is spurious directly from a P-value. Considering the counterpart of that probability, we term this method POFIG: the Probability that a Finding is Genuine. Our approach shares FPRP's simplicity, but gives a valid probability that a finding is spurious given a P-value. In addition to straightforward interpretation, POFIG has desirable statistical properties. The POFIG average across a set of tentative associations provides an estimated proportion of false discoveries in that set. POFIGs are easily combined across studies and are immune to multiple testing and selection bias. We illustrate an application of POFIG method via analysis of GWAS associations with Crohn's disease. C1 [Kuo, Chia-Ling] Univ Connecticut, Dept Community Med & Hlth Care, Farmington, CT 06032 USA. [Vsevolozhskaya, Olga A.] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Zaykin, Dmitri V.] NIEHS, NIH, Res Triangle Pk, NC USA. RP Zaykin, DV (reprint author), Univ Connecticut, Dept Community Med & Hlth Care, Farmington, CT 06032 USA. EM dmitri.zaykin@nih.gov FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 0 Z9 0 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 8 PY 2015 VL 10 IS 5 AR e0124107 DI 10.1371/journal.pone.0124107 PG 24 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CL2IX UT WOS:000356768100026 PM 25955023 ER PT J AU Nansel, TR Laffel, LMB Haynie, DL Mehta, SN Lipsky, LM Volkening, LK Butler, DA Higgins, LA Liu, AY AF Nansel, Tonja R. Laffel, Lori M. B. Haynie, Denise L. Mehta, Sanjeev N. Lipsky, Leah M. Volkening, Lisa K. Butler, Deborah A. Higgins, Laurie A. Liu, Aiyi TI Improving dietary quality in youth with type 1 diabetes: randomized clinical trial of a family-based behavioral intervention SO INTERNATIONAL JOURNAL OF BEHAVIORAL NUTRITION AND PHYSICAL ACTIVITY LA English DT Article DE Behavioral intervention; Nutrition; Diet; Type 1 diabetes; Children; Adolescents ID NUTRITION EXAMINATION SURVEY; CARDIOVASCULAR-DISEASE RISK; WHOLE-GRAIN INTAKE; GLYCEMIC CONTROL; NATIONAL-HEALTH; NUTRIENT INTAKE; WEIGHT-GAIN; DASH DIET; CHILDREN; ADOLESCENTS AB Background: Diets of children with type 1 diabetes are low in fruits, vegetables, and whole grains, and high in foods of minimal nutritional value, increasing risk for future adverse health outcomes. This 18-month randomized clinical trial tested the effect of a family-based behavioral intervention integrating motivational interviewing, active learning, and applied problem-solving on the primary outcomes of dietary intake and glycemic control among youth with type 1 diabetes. Methods: A parallel-group study with equal randomization was conducted at an outpatient, free-standing, multidisciplinary tertiary diabetes center in the United States. Eligible youth were those age 8-16 years with type 1 diabetes diagnosis >= 1 year and hemoglobin A1c (HbA1c) >= 6.5% and <= 10.0%. Participants were 136 parent-youth dyads (treatment n = 66, control n = 70). The intervention consisted of 9 in-clinic sessions delivered to the child and parent; control condition comprised equivalent assessments and number of contacts without dietary advice. Dietary intake was assessed using 3-day diet records at 6 time points across the 18-month study. Dietary outcomes included the Healthy Eating Index-2005 (HEI2005; index measuring conformance to the 2005 United States Dietary Guidelines for Americans) and Whole Plant Food Density (WPFD; number of cup or ounce equivalents per 1000 kcal of whole grains, whole fruit, vegetables, legumes, nuts, and seeds consumed). HbA1c was obtained every 3 months. Overall comparison of outcome variables between intervention and usual care groups was conducted using permutation tests. Results: There was a positive intervention effect across the study duration for HEI2005 (p = .015) and WPFD (p = .004). At 18 months, HEI2005 was 7.2 greater (mean +/- SE 64.6 +/- 2.0 versus 57.4 +/- 1.6), and WPFD was 0.5 greater (2.2 +/- 0.1 versus 1.7 +/- 0.1) in the intervention group versus control. There was no difference between groups in HbA1c across the study duration. Conclusions: This behavioral nutrition intervention improved dietary quality among youth with type 1 diabetes, but did not impact glycemic control. Findings indicate the potential utility of incorporating such strategies into clinical care, and suggest that improvement in diet quality can be achieved in families living with this burdensome disease. C1 [Nansel, Tonja R.; Haynie, Denise L.; Lipsky, Leah M.; Liu, Aiyi] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Hlth Behav Branch, Bethesda, MD 20892 USA. [Laffel, Lori M. B.; Mehta, Sanjeev N.; Volkening, Lisa K.; Butler, Deborah A.; Higgins, Laurie A.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Pediat Adolescent & Young Adult Sect,Genet & Epid, Boston, MA 02115 USA. RP Nansel, TR (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Hlth Behav Branch, 6100 Execut Blvd Rm 7B13R,MSC 7510, Bethesda, MD 20892 USA. EM nanselt@mail.nih.gov OI Nansel, Tonja/0000-0002-8298-7595; Liu, Aiyi/0000-0002-6618-5082; Haynie, Denise/0000-0002-8270-6079; Lipsky, Leah/0000-0003-2645-4388 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development Intramural Research Program [HHSN267200703434C, HHSN2752008000031/HHSN275002]; National Institute of Diabetes and Digestive and Kidney Diseases Diabetes Research Center [P30DK036836] FX This research was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Intramural Research Program (contract #HHSN267200703434C and #HHSN2752008000031/HHSN275002). Support for the research infrastructure for study performance at the clinical site was provided to the Joslin Diabetes Center by the National Institute of Diabetes and Digestive and Kidney Diseases Diabetes Research Center grant P30DK036836. NR 52 TC 8 Z9 8 U1 2 U2 16 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5868 J9 INT J BEHAV NUTR PHY JI Int. J. Behav. Nutr. Phys. Act. PD MAY 8 PY 2015 VL 12 AR 58 DI 10.1186/s12966-015-0214-4 PG 11 WC Nutrition & Dietetics; Physiology SC Nutrition & Dietetics; Physiology GA CI5ZR UT WOS:000354838900001 PM 25952160 ER PT J AU Sabatino, SA White, MC Thompson, TD Klabunde, CN AF Sabatino, Susan A. White, Mary C. Thompson, Trevor D. Klabunde, Carrie N. TI Cancer Screening Test Use - United States, 2013 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article ID INCOME C1 [Sabatino, Susan A.; White, Mary C.; Thompson, Trevor D.] CDC, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. [Klabunde, Carrie N.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Sabatino, SA (reprint author), CDC, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. EM ssabatino@cdc.gov NR 10 TC 41 Z9 41 U1 1 U2 4 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 0149-2195 EI 1545-861X J9 MMWR-MORBID MORTAL W JI MMWR-Morb. Mortal. Wkly. Rep. PD MAY 8 PY 2015 VL 64 IS 17 BP 464 EP 468 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CI2RP UT WOS:000354595000004 PM 25950253 ER PT J AU Christie, A Davies-Wayne, GJ Cordier-Lasalle, T Blackley, DJ Laney, AS Williams, DE Shinde, SA Badio, M Lo, T Mate, SE Ladner, JT Wiley, MR Kugelman, JR Palacios, G Holbrook, MR Janosko, KB de Wit, E van Doremalen, N Munster, VJ Pettitt, J Schoepp, RJ Verhenne, L Evlampidou, I Kollie, KK Sieh, SB Gasasira, A Bolay, F Kateh, FN Nyenswah, TG De Cock, KM AF Christie, Athalia Davies-Wayne, Gloria J. Cordier-Lasalle, Thierry Blackley, David J. Laney, A. Scott Williams, Desmond E. Shinde, Shivam A. Badio, Moses Lo, Terrence Mate, Suzanne E. Ladner, Jason T. Wiley, Michael R. Kugelman, Jeffrey R. Palacios, Gustavo Holbrook, Michael R. Janosko, Krisztina B. de Wit, Emmie van Doremalen, Neeltje Munster, Vincent J. Pettitt, James Schoepp, Randal J. Verhenne, Leen Evlampidou, Iro Kollie, Karsor K. Sieh, Sonpon B. Gasasira, Alex Bolay, Fatorma Kateh, Francis N. Nyenswah, Tolbert G. De Cock, Kevin M. TI Possible Sexual Transmission of Ebola Virus - Liberia, 2015 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article ID OUTBREAK; KIKWIT; CONGO C1 [Christie, Athalia; Blackley, David J.; Laney, A. Scott; Williams, Desmond E.; Lo, Terrence; De Cock, Kevin M.] CDC, Atlanta, GA 30333 USA. [Davies-Wayne, Gloria J.; Cordier-Lasalle, Thierry; Shinde, Shivam A.; Gasasira, Alex] World Hlth Org, Geneva, Switzerland. [Badio, Moses; Kollie, Karsor K.; Sieh, Sonpon B.; Kateh, Francis N.; Nyenswah, Tolbert G.] Minist Hlth & Social Welf, Monrovia, Liberia. [Mate, Suzanne E.; Ladner, Jason T.; Wiley, Michael R.; Kugelman, Jeffrey R.; Palacios, Gustavo; Schoepp, Randal J.] US Army Med Res Inst Infect Dis, Ft Detrick, MD USA. [Holbrook, Michael R.; Janosko, Krisztina B.; de Wit, Emmie; van Doremalen, Neeltje; Munster, Vincent J.; Pettitt, James] NIH, Bethesda, MD USA. [Verhenne, Leen; Evlampidou, Iro] Med Sans Frontieres, Paris, France. [Bolay, Fatorma] Liberian Inst Biomed Res, Monrovia, Liberia. RP Christie, A (reprint author), CDC, Atlanta, GA 30333 USA. EM akc9@cdc.gov RI Palacios, Gustavo/I-7773-2015; OI Palacios, Gustavo/0000-0001-5062-1938; de Wit, Emmie/0000-0002-9763-7758; Munster, Vincent/0000-0002-2288-3196 NR 9 TC 58 Z9 60 U1 0 U2 30 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 0149-2195 EI 1545-861X J9 MMWR-MORBID MORTAL W JI MMWR-Morb. Mortal. Wkly. Rep. PD MAY 8 PY 2015 VL 64 IS 17 BP 479 EP 481 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CI2RP UT WOS:000354595000006 PM 25950255 ER PT J AU Barry, C AF Barry, Clifton TI More than just bugs in spit SO SCIENCE LA English DT Editorial Material ID TREHALOSE ANALOGS; TUBERCULOSIS; MOXIFLOXACIN; LESIONS C1 [Barry, Clifton] NIAID, TB Res Sect, NIH, Bethesda, MD 20892 USA. [Barry, Clifton] Univ Cape Town, Dept Clin Lab Sci, ZA-7925 Cape Town, South Africa. [Barry, Clifton] Univ Stellenbosch, Dept Mol Biol & Human Genet, ZA-7600 Stellenbosch, South Africa. RP Barry, C (reprint author), NIAID, TB Res Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM cbarry@niaid.nih.gov RI Barry, III, Clifton/H-3839-2012 NR 12 TC 1 Z9 1 U1 0 U2 5 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 MAY 8 PY 2015 VL 348 IS 6235 BP 633 EP 634 DI 10.1126/science.aaa2886 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CH5AI UT WOS:000354045700026 PM 25953992 ER PT J AU Ardlie, KG DeLuca, DS Segre, AV Sullivan, TJ Young, TR Gelfand, ET Trowbridge, CA Maller, JB Tukiainen, T Lek, M Ward, LD Kheradpour, P Iriarte, B Meng, Y Palmer, CD Esko, T Winckler, W Hirschhorn, JN Kellis, M MacArthur, DG Getz, G Shabalin, AA Li, G Zhou, YH Nobel, AB Rusyn, I Wright, FA Lappalainen, T Ferreira, PG Ongen, H Rivas, MA Battle, A Mostafavi, S Monlong, J Sammeth, M Mele, M Reverter, F Goldmann, JM Koller, D Guigo, R McCarthy, MI Dermitzakis, ET Gamazon, ER Im, HK Konkashbaev, A Nicolae, DL Cox, NJ Flutre, T Wen, XQ Stephens, M Pritchard, JK Tu, ZD Zhang, B Huang, T Long, Q Lin, L Yang, JL Zhu, J Liu, J Brown, A Mestichelli, B Tidwell, D Lo, E Salvatore, M Shad, S Thomas, JA Lonsdale, JT Moser, MT Gillard, BM Karasik, E Ramsey, K Choi, C Foster, BA Syron, J Fleming, J Magazine, H Hasz, R Walters, GD Bridge, JP Miklos, M Sullivan, S Barker, LK Traino, HM Mosavel, M Siminoff, LA Valley, DR Rohrer, DC Jewell, SD Branton, PA Sobin, LH Barcus, M Qi, LQ McLean, J Hariharan, P Um, KS Wu, SP Tabor, D Shive, C Smith, AM Buia, SA Undale, AH Robinson, KL Roche, N Valentino, KM Britton, A Burges, R Bradbury, D Hambright, KW Seleski, J Korzeniewski, GE Erickson, K Marcus, Y Tejada, J Taherian, M Lu, CR Basile, M Mash, DC Volpi, S Struewing, JP Temple, GF Boyer, J Colantuoni, D Little, R Koester, S Carithers, LJ Moore, HM Guan, P Compton, C Sawyer, SJ Demchok, JP Vaught, JB Rabiner, CA Lockhart, NC Ardlie, KG Getz, G Wright, FA Kellis, M Volpi, S Dermitzakis, ET AF Ardlie, Kristin G. DeLuca, David S. Segre, Ayellet V. Sullivan, Timothy J. Young, Taylor R. Gelfand, Ellen T. Trowbridge, Casandra A. Maller, Julian B. Tukiainen, Taru Lek, Monkol Ward, Lucas D. Kheradpour, Pouya Iriarte, Benjamin Meng, Yan Palmer, Cameron D. Esko, Tonu Winckler, Wendy Hirschhorn, Joel N. Kellis, Manolis MacArthur, Daniel G. Getz, Gad Shabalin, Andrey A. Li, Gen Zhou, Yi-Hui Nobel, Andrew B. Rusyn, Ivan Wright, Fred A. Lappalainen, Tuuli Ferreira, Pedro G. Ongen, Halit Rivas, Manuel A. Battle, Alexis Mostafavi, Sara Monlong, Jean Sammeth, Michael Mele, Marta Reverter, Ferran Goldmann, Jakob M. Koller, Daphne Guigo, Roderic McCarthy, Mark I. Dermitzakis, Emmanouil T. Gamazon, Eric R. Im, Hae Kyung Konkashbaev, Anuar Nicolae, Dan L. Cox, Nancy J. Flutre, Timothee Wen, Xiaoquan Stephens, Matthew Pritchard, Jonathan K. Tu, Zhidong Zhang, Bin Huang, Tao Long, Quan Lin, Luan Yang, Jialiang Zhu, Jun Liu, Jun Brown, Amanda Mestichelli, Bernadette Tidwell, Denee Lo, Edmund Salvatore, Michael Shad, Saboor Thomas, Jeffrey A. Lonsdale, John T. Moser, Michael T. Gillard, Bryan M. Karasik, Ellen Ramsey, Kimberly Choi, Christopher Foster, Barbara A. Syron, John Fleming, Johnell Magazine, Harold Hasz, Rick Walters, Gary D. Bridge, Jason P. Miklos, Mark Sullivan, Susan Barker, Laura K. Traino, Heather M. Mosavel, Maghboeba Siminoff, Laura A. Valley, Dana R. Rohrer, Daniel C. Jewell, Scott D. Branton, Philip A. Sobin, Leslie H. Barcus, Mary Qi, Liqun McLean, Jeffrey Hariharan, Pushpa Um, Ki Sung Wu, Shenpei Tabor, David Shive, Charles Smith, Anna M. Buia, Stephen A. Undale, Anita H. Robinson, Karna L. Roche, Nancy Valentino, Kimberly M. Britton, Angela Burges, Robin Bradbury, Debra Hambright, Kenneth W. Seleski, John Korzeniewski, Greg E. Erickson, Kenyon Marcus, Yvonne Tejada, Jorge Taherian, Mehran Lu, Chunrong Basile, Margaret Mash, Deborah C. Volpi, Simona Struewing, Jeffery P. Temple, Gary F. Boyer, Joy Colantuoni, Deborah Little, Roger Koester, Susan Carithers, Latarsha J. Moore, Helen M. Guan, Ping Compton, Carolyn Sawyer, Sherilyn J. Demchok, Joanne P. Vaught, Jimmie B. Rabiner, Chana A. Lockhart, Nicole C. Ardlie, Kristin G. Getz, Gad Wright, Fred A. Kellis, Manolis Volpi, Simona Dermitzakis, Emmanouil T. CA GTEx Consortium TI The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans SO SCIENCE LA English DT Article ID GENOME-WIDE ASSOCIATION; HUMAN TRANSCRIPTOME; VARIANTS; DISEASE; IDENTIFICATION; LOCI; ARCHITECTURE; INDIVIDUALS; RESOURCE; SYSTEMS AB Understanding the functional consequences of genetic variation, and how it affects complex human disease and quantitative traits, remains a critical challenge for biomedicine. We present an analysis of RNA sequencing data from 1641 samples across 43 tissues from 175 individuals, generated as part of the pilot phase of the Genotype-Tissue Expression (GTEx) project. We describe the landscape of gene expression across tissues, catalog thousands of tissue-specific and shared regulatory expression quantitative trait loci (eQTL) variants, describe complex network relationships, and identify signals from genome-wide association studies explained by eQTLs. These findings provide a systematic understanding of the cellular and biological consequences of human genetic variation and of the heterogeneity of such effects among a diverse set of human tissues. C1 [DeLuca, David S.; Segre, Ayellet V.; Sullivan, Timothy J.; Young, Taylor R.; Gelfand, Ellen T.; Trowbridge, Casandra A.; Maller, Julian B.; Tukiainen, Taru; Lek, Monkol; Ward, Lucas D.; Kheradpour, Pouya; Meng, Yan; Palmer, Cameron D.; Esko, Tonu; Winckler, Wendy; Hirschhorn, Joel N.; MacArthur, Daniel G.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Maller, Julian B.; Tukiainen, Taru; Lek, Monkol; MacArthur, Daniel G.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Ward, Lucas D.; Kheradpour, Pouya; Iriarte, Benjamin] MIT, MIT Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Palmer, Cameron D.; Esko, Tonu; Hirschhorn, Joel N.] Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA 02115 USA. [Palmer, Cameron D.; Esko, Tonu; Hirschhorn, Joel N.] Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Esko, Tonu] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia. Massachusetts Gen Hosp, Canc Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Shabalin, Andrey A.] Virginia Commonwealth Univ, Ctr Biomarker Res & Personalized Med, Richmond, VA 23298 USA. [Li, Gen; Nobel, Andrew B.] Univ N Carolina, Dept Stat & Operat Res, Chapel Hill, NC 27599 USA. [Li, Gen; Nobel, Andrew B.] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. [Zhou, Yi-Hui] N Carolina State Univ, Bioinformat Res Ctr, Raleigh, NC 27695 USA. [Zhou, Yi-Hui] N Carolina State Univ, Dept Stat, Raleigh, NC 27695 USA. [Zhou, Yi-Hui] N Carolina State Univ, Dept Biol Sci, Raleigh, NC 27695 USA. [Rusyn, Ivan] Univ N Carolina, Dept Environm Sci & Engn, Chapel Hill, NC 27599 USA. [Rusyn, Ivan] Texas A&M Univ, Dept Vet Integrat Biosci, College Stn, TX 77843 USA. [Lappalainen, Tuuli; Ferreira, Pedro G.; Ongen, Halit] Univ Geneva, Sch Med, Dept Genet Med & Dev, CH-1211 Geneva, Switzerland. [Lappalainen, Tuuli; Ferreira, Pedro G.; Ongen, Halit] Univ Geneva, Inst Genet & Genom Geneva iG3, CH-1211 Geneva, Switzerland. [Lappalainen, Tuuli; Ferreira, Pedro G.; Ongen, Halit] Swiss Inst Bioinformat, CH-1211 Geneva, Switzerland. [Lappalainen, Tuuli] Stanford Univ, Dept Genet, Stanford, CA 94305 USA. [Lappalainen, Tuuli] New York Genome Ctr, New York, NY 10011 USA. [Lappalainen, Tuuli] Columbia Univ, Med Ctr, Dept Syst Biol, New York, NY 10032 USA. [Rivas, Manuel A.; McCarthy, Mark I.] Univ Oxford, Nuffield Dept Clin Med, Wellcome Trust Ctr Human Genet Res, Oxford OX3 7BN, England. [Battle, Alexis; Mostafavi, Sara; Koller, Daphne] Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA. [Battle, Alexis] Johns Hopkins Univ, Dept Comp Sci, Baltimore, MD 21218 USA. [Monlong, Jean; Sammeth, Michael; Mele, Marta; Reverter, Ferran; Goldmann, Jakob M.; Guigo, Roderic] CRG, Barcelona 08003, Catalonia, Spain. [Monlong, Jean; Sammeth, Michael; Mele, Marta; Guigo, Roderic] Univ Pompeu Fabra, Barcelona 08003, Catalonia, Spain. [Monlong, Jean] McGill Univ, Human Genet Dept, Montreal, PQ H3A 0G1, Canada. [Sammeth, Michael] Natl Inst Sci Comp, BR-25651075 Rio De Janeiro, Brazil. [Mele, Marta] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Reverter, Ferran] Univ Barcelona, E-08028 Barcelona, Spain. [Goldmann, Jakob M.] Radboud Univ Nijmegen, NL-6525 ED Nijmegen, Netherlands. [Guigo, Roderic] Inst Hosp Mar Invest Med IMIM, Barcelona 08003, Spain. [McCarthy, Mark I.] Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX3 7LJ, England. [McCarthy, Mark I.] Churchill Hosp, Oxford NIHR Biomed Res Ctr, Oxford OX3 7LJ, England. [Gamazon, Eric R.; Im, Hae Kyung; Konkashbaev, Anuar; Nicolae, Dan L.; Cox, Nancy J.] Univ Chicago, Dept Med, Sect Genet Med, Chicago, IL 60637 USA. [Gamazon, Eric R.; Im, Hae Kyung; Konkashbaev, Anuar; Nicolae, Dan L.; Cox, Nancy J.] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Gamazon, Eric R.; Konkashbaev, Anuar; Cox, Nancy J.] Vanderbilt Univ, Dept Med, Div Genet Med, Nashville, TN 37232 USA. [Flutre, Timothee; Stephens, Matthew; Pritchard, Jonathan K.] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Flutre, Timothee] INRA, Dept Plant Biol & Breeding, UMR 1334, AGAP, F-34060 Montpellier, France. [Wen, Xiaoquan] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Stephens, Matthew] Univ Chicago, Dept Stat, Chicago, IL 60637 USA. [Pritchard, Jonathan K.] Stanford Univ, Dept Genet & Biol, Stanford, CA 94305 USA. [Pritchard, Jonathan K.] Univ Chicago, Howard Hughes Med Inst, Chicago, IL 60637 USA. [Tu, Zhidong; Zhang, Bin; Huang, Tao; Long, Quan; Lin, Luan; Yang, Jialiang; Zhu, Jun] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Tu, Zhidong; Zhang, Bin; Huang, Tao; Long, Quan; Lin, Luan; Yang, Jialiang; Zhu, Jun] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA. [Liu, Jun] Harvard Univ, Dept Stat, Cambridge, MA 02138 USA. [Brown, Amanda; Mestichelli, Bernadette; Tidwell, Denee; Lo, Edmund; Salvatore, Michael; Shad, Saboor; Thomas, Jeffrey A.; Lonsdale, John T.] Natl Dis Res Interchange, Philadelphia, PA 19103 USA. [Moser, Michael T.; Gillard, Bryan M.; Karasik, Ellen; Ramsey, Kimberly; Choi, Christopher; Foster, Barbara A.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Syron, John; Fleming, Johnell; Magazine, Harold] Sci Care Inc, Phoenix, AZ USA. [Hasz, Rick] Gift Life Donor Program, Philadelphia, PA 19103 USA. [Walters, Gary D.] LifeNet Hlth, Virginia Beach, VA 23453 USA. [Bridge, Jason P.; Miklos, Mark; Sullivan, Susan] UNYTS, Buffalo, NY 14203 USA. [Barker, Laura K.; Traino, Heather M.; Mosavel, Maghboeba; Siminoff, Laura A.] Virginia Commonwealth Univ, Richmond, VA 23298 USA. [Traino, Heather M.; Siminoff, Laura A.] Temple Univ, Dept Publ Hlth, Philadelphia, PA 19122 USA. [Valley, Dana R.; Rohrer, Daniel C.; Jewell, Scott D.] Van Andel Res Inst, Grand Rapids, MI 49503 USA. [Branton, Philip A.; Carithers, Latarsha J.; Moore, Helen M.; Guan, Ping; Compton, Carolyn; Sawyer, Sherilyn J.; Vaught, Jimmie B.; Rabiner, Chana A.; Lockhart, Nicole C.] NCI, Biorepositories & Biospecimen Res Branch, Bethesda, MD 20892 USA. [Sobin, Leslie H.; Barcus, Mary; Qi, Liqun; McLean, Jeffrey; Hariharan, Pushpa; Um, Ki Sung; Wu, Shenpei; Tabor, David; Shive, Charles; Smith, Anna M.; Buia, Stephen A.; Undale, Anita H.; Robinson, Karna L.; Roche, Nancy; Valentino, Kimberly M.; Britton, Angela; Burges, Robin; Bradbury, Debra; Hambright, Kenneth W.; Korzeniewski, Greg E.] Leidos Biomed Res Inc, Clin Res Directorate, Biospecimen Res Grp, Rockville, MD 20852 USA. [Seleski, John] iDoxSolutions Inc, Bethesda, MD 20814 USA. [Erickson, Kenyon] Sapient Govt Serv, Arlington, VA 22201 USA. [Marcus, Yvonne; Tejada, Jorge; Taherian, Mehran; Lu, Chunrong; Basile, Margaret; Mash, Deborah C.] Univ Miami, Miller Sch Med, Dept Neurol, Brain Endowment Bank, Miami, FL 33136 USA. [Struewing, Jeffery P.; Temple, Gary F.; Colantuoni, Deborah] NHGRI, Div Genom Med, Bethesda, MD 20892 USA. [Boyer, Joy; Lockhart, Nicole C.] NHGRI, Div Genom & Soc, Bethesda, MD 20892 USA. [Little, Roger] NIMH, Off Sci Policy Planning & Commun, Bethesda, MD 20892 USA. [Koester, Susan] NIMH, Div Neurosci & Basic Behav Sci, Bethesda, MD 20892 USA. [Demchok, Joanne P.] NCI, Canc Diag Program, Bethesda, MD 20892 USA. RP Ardlie, KG (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. EM kardlie@broadinstitute.org; emmanouil.dermitzakis@unige.ch RI Guigo, Roderic/D-1303-2010; reverter, ferran/I-1547-2015; Sammeth, Michael/C-1157-2014; Rusyn, Ivan/S-2426-2016; OI Guigo, Roderic/0000-0002-5738-4477; reverter, ferran/0000-0002-9489-3350; Sammeth, Michael/0000-0002-6528-9883; Monlong, Jean/0000-0002-9737-5516; Wen, Xiaoquan/0000-0001-8990-2737 FU Common Fund of the Office of the Director, U.S. National Institutes of Health; NCI; NHGRI; NHLBI; NIDA; NIMH; NIA; NIAID; NINDS through NIH [HHSN261200800001E, 10XS170, 10XS171, 12ST1039, 10ST1035, HHSN268201000029C]; European Research Council; Swiss National Science Foundation; Louis-Jeantet Foundation; Wellcome Trust [098381]; Clarendon Scholarship; NDM Studentship; Univ. of Oxford Green Templeton College Award; NIH [R01 DA006227-17, R01 MH090941, R01 MH090951, R01 MH090937, R01 MH090936, R01 MH090948, R01 GM104371, R01AG046170, R01CA163772, U01AI111598-01] FX We thank the donors and their families for their generous gifts of organ donation for transplantation and tissue donations for the GTEx research study; the Genomics Platform at the Broad Institute for data generation; J. Nedzel, K. Huang, and K. Hadley for work on the GTEx Portal; L. Gaffney for help with figures; and members of the Analysis Working Group for scientific editing and feedback. The primary and processed data used to generate the analyses presented here are available in the following locations: all primary sequence and clinical data files, and any other protected data, are deposited in and available from dbGaP (www.ncbi.nlm.nih.gov/gap) (phs000424.v3.p1, except for whole-exome sequencing data, which are part of phs000424.v5.p1); derived analysis files are available on the GTEx Portal (www.gtexportal.org). Biospecimens remaining from the study may be requested for research studies. The sample request form, biospecimen access policy, and material transfer agreement (MTA) are available on the GTEx Portal (www.gtexportal.org/home/samplesPage). Supported by the Common Fund of the Office of the Director, U.S. National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, NIA, NIAID, and NINDS through NIH contracts HHSN261200800001E (Leidos Prime contract with NCI), 10XS170 (NDRI), 10XS171 (Roswell Park Cancer Institute), 10X172 (Science Care Inc.), 12ST1039 (IDOX), 10ST1035 (Van Andel Institute), and HHSN268201000029C (Broad Institute) and through NIH grants R01 DA006227-17 (Univ. of Miami Brain Bank), R01 MH090941 (Univ. of Geneva), R01 MH090951 and R01 MH090937 (Univ. of Chicago), R01 MH090936 (Univ. of North Carolina-Chapel Hill), R01 MH090948 (Harvard Univ.), R01 GM104371 (Massachusetts General Hospital), and R01AG046170, R01CA163772, and U01AI111598-01 (Icahn School of Medicine, Mount Sinai). Additional support: European Research Council, Swiss National Science Foundation, and Louis-Jeantet Foundation (E.T.D.); Wellcome Trust grant 098381 (M.I.M.); Clarendon Scholarship, a NDM Studentship, and a Univ. of Oxford Green Templeton College Award (M.A.R.). J.K.P. is compensated for his work on the scientific advisory board for 23andMe and computational advisory board for DNANexus; W.W. is an employee and shareholder of Novartis Inc.; A. Battle is a shareholder of Google, Inc.; J. Fleming is executive director of the American Medical and Research Association; and J.B.V. and R. Little serve on the board of NDRI. Author contributions: The GTEx Consortium contributed collectively to this study. Biospecimens were provided by the Biospecimen source sites and the brain bank operations, and processed by the LDACC and comprehensive biospecimen resource. Pathological review of specimens was conducted by the pathology resource center, and all donor data entry and review by the comprehensive data resource. Data generation was undertaken by the Laboratory, Data Analysis and Coordinating Center (LDACC), and analyses were performed by all members of the Analysis Working Group. Project activities were coordinated by caHUB operations and overseen by the NHGRI, NIMH, and NCI project teams. We acknowledge the following investigators of the Analysis Working Group who contributed substantially to analyses presented here. Transcriptome variation: D.S.D., P.G.F. Single-tissue eQTL analysis: A.A.S., D.S.D., A.V.S. Multitissue eQTL analysis: T.F., X.W., A.A.S., G.L. Allele-specific expression: T.L. Splice QTLs: J.M., H.O. Functional annotation: L.D.W., P.K. Network Analyses: A. Battle, S.M., Z.T., T.H., B.I. Protein-truncating analyses: M.A.R., M.; L. GWAS analysis: E.R.G., A.V.S., L.D.W. NR 45 TC 309 Z9 311 U1 16 U2 73 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 MAY 8 PY 2015 VL 348 IS 6235 BP 648 EP 660 DI 10.1126/science.1262110 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CH5AI UT WOS:000354045700036 ER PT J AU Mina, MJ Metcalf, CJE de Swart, RL Osterhaus, ADME Grenfell, BT AF Mina, Michael J. Metcalf, C. Jessica E. de Swart, Rik L. Osterhaus, A. D. M. E. Grenfell, Bryan T. TI Long-term measles-induced immunomodulation increases overall childhood infectious disease mortality SO SCIENCE LA English DT Article ID CELL-MEDIATED-IMMUNITY; GUINEA-BISSAU; RURAL BANGLADESH; EXCESS MORTALITY; T-CELLS; VACCINATION; VIRUS; MEMORY; COMMUNITY; REDUCTION AB Immunosuppression after measles is known to predispose people to opportunistic infections for a period of several weeks to months. Using population-level data, we show that measles has a more prolonged effect on host resistance, extending over 2 to 3 years. We find that nonmeasles infectious disease mortality in high-income countries is tightly coupled to measles incidence at this lag, in both the pre- and post-vaccine eras. We conclude that long-term immunologic sequelae of measles drive interannual fluctuations in nonmeasles deaths. This is consistent with recent experimental work that attributes the immunosuppressive effects of measles to depletion of B and T lymphocytes. Our data provide an explanation for the long-term benefits of measles vaccination in preventing all-cause infectious disease. By preventing measles-associated immune memory loss, vaccination protects polymicrobial herd immunity. C1 [Mina, Michael J.; Metcalf, C. Jessica E.; Grenfell, Bryan T.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Mina, Michael J.] Emory Univ, Sch Med, Med Scientist Training Program, Atlanta, GA USA. [Metcalf, C. Jessica E.; Grenfell, Bryan T.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [de Swart, Rik L.; Osterhaus, A. D. M. E.] Erasmus Univ, Med Ctr, Dept Virosci, Rotterdam, Netherlands. RP Mina, MJ (reprint author), Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. EM michael.j.mina@gmail.com OI Mina, Michael/0000-0002-0674-5762 FU Bill and Melinda Gates Foundation; Science and Technology Directorate of the Department of Homeland Security [HSHQDC-12-C-00058]; RAPIDD program of the Science and Technology Directorate of the Department of Homeland Security; Fogarty International Center, National Institutes of Health FX Data for analyses regarding England and Wales were retrieved from the Office of Population Censuses and Surveys and the Office for National Statistics (www.ons.gov.uk). We thank P. Rohani for supplying us with historical data on pertussis, as originally described in (34). Data for U.S. analyses were retrieved from the U.S. Centers for Disease Control and Prevention, National Center for Health Statistics (www.cdc.gov/nchs). Data for Denmark was retrieved from Statistics Denmark (www.statbank.dk) and WHO (www.apps.who.int). This work is funded by the Bill and Melinda Gates Foundation, the Science and Technology Directorate of the Department of Homeland Security [contract HSHQDC-12-C-00058 (B.T.G. and C.J.E.M.)], and the RAPIDD program of the Science and Technology Directorate of the Department of Homeland Security and the Fogarty International Center, National Institutes of Health (C.J.E.M. and B.T.G). NR 40 TC 36 Z9 36 U1 5 U2 38 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 MAY 8 PY 2015 VL 348 IS 6235 BP 694 EP 699 DI 10.1126/science.aaa3662 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CH5AI UT WOS:000354045700046 PM 25954009 ER PT J AU Kalra, N Zhang, JL Thomas, A Xi, LQ Cheung, M Talarchek, J Burkett, S Tsokos, MG Chen, YB Raffeld, M Miettinen, M Pastan, I Testa, JR Hassan, R AF Kalra, Neetu Zhang, Jingli Thomas, Anish Xi, Liqiang Cheung, Mitchell Talarchek, Jacqueline Burkett, Sandra Tsokos, Maria G. Chen, Yuanbin Raffeld, Mark Miettinen, Markku Pastan, Ira Testa, Joseph R. Hassan, Raffit TI Mesothelioma patient derived tumor xenografts with defined BAP1 mutations that mimic the molecular characteristics of human malignant mesothelioma SO BMC CANCER LA English DT Article DE Mesothelioma; Malignant effusions; BAP1; CDKN2A; Patient derived tumor xenografts ID CELL LUNG-CANCER; PLEURAL MESOTHELIOMA; GENE; LINES; ESTABLISHMENT; DELETION; SENSITIVITY; SUPPRESSOR; VARIANT; EGFR AB Background: The development and evaluation of new therapeutic approaches for malignant mesothelioma has been sparse due, in part, to lack of suitable tumor models. Methods: We established primary mesothelioma cultures from pleural and ascitic fluids of five patients with advanced mesothelioma. Electron microscopy and immunohistochemistry (IHC) confirmed their mesothelial origin. Patient derived xenografts were generated by injecting the cells in nude or SCID mice, and malignant potential of the cells was analyzed by soft agar colony assay. Molecular profiles of the primary patient tumors, early passage cell cultures, and patient derived xenografts were assessed using mutational analysis, fluorescence in situ hybridization (FISH) analysis and IHC. Results: Primary cultures from all five tumors exhibited morphologic and IHC features consistent to those of mesothelioma cells. Mutations of BAP1 and CDKN2A were each detected in four tumors. BAP1 mutation was associated with the lack of expression of BAP1 protein. Three cell cultures, all of which were derived from BAP1 mutant primary tumors, exhibited anchorage independent growth and also formed tumors in mice, suggesting that BAP1 loss may enhance tumor growth in vivo. Both early passage cell cultures and mouse xenograft tumors harbored BAP1 mutations and CDKN2A deletions identical to those found in the corresponding primary patient tumors. Conclusions: The mesothelioma patient derived tumor xenografts with mutational alterations that mimic those observed in patient tumors which we established can be used for preclinical development of novel drug regimens and for studying the functional aspects of BAP1 biology in mesothelioma. C1 [Kalra, Neetu; Zhang, Jingli; Thomas, Anish; Chen, Yuanbin; Hassan, Raffit] NCI, Thorac & GI Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Xi, Liqiang; Raffeld, Mark; Miettinen, Markku] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Cheung, Mitchell; Talarchek, Jacqueline; Testa, Joseph R.] Fox Chase Canc Ctr, Canc Biol Program, Philadelphia, PA 19111 USA. [Burkett, Sandra] NCI, Mol Cytogenet Core Facil, Frederick, MD 21702 USA. [Tsokos, Maria G.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Pastan, Ira] NCI, Ctr Canc Res, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Hassan, R (reprint author), NCI, Thorac & GI Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM hassanr@mail.nih.gov OI Thomas, Anish/0000-0003-3293-3115 FU NIH, National Cancer Institute, Center for Cancer Research; NCI [R01 CA175691]; Mesothelioma Applied Research Foundation FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; additional partial support was provided by NCI R01 CA175691 (J.R.T) and the Mesothelioma Applied Research Foundation (M.C.). NR 32 TC 4 Z9 4 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD MAY 8 PY 2015 VL 15 AR 376 DI 10.1186/s12885-015-1362-2 PG 11 WC Oncology SC Oncology GA CI0LV UT WOS:000354429500001 PM 25952750 ER PT J AU Portugal, S Tipton, CM Sohn, H Kone, Y Wang, J Li, SP Skinner, J Virtaneva, K Sturdevant, DE Porcella, SF Doumbo, OK Doumbo, S Kayentao, K Ongoiba, A Traore, B Sanz, I Pierce, SK Crompton, PD AF Portugal, Silvia Tipton, Christopher M. Sohn, Haewon Kone, Younoussou Wang, Jing Li, Shanping Skinner, Jeff Virtaneva, Kimmo Sturdevant, Daniel E. Porcella, Stephen F. Doumbo, Ogobara K. Doumbo, Safiatou Kayentao, Kassoum Ongoiba, Aissata Traore, Boubacar Sanz, Inaki Pierce, Susan K. Crompton, Peter D. TI Malaria-associated atypical memory B cells exhibit markedly reduced B cell receptor signaling and effector function SO ELIFE LA English DT Article ID PLASMODIUM-FALCIPARUM; ANTIBODY-RESPONSES; UNSTABLE MALARIA; ENDEMIC AREA; INDIVIDUALS; ACTIVATION; PROLIFERATION; TRANSMISSION; MEROZOITE; PROMOTES AB Protective antibodies in Plasmodium falciparum malaria are only acquired after years of repeated infections. Chronic malaria exposure is associated with a large increase in atypical memory B cells (MBCs) that resemble B cells expanded in a variety of persistent viral infections. Understanding the function of atypical MBCs and their relationship to classical MBCs will be critical to developing effective vaccines for malaria and other chronic infections. We show that VH gene repertoires and somatic hypermutation rates of atypical and classical MBCs are indistinguishable indicating a common developmental history. Atypical MBCs express an array of inhibitory receptors and B cell receptor (BCR) signaling is stunted in atypical MBCs resulting in impaired B cell responses including proliferation, cytokine production and antibody secretion. Thus, in response to chronic malaria exposure, atypical MBCs appear to differentiate from classical MBCs becoming refractory to BCR-mediated activation and potentially interfering with the acquisition of malaria immunity. C1 [Portugal, Silvia; Sohn, Haewon; Wang, Jing; Li, Shanping; Skinner, Jeff; Pierce, Susan K.; Crompton, Peter D.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Tipton, Christopher M.; Sanz, Inaki] Emory Univ, Dept Med, Div Rheumatol, Lowance Ctr Human Immunol, Atlanta, GA 30322 USA. [Tipton, Christopher M.] Emory Univ, Dept Pediat, Div Rheumatol, Lowance Ctr Human Immunol, Atlanta, GA 30322 USA. [Kone, Younoussou; Doumbo, Ogobara K.; Doumbo, Safiatou; Kayentao, Kassoum; Ongoiba, Aissata; Traore, Boubacar] Univ Sci Tech & Technol Bamako, Dept Epidemiol Parasit Dis, Int Ctr Excellence Res, Malaria Res & Training Ctr, Bamako, Mali. [Virtaneva, Kimmo; Sturdevant, Daniel E.; Porcella, Stephen F.] NIAID, Rocky Mt Lab Res Technol Sect, Genom Unit, NIH, Hamilton, MT USA. RP Crompton, PD (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM pcrompton@niaid.nih.gov RI Crompton, Peter/N-1130-2016; OI Skinner, Jeff/0000-0001-5697-0442 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases [Z01 AI000949-02 LIG]; National Institutes of Health (NIH) FX Division of Intramural Research, National Institute of Allergy and Infectious Diseases Z01 AI000949-02 LIG Peter D Crompton; National Institutes of Health (NIH) Peter D Crompton NR 56 TC 20 Z9 20 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 MAY 8 PY 2015 VL 4 AR e07218 DI 10.7554/eLife.07218 PG 21 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DJ5SH UT WOS:000374269900001 ER PT J AU SanGiovanni, JP Chen, J Gupta, AS Smith, LEH Sapieha, P Lee, PH AF SanGiovanni, John Paul Chen, Jing Gupta, Ankur S. Smith, Lois E. H. Sapieha, Przemyslaw Lee, Phil H. TI Netrin-1-DCC Signaling Systems and Age-Related Macular Degeneration SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; ANGIOGENESIS; HYPOXIA; DISEASE; GROWTH AB We conducted a nested candidate gene study and pathway-based enrichment analysis on data from a multi-national 77,000-person project on the molecular genetics of age-related macular degeneration (AMD) to identify AMD-associated DNA-sequence variants in genes encoding constituents of a netrin-1 (NTN1)-based signaling pathway that converges on DNA-binding transcription complexes through a 3'-5'-cyclic adenosine monophosphate-calcineurin (cAMP-CN)-dependent axis. AMD-associated single nucleotide polymorphisms (SNPs) existed in 9 linkage disequilibrium-independent genomic regions; these included loci overlapping NTN1 (rs9899630, P <= 9.48 x 10(-5)), DCC (Deleted in Colorectal Cancer)-the gene encoding a primary NTN1 receptor (rs8097127, P <= 3.03 x 10(-5)), and 6 other netrin-related genes. Analysis of the NTN1-DCC pathway with exact methods demonstrated robust enrichment with AMD-associated SNPs (corrected P-value = 0.038), supporting the idea that processes driven by NTN1-DCC signaling systems operate in advanced AMD. The NTN1-DCC pathway contains targets of FDA-approved drugs and may offer promise for guiding applied clinical research on preventive and therapeutic interventions for AMD. C1 [SanGiovanni, John Paul] NIAAA, Sect Nutr Neurosci, NIH, Bethesda, MD 20892 USA. [Chen, Jing; Smith, Lois E. H.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston Childrens Hosp, Boston, MA USA. [Gupta, Ankur S.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Sapieha, Przemyslaw] Univ Montreal, Dept Ophthalmol, Maisonneuve Rosemont Hosp, Res Ctr, Montreal, PQ, Canada. [Lee, Phil H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Analyt & Translat Genet Unit,Ctr Human Genet Res, Boston, MA USA. RP SanGiovanni, JP (reprint author), NIAAA, Sect Nutr Neurosci, NIH, Bethesda, MD 20892 USA. EM jpsangio@post.harvard.edu FU Canadian Institutes of Health Research [221478]; Foundation Fighting Blindness; U.S. National Institute of Mental Health (NIMH) grant [K99MH101367]; U.S. National Eye Institute [NEI EY022274, EY017017, PO1 HD18655, R01 EY024963]; Lowey Medical Research Institute; European Commission FP7 Project [305485]; NIH Intramural Research Program; Bright Focus Foundation FX PS holds a Canada Research Chair in Retinal Cell Biology and is supported by operating grants from the Canadian Institutes of Health Research (221478) and the Foundation Fighting Blindness. PHL is supported by U.S. National Institute of Mental Health (NIMH) grant K99MH101367. LEHS was supported by grants from the U.S. National Eye Institute (NEI EY022274, EY017017, PO1 HD18655), The Lowey Medical Research Institute, European Commission FP7 Project 305485 PREVENT-ROP. JPSG was supported by the NIH Intramural Research Program. JC was supported by the Bright Focus Foundation and a grant from the U.S. National Eye Institute (R01 EY024963). None of these funders had a role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; Extant GWA study findings were published by Fritsche et al.[12] The data used for the original genetic analyses were obtained from the NEI Study of Age-Related Macular Degeneration (NEI-AMD) Database found at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id = phs000182.v2.p1 (dbGaP Study Accession: phs000182.v2.p1). We thank NEI-AMD and AGC participants and the NEI-AMD and AGC Research Groups for their valuable contributions to this research project. JPSG was supported by the NIH Intramural Research Program. PS holds a Canada Research Chair in Retinal Cell Biology and is supported by operating grants from the Canadian Institutes of Health Research (221478) and the Foundation Fighting Blindness. NR 24 TC 1 Z9 1 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 7 PY 2015 VL 10 IS 5 AR e0125548 DI 10.1371/journal.pone.0125548 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DA4RU UT WOS:000367788800006 PM 25950802 ER PT J AU Cui, YZ Onozawa, M Garber, HR Samsel, L Wang, ZY McCoy, JP Burkett, S Wu, XL Aplan, PD Mackall, CL AF Cui, Yongzhi Onozawa, Masahiro Garber, Haven R. Samsel, Leigh Wang, Ziyao McCoy, J. Philip Burkett, Sandra Wu, Xiaolin Aplan, Peter D. Mackall, Crystal L. TI Thymic expression of a T-cell receptor targeting a tumor-associated antigen coexpressed in the thymus induces T-ALL SO BLOOD LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; VIVO ANTITUMOR EFFICACY; GENE-THERAPY; CANCER REGRESSION; TRANSGENIC MICE; HIGH AVIDITY; ALPHA-GENES; IN-VITRO; SCID-X1; LYMPHOCYTES AB T-cell receptors (TCRs) and chimeric antigen receptors recognizing tumor-associated antigens (TAAs) can now be engineered to be expressed on a wide array of immune effectors. Engineered receptors targeting TAAs have most commonly been expressed on mature T cells, however, some have postulated that receptor expression on immune progenitors could yield T cells with enhanced potency. We generated mice (survivin-TCR-transgenic [Sur-TCR-Tg]) expressing a TCR recognizing the immunodominant epitope (Sur(20-28)) of murine survivin during early stages of thymopoiesis. Spontaneous T-cell acute lymphoblastic leukemia (T-ALL) occurred in 100% of Sur-TCR-Tg mice derived from 3 separate founders. The leukemias expressed the Sur-TCR and signaled in response to the Sur(20-28) peptide. In preleukemic mice, we observed increased cycling of double-negative thymocytes expressing the Sur-TCR and increased nuclear translocation of nuclear factor of activated T cells, consistent with TCR signaling induced by survivin expression in the murine thymus. beta 2M(-/-) Sur-TCR-Tg mice, which cannot effectively present survivin peptides on class I major histocompatibility complex, had significantly diminished rates of leukemia. We conclude that TCR signaling during the early stages of thymopoiesis mediates an oncogenic signal, and therefore expression of signaling receptors on developing thymocytes with specificity for TAAs expressed in the thymus could pose a risk for neoplasia, independent of insertional mutagenesis. C1 [Cui, Yongzhi; Garber, Haven R.; Wang, Ziyao; Mackall, Crystal L.] NCI, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Onozawa, Masahiro; Aplan, Peter D.] NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Samsel, Leigh; McCoy, J. Philip] NHLBI, Flow Cytometry Core Facil, NIH, Bethesda, MD 20892 USA. [Burkett, Sandra] NCI, Mol Cytogenet Core, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21701 USA. [Wu, Xiaolin] Leidos Biomed Res Inc, Canc Res Technol Program, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Mackall, CL (reprint author), NCI, Pediat Oncol Branch, Ctr Canc Res, 10-CRC,1W-3750,MSC 1104,10 Ctr Dr, Bethesda, MD 20892 USA. EM mackallc@mail.nih.gov RI Aplan, Peter/K-9064-2016; OI Garber, Haven/0000-0002-8221-2167 FU NCI, NIH; Frederick National Laboratory for Cancer Research, NIH [HHSN261200800001E] FX This work was supported by the Intramural Research Program of the NCI, NIH. This project has been funded in part with federal funds from the Frederick National Laboratory for Cancer Research, NIH, under contract HHSN261200800001E. NR 52 TC 2 Z9 2 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAY 7 PY 2015 VL 125 IS 19 BP 2958 EP 2967 DI 10.1182/blood-2014-10-609271 PG 10 WC Hematology SC Hematology GA CJ7OX UT WOS:000355687500016 PM 25814528 ER PT J AU Ledgerwood, JE Bellamy, AR Belshe, R Bernstein, DI Edupuganti, S Patel, SM Renehan, P Zajdowicz, T Schwartz, R Koup, R Bailer, RT Yamshchikov, GV Enama, ME Sarwar, U Larkin, B Graham, BS AF Ledgerwood, Julie E. Bellamy, Abbie R. Belshe, Robert Bernstein, David I. Edupuganti, Srilatha Patel, Shital M. Renehan, Phyllis Zajdowicz, Thad Schwartz, Richard Koup, Richard Bailer, Robert T. Yamshchikov, Galina V. Enama, Mary E. Sarwar, Uzma Larkin, Brenda Graham, Barney S. CA VRC 701 Study Team TI DNA Priming for Seasonal Influenza Vaccine: A Phase 1b Double-Blind Randomized Clinical Trial SO PLOS ONE LA English DT Article ID INTERVAL AB Background The efficacy of current influenza vaccines is limited in vulnerable populations. DNA vaccines can be produced rapidly, and may offer a potential strategy to improve vaccine immunogenicity, indicated by studies with H5 influenza DNA vaccine prime followed by inactivated vaccine boost. Methods Four sites enrolled healthy adults, randomized to receive 2011/12 seasonal influenza DNA vaccine prime (n=65) or phosphate buffered saline (PBS) (n=66) administered intramuscularly with Biojector. All subjects received the 2012/13 seasonal inactivated influenza vaccine, trivalent (IIV3) 36 weeks after the priming injection. Vaccine safety and tolerability was the primary objective and measurement of antibody response by hemagglutination inhibition (HAI) was the secondary objective. Results The DNA vaccine prime-IIV3 boost regimen was safe and well tolerated. Significant differences in HAI responses between the DNA vaccine prime and the PBS prime groups were not detected in this study. Conclusion While DNA priming significantly improved the response to a conventional monovalent H5 vaccine in a previous study, it was not effective in adults using seasonal influenza strains, possibly due to pre-existing immunity to the prime, unmatched prime and boost antigens, or the lengthy 36 week boost interval. Careful optimization of the DNA prime-IIV3 boost regimen as related to antigen matching, interval between vaccinations, and pre-existing immune responses to influenza is likely to be needed in further evaluations of this vaccine strategy. In particular, testing this concept in younger age groups with less prior exposure to seasonal influenza strains may be informative. C1 [Ledgerwood, Julie E.; Schwartz, Richard; Koup, Richard; Bailer, Robert T.; Yamshchikov, Galina V.; Enama, Mary E.; Sarwar, Uzma; Larkin, Brenda; Graham, Barney S.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Bellamy, Abbie R.; Renehan, Phyllis; Zajdowicz, Thad] EMMES Corp, Rockville, MD USA. [Belshe, Robert] St Louis Univ, Edward A Daisy Res Ctr, St Louis, MO 63103 USA. [Bernstein, David I.] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. [Edupuganti, Srilatha] Emory Univ, Sch Med, Dept Med, Div Infect Dis, Atlanta, GA USA. [Patel, Shital M.] Baylor Coll Med, Dept Med & Mol Virol & Microbiol, Houston, TX 77030 USA. RP Ledgerwood, JE (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM Ledgerwood@mail.nih.gov FU National Institute of Allergy and Infectious Diseases (NIAID) Intramural Research program; EMMES Corporation; [HHSN272201000049I] FX This clinical study was conducted with funding and support by the National Institute of Allergy and Infectious Diseases (NIAID) Intramural Research program, using resources provided by the American Recovery and Reinvestment Act of 2009 (Recovery Act), and contract #HHSN272201000049I awarded to the EMMES Corporation (AB, TZ, PR, RB, RTB, DB, SE, SP). The EMMES Corporation provided support in the form of salaries for authors AB, PR and TZ, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section. NR 11 TC 2 Z9 2 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 MAY 7 PY 2015 VL 10 IS 5 AR UNSP e0125914 DI 10.1371/journal.pone.0125914 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CH7KF UT WOS:000354214400054 PM 25950433 ER PT J AU Mohandas, R Segal, MS Huo, TY Handberg, EM Petersen, JW Johnson, BD Sopko, G Merz, CNB Pepine, CJ AF Mohandas, Rajesh Segal, Mark S. Huo, Tianyao Handberg, Eileen M. Petersen, John W. Johnson, B. Delia Sopko, George Merz, C. Noel Bairey Pepine, Carl J. TI Renal Function and Coronary Microvascular Dysfunction in Women with Symptoms/Signs of Ischemia SO PLOS ONE LA English DT Article ID CHRONIC KIDNEY-DISEASE; SYNDROME EVALUATION WISE; ARTERY-DISEASE; FLOW RESERVE; CARDIOVASCULAR EVENTS; MYOCARDIAL-PERFUSION; CHEST-PAIN; INFLAMMATION; REACTIVITY; ADENOSINE AB Objectives Chronic kidney disease (CKD) is more prevalent among women and is associated with adverse cardiovascular events. Among women with symptoms and signs of ischemia enrolled in the Women's Ischemia Syndrome Evaluation (WISE), a relatively high mortality rate was observed in those with no obstructive coronary artery disease. Coronary microvascular dysfunction or reduced coronary flow reserve (CFR) was a strong and independent predictor of adverse outcomes. The objective of this analysis was to determine if renal function was associated with coronary microvascular dysfunction in women with signs and symptoms of ischemia. Methods The WISE was a multicenter, prospective, cohort study of women undergoing coronary angiography for suspected ischemia. Among 198 women with additional measurements of CFR, we determined the estimated glomerular filtration rate (eGFR) with the CKD-EPI equation. We tested the association between eGFR and CFR with regression analysis. Results The median eGFR was 89 ml/min. The eGFR correlated with CFR (r = 0.22; P = 0.002). This association persisted even after covariate adjustment. Each 10-unit decrease in eGFR was associated with a 0.04-unit decrease in CFR (P = 0.04). There was a strong interaction between eGFR and age (P = 0.006): in those >= 60 years old, GFR was strongly correlated with CFR (r = 0.55; P< 0.0001). No significant correlation was noted in those < 60 years old. Conclusions Reduced renal function was significantly associated with lower CFR in women with symptoms and signs of ischemia. Coronary microvascular dysfunction warrants additional study as a mechanism contributing to increased risk of cardiovascular events in CKD. C1 [Mohandas, Rajesh; Segal, Mark S.] North Florida South Georgia Vet Hlth Syst, Nephrol & Hypertens Sect, Gainesville, FL USA. [Mohandas, Rajesh; Segal, Mark S.] Univ Florida, Div Nephrol Hypertens & Transplantat, Gainesville, FL USA. [Huo, Tianyao; Handberg, Eileen M.; Petersen, John W.; Pepine, Carl J.] Univ Florida, Div Cardiovasc Med, Gainesville, FL 32611 USA. [Johnson, B. Delia] Univ Pittsburgh, Pittsburgh, PA USA. [Sopko, George] NIH, Bethesda, MD 20892 USA. [Merz, C. Noel Bairey] Cedars Sinai Med Ctr, Barbra Streisand Womens Heart Ctr, Los Angeles, CA 90048 USA. RP Pepine, CJ (reprint author), Univ Florida, Div Cardiovasc Med, Gainesville, FL 32611 USA. EM carl.pepine@medicine.ufl.edu OI Mohandas, Rajesh/0000-0002-4430-8678 FU National Heart, Lung and Blood Institutes from National Institute on Aging [N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164, U0164829, U01 HL649141, U01 HL649241, T32HL69751, R01 HL090957, 1R03AG032631]; GCRC from National Center for Research Resources [MO1-RR00425]; National Center for Advancing Translational Sciences Grant [UL1TR000124]; Gustavus and Louis Pfeiffer Research Foundation, Danville, NJ; Women's Guild of Cedars-Sinai Medical Center, Los Angeles, CA; Ladies Hospital Aid Society of Western Pennsylvania, Pittsburgh, PA; QMED, Inc., Laurence Harbor, NJ; Edythe L. Broad Women's Heart Research Fellowship, Cedars-Sinai Medical Center, Los Angeles, CA; Barbra Streisand Women's Cardiovascular Research and Education Program, Cedars-Sinai Medical Center, Los Angeles, CA; Society for Women's Health Research (SWHR), Washington, D.C.; Linda Joy Pollin Women's Heart Health Program, Los Angeles, CA; NIH/NCATS [UL1 TR000064] FX Funding: This work was supported by contracts from the National Heart, Lung and Blood Institutes nos. N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164, grants U0164829, U01 HL649141, U01 HL649241, T32HL69751, R01 HL090957, 1R03AG032631 from the National Institute on Aging, GCRC grant MO1-RR00425 from the National Center for Research Resources, the National Center for Advancing Translational Sciences Grant UL1TR000124, and grants from the Gustavus and Louis Pfeiffer Research Foundation, Danville, NJ, The Women's Guild of Cedars-Sinai Medical Center, Los Angeles, CA, The Ladies Hospital Aid Society of Western Pennsylvania, Pittsburgh, PA, and QMED, Inc., Laurence Harbor, NJ, the Edythe L. Broad Women's Heart Research Fellowship, Cedars-Sinai Medical Center, Los Angeles, CA, the Barbra Streisand Women's Cardiovascular Research and Education Program, Cedars-Sinai Medical Center, Los Angeles, CA, The Society for Women's Health Research (SWHR), Washington, D.C., and the Linda Joy Pollin Women's Heart Health Program, Los Angeles, CA. Dr. Pepine receives funding from the NIH/NCATS Clinical and Translational Science Award to the University of Florida UL1 TR000064. No funders or sponsors had a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 0 Z9 0 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 MAY 7 PY 2015 VL 10 IS 5 AR e0125374 DI 10.1371/journal.pone.0125374 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CH7KF UT WOS:000354214400030 PM 25951606 ER PT J AU Sullivan, DJ Liu, Y Mott, BT Kaludov, N Martinov, MN AF Sullivan, David J. Liu, Yi Mott, Bryan T. Kaludov, Nikola Martinov, Martin N. TI Discovery of Novel Liver-Stage Antimalarials through Quantum Similarity SO PLOS ONE LA English DT Article ID MOLECULAR-INTERACTIONS; CETHROMYCIN; POTENT; DRUG AB Without quantum theory any understanding of molecular interactions is incomplete. In principal, chemistry, and even biology, can be fully derived from non-relativistic quantum mechanics. In practice, conventional quantum chemical calculations are computationally too intensive and time consuming to be useful for drug discovery on more than a limited basis. A previously described, original, quantum-based computational process for drug discovery and design bridges this gap between theory and practice, and allows the application of quantum methods to large-scale in silico identification of active compounds. Here, we show the results of this quantum-similarity approach applied to the discovery of novel liver-stage antimalarials. Testing of only five of the model-predicted compounds in vitro and in vivo hepatic stage drug inhibition assays with P. berghei identified four novel chemical structures representing three separate quantum classes of liver-stage antimalarials. All four compounds inhibited liver-stage Plasmodium as a single oral dose in the quantitative PCR mouse liver-stage sporozoites-challenge model. One of the newly identified compounds, cethromycin [ABT-773], a macrolide-quinoline hybrid, is a drug with an extensive (over 5,000 people) safety profile warranting its exploitation as a new weapon for the current effort of malaria eradication. The results of our molecular modeling exceed current state-of-the-art computational methods. Drug discovery through quantum similarity is data-driven, agnostic to any particular target or disease process that can evaluate multiple phenotypic, target-specific, or co-crystal structural data. This allows the incorporation of additional pharmacological requirements, as well as rapid exploration of novel chemical spaces for therapeutic applications. C1 [Sullivan, David J.; Liu, Yi] Johns Hopkins Bloomberg Sch Publ Hlth, W Harry Feinstone Dept Mol Micorbiol & Immunol, Baltimore, MD 21205 USA. [Mott, Bryan T.] NIH, Div Preclin Innovat, Natl Ctr Adv Translat Sci, Rockville, MD USA. [Kaludov, Nikola; Martinov, Martin N.] Gradient Biomodeling LLC, Park City, UT USA. RP Sullivan, DJ (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, W Harry Feinstone Dept Mol Micorbiol & Immunol, Baltimore, MD 21205 USA. EM dsulliv7@jhmi.edu; martinov.mn@gradientbiomodeling.com FU Bill & Melinda Gates Foundation [OPP1069420]; Johns Hopkins Malaria Research Institute; Bloomberg Family Foundation; Gradient Biomodeling LLC FX Funding: The research was supported by the Bill & Melinda Gates Foundation round 9 Grand Challenges Explorations award (OPP1069420) to DJS and MNM. DJS also acknowledges support from the Johns Hopkins Malaria Research Institute and The Bloomberg Family Foundation. Gradient Biomodeling LLC provided support in the form of salaries for authors NK and MM. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the author contributions section. NR 34 TC 1 Z9 1 U1 3 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 MAY 7 PY 2015 VL 10 IS 5 AR e0125593 DI 10.1371/journal.pone.0125593 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CH7KF UT WOS:000354214400037 PM 25951139 ER PT J AU Niceta, M Stellacci, E Gripp, KW Zampino, G Kousi, M Anselmi, M Traversa, A Ciolfi, A Stabley, D Bruselles, A Caputo, V Cecchetti, S Prudente, S Fiorenza, MT Boitani, C Philip, N Niyazov, D Leoni, C Nakane, T Keppler-Noreuil, K Braddock, SR Gillessen-Kaesbach, G Palleschi, A Campeau, PM Lee, BHL Pouponnot, C Stella, L Bocchinfuso, G Katsanis, N Sol-Church, K Tartaglia, M AF Niceta, Marcello Stellacci, Emilia Gripp, Karen W. Zampino, Giuseppe Kousi, Maria Anselmi, Massimiliano Traversa, Alice Ciolfi, Andrea Stabley, Deborah Bruselles, Alessandro Caputo, Viviana Cecchetti, Serena Prudente, Sabrina Fiorenza, Maria T. Boitani, Carla Philip, Nicole Niyazov, Dmitriy Leoni, Chiara Nakane, Takaya Keppler-Noreuil, Kim Braddock, Stephen R. Gillessen-Kaesbach, Gabriele Palleschi, Antonio Campeau, Philippe M. Lee, Brendan H. L. Pouponnot, Celio Stella, Lorenzo Bocchinfuso, Gianfranco Katsanis, Nicholas Sol-Church, Katia Tartaglia, Marco TI Mutations Impairing GSK3-Mediated MAF Phosphorylation Cause Cataract, Deafness, Intellectual Disability, Seizures, and a Down Syndrome-like Facies SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID FINE-LUBINSKY-SYNDROME; BZIP TRANSCRIPTION FACTOR; DNA-BINDING DOMAIN; C-MAF; MENTAL-RETARDATION; CONGENITAL CATARACT; SENSORINEURAL DEAFNESS; SHORT STATURE; DIFFERENTIATION; ACTIVATION AB Transcription factors operate in developmental processes to mediate inductive events and cell competence, and perturbation of their function or regulation can dramatically affect morphogenesis, organogenesis, and growth. We report that a narrow spectrum of amino-acid substitutions within the transactivation domain of the v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog (MAF), a leucine zipper-containing transcription factor of the AP1 superfamily, profoundly affect development. Seven different de novo missense mutations involving conserved residues of the four GSK3 phosphorylation motifs were identified in eight unrelated individuals. The distinctive clinical phenotype, for which we propose the eponym Ayme-Gripp syndrome, is not limited to lens and eye defects as previously reported for MAF/Maf loss of function but includes sensorineural deafness, intellectual disability, seizures, brachycephaly, distinctive flat facial appearance, skeletal anomalies, mammary gland hypoplasia, and reduced growth. Disease-causing mutations were demonstrated to impair proper MAF phosphorylation, ubiquitination and proteasomal degradation, perturbed gene expression in primary skin fibroblasts, and induced neurodevelopmental defects in an in vivo model. Our findings nosologically and clinically delineate a previously poorly understood recognizable multisystem disorder, provide evidence for MAF governing a wider range of developmental programs than previously appreciated, and describe a novel instance of protein dosage effect severely perturbing development. C1 [Niceta, Marcello; Stellacci, Emilia; Traversa, Alice; Ciolfi, Andrea; Bruselles, Alessandro; Tartaglia, Marco] Ist Super Sanita, Dipartimento Ematol Oncol & Med Mol, I-00161 Rome, Italy. [Niceta, Marcello; Tartaglia, Marco] Osped Pediat Bambino Gesu IRCSS, Polo Ric Malattie Rare, I-00146 Rome, Italy. [Gripp, Karen W.] Alfred I DuPont Hosp Children, Div Med Genet, Wilmington, DE 19803 USA. [Zampino, Giuseppe; Leoni, Chiara] Univ Cattolica Sacro Cuore, Ist Pediat, I-00168 Rome, Italy. [Kousi, Maria; Katsanis, Nicholas] Duke Univ, Dept Cell Biol, Ctr Human Dis Modeling, Durham, NC 27710 USA. [Anselmi, Massimiliano; Palleschi, Antonio; Stella, Lorenzo; Bocchinfuso, Gianfranco] Univ Roma Tor Vergata, Dipartimento Sci & Tecnol Chim, I-00133 Rome, Italy. [Traversa, Alice; Caputo, Viviana] Univ Roma La Sapienza, Dipartimento Med Sperimentale, I-00161 Rome, Italy. [Stabley, Deborah; Sol-Church, Katia] Alfred I DuPont Hosp Children, Ctr Pediat Res, Wilmington, DE 19803 USA. [Cecchetti, Serena] Ist Super Sanita, Dipartimento Biol Cellulare & Neurosci, I-00161 Rome, Italy. [Prudente, Sabrina] IRCCS Casa Sollievo Sofferenza, Mendel Lab, I-00198 Rome, Italy. [Fiorenza, Maria T.] Univ Roma La Sapienza, Sez Neurosci, Dipartimento Psicol, I-00161 Rome, Italy. [Boitani, Carla] Univ Roma La Sapienza, Sez Istol & Embriol Med, Dipartimento Sci Anat Istol Medicolegali & Appara, I-00161 Rome, Italy. [Philip, Nicole] Hop Enfants La Timone, Dept Med Genet, F-13385 Marseille, France. [Niyazov, Dmitriy] Ochsner Hlth Syst, Div Med Genet, New Orleans, LA 70121 USA. [Nakane, Takaya] Univ Yamanashi, Ctr Genet Med, Dept Pediat, Chuo Ku, Yamanashi 4093898, Japan. [Keppler-Noreuil, Kim] NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA. [Braddock, Stephen R.] St Louis Univ, Sch Med, Dept Pediat, St Louis, MO 63104 USA. [Gillessen-Kaesbach, Gabriele] Med Univ Lubeck, Inst Humangenet, D-23538 Lubeck, Germany. [Campeau, Philippe M.] Univ Montreal, St Justine Hosp, Dept Pediat, Montreal, PQ H3T 1C5, Canada. [Lee, Brendan H. L.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Pouponnot, Celio] Univ Paris 11, Inst Curie Ctr Rech, CNRS, INSERM,U1021,UMR 3347, F-91405 Orsay, France. RP Tartaglia, M (reprint author), Ist Super Sanita, Dipartimento Ematol Oncol & Med Mol, Viale Regina Elena 299, I-00161 Rome, Italy. EM marco.tartaglia@iss.it RI Campeau, Philippe/J-8614-2015; Cecchetti, Serena/N-1061-2015; Anselmi, Massimiliano/H-9950-2014; Stella, Lorenzo/A-7996-2010; Prudente, Sabrina/H-2886-2016; Philip, Nicole/I-2881-2016; stellacci, emilia/J-2747-2014; OI Katsanis, Nicholas/0000-0002-2480-0171; Campeau, Philippe/0000-0001-9713-7107; Anselmi, Massimiliano/0000-0001-5711-770X; Stella, Lorenzo/0000-0002-5489-7381; Prudente, Sabrina/0000-0001-9220-8981; Ciolfi, Andrea/0000-0002-6191-0978; Bocchinfuso, Gianfranco/0000-0002-5556-7691; Tartaglia, Marco/0000-0001-7736-9672; Fiorenza, Maria Teresa/0000-0002-5079-4019 FU Telethon [GGP13107]; Istituto Superiore di Sanita; Nemours Foundation; NIH [P20GM103464, P20GM103446, P50MH094268]; company BVLGARI FX We are grateful to the individuals and their families who contributed to this study. We thank Serenella Venanzi, Chiara Di Claudio, and Francesca Maiorca (ISS, Rome, Italy) for skillful technical assistance. We acknowledge submission of several DNA samples to the Center for Mendelian Genomics (CMG) in Seattle, WA; disease gene identification occurred prior to and without the use of data from the CMG. We thank BGI (Hong Kong) for the high-quality sequencing raw data. M.T., G.B., and L.S. acknowledge CINECA for computational resources (WES data and structural analyses). This work was supported in part by grants from Telethon (GGP13107 to M.T.), Istituto Superiore di Sanita (Ricerca Corrente 2013 to M.T.), Nemours Foundation (to K.S.-C.) and NIH (P20GM103464 and P20GM103446 to K.S.-C.; P50MH094268 to N.K.), and the financial support from the company BVLGARI. This work is dedicated to the memory of Luciano Cianetti (ISS, Rome, Italy). NR 43 TC 14 Z9 15 U1 2 U2 9 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 MAY 7 PY 2015 VL 96 IS 5 BP 816 EP 825 DI 10.1016/j.ajhg.2015.03.001 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA CH7AZ UT WOS:000354189300012 PM 25865493 ER PT J AU Greer, EL Blanco, MA Gu, L Sendinc, E Liu, JZ Aristizabal-Corrales, D Hsu, CH Aravind, L He, C Shi, Y AF Greer, Eric Lieberman Blanco, Mario Andres Gu, Lei Sendinc, Erdem Liu, Jianzhao Aristizabal-Corrales, David Hsu, Chih-Hung Aravind, L. He, Chuan Shi, Yang TI DNA Methylation on N-6-Adenine in C-elegans SO CELL LA English DT Article ID EPIGENETIC INHERITANCE; CAENORHABDITIS-ELEGANS; HISTONE METHYLATION; MOUSE; RNA; MECHANISMS; MEMORY; INACTIVATION; GENERATIONS; DEMETHYLASE AB In mammalian cells, DNA methylation on the fifth position of cytosine (5mC) plays an important role as an epigenetic mark. However, DNA methylation was considered to be absent in C. elegans because of the lack of detectable 5mC, as well as homologs of the cytosine DNA methyltransferases. Here, using multiple approaches, we demonstrate the presence of adenine N-6-methylation (6mA) in C. elegans DNA. We further demonstrate that this modification increases trans-generationally in a paradigm of epigenetic inheritance. Importantly, we identify a DNA demethylase, NMAD-1, and a potential DNA methyltransferase, DAMT-1, which regulate 6mA levels and crosstalk between methylations of histone H3K4 and adenines and control the epigenetic inheritance of phenotypes associated with the loss of the H3K4me2 demethylase spr-5. Together, these data identify a DNA modification in C. elegans and raise the exciting possibility that 6mA may be a carrier of heritable epigenetic information in eukaryotes. C1 [Greer, Eric Lieberman; Blanco, Mario Andres; Gu, Lei; Sendinc, Erdem; Aristizabal-Corrales, David; Hsu, Chih-Hung; Shi, Yang] Childrens Hosp, Div Newborn Med, Boston, MA 02115 USA. [Greer, Eric Lieberman; Blanco, Mario Andres; Gu, Lei; Sendinc, Erdem; Aristizabal-Corrales, David; Hsu, Chih-Hung; Shi, Yang] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Liu, Jianzhao; He, Chuan] Univ Chicago, Howard Hughes Med Inst, Dept Chem, Chicago, IL 60637 USA. [Liu, Jianzhao; He, Chuan] Univ Chicago, Howard Hughes Med Inst, Inst Biophys Dynam, Chicago, IL 60637 USA. [Aravind, L.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Greer, EL (reprint author), Childrens Hosp, Div Newborn Med, 300 Longwood Ave, Boston, MA 02115 USA. EM eric.greer@childrens.harvard.edu; yshi@hms.harvard.edu RI Liu, Jianzhao/E-9165-2011; OI Liu, Jianzhao/0000-0001-9465-6075; Greer, Eric/0000-0002-7501-7371 FU NIH Office of Research Infrastructure Programs [P40OD010440]; Tufts University Core Facility Genomics Core; University of Massachusetts Medical School Deep Sequencing Core; Helen Hay Whitney postdoctoral fellowship; National Institute on Aging of the NIH [K99AG043550]; NIH NRSA postdoctoral fellowship [1F32CA180450-01]; Leukemia & Lymphoma Society [3353-15]; National Library of Health, NIH; U.S. department of Health and Human Services; NIH [K99AG043550, GM058012, CA118487, MH096066]; Ellison Foundation; Samual Waxman Cancer Research Foundation [SWCRF-1856] FX We thank members of the Shi lab for helpful discussions, Elizabeth Pollina for feedback on the manuscript, and Madeline Schuck and LaVondea Elow for technical and administrative support. We thank the Caenorhabditis Genetics Center, which is funded by NIH Office of Research Infrastructure Programs (P40OD010440) for C. elegans strains, and the Tufts University Core Facility Genomics Core and the University of Massachusetts Medical School Deep Sequencing Core for MeDIP-seq and SMRT sequencing, respectively. E.L.G. was supported by a Helen Hay Whitney postdoctoral fellowship and a National Institute on Aging of the NIH grant (K99AG043550). M.A.B. was supported by an NIH NRSA postdoctoral fellowship (1F32CA180450-01) and is currently supported by a Special Fellow award from the Leukemia & Lymphoma Society (3353-15). L.A. was supported by funds of the Intramural Research Program of the National Library of Health, NIH, and U.S. department of Health and Human Services. C.H. is a Howard Hughes Medical Institute investigator. This work was supported by NIH grants to Y.S. (GM058012, CA118487, and MH096066) and E.L.G. (K99AG043550), by an Ellison Foundation Senior Scholar Award to Y.S, and by a Samual Waxman Cancer Research Foundation grant to Y.S. (SWCRF-1856). Y.S. is an American Cancer Society Research Professor. Y.S. is also a cofounder of Constellation Pharmaceuticals Inc. and is a member of its scientific advisory board. NR 46 TC 69 Z9 75 U1 17 U2 64 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD MAY 7 PY 2015 VL 161 IS 4 BP 868 EP 878 DI 10.1016/j.cell.2015.04.005 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CH6VT UT WOS:000354175200019 PM 25936839 ER PT J AU Gupta, K Zamanian, M Bae, C Milescu, M Krepkiy, D Tilley, DC Sack, JT Yarov-Yarovoy, V Il Kim, J Swartz, KJ AF Gupta, Kanchan Zamanian, Maryam Bae, Chanhyung Milescu, Mirela Krepkiy, Dmitriy Tilley, Drew C. Sack, Jon T. Yarov-Yarovoy, Vladimir Il Kim, Jae Swartz, Kenton J. TI Tarantula toxins use common surfaces for interacting with Kv and ASIC ion channels SO ELIFE LA English DT Article ID VOLTAGE-SENSOR TOXIN; DEPENDENT K+ CHANNEL; PROTEIN-PROTEIN DOCKING; GATING MODIFIER TOXINS; ALPHA-SCORPION TOXIN; SODIUM-CHANNELS; STRUCTURE PREDICTION; POTASSIUM CHANNELS; LIPID-MEMBRANES; MOLECULAR DETERMINANTS AB Tarantula toxins that bind to voltage-sensing domains of voltage-activated ion channels are thought to partition into the membrane and bind to the channel within the bilayer. While no structures of a voltage-sensor toxin bound to a channel have been solved, a structural homolog, psalmotoxin (PcTx1), was recently crystalized in complex with the extracellular domain of an acid sensing ion channel (ASIC). In the present study we use spectroscopic, biophysical and computational approaches to compare membrane interaction properties and channel binding surfaces of PcTx1 with the voltage-sensor toxin guangxitoxin (GxTx-1E). Our results show that both types of tarantula toxins interact with membranes, but that voltage-sensor toxins partition deeper into the bilayer. In addition, our results suggest that tarantula toxins have evolved a similar concave surface for clamping onto alpha-helices that is effective in aqueous or lipidic physical environments. C1 [Gupta, Kanchan; Zamanian, Maryam; Bae, Chanhyung; Milescu, Mirela; Krepkiy, Dmitriy; Swartz, Kenton J.] NIH, Porter Neurosci Res Ctr, Mol Physiol & Biophys Sect, Bethesda, MD 20892 USA. [Gupta, Kanchan; Zamanian, Maryam; Bae, Chanhyung; Milescu, Mirela; Krepkiy, Dmitriy; Swartz, Kenton J.] NINDS, NIH, Bethesda, MD 20892 USA. [Tilley, Drew C.; Sack, Jon T.; Yarov-Yarovoy, Vladimir] Univ Calif Davis, Dept Physiol & Membrane Biol, Davis, CA 95616 USA. [Bae, Chanhyung; Il Kim, Jae] Gwangju Inst Sci & Technol, Dept Life Sci, Gwangju, South Korea. [Milescu, Mirela] Univ Missouri, Div Biol, Columbia, MO 65211 USA. RP Swartz, KJ (reprint author), NIH, Porter Neurosci Res Ctr, Mol Physiol & Biophys Sect, Bldg 10, Bethesda, MD 20892 USA. EM swartzk@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke (NINDS) [ZIA NS002945-18, 1U01NS090581]; National Institutes of Health (NIH) [T32HL086350]; Ministry of Education, Science and Technology Basic Science Research program through the National Research Foundation of Korea [2013R1A1A2009798] FX National Institute of Neurological Disorders and Stroke (NINDS) Intramural Research Program, ZIA NS002945-18 Kenton J Swartz; National Institutes of Health (NIH) T32HL086350 Drew C Tilley; Ministry of Education, Science and Technology Basic Science Research program through the National Research Foundation of Korea, 2013R1A1A2009798 Jae Il Kim; National Institute of Neurological Disorders and Stroke (NINDS) 1U01NS090581 Jon T Sack, Vladimir Yarov-Yarovoy NR 74 TC 10 Z9 10 U1 1 U2 4 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD MAY 7 PY 2015 VL 4 AR e06774 DI 10.7554/eLife.06774 PG 20 WC Biology SC Life Sciences & Biomedicine - Other Topics GA CH8CH UT WOS:000354263000002 PM 25948544 ER PT J AU Battle, KE Cameron, E Guerra, CA Golding, N Duda, KA Howes, RE Elyazar, IRF Price, RN Baird, JK Reiner, RC Smith, DL Gething, PW Hay, SI AF Battle, Katherine E. Cameron, Ewan Guerra, Carlos A. Golding, Nick Duda, Kirsten A. Howes, Rosalind E. Elyazar, Iqbal R. F. Price, Ric N. Baird, J. Kevin Reiner, Robert C., Jr. Smith, David L. Gething, Peter W. Hay, Simon I. TI Defining the relationship between Plasmodium vivax parasite rate and clinical disease SO MALARIA JOURNAL LA English DT Article DE Malaria; Plasmodium vivax; Epidemiology; Incidence; Prevalence; Model ID GLOBAL DISTRIBUTION; FALCIPARUM MALARIA; BURDEN; AFRICA; TRANSMISSION; POPULATION; ENDEMICITY; MORTALITY; MORBIDITY; CHILDREN AB Background: Though essential to the development and evaluation of national malaria control programmes, precise enumeration of the clinical illness burden of malaria in endemic countries remains challenging where local surveillance systems are incomplete. Strategies to infer annual incidence rates from parasite prevalence survey compilations have proven effective in the specific case of Plasmodium falciparum, but have yet to be developed for Plasmodium vivax. Moreover, defining the relationship between Plasmodium vivax prevalence and clinical incidence may also allow levels of endemicity to be inferred for areas where the information balance is reversed, that is, incident case numbers are more widely gathered than parasite surveys; both applications ultimately facilitating cartographic estimates of Plasmodium vivax transmission intensity and its ensuring disease burden. Methods: A search for active case detection surveys was conducted and the recorded incidence values were matched to local, contemporary parasite rate measures and classified to geographic zones of differing relapse phenotypes. A hierarchical Bayesian model was fitted to these data to quantify the relationship between prevalence and incidence while accounting for variation among relapse zones. Results: The model, fitted with 176 concurrently measured Plasmodium vivax incidence and prevalence records, was a linear regression of the logarithm of incidence against the logarithm of age-standardized prevalence. Specific relationships for the six relapse zones where data were available were drawn, as well as a pooled overall relationship. The slope of the curves varied among relapse zones; zones with short predicted time to relapse had steeper slopes than those observed to contain long-latency relapse phenotypes. Conclusions: The fitted relationships, along with appropriate uncertainty metrics, allow for estimates of clinical incidence of known confidence to be made from wherever Plasmodium vivax prevalence data are available. This is a prerequisite for cartographic-based inferences about the global burden of morbidity due to Plasmodium vivax, which will be used to inform control efforts. C1 [Battle, Katherine E.; Cameron, Ewan; Duda, Kirsten A.; Howes, Rosalind E.; Smith, David L.; Gething, Peter W.] Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Oxford, England. [Guerra, Carlos A.; Smith, David L.] Sanaria Inst Global Hlth & Trop Med, Rockville, MD USA. [Golding, Nick; Hay, Simon I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Elyazar, Iqbal R. F.; Baird, J. Kevin] Eijkman Oxford Clin Res Unit, Jakarta, Indonesia. [Price, Ric N.] Charles Darwin Univ, Menzies Sch Hlth Res, Global & Trop Hlth Div, Darwin, NT 0909, Australia. [Price, Ric N.; Baird, J. Kevin] Univ Oxford, Ctr Trop Med & Global Hlth, Nuffield Dept Med, Oxford, England. [Reiner, Robert C., Jr.] Indiana Univ, Sch Publ Hlth, Bloomington, IN USA. [Reiner, Robert C., Jr.; Smith, David L.; Hay, Simon I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Hay, Simon I.] Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98121 USA. RP Battle, KE (reprint author), Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Tinbergen Bldg,South Parks Rd, Oxford, England. EM katherine.battle@zoo.ox.ac.uk RI Hay, Simon/F-8967-2015; OI Hay, Simon/0000-0002-0611-7272; Price, Richard/0000-0003-2000-2874; Golding, Nick/0000-0001-8916-5570; Gething, Peter/0000-0001-6759-5449 FU Wellcome Trust [095066]; Bill & Melinda Gates Foundation [OPP1053338, OPP1068048, OPP1106023, OPP1110495]; Public Health and Tropical Medicine Fellowship of the Wellcome Trust [B9RZGS0]; Wellcome Trust grant [B9RJIXO]; UK Medical Research Council (MRC) [K00669X]; UK Department for International Development (DFID) under MRC/DFID Concordat agreement [K00669X]; RAPIDD program of the Science & Technology Directorate; Department of Homeland Security; Fogarty International Center, National Institutes of Health; [091625] FX SIH is funded by a Senior Research Fellowship from the Wellcome Trust (095066), which also supports KEB, KAD and REH. NG is funded by a grant from the Bill & Melinda Gates Foundation (OPP1053338). IRFE is funded by a Public Health and Tropical Medicine Fellowship of the Wellcome Trust (B9RZGS0). RNP is a Wellcome Trust Senior Fellow in Clinical Science (091625). JKB is supported by Wellcome Trust grant (B9RJIXO). PWG is a Career Development Fellow (#K00669X) jointly funded by the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement and receives support from the Bill & Melinda Gates Foundation (#OPP1068048, #OPP1106023), which also supports EC. DLS is funded by a grant from the Bill & Melinda Gates Foundation (OPP1110495), which also supports RCR. RCR, DLS and SIH also 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. NR 38 TC 1 Z9 1 U1 3 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 MAY 7 PY 2015 VL 14 AR 191 DI 10.1186/s12936-015-0706-3 PG 14 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA CI0MZ UT WOS:000354432600001 PM 25948111 ER PT J AU Rysavy, MA Li, L Bell, EF Das, A Hintz, SR Stoll, BJ Vohr, BR Carlo, WA Shankaran, S Walsh, MC Tyson, JE Cotten, CM Smith, PB Murray, JC Colaizy, TT Brumbaugh, JE Higgins, RD AF Rysavy, Matthew A. Li, Lei Bell, Edward F. Das, Abhik Hintz, Susan R. Stoll, Barbara J. Vohr, Betty R. Carlo, Waldemar A. Shankaran, Seetha Walsh, Michele C. Tyson, Jon E. Cotten, C. Michael Smith, P. Brian Murray, Jeffrey C. Colaizy, Tarah T. Brumbaugh, Jane E. Higgins, Rosemary D. CA Eunice Kennedy Shriver Natl Inst TI Between-Hospital Variation in Treatment and Outcomes in Extremely Preterm Infants SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID BIRTH-WEIGHT INFANTS; NEONATAL RESEARCH NETWORK; GESTATIONAL-AGE; NEURODEVELOPMENTAL OUTCOMES; INTENSIVE-CARE; COGNITIVE FUNCTION; VIABILITY; BORN; MORTALITY; PREGNANCY AB BACKGROUND Between-hospital variation in outcomes among extremely preterm infants is largely unexplained and may reflect differences in hospital practices regarding the initiation of active lifesaving treatment as compared with comfort care after birth. METHODS We studied infants born between April 2006 and March 2011 at 24 hospitals included in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Data were collected for 4987 infants born before 27 weeks of gestation without congenital anomalies. Active treatment was defined as any potentially lifesaving intervention administered after birth. Survival and neurodevelopmental impairment at 18 to 22 months of corrected age were assessed in 4704 children (94.3%). RESULTS Overall rates of active treatment ranged from 22.1% (interquartile range [IQR], 7.7 to 100) among infants born at 22 weeks of gestation to 99.8% (IQR, 100 to 100) among those born at 26 weeks of gestation. Overall rates of survival and survival without severe impairment ranged from 5.1% (IQR, 0 to 10.6) and 3.4% (IQR, 0 to 6.9), respectively, among children born at 22 weeks of gestation to 81.4% (IQR, 78.2 to 84.0) and 75.6% (IQR, 69.5 to 80.0), respectively, among those born at 26 weeks of gestation. Hospital rates of active treatment accounted for 78% and 75% of the between-hospital variation in survival and survival without severe impairment, respectively, among children born at 22 or 23 weeks of gestation, and accounted for 22% and 16%, respectively, among those born at 24 weeks of gestation, but the rates did not account for any of the variation in outcomes among those born at 25 or 26 weeks of gestation. CONCLUSIONS Differences in hospital practices regarding the initiation of active treatment in infants born at 22, 23, or 24 weeks of gestation explain some of the between-hospital variation in survival and survival without impairment among such patients. (Funded by the National Institutes of Health.) C1 [Rysavy, Matthew A.; Bell, Edward F.; Murray, Jeffrey C.; Colaizy, Tarah T.; Brumbaugh, Jane E.] Univ Iowa, Stead Family Dept Pediat, Iowa City, IA 52242 USA. [Rysavy, Matthew A.] Univ Iowa, Dept Epidemiol, Iowa City, IA 52242 USA. [Li, Lei] RTI Int, Social Stat & Environm Sci Unit, Res Triangle Pk, NC USA. [Das, Abhik] RTI Int, Social Stat & Environm Sci Unit, Rockville, MD USA. [Hintz, Susan R.] Stanford Univ, Sch Med, Dept Pediat, Palo Alto, CA 94304 USA. [Stoll, Barbara J.] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA. [Stoll, Barbara J.] Childrens Healthcare Atlanta, Atlanta, GA USA. [Vohr, Betty R.] Brown Univ, Women & Infants Hosp, Dept Pediat, Providence, RI 02908 USA. [Carlo, Waldemar A.] Univ Alabama Birmingham, Dept Pediat, Birmingham, AL USA. [Shankaran, Seetha] Wayne State Univ, Dept Pediat, Detroit, MI 48202 USA. [Walsh, Michele C.] Case Western Reserve Univ, Rainbow Babies & Childrens Hosp, Dept Pediat, Cleveland, OH 44106 USA. [Tyson, Jon E.] Univ Texas Med Sch Houston, Dept Pediat, Houston, TX USA. [Cotten, C. Michael; Smith, P. Brian] Duke Univ, Dept Pediat, Durham, NC 27706 USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Bell, EF (reprint author), Univ Iowa, Dept Pediat, 200 Hawkins Dr, Iowa City, IA 52242 USA. EM edward-bell@uiowa.edu FU National Institutes of Health FX Funded by the National Institutes of Health. NR 39 TC 80 Z9 81 U1 0 U2 8 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 7 PY 2015 VL 372 IS 19 BP 1801 EP 1811 DI 10.1056/NEJMoa1410689 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA CH4BB UT WOS:000353974700005 PM 25946279 ER PT J AU Koulaouzidis, A Iakovidis, DK Karargyris, A Rondonotti, E AF Koulaouzidis, Anastasios Iakovidis, Dimitris K. Karargyris, Alexandros Rondonotti, Emanuele TI Wireless endoscopy in 2020: Will it still be a capsule? SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Editorial Material DE Capsule endoscopy; Hardware; Future; Development ID ACCURATE LESION LOCALIZATION; SMALL-BOWEL; GASTROINTESTINAL-TRACT; HEALTHY-VOLUNTEERS; FUTURE-DIRECTIONS; DRUG-DELIVERY; VIDEO; SYSTEMS; ENDOMICROSCOPY; TECHNOLOGIES AB Currently, the major problem of all existing commercial capsule devices is the lack of control of movement. In the future, with an interface application, the clinician will be able to stop and direct the device into points of interest for detailed inspection/diagnosis, and therapy delivery. This editorial presents current commercially-available new designs, European projects and delivery capsule and gives an overview of the progress required and progress that will be achieved -according to the opinion of the authors- in the next 5 year leading to 2020. C1 [Koulaouzidis, Anastasios] Royal Infirm Edinburgh NHS Trust, Endoscopy Unit, Edinburgh EH16 4SA, Midlothian, Scotland. [Iakovidis, Dimitris K.] Technol Educ Inst Cent Greece, Dept Comp Engn, Lamia 35100, Greece. [Karargyris, Alexandros] NIH, Bethesda, MD 20810 USA. [Rondonotti, Emanuele] Osped Valduce, Dept Gastroenterol, I-22100 Como, Italy. RP Koulaouzidis, A (reprint author), Royal Infirm Edinburgh NHS Trust, Endoscopy Unit, 51 Little France Crescent, Edinburgh EH16 4SA, Midlothian, Scotland. EM akoulaouzidis@hotmail.com NR 74 TC 15 Z9 16 U1 2 U2 18 PU BAISHIDENG PUBLISHING GROUP INC PI PLEASANTON PA 8226 REGENCY DR, PLEASANTON, CA 94588 USA SN 1007-9327 EI 2219-2840 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD MAY 7 PY 2015 VL 21 IS 17 BP 5119 EP 5130 DI 10.3748/wjg.v21.i17.5119 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CH1ID UT WOS:000353774100002 PM 25954085 ER PT J AU Saunders, A Oldenburg, IA Berezovskii, VK Johnson, CA Kingery, ND Elliott, HL Xie, T Gerfen, CR Sabatini, BL AF Saunders, Arpiar Oldenburg, Ian A. Berezovskii, Vladimir K. Johnson, Caroline A. Kingery, Nathan D. Elliott, Hunter L. Xie, Tiao Gerfen, Charles R. Sabatini, Bernardo L. TI A direct GABAergic output from the basal ganglia to frontal cortex SO NATURE LA English DT Article ID GREEN FLUORESCENT PROTEIN; GLOBUS-PALLIDUS; CHOLINERGIC NEURONS; INDIRECT PATHWAYS; CRE-RECOMBINASE; NUCLEUS BASALIS; DRIVER LINES; SCHIZOPHRENIA; FOREBRAIN; RAT AB The basal ganglia are phylogenetically conserved subcortical nuclei necessary for coordinated motor action and reward learning(1). Current models postulate that the basal ganglia modulate cerebral cortex indirectly via an inhibitory output to thalamus, bidirectionally controlled by direct-and indirect-pathway striatal projection neurons (dSPNs and iSPNs, respectively)(2-4). The basal ganglia thalamic output sculpts cortical activity by interacting with signals from sensory and motor systems(5). Here we describe a direct projection from the globus pallidus externus (GP), a central nucleus of the basal ganglia, to frontal regions of the cerebral cortex (FC). Two cell types make up the GP-FC projection, distinguished by their electrophysiological properties, cortical projections and expression of choline acetyltransferase (ChAT), a synthetic enzyme for the neurotransmitter acetylcholine (ACh). Despite these differences, ChAT(+) cells, which have been historically identified as an extension of the nucleus basalis, as well asChAT(-) cells, release the inhibitory neurotransmitter GABA (c-aminobutyric acid) and are inhibited by iSPNs and dSPNs of dorsal striatum. Thus, GP-FC cells comprise a direct GABAergic/cholinergic projection under the control of striatum that activates frontal cortex in vivo. Furthermore, iSPN inhibition of GP-FC cells is sensitive to dopamine 2 receptor signalling, revealing a pathway by which drugs that target dopamine receptors for the treatment of neuropsychiatric disorders can act in the basal ganglia to modulate frontal cortices. C1 [Saunders, Arpiar; Oldenburg, Ian A.; Berezovskii, Vladimir K.; Johnson, Caroline A.; Sabatini, Bernardo L.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Dept Neurobiol, Boston, MA 02115 USA. [Kingery, Nathan D.] Harvard Univ, Sch Med, Dept Neurobiol, Neurobiol Imaging Facil, Boston, MA 02115 USA. [Elliott, Hunter L.; Xie, Tiao] Harvard Univ, Sch Med, Image & Data Anal Core, Boston, MA 02115 USA. [Gerfen, Charles R.] NIMH, Lab Syst Neurosci, Bethesda, MD 20892 USA. RP Sabatini, BL (reprint author), Harvard Univ, Sch Med, Howard Hughes Med Inst, Dept Neurobiol, 220 Longwood Ave, Boston, MA 02115 USA. EM bsabatini@hms.harvard.edu OI Berezovskii, Vladimir/0000-0003-4077-3940 FU National Institutes of Health [F31 NS074842, F31-MH093026-01A1, P30 EY12196]; NINDS P30 Core Center grant [NS072030]; NIH [R01 NS046579] FX The authors thank the Lowell laboratory at Beth Israel Deaconess Medical Center for the gift of the DIO-synaptophysin-mCherry and DIO-synaptophysin-GFP rAAVs, R. Pemberton for technical support and F. Krienen, N. Duggan, P. Kaeser and members of the Sabatini laboratory for helpful discussions. This work was supported by grants from the National Institutes of Health (F31 NS074842) to A.S., (F31-MH093026-01A1) to I.A.O., (P30 EY12196) to the Vision Core and NINDS P30 Core Center grant (#NS072030) to the Neural Imaging Center and Neurobiology Imaging Center in the Department of Neurobiology at Harvard Medical School and a NIH grant (R01 NS046579) to B.L.S. NR 44 TC 51 Z9 51 U1 3 U2 26 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 MAY 7 PY 2015 VL 521 IS 7550 BP 85 EP U193 DI 10.1038/nature14179 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CH4YS UT WOS:000354040900038 PM 25739505 ER PT J AU King, AA de Celles, MD Magpantay, FMG Rohani, P AF King, Aaron A. de Celles, Matthieu Domenech Magpantay, Felicia M. G. Rohani, Pejman TI Avoidable errors in the modelling of outbreaks of emerging pathogens, with special reference to Ebola SO PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE Ebola virus disease; forecast; emerging infectious disease ID TRANSMISSION DYNAMICS; RESPIRATORY SYNDROME; MOUTH EPIDEMIC; DISEASE; INTERVENTIONS; INFERENCE; IMPACT; FOOT AB As an emergent infectious disease outbreak unfolds, public health response is reliant on information on key epidemiological quantities, such as transmission potential and serial interval. Increasingly, transmission models fit to incidence data are used to estimate these parameters and guide policy. Some widely used modelling practices lead to potentially large errors in parameter estimates and, consequently, errors in model-based forecasts. Even more worryingly, in such situations, confidence in parameter estimates and forecasts can itself be far overestimated, leading to the potential for large errors that mask their own presence. Fortunately, straightforward and computationally inexpensive alternatives exist that avoid these problems. Here, we first use a simulation study to demonstrate potential pitfalls of the standard practice of fitting deterministic models to cumulative incidence data. Next, we demonstrate an alternative based on stochastic models fit to raw data from an early phase of 2014 West Africa Ebola virus disease outbreak. We show not only that bias is thereby reduced, but that uncertainty in estimates and forecasts is better quantified and that, critically, lack of model fit is more readily diagnosed. We conclude with a short list of principles to guide the modelling response to future infectious disease outbreaks. C1 [King, Aaron A.; de Celles, Matthieu Domenech; Magpantay, Felicia M. G.; Rohani, Pejman] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. [King, Aaron A.; Rohani, Pejman] Univ Michigan, Ctr Study Complex Syst, Ann Arbor, MI 48109 USA. [King, Aaron A.] Univ Michigan, Dept Math, Ann Arbor, MI 48109 USA. [King, Aaron A.; Rohani, Pejman] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP King, AA (reprint author), Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. EM kingaa@umich.edu OI King, Aaron/0000-0001-6159-3207 FU Research and Policy in Infectious Disease Dynamics program of the Science and Technology Directorate; Department of Homeland Security; Fogarty International Center; National Institutes of Health; MIDAS, National Institute of General Medical Sciences [U54-GM111274, U01-GM110744] FX P.R. and A.A.K. are supported by the Research and Policy in Infectious Disease Dynamics program of the Science and Technology Directorate, Department of Homeland Security, the Fogarty International Center, National Institutes of Health and by MIDAS, National Institute of General Medical Sciences U54-GM111274 and U01-GM110744. NR 19 TC 17 Z9 17 U1 2 U2 33 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8452 EI 1471-2954 J9 P ROY SOC B-BIOL SCI JI Proc. R. Soc. B-Biol. Sci. PD MAY 7 PY 2015 VL 282 IS 1806 AR UNSP 20150347 DI 10.1098/rspb.2015.0347 PG 7 WC Biology; Ecology; Evolutionary Biology SC Life Sciences & Biomedicine - Other Topics; Environmental Sciences & Ecology; Evolutionary Biology GA CG5RG UT WOS:000353351000029 PM 25833863 ER PT J AU Douglas, ZH Maniscalco, B Hallett, M Wassermann, EM He, BYJ AF Douglas, Zachary H. Maniscalco, Brian Hallett, Mark Wassermann, Eric M. He, Biyu J. TI Modulating Conscious Movement Intention by Noninvasive Brain Stimulation and the Underlying Neural Mechanisms SO JOURNAL OF NEUROSCIENCE LA English DT Article DE EEG; movement intention; slow cortical potential; spontaneous activity; tDCS; volition ID INFERIOR PARIETAL LOBULE; HIGH-RESOLUTION EEG; MOTOR CORTEX; PERCEPTUAL DECISIONS; VOLUNTARY MOVEMENT; INTERNAL-MODEL; HD-TDCS; AWARENESS; HUMANS; AREAS AB Conscious intention is a fundamental aspect of the human experience. Despite long-standing interest in the basis and implications of intention, its underlying neurobiological mechanisms remain poorly understood. Using high-definition transcranial DC stimulation (tDCS), we observed that enhancing spontaneous neuronal excitability in both the angular gyrus and the primary motor cortex caused the reported time of conscious movement intention to be similar to 60-70 ms earlier. Slow brain waves recorded similar to 2-3 s before movement onset, as well as hundreds of milliseconds after movement onset, independently correlated with the modulation of conscious intention by brain stimulation. These brain activities together accounted for 81% of interindividual variability in the modulation of movement intention by brain stimulation. A computational model using coupled leaky integrator units with biophysically plausible assumptions about the effect of tDCS captured the effects of stimulation on both neural activity and behavior. These results reveal a temporally extended brain process underlying conscious movement intention that spans seconds around movement commencement. C1 [Douglas, Zachary H.; Maniscalco, Brian; Hallett, Mark; Wassermann, Eric M.; He, Biyu J.] NINDS, NIH, Bethesda, MD 20892 USA. RP He, BYJ (reprint author), 10 Ctr Dr,Bldg 10,Room B1D728, Bethesda, MD 20892 USA. EM biyu.jade.he@gmail.com OI He, Biyu/0000-0003-1549-1351 FU Intramural Research Program of the National Institutes of Health/National Institute of Neurological Disorders and Stroke FX This research was supported by the Intramural Research Program of the National Institutes of Health/National Institute of Neurological Disorders and Stroke. We thank Irene McClain for medical coverage; Adam Steel for assistance with the Brainsight system; and Qi Li, Alex Baria, and Amy Lin for help with setting up EEG electrodes. NR 90 TC 7 Z9 7 U1 3 U2 15 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 MAY 6 PY 2015 VL 35 IS 18 BP 7239 EP 7255 DI 10.1523/JNEUROSCI.4894-14.2015 PG 17 WC Neurosciences SC Neurosciences & Neurology GA CL0YG UT WOS:000356668400022 PM 25948272 ER PT J AU Turtzo, LC Budde, MD Dean, DD Gold, EM Lewis, BK Janes, L Lescher, J Coppola, T Yarnell, A Grunberg, NE Frank, JA AF Turtzo, L. Christine Budde, Matthew D. Dean, Dana D. Gold, Eric M. Lewis, Bobbi K. Janes, Lindsay Lescher, Jacob Coppola, Tiziana Yarnell, Angela Grunberg, Neil E. Frank, Joseph A. TI Failure of Intravenous or Intracardiac Delivery of Mesenchymal Stromal Cells to Improve Outcomes after Focal Traumatic Brain Injury in the Female Rat SO PLOS ONE LA English DT Article ID MARROW MONONUCLEAR-CELLS; ACTIVATED MICROGLIAL/MACROPHAGE RESPONSE; PROMOTES FUNCTIONAL RECOVERY; STEM-CELLS; ISCHEMIC-STROKE; GRAFT-SURVIVAL; DONOR GENDER; ADULT RATS; TRANSPLANTATION; THERAPY AB Mesenchymal stromal cells secrete a variety of anti-inflammatory factors and may provide a regenerative medicine option for the treatment of traumatic brain injury. The present study investigates the efficacy of multiple intravenous or intracardiac administrations of rat mesenchymal stromal cells or human mesenchymal stromal cells in female rats after controlled cortical impact by in vivo MRI, neurobehavior, and histopathology evaluation. Neither intravenous nor intracardiac administration of mesenchymal stromal cells derived from either rats or humans improved MRI measures of lesion volume or neurobehavioral outcome compared to saline treatment. Few mesenchymal stromal cells (<0.0005% of injected dose) were found within 3 days of last dosage at the site of injury after either delivery route, with no mesenchymal stromal cells being detectable in brain at 30 or 56 days post-injury. These findings suggest that non-autologous mesenchymal stromal cells therapy via intravenous or intracardiac administration is not a promising treatment after focal contusion traumatic brain injury in this female rodent model. C1 [Turtzo, L. Christine; Gold, Eric M.; Janes, Lindsay; Lescher, Jacob] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Turtzo, L. Christine; Budde, Matthew D.; Dean, Dana D.; Gold, Eric M.; Lewis, Bobbi K.; Janes, Lindsay; Lescher, Jacob; Coppola, Tiziana; Frank, Joseph A.] NIH, Frank Lab, Bethesda, MD 20892 USA. [Yarnell, Angela; Grunberg, Neil E.] Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, Bethesda, MD 20814 USA. [Frank, Joseph A.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. RP Turtzo, LC (reprint author), Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. EM l.turtzo@nih.gov FU Center for Neuroscience and Regenerative Medicine [300604-8.01-60855, 305500-8.01-60855]; National Institutes of Health's Intramural Research Program FX This work was supported by funding from the the Center for Neuroscience and Regenerative Medicine (http://www.usuhs.mil/cnrm/) as administered by the Henry M. Jackson Foundation (http://www.hjf.org) (Henry M. Jackson Award #300604-8.01-60855 [JAF] and #305500-8.01-60855 [LCT]) and by the National Institutes of Health's Intramural Research Program (http://irp.nih.gov/) (JAF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 69 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 MAY 6 PY 2015 VL 10 IS 5 AR UNSP e0126551 DI 10.1371/journal.pone.0126551 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CH5BQ UT WOS:000354049700137 PM 25946089 ER PT J AU D'Ambrosio, MV Bakalar, M Bennuru, S Reber, C Skandarajah, A Nilsson, L Switz, N Kamgno, J Pion, S Boussinesq, M Nutman, TB Fletcher, DA AF D'Ambrosio, Michael V. Bakalar, Matthew Bennuru, Sasisekhar Reber, Clay Skandarajah, Arunan Nilsson, Lina Switz, Neil Kamgno, Joseph Pion, Sebastien Boussinesq, Michel Nutman, Thomas B. Fletcher, Daniel A. TI Point-of-care quantification of blood-borne filarial parasites with a mobile phone microscope SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID LOA LOA INFECTION; MACROFILARICIDAL ACTIVITY; DOXYCYCLINE; MICROFILAREMIA; LOIASIS; TRIAL; AREA AB Parasitic helminths cause debilitating diseases that affect millions of people in primarily low-resource settings. Efforts to eliminate onchocerciasis and lymphatic filariasis in Central Africa through mass drug administration have been suspended because of ivermectin-associated serious adverse events, including death, in patients infected with the filarial parasite Loa loa. To safely administer ivermectin for onchocerciasis or lymphatic filariasis in regions co-endemic with L. loa, a strategy termed "test and (not) treat" has been proposed whereby those with high levels of L. loa microfilariae (>30,000/ml) that put them at risk for life-threatening serious adverse events are identified and excluded from mass drug administration. To enable this, we developed a mobile phone-based video microscope that automatically quantifies L. loa microfilariae in whole blood loaded directly into a small glass capillary from a fingerprick without the need for conventional sample preparation or staining. This point-of-care device automatically captures and analyzes videos of microfilarial motion in whole blood using motorized sample scanning and onboard motion detection, minimizing input from health care workers and providing a quantification of microfilariae per milliliter of whole blood in under 2 min. To validate performance and usability of the mobile phone microscope, we tested 33 potentially Loa-infected patients in Cameroon and confirmed that automated counts correlated with manual thick smear counts (94% specificity; 100% sensitivity). Use of this technology to exclude patients from ivermectin-based treatment at the point of care in Loa-endemic regions would allow resumption/expansion of mass drug administration programs for onchocerciasis and lymphatic filariasis in Central Africa. C1 [D'Ambrosio, Michael V.; Bakalar, Matthew; Reber, Clay; Skandarajah, Arunan; Nilsson, Lina; Switz, Neil; Fletcher, Daniel A.] Univ Calif Berkeley, Dept Bioengn, Berkeley, CA 94720 USA. [Bennuru, Sasisekhar; Nutman, Thomas B.] NIAID, Parasit Dis Lab, Bethesda, MD 20892 USA. [Switz, Neil; Fletcher, Daniel A.] Univ Calif Berkeley, Biophys Grad Grp, Berkeley, CA 94720 USA. [Kamgno, Joseph; Pion, Sebastien] Ctr Res Filariasis & Other Trop Dis, Yaounde, Cameroon. [Kamgno, Joseph] Univ Yaounde I, Fac Med & Biomed Sci, Yaounde, Cameroon. [Pion, Sebastien; Boussinesq, Michel] Inst Rech Dev, UMI 233, Montpellier, France. [Pion, Sebastien; Boussinesq, Michel] Univ Montpellier, F-34059 Montpellier, France. RP Fletcher, DA (reprint author), Univ Calif Berkeley, Dept Bioengn, Berkeley, CA 94720 USA. EM tnutman@niaid.nih.gov; fletch@berkeley.edu RI Boussinesq, Michel/J-7256-2016; Emchi, Karma/Q-1952-2016 OI Boussinesq, Michel/0000-0001-6312-0681; FU Bill and Melinda Gates Foundation; Blum Center for Developing Economies at University of California (UC) Berkeley; U.S. Agency for International Development through the Development Innovation Lab at UC Berkeley; Purnendu Chatterjee Chair fund; Division of Intramural Research of the National Institute of Allergy and Infectious Diseases FX This work was supported in part by the Bill and Melinda Gates Foundation, the Blum Center for Developing Economies at University of California (UC) Berkeley, U.S. Agency for International Development through the Development Innovation Lab at UC Berkeley, the Purnendu Chatterjee Chair fund, and the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases. NR 21 TC 34 Z9 34 U1 4 U2 19 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD MAY 6 PY 2015 VL 7 IS 286 AR 286re4 DI 10.1126/scitranslmed.aaa3480 PG 8 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA CI0MP UT WOS:000354431600001 PM 25947164 ER PT J AU Krause, PR Bryant, PR Clark, T Dempsey, W Henchal, E Michael, NL Regules, JA Gruber, MF AF Krause, Philip R. Bryant, Paula R. Clark, Thomas Dempsey, Walla Henchal, Erik Michael, Nelson L. Regules, Jason A. Gruber, Marion F. TI Immunology of protection from Ebola virus infection SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID NONHUMAN-PRIMATES; WEST-AFRICA; IMMUNITY; ANTIBODIES; CHALLENGE; DISEASE AB A December 2014 meeting reviewed Ebola virus immunology relevant to vaccine development, including Ebola prevention, immunity, assay standardization, and regulatory considerations. Vaccinated humans appear to achieve immune responses comparable in magnitude with those associated with protection in nonhuman primates, suggesting that immunological data could be used to demonstrate vaccine efficacy. C1 [Krause, Philip R.; Henchal, Erik; Gruber, Marion F.] US FDA, Off Vaccines Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Bryant, Paula R.; Dempsey, Walla] NIAID, Div Microbial & Infect Dis, NIH, Bethesda, MD 20892 USA. [Clark, Thomas] Ctr Dis Control & Prevent, Atlanta, GA USA. [Michael, Nelson L.; Regules, Jason A.] Walter Reed Army Inst Res, Silver Spring, MD USA. RP Krause, PR (reprint author), US FDA, Off Vaccines Res & Review, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM philip.krause@fda.hhs.gov FU FDA; NIAID; CDC; Biomedical Advanced Research and Development Authority; U.S. Department of Defense FX We appreciate financial and logistical support for the meeting from FDA, NIAID, CDC, Biomedical Advanced Research and Development Authority, and U.S. Department of Defense. NR 25 TC 2 Z9 2 U1 1 U2 15 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 MAY 6 PY 2015 VL 7 IS 286 AR 286ps11 DI 10.1126/scitranslmed.aaa8202 PG 4 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA CI0MP UT WOS:000354431600003 PM 25947159 ER PT J AU Belmonte, JCI Callaway, EM Churchland, P Caddick, SJ Feng, G Homanics, GE Lee, KF Leopold, DA Miller, CT Mitchell, JF Mitalipov, S Moutri, AR Movshon, JA Okano, H Reynolds, JH Ringach, D Sejnowski, TJ Silva, AC Strick, PL Wu, J Zhang, F AF Belmonte, Juan Carlos Izpisua Callaway, Edward M. Churchland, Patricia Caddick, Sarah J. Feng, Guoping Homanics, Gregg E. Lee, Kuo-Fen Leopold, David A. Miller, Cory T. Mitchell, Jude F. Mitalipov, Shoukhrat Moutri, Alysson R. Movshon, J. Anthony Okano, Hideyuki Reynolds, John H. Ringach, Dario Sejnowski, Terrence J. Silva, Afonso C. Strick, Peter L. Wu, Jun Zhang, Feng TI Brains, Genes, and Primates SO NEURON LA English DT Review ID EMBRYONIC STEM-CELLS; MARMOSET CALLITHRIX-JACCHUS; COVERT SPATIAL ATTENTION; LONG-TERM PROLIFERATION; ZINC-FINGER NUCLEASES; PRIMORDIAL GERM-CELLS; VISUAL AREA V4; NONHUMAN PRIMATE; COMMON MARMOSET; NEUROSCIENCE RESEARCH AB One of the great strengths of the mouse model is the wide array of genetic tools that have been developed. Striking examples include methods for directed modification of the genome, and for regulated expression or inactivation of genes. Within neuroscience, it is now routine to express reporter genes, neuronal activity indicators, and opsins in specific neuronal types in the mouse. However, there are considerable anatomical, physiological, cognitive, and behavioral differences between the mouse and the human that, in some areas of inquiry, limit the degree to which insights derived from the mouse can be applied to understanding human neurobiology. Several recent advances have now brought into reach the goal of applying these tools to understanding the primate brain. Here we describe these advances, consider their potential to advance our understanding of the human brain and brain disorders, discuss bioethical considerations, and describe what will be needed to move forward. C1 [Callaway, Edward M.; Reynolds, John H.] Salk Inst Biol Studies, Syst Neurobiol Lab, La Jolla, CA 92037 USA. [Belmonte, Juan Carlos Izpisua; Wu, Jun] Salk Inst Biol Studies, Gene Express Lab, La Jolla, CA 92037 USA. [Churchland, Patricia] Univ Calif San Diego, Dept Philosophy, La Jolla, CA 92093 USA. [Caddick, Sarah J.] Gatsby Charitable Fdn, London SW1V 1AP, England. [Feng, Guoping] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Homanics, Gregg E.] Univ Pittsburgh, Dept Anesthesiol & Pharmacol, Pittsburgh, PA 15261 USA. [Homanics, Gregg E.] Univ Pittsburgh, Dept Biol Chem, Pittsburgh, PA 15261 USA. [Lee, Kuo-Fen] Salk Inst Biol Studies, Clayton Fdn Labs Peptide Biol, La Jolla, CA 92037 USA. [Leopold, David A.] NIMH, Sect Cognit Neurophysiol & Imaging, Neuropsychol Lab, NIH, Bethesda, MD 20192 USA. [Miller, Cory T.] Univ Calif San Diego, Dept Psychol, La Jolla, CA 92093 USA. [Miller, Cory T.] Univ Calif San Diego, Neurosci Grad Program, La Jolla, CA 92093 USA. [Mitchell, Jude F.] Univ Rochester, Brain & Cognit Sci, Rochester, NY 14627 USA. [Mitalipov, Shoukhrat] Oregon Hlth & Sci Univ, Ctr Embryon Cell & Gene Therapy, Portland, OR 97239 USA. [Mitalipov, Shoukhrat] Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Div Reprod & Dev Sci, Beaverton, OR 97006 USA. [Moutri, Alysson R.] Rady Childrens Hosp San Diego, Dept Pediat, Sch Med, La Jolla, CA 92093 USA. [Moutri, Alysson R.] Dept Cellular & Mol Med, Stem Cell Program, La Jolla, CA 92093 USA. [Movshon, J. Anthony] NYU, Ctr Neural Sci, New York, NY 10003 USA. [Okano, Hideyuki] Keio Univ, Sch Med, Dept Physiol, Shinjuku Ku, Tokyo 1608582, Japan. [Okano, Hideyuki] RIKEN, Brain Sci Inst, Lab Marmoset Neural Architecture, Wako, Saitama 3510198, Japan. [Ringach, Dario] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurobiol, Los Angeles, CA 92093 USA. [Ringach, Dario] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychol, Los Angeles, CA 92093 USA. [Sejnowski, Terrence J.] Salk Inst Biol Studies, Computat Neurobiol Lab, La Jolla, CA 92037 USA. [Silva, Afonso C.] NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Strick, Peter L.] Univ Pittsburgh, Sch Med, Brain Inst, Pittsburgh, PA 15261 USA. [Strick, Peter L.] Univ Pittsburgh, Sch Med, Ctr Neural Basis Cognit, Pittsburgh, PA 15261 USA. [Strick, Peter L.] Univ Pittsburgh, Sch Med, Dept Neurobiol, Pittsburgh, PA 15261 USA. [Strick, Peter L.] Dept Vet Affairs Med Ctr, Res Serv, Pittsburgh, PA 15261 USA. [Zhang, Feng] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Zhang, Feng] MIT, McGovern Inst Brain Res, Cambridge, MA 02139 USA. [Zhang, Feng] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Zhang, Feng] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Zhang, Feng] Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA. RP Reynolds, JH (reprint author), Salk Inst Biol Studies, Syst Neurobiol Lab, 10010 North Torrey Pines Rd, La Jolla, CA 92037 USA. EM reynolds@salk.edu RI Hidokano, Hideyuki/J-5973-2013; Callaway, Edward/D-4336-2011 OI Wu, Jun/0000-0001-9863-1668; Leopold, David/0000-0002-1345-6360; Callaway, Edward/0000-0002-6366-5267 FU Gatsby Charitable Foundation; Crick Jacobs Center of the Salk Institute; Salk Innovation Award; National Institutes of Health [R01 EY021827, R01-HD063276, R01-HD057121, R01-HD059946, R01-EY021214, P51-OD011092]; Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS); Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT); U.S. National Institutes of Health, NINDS; NIMH; G. Harlod and Leila Y. Mathers Charitable Foundation; Leona M. and Harry B. Helmsley Charitable Trust [2012-PG-MED002]; Poitras Center for Affective Disorders Research at McGovern Institute for Brain Research at MIT; Stanley Center for Psychiatric Research at Broad Institute of MIT and Harvard; Science Innovation Award from Brain Research Foundation; Salk Innovation Grant; Clayton Foundation; National Institute of Aging; National Institute of Neurological Disorders and Stokes; NSF-IDBR; NIDCD; Leducq Foundation; OHSU institutional funds; NIH Director's New Innovator Award Program [1-DP2-OD006495-01]; NARSAD Independent Investigator Grant; NEI; Howard Hughes Medical Institute; Office of Naval Research; NINDS, NIH; National Institutes of Health (through NIMH) [5DP1-MH100706]; National Institutes of Health (through NIDDK) [5R01-DK097768]; National Science Foundation; Keck, New York Stem Cell; Damon Runyon Foundation; Searle Scholars Foundation; Merkin Foundation; Vallee Foundation; Bob Metcalfe; San Bio Co. Ltd. FX We thank the following for thoughtful conversations that were helpful in preparing this manuscript: Michael C. Avery, Michele Basso, Hagai Bergman, Robert Desimone, Vince Ferrera, Fred H. Gage, Paul Glimcher, Josh Gold, Mickey Goldberg, Neng Gong, John D. Harding, Atsushi Iriki, Leah Krubitzer, Mathias Leblanc, Daeyol Lee, Steve Lisberger, Julio Martinez-Trujillo, John Maunsell, Samuel L. Pfaff, Michael Platt, Mu-ming Poo, Nicholas Priebe, Louise Reichardt, Jeff Schall, Steve Scott, John Spiro, Stefan Treue, Inder M. Verma, and Bob Wurtz. Work in the laboratory of J.H.R. was supported, in part, by the Gatsby Charitable Foundation; the Crick Jacobs Center of the Salk Institute; a Salk Innovation Award; the National Institutes of Health (R01 EY021827); Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS); the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT); and the Intramural Research Program of the U.S. National Institutes of Health, NINDS, and NIMH. Work in the laboratory of J.C.I.B. was supported by the G. Harlod and Leila Y. Mathers Charitable Foundation and by The Leona M. and Harry B. Helmsley Charitable Trust (2012-PG-MED002). Work in the laboratory of G.F. was supported by Poitras Center for Affective Disorders Research at McGovern Institute for Brain Research at MIT, Stanley Center for Psychiatric Research at Broad Institute of MIT and Harvard, and a Science Innovation Award from Brain Research Foundation. Work in the laboratory of K.-F.L. was supported by a Salk Innovation Grant, the Clayton Foundation, the National Institute of Aging, and the National Institute of Neurological Disorders and Stokes. Work in the laboratory of D. A. L. was supported, in part, by the Intramural Research Program of the U.S. National Institutes of Health, NINDS, and NIMH. Work in the laboratory of C.T.M. was supported by NSF-IDBR, NIDCD, and NIMH. Work in the laboratory of J.F.M. was supported by NIH (R21 MH104756). Work in the laboratory of S. M. was supported by grants R01-HD063276, R01-HD057121, R01-HD059946, R01-EY021214, and P51-OD011092 from National Institutes of Health; a grant from the Leducq Foundation; and OHSU institutional funds. Work in the laboratory of A.R.M. was supported by NIH Director's New Innovator Award Program (1-DP2-OD006495-01) and a NARSAD Independent Investigator Grant. Work in the laboratory of D.R. was supported by NEI. Work in the laboratory of T.J.S. was supported by Howard Hughes Medical Institute and Office of Naval Research. Work in the laboratory of A. C. S. was supported by The Intramural Research Program of the NINDS, NIH. Work in the laboratory of F.Z. was supported by the National Institutes of Health (through NIMH, 5DP1-MH100706, and NIDDK, 5R01-DK097768); a Waterman Award from the National Science Foundation; the Keck, New York Stem Cell; Damon Runyon, Searle Scholars, Merkin, and Vallee Foundations; and Bob Metcalfe. F.Z. is a New York Stem Cell Foundation Robertson Investigator. S.M. is a founder of Mitogenome Therapeutics Inc. H.O. is a Founding Scientist and a paid SAB of San Bio Co. Ltd. F.Z. is a founder of Editas Medicine and a scientific advisor for Editas Medicine and Horizon Discovery. NR 140 TC 38 Z9 39 U1 8 U2 40 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 MAY 6 PY 2015 VL 86 IS 3 BP 617 EP 631 DI 10.1016/j.neuron.2015.03.021 PG 15 WC Neurosciences SC Neurosciences & Neurology GA CH5IV UT WOS:000354069800006 ER PT J AU Tycko, R AF Tycko, Robert TI Amyloid Polymorphism: Structural Basis and Neurobiological Relevance SO NEURON LA English DT Review ID SOLID-STATE NMR; NUCLEAR-MAGNETIC-RESONANCE; ALZHEIMERS-DISEASE BRAIN; BETA-SHEET STRUCTURE; HUMAN PRION PROTEIN; PAIRED HELICAL FILAMENTS; POSITRON-EMISSION-TOMOGRAPHY; ALPHA-SYNUCLEIN STRAINS; PITTSBURGH COMPOUND-B; X-RAY-DIFFRACTION AB Our understanding of the molecular structures of amyloid fibrils that are associated with neurodegenerative diseases, of mechanisms by which disease-associated peptides and proteins aggregate into fibrils, and of structural properties of aggregation intermediates has advanced considerably in recent years. Detailed molecular structural models for certain fibrils and aggregation intermediates are now available. It is now well established that amyloid fibrils are generally polymorphic at the molecular level, with a given peptide or protein being capable of forming a variety of distinct, self-propagating fibril structures. Recent results from structural studies and from studies involving cell cultures, transgenic animals, and human tissue provide initial evidence that molecular structural variations in amyloid fibrils and related aggregates may correlate with or even produce variations in disease development. This article reviews our current knowledge of the structural and mechanistic aspects of amyloid formation, as well as current evidence for the biological relevance of structural variations. C1 NIDDK, Lab Chem Phys, NIH, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIDDK, Lab Chem Phys, NIH, Bethesda, MD 20892 USA. EM robertty@mail.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases, a component of the National Institutes of Health FX This work has been supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases, a component of the National Institutes of Health. I thank Drs. Zhiping Jiang and Jennifer C. Lee of the National Heart, Lung, and Blood Institute for providing the TEM image of recombinant alpha-synuclein fibrils in Figure 1C. NR 143 TC 29 Z9 29 U1 11 U2 83 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 MAY 6 PY 2015 VL 86 IS 3 BP 632 EP 645 DI 10.1016/j.neuron.2015.03.017 PG 14 WC Neurosciences SC Neurosciences & Neurology GA CH5IV UT WOS:000354069800007 PM 25950632 ER PT J AU Basore, K Cheng, Y Kushwaha, AK Nguyen, ST Desai, SA AF Basore, Katherine Cheng, Yang Kushwaha, Ambuj K. Nguyen, Son T. Desai, Sanjay A. TI How do antimalarial drugs reach their intracellular targets? SO FRONTIERS IN PHARMACOLOGY LA English DT Review DE antimalarials; drug uptake; plasmodial surface anion channel; plasmodium falciparum; drug absorption; lipid diffusion of drugs ID FALCIPARUM-INFECTED ERYTHROCYTES; SURFACE ANION CHANNEL; PFNT1 NUCLEOSIDE TRANSPORTER; RED-BLOOD-CELLS; PLASMODIUM-FALCIPARUM; MALARIA PARASITE; NUTRIENT-UPTAKE; TOXOPLASMA-GONDII; PARASITOPHOROUS VACUOLE; HOST ERYTHROCYTES AB Drugs represent the primary treatment available for human malaria, as caused by Plasmodium spp. Currently approved drugs and antimalarial drug leads generally work against parasite enzymes or activities within infected erythrocytes. To reach their specific targets, these chemicals must cross at least three membranes beginning with the host cell membrane. Uptake at each membrane may involve partitioning and diffusion through the lipid bilayer or facilitated transport through channels or carriers. Here, we review the features of available antimalarials and examine whether transporters may be required for their uptake. Our computational analysis suggests that most antimalarials have high intrinsic membrane permeability, obviating the need for uptake via transporters; a subset of compounds appear to require facilitated uptake. We also review parasite and host transporters that may contribute to drug uptake. Broad permeability channels at the erythrocyte and parasitophorous vacuolar membranes of infected cells relax permeability constraints on antimalarial drug design; however, this uptake mechanism is prone to acquired resistance as the parasite may alter channel activity to reduce drug uptake. A better understanding of how antimalarial drugs reach their intracellular targets is critical to prioritizing drug leads for antimalarial development and may reveal new targets for therapeutic intervention. C1 [Basore, Katherine; Cheng, Yang; Kushwaha, Ambuj K.; Desai, Sanjay A.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Nguyen, Son T.] Microbiotix Inc, Worcester, MA USA. RP Desai, SA (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Room 3W-01,Twinbrook 3,12735 Twinbrook Pkwy, Rockville, MD 20852 USA. EM sdesai@niaid.nih.gov OI Basore, Katherine/0000-0001-5974-0968 FU Intramural Research Program of the National Institutes of Health, National Institute of Allergy; Infectious Diseases and Microbiotix, Inc. FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases and Microbiotix, Inc., which has a cooperative research and development agreement (CRADA) with NIAID. NR 67 TC 3 Z9 3 U1 1 U2 5 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1663-9812 J9 FRONT PHARMACOL JI Front. Pharmacol. PD MAY 5 PY 2015 VL 6 AR 91 DI 10.3389/fphar.2015.00091 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CW5LT UT WOS:000365037600001 PM 25999857 ER PT J AU Verner, MA Longnecker, MP AF Verner, Marc-Andre Longnecker, Matthew P. TI Comment on "Enhanced Elimination of Perfluorooctanesulfonic Acid by Menstruating Women: Evidence from Population-Based Pharmacokinetic Modeling" SO ENVIRONMENTAL SCIENCE & TECHNOLOGY LA English DT Letter ID BLOOD-LOSS; PERFLUOROALKYL ACIDS; FLUID C1 [Verner, Marc-Andre] Univ Montreal, Sch Publ Hlth, Dept Occupat & Environm Hlth, Montreal, PQ H3T 1A8, Canada. [Verner, Marc-Andre] Univ Montreal, Univ Montreal Publ Hlth Res Inst IRSPUM, Montreal, PQ H3T 1J4, Canada. [Longnecker, Matthew P.] NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Longnecker, MP (reprint author), NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM longnec1@niehs.nih.gov OI Longnecker, Matthew/0000-0001-6073-5322 NR 14 TC 2 Z9 2 U1 2 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0013-936X EI 1520-5851 J9 ENVIRON SCI TECHNOL JI Environ. Sci. Technol. PD MAY 5 PY 2015 VL 49 IS 9 BP 5836 EP 5837 DI 10.1021/acs.est.5b00187 PG 2 WC Engineering, Environmental; Environmental Sciences SC Engineering; Environmental Sciences & Ecology GA CH6OL UT WOS:000354155800070 PM 25871968 ER PT J AU Hsieh, P Pearlman, AH AF Hsieh, Peggy Pearlman, Alexander H. TI EGFR inhibits DNA mismatch repair SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID PCNA FUNCTION; CANCER; PHOSPHORYLATION; ENDONUCLEASE; STABILITY; MECHANISM; BIOLOGY; NETWORK C1 [Hsieh, Peggy; Pearlman, Alexander H.] NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Hsieh, P (reprint author), NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. EM peggyh@niddk.nih.gov FU Intramural NIH HHS NR 18 TC 3 Z9 3 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 5 PY 2015 VL 112 IS 18 BP 5556 EP 5557 DI 10.1073/pnas.1505168112 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CH3TS UT WOS:000353953800029 PM 25918402 ER PT J AU Van Boeckel, TP Brower, C Gilbert, M Grenfell, BT Levin, SA Robinson, TP Teillant, A Laxminarayan, R AF Van Boeckel, Thomas P. Brower, Charles Gilbert, Marius Grenfell, Bryan T. Levin, Simon A. Robinson, Timothy P. Teillant, Aude Laxminarayan, Ramanan TI Global trends in antimicrobial use in food animals SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE antimicrobials; livestock; mapping; drug resistance; linear regression ID ANTIBIOTIC-RESISTANCE; HUMAN HEALTH; INTENSIFICATION; ENVIRONMENT; BACTERIA; AGRICULTURE; ASSOCIATION; CONSUMPTION; PREVALENCE; MALARIA AB Demand for animal protein for human consumption is rising globally at an unprecedented rate. Modern animal production practices are associated with regular use of antimicrobials, potentially increasing selection pressure on bacteria to become resistant. Despite the significant potential consequences for antimicrobial resistance, there has been no quantitative measurement of global antimicrobial consumption by livestock. We address this gap by using Bayesian statistical models combining maps of livestock densities, economic projections of demand for meat products, and current estimates of antimicrobial consumption in high-income countries to map antimicrobial use in food animals for 2010 and 2030. We estimate that the global average annual consumption of antimicrobials per kilogram of animal produced was 45 mg.kg(-1), 148 mg.kg(-1), and 172 mg.kg(-1) for cattle, chicken, and pigs, respectively. Starting from this baseline, we estimate that between 2010 and 2030, the global consumption of antimicrobials will increase by 67%, from 63,151 +/- 1,560 tons to 105,596 +/- 3,605 tons. Up to a third of the increase in consumption in livestock between 2010 and 2030 is imputable to shifting production practices in middle-income countries where extensive farming systems will be replaced by large-scale intensive farming operations that routinely use antimicrobials in subtherapeutic doses. For Brazil, Russia, India, China, and South Africa, the increase in antimicrobial consumption will be 99%, up to seven times the projected population growth in this group of countries. Better understanding of the consequences of the uninhibited growth in veterinary antimicrobial consumption is needed to assess its potential effects on animal and human health. C1 [Van Boeckel, Thomas P.; Grenfell, Bryan T.; Levin, Simon A.; Teillant, Aude] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Brower, Charles; Laxminarayan, Ramanan] Ctr Dis Dynam Econ & Policy, Washington, DC 20036 USA. [Gilbert, Marius] Univ Libre Bruxelles, B-1050 Brussels, Belgium. [Gilbert, Marius] Fonds Natl Rech Sci, B-1000 Brussels, Belgium. [Grenfell, Bryan T.; Teillant, Aude; Laxminarayan, Ramanan] Princeton Environm Inst, Princeton, NJ 08544 USA. [Grenfell, Bryan T.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Levin, Simon A.] Beijer Inst Ecol Econ, S-10405 Stockholm, Sweden. [Levin, Simon A.] Resources Future Inc, Washington, DC 20036 USA. [Robinson, Timothy P.] Int Livestock Res Inst, Nairobi 00100, Kenya. [Laxminarayan, Ramanan] Publ Hlth Fdn India, New Delhi 110070, India. RP Van Boeckel, TP (reprint author), Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. EM thomas.van.boeckel@gmail.com; slevin@princeton.edu; ramanan@cddep.org FU Organization for Economic Co-operation and Development (SRM) [500026083]; Science and Technology Directorate, Department of Homeland Security [HSHQDC-12-C-00058]; Research and Policy for Infectious Disease Dynamics program of the Science and Technology Directorate, Department of Homeland Security; Bill & Melinda Gates Foundation; Fogarty International Center, National Institutes of Health; Princeton University through Grand Challenges Program FX Data collection was supported by the Organization for Economic Co-operation and Development (SRM 500026083). B.T.G. and T.P.V.B. were supported by the Science and Technology Directorate, Department of Homeland Security, Contract HSHQDC-12-C-00058. B.T.G. and SAL. were supported by the Research and Policy for Infectious Disease Dynamics program of the Science and Technology Directorate, Department of Homeland Security. B.T.G. was supported by the Bill & Melinda Gates Foundation and by the Fogarty International Center, National Institutes of Health. SAL., A.T., and R.L. were supported by Princeton University through its Grand Challenges Program. NR 51 TC 88 Z9 89 U1 52 U2 203 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 MAY 5 PY 2015 VL 112 IS 18 BP 5649 EP 5654 DI 10.1073/pnas.1503141112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CH3TS UT WOS:000353953800045 PM 25792457 ER PT J AU Davis, FM Janoshazi, A Janardhan, KS Steinckwich, N D'Agostin, DM Petranka, JG Desai, PN Roberts-Thomson, SJ Bird, GS Tucker, DK Fenton, SE Feske, S Monteith, GR Putney, JW AF Davis, Felicity M. Janoshazi, Agnes Janardhan, Kyathanahalli S. Steinckwich, Natacha D'Agostin, Diane M. Petranka, John G. Desai, Pooja N. Roberts-Thomson, Sarah J. Bird, Gary S. Tucker, Deirdre K. Fenton, Suzanne E. Feske, Stefan Monteith, Gregory R. Putney, James W., Jr. TI Essential role of Orai1 store-operated calcium channels in lactation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE calcium signaling; calcium channels; lactation; mammary gland; store-operated calcium entry ID MAMMARY EPITHELIAL-CELLS; PLASMA-MEMBRANE; SENSING RECEPTOR; TRANSGENIC MICE; BREAST-CANCER; GLAND; EXPRESSION; TRANSPORT; GENE; OXYTOCIN AB The nourishment of neonates by nursing is the defining characteristic of mammals. However, despite considerable research into the neural control of lactation, an understanding of the signaling mechanisms underlying the production and expulsion of milk by mammary epithelial cells during lactation remains largely unknown. Here we demonstrate that a store-operated Ca2+ channel subunit, Orai1, is required for both optimal Ca2+ transport into milk and for milk ejection. Using a novel, 3D imaging strategy, we visualized live oxytocin-induced alveolar unit contractions in the mammary gland, and we demonstrated that in this model milk is ejected by way of pulsatile contractions of these alveolar units. In mammary glands of Orai1 knockout mice, these contractions are infrequent and poorly coordinated. We reveal that oxytocin also induces a large transient release of stored Ca2+ in mammary myoepithelial cells followed by slow, irregular Ca2+ oscillations. These oscillations, and not the initial Ca2+ transient, are mediated exclusively by Orai1 and are absolutely required for milk ejection and pup survival, an observation that redefines the signaling processes responsible for milk ejection. These findings clearly demonstrate that Ca2+ is not just a substrate for nutritional enrichment in mammals but is also a master regulator of the spatiotemporal signaling events underpinning mammary alveolar unit contraction. Orai1-dependent Ca2+ oscillations may represent a conserved language in myoepithelial cells of other secretory epithelia, such as sweat glands, potentially shedding light on other Orai1 channelopathies, including anhidrosis (an inability to sweat). C1 [Davis, Felicity M.; Janoshazi, Agnes; Steinckwich, Natacha; D'Agostin, Diane M.; Petranka, John G.; Desai, Pooja N.; Bird, Gary S.; Putney, James W., Jr.] NIEHS, Dept Hlth & Human Serv, Signal Transduct Lab, NIH, Res Triangle Pk, NC 27709 USA. [Tucker, Deirdre K.; Fenton, Suzanne E.] NIEHS, Natl Toxicol Program Lab, NIH, Res Triangle Pk, NC 27709 USA. [Janardhan, Kyathanahalli S.] Integrated Lab Syst Inc, Res Triangle Pk, NC 27709 USA. [Roberts-Thomson, Sarah J.; Monteith, Gregory R.] Univ Queensland, Sch Pharm, Brisbane, Qld 4102, Australia. [Feske, Stefan] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA. RP Putney, JW (reprint author), NIEHS, Dept Hlth & Human Serv, Signal Transduct Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM putney@niehs.nih.gov RI Roberts-Thomson, Sarah/B-4282-2011; Davis, Felicity/P-1387-2016; Monteith, Gregory/B-1626-2008; OI Roberts-Thomson, Sarah/0000-0001-8202-5786; Davis, Felicity/0000-0001-9112-118X; Monteith, Gregory/0000-0002-4345-530X; Feske, Stefan/0000-0001-5431-8178 FU Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences; NIH [AI097302]; National Health and Medical Research Council [631347] FX We thank Jeff Tucker, Page Myers, John Brodie, Maria Sifre, Pamela Ovwigho, the Pathology Support Group, and Julie Foley for technical assistance. This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences; NIH Grant AI097302 (to S.F.); and National Health and Medical Research Council Grant 631347 (to G.R.M. and S.J.R.-T.). NR 33 TC 13 Z9 14 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 MAY 5 PY 2015 VL 112 IS 18 BP 5827 EP 5832 DI 10.1073/pnas.1502264112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CH3TS UT WOS:000353953800075 PM 25902527 ER PT J AU Etzion, O Ghany, MG AF Etzion, Ohad Ghany, Marc G. TI A Cure for the High Cost of Hepatitis C Virus Treatment SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID UNITED-STATES; MORTALITY C1 [Etzion, Ohad; Ghany, Marc G.] NIDDK, NIH, Bethesda, MD 20892 USA. RP Ghany, MG (reprint author), NIDDK, Liver Dis Branch, NIH, Bldg 10,Room 9B-16,10 Ctr Dr,MSC 1800, Bethesda, MD 20892 USA. EM MarcG@intra.niddk.nih.gov FU Intramural NIH HHS NR 8 TC 7 Z9 7 U1 1 U2 2 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 MAY 5 PY 2015 VL 162 IS 9 BP 660 EP U151 DI 10.7326/M15-0674 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA CH6AZ UT WOS:000354119100015 PM 25820765 ER PT J AU Nguyen, TA Sarkar, P Veetil, JV Davis, KA Puhl, HL Vogel, SS AF Nguyen, Tuan A. Sarkar, Pabak Veetil, Jithesh V. Davis, Kaitlin A. Puhl, Henry L., III Vogel, Steven S. TI Covert Changes in CaMKII Holoenzyme Structure Identified for Activation and Subsequent Interactions SO BIOPHYSICAL JOURNAL LA English DT Article ID PROTEIN-KINASE-II; D-ASPARTATE RECEPTOR; POSTSYNAPTIC DENSITY; MUTATIONAL ANALYSIS; INHIBITOR PROTEIN; ALPHA-ACTININ; NR2B SUBUNIT; CALMODULIN; CALCIUM/CALMODULIN; AUTOPHOSPHORYLATION AB Between 8 to 14 calcium-calmodulin (Ca2+/CaM) dependent protein kinase-II (CaMKII) subunits form a complex that modulates synaptic activity. In living cells, the autoinhibited holoenzyme is organized as catalytic-domain pairs distributed around a central oligomerization-domain core. The functional significance of catalytic-domain pairing is not known. In a provocative model, catalytic-domain pairing was hypothesized to prevent ATP access to catalytic sites. If correct, kinase-activity would require catalytic-domain pair separation. Simultaneous homo-FRET and fluorescence correlation spectroscopy was used to detect structural changes correlated with kinase activation under physiological conditions. Saturating Ca2+/CaM triggered Threonine-286 autophosphorylation and a large increase in CaMKII holoenzyme hydrodynamic volume without any appreciable change in catalytic-domain pair proximity or subunit stoichiometry. An alternative hypothesis is that two appropriately positioned Threonine-286 interaction-sites (T-sites), each located on the catalytic-domain of a pair, are required for holoenzyme interactions with target proteins. Addition of a T-site ligand, in the presence of Ca2+/CaM, elicited a large decrease in catalytic-domain homo-FRET, which was blocked by mutating the T-site (I205K). Apparently catalytic-domain pairing is altered to allow T-site interactions. C1 [Nguyen, Tuan A.; Sarkar, Pabak; Veetil, Jithesh V.; Davis, Kaitlin A.; Puhl, Henry L., III; Vogel, Steven S.] NIAAA, Lab Mol Physiol, NIH, Rockville, MD 20852 USA. RP Vogel, SS (reprint author), NIAAA, Lab Mol Physiol, NIH, Rockville, MD 20852 USA. EM stevevog@mail.nih.gov FU intramural program of the National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD [20892] FX This work was funded by the intramural program of the National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892. NR 57 TC 3 Z9 3 U1 4 U2 11 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 MAY 5 PY 2015 VL 108 IS 9 BP 2158 EP 2170 DI 10.1016/j.bpj.2015.03.028 PG 13 WC Biophysics SC Biophysics GA CH4EW UT WOS:000353986900011 PM 25954874 ER PT J AU McNally, EM Kaltman, JR Benson, DW Canter, CE Cripe, LH Duan, DS Finder, JD Hoffman, EP Judge, DP Kertesz, N Kinnett, K Kirsch, R Metzger, JM Pearson, GD Rafael-Fortney, JA Raman, SV Spurney, CF Targum, SL Wagner, KR Markham, LW AF McNally, Elizabeth M. Kaltman, Jonathan R. Benson, D. Woodrow Canter, Charles E. Cripe, Linda H. Duan, Dongsheng Finder, Jonathan D. Hoffman, Eric P. Judge, Daniel P. Kertesz, Naomi Kinnett, Kathi Kirsch, Roxanne Metzger, Joseph M. Pearson, Gail D. Rafael-Fortney, Jill A. Raman, Subha V. Spurney, Christopher F. Targum, Shari L. Wagner, Kathryn R. Markham, Larry W. TI Contemporary Cardiac Issues in Duchenne Muscular Dystrophy SO CIRCULATION LA English DT Article DE cardiomyopathy; dystrophin; heart failure; magnetic resonance imaging; muscular dystrophy ID CONVERTING-ENZYME-INHIBITORS; MDX MOUSE MODEL; DEFICIENT CARDIOMYOPATHY; HEART-FAILURE; VENTRICULAR DYSFUNCTION; DILATED CARDIOMYOPATHY; STEROID-THERAPY; SKELETAL-MUSCLE; LIFE EXPECTANCY; BETA-BLOCKERS C1 [McNally, Elizabeth M.] Northwestern Univ, Ctr Genet Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Kaltman, Jonathan R.; Pearson, Gail D.] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20817 USA. [Benson, D. Woodrow] Childrens Hosp Wisconsin, Div Cardiol, Milwaukee, WI 53201 USA. [Canter, Charles E.] Washington Univ, Dept Pediat, St Louis, MO 63130 USA. [Cripe, Linda H.; Kertesz, Naomi] Nationwide Childrens Hosp, Ctr Heart, Columbus, OH USA. [Duan, Dongsheng] Univ Missouri, Sch Med, Dept Mol Microbiol & Immunol, Columbia, MO 65211 USA. [Finder, Jonathan D.] Childrens Hosp Pittsburgh, Div Pulm Med, Pittsburgh, PA USA. [Hoffman, Eric P.] Childrens Natl Hlth Syst, Med Genet Res Ctr, Washington, DC USA. [Spurney, Christopher F.] Childrens Natl Hlth Syst, Div Cardiol, Childrens Natl Heart Inst, Med Genet Res Ctr, Washington, DC USA. [Judge, Daniel P.] Johns Hopkins Sch Med, Div Cardiol, Baltimore, MD USA. [Kinnett, Kathi] Parent Project Muscular Dystrophy, Middletown, OH USA. [Kirsch, Roxanne] Childrens Hosp Philadelphia, Div Cardiac Crit Care, Philadelphia, PA USA. [Metzger, Joseph M.] Univ Minnesota, Sch Med, Dept Integrat Biol & Physiol, Minneapolis, MN 55455 USA. [Rafael-Fortney, Jill A.] Ohio State Univ, Dept Mol & Cellular Biochem, Columbus, OH 43210 USA. [Raman, Subha V.] Ohio State Univ, Div Cardiovasc Med, Columbus, OH 43210 USA. [Targum, Shari L.] US FDA, Div Cardiovasc & Renal Prod, Silver Spring, MD USA. [Wagner, Kathryn R.] Kennedy Krieger Inst, Hugo W Moser Res Inst, Baltimore, MD USA. [Markham, Larry W.] Vanderbilt Univ, Dept Pediat, Div Pediat Cardiol, Nashville, TN 37232 USA. RP McNally, EM (reprint author), Northwestern Univ, Ctr Genet Med, Feinberg Sch Med, 303 E Super St,7-123, Chicago, IL 60611 USA. EM Elizabeth.mcnally@northwestern.edu; kaltmanj@nhlbi.nih.gov; larry.markham@Vanderbilt.Edu FU Siemens FX The views expressed in this article do not necessarily relied those of the National Heart, Lung, and Blood Institute; US Food and Drug Administration; or National Institutes of Health. This article reflects the views of the author and should not be construed to represent the US Food and Drug Administration's views or policies. Dr Raman receives institutional research support from Siemens. Dr Duan is a member of the Scientific Advisory Board for Solid GT, LLC, a venture company founded to advance gene therapy for DMD, Working Group members: co-chairs: Elizabeth McNally, MD, PhD, University of Chicago; Larry Markham, MD, Vanderbilt University. Members: D. Woodrow Benson, MD, PhD, Children's Hospital of Wisconsin: Charles Canter, MD, St. Louis Children's Hospital; Linda Cripe, MD, Nation id Children's Hospital; Dongshene Duan, PhD, University of Missouri; Jonathan Finder, MD, Children's Hospital of Pittsburgh: William Groh, MD, MPH, Krannert Institute of Cardiology; Eric Hoffman, PhD, Children's National Medical Center; Daniel Judge, MD, Johns Hopkins University; David Kass, MD, Johns Hopkins University; Naomi Keriesz, MD, Nationwide Children's Hospital; Roxanne Kirsch, MD, Children's Hospital of Philadelphia; Joseph M. Metzger, PhD, University of Minnesota; Jill Rafael-Fortney, PhD, Ohio State University; Subha Raman, MD, Ohio State University; Christopher Spurney, MD, Children's National Medical Center; Lee Sweeney, PhD, Penn Rare Disease Center; Shari Targum, MD, Food and Drug Administration; Kathryn Wagner, MD, PhD, Johns Hopkins University. Parent Project Muscular Dystrophy staff: Brian Denger; Pat Furlong; Sharon Hesterlee, PhD: Kathi Kinnett, MSN, CNP. National Institutes of Health staff: Kristin Burns, MD; Jonathan Kaltman, MD; Glen Nuckolls, PhD; Gail Pearson, MD, ScR John Porter, PhD. The other authors report no conflicts. NR 77 TC 25 Z9 25 U1 0 U2 15 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAY 5 PY 2015 VL 131 IS 18 BP 1590 EP 1598 DI 10.1161/CIRCULATIONAHA.114.015151 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CH2ZO UT WOS:000353895100012 PM 25940966 ER PT J AU Lee, JT Moore, CE Radcliffe, JD AF Lee, Jennifer T. Moore, Carolyn E. Radcliffe, John D. TI Consumption of Calcium-Fortified Cereal Bars to Improve Dietary Calcium Intake of Healthy Women: Randomized Controlled Feasibility Study SO PLOS ONE LA English DT Article ID DAIRY CONSUMPTION; MILK AB Calcium is an important structural component of the skeletal system. Although an adequate intake of calcium helps to maintain bone health and reduce the risk of osteoporosis, many women do not meet recommended daily intakes of calcium. Previous interventions studies designed to increase dietary intake of women have utilized primarily dairy sources of calcium or supplements. However, lactose intolerance, milk protein allergies, or food preferences may lead many women to exclude important dairy sources of dietary calcium. Therefore, we undertook a 9 week randomized crossover design trial to examine the potential benefit of including a non-dairy source of calcium in the diet of women. Following a 3 week run-in baseline period, 35 healthy women > 18 years were randomized by crossover design into either Group I or Group II. Group I added 2 calcium-fortified cereal bars daily (total of 400 mg calcium/day) (intervention) to their usual diet and Group II continued their usual diet (control). At the end of 3 weeks, diets were switched for another 3 weeks. Intakes of calcium and energy were estimated from 3-day diet and supplemental diaries. Wilcoxon signed-rank tests were used for within group comparisons and Mann Whitney U tests were used for between group comparisons of calcium and energy intake. Dietary calcium was significantly higher during intervention (1071 mg/d) when participants consumed 2 calcium-fortified cereal bars daily than during the baseline (720 mg/d, P < 0.0001) or control diets (775 mg/d, P = 0.0001) periods. Furthermore, the addition of 2 calcium-fortified cereal bars daily for the 3 week intervention did not significantly increase total energy intake or result in weight gain. In conclusion, consumption of calcium-fortified cereal bars significantly increased calcium intake of women. Further research examining the potential ability of fortified cereal bars to help maintain and improve bone health of women is warranted. C1 [Lee, Jennifer T.] NCI, Epidemiol & Genom Res Program, NIH, Rockville, MD USA. [Moore, Carolyn E.; Radcliffe, John D.] Texas Womans Univ, Dept Nutr Nutr & Food Sci, Houston, TX 77030 USA. RP Moore, CE (reprint author), Texas Womans Univ, Dept Nutr Nutr & Food Sci, Houston, TX 77030 USA. EM Cmoore8@twu.edu NR 10 TC 1 Z9 1 U1 0 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 MAY 5 PY 2015 VL 10 IS 5 AR e0125207 DI 10.1371/journal.pone.0125207 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CH3PT UT WOS:000353943400026 PM 25941810 ER PT J AU Mcgowan, I Cranston, RD Duffill, K Siegel, A Engstrom, JC Nikiforov, A Jacobson, C Rehman, KK Elliott, J Khanukhova, E Abebe, K Mauck, C Spiegel, HML Dezzutti, CS Rohan, LC Marzinke, MA Hiruy, H Hendrix, CW Richardson-Harman, N Anton, PA AF Mcgowan, Ian Cranston, Ross D. Duffill, Kathryn Siegel, Aaron Engstrom, Jarret C. Nikiforov, Alexyi Jacobson, Cindy Rehman, Khaja K. Elliott, Julie Khanukhova, Elena Abebe, Kaleab Mauck, Christine Spiegel, Hans M. L. Dezzutti, Charlene S. Rohan, Lisa C. Marzinke, Mark A. Hiruy, Hiwot Hendrix, Craig W. Richardson-Harman, Nicola Anton, Peter A. TI A Phase 1 Randomized, Open Label, Rectal Safety, Acceptability, Pharmacokinetic, and Pharmacodynamic Study of Three Formulations of Tenofovir 1% Gel (the CHARM-01 Study) SO PLOS ONE LA English DT Article ID PREEXPOSURE PROPHYLAXIS; ORAL TENOFOVIR; HIV-INFECTION; AFRICAN WOMEN; MICROBICIDE; TISSUE; INFLAMMATION; TRIALS AB Objectives The CHARM-01 study characterized the safety, acceptability, pharmacokinetics (PK), and pharmacodynamics (PD) of three tenofovir (TFV) gels for rectal application. The vaginal formulation (VF) gel was previously used in the CAPRISA 004 and VOICE vaginal microbicide Phase 2B trials and the RMP-02/MTN-006 Phase 1 rectal safety study. The reduced glycerin VF (RGVF) gel was used in the MTN-007 Phase 1 rectal microbicide trial and is currently being evaluated in the MTN-017 Phase 2 rectal microbicide trial. A third rectal specific formulation (RF) gel was also evaluated in the CHARM-01 study. Methods Participants received 4 mL of the three TFV gels in a blinded, crossover design: seven daily doses of RGVF, seven daily doses of RF, and six daily doses of placebo followed by one dose of VF, in a randomized sequence. Safety, acceptability, compartmental PK, and explant PD were monitored throughout the trial. Results All three gels were found to be safe and acceptable. RF and RGVF PK were not significantly different. Median mucosal mononuclear cell (MMC) TFV-DP trended toward higher values for RF compared to RGVF (1136 and 320 fmol/10(6) cells respectively). Use of each gel in vivo was associated with significant inhibition of ex vivo colorectal tissue HIV infection. There was also a significant negative correlation between the tissue levels of TFV, tissue TFV-DP, MMC TFV-DP, rectal fluid TFV, and explant HIV-1 infection. Conclusions All three formulations were found to be safe and acceptable. However, the safety profile of the VF gel was only based on exposure to one dose whereas participants received seven doses of the RGVF and RF gels. There was a trend towards higher tissue MMC levels of TFV-DP associated with use of the RF gel. Use of all gels was associated with significant inhibition of ex vivo tissue HIV infection. C1 [Mcgowan, Ian; Cranston, Ross D.; Abebe, Kaleab; Dezzutti, Charlene S.; Rohan, Lisa C.] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Mcgowan, Ian; Duffill, Kathryn; Siegel, Aaron; Engstrom, Jarret C.; Nikiforov, Alexyi; Jacobson, Cindy; Rehman, Khaja K.; Dezzutti, Charlene S.; Rohan, Lisa C.] Magee Womens Res Inst, Pittsburgh, PA USA. [Elliott, Julie; Khanukhova, Elena; Anton, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Mauck, Christine] CONRAD, Arlington, VA USA. [Spiegel, Hans M. L.] NIAID, HJF DAIDS, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Marzinke, Mark A.; Hiruy, Hiwot; Hendrix, Craig W.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Richardson-Harman, Nicola] Alpha StatConsult LLC, Damascus, MD USA. RP Mcgowan, I (reprint author), Univ Pittsburgh, Pittsburgh, PA 15260 USA. EM imcgowan@pitt.edu RI Hendrix, Craig/G-4182-2014; OI Hendrix, Craig/0000-0002-5696-8665; Abebe, Kaleab/0000-0002-3644-8419; Cranston, Ross/0000-0002-2687-6217 FU U19 grant under the Integrated Preclinical-Clinical Program for HIV Topical Microbicides (IPCP-HTM), Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH) [AI082637]; NIH/NIAID/DAIDS [HHSN272201000001C]; Alpha StatConsult, LLC FX The study was funded by a U19 grant under the Integrated Preclinical-Clinical Program for HIV Topical Microbicides (IPCP-HTM), Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH) (AI082637). The CHARM-01 study was registered at http://www.ClinicalTrials.gov (NCT01575405). The PK/PD analysis of CHARM-01 data was supported through a NIH/NIAID/DAIDS contract (HHSN272201000001C) to Advanced BioScience Laboratories, Inc., Rockville, MD. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Co-author Nicola Richardson-Harman is employed by Alpha StatConsult, LLC. Alpha StatConsult, LLC provided support in the form of salary for author NR-H, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The coauthor NR-H, as a statistical consultant, analyzed data and contributed to the statistical sections of the manuscript. The specific role of this author is articulated in the 'author contributions' section. NR 32 TC 9 Z9 9 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 5 PY 2015 VL 10 IS 5 AR UNSP e0125363 DI 10.1371/journal.pone.0125363 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CH3PT UT WOS:000353943400032 PM 25942472 ER PT J AU Ohta, N Ishiguro, S Kawabata, A Uppalapati, D Pyle, M Troyer, D De, S Zhang, YQ Becker, KG Tamura, M AF Ohta, Naomi Ishiguro, Susumu Kawabata, Atsushi Uppalapati, Deepthi Pyle, Marla Troyer, Deryl De, Supriyo Zhang, Yongqing Becker, Kevin G. Tamura, Masaaki TI Human Umbilical Cord Matrix Mesenchymal Stem Cells Suppress the Growth of Breast Cancer by Expression of Tumor Suppressor Genes SO PLOS ONE LA English DT Article ID LUNG ADENOCARCINOMA; IN-VITRO; METASTASIS; SURVIVAL; MICE; TRANSPLANTATION; PROLIFERATION; TUMORIGENESIS; SERPINE2; THERAPY AB Human and rat umbilical cord matrix mesenchymal stem cells (UCMSC) possess the ability to control the growth of breast carcinoma cells. Comparative analyses of two types of UCMSC suggest that rat UCMSC-dependent growth regulation is significantly stronger than that of human UCMSC. Their different tumoricidal abilities were clarified by analyzing gene expression profiles in the two types of UCMSC. Microarray analysis revealed differential gene expression between untreated naive UCMSC and those co-cultured with species-matched breast carcinoma cells. The analyses screened 17 differentially expressed genes that are commonly detected in both human and rat UCMSC. The comparison between the two sets of gene expression profiles identified two tumor suppressor genes, adipose-differentiation related protein (ADRP) and follistatin (FST), that were specifically up-regulated in rat UCMSC, but down-regulated in human UCMSC when they were co-cultured with the corresponding species' breast carcinoma cells. Over-expression of FST, but not ADRP, in human UCMSC enhanced their ability to suppress the growth of MDA-231 cells. The growth of MDA-231 cells was also significantly lower when they were cultured in medium conditioned with FST, but not ADRP over-expressing human UCMSC. In the breast carcinoma lung metastasis model generated with MDA-231 cells, systemic treatment with FST-over-expressing human UCMSC significantly attenuated the tumor burden. These results suggest that FST may play an important role in exhibiting stronger tumoricidal ability in rat UCMSC than human UCMSC and also implies that human UCMSC can be transformed into stronger tumoricidal cells by enhancing tumor suppressor gene expression. C1 [Ohta, Naomi; Ishiguro, Susumu; Kawabata, Atsushi; Uppalapati, Deepthi; Pyle, Marla; Troyer, Deryl; Tamura, Masaaki] Kansas State Univ, Dept Anat & Physiol, Coll Vet Med, Manhattan, KS 66506 USA. [De, Supriyo; Zhang, Yongqing; Becker, Kevin G.] NIA, Gene Express & Genom Unit, NIH Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. RP Tamura, M (reprint author), Kansas State Univ, Dept Anat & Physiol, Coll Vet Med, Manhattan, KS 66506 USA. EM mtamura@vet.ksu.edu OI De, Supriyo/0000-0002-2075-7655; Ohta, Naomi/0000-0001-5790-3137 FU Intramural Research Program of the National Institutes of Health, National Institute on Aging; Kansas State University Johnson Cancer Research Center; National Institutes of Health [P20 RR017686, P20 RR015563, P20 GM103418]; Kansas State University Targeted Excellence Research Grant; Kansas State Legislature; Kansas State University College of Veterinary Medicine Dean's Fund FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging, Kansas State University Johnson Cancer Research Center, Kansas State University College of Veterinary Medicine Dean's Fund, National Institutes of Health P20 RR017686, P20 RR015563, P20 GM103418, Kansas State University Targeted Excellence Research Grant, and the Kansas State Legislature. MT received the funding. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 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 MAY 5 PY 2015 VL 10 IS 5 AR e0123756 DI 10.1371/journal.pone.0123756 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CH3PT UT WOS:000353943400007 PM 25942583 ER PT J AU Viollet, C Davis, DA Reczko, M Ziegelbauer, JM Pezzella, F Ragoussis, J Yarchoan, R AF Viollet, Coralie Davis, David A. Reczko, Martin Ziegelbauer, Joseph M. Pezzella, Francesco Ragoussis, Jiannis Yarchoan, Robert TI Next-Generation Sequencing Analysis Reveals Differential Expression Profiles of MiRNA-mRNA Target Pairs in KSHV-Infected Cells SO PLOS ONE LA English DT Article ID PRIMARY EFFUSION LYMPHOMA; INFLAMMATORY-CYTOKINE EXPRESSION; VIRUS-ENCODED MICRORNAS; NF-KAPPA-B; KAPOSIS-SARCOMA; ENDOTHELIAL-CELLS; DNA-SEQUENCES; HERPESVIRUS-INFECTION; GENE-EXPRESSION; FEEDBACK LOOP AB Kaposi's sarcoma associated herpesvirus (KSHV) causes several tumors, including primary effusion lymphoma (PEL) and Kaposi's sarcoma (KS). Cellular and viral microRNAs (miRNAs) have been shown to play important roles in regulating gene expression. A better knowledge of the miRNA-mediated pathways affected by KSHV infection is therefore important for understanding viral infection and tumor pathogenesis. In this study, we used deep sequencing to analyze miRNA and cellular mRNA expression in a cell line with latent KSHV infection (SLKK) as compared to the uninfected SLK line. This approach revealed 153 differentially expressed human miRNAs, eight of which were independently confirmed by qRT-PCR. KSHV infection led to the dysregulation of similar to 15% of the human miRNA pool and most of these cellular miRNAs were down-regulated, including nearly all members of the 14q32 miRNA cluster, a genomic locus linked to cancer and that is deleted in a number of PEL cell lines. Furthermore, we identified 48 miRNAs that were associated with a total of 1,117 predicted or experimentally validated target mRNAs; of these mRNAs, a majority (73%) were inversely correlated to expression changes of their respective miRNAs, suggesting miRNA-mediated silencing mechanisms were involved in a number of these alterations. Several dysregulated miRNA-mRNA pairs may facilitate KSHV infection or tumor formation, such as up-regulated miR-708-5p, associated with a decrease in pro-apoptotic caspase-2 and leukemia inhibitory factor LIF, or down-regulated miR-409-5p, associated with an increase in the p53-inhibitor MDM2. Transfection of miRNA mimics provided further evidence that changes in miRNAs are driving some observed mRNA changes. Using filtered datasets, we also identified several canonical pathways that were significantly enriched in differentially expressed miRNA-mRNA pairs, such as the epithelial-to-mesenchymal transition and the interleukin-8 signaling pathways. Overall, our data provide a more detailed understanding of KSHV latency and guide further studies of the biological significance of these changes. C1 [Viollet, Coralie; Davis, David A.; Ziegelbauer, Joseph M.; Yarchoan, Robert] NCI, HIV & AIDS Malignancy Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Viollet, Coralie; Ragoussis, Jiannis] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Reczko, Martin; Ragoussis, Jiannis] Alexander Fleming Biomed Sci Res Ctr, Inst Mol Oncol, Vari, Greece. [Pezzella, Francesco] Univ Oxford, Nuffield Div Clin Lab Sci, Oxford, England. [Ragoussis, Jiannis] McGill Univ, Montreal, PQ, Canada. [Ragoussis, Jiannis] Genome Quebec Innovat Ctr, Montreal, PQ, Canada. RP Ragoussis, J (reprint author), Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. EM ioannis.ragoussis@mcgill.ca; robert.yarchoan@nih.gov OI Reczko, Martin/0000-0002-0005-8718 FU National Institutes of Health, National Cancer Institute; Wellcome Trust [095493] FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute (https://ccr.cancer. gov/), and by the Wellcome Trust PhD Studentship http://www.wellcome.ac.uk/Funding/Biomedicalscience/index. htm), Award Number 095493. The funders had no role in study design, data collectionand analysis, decision to publish, or preparation of the manuscript. NR 59 TC 4 Z9 4 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 5 PY 2015 VL 10 IS 5 AR e0126439 DI 10.1371/journal.pone.0126439 PG 23 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CH3PT UT WOS:000353943400071 PM 25942495 ER PT J AU Miller, FG AF Miller, Franklin G. TI Expanding Long-term Care Options for Persons With Serious Mental Illness SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Miller, Franklin G.] NIH, Dept Bioeth, Bethesda, MD 20892 USA. RP Miller, FG (reprint author), NIH, Ctr Clin, Dept Bioeth, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM fmiller@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 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 MAY 5 PY 2015 VL 313 IS 17 BP 1757 EP 1757 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA CH3HQ UT WOS:000353921000031 PM 25942735 ER PT J AU Harrington, RA Barac, A Brush, JE Hill, JA Krumholz, HM Lauer, MS Sivaram, CA Taubman, MB Williams, JL AF Harrington, Robert A. Barac, Ana Brush, John E. Hill, Joseph A. Krumholz, Harlan M. Lauer, Michael S. Sivaram, Chittur A. Taubman, Mark B. Williams, Jeffrey L. TI COCATS 4 Task Force 15: Training in Cardiovascular Research and Scholarly Activity SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE ACC Training Statement; clinical competence; COCATS; fellowship training; research C1 [Harrington, Robert A.] Stanford Univ, Dept Med, Med, Chair, Stanford, CA 94305 USA. [Barac, Ana] MedStar Heart & Vasc Inst, Cardio Oncol Program, Washington, DC USA. [Hill, Joseph A.] UT SW Med Center, Med & Mol Biol, Dallas, TX USA. [Krumholz, Harlan M.] Yale Univ, Sch Med, Med & Epidemiol & Publ Hlth, New Haven, CT 06520 USA. [Lauer, Michael S.] Natl Heart Lung & Blood Inst, Div Cardiovasc Sci, Bethesda, MD USA. [Sivaram, Chittur A.] Univ Oklahoma, Hlth Sci Ctr, Program Cardiovasc Sect, Norman, OK 73019 USA. [Taubman, Mark B.] Univ Rochester, Med Ctr, Med, Rochester, NY 14627 USA. RP Harrington, RA (reprint author), Stanford Univ, Dept Med, Med, Chair, Stanford, CA 94305 USA. NR 4 TC 8 Z9 8 U1 0 U2 1 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 MAY 5 PY 2015 VL 65 IS 17 BP 1899 EP 1906 DI 10.1016/j.jacc.2015.03.032 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CG9OA UT WOS:000353644200017 PM 25777645 ER PT J AU Tsuda, Y Parkins, CJ Caposio, P Feldmann, F Botto, S Ball, S Messaoudi, I Cicin-Sain, L Feldmann, H Jarvis, MA AF Tsuda, Yoshimi Parkins, Christopher J. Caposio, Patrizia Feldmann, Friederike Botto, Sara Ball, Susan Messaoudi, Ilhem Cicin-Sain, Luka Feldmann, Heinz Jarvis, Michael A. TI A cytomegalovirus-based vaccine provides long-lasting protection against lethal Ebola virus challenge after a single dose SO VACCINE LA English DT Article DE Ebolavirus; Vaccine; Disseminating; Great apes; Cytomegalovirus; Mouse; Protection; Durable; Ebola ID T-CELL RESPONSES; WILD CHIMPANZEES; VIRAL-INFECTION; TRANSMISSION; OUTBREAK; EFFECTOR; GORILLAS; DECLINE; AFRICA; WOMEN AB Ebola virus (Zaire ebolavirus; EBOV) is a highly lethal hemorrhagic disease virus that most recently was responsible for two independent 2014 outbreaks in multiple countries in Western Africa, and the Democratic Republic of the Congo, respectively. Herein, we show that a cytomegalovirus (CMV)-based vaccine provides durable protective immunity from Ebola virus following a single vaccine dose. This study has implications for human vaccination against ebolaviruses, as well as for development of a 'disseminating' vaccine to target these viruses in wild African great apes. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Tsuda, Yoshimi; Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT USA. [Parkins, Christopher J.; Caposio, Patrizia; Botto, Sara] Oregon Hlth & Sci Univ, Vaccine & Gene Therapy Inst, Portland, OR 97201 USA. [Feldmann, Friederike] NIAID, Rocky Mt Vet Branch, NIH, Hamilton, MT USA. [Ball, Susan] Univ Plymouth, Ctr Biostat Bioinformat & Biomarkers, Plymouth PL4 8AA, Devon, England. [Messaoudi, Ilhem] Univ Calif Riverside, Sch Med, Riverside, CA 92521 USA. [Cicin-Sain, Luka] Helmholtz Ctr Infect Res, Braunschweig, Germany. [Jarvis, Michael A.] Univ Plymouth, Sch Biomed & Healthcare Sci, Plymouth PL4 8AA, Devon, England. RP Jarvis, MA (reprint author), Univ Plymouth, Sch Biomed & Healthcare Sci, Plymouth PL4 8AA, Devon, England. EM michael.jarvis@plymouth.ac.uk OI Cicin-Sain, Luka/0000-0003-3978-778X FU R21 [AI088442]; Intramural Research Program of the NIAID, NIH; University of Plymouth, School of Biomedical and Healthcare Sciences FX We thank Dr U. Koszinowski (Max von Pettenkofer-Institute, Ludwig-Maximilians-University, Germany) for providing the pSMfr3 MCMV BAC, and Dr D. Court (NCI-Frederick, MD) for providing the lambda-based recombination system used to construct the original MCMV/ZEBOV-NPCTL construct. We appreciate K. Marshall (VGTI, OR) and J. Bailey (NIAID, MT) for their organization and coordination of animals used in the study. We also thank the members of Rocky Mountain Veterinary Branch (DIR, NIAID, NIH) for assistance with animal care. Finally, we thank Drs H. Ebihara (DIR, NIAID, NIH), A. Marzi (DIR, NIAID, NIH), P. Barry (University of California at Davis, CA), M. Cranfield (Mountain Gorilla Veterinary Project, Baltimore, MD) for insightful discussions. This study was supported by R21 (AI088442) and the Intramural Research Program of the NIAID, NIH; and University of Plymouth, School of Biomedical and Healthcare Sciences internal funding. NR 37 TC 7 Z9 7 U1 2 U2 37 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 MAY 5 PY 2015 VL 33 IS 19 BP 2261 EP 2266 DI 10.1016/j.vaccine.2015.03.029 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA CH0TI UT WOS:000353734900011 PM 25820063 ER PT J AU Nicholson, JM Macedo, JC Mattingly, AJ Wangsa, D Camps, J Lima, V Gomes, AM Doria, S Ried, T Logarinho, E Cimini, D AF Nicholson, Joshua M. Macedo, Joana C. Mattingly, Aaron J. Wangsa, Darawalee Camps, Jordi Lima, Vera Gomes, Ana M. Doria, Sofia Ried, Thomas Logarinho, Elsa Cimini, Daniela TI Chromosome mis-segregation and cytokinesis failure in trisomic human cells SO ELIFE LA English DT Article ID PHA-STIMULATED LYMPHOCYTES; CANCER-CELLS; COLORECTAL-CANCER; CENTROSOME AMPLIFICATION; SPORADIC ANEUPLOIDY; GENETIC INSTABILITY; CLEAVAGE FAILURE; CLONAL EVOLUTION; MAMMALIAN-CELLS; TRANSCRIPTOME AB Cancer cells display aneuploid karyotypes and typically mis-segregate chromosomes at high rates, a phenotype referred to as chromosomal instability (CIN). To test the effects of aneuploidy on chromosome segregation and other mitotic phenotypes we used the colorectal cancer cell line DLD1 (2n = 46) and two variants with trisomy 7 or 13 (DLD1+7 and DLD1+13), as well as euploid and trisomy 13 amniocytes (AF and AF+13). We found that trisomic cells displayed higher rates of chromosome mis-segregation compared to their euploid counterparts. Furthermore, cells with trisomy 13 displayed a distinctive cytokinesis failure phenotype. We showed that up-regulation of SPG20 expression, brought about by trisomy 13 in DLD1+13 and AF+13 cells, is sufficient for the cytokinesis failure phenotype. Overall, our study shows that aneuploidy can induce chromosome mis-segregation. Moreover, we identified a trisomy 13-specific mitotic phenotype that is driven by up-regulation of a gene encoded on the aneuploid chromosome. C1 [Nicholson, Joshua M.; Mattingly, Aaron J.; Cimini, Daniela] Virginia Tech, Dept Biol Sci, Blacksburg, VA USA. [Nicholson, Joshua M.; Cimini, Daniela] Virginia Tech, Virginia Bioinformat Inst, Blacksburg, VA USA. [Macedo, Joana C.; Gomes, Ana M.; Logarinho, Elsa] Univ Porto, Inst Biol Mol & Celular, Aging & Aneuploidy Lab, P-4100 Oporto, Portugal. [Macedo, Joana C.; Logarinho, Elsa] Univ Porto, Inst Invest & Inovacao Saude I3S, P-4100 Oporto, Portugal. [Macedo, Joana C.; Logarinho, Elsa] Univ Porto, Fac Med, Dept Expt Biol, Cell Div Unit, P-4100 Oporto, Portugal. [Wangsa, Darawalee; Camps, Jordi; Ried, Thomas] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Lima, Vera; Doria, Sofia] Univ Porto, Fac Med, Dept Genet, P-4100 Oporto, Portugal. RP Logarinho, E (reprint author), Univ Porto, Inst Biol Mol & Celular, Aging & Aneuploidy Lab, P-4100 Oporto, Portugal. EM elsa.logarinho@ibmc.up.pt; cimini@vt.edu OI Cimini, Daniela/0000-0002-4082-4894 FU National Science Foundation (NSF) [MCB-0842551]; Human Frontier Science Program (HFSP) [RGY0069/2010]; Programa Operacional Regional do Norte [NORTE-07-0124-FEDER-000003]; Fundacao para a Ciencia e a Tecnologia [SFRH/BD/74002/2010] FX National Science Foundation (NSF) MCB-0842551 Daniela Cimini; Human Frontier Science Program (HFSP) RGY0069/2010 Daniela Cimini; Programa Operacional Regional do Norte NORTE-07-0124-FEDER-000003 Elsa Logarinho; Fundacao para a Ciencia e a Tecnologia SFRH/BD/74002/2010 Joana C Macedo NR 77 TC 13 Z9 13 U1 2 U2 2 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD MAY 5 PY 2015 VL 4 AR e05068 DI 10.7554/eLife.05068 PG 23 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DJ5PP UT WOS:000374262200001 ER PT J AU Masison, DC Reidy, M AF Masison, Daniel C. Reidy, Michael TI Yeast prions are useful for studying protein chaperones and protein quality control SO PRION LA English DT Article DE prion; chaperone; yeast; protein quality control; NEF; nucleotide exchange factor; CTD; C-terminal domain; NBD; nucleotide-binding domain ID II HSP40 SIS1; SACCHAROMYCES-CEREVISIAE; PSI+ PRION; AGGREGATED PROTEINS; HSP70 CHAPERONES; URE3 PRION; ANTAGONISTIC INTERACTIONS; GUANIDINE-HYDROCHLORIDE; HSP100 CHAPERONES; SUBSTRATE-BINDING AB Protein chaperones help proteins adopt and maintain native conformations and play vital roles in cellular processes where proteins are partially folded. They comprise a major part of the cellular protein quality control system that protects the integrity of the proteome. Many disorders are caused when proteins misfold despite this protection. Yeast prions are fibrous amyloid aggregates of misfolded proteins. The normal action of chaperones on yeast prions breaks the fibers into pieces, which results in prion replication. Because this process is necessary for propagation of yeast prions, even small differences in activity of many chaperones noticeably affect prion phenotypes. Several other factors involved in protein processing also influence formation, propagation or elimination of prions in yeast. Thus, in much the same way that the dependency of viruses on cellular functions has allowed us to learn much about cell biology, the dependency of yeast prions on chaperones presents a unique and sensitive way to monitor the functions and interactions of many components of the cell's protein quality control system. Our recent work illustrates the utility of this system for identifying and defining chaperone machinery interactions. C1 [Masison, Daniel C.; Reidy, Michael] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Masison, DC (reprint author), NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. EM danielmas@helix.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH), National Institute of Diabetes, Digestive and Kidney Diseases FX This work was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Diabetes, Digestive and Kidney Diseases. NR 68 TC 4 Z9 4 U1 2 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1933-6896 EI 1933-690X J9 PRION JI Prion PD MAY 4 PY 2015 VL 9 IS 3 BP 174 EP 183 DI 10.1080/19336896.2015.1027856 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CL3VF UT WOS:000356878400002 PM 26110609 ER PT J AU Lusvarghi, S Ghirlando, R Wong, CH Bewley, CA AF Lusvarghi, Sabrina Ghirlando, Rodolfo Wong, Chi-Huey Bewley, Carole A. TI Glycopeptide Mimetics Recapitulate High-Mannose-Type Oligosaccharide Binding and Function SO ANGEWANDTE CHEMIE-INTERNATIONAL EDITION LA English DT Article DE antiviral agents; carbohydrates; glycans; multivalency; oligomerization ID CARBOHYDRATE-BINDING; LECTIN GRIFFITHSIN; CROSS-LINKING; ANTIBODY; POTENT; GLYCOPROTEINS; PROTEIN; GLYCANS; DOMAIN; HIV-1 AB High-mannose-type glycans (HMTGs) decorating viral spike proteins are targets for virus neutralization. For carbohydrate-binding proteins, multivalency is important for high avidity binding and potent inhibition. To define the chemical determinants controlling multivalent interactions we designed glycopeptide HMTG mimetics with systematically varied mannose valency and spacing. Using the potent antiviral lectin griffithsin (GRFT) as a model, we identified by NMR spectroscopy, SPR, analytical ultracentrifugation, and microcalorimetry glycopeptides that fully recapitulate the specificity and kinetics of binding to Man(9)GlcNAc(2)Asn and a synthetic nonamannoside. We find that mannose spacing and valency dictate whether glycopeptides engage GRFT in a face-to-face or an intermolecular binding mode. Surprisingly, although face-to-face interactions are of higher affinity, intermolecular interactions are longer lived. These findings yield key insights into mechanisms involved in glycan-mediated viral inhibition. C1 [Lusvarghi, Sabrina; Bewley, Carole A.] NIDDK, Bioorgan Chem Lab, Bethesda, MD 20892 USA. [Ghirlando, Rodolfo] NIDDK, Mol Biol Lab, Bethesda, MD 20892 USA. [Wong, Chi-Huey] Acad Sinica, Genom Res Ctr, Taipei 115, Taiwan. RP Bewley, CA (reprint author), NIDDK, Bioorgan Chem Lab, Bethesda, MD 20892 USA. EM caroleb@mail.nih.gov FU AIDS Targeted Antiviral Program, Office of the Director, NIH; Intramural Research Program of the National Institutes of Health (NIDDK) FX We thank J. Lloyd for HRMS data, R.O'Connor for NMR support, and L.-X. Wang and C. Toonstra for Man-9. This work was supported by the AIDS Targeted Antiviral Program, Office of the Director, NIH (C.A.B.), and the Intramural Research Program of the National Institutes of Health (NIDDK). NR 19 TC 2 Z9 2 U1 2 U2 30 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 MAY 4 PY 2015 VL 54 IS 19 BP 5603 EP 5608 DI 10.1002/anie.201500157 PG 6 WC Chemistry, Multidisciplinary SC Chemistry GA CH7CN UT WOS:000354193300012 PM 25776945 ER PT J AU Pawlak, JB Gential, GPP Ruckwardt, TJ Bremmers, JS Meeuwenoord, NJ Ossendorp, FA Overkleeft, HS Filippov, DV van Kasteren, SI AF Pawlak, Joanna B. Gential, Geoffroy P. P. Ruckwardt, Tracy J. Bremmers, Jessica S. Meeuwenoord, Nico J. Ossendorp, Ferry A. Overkleeft, Herman S. Filippov, Dmitri V. van Kasteren, Sander I. TI Bioorthogonal Deprotection on the Dendritic Cell Surface for Chemical Control of Antigen Cross-Presentation SO ANGEWANDTE CHEMIE-INTERNATIONAL EDITION LA English DT Article DE antigens; azides; bioorthogonal chemistry; cell recognition; Staudinger reduction ID MHC CLASS-I; NEWLY SYNTHESIZED PROTEINS; STAUDINGER REACTION; CLICK CHEMISTRY; BONE-MARROW; T-CELLS; COMPLEX; MOLECULES; PEPTIDE; EPITOPE AB The activation of CD8(+) T-cells requires the uptake of exogenous polypeptide antigens and proteolytic processing of these antigens to octamer or nonamer peptides, which are loaded on MHC-I complexes and presented to the T-cell. By using an azide as a bioorthogonal protecting group rather than as a ligation handle, masked antigens were generated-antigens that are not recognized by their cognate T-cell unless they are deprotected on the cell using a Staudinger reduction. C1 [Pawlak, Joanna B.; Gential, Geoffroy P. P.; Bremmers, Jessica S.; Meeuwenoord, Nico J.; Overkleeft, Herman S.; Filippov, Dmitri V.; van Kasteren, Sander I.] Leiden Univ, Leiden Inst Chem, NL-2333 CC Leiden, Netherlands. [Pawlak, Joanna B.; Gential, Geoffroy P. P.; Bremmers, Jessica S.; Meeuwenoord, Nico J.; Overkleeft, Herman S.; Filippov, Dmitri V.; van Kasteren, Sander I.] Leiden Univ, Inst Chem Immunol, NL-2333 CC Leiden, Netherlands. [Ruckwardt, Tracy J.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Ossendorp, Ferry A.] Leiden Univ Med Ctr, Dept Immunohematol & Blood Transfus, NL-2300 RC Leiden, Netherlands. [Ossendorp, Ferry A.] Inst Chem Immunol, NL-2300 RC Leiden, Netherlands. RP van Kasteren, SI (reprint author), Leiden Univ, Leiden Inst Chem, Einsteinweg 55, NL-2333 CC Leiden, Netherlands. EM s.i.van.kasteren@chem.leidenuniv.nl FU Netherlands Organization for Scientific Research; Veni grant from the Netherlands Organization for Scientific Research [700.59.402]; ERC [639005]; intramural NIAID funding FX P.P.G., F.A.O., and D.V.F. received funding from the Netherlands Organization for Scientific Research. S.I.v.K. was supported by a Veni grant from the Netherlands Organization for Scientific Research (700.59.402) and an ERC Starting Grant (639005). T.J.R. is a member of the Viral Pathogenesis Laboratory (Barney Graham/NIAID/VRC) and is supported by intramural NIAID funding. NR 43 TC 6 Z9 7 U1 3 U2 49 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 MAY 4 PY 2015 VL 54 IS 19 BP 5628 EP 5631 DI 10.1002/anie.201500301 PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA CH7CN UT WOS:000354193300017 PM 25784151 ER PT J AU Klein, WMP Hamilton, JG Harris, PR Han, PKJ AF Klein, William M. P. Hamilton, Jada G. Harris, Peter R. Han, Paul K. J. TI Health Messaging to Individuals Who Perceive Ambiguity in Health Communications: The Promise of Self-Affirmation SO JOURNAL OF HEALTH COMMUNICATION LA English DT Article ID CANCER PREVENTION RECOMMENDATIONS; RANDOMIZED CONTROLLED-TRIAL; IMPLEMENTATION INTENTIONS; ALCOHOL-CONSUMPTION; RISK INFORMATION; POSITIVE-AFFECT; UNITED-STATES; ASSOCIATION; PERCEPTIONS; INTERVENTION AB The perception that extant health messages about risk factors for a disease are ambiguous can be associated with greater anxiety and reduced interest in taking precautionary action. In this experiment, 247 female alcohol consumers who perceived varying degrees of ambiguity in current cancer prevention messages read an unambiguous article about the documented link between alcohol consumption and breast cancer. Before reading the article, half were given the opportunity to self-affirm by reflecting on an important value-a technique previously shown to enhance receptivity to threatening messages. The authors found that self-affirmation increased message acceptance among those who perceived relatively higher levels of ambiguity in cancer communications. Also, the relation between perceived ambiguity and risk perception became positive among self-affirmed participants, suggesting they had become less defensive. Self-affirmation may be an effective technique to use when delivering health communications to audiences who perceive a lack of consistency in prevention messages. C1 [Klein, William M. P.] NCI, Behav Res Program, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Klein, William M. P.] Univ Pittsburgh, Pittsburgh, PA USA. [Hamilton, Jada G.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Harris, Peter R.] Univ Sussex, Brighton, Sussex, England. [Han, Paul K. J.] Maine Med Ctr, Ctr Outcomes Res & Evaluat, Portland, ME 04102 USA. RP Klein, WMP (reprint author), NCI, Behav Res Program, Div Canc Control & Populat Sci, NIH, 9609 Med Ctr Dr,Room 3E140, Bethesda, MD 20892 USA. EM kleinwm@mail.nih.gov OI Han, Paul/0000-0003-0165-1940 NR 50 TC 0 Z9 0 U1 0 U2 10 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1081-0730 EI 1087-0415 J9 J HEALTH COMMUN JI J. Health Commun. PD MAY 4 PY 2015 VL 20 IS 5 BP 566 EP 572 DI 10.1080/10810730.2014.999892 PG 7 WC Communication; Information Science & Library Science SC Communication; Information Science & Library Science GA CG7JT UT WOS:000353480000008 PM 25806652 ER PT J AU Zhao, XQ Mao, QN Kreps, GL Yu, GM Li, YH Chou, SWY Perkosie, A Nie, XQ Xu, ZH Song, MJ Kim, P AF Zhao, Xiaoquan Mao, Qunan Kreps, Gary L. Yu, Guoming Li, Yinghua Chou, Sylvia Wen-Ying Perkosie, Alexander Nie, Xueqiong Xu, Zihoa Song, Meijie Kim, Paula TI Cancer Information Seekers in China: A Preliminary Profile SO JOURNAL OF HEALTH COMMUNICATION LA English DT Article ID NATIONAL TRENDS SURVEY; ONLINE HEALTH INFORMATION; BEHAVIORAL-MODEL; SCREENING BEHAVIOR; SEEKING BEHAVIOR; CARE; PERCEPTION; KNOWLEDGE; BELIEFS; WOMEN AB Cancer is now the leading cause of death in China. Effective communication about cancer risk and prevention is an important component of cancer control. Yet, research in this area is very limited in China. This study used probability sample survey data from 2 Chinese cities (Beijing and Hefei, Anhui Province) to investigate potential predictors of self-initiated cancer information seeking. Analysis showed that cancer information seekers in China were likely to be married, relatively educated, earning modest incomes, living in rural areas, smoking occasionally, having a family cancer history, relatively trusting of the media for health information, somewhat knowledgeable about cancer, having nonfatalistic attitudes about cancer, and seeing a personal need for more cancer information. The pattern of results, particularly the lack of influence of personal health and risk perception factors, highlights the possibility that seeking for others might be more prevalent than seeking for self in China. Overall, findings suggest that emphasizing family need and mobilizing family support might be a productive approach to cancer communication interventions in China. C1 [Zhao, Xiaoquan; Kreps, Gary L.; Kim, Paula] George Mason Univ, Dept Commun, Fairfax, VA 22030 USA. [Mao, Qunan; Li, Yinghua; Nie, Xueqiong] China Minist Hlth, Beijing, Peoples R China. [Yu, Guoming; Xu, Zihoa; Song, Meijie] Renmin Univ, Beijing, Peoples R China. [Chou, Sylvia Wen-Ying] NIH, Hlth Commun & Informat Res Branch, Bethesda, MD 20892 USA. [Perkosie, Alexander] NCI, Rockville, MD USA. RP Zhao, XQ (reprint author), George Mason Univ, Dept Commun, 4400 Univ Dr,3D6, Fairfax, VA 22030 USA. EM xzhao3@gmu.edu NR 50 TC 1 Z9 1 U1 3 U2 15 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1081-0730 EI 1087-0415 J9 J HEALTH COMMUN JI J. Health Commun. PD MAY 4 PY 2015 VL 20 IS 5 BP 616 EP 626 DI 10.1080/10810730.2015.1012244 PG 11 WC Communication; Information Science & Library Science SC Communication; Information Science & Library Science GA CG7JT UT WOS:000353480000014 PM 25845031 ER PT J AU Murthy, SRK Sherrin, T Jansen, C Nijholt, I Robles, M Dolga, AM Andreotti, N Sabatier, JM Knaus, HG Penner, R Todorovic, C Blank, T AF Murthy, Saravana R. K. Sherrin, Tessi Jansen, Chad Nijholt, Ingrid Robles, Michael Dolga, Amalia M. Andreotti, Nicolas Sabatier, Jean-Marc Knaus, Hans-Guenther Penner, Reinhold Todorovic, Cedomir Blank, Thomas TI Small-Conductance Ca2+-Activated Potassium Type 2 Channels Regulate the Formation of Contextual Fear Memory SO PLOS ONE LA English DT Article ID LONG-TERM POTENTIATION; K+ CHANNELS; SYNAPTIC PLASTICITY; CONJUNCTIVE REPRESENTATIONS; SK2 CHANNELS; C-TERMINUS; HIPPOCAMPUS; BRAIN; RECEPTORS; EXPRESSION AB Small-conductance, Ca2+ activated K+ channels (SK channels) are expressed at high levels in brain regions responsible for learning and memory. In the current study we characterized the contribution of SK2 channels to synaptic plasticity and to different phases of hippocampal memory formation. Selective SK2 antisense-treatment facilitated basal synaptic transmission and theta-burst induced LTP in hippocampal brain slices. Using the selective SK2 antagonist Lei-Dab(7) or SK2 antisense probes, we found that hippocampal SK2 channels are critical during two different time windows: 1) blockade of SK2 channels before the training impaired fear memory, whereas, 2) blockade of SK2 channels immediately after the training enhanced contextual fear memory. We provided the evidence that the post-training cleavage of the SK2 channels was responsible for the observed bidirectional effect of SK2 channel blockade on memory consolidation. Thus, Lei-Dab(7)-injection before training impaired the C-terminal cleavage of SK2 channels, while Lei-Dab(7) given immediately after training facilitated the C-terminal cleavage. Application of the synthetic peptide comprising a leucine-zipper domain of the C-terminal fragment to Jurkat cells impaired SK2 channel-mediated currents, indicating that the endogenously cleaved fragment might exert its effects on memory formation by blocking SK2 channel-mediated currents. Our present findings suggest that SK2 channel proteins contribute to synaptic plasticity and memory not only as ion channels but also by additionally generating a SK2 C-terminal fragment, involved in both processes. The modulation of fear memory by down-regulating SK2 C-terminal cleavage might have applicability in the treatment of anxiety disorders in which fear conditioning is enhanced. C1 [Murthy, Saravana R. K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cellular Neurobiol Sect, Program Dev Neurosci, Bethesda, MD USA. [Sherrin, Tessi; Jansen, Chad; Robles, Michael; Penner, Reinhold; Todorovic, Cedomir; Blank, Thomas] Univ Hawaii, John A Burns Sch Med, Dept Cell & Mol Biol, Honolulu, HI 96822 USA. [Jansen, Chad; Penner, Reinhold] Queens Med Ctr, Lab Cell & Mol Signaling, Honolulu, HI USA. [Nijholt, Ingrid] Isala Acad, Isala Clin, Zwolle, Netherlands. [Dolga, Amalia M.] Univ Marburg, Dept Pharmacol & Toxicol, Marburg, Germany. [Andreotti, Nicolas; Sabatier, Jean-Marc] Lab INSERM UMR1097, Marseille 09, France. [Knaus, Hans-Guenther] Med Univ Innsbruck, Div Mol & Cellular Pharmacol, A-6020 Innsbruck, Austria. [Blank, Thomas] Univ Freiburg, Inst Neuropathol, D-79106 Freiburg, Germany. RP Todorovic, C (reprint author), Univ Hawaii, John A Burns Sch Med, Dept Cell & Mol Biol, Honolulu, HI 96822 USA. EM cedomir@hawaii.edu OI SABATIER, Jean-Marc/0000-0002-9040-5647 FU National Institutes of Health [G12MD007601, U54MD008149, MH086733]; Angus Foundation [115054959]; Hawaiian Community Foundation [13ADVC-60319] FX This work was supported by the National Institutes of Health grants G12MD007601, U54MD008149 and MH086733. Additional funding was provided by grants from the Angus Foundation (115054959) and the Hawaiian Community Foundation (13ADVC-60319). NR 34 TC 1 Z9 1 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 4 PY 2015 VL 10 IS 5 AR e0127264 DI 10.1371/journal.pone.0127264 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CH3PP UT WOS:000353943000164 PM 25938421 ER PT J AU Roh, SS Smith, LE Lee, JS Via, LE Barry, CE Alland, D Chakravorty, S AF Roh, Sandy S. Smith, Laura E. Lee, Jong Seok Via, Laura E. Barry, Clifton E., III Alland, David Chakravorty, Soumitesh TI Comparative Evaluation of Sloppy Molecular Beacon and Dual-Labeled Probe Melting Temperature Assays to Identify Mutations in Mycobacterium tuberculosis Resulting in Rifampin, Fluoroquinolone and Aminoglycoside Resistance SO PLOS ONE LA English DT Article ID REAL-TIME PCR; DRUG-RESISTANCE; CURVE ANALYSIS; GENES; CHINA; SUSCEPTIBILITY; DIAGNOSTICS; IDENTIFICATION; SPECIMENS; OFLOXACIN AB Several molecular assays to detect resistance to Rifampin, the Fluoroquinolones, and Aminoglycosides in Mycobacterium tuberculosis (M. tuberculosis) have been recently described. A systematic approach for comparing these assays in the laboratory is needed in order to determine the relative advantage of each assay and to decide which ones should be advanced to evaluation. We performed an analytic comparison of a Sloppy Molecular Beacon (SMB) melting temperature (Tm) assay and a Dual labeled probe (DLP) Tm assay. Both assays targeted the M. tuberculosis rpoB, gyrA, rrs genes and the eis promoter region. The sensitivity and specificity to detect mutations, analytic limit of detection (LOD) and the detection of heteroresistance were tested using a panel of 56 clinical DNA samples from drug resistant M. tuberculosis strains. Both SMB and DLP assays detected 29/29 (100%) samples with rpoB RRDR mutations and 3/3 (100%) samples with eis promoter mutations correctly. The SMB assay detected all 17/17 gyrA mutants and 22/22 rrs mutants, while the DLP assay detected 16/17 (94%) gyrA mutants and 12/22 (55%) rrs mutants. Both assays showed comparable LODs for detecting rpoB and eis mutations; however, the SMB assay LODs were at least two logs better for detecting wild type and mutants in gyrA and rrs targets. The SMB assay was also moderately better at detecting heteroresistance. In summary, both assays appeared to be promising methods to detect drug resistance associated mutations in M. tuberculosis; however, the relative advantage of each assay varied under each test condition. C1 [Roh, Sandy S.; Smith, Laura E.; Alland, David; Chakravorty, Soumitesh] Rutgers State Univ, Dept Med, New Jersey Med Sch, Newark, NJ 07102 USA. [Lee, Jong Seok] Int TB Res Ctr, Dept Microbiol, Chang Won, Gyeongsang, South Korea. [Via, Laura E.; Barry, Clifton E., III] NIAID, TB Res Sect, LCID, NIH, Bethesda, MD 20892 USA. RP Chakravorty, S (reprint author), Rutgers State Univ, Dept Med, New Jersey Med Sch, Newark, NJ 07102 USA. EM chakraso@njms.rutgers.edu RI Barry, III, Clifton/H-3839-2012 FU U.S. National Institutes of Health (NIH) grant [AI080653]; NIAID, NIH FX This work was supported by the U.S. National Institutes of Health (NIH) grant AI080653 (DA, LES, SC and SSR). Partial funding for the clinical study in Masan, South Korea was provided by the intramural research program of NIAID, NIH (CEB and LEV). NR 36 TC 4 Z9 4 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 4 PY 2015 VL 10 IS 5 AR UNSP e0126257 DI 10.1371/journal.pone.0126257 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CH3PP UT WOS:000353943000156 PM 25938476 ER PT J AU Xue, ZQ He, ZW Yu, JJ Cai, Y Qiu, WY Pan, AH Gai, WP Cai, HB Luo, XG Ma, C Yan, XX AF Xue, Zhi-Qin He, Zheng-Wen Yu, Jian-Jun Cai, Yan Qiu, Wen-Ying Pan, Aihua Gai, Wei-Ping Cai, Huaibin Luo, Xue-Gang Ma, Chao Yan, Xiao-Xin TI Non-neuronal and neuronal BACE1 elevation in association with angiopathic and leptomeningeal beta-amyloid deposition in the human brain SO BMC NEUROLOGY LA English DT Article DE Amyloidosis; Brain aging; Blood brain barrier; Dementia; Neurodegeneration ID ALZHEIMERS-DISEASE PATHOGENESIS; SMOOTH-MUSCLE-CELLS; ENDOTHELIAL-CELLS; BETA-SECRETASE-1 ELEVATION; PRECURSOR PROTEIN; CLEARANCE; AMYLOIDOGENESIS; PATHOLOGY; FORM; CNS AB Background: Cerebral amyloid angiopathy (CAA) refers to the deposition of beta-amyloid (A beta) peptides in the wall of brain vasculature, commonly involving capillaries and arterioles. Also being considered a part of CAA is the A beta deposition in leptomeninge. The cellular origin of angiopathic A beta and the pathogenic course of CAA remain incompletely understood. Methods: The present study was aimed to explore the pathogenic course of CAA in the human cerebrum via examination of changes in beta-secretase-1 (BACE1), the obligatory A beta producing enzyme, relative to A beta and other cellular markers, by neuroanatomical and biochemical characterizations with postmortem brain samples and primary cell cultures. Results: Immunoreactivity (IR) for BACE1 was essentially not visible at vasculature in cases without cerebral amyloidosis (control group, n = 15, age = 86.1 +/- 10.3 year). In cases with brain amyloid pathology (n = 15, age = 78.7 +/- 12.7 year), increased BACE1 IR was identified locally at capillaries, arterioles and along the pia, localizing to endothelia, perivascular dystrophic neurites and meningeal cells, and often coexisting with vascular iron deposition. Double immunofluorescence with densitometric analysis confirmed a site-specific BACE1 elevation at cerebral arterioles in the development of vascular A beta deposition. Levels of BACE1 protein, activity and its immediate product (C99) were elevated in leptomeningeal lysates from cases with CAA relative to controls. The expression of BACE1 and other amyloidogenic proteins in the endothelial and meningeal cells was confirmed in primary cultures prepared from human leptomeningeal and arteriolar biopsies. Conclusion: These results suggest that BACE1 elevation in the endothelia and perivascular neurites may be involved in angiopathic A beta deposition, while BACE1 elevation in meningeal cells might contribute A beta to leptomeningeal amyloidosis. C1 [Xue, Zhi-Qin; Cai, Yan; Pan, Aihua; Luo, Xue-Gang; Yan, Xiao-Xin] Cent S Univ, Sch Basic Med Sci, Dept Anat & Neurobiol, Changsha 410013, Hunan, Peoples R China. [Xue, Zhi-Qin] Xinjiang Med Univ, Dept Anat, Xinjiang 830011, Peoples R China. [He, Zheng-Wen; Yu, Jian-Jun] Cent S Univ, Affiliated Tumor Hosp, Changsha 410006, Hunan, Peoples R China. [Qiu, Wen-Ying; Ma, Chao] Chinese Acad Med Sci, Peking Union Med Coll, Dept Human Anat Histol & Embryol, Inst Basic Med Sci,Neurosci Ctr,Sch Basic Med, Beijing 100730, Peoples R China. [Gai, Wei-Ping] Flinders Univ S Australia, Sch Med, Dept Surg, Bedford Pk, SA 5042, Australia. [Gai, Wei-Ping] Flinders Univ S Australia, Sch Med, Ctr Neurosci, Bedford Pk, SA 5042, Australia. [Cai, Huaibin] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Yan, XX (reprint author), Cent S Univ, Sch Basic Med Sci, Dept Anat & Neurobiol, Changsha 410013, Hunan, Peoples R China. EM yanxiaoxin@csu.edu.cn FU National Natural Science Foundation of China [81171091, 81171160]; National Institute on Aging; China Human Brain Banking Consortium; NHMRC [535014]; Flinders fellowship FX This study was supported by National Natural Science Foundation of China (81171091, 81171160), an intramural program of the National Institute on Aging, a joint Flinders-Xiangya seeding grant and the China Human Brain Banking Consortium. WPC was supported by NHMRC fellowship ID 535014 and a Flinders fellowship. We thank the Human Brain Banks at PUMC and XYSM for providing postmortem human brain samples, and Edward Koo and Samuel E. Gandy for providing antibodies. NR 47 TC 2 Z9 3 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2377 J9 BMC NEUROL JI BMC Neurol. PD MAY 2 PY 2015 VL 15 AR 71 DI 10.1186/s12883-015-0327-z PG 15 WC Clinical Neurology SC Neurosciences & Neurology GA CH7XS UT WOS:000354250600001 PM 25934480 ER PT J AU Sankineni, S Brown, AM Fascelli, M Law, YM Pinto, PA Choyke, PL Turkbey, B AF Sankineni, Sandeep Brown, Anna M. Fascelli, Michele Law, Yan Mee Pinto, Peter A. Choyke, Peter L. Turkbey, Baris TI Lymph Node Staging in Prostate Cancer SO CURRENT UROLOGY REPORTS LA English DT Article DE Prostate cancer; Lymph node staging; Imaging ID POSITRON-EMISSION-TOMOGRAPHY; ULTRASMALL SUPERPARAMAGNETIC PARTICLES; IN-111 CAPROMAB PENDETIDE; RADICAL PROSTATECTOMY; IRON-OXIDE; HIGH-RISK; PELVIC MALIGNANCIES; BIOCHEMICAL RELAPSE; RECTAL-CANCER; METASTASES AB Nodal staging is important in prostate cancer treatment. While surgical lymph node dissection is the classic method of determining whether lymph nodes harbor malignancy, this is a very invasive technique. Current noninvasive approaches to identifying malignant lymph nodes are limited. Conventional imaging methods rely on size and morphology of lymph nodes and have notoriously low sensitivity for detecting malignant nodes. New imaging techniques such as targeted positron emission tomography (PET) imaging and magnetic resonance lymphography (MRL) with iron oxide particles are promising for nodal staging of prostate cancer. In this review, the strengths and limitations of imaging techniques for lymph node staging of prostate cancer are discussed. C1 [Sankineni, Sandeep; Brown, Anna M.; Choyke, Peter L.; Turkbey, Baris] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Brown, Anna M.] Duke Univ, Sch Med, Durham, NC USA. [Fascelli, Michele; Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD USA. [Fascelli, Michele] Thomas Jefferson Univ, Sidney Kimmel Med Coll, Philadelphia, PA 19107 USA. [Law, Yan Mee] Singapore Gen Hosp, Dept Diagnost Radiol, Singapore, Singapore. RP Turkbey, B (reprint author), NCI, Mol Imaging Program, NIH, 10 Ctr Dr,Bldg 10,Room B3B85, Bethesda, MD 20892 USA. EM turkbeyi@mail.nih.gov NR 65 TC 7 Z9 7 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1527-2737 J9 CURR UROL REP JI Curr. Urol. Rep. PD MAY PY 2015 VL 16 IS 5 DI 10.1007/s11934-015-0505-y PG 9 WC Urology & Nephrology SC Urology & Nephrology GA CF9BV UT WOS:000352857500006 PM 25773350 ER PT J AU Patil, CL Turab, A Ambikapathi, R Nesamvuni, C Chandyo, RK Bose, A Islam, MM Ahmed, AMS Olortegui, MP de Moraes, ML Caulfield, LE AF Patil, Crystal L. Turab, Ali Ambikapathi, Ramya Nesamvuni, Cebisa Chandyo, Ram Krishna Bose, Anuradha Islam, M. Munirul Ahmed, A. M. Shamsir Olortegui, Maribel Paredes de Moraes, Milena Lima Caulfield, Laura E. CA MAL-ED Network TI Early interruption of exclusive breastfeeding: results from the eight-country MAL-ED study SO JOURNAL OF HEALTH POPULATION AND NUTRITION LA English DT Article DE Breastfeeding; Prelacteal feeding; Colostrum; MAL-ED; Nepal; Bangladesh; Pakistan; India; Brazil; Peru; Tanzania; South Africa ID RISK-FACTORS; BIRTH COHORT; CHILD DEATHS; INITIATION; DELIVERY; UNDERNUTRITION; INFANTS; HEALTH; BRAZIL; SITE AB We report the infant feeding experiences in the first month of life for 2,053 infants participating in "Malnutrition and Enteric Infections: Consequences for Child Health and Development" (MAL-ED). Eight sites (in Bangladesh, India, Nepal, Pakistan, Brazil, Peru, South Africa, Tanzania), each followed a cohort of children from birth (by day 17), collecting detailed information on infant feeding practices, diet and illness episodes. Mothers were queried twice weekly regarding health status, breastfeeding and the introduction (or no) of non-breast milk liquids and foods. Here, our goal is to describe the early infant feeding practices in the cohort and evaluate factors associated with termination of exclusive breastfeeding in the first month of life. With data from enrollment to a visit at 28-33 days of life, we characterized exclusive, predominant or partial breastfeeding (using a median of 6-9 visits per child across the sites). Only 6 of 2,053 infants were never breastfed. By one month, the prevalences of exclusive breastfeeding were < 60% in 6 of 8 sites, and of partial breastfeeding (or no) were > 20% in 6 of 8 sites. Logistic regression revealed that prelacteal feeding (given to 4-63% of infants) increased the likelihood of partial breastfeeding (Odds Ratio (OR): 1.48 (95% confidence interval (CI): 1.04, 2.10), as did the withholding of colostrum (2-16% of infants) (OR: 1.63: 1.01, 2.62), and being a first-time mother (OR: 1.38:1.10, 1.75). Our results reveal diversity across these sites, but an overall trend of early transition away from exclusive breastfeeding in the first month of life. Interventions which introduce or reinforce the WHO/UNICEF Ten Steps for Successful Breastfeeding are needed in these sites to improve breastfeeding initiation, to reinforce exclusive breastfeeding and delay introduction of non-breast milk foods and/or liquids. C1 [de Moraes, Milena Lima; Caulfield, Laura E.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, 615 North Wolfe St,W2041, Baltimore, MD 21205 USA. [Patil, Crystal L.] Univ Illinois, Coll Nursing, Dept Women Children & Family Hlth Sci, Chicago, IL USA. [Turab, Ali] Aga Khan Univ, Dept Pediat & Child Hlth, Karachi, Pakistan. [Ambikapathi, Ramya] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Nesamvuni, Cebisa] Univ Venda, Sch Hlth Sci, Dept Nutr, Thohoyandou, Limpopo Provinc, South Africa. [Chandyo, Ram Krishna] Univ Bergen, Ctr Int Hlth, N-5020 Bergen, Norway. [Chandyo, Ram Krishna] Tribhuvan Univ, Dept Child Hlth & Inst Med, Kathmandu, Nepal. [Bose, Anuradha] Christian Med Coll & Hosp, Vellore, Tamil Nadu, India. [Islam, M. Munirul] Int Ctr Diarrhoeal Dis Res, Ctr Nutr & Food Secur, Dhaka 1000, Bangladesh. [Ahmed, A. M. Shamsir] AB PRISMA, Biomed Invest Unit, Iquitos, Peru. [Olortegui, Maribel Paredes] Univ Estadual Ceara, Dept Nutr, Fortaleza, Ceara, Brazil. RP Caulfield, LE (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, 615 North Wolfe St,W2041, Baltimore, MD 21205 USA. EM lcaulfie@jhsph.edu OI Lima de Moraes, Milena/0000-0003-1222-8400 FU Bill & Melinda Gates Foundation; Foundation for the NIH; National Institutes of Health/Fogarty International Center FX The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development Project (MAL-ED) is carried out as a collaborative project supported by the Bill & Melinda Gates Foundation, the Foundation for the NIH and the National Institutes of Health/Fogarty International Center. The authors thank the staff and participants of the MAL-ED Network Project for their important contributions. NR 61 TC 5 Z9 5 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1606-0997 EI 2072-1315 J9 J HEALTH POPUL NUTR JI J. Heatlh Popul. Nutr. PD MAY 1 PY 2015 VL 34 AR 10 DI 10.1186/s41043-015-0004-2 PG 10 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA DF9EW UT WOS:000371664800002 PM 26825923 ER PT J AU Doshi, M Goggins, M Norman, S Ho, S Winkler, C Kopp, J AF Doshi, M. Goggins, M. Norman, S. Ho, S. Winkler, C. Kopp, J. TI APOL1 Risk Alleles in Live and Deceased Kidney Donors Are Associated With Shorter Renal Allograft Survival SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT American Transplant Congress CY MAY 02-06, 2015 CL Philadelphia, PA C1 [Doshi, M.] Wayne State Univ, Med, Detroit, MI USA. [Goggins, M.] Henry Ford Transplant Inst, Med, Detroit, MI USA. [Norman, S.] Univ Michigan, Med, Ann Arbor, MI 48109 USA. [Ho, S.] Gift Life, Ann Arbor, MI USA. [Winkler, C.] NCI, NIH, Bethesda, MD 20892 USA. [Kopp, J.] NIDDK, 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 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2015 VL 15 SU 3 SI SI MA 456 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA DD7SK UT WOS:000370124200357 ER PT J AU Doshi, M Goggines, M Winkler, C Kopp, J AF Doshi, M. Goggines, M. Winkler, C. Kopp, J. TI < i > APOL1 High-Risk Genotype in African American Live Kidney Donors Is Not Associated With Post-Donation Development of Hypertension and Kidney Disease SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT American Transplant Congress CY MAY 02-06, 2015 CL Philadelphia, PA C1 [Doshi, M.] Wayne State Univ, Detroit, MI USA. [Goggines, M.] Henry Ford Transplant Inst, Detroit, MI USA. [Winkler, C.] NCI, Frederick, MD 21701 USA. [Winkler, C.] Leidos, Frederick, MD USA. [Kopp, J.] NIDDK, Bethseda, 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 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2015 VL 15 SU 3 SI SI MA 957 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA DD7SK UT WOS:000370124200100 ER PT J AU Engels, E Segev, D Snyder, J Kasiske, B Yanik, E AF Engels, E. Segev, D. Snyder, J. Kasiske, B. Yanik, E. TI Discrepancies Between the US Transplant Registry and Cancer Registries Regarding Cancer Diagnoses in Transplant Recipients SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT American Transplant Congress CY MAY 02-06, 2015 CL Philadelphia, PA C1 [Engels, E.; Yanik, E.] NCI, Bethesda, MD 20892 USA. [Segev, D.] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. [Snyder, J.; Kasiske, B.] SRTR, Minneapolis, MN 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 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2015 VL 15 SU 3 SI SI MA 331 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA DD7SK UT WOS:000370124202354 ER PT J AU Feng, S Bucuvalas, J Demetris, A Spain, K Mazariegos, G Burrell, B AF Feng, S. Bucuvalas, J. Demetris, A. Spain, K. Mazariegos, G. Burrell, B. CA iWITH Investigators TI Deceased Donor and Class II Donor Specific Antibody Predict Interface Activity While Increased Age at Time of Biopsy Predicts Fibrosis in Long-Term Pediatric Liver Allografts With Normal Liver Tests: iWITH Clinical Trial SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT American Transplant Congress CY MAY 02-06, 2015 CL Philadelphia, PA C1 [Feng, S.] UCSF, San Francisco, CA USA. [Bucuvalas, J.] Univ Cincinnati, Cincinnati, OH USA. [Demetris, A.; Mazariegos, G.] Univ Pittsburgh, Pittsburgh, PA USA. [Spain, K.] Rho, Chapel Hill, NC USA. [Burrell, B.] ITN, Bethesda, MD USA. [iWITH Investigators] NIAID, NIDDK, ITN, 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 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2015 VL 15 SU 3 SI SI MA 493 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA DD7SK UT WOS:000370124200157 ER PT J AU Singh, A Corcoran, P Lewis, B Thomas, M Ayers, D Horvath, K Mohiuddin, M AF Singh, A. Corcoran, P. Lewis, B. Thomas, M. Ayers, D. Horvath, K. Mohiuddin, M. TI Cardiac Xenotransplantation: Reconstituted B Cells After Rituxan Treatment Maintain Their Repertoire But Have a Muted Response to Xenoantigens SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT American Transplant Congress CY MAY 02-06, 2015 CL Philadelphia, PA C1 [Singh, A.; Corcoran, P.; Horvath, K.; Mohiuddin, M.] NHLBI, CSRP, NIH, Bethesda, MD 20892 USA. [Lewis, B.; Thomas, M.] NIH, DVR, ORS, Bethesda, MD 20892 USA. [Ayers, D.] Revivicor Inc, Blacksburg, VA USA. RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X 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 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2015 VL 15 SU 3 SI SI MA 762 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA DD7SK UT WOS:000370124201447 ER PT J AU Suessmuth, Y Stempora, L Johnson, B Cheeseman, J Morrison, Y Bridges, N Ikle, D Tomlanovich, S Stock, P Mannon, R Newell, K Larsen, C Mehta, A AF Suessmuth, Y. Stempora, L. Johnson, B. Cheeseman, J. Morrison, Y. Bridges, N. Ikle, D. Tomlanovich, S. Stock, P. Mannon, R. Newell, K. Larsen, C. Mehta, A. TI Immune Phenotyping of Peripheral Blood Samples from the CTOT-10 Belatacept Study SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT American Transplant Congress CY MAY 02-06, 2015 CL Philadelphia, PA C1 [Suessmuth, Y.; Stempora, L.; Johnson, B.; Cheeseman, J.; Newell, K.; Larsen, C.; Mehta, A.] Emory Transplant Ctr, Atlanta, GA USA. [Mannon, R.] Univ Alabama Birmingham, Birmingham, AL USA. [Tomlanovich, S.; Stock, P.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Morrison, Y.; Bridges, N.] NIAID, NIH, Bethesda, MD 20892 USA. [Ikle, D.] Rho, Chapel Hill, NC 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 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2015 VL 15 SU 3 SI SI MA 3047 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA DD7SK UT WOS:000370124201454 ER PT J AU Yanik, E Chinnakotla, S Israni, A Snyder, J Gustafson, S Engels, E AF Yanik, E. Chinnakotla, S. Israni, A. Snyder, J. Gustafson, S. Engels, E. TI Associations Between Sirolimus Use and Outcomes After Liver Transplant for Hepatocellular Carcinoma SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT American Transplant Congress CY MAY 02-06, 2015 CL Philadelphia, PA C1 [Yanik, E.; Engels, E.] NCI, Bethesda, MD 20892 USA. [Chinnakotla, S.; Israni, A.; Snyder, J.] Univ Minnesota, Minneapolis, MN USA. [Israni, A.; Snyder, J.; Gustafson, S.] Sci Reg Transplant Recipients, Minneapolis, MN 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 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2015 VL 15 SU 3 SI SI MA 1280 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA DD7SK UT WOS:000370124202310 ER PT J AU Yanik, E Smith, J Shiels, M Clarke, C Lynch, C Kahn, A Koch, L Pawlish, K Engels, E AF Yanik, E. Smith, J. Shiels, M. Clarke, C. Lynch, C. Kahn, A. Koch, L. Pawlish, K. Engels, E. TI Elevated Cancer Risk Among US Pediatric Solid Organ Transplant Recipients SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT American Transplant Congress CY MAY 02-06, 2015 CL Philadelphia, PA C1 [Yanik, E.; Shiels, M.; Engels, E.] NCI, Bethesda, MD 20892 USA. [Smith, J.] Seattle Childrens Hosp, Seattle, WA USA. [Clarke, C.] Canc Prev Inst CA, Fremont, CA USA. [Lynch, C.] Univ Iowa, Iowa City, IA USA. [Kahn, A.] NY St Canc Reg, Albany, NY USA. [Koch, L.] IL St Canc Reg, Springfield, IL USA. [Pawlish, K.] NJ St Canc Reg, Trenton, NJ 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 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2015 VL 15 SU 3 SI SI MA 307 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA DD7SK UT WOS:000370124200412 ER PT J AU Manini, AF Yiannoulos, G Bergamaschi, MM Hernandez, S Olmedo, R Barnes, AJ Winkel, G Sinha, R Jutras-Aswad, D Huestis, MA Hurd, YL AF Manini, Alex F. Yiannoulos, Georgia Bergamaschi, Mateus M. Hernandez, Stephanie Olmedo, Ruben Barnes, Allan J. Winkel, Gary Sinha, Rajita Jutras-Aswad, Didier Huestis, Marilyn A. Hurd, Yasmin L. TI Safety and Pharmacokinetics of Oral Cannabidiol When Administered Concomitantly With Intravenous Fentanyl in Humans SO JOURNAL OF ADDICTION MEDICINE LA English DT Article DE cannabidiol; cannabis; opioid dependence; pharmacokinetics ID CANNABINOID RECEPTOR; OPIOID RECEPTORS; NEURAL BASIS; NUCLEUS; PLASMA; CB1; DELTA-9-TETRAHYDROCANNABINOL; SCHIZOPHRENIA; INHIBITION; HYDROLYSIS AB Objectives: Cannabidiol (CBD) is hypothesized as a potential treatment for opioid addiction, with safety studies an important first step for medication development. We determined CBD safety and pharmacokinetics when administered concomitantly with a high-potency opioid in healthy subjects. Methods: This double-blind, placebo-controlled cross-over study of CBD, coadministered with intravenous fentanyl, was conducted at the Clinical Research Center in Mount Sinai Hospital, a tertiary care medical center in New York City. Participants were healthy volunteers aged 21 to 65 years with prior opioid exposure, regardless of the route. Blood samples were obtained before and after 400 or 800 mg of CBD pretreatment, followed by a single 0.5 (session 1) or 1.0 mu g/kg (session 2) of intravenous fentanyl dose. The primary outcome was the Systematic Assessment for Treatment Emergent Events (SAFTEE) to assess safety and adverse effects. CBD peak plasma concentrations, time to reach peak plasma concentrations (t(max)), and area under the curve (AUC) were measured. Results: SAFTEE data were similar between groups without respiratory depression or cardiovascular complications during any test session. After low-dose CBD, t(max) occurred at 3 and 1.5 hours in sessions 1 and 2, respectively. After high-dose CBD, tmax occurred at 3 and 4 hours in sessions 1 and 2, respectively. There were no significant differences in plasma CBD or cortisol (AUC P = NS) between sessions. Conclusions: Cannabidiol does not exacerbate adverse effects associated with intravenous fentanyl administration. Coadministration of CBD and opioids was safe and well tolerated. These data provide the foundation for future studies examining CBD as a potential treatment for opioid abuse. C1 [Manini, Alex F.; Hernandez, Stephanie; Olmedo, Ruben] Icahn Sch Med Mt Sinai, Div Med Toxicol, Dept Emergency Med, New York, NY 10029 USA. [Yiannoulos, Georgia; Hurd, Yasmin L.] Icahn Sch Med Mt Sinai, Dept Psychiat, Bronx, NY USA. [Yiannoulos, Georgia; Hurd, Yasmin L.] Icahn Sch Med Mt Sinai, Dept Neurosci, Bronx, NY USA. [Yiannoulos, Georgia; Hurd, Yasmin L.] James J Peters VA Med Ctr, Bronx, NY USA. [Bergamaschi, Mateus M.] Univ Sao Paulo, Dept Clin Toxicol & Food Sci Anal, Sch Pharmaceut Sci Ribeirao Preto, BR-05508 Sao Paulo, Brazil. [Barnes, Allan J.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab, Intramural Res Program, NIH, Baltimore, MD USA. [Winkel, Gary] Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA. [Sinha, Rajita] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Jutras-Aswad, Didier] Univ Montreal, Ctr Hosp Univ Montreal, Res Ctr, Montreal, PQ, Canada. [Jutras-Aswad, Didier] Univ Montreal, Dept Psychiat, Montreal, PQ H3C 3J7, Canada. RP Hurd, YL (reprint author), Icahn Sch Med Mt Sinai, New York, NY 10029 USA. EM yasmin.hurd@mssm.edu FU National Institutes of Health [DA027781]; CTSA [UL1RR029887] FX Supported by a research grant from the National Institutes of Health grant DA027781 (YLH) and CTSA (UL1RR029887). NR 39 TC 2 Z9 2 U1 2 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1932-0620 EI 1935-3227 J9 J ADDICT MED JI J. Addict. Med. PD MAY-JUN PY 2015 VL 9 IS 3 BP 204 EP 210 DI 10.1097/ADM.0000000000000118 PG 7 WC Substance Abuse SC Substance Abuse GA DD1VH UT WOS:000369710200006 PM 25748562 ER PT J AU Via, LE Savic, R Weiner, DM Zimmerman, MD Prideaux, B Irwin, SM Lyon, E O'Brien, P Gopal, P Eum, S Lee, M Lanoix, JP Dutta, NK Shim, T Cho, JS Kim, W Karakousis, PC Lenaerts, A Nuermberger, E Barry, CE Dartois, V AF Via, Laura E. Savic, Rada Weiner, Danielle M. Zimmerman, Matthew D. Prideaux, Brendan Irwin, Scott M. Lyon, Eddie O'Brien, Paul Gopal, Pooja Eum, Seokyong Lee, Myungsun Lanoix, Jean-Philippe Dutta, Noton K. Shim, TaeSun Cho, Jeong Su Kim, Wooshik Karakousis, Petros C. Lenaerts, Anne Nuermberger, Eric Barry, Clifton E., III Dartois, Veronique TI Host-Mediated Bioactivation of Pyrazinamide: Implications for Efficacy, Resistance, and Therapeutic Alternatives SO ACS INFECTIOUS DISEASES LA English DT Article DE pyrazinamide; pyrazinoic acid; bioactivation; Mycobacterium tuberculosis; host metabolism ID MYCOBACTERIUM-TUBERCULOSIS; XANTHINE-OXIDASE; PYRAZINOIC ACID; IN-VITRO; POPULATION PHARMACOKINETICS; RABBIT MODEL; MURINE MODEL; GUINEA-PIGS; SUSCEPTIBILITY; ALLOPURINOL AB Pyrazinamide has played a critical role in shortening therapy against drug-sensitive, drug-resistant, active, and latent tuberculosis (TB). Despite widespread recognition of its therapeutic importance, the sterilizing properties of this 60-year-old drug remain an enigma given its rather poor activity in vitro. Here we revisit long-standing paradigms and offer pharmacokinetic explanations for the apparent disconnect between in vitro activity and clinical impact. We show substantial host-mediated conversion of prodrug pyrazinamide (PZA) to the active form, pyrazinoic acid (POA), in TB patients and in animal models. We demonstrate favorable penetration of this pool of circulating POA from plasma into lung tissue and granulomas, where the pathogen resides. In standardized growth inhibition experiments, we show that POA exhibits superior in vitro potency compared to PZA, indicating that the vascular supply of host-derived POA may contribute to the in vivo efficacy of PZA, thereby reducing the apparent discrepancy between in vitro and in vivo activity. However, the results also raise the possibility that subinhibitory concentrations of POA generated by the host could fuel the emergence of resistance to both PZA and POA. In contrast to widespread expectations, we demonstrate good oral bioavailability and exposure in preclinical species in pharmacokinetic studies of oral POA. Baseline exposure of oral POA can be further increased by the xanthine oxidase inhibitor and approved gout drug allopurinol. These promising results pave the way for clinical investigations of oral POA as a therapeutic alternative or an add-on to overcome PZA resistance and salvage this essential TB drug. C1 [Via, Laura E.; Weiner, Danielle M.; Barry, Clifton E., III] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Savic, Rada] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, Sch Pharm, San Francisco, CA 94143 USA. [Savic, Rada] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, Sch Med, San Francisco, CA 94143 USA. [Zimmerman, Matthew D.; Prideaux, Brendan; O'Brien, Paul; Dartois, Veronique] Rutgers State Univ, New Jersey Med Sch, Publ Hlth Res Inst, 225 Warren St, Newark, NJ 07103 USA. [Irwin, Scott M.; Lyon, Eddie; Lenaerts, Anne] Colorado State Univ, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80523 USA. [Gopal, Pooja] Natl Univ Singapore, Natl Univ Hlth Syst, Yong Loo Lin Sch Med, Dept Microbiol, Singapore 117597, Singapore. [Eum, Seokyong; Lee, Myungsun] Int TB Res Ctr, Masan 631710, Kyeungsangnam D, South Korea. [Lanoix, Jean-Philippe; Dutta, Noton K.; Karakousis, Petros C.; Nuermberger, Eric] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21287 USA. [Shim, TaeSun] Asan Med Ctr, Seoul 138736, South Korea. [Cho, Jeong Su] Pusan Natl Univ Hosp, Busan 602739, South Korea. [Kim, Wooshik] Natl Med Ctr, Seoul 100799, South Korea. RP Dartois, V (reprint author), Rutgers State Univ, New Jersey Med Sch, Publ Hlth Res Inst, 225 Warren St, Newark, NJ 07103 USA. EM veronique.dartois@rutgers.edu RI Barry, III, Clifton/H-3839-2012; Lenaerts, Anne/F-1353-2017 FU NIH [1R01AI106398-01, P30AI094189, R01AI083125, R01HL106786]; Bill and Melinda Gates Foundation [OPP1066499, OPP1037174, OPP1033596]; National Medical Research Council, Singapore Ministry of Health [TCR12dec007]; Intramural Research Program of NIAID; Korean Centers for Disease Control of the Korean Ministry of Health and Welfare FX We are grateful to Thomas Dick for many stimulating discussions and for reviewing the manuscript, and to Barry Kreiswirth and Kyu Rhee for sharing their extensive knowledge of PZA and POA. We wish to thank the patients who enrolled in the study and the clinical teams from the three Korean centers. We are grateful to all veterinarian and animal staff from the various sites where in vivo pharmacokinetic studies were conducted, Xiaohua Li and Firat Kaya for biological sample analysis, and Srijib Goswami for help with the graphics. This work was carried out with funding from NIH grants 1R01AI106398-01 (RS and VD), P30AI094189 (EN), R01AI083125 and R01HL106786 (PKC); from grants OPP1066499 (VD), OPP1037174 (EN) and OPP1033596 (AL) from the Bill and Melinda Gates Foundation; TCR12dec007 from the National Medical Research Council, Singapore Ministry of Health (PG); the Intramural Research Program of NIAID (CEB), as well as funding from the Korean Centers for Disease Control of the Korean Ministry of Health and Welfare to the International Tuberculosis Research Center. NR 64 TC 17 Z9 17 U1 3 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 2373-8227 J9 ACS INFECT DIS JI ACS Infect. Dis. PD MAY PY 2015 VL 1 IS 5 BP 203 EP 214 DI 10.1021/id500028m PG 12 WC Chemistry, Medicinal; Infectious Diseases SC Pharmacology & Pharmacy; Infectious Diseases GA DB4DK UT WOS:000368463500003 PM 26086040 ER PT J AU Lin, YC Winokur, P Blake, A Wu, TX Romm, E Bielekova, B AF Lin, Yen Chih Winokur, Paige Blake, Andrew Wu, Tianxia Romm, Elena Bielekova, Bibiana TI Daclizumab reverses intrathecal immune cell abnormalities in multiple sclerosis SO ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY LA English DT Article ID HIGH-YIELD PROCESS; DELTA T-CELLS; CEREBROSPINAL-FLUID; DISEASE PROGRESSION; MONOCLONAL-ANTIBODY; CNS REMYELINATION; DOUBLE-BLIND; ALPHA-CHAIN; RECEPTOR; THERAPY AB Objective: Novel treatments such as natalizumab and fingolimod achieve their therapeutic efficacy in multiple sclerosis (MS) by blocking access of subsets of immune cells into the central nervous system, thus creating nonphysiological intrathecal immunity. In contrast, daclizumab, a humanized monoclonal antibody against the alpha chain of the IL-2 receptor, has a unique mechanism of action with multiple direct effects on innate immunity. As cellular intrathecal abnormalities corresponding to MS have been well defined, we asked how daclizumab therapy affects these immunological hallmarks of the MS disease process. Methods: Nineteen subpopulations of immune cells were assessed in a blinded fashion in the blood and 50-fold concentrated cerebrospinal fluid (CSF) cell pellet in 32 patients with untreated relapsing-remitting MS (RRMS), 22 daclizumab-treated RRMS patients, and 11 healthy donors (HDs) using 12-color flow cytometry. Results: Long-term daclizumab therapy normalized all immunophenotyping abnormalities differentiating untreated RRMS patients from HDs. Specifically, strong enrichment of adaptive immune cells (CD4(+) and CD8(+) T cells and B cells) in the CSF was reversed. Similarly, daclizumab controlled MS-related increases in the innate lymphoid cells (ILCs) and lymphoid tissue inducer cells in the blood and CSF, and reverted the diminished proportion of intrathecal monocytes. The only marker that distinguished daclizumab-treated MS patients from HDs was the expansion of immunoregulatory CD56(bright) NK cells. Interpretation: Normalization of immunological abnormalities associated with MS by long-term daclizumab therapy suggests that this drug's effects on ILCs, NK cells, and dendritic cell-mediated antigen presentation to CD4(+) and CD8(+) T cells are critical in regulating the MS disease process. C1 [Lin, Yen Chih; Winokur, Paige; Blake, Andrew; Romm, Elena; Bielekova, Bibiana] NINDS, Neuroimmunol Branch, Neuroimmunol Dis Unit, NIH, Bethesda, MD 20892 USA. [Wu, Tianxia] NINDS, Clin Neurosci Program, NIH, Bethesda, MD 20892 USA. [Bielekova, Bibiana] NIH, NIH Ctr Human Immunol CHI, Bethesda, MD 20892 USA. RP Bielekova, B (reprint author), NINDS, Neuroimmunol Branch NIB, NIH, Bethesda, MD 20892 USA. EM Bibi.Bielekova@nih.gov NR 42 TC 12 Z9 12 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2328-9503 J9 ANN CLIN TRANSL NEUR JI Ann. Clin. Transl. Neurol. PD MAY PY 2015 VL 2 IS 5 BP 445 EP 455 DI 10.1002/acn3.181 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CZ3CQ UT WOS:000366982200001 PM 26000318 ER PT J AU Iadarola, ND Niciu, MJ Richards, EM Vande Voort, JL Ballard, ED Lundin, NB Nugent, AC Machado-Vieira, R Zarate, CA AF Iadarola, Nicolas D. Niciu, Mark J. Richards, Erica M. Vande Voort, Jennifer L. Ballard, Elizabeth D. Lundin, Nancy B. Nugent, Allison C. Machado-Vieira, Rodrigo Zarate, Carlos A., Jr. TI Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: a perspective review SO THERAPEUTIC ADVANCES IN CHRONIC DISEASE LA English DT Review DE ketamine; glutamate; N-methyl-D-aspartate receptor; NR2B; antagonist; major depressive disorder; bipolar disorder; bipolar depression; treatment-resistant depression ID TREATMENT-RESISTANT DEPRESSION; ADD-ON TRIAL; RAPID ANTIDEPRESSANT ACTIONS; RANDOMIZED CONTROLLED-TRIAL; RECEIVING HOSPICE CARE; LOW-DOSE KETAMINE; PROOF-OF-CONCEPT; BIPOLAR DEPRESSION; MAJOR DEPRESSION; SUICIDAL IDEATION AB Current pharmacotherapies for major depressive disorder (MDD) and bipolar depression (BDep) have a distinct lag of onset that can generate great distress and impairment in patients. Furthermore, as demonstrated by several real-world effectiveness trials, their efficacy is limited. All approved antidepressant medications for MDD primarily act through monoaminergic mechanisms, agonists or antagonists with varying affinities for serotonin, norepinephrine and dopamine. The glutamate system has received much attention in recent years as an avenue for developing novel therapeutics. A single subanesthetic dose infusion of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has been shown to have rapid and potent antidepressant effects in treatment-resistant MDD and BDep. In a reverse translational framework, ketamine's clinical efficacy has inspired many preclinical studies to explore glutamatergic mechanisms of antidepressant action. These studies have revealed enhanced synaptic plasticity/synaptogenesis via numerous molecular and cellular mechanisms: release of local translational inhibition of brain-derived neurotrophic factor and secretion from dendritic spines, mammalian target of rapamycin activation and glycogen synthase kinase-3 inhibition. Current efforts are focused on extending ketamine's antidepressant efficacy, uncovering the neurobiological mechanisms responsible for ketamine's antidepressant activity in biologically enriched subgroups, and identifying treatment response biomarkers to personalize antidepressant selection. Other NMDA receptor antagonists have been studied both preclinically and clinically, which have revealed relatively modest antidepressant effects compared with ketamine but potentially other favorable characteristics, for example, decreased dissociative or psychotomimetic effects; therefore, there is great interest in developing novel glutamatergic antidepressants with greater target specificity and/or decreased adverse effects. C1 [Iadarola, Nicolas D.; Niciu, Mark J.; Richards, Erica M.; Vande Voort, Jennifer L.; Ballard, Elizabeth D.; Lundin, Nancy B.; Nugent, Allison C.; Machado-Vieira, Rodrigo; Zarate, Carlos A., Jr.] NIMH, NIH, Expt Therapeut & Pathophysiol Branch, Bethesda, MD 20892 USA. RP Zarate, CA (reprint author), NIMH, NIH, Expt Therapeut & Pathophysiol Branch, 10 Ctr Dr Bldg,10 CRC,Room 7-5545, Bethesda, MD 20892 USA. EM zaratec@mail.nih.gov RI MACHADO-VIEIRA, RODRIGO/D-8293-2012; Niciu, Mark/J-1766-2014; OI MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190; Niciu, Mark/0000-0002-5612-3021; Nugent, Allison/0000-0003-2569-2480 NR 104 TC 36 Z9 36 U1 8 U2 26 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 2040-6223 EI 2040-6231 J9 THER ADV CHRONIC DIS JI Ther. Adv. Chronic Dis. PD MAY PY 2015 VL 6 IS 3 BP 97 EP 114 DI 10.1177/2040622315579059 PG 18 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CZ0VC UT WOS:000366823100002 PM 25954495 ER PT J AU Taplin, SH Weaver, S Chollette, V Marks, LB Jacobs, A Schiff, G Stricker, CT Bruinooge, SS Salas, E AF Taplin, Stephen H. Weaver, Sallie Chollette, Veronica Marks, Lawrence B. Jacobs, Andrew Schiff, Gordon Stricker, Carrie T. Bruinooge, Suanna S. Salas, Eduardo TI Teams and Teamwork During a Cancer Diagnosis: Interdependency Within and Between Teams SO JOURNAL OF ONCOLOGY PRACTICE LA English DT Article ID HEALTH-CARE; FOLLOW-UP; CLINICAL-PRACTICE; QUALITY; INTERFACES; ONCOLOGY; SYSTEMS; WOMEN AB This article discusses the care process among three groups (primary care, radiology, and surgery) aiding a 57-year-old woman during her screening mammography and diagnosis of breast cancer. This is the first in a series of articles exploring principles and topics relevant to teams guiding clinicians involved in cancer care. The challenges demonstrated in this case illustrate how clinicians work within and between groups to deliver this first phase of cancer care. The case helps demonstrate the differences between groups and teams. Focusing on the patient and the overall process of care coordination can help move groups toward becoming teams who deliver better care by identifying and managing goals, roles, and interdependent care tasks. Care providers and researchers can use the case to consider their own work and essential aspects of teamwork needed to improve care, patient outcomes, and the evidence that supports each. C1 NCI, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Armstrong Inst Patient Safety & Qual, Baltimore, MD USA. Univ N Carolina, Chapel Hill, NC USA. Virginia Mason Hosp & Med Ctr, Seattle, WA USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. Amer Soc Clin Oncol, Alexandria, VA USA. Univ Cent Florida, Orlando, FL 32816 USA. RP Taplin, SH (reprint author), NCI, Healthcare Delivery Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM taplins@mail.nih.gov NR 37 TC 13 Z9 13 U1 3 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 1554-7477 EI 1935-469X J9 J ONCOL PRACT JI J. Oncol. Pract. PD MAY PY 2015 VL 11 IS 3 BP 231 EP + DI 10.1200/JOP.2014.003376 PG 11 WC Health Care Sciences & Services SC Health Care Sciences & Services GA CY1PL UT WOS:000366179600047 PM 25873059 ER PT J AU Taplin, SH Weaver, S Salas, E Chollette, V Edwards, HM Bruinooge, SS Kosty, MP AF Taplin, Stephen H. Weaver, Sallie Salas, Eduardo Chollette, Veronica Edwards, Heather M. Bruinooge, Suanna S. Kosty, Michael P. TI Reviewing Cancer Care Team Effectiveness SO JOURNAL OF ONCOLOGY PRACTICE LA English DT Review ID MULTIDISCIPLINARY TEAM; COLORECTAL-CANCER; NATIONAL-SURVEY; LUNG-CANCER; HEALTH-CARE; MANAGEMENT; QUALITY; WORKING; IMPACT; INTERVENTION AB Purpose: The management of cancer varies across its type, stage, and natural history. This necessitates involvement of a variety of individuals and groups across a number of provider types. Evidence from other fields suggests that a team-based approach helps organize and optimize tasks that involve individuals and groups, but team effectiveness has not been fully evaluated in oncology-related care. Methods: We undertook a systematic review of literature published between 2009 and 2014 to identify studies of all teams with clear membership, a comparator group, and patient-level metrics of cancer care. When those teams included two or more people with specialty training relevant to the care of patients with cancer, we called them multidisciplinary care teams (MDTs). After reviews and exclusions, 16 studies were thoroughly evaluated: two addressing screening and diagnosis, 11 addressing treatment, two addressing palliative care, and one addressing end-of-life care. The studies included a variety of end points (eg, adherence to quality indicators, patient satisfaction with care, mortality). Results: Teams for screening and its follow-up improved screening use and reduced time to follow-up colonoscopy after an abnormal screen. Discussion of cases within MDTs improved the planning of therapy, adherence to recommended preoperative assessment, pain control, and adherence to medications. We did not see convincing evidence that MDTs affect patient survival or cost of care, or studies of how or which MDT processes and structures were associated with success. Conclusion: Further research should focus on the association between team processes and structures, efficiency in delivery of care, and mortality. C1 NCI, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Armstrong Inst Patient Safety & Qual, Baltimore, MD USA. Frederick Natl Lab Canc Res, Leidos Biomed Res, Frederick, MD USA. Univ Cent Florida, Orlando, FL 32816 USA. Amer Soc Clin Oncol, Alexandria, VA USA. Scripps Clin, La Jolla, CA 92037 USA. RP Taplin, SH (reprint author), NCI, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,3E522, Rockville, MD 20850 USA. EM taplins@mail.nih.gov FU CCR NIH HHS [HHSN261200800001C]; NCI NIH HHS [HHSN261200800001E] NR 47 TC 16 Z9 16 U1 3 U2 6 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 1554-7477 EI 1935-469X J9 J ONCOL PRACT JI J. Oncol. Pract. PD MAY PY 2015 VL 11 IS 3 BP 239 EP + DI 10.1200/JOP.2014.003350 PG 10 WC Health Care Sciences & Services SC Health Care Sciences & Services GA CY1PL UT WOS:000366179600048 PM 25873056 ER PT J AU Suneja, G Boyer, M Yehia, BR Shiels, MS Engels, EA Bekelman, JE Long, JA AF Suneja, Gita Boyer, Matthew Yehia, Baligh R. Shiels, Meredith S. Engels, Eric A. Bekelman, Justin E. Long, Judith A. TI Cancer Treatment in Patients With HIV Infection and Non-AIDS-Defining Cancers: A Survey of US Oncologists SO JOURNAL OF ONCOLOGY PRACTICE LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; UNITED-STATES; LUNG-CANCER; IMMUNODEFICIENCY; INDIVIDUALS; POPULATION; CARE; CHEMOTHERAPY; ASSOCIATION; GUIDELINES AB Purpose: HIV-infected individuals with non-AIDS-defining cancers are less likely to receive cancer treatment compared with uninfected individuals. We sought to identify provider-level factors influencing the delivery of oncology care to HIV-infected patients. Methods: A survey was mailed to 500 randomly selected US medical and radiation oncologists. The primary outcome was delivery of standard treatment, assessed by responses to three specialty-specific management questions. We used the chi(2) test to evaluate associations between delivery of standard treatment, provider demographics, and perceptions of HIV-infected individuals. Multivariable logistic regression identified associations using factor analysis to combine several correlated survey questions. Results: Our response rate was 60%; 69% of respondents felt that available cancer management guidelines were insufficient for the care of HIV-infected patients with cancer; 45% never or rarely discussed their cancer management plan with an HIV specialist; 20% and 15% of providers were not comfortable discussing cancer treatment adverse effects and prognosis with their HIV-infected patients with cancer, respectively; 79% indicated that they would provide standard cancer treatment to HIV-infected patients. In multivariable analysis, physicians comfortable discussing adverse effects and prognosis were more likely to provide standard cancer treatment (adjusted odds ratio, 1.52; 95% CI, 1.12 to 2.07). Physicians with concerns about toxicity and efficacy of treatment were significantly less likely to provide standard cancer treatment (adjusted odds ratio, 0.67; 95% CI, 0.53 to 0.85). Conclusion: Provider-level factors are associated with delivery of nonstandard cancer treatment to HIV-infected patients. Policy change, provider education, and multidisciplinary collaboration are needed to improve access to cancer treatment. C1 Univ Utah, Salt Lake City, UT USA. Marshall Univ, Huntington, WV USA. Univ Penn, Philadelphia, PA 19104 USA. Vet Affairs Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. NCI, Bethesda, MD 20892 USA. RP Suneja, G (reprint author), Huntsman Canc Hosp, 1950 Cir Hope,Room 1570, Salt Lake City, UT 84112 USA. EM gita.suneja@icloud.com NR 27 TC 3 Z9 3 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 1554-7477 EI 1935-469X J9 J ONCOL PRACT JI J. Oncol. Pract. PD MAY PY 2015 VL 11 IS 3 BP E380 EP E387 DI 10.1200/JOP.2014.002709 PG 8 WC Health Care Sciences & Services SC Health Care Sciences & Services GA CY1PL UT WOS:000366179600014 PM 25873060 ER PT J AU Lutsey, PL Michos, ED Misialek, JR Pankow, JS Loehr, L Selvin, E Reis, JP Gross, M Eckfeldt, JH Folsom, AR AF Lutsey, Pamela L. Michos, Erin D. Misialek, Jeffrey R. Pankow, James S. Loehr, Laura Selvin, Elizabeth Reis, Jared P. Gross, Myron Eckfeldt, John H. Folsom, Aaron R. TI Race and Vitamin D Binding Protein Gene Polymorphisms Modify the Association of 25-Hydroxyvitamin D and Incident Heart Failure The ARIC (Atherosclerosis Risk in Communities) Study SO JACC-HEART FAILURE LA English DT Article DE ARIC; heart failure; race; vitamin D; vitamin D binding protein ID NUTRITION EXAMINATION SURVEY; NATIONAL-HEALTH; D DEFICIENCY; DISEASE; METAANALYSIS; AMERICANS; DEATH AB OBJECTIVES This study sought to determine if low serum 25-hydroxyvitamin D (25[OH]D) is associated with incident heart failure (HF) and if the association is: 1) partly mediated by traditional cardiovascular risk factors; 2) stronger among whites than blacks; and 3) stronger among those genetically predisposed to having high levels of vitamin D binding protein (DBP). BACKGROUND Suboptimal 25(OH)D is a potential cardiovascular risk factor. METHODS A total of 12,215 ARIC (Atherosclerosis Risk in Communities) study participants free of HF at baseline (1990 to 1992; median age, 56; 24% black) were followed through 2010. Total serum 25(OH)D was measured at baseline using liquid chromatography-mass spectrometry. Incident HF events were identified by a hospital discharge code of ICD9-428 and parallel International Classification of Diseases codes for HF deaths. RESULTS During 21 years of follow-up, 1,799 incident HF events accrued. The association between 25(OH)D and HF varied by race (p-interaction = 0.02). Among whites, risk was 2-fold higher for those in the lowest (<= 17 ng/ml) versus highest (>= 31 ng/ml) quintile of 25(OH)D. The association was attenuated but remained significant with covariate adjustment. In blacks there was no overall association. In both races, those with low 25(OH)D and the rs7041 G allele, which predisposes to high DBP, were at greater risk (p-interaction = 0.01). CONCLUSIONS Low serum 25(OH)D was independently associated with incident HF among whites, but not among blacks. However, in both races, low 25(OH)D was associated with HF risk among those genetically predisposed to high DBP. These findings provide novel insight into metabolic differences that may underlie racial variation in the association between 25(OH)D and cardiovascular risk. (C) 2015 by the American College of Cardiology Foundation. C1 [Lutsey, Pamela L.; Misialek, Jeffrey R.; Pankow, James S.; Folsom, Aaron R.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN 55454 USA. [Michos, Erin D.] Johns Hopkins Univ, Div Cardiol, Baltimore, MD USA. [Loehr, Laura] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Selvin, Elizabeth] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Selvin, Elizabeth] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Reis, Jared P.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Gross, Myron; Eckfeldt, John H.] Univ Minnesota, Lab Med & Pathol, Minneapolis, MN USA. RP Lutsey, PL (reprint author), Univ Minnesota, Div Epidemiol & Community Hlth, 1300 South 2nd St,Suite 300, Minneapolis, MN 55454 USA. EM lutsey@umn.edu OI Pankow, James/0000-0001-7076-483X FU National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C]; National Heart, Lung, and Blood Institute CARe (Candidate Gene Resource) grant [N01-HC-65226]; National Institutes of Health National Heart, Lung, and Blood Institute [R01 HL103706]; National Institutes of Health Office of Dietary Supplements [R01 HL103706-S1]; National Institute of Diabetes and Digestive and Kidney Diseases [R01 DK089174] FX The ARIC study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). Reagents for the C-reactive protein and serum albumin assays were donated by the manufacturers. Genotyping was supported through the National Heart, Lung, and Blood Institute CARe (Candidate Gene Resource) grant (N01-HC-65226). Dr. Lutsey has received grant support from the National Institutes of Health National Heart, Lung, and Blood Institute (R01 HL103706) and the National Institutes of Health Office of Dietary Supplements (R01 HL103706-S1). Dr. Selvin has received grant support from the National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK089174). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 29 TC 11 Z9 11 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-1779 EI 2213-1787 J9 JACC-HEART FAIL JI JACC-Heart Fail. PD MAY PY 2015 VL 3 IS 5 BP 347 EP 356 DI 10.1016/j.jchf.2014.11.013 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CX4EK UT WOS:000365651400001 PM 25863973 ER PT J AU Strupnska, M Rostafinska-Suchar, G Pirianowicz-Chaber, E Grabczuk, M Jozwenko, M Kowalczyk, H Szuba, J Wojcicka, M Chen, T Mazurek, AP AF Strupnska, Marzanna Rostafinska-Suchar, Grazyna Pirianowicz-Chaber, Elzbieta Grabczuk, Mateusz Jozwenko, Magdalena Kowalczyk, Hubert Szuba, Joanna Wojcicka, Monika Chen, Tracy Mazurek, Aleksander P. TI SYNTHESIS AND STUDY OF HALOGENATED BENZYLAMIDES OF SOME ISOCYCLIC AND HETEROCYCLIC ACIDS AS POTENTIAL ANTICONVULSANTS SO ACTA POLONIAE PHARMACEUTICA LA English DT Article DE anticonvulsants; chlorobenzylamides; fluorobenzylamides of isocyclic and heterocyclic acids ID DERIVATIVES; SEIZURE AB A series of potential anticonvulsants have been synthesized. There are eight fluorobenzylamides and three chlorobenzylamides of isocyclic or heterocyclic acids. Two not halogenated benzylamides were also synthesized to compare the effect of halogenation. The aim of the research performed was to evaluate whether halogenation of the mother structure is able to improve its anticonvulsant activity. The compounds were tested in Anticonvulsant Screening Project (ASP) of Antiepileptic Drug Development Program (ADDP) of NIH. Compound 1 showed MES ED50 = 80.32 mg/kg, PI = 3.16. Compound 7 showed CKM ED50 = 56.72 mg/kg. Compound 8 showed MES ED50= 34.23 mg/kg and scPTZ ED50 > 300 mg/kg, PI = 8.53.Compound 13 showed 6Hz ED50 = 78.96, PI = 3.37. The results indicate that fluorination does not improve activity, whereas chlorination in our experiment even reduces it. C1 [Strupnska, Marzanna; Rostafinska-Suchar, Grazyna; Pirianowicz-Chaber, Elzbieta; Grabczuk, Mateusz; Jozwenko, Magdalena; Kowalczyk, Hubert; Szuba, Joanna; Wojcicka, Monika; Mazurek, Aleksander P.] Med Univ Warsaw, Dept Drug Chem, PL-02097 Warsaw, Poland. [Chen, Tracy] NINDS, Epilepsy Branch, Rockville, MA 20852 USA. [Mazurek, Aleksander P.] Natl Med Inst, PL-00725 Warsaw, Poland. RP Strupnska, M (reprint author), Med Univ Warsaw, Dept Drug Chem, Banacha 1, PL-02097 Warsaw, Poland. EM marzanna.strupinska@wum.edu.pl FU Warsaw Medical University; National Science Centre [2011/01/B/NZ4/01065]; National Institute of Neurological Disorders and Stroke (NINDS) FX This investigation was supported in part by Warsaw Medical University, National Science Centre (Grant 2011/01/B/NZ4/01065) and National Institute of Neurological Disorders and Stroke (NINDS). The authors would like to thank Prof. Ryszard Paruszewski for the co-operation and enabling us to conduct pharmacological studies at the National Institute of Neurological Disorders and Stroke, within the programme of the Anticonvulsant Screening Project (ASP). NR 16 TC 0 Z9 0 U1 1 U2 1 PU POLSKIE TOWARZYSTWO FARMACEUTYCZNE PI WARSAW PA DLUGA 16, 00-238 WARSAW, POLAND SN 0001-6837 J9 ACTA POL PHARM JI ACTA POL. PHARM. PD MAY-JUN PY 2015 VL 72 IS 3 BP 489 EP 496 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CU3QN UT WOS:000363440000009 PM 26642657 ER PT J AU Arenas-Hernandez, M Sanchez-Rodriguez, EN Mial, TN Robertson, SA Gomez-Lopez, N AF Arenas-Hernandez, Marcia Sanchez-Rodriguez, Elly N. Mial, Tara N. Robertson, Sarah A. Gomez-Lopez, Nardhy TI Isolation of Leukocytes from the Murine Tissues at the Maternal-Fetal Interface SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Immunology; Issue 99; Decidua; Dissociation; Isolation; Leukocytes; Myometrium; Placenta; Pregnancy; Uterus ID NATURAL-KILLER-CELLS; REGULATORY T-CELLS; PRETERM LABOR; PATERNAL ALLOANTIGENS; STEM-CELLS; PREGNANCY; TOLERANCE; MICE; IMPLANTATION; DECIDUA AB Immune tolerance in pregnancy requires that the immune system of the mother undergoes distinctive changes in order to accept and nurture the developing fetus. This tolerance is initiated during coitus, established during fecundation and implantation, and maintained throughout pregnancy. Active cellular and molecular mediators of maternal-fetal tolerance are enriched at the site of contact between fetal and maternal tissues, known as the maternal-fetal interface, which includes the placenta and the uterine and decidual tissues. This interface is comprised of stromal cells and infiltrating leukocytes, and their abundance and phenotypic characteristics change over the course of pregnancy. Infiltrating leukocytes at the maternal-fetal interface include neutrophils, macrophages, dendritic cells, mast cells, T cells, B cells, NK cells, and NKT cells that together create the local micro-environment that sustains pregnancy. An imbalance among these cells or any inappropriate alteration in their phenotypes is considered a mechanism of disease in pregnancy. Therefore, the study of leukocytes that infiltrate the maternal-fetal interface is essential in order to elucidate the immune mechanisms that lead to pregnancy-related complications. Described herein is a protocol that uses a combination of gentle mechanical dissociation followed by a robust enzymatic disaggregation with a proteolytic and collagenolytic enzymatic cocktail to isolate the infiltrating leukocytes from the murine tissues at the maternal-fetal interface. This protocol allows for the isolation of high numbers of viable leukocytes (> 70%) with sufficiently conserved antigenic and functional properties. Isolated leukocytes can then be analyzed by several techniques, including immunophenotyping, cell sorting, imaging, immunoblotting, mRNA expression, cell culture, and in vitro functional assays such as mixed leukocyte reactions, proliferation, or cytotoxicity assays. C1 [Arenas-Hernandez, Marcia; Sanchez-Rodriguez, Elly N.; Mial, Tara N.; Gomez-Lopez, Nardhy] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48202 USA. [Robertson, Sarah A.] Univ Adelaide, Robinson Res Inst, Res Ctr Reprod Hlth, Sch Paediat & Reprod Hlth, Adelaide, SA 5005, Australia. [Gomez-Lopez, Nardhy] Wayne State Univ, Sch Med, Dept Immunol & Microbiol, Detroit, MI 48202 USA. [Gomez-Lopez, Nardhy] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. RP Gomez-Lopez, N (reprint author), Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48202 USA. EM ngomezlo@med.wayne.edu RI Gomez-Lopez, Nardhy/R-7664-2016 OI Gomez-Lopez, Nardhy/0000-0002-3406-5262 FU Wayne State University Perinatal Initiative in Maternal, Perinatal and Child Health FX NGL was supported by the Wayne State University Perinatal Initiative in Maternal, Perinatal and Child Health. We gratefully acknowledge Maureen McGerty and Amy E. Furcron (Wayne State University) for their critical reading of the manuscript. NR 50 TC 1 Z9 1 U1 2 U2 9 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 MAY PY 2015 IS 99 AR e52866 DI 10.3791/52866 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CR7MV UT WOS:000361535300073 PM 26067389 ER PT J AU Coffey, A Johnson, MD Berry, DL AF Coffey, Anna Johnson, Michael D. Berry, Deborah L. TI SpOT the Correct Tissue Every Time in Multi-tissue Blocks SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Structural Biology; Issue 99; Tissue Microarrays; Multi-Tissue Paraffin Blocks; Tissue Orientation; Histology; Immunohistochemistry ID MICROARRAY AB Multi-tissue paraffin blocks provide high throughput analysis with increased efficiency, experimental uniformity, and reduced time and cost. Tissue microarrays make up the majority of multi-tissue paraffin blocks, but increasingly, researchers are using non-arrayed blocks containing larger tissues from multiple individuals which can provide many of the advantages of tissue microarrays without substantial investment in planning and equipment. A critical component of any multi-tissue analysis is the orientation method used to identify each individual tissue. Although methods exist to maintain proper orientation and identification of tissues in multi-tissue blocks, most are not well-suited to non-arrayed blocks, may consume valuable space within an array and/or are difficult to produce in the standard histology laboratory. The Specimen Orientation Tag (SpOT) is a simple, low cost orientation tool that is clearly visible in paraffin blocks and all tissue sections for reliable specimen identification in arrayed and non-arrayed layouts. The SpOT provides advantages over existing orientation methods for non-arrayed blocks as it does not require any direct modification to the tissue and allows for flexibility in the arrangement of tissue pieces. C1 [Coffey, Anna] Frederick Natl Lab Canc Res, Ctr Adv Preclin Res, Frederick, MD USA. [Coffey, Anna] Leidos Biomed Res Inc, Leiden, Netherlands. [Johnson, Michael D.; Berry, Deborah L.] Georgetown Univ, Dept Oncol, Washington, DC 20057 USA. RP Berry, DL (reprint author), Georgetown Univ, Dept Oncol, Washington, DC 20057 USA. EM dlb82@georgetown.edu FU NIH/NCI [P30-CA051008] FX The authors would like to thank Dr. Brent Harris for providing critical review of the manuscript. These studies were conducted at the Lombardi Comprehensive Cancer Center Histopathology & Tissue Shared resource which is supported in part by NIH/NCI grant P30-CA051008. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. NR 15 TC 0 Z9 0 U1 0 U2 0 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 MAY PY 2015 IS 99 AR e52868 DI 10.3791/52868 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CR7MV UT WOS:000361535300074 PM 26067587 ER PT J AU Ohkuni, K Takahashi, Y Basrai, MA AF Ohkuni, Kentaro Takahashi, Yoshimitsu Basrai, Munira A. TI Protein Purification Technique that Allows Detection of Sumoylation and Ubiquitination of Budding Yeast Kinetochore Proteins Ndc10 and Ndc80 SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Microbiology; Issue 99; Saccharomyces cerevisiae; Kinetochore protein; Ndc10; Ndc80; Sumoylation; Ubiquitination; Post-translational modifications; Protein extracts ID HISTONE H3 VARIANT; LOCALIZATION; LIGASE; KINASE; CSE4 AB Post-translational Modifications (PTMs), such as phosphorylation, methylation, acetylation, ubiquitination, and sumoylation, regulate the cellular function of many proteins. PTMs of kinetochore proteins that associate with centromeric DNA mediate faithful chromosome segregation to maintain genome stability. Biochemical approaches such as mass spectrometry and western blot analysis are most commonly used for identification of PTMs. Here, a protein purification method is described that allows the detection of both sumoylation and ubiquitination of the kinetochore proteins, Ndc10 and Ndc80, in Saccharomyces cerevisiae. A strain that expresses polyhistidine-Flag-tagged Smt3 (HF-Smt3) and Myc-tagged Ndc10 or Ndc80 was constructed and used for our studies. For detection of sumoylation, we devised a protocol to affinity purify His-tagged sumoylated proteins by using nickel beads and used western blot analysis with anti-Myc antibody to detect sumoylated Ndc10 and Ndc80. For detection of ubiquitination, we devised a protocol for immunoprecipitation of Myc-tagged proteins and used western blot analysis with anti-Ub antibody to show that Ndc10 and Ndc80 are ubiquitinated. Our results show that epitope tagged-protein of interest in the His-Flag tagged Smt3 strain facilitates the detection of multiple PTMs. Future studies should allow exploitation of this technique to identify and characterize protein interactions that are dependent on a specific PTM. C1 [Ohkuni, Kentaro; Takahashi, Yoshimitsu; Basrai, Munira A.] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Basrai, MA (reprint author), NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM basraim@mail.nih.gov FU National Institutes of Health Intramural Research Program FX We thank Dr. Oliver Kerscher for support and advice and members of the Basrai laboratory for their support and comments on the paper. This work was supported by the National Institutes of Health Intramural Research Program. NR 15 TC 0 Z9 0 U1 1 U2 3 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 MAY PY 2015 IS 99 AR e52482 DI 10.3791/52482 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CR7MV UT WOS:000361535300013 PM 25992961 ER PT J AU Xu, Y Plazyo, O Romero, R Hassan, SS Gomez-Lopez, N AF Xu, Yi Plazyo, Olesya Romero, Roberto Hassan, Sonia S. Gomez-Lopez, Nardhy TI Isolation of Leukocytes from the Human Maternal-fetal Interface SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Immunology; Issue 99; Accutase; Decidua Basalis; Decidua Parietalis; Flow Cytometry; Immunophenotyping; Pregnancy ID FLOW-CYTOMETRIC ANALYSIS; NATURAL-KILLER-CELLS; HUMAN TERM PREGNANCY; DECIDUA BASALIS; GRANULATED LYMPHOCYTES; GROWTH RESTRICTION; HUMAN PARTURITION; STROMAL CELLS; PLACENTAL BED; IMMUNE CELLS AB Pregnancy is characterized by the infiltration of leukocytes in the reproductive tissues and at the maternal-fetal interface (decidua basalis and decidua parietalis). This interface is the anatomical site of contact between maternal and fetal tissues; therefore, it is an immunological site of action during pregnancy. Infiltrating leukocytes at the maternal-fetal interface play a central role in implantation, pregnancy maintenance, and timing of delivery. Therefore, phenotypic and functional characterizations of these leukocytes will provide insight into the mechanisms that lead to pregnancy disorders. Several protocols have been described in order to isolate infiltrating leukocytes from the decidua basalis and decidua parietalis; however, the lack of consistency in the reagents, enzymes, and times of incubation makes it difficult to compare these results. Described herein is a novel approach that combines the use of gentle mechanical and enzymatic dissociation techniques to preserve the viability and integrity of extracellular and intracellular markers in leukocytes isolated from the human tissues at the maternal-fetal interface. Aside from immunophenotyping, cell culture, and cell sorting, the future applications of this protocol are numerous and varied. Following this protocol, the isolated leukocytes can be used to determine DNA methylation, expression of target genes, in vitro leukocyte functionality (i. e., phagocytosis, cytotoxicity, T-cell proliferation, and plasticity, etc.), and the production of reactive oxygen species at the maternal-fetal interface. Additionally, using the described protocol, this laboratory has been able to describe new and rare leukocytes at the maternal-fetal interface. C1 [Xu, Yi; Plazyo, Olesya; Romero, Roberto; Hassan, Sonia S.; Gomez-Lopez, Nardhy] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI 48201 USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Romero, Roberto] Wayne State Univ, Dept Mol Obstet & Genet, Detroit, MI 48202 USA. [Hassan, Sonia S.; Gomez-Lopez, Nardhy] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48202 USA. [Gomez-Lopez, Nardhy] Wayne State Univ, Sch Med, Dept Immunol & Microbiol, Detroit, MI 48202 USA. RP Gomez-Lopez, N (reprint author), NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI 48201 USA. EM ngomezlo@med.wayne.edu RI Gomez-Lopez, Nardhy/R-7664-2016 OI Gomez-Lopez, Nardhy/0000-0002-3406-5262 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH/DHHS; Wayne State University Perinatal Initiative in Maternal, Perinatal and Child Health FX This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH/DHHS. This work was also supported, in part, by the Wayne State University Perinatal Initiative in Maternal, Perinatal and Child Health. We gratefully acknowledge Maureen McGerty (Wayne State University) for her critical readings of the manuscript. NR 53 TC 2 Z9 2 U1 0 U2 2 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 MAY PY 2015 IS 99 AR e52863 DI 10.3791/52863 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CR7MV UT WOS:000361535300072 PM 26067211 ER PT J AU Palant, C Chawla, L Faselis, C Li, P Kimmel, PL Amdur, R AF Palant, Carlos Chawla, Lakhmir Faselis, Charles Li, Ping Kimmel, Paul L. Amdur, Richard TI THE ASSOCIATION OF SERUM CREATININE VARIABILITY AND PROGRESSION TO CKD SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Meeting Abstract CT 52nd Congress of the European-Renal-Association-European-Dialysis-and-Transplant-Assocation CY MAY 28-31, 2015 CL London, ENGLAND SP European Renal Assoc, European Dialysis & Transplant Assoc C1 [Palant, Carlos; Chawla, Lakhmir; Faselis, Charles; Li, Ping; Amdur, Richard] Washington DC VA Med Ctr, Med Serv, Washington, DC USA. [Palant, Carlos; Chawla, Lakhmir; Faselis, Charles; Li, Ping; Kimmel, Paul L.] George Washington Univ, Sch Med, Washington, DC USA. [Kimmel, Paul L.] NIDDK, NIH, Bethesda, MD 20892 USA. [Amdur, Richard] George Washington Univ, Sch Med, Washington, DC USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0931-0509 EI 1460-2385 J9 NEPHROL DIAL TRANSPL JI Nephrol. Dial. Transplant. PD MAY PY 2015 VL 30 SU 3 MA FP322 DI 10.1093/ndt/gfv175.4 PG 1 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA CR3FD UT WOS:000361215100371 ER PT J AU Szalay, C Erdelyi, K Kokeny, G Pacher, P Hamar, P AF Szalay, Csaba Erdelyi, Katalin Koekeny, Gabor Pacher, Pal Hamar, Peter TI OXIDATIVE/NITRATIVE STRESS AND INFLAMMATION DRIVE PROGRESSION OF DOXORUBICIN-INDUCED RENAL FIBROSIS IN RATS AS REVEALED BY COMPARING A NORMAL AND A FIBROSIS-RESISTANT RAT STRAIN SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Meeting Abstract CT 52nd Congress of the European-Renal-Association-European-Dialysis-and-Transplant-Assocation CY MAY 28-31, 2015 CL London, ENGLAND SP European Renal Assoc, European Dialysis & Transplant Assoc C1 [Szalay, Csaba; Koekeny, Gabor; Hamar, Peter] Semmelweis Univ, Inst Pathophysiol, H-1085 Budapest, Hungary. [Erdelyi, Katalin; Pacher, Pal] NIH, Alcohol Abuse, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0931-0509 EI 1460-2385 J9 NEPHROL DIAL TRANSPL JI Nephrol. Dial. Transplant. PD MAY PY 2015 VL 30 SU 3 MA SP320 DI 10.1093/ndt/gfv191.40 PG 1 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA CR3FD UT WOS:000361215102186 ER PT J AU Faure, G Koonin, EV AF Faure, Guilhem Koonin, Eugene V. TI Universal distribution of mutational effects on protein stability, uncoupling of protein robustness from sequence evolution and distinct evolutionary modes of prokaryotic and eukaryotic proteins SO PHYSICAL BIOLOGY LA English DT Article DE protein evolution; mutational robustness; protein core protein surface; hyperthermophiles ID STRUCTURAL-FUNCTIONAL CONSTRAINTS; OVERDISPERSED MOLECULAR CLOCK; HIGHLY EXPRESSED PROTEINS; GENE DISPENSABILITY; SUBSTITUTION RATES; PREDICTION; SELECTION; YEAST; DETERMINANTS; DATABASE AB Robustness to destabilizing effects of mutations is thought of as a key factor of protein evolution. The connections between two measures of robustness, the relative core size and the computationally estimated effect of mutations on protein stability (Delta Delta G), protein abundance and the selection pressure on protein-coding genes (dN/dS) were analyzed for the organisms with a large number of available protein structures including four eukaryotes, two bacteria and one archaeon. The distribution of the effects of mutations in the core on protein stability is universal and indistinguishable in eukaryotes and bacteria, centered at slightly destabilizing amino acid replacements, and with a heavy tail of more strongly destabilizing replacements. The distribution of mutational effects in the hyperthermophilic archaeon Thermococcus gammatolerans is significantly shifted toward strongly destabilizing replacements which is indicative of stronger constraints that are imposed on proteins in hyperthermophiles. The median effect of mutations is strongly, positively correlated with the relative core size, in evidence of the congruence between the two measures of protein robustness. However, both measures show only limited correlations to the expression level and selection pressure on protein-coding genes. Thus, the degree of robustness reflected in the universal distribution of mutational effects appears to be a fundamental, ancient feature of globular protein folds whereas the observed variations are largely neutral and uncoupled from short term protein evolution. A weak anticorrelation between protein core size and selection pressure is observed only for surface residues in prokaryotes but a stronger anticorrelation is observed for all residues in eukaryotic proteins. This substantial difference between proteins of prokaryotes and eukaryotes is likely to stem from the demonstrable higher compactness of prokaryotic proteins. C1 [Faure, Guilhem; Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov FU US Department of Health and Human Services FX The authors thank Yuri I Wolf for critical reading of the manuscript and numerous helpful suggestions, and the Koonin group members for useful discussions. The authors' research is supported by intramural funds of the US Department of Health and Human Services (to the National Library of Medicine). NR 75 TC 6 Z9 6 U1 1 U2 11 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 1478-3967 EI 1478-3975 J9 PHYS BIOL JI Phys. Biol. PD MAY PY 2015 VL 12 IS 3 AR 035001 DI 10.1088/1478-3975/12/3/035001 PG 15 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA CS1OO UT WOS:000361836300002 PM 25927823 ER PT J AU Tong, SQ Chen, L Zhang, Q Liu, J Yan, JZ Ito, Y AF Tong, Shengqiang Chen, Lin Zhang, Qing Liu, Jian Yan, Jizhong Ito, Yoichiro TI Separation of Catalpol from Rehmannia glutinosa Libosch by High-Speed Countercurrent Chromatography SO JOURNAL OF CHROMATOGRAPHIC SCIENCE LA English DT Article ID CENTRIFUGAL PARTITION CHROMATOGRAPHY; PREPARATIVE ISOLATION; IRIDOID GLUCOSIDES; PURIFICATION; CELLS; GLYCOSIDES AB The bioactive iridoid component catalpol was successfully separated by high-speed countercurrent chromatography with high purity from the partially purified crude extract of Rehmannia glutinosa. A polar two-phase solvent system composed of ethyl acetate-n-butanolwater (2: 1: 3, v/v/v) was selected by thin-layer chromatography and run on a preparative scale where the lower aqueous phase was used as the mobile phase with a head-to-tail elution mode. A 105 mg quantity of the partially purified sample containing 39.2% catalpol was loaded on a 270-mL capacity high-speed countercurrent separation column, yielding 35 mg of catalpol at 95.6% purity. The chemical structure of catalpol was determined by comparison with the high-performance liquid chromatography retention time of standard substance as well as the H-1 NMR spectrum. C1 [Tong, Shengqiang; Chen, Lin; Zhang, Qing; Liu, Jian; Yan, Jizhong] Zhejiang Univ Technol, Coll Pharmaceut Sci, Hangzhou, Zhejiang, Peoples R China. [Tong, Shengqiang; Ito, Yoichiro] NHLBI, Lab Bioseparat Technol, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. [Chen, Lin] Zhejiang Inst Tradit Chinese Med & Nat Drug, Hangzhou, Zhejiang, Peoples R China. RP Tong, SQ (reprint author), Zhejiang Univ Technol, Coll Pharmaceut Sci, Hangzhou, Zhejiang, Peoples R China. EM sqtong@zjut.edu.cn FU National Natural Science Foundation of China [21105090]; Department of Education of Zhejiang Province of China [pd2013031]; Innovative Program for the Undergraduates of Zhejiang University of Technology [2013059] FX This work was financially supported by National Natural Science Foundation of China (No. 21105090), Department of Education of Zhejiang Province of China (pd2013031) and Innovative Program for the Undergraduates of Zhejiang University of Technology (2013059). S.Q. Tong thanks Personnel Department of Zhejiang University of Technology for providing the visiting scholar program (2011). NR 19 TC 2 Z9 3 U1 4 U2 15 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0021-9665 EI 1945-239X J9 J CHROMATOGR SCI JI J. Chromatogr. Sci. PD MAY-JUN PY 2015 VL 53 IS 5 BP 725 EP 729 DI 10.1093/chromsci/bmu114 PG 5 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA CQ8CK UT WOS:000360833600011 PM 25214499 ER PT J AU Barsell, A Allawh, R Tamura, D Hill, S Kraemer, K DiGiovanna, J AF Barsell, Alexandra Allawh, Rina Tamura, Deborah Hill, Suvimol Kraemer, Kenneth DiGiovanna, John TI The significance of bone abnormalities in trichothiodystrophy SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Meeting Abstract C1 [Barsell, Alexandra; Allawh, Rina] George Washington Univ, Sch Med, Washington, DC USA. [Tamura, Deborah; Kraemer, Kenneth; DiGiovanna, John] NCI, Dermatol Branch, Bethesda, MD 20892 USA. [Hill, Suvimol] NIH, Radiol & Imaging Sci Clin Ctr, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. 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Agents PD MAY PY 2015 VL 45 SU 2 MA P1-GR07 BP S72 EP S72 PG 1 WC Infectious Diseases; Microbiology; Pharmacology & Pharmacy SC Infectious Diseases; Microbiology; Pharmacology & Pharmacy GA CQ6HL UT WOS:000360705100040 ER PT J AU Kim, S Cha, JO Kim, IH Kim, HS Park, C Yu, JY AF Kim, S. Cha, J. O. Kim, I. H. Kim, H. S. Park, C. Yu, J-Y. TI Identification and characterization of IMP-1 metallo-beta-lactamase producing Acinetobacter species from non-tertiary hospitals SO INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS LA English DT Meeting Abstract CT 10th International Symposium on Antimicrobial Agents and Resistance (ISAAR) CY MAY 14-15, 2015 CL Incheon, SOUTH KOREA C1 [Kim, S.; Cha, J. O.; Kim, I. H.; Kim, H. S.; Park, C.; Yu, J-Y.] Natl Inst Hlth, Div Antimicrobial Resistance, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-8579 EI 1872-7913 J9 INT J ANTIMICROB AG JI Int. J. Antimicrob. Agents PD MAY PY 2015 VL 45 SU 2 MA P1-GR04 BP S71 EP S71 PG 1 WC Infectious Diseases; Microbiology; Pharmacology & Pharmacy SC Infectious Diseases; Microbiology; Pharmacology & Pharmacy GA CQ6HL UT WOS:000360705100037 ER PT J AU Afione, S DiMattia, MA Halder, S Di Pasquale, G Agbandje-McKenna, M Chiorini, J AF Afione, Sandra DiMattia, Michael A. Halder, Sujata Di Pasquale, Giovanni Agbandje-McKenna, Mavis Chiorini, John TI Identification and Mutagenesis of the AAV5 Sialic Acid Binding Region SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 18th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 13-16, 2015 CL New Orleans, LA SP Amer Soc Gene & Cell Therapy C1 [Afione, Sandra; Halder, Sujata; Di Pasquale, Giovanni; Chiorini, John] NIDCR, NIH, Bethesda, MD USA. [DiMattia, Michael A.; Agbandje-McKenna, Mavis] Univ Florida, Gainesville, FL USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2015 VL 23 SU 1 MA 91 BP S39 EP S39 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CP5UY UT WOS:000359951700093 ER PT J AU Albright, BH Madigan, V Rao, L Chiorini, JA Agbandje-McKenna, M Asokan, A AF Albright, Blake H. Madigan, Victoria Rao, Lavanya Chiorini, John A. Agbandje-McKenna, Mavis Asokan, Aravind TI Combinatorial Engineering of a Receptor Footprint on AAV Serotype 4 Yields Novel Vectors SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 18th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 13-16, 2015 CL New Orleans, LA SP Amer Soc Gene & Cell Therapy C1 [Albright, Blake H.; Madigan, Victoria; Rao, Lavanya; Asokan, Aravind] Univ N Carolina, Gene Therapy Ctr, Chapel Hill, NC USA. [Chiorini, John A.] NIH, Bethesda, MD 20892 USA. [Agbandje-McKenna, Mavis] Univ Florida, Gainesville, FL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2015 VL 23 SU 1 MA 302 BP S122 EP S122 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CP5UY UT WOS:000359951700307 ER PT J AU Beane, JD Lee, G Zheng, ZL Gandhi, N Abate-Daga, D Bharathan, M Black, M Mendel, M Yu, ZY Kassim, SH Chandran, S Giedlin, MA Ando, D Rebar, E Reik, A Holmes, MC Gregory, PD Restifo, NP Rosenberg, SA Morgan, RA Feldman, SA AF Beane, Joal D. Lee, Gary Zheng, Zhili Gandhi, Nimisha Abate-Daga, Daniel Bharathan, Mini Black, Mary Mendel, Matthew Yu, Zhiya Kassim, Sadik H. Chandran, Smita Giedlin, Martin A. Ando, Dale Rebar, Ed Reik, Andreas Holmes, Michael C. Gregory, Philip D. Restifo, Nicholas P. Rosenberg, Steven A. Morgan, Richard A. Feldman, Steven A. TI Clinical Scale Zinc Finger Nuclease (ZFN)-Driven Gene-Editing of PD-1 in Tumor Infiltrating Lymphocytes (TIL) for the Potential Treatment of Metastatic Melanoma SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 18th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 13-16, 2015 CL New Orleans, LA SP Amer Soc Gene & Cell Therapy C1 [Beane, Joal D.; Zheng, Zhili; Abate-Daga, Daniel; Bharathan, Mini; Black, Mary; Yu, Zhiya; Kassim, Sadik H.; Chandran, Smita; Restifo, Nicholas P.; Rosenberg, Steven A.; Morgan, Richard A.; Feldman, Steven A.] NCI, Surg Branch, Bethesda, MD 20892 USA. [Lee, Gary; Gandhi, Nimisha; Mendel, Matthew; Giedlin, Martin A.; Ando, Dale; Rebar, Ed; Reik, Andreas; Holmes, Michael C.; Gregory, Philip D.] Sangamo BioSci Inc, Richmond, CA USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2015 VL 23 SU 1 MA 77 BP S33 EP S34 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CP5UY UT WOS:000359951700079 ER PT J AU Byrd, T Fousek, K Pignata, A Szot, C Bielamowicz, K Wakefield, A Seaman, S Fletcher, B Hegde, M St Croix, B Ahmed, N AF Byrd, Tiara Fousek, Kristen Pignata, Antonella Szot, Christopher Bielamowicz, Kevin Wakefield, Amanda Seaman, Steven Fletcher, Bradley Hegde, Meenakshi St Croix, Brad Ahmed, Nabil TI Triple-Negative Breast Cancer Cells and Tumor Endothelium Are Killed by Targeting Tumor Endothelial Marker 8 (TEM8) SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 18th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 13-16, 2015 CL New Orleans, LA SP Amer Soc Gene & Cell Therapy C1 [Byrd, Tiara; Fousek, Kristen; Ahmed, Nabil] Baylor Coll Med, Translat Biol & Mol Med, Houston, TX 77030 USA. 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TI Adeno-Associated Viral Gene Therapy To Treat Niemann-Pick Disease, Type C1 SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 18th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 13-16, 2015 CL New Orleans, LA SP Amer Soc Gene & Cell Therapy C1 [Chandler, Randy J.; Incao, Arturo A.; Pavan, William J.; Venditti, Charles P.] NHGRI, NIH, Bethesda, MD 20892 USA. [Williams, Ian M.; Porter, Forbes D.] NICHHD, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2015 VL 23 SU 1 MA 198 BP S79 EP S79 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CP5UY UT WOS:000359951700199 ER PT J AU Christopher, DM Billheimer, J Marchadier, D Susztak, K Remaley, A Wilson, J Rader, DJ AF Christopher, Devin M. Billheimer, Jeff Marchadier, Dawn Susztak, Katalin Remaley, Alan Wilson, James Rader, Daniel J. TI AAV-Mediated Gene Transfer as a Therapeutic Approach for Familial LCAT Deficiency SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 18th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 13-16, 2015 CL New Orleans, LA SP Amer Soc Gene & Cell Therapy C1 [Christopher, Devin M.; Billheimer, Jeff; Marchadier, Dawn; Susztak, Katalin; Wilson, James; Rader, Daniel J.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Remaley, Alan] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2015 VL 23 SU 1 MA 9 BP S4 EP S4 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CP5UY UT WOS:000359951700010 ER PT J AU Cooper, AR Shaw, KL Lill, GR Sokolic, R Candotti, F Kohn, DB AF Cooper, Aaron R. Shaw, Kit L. Lill, Georgia R. Sokolic, Robert Candotti, Fabio Kohn, Donald B. TI Barcoding as a Tool To Predict Integrating Vector Genotoxicity in HSPCs SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 18th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 13-16, 2015 CL New Orleans, LA SP Amer Soc Gene & Cell Therapy C1 [Cooper, Aaron R.; Shaw, Kit L.; Lill, Georgia R.; Sokolic, Robert; Candotti, Fabio; Kohn, Donald B.] Georgetown Univ, Microbiol & Immunol, Washington, DC 20057 USA. [Cooper, Aaron R.] NHLBI, Mol Hematopoiesis Sect, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2015 VL 23 SU 1 MA 241 BP S94 EP S95 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CP5UY UT WOS:000359951700242 ER PT J AU Cooper, AR Shaw, KL Lill, GR Sokolic, R Candotti, F Kohn, DB AF Cooper, Aaron R. Shaw, Kit L. Lill, Georgia R. Sokolic, Robert Candotti, Fabio Kohn, Donald B. TI Stable and Clinically Benign Clonal Dominance in an ADA-SCID Patient Treated With Retroviral Gene Therapy SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 18th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 13-16, 2015 CL New Orleans, LA SP Amer Soc Gene & Cell Therapy C1 [Cooper, Aaron R.] Univ Calif Los Angeles, Mol Biol Interdept PhD Program, Los Angeles, CA USA. [Shaw, Kit L.; Lill, Georgia R.; Kohn, Donald B.] Univ Calif Los Angeles, Microbiol Immunol & Mol Genet, Los Angeles, CA USA. 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TI Transfection of Neutrophils from X-Linked Chronic Granulomatous Disease Patients with gp91phox mRNA Restores Oxidase Activity with High Efficiency and Viability SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 18th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 13-16, 2015 CL New Orleans, LA SP Amer Soc Gene & Cell Therapy C1 [De Ravin, Suk See; Choi, Uimook; Chu, Jessica; Theobald, Narda; Koontz, Sherry; Lee, Janet; Zarember, Kol; Malech, Harry L.] NIAID, Host Def Lab, Bethesda, MD 20892 USA. [Hanh Khuu; Cantilena, Cathy] Ctr Clin, Dept Transfus Med, Bethesda, MD USA. [Li, Linhong; Peshwa, Madhusudan V.] MaxCyte Inc, Gaithersburg, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2015 VL 23 SU 1 MA 298 BP S120 EP S121 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CP5UY UT WOS:000359951700303 ER PT J AU De Ravin, SS Reik, A Liu, PQ Li, LH Peshwa, MV Theobald, N Choi, U Lee, J Koontz, S Lee, G Gregory, PD Urnov, FD Malech, HL AF De Ravin, Suk See Reik, Andreas Liu, Pei-Qi Li, Linhong Peshwa, Madhusudan V. Theobald, Narda Choi, Uimook Lee, Janet Koontz, Sherry Lee, Gary Gregory, Philip D. Urnov, Fyodor D. Malech, Harry L. TI Genome Editing of Primary Human CD34(+) Hematopoietic Stem Cells Enables a Safe Harbor Targeted Gene Addition Therapeutic Strategy for Chronic Granulomatous Disease SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 18th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 13-16, 2015 CL New Orleans, LA SP Amer Soc Gene & Cell Therapy C1 [De Ravin, Suk See; Theobald, Narda; Choi, Uimook; Lee, Janet; Koontz, Sherry; Malech, Harry L.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Reik, Andreas; Liu, Pei-Qi; Lee, Gary; Gregory, Philip D.; Urnov, Fyodor D.] Sangamo BioSci Inc, Richmond, CA USA. [Li, Linhong; Peshwa, Madhusudan V.] MaxCyte Inc, Gaithersburg, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2015 VL 23 SU 1 MA 54 BP S24 EP S24 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CP5UY UT WOS:000359951700056 ER PT J AU Di Pasquale, G Rivero, PP Tora, M Swaim, WD Sheikh, T Teos, L Afione, S Zheng, CY Alevizos, I Weigert, R Chiorini, JA AF Di Pasquale, Giovanni Rivero, Paola Perez Tora, M. Swaim, William D. Sheikh, Tayyab Teos, Leyla Afione, Sandra Zheng, Changyu Alevizos, Ilias Weigert, Roberto Chiorini, John A. TI Transduction of Salivary Gland Acinar Cells in Rodents with Adeno Associated Viral Vectors Results in Persistent Exocrine and Endocrine Release of Recombinant Proteins SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 18th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 13-16, 2015 CL New Orleans, LA SP Amer Soc Gene & Cell Therapy C1 [Di Pasquale, Giovanni; Rivero, Paola Perez; Swaim, William D.; Sheikh, Tayyab; Teos, Leyla; Afione, Sandra; Zheng, Changyu; Alevizos, Ilias; Chiorini, John A.] NIDCR, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. [Tora, M.; Weigert, Roberto] NIDCR, Intracellular Membrane Trafficking Unit, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2015 VL 23 SU 1 MA 552 BP S221 EP S221 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CP5UY UT WOS:000359951700554 ER PT J AU Gaspar, HB Buckland, K Carbonaro, DA Shaw, K Barman, P Davila, A Gilmour, KC Booth, C Terrazs, D Cornetta, K Paruzynski, A Schmidt, M Sokolic, R Candotti, F Thrasher, AJ Kohn, DB AF Gaspar, Hubert B. Buckland, Karen Carbonaro, Denise A. Shaw, Kit Barman, Provobati Davila, Alejandra Gilmour, Kimberly C. Booth, Claire Terrazs, Dayna Cornetta, Kenneth Paruzynski, Anna Schmidt, Manfred Sokolic, Robert Candotti, Fabio Thrasher, Adrian J. Kohn, Donald B. TI Immunological and Metabolic Correction After Lentiviral Vector Gene Therapy for ADA Deficiency SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 18th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 13-16, 2015 CL New Orleans, LA SP Amer Soc Gene & Cell Therapy C1 [Gaspar, Hubert B.; Buckland, Karen; Gilmour, Kimberly C.; Booth, Claire; Thrasher, Adrian J.] UCL, London, England. [Carbonaro, Denise A.; Shaw, Kit; Barman, Provobati; Davila, Alejandra; Terrazs, Dayna; Kohn, Donald B.] Univ Calif Los Angeles, Los Angeles, CA USA. [Cornetta, Kenneth] Indiana Univ, Indianapolis, IN 46204 USA. [Paruzynski, Anna; Schmidt, Manfred] Heidelberg Univ, Heidelberg, Germany. [Sokolic, Robert; Candotti, Fabio] NIH, Bethesda, MD 20892 USA. RI Booth, Claire/I-3667-2016 OI Booth, Claire/0000-0002-2626-5037 NR 0 TC 3 Z9 3 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2015 VL 23 SU 1 MA C-8 BP S102 EP S103 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CP5UY UT WOS:000359951700262 ER PT J AU Haddad, MR Martinelli, D Choi, EY Zerfas, PM Sullivan, P Goldstein, DS Abebe, DT Centeno, JA Kaler, SG AF Haddad, Marie Reine Martinelli, Diego Choi, Eun-Young Zerfas, Patricia M. Sullivan, Patricia Goldstein, David S. Abebe, Daniel T. Centeno, Jose A. Kaler, Stephen G. TI Survival, Growth, and Neurobehavioral Outcomes in a Mouse Model of Menkes Disease With CSF-Directed AAV9 and Subcutaneous Copper Histidine SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 18th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 13-16, 2015 CL New Orleans, LA SP Amer Soc Gene & Cell Therapy C1 [Haddad, Marie Reine; Martinelli, Diego; Choi, Eun-Young; Kaler, Stephen G.] NICHD, Sect Translat Neurosci, Program Mol Med, NIH, Bethesda, MD USA. [Zerfas, Patricia M.] NIH, Diagnost & Res Serv Branch, OD, Bethesda, MD 20892 USA. [Sullivan, Patricia; Goldstein, David S.] NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. [Abebe, Daniel T.] NICHD, Res Anim Management Branch, NIH, Bethesda, MD USA. [Centeno, Jose A.] Andrews AFB, Malcolm Grow, Joint Pathol Ctr, Div Biophys Toxicol, Camp Springs, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2015 VL 23 SU 1 MA 197 BP S78 EP S78 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CP5UY UT WOS:000359951700198 ER PT J AU Howard, DB Fortuno, LV Harvey, BK AF Howard, Doug B. Fortuno, Lowella V. Harvey, Brandon K. TI Stability and Inactivation of AAV Serotype 1 Vectors SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 18th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 13-16, 2015 CL New Orleans, LA SP Amer Soc Gene & Cell Therapy C1 [Howard, Doug B.; Fortuno, Lowella V.; Harvey, Brandon K.] NIDA, Optogenet & Transgen Technol Core, NIH, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2015 VL 23 SU 1 MA 97 BP S41 EP S41 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CP5UY UT WOS:000359951700099 ER PT J AU Ildefonso, CJ Jaime, H Li, QH Rahman, MM McFadden, G Lewin, AS AF Ildefonso, Cristhian J. Jaime, Henrique Li, Qiuhong Rahman, Masmudur M. McFadden, Grant Lewin, Alfred S. TI Gene Therapy Delivering Anti-inflammatory Viral Proteins for Ocular Inflammation SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 18th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 13-16, 2015 CL New Orleans, LA SP Amer Soc Gene & Cell Therapy C1 [Ildefonso, Cristhian J.; Rahman, Masmudur M.; McFadden, Grant; Lewin, Alfred S.] Univ Florida Coll Med, Mol Genet & Microbiol, Gainesville, FL USA. [Jaime, Henrique] NIH, Bethesda, MD 20892 USA. [Li, Qiuhong] Univ Florida Coll Med, Ophthalmol, Gainesville, FL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2015 VL 23 SU 1 MA 607 BP S241 EP S241 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CP5UY UT WOS:000359951700609 ER PT J AU Isaev, AA Eremin, II Pulin, AA Deev, RV Tomilin, AN Liskovykh, MA Larionov, V Kouprina, N Iur'eva, K Zorin, VL Bozo, IY Kotenko, KV AF Isaev, Artur A. Eremin, Ilya I. Pulin, Andrey A. Deev, Roman V. Tomilin, Alexey N. Liskovykh, Michail A. Larionov, Vladimir Kouprina, Natalia Iur'eva, Kseniya Zorin, Vadim L. Bozo, Ilya Ya Kotenko, Konstantin V. TI Development of Human Artificial Chromosomes for Gene Cell Therapy of Muscular Dystrophies SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 18th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 13-16, 2015 CL New Orleans, LA SP Amer Soc Gene & Cell Therapy C1 [Isaev, Artur A.; Deev, Roman V.; Iur'eva, Kseniya; Zorin, Vadim L.; Bozo, Ilya Ya] Human Stem Cells Inst OJSC, Moscow, Russia. [Eremin, Ilya I.; Pulin, Andrey A.; Deev, Roman V.; Zorin, Vadim L.; Bozo, Ilya Ya; Kotenko, Konstantin V.] Burnasyan Fed Med Biophys Ctr FMBA Russia, State Res Ctr, Moscow, Russia. [Tomilin, Alexey N.; Liskovykh, Michail A.] Russian Acad Sci, Inst Cytol, St Petersburg 194064, Russia. [Larionov, Vladimir; Kouprina, Natalia] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2015 VL 23 SU 1 MA 404 BP S160 EP S160 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CP5UY UT WOS:000359951700408 ER PT J AU Jessup, JM Mattoo, AR Korokhov, N AF Jessup, John M. Mattoo, Abid R. Korokhov, Nikolay TI Replicating Oncolytic Chimeric Adenovirus Expressing shRNA Improves Inhibition of Human Colorectal Carcinoma (CRC) Growth SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 18th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 13-16, 2015 CL New Orleans, LA SP Amer Soc Gene & Cell Therapy C1 [Jessup, John M.; Mattoo, Abid R.; Korokhov, Nikolay] NCI, Lab Expt Carcinogenesis, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2015 VL 23 SU 1 MA 109 BP S46 EP S46 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CP5UY UT WOS:000359951700111 ER PT J AU Lee, YM Kwon, J Weinstein, DA Chou, JY AF Lee, Young Mok Kwon, Joonhyun Weinstein, David A. Chou, Janice Y. TI Correction of Metabolic Abnormalities in Murine Glycogen Storage Disease Type Ib by Gene Therapy SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 18th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 13-16, 2015 CL New Orleans, LA SP Amer Soc Gene & Cell Therapy C1 [Lee, Young Mok; Kwon, Joonhyun; Chou, Janice Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Cellular Differentiat, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. [Lee, Young Mok; Weinstein, David A.] Univ Florida, Dept Pediat, Div Pediat Endocrinol, Glycogen Storage Dis Program, Gainesville, FL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2015 VL 23 SU 1 MA 376 BP S150 EP S150 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CP5UY UT WOS:000359951700380 ER PT J AU Li, LH De Ravin, SS Allen, C Natarajan, P Malech, HL Peshwa, MV AF Li, Linhong De Ravin, Suk See Allen, Cornell Natarajan, Pachai Malech, Harry L. Peshwa, Madhusudan V. TI Efficient Functional Oxidase Correction after CRISPR-Oligomer Gene Repair in X-CGD Patient Hematopoietic Stem Cells (HSC) Using Non-Viral, cGMP Compliant, Scalable, Closed System SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 18th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 13-16, 2015 CL New Orleans, LA SP Amer Soc Gene & Cell Therapy C1 [Li, Linhong; Allen, Cornell; Natarajan, Pachai; Peshwa, Madhusudan V.] MaxCyte Inc, Gaithersburg, MD USA. [De Ravin, Suk See; Malech, Harry L.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2015 VL 23 SU 1 MA 299 BP S121 EP S121 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CP5UY UT WOS:000359951700304 ER PT J AU Lynn, RC Poussin, M Feng, Y Schutsky, K Kalota, A Low, PS Dimitrov, DS Powell, DJ AF Lynn, Rachel C. Poussin, Mathilde Feng, Yang Schutsky, Keith Kalota, Anna Low, Philip S. Dimitrov, Dimiter S. Powell, Daniel J., Jr. TI Exploring On-Target Hematopoietic Toxicity With Highly Potent, High Affinity FR beta-Specific CAR T Cells for AML SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 18th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 13-16, 2015 CL New Orleans, LA SP Amer Soc Gene & Cell Therapy C1 [Lynn, Rachel C.; Poussin, Mathilde; Schutsky, Keith; Kalota, Anna; Powell, Daniel J., Jr.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Low, Philip S.] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. [Feng, Yang; Dimitrov, Dimiter S.] NCI, Prot Interact Sect, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2015 VL 23 SU 1 MA 285 BP S114 EP S114 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CP5UY UT WOS:000359951700290 ER PT J AU Melchiori, L Williams, DD Binder-Scholl, GK Wong, R Kreutz, M Tayton-Martin, HK Stadtmauer, E Vogl, DT Merchant, M Tap, W D'Angelo, S Davila, E Fortin, M Peretz, Y Rapoport, AP Mackall, C Jakobsen, BK AF Melchiori, Luca Williams, Daniel D. Binder-Scholl, Gwendolyn K. Wong, Ryan Kreutz, Martin Tayton-Martin, Helen K. Stadtmauer, Edward Vogl, Dan T. Merchant, Melinda Tap, William D'Angelo, Sandra Davila, Eduardo Fortin, Marylene Peretz, Yoav Rapoport, Aaron P. Mackall, Crystal Jakobsen, Bent K. TI Enhanced-Affinity NY-ESO-1-Specific T Cells Exhibit Extended Functionality without Exhaustion in a Pattern of Effector and Memory Programming in Multiple Cancer Indications SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 18th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 13-16, 2015 CL New Orleans, LA SP Amer Soc Gene & Cell Therapy C1 [Melchiori, Luca; Williams, Daniel D.; Binder-Scholl, Gwendolyn K.; Wong, Ryan; Kreutz, Martin; Tayton-Martin, Helen K.; Jakobsen, Bent K.] Adaptimmune, Oxford, England. [Davila, Eduardo; Rapoport, Aaron P.] Univ Maryland, Baltimore, MD 21201 USA. [Stadtmauer, Edward; Vogl, Dan T.] Univ Penn, Philadelphia, PA 19104 USA. [Merchant, Melinda; Mackall, Crystal] NCI, Bethesda, MD 20892 USA. [Tap, William; D'Angelo, Sandra] Mem Solan Kettering Canc Ctr, New York, NY USA. [Fortin, Marylene; Peretz, Yoav] ImmuneCarta, Montreal, PQ, Canada. NR 0 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2015 VL 23 SU 1 MA 511 BP S204 EP S205 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CP5UY UT WOS:000359951700514 ER PT J AU Merling, RK De Ravin, SS Sweeney, CL Kuhns, DB Di Pasquale, G Chiorini, JA Malech, HL AF Merling, Randall K. De Ravin, Suk See Sweeney, Colin L. Kuhns, Douglas B. Di Pasquale, Giovanni Chiorini, John A. Malech, Harry L. TI ZFN-Mediated Minigene or Dinucleotide Gene Correction of p47(phox) Deficient Autosomal Recessive Chronic Granulomatous Disease iPSC to Generate Oxidase Functional Neutrophils SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 18th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 13-16, 2015 CL New Orleans, LA SP Amer Soc Gene & Cell Therapy C1 [Merling, Randall K.; De Ravin, Suk See; Sweeney, Colin L.; Malech, Harry L.] NIAID, Lab Host Def, NIH, Bethesda, MD 20892 USA. [Kuhns, Douglas B.] NIAID, Neutrophil Monitoring Lab, Appl Dev Res Directorate, Leidos Biomed Res Inc,NIH, Frederick, MD USA. [Di Pasquale, Giovanni; Chiorini, John A.] Natl Inst Dent & Craniofacial Res, Adeno Associated Virus Sect, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2015 VL 23 SU 1 MA 332 BP S133 EP S133 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CP5UY UT WOS:000359951700336 ER PT J AU Mookherjee, S Hiriyanna, S Kaneshiro, K Qian, HH Li, TS Khanna, H Colosi, P Swaroop, A Wu, ZJ AF Mookherjee, Suddhasil Hiriyanna, Suja Kaneshiro, Kayleigh Qian, Haohua Li, Tiansen Khanna, Hemant Colosi, Peter Swaroop, Anand Wu, Zhijian TI Gene Therapy Rescues Cone Function and Viability in an Rp2 Knockout Mouse Model for X-Linked Retinitis Pigmentosa Over a Wide Dose Range and a Broad Therapeutic Time Window SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 18th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 13-16, 2015 CL New Orleans, LA SP Amer Soc Gene & Cell Therapy C1 [Mookherjee, Suddhasil; Hiriyanna, Suja; Kaneshiro, Kayleigh; Colosi, Peter; Wu, Zhijian] NEI, Ocular Gene Therapy Core, NIH, Bethesda, MD 20892 USA. [Li, Tiansen; Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. [Khanna, Hemant] Univ Massachusetts, Sch Med, Dept Ophthalmol, Worcester, MA USA. [Qian, Haohua] NEI, Visual Funct Core, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2015 VL 23 SU 1 MA 714 BP S285 EP S285 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CP5UY UT WOS:000359951700716 ER PT J AU Punwani, D Stillion, M Yu, J Malech, HL Carbonaro, D Kohn, DB McIvor, S Puck, JM Cowan, MJ AF Punwani, Divya Stillion, Misako Yu, Jason Malech, Harry L. Carbonaro, Denise Kohn, Donald B. McIvor, Scott Puck, Jennifer M. Cowan, Morton J. TI Lentivirus Vector Mediated Gene Correction in Artemis-Deficient Severe Combined Immunodeficiency SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 18th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 13-16, 2015 CL New Orleans, LA SP Amer Soc Gene & Cell Therapy C1 [Punwani, Divya; Stillion, Misako; Yu, Jason; Puck, Jennifer M.; Cowan, Morton J.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Malech, Harry L.] NIAID, Bethesda, MD 20892 USA. [Carbonaro, Denise; Kohn, Donald B.] Univ Calif Los Angeles, Los Angeles, CA USA. [McIvor, Scott] Univ Minnesota, Minneapolis, MN USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2015 VL 23 SU 1 MA 292 BP S117 EP S118 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CP5UY UT WOS:000359951700297 ER PT J AU Richie, CT Fortuno, LV Zhang, YJ Pickel, J Harvey, BK AF Richie, Christopher T. Fortuno, Lowella V. Zhang, YaJun Pickel, James Harvey, Brandon K. TI Development of CRISPR Toolkit for Knock-In Transgene Targeting to the Rat Rosa26 Locus SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 18th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 13-16, 2015 CL New Orleans, LA SP Amer Soc Gene & Cell Therapy C1 [Richie, Christopher T.; Fortuno, Lowella V.; Zhang, YaJun; Harvey, Brandon K.] NIDA, Optogenet & Transgen Technol Core, Baltimore, MD USA. [Pickel, James] NIMH, Transgen Core Facil, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2015 VL 23 SU 1 MA 569 BP S227 EP S227 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CP5UY UT WOS:000359951700571 ER PT J AU Schneller, J Senac, J Chandler, R Venditti, CP AF Schneller, Jessica Senac, Julien Chandler, Randy Venditti, Charles P. TI An Internally Tagged Methylmalonyl-CoA Mutase (Mut) Displays In Vivo Activity after AAV9 Mediated Gene Delivery SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 18th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 13-16, 2015 CL New Orleans, LA SP Amer Soc Gene & Cell Therapy C1 [Schneller, Jessica] SUNY Stony Brook, Biomed Engn, Stony Brook, NY 11794 USA. [Schneller, Jessica; Senac, Julien; Chandler, Randy; Venditti, Charles P.] NHGRI, Organ Acid Res Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2015 VL 23 SU 1 MA 176 BP S70 EP S70 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CP5UY UT WOS:000359951700177 ER PT J AU Sieving, PA Vijayasarathy, C Ou, JX Ziccardi, L Chen, S Zeng, Y Marangoni, D Li, W Wu, ZJ Wei, LL Bush, RA AF Sieving, Paul A. Vijayasarathy, Camasamudram Ou, Jinxing Ziccardi, Lucia Chen, Shan Zeng, Yong Marangoni, Dario Li, Wei Wu, Zhijian Wei, Lisa L. Bush, Ronald A. TI Human Gene Therapy for a Synaptic Disease: X-Linked Retinoschisis (XLRS) SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 18th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 13-16, 2015 CL New Orleans, LA SP Amer Soc Gene & Cell Therapy C1 [Sieving, Paul A.; Ou, Jinxing; Chen, Shan; Li, Wei; Wu, Zhijian; Wei, Lisa L.] NEI, Bethesda, MD 20892 USA. [Vijayasarathy, Camasamudram; Ziccardi, Lucia; Zeng, Yong; Marangoni, Dario; Bush, Ronald A.] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2015 VL 23 SU 1 MA 600 BP S238 EP S238 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CP5UY UT WOS:000359951700602 ER PT J AU Sweeney, CL Zou, JZ Choi, U Merling, RK DeRavin, SS Malech, HL AF Sweeney, Colin L. Zou, Jizhong Choi, Uimook Merling, Randall K. DeRavin, Suk See Malech, Harry L. TI Seamless Targeted Correction of CYBB Exon 5 Mutations Restores Granulocyte Function in X-Linked Chronic Granulomatous Disease iPSCs SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 18th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 13-16, 2015 CL New Orleans, LA SP Amer Soc Gene & Cell Therapy C1 [Sweeney, Colin L.; Choi, Uimook; Merling, Randall K.; DeRavin, Suk See; Malech, Harry L.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Zou, Jizhong] NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2015 VL 23 SU 1 MA 57 BP S25 EP S25 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CP5UY UT WOS:000359951700059 ER PT J AU Uchida, N Platner, C Ballantine, J Hsieh, MM Mozer, B Mitchell, LG Washington, KN Tisdale, JF AF Uchida, Naoya Platner, Charlotte Ballantine, Josiah Hsieh, Matthew M. Mozer, Brian Mitchell, Lloyd G. Washington, Kareem N. Tisdale, John F. TI Optimization of RNA Trans-Splicing for the beta-Globin Gene; Detecting Trans-Splicing Events Targeting Endogenous beta-Globin Pre-mRNA in Human Erythroid Cells SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 18th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 13-16, 2015 CL New Orleans, LA SP Amer Soc Gene & Cell Therapy C1 [Uchida, Naoya; Platner, Charlotte; Ballantine, Josiah; Hsieh, Matthew M.; Tisdale, John F.] NIDDK, MCHB, NHLBI, NIH, Bethesda, MD USA. [Mozer, Brian; Mitchell, Lloyd G.] RetroTherapy, Bethesda, MD USA. [Washington, Kareem N.] Howard Univ, Genet & Human Genet, Washington, DC 20059 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2015 VL 23 SU 1 MA 440 BP S174 EP S174 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CP5UY UT WOS:000359951700444 ER PT J AU Uchida, N Weitzel, RP Platner, C Ballantine, J Bonifacino, AC Price, SD Krouse, AE Metzger, ME Donahue, RE Tisdale, JF AF Uchida, Naoya Weitzel, R. Patrick Platner, Charlotte Ballantine, Josiah Bonifacino, Aylin C. Price, Sandra D. Krouse, Allen E. Metzger, Mark E. Donahue, Robert E. Tisdale, John F. TI Myeloablative Conditioning Is Required for Effi cient Engraftment of Gene-Modifi ed Cells and Prevention of Antibody Production Against Transgene Products in a Rhesus Stem Cell Gene Therapy Model SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 18th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 13-16, 2015 CL New Orleans, LA SP Amer Soc Gene & Cell Therapy C1 [Uchida, Naoya; Weitzel, R. Patrick; Platner, Charlotte; Ballantine, Josiah; Tisdale, John F.] NIDDK, MCHB, NHLBI, NIH, Bethesda, MD 20892 USA. [Bonifacino, Aylin C.; Price, Sandra D.; Krouse, Allen E.; Metzger, Mark E.; Donahue, Robert E.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2015 VL 23 SU 1 MA 294 BP S118 EP S119 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CP5UY UT WOS:000359951700299 ER PT J AU Zhang, CB Li, LP Liu, DX AF Zhang, Chunbo Li, Leping Liu, Dexi TI Transcription Factor Binding Site in Plasmid Regulates Persistence of Transgene Expression in Mouse Liver SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 18th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 13-16, 2015 CL New Orleans, LA SP Amer Soc Gene & Cell Therapy C1 [Zhang, Chunbo; Liu, Dexi] Univ Georgia, Coll Pharm, Dept Pharmaceut & Biomed Sci, Athens, GA 30602 USA. [Li, Leping] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. [Zhang, Chunbo] Nanchang Univ, Sch Pharm, Nanchang, Jiangxi, Peoples R China. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2015 VL 23 SU 1 MA 147 BP S59 EP S60 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CP5UY UT WOS:000359951700149 ER PT J AU Zheng, CY Baum, BJ Liu, XB Goldsmith, CM Perez, P Jang, SI Cotrim, AP McCullagh, L Ambudkar, IS Alevizos, I AF Zheng, Changyu Baum, Bruce J. Liu, Xibao Goldsmith, Corinne M. Perez, Paola Jang, Shyh-Ing Cotrim, Ana P. McCullagh, Linda Ambudkar, Indu S. Alevizos, Ilias TI Persistence of hAQP1 Expression in Human Salivary Gland Cells Following AdhAQP1 Transduction Is Associated With a Lack of Methylation of hCMV Promoter SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 18th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 13-16, 2015 CL New Orleans, LA SP Amer Soc Gene & Cell Therapy C1 [Zheng, Changyu; Baum, Bruce J.; Liu, Xibao; Goldsmith, Corinne M.; Perez, Paola; Jang, Shyh-Ing; Cotrim, Ana P.; McCullagh, Linda; Ambudkar, Indu S.; Alevizos, Ilias] NIDCR, MPTB, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2015 VL 23 SU 1 MA 325 BP S131 EP S131 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CP5UY UT WOS:000359951700330 ER PT J AU Zhu, W Shen, FX Zhan, L Kang, S Zhang, R Zou, DQ Forsayeth, J Wu, ZJ Colosi, P Su, H AF Zhu, Wan Shen, Fanxia Zhan, Lei Kang, Shuai Zhang, Rui Zou, Dingquan Forsayeth, John Wu, Zhijian Colosi, Peter Su, Hua TI Intravenous Delivery of AAV9-CMV-sFLT1 Reduces the Severity of Brain Arteriovenous Malformation Without Causing Significant Side Effects in a Mouse Model SO MOLECULAR THERAPY LA English DT Meeting Abstract CT 18th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) CY MAY 13-16, 2015 CL New Orleans, LA SP Amer Soc Gene & Cell Therapy C1 [Zhu, Wan; Shen, Fanxia; Zhan, Lei; Kang, Shuai; Zhang, Rui; Zou, Dingquan; Su, Hua] Univ Calif San Francisco, Anesthesia & Perioperat Care, San Francisco, CA 94143 USA. [Forsayeth, John] Univ Calif San Francisco, Neurol Surg, San Francisco, CA 94143 USA. [Wu, Zhijian] NEI, Ocular Gene Therapy Core, NIH, Bethesda, MD 20892 USA. [Colosi, Peter] BioMarin Pharmaceut, Novato, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAY PY 2015 VL 23 SU 1 MA 385 BP S153 EP S153 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA CP5UY UT WOS:000359951700389 ER PT J AU Sworder, BJ Yoshizawa, S Mishra, PJ Cherman, N Kuznetsov, SA Merlino, G Balakumaran, A Robey, PG AF Sworder, Brian J. Yoshizawa, Sayuri Mishra, Prasun J. Cherman, Natasha Kuznetsov, Sergei A. Merlino, Glenn Balakumaran, Arun Robey, Pamela G. TI Molecular profile of clonal strains of human skeletal stem/progenitor cells with different potencies SO STEM CELL RESEARCH LA English DT Article ID MARROW STROMAL CELLS; MESENCHYMAL STEM-CELLS; HUMAN BONE-MARROW; IN-VIVO; EXPRESSION; RECEPTOR; FIBROBLASTS; NICHE; VITRO; GENE AB Bone marrow stromal cells (BMSCs, also known as bone marrow-derived mesenchymal stem cells) are fibroblastic reticular cells, a subset of which is composed of multipotent skeletal stem cells (SSCs). SSCs/BMSCs are able to recreate a bone/marrow organ in vivo. To determine differences between clonogenic multipotent SSCs and similarly clonogenic but non-multipotent BMSCs, we established single colony-derived strains (SCDSs, initiated by individual Colony Forming Unit-Fibroblasts) and determined their differentiation capacity by vivo transplantation. In this series of human SCDSs (N = 24), 20.8% formed fibrous tissue (F), 66.7% formed bone (B), and 12.5% formed a bone/marrow organ, and thus were multipotent (M). RNA isolated from 12 SCDSs just prior to transplantation was analyzed by microarray. Although highly similar, there was variability from one SCDS to another, and SCDSs did not strictly segregate into the three functional groups (F, B or M) by unsupervised hierarchical clustering. We then compared 3 F-SCDSs to 3 M-SCDSs that did segregate. Genes associated with skeletogenesis, osteoblastogeneis, hematopoiesis, and extracellular matrix were over-represented in M-SCDSs compared with F-SCDSs. These results highlight the heterogeneity of SSCs/BMSCs, even between functionally similar SCDSs, but also indicate that differences can be detected that may shed light on the character of the SSC. Published by Elsevier B.V. C1 [Sworder, Brian J.; Yoshizawa, Sayuri; Cherman, Natasha; Kuznetsov, Sergei A.; Balakumaran, Arun; Robey, Pamela G.] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Sworder, Brian J.] Boston Univ, Sch Med, Grad Program Mol Med, Boston, MA 02215 USA. [Mishra, Prasun J.; Merlino, Glenn] NCI, Lab Canc Biol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Robey, PG (reprint author), Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM probey@dir.nidcr.nih.gov RI Robey, Pamela/H-1429-2011; OI Robey, Pamela/0000-0002-5316-5576; Sworder, Brian/0000-0002-5902-5507 FU DIR, NIDCR [1ZIADE000380]; CCR, NCI [ZIABC008756] FX This work was supported by the DIR, NIDCR (1ZIADE000380), and by the CCR, NCI (ZIABC008756), both a part of the IRP, NIH, DHHS. We thank Zimmer for providing the HA/TCP ceramic particles, and Ms. Li Li for her outstanding histological technical assistance. NR 37 TC 5 Z9 5 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1873-5061 EI 1876-7753 J9 STEM CELL RES JI Stem Cell Res. PD MAY PY 2015 VL 14 IS 3 BP 297 EP 306 DI 10.1016/j.scr.2015.02.005 PG 10 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA CP6JR UT WOS:000359993400005 PM 25814434 ER PT J AU Pripuzova, NS Getie-Kebtie, M Grunseich, C Sweeney, C Malech, H Alterman, MA AF Pripuzova, Natalia S. Getie-Kebtie, Melkamu Grunseich, Christopher Sweeney, Colin Malech, Harry Alterman, Michail A. TI Development of a protein marker panel for characterization of human induced pluripotent stem cells (hiPSCs) using global quantitative proteome analysis SO STEM CELL RESEARCH LA English DT Article ID HUMAN PERIPHERAL-BLOOD; HUMAN SOMATIC-CELLS; IPS CELLS; EPIGENETIC MEMORY; ENERGY-METABOLISM; GENE-EXPRESSION; MS/MS ANALYSIS; STROMAL CELLS; HUMAN ES; GENERATION AB The emergence of new methods for reprogramming of adult somatic cells into induced pluripotent stem cells (iPSC) led to the development of new approaches in drug discovery and regenerative medicine. Investigation of the molecular mechanisms underlying the self-renewal, expansion and differentiation of human iPSC (hiPSC) should lead to improvements in the manufacture of safe and reliable cell therapy products. The goal of our study was qualitative and quantitative proteomic characterizations of hiPSC by means of electrospray ionization (ESI)-MSe and MALDI-TOF/TOF mass spectrometry (MS). Proteomes of hiPSCs of different somatic origins: fibroblasts and peripheral blood CD34(+) cells, reprogrammed by the same technique, were compared with the original somatic cells and hESC. Quantitative proteomic comparison revealed approximately 220 proteins commonly up-regulated in all three pluripotent stem cell lines compared to the primary cells. Expression of 21 proteins previously reported as pluripotency markers was up-regulated in both hiPSCs (8 were confirmed by Western blot). A number of novel candidate marker proteins with the highest fold-change difference between hiPSCs/hESC and somatic cells discovered by MS were confirmed by Western blot. A panel of 22 candidate marker proteins of hiPSC was developed and expression of these proteins was confirmed in 8 additional hiPSC lines. Published by Elsevier B.V. C1 [Pripuzova, Natalia S.; Getie-Kebtie, Melkamu; Alterman, Michail A.] US FDA, Tumor Vaccines & Biotechnol Branch, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Grunseich, Christopher] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Sweeney, Colin; Malech, Harry] NIAID, Lab Host Def, NIH, Bethesda, MD 20892 USA. RP Alterman, MA (reprint author), US FDA, Tumor Vaccines & Biotechnol Branch, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. EM Michail.Alterman@fda.hhs.gov OI Malech, Harry/0000-0001-5874-5775 NR 59 TC 1 Z9 1 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1873-5061 EI 1876-7753 J9 STEM CELL RES JI Stem Cell Res. PD MAY PY 2015 VL 14 IS 3 BP 323 EP 338 DI 10.1016/j.scr.2015.01.009 PG 16 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA CP6JR UT WOS:000359993400007 PM 25840413 ER PT J AU Ottenbacher, A Yu, M Moser, RP Phillips, SM Alfano, C Perna, FM AF Ottenbacher, Allison Yu, Mandi Moser, Richard P. Phillips, Siobhan M. Alfano, Catherine Perna, Frank M. TI Population Estimates of Meeting Strength Training and Aerobic Guidelines, by Gender and Cancer Survivorship Status: Findings From the Health Information National Trends Survey (HINTS) SO JOURNAL OF PHYSICAL ACTIVITY & HEALTH LA English DT Article DE exercise; chronic disease; resistance training; guidelines and recommendations ID BREAST-CANCER; PHYSICAL-ACTIVITY; EXERCISE; METAANALYSIS; LYMPHEDEMA; TRIAL; WOMEN AB Background: Evidence is building that strength training may reduce complications associated with cancer such as fatigue, muscle wasting, and lymphedema, particularly among breast and prostate cancer survivors. Population estimates are available for rates of aerobic physical activity; however, data on strength training in this population are limited. The objective of this study was to identify rates of meeting public health recommendations for strength training and aerobic activity among cancer survivors and individuals with no cancer history. Methods: Data from the Health Information National Trends Survey (HINTS), Iteration 4 Cycle 1 and Cycle 2 were combined to conduct the analyses. Missing data were imputed, and weighted statistical analyses were conducted in SAS. Results: The proportion of individuals meeting both strength training and aerobic guidelines were low for both cancer survivors and those without a history of cancer. The odds of meeting strength training guidelines were significantly lower for women with a history of any cancer except breast, compared with women with no history of cancer (OR: 0.70, 95% CI: 0.51-0.96). Conclusions: More work needs to be done to understand why women with cancers other than breast, may be less inclined to engage in aerobic physical activity and strength training. C1 [Ottenbacher, Allison] NCI, Sci Res & Technol Branch, Rockville, MD 20892 USA. [Yu, Mandi] NCI, Surveillance Res Program, Rockville, MD USA. [Moser, Richard P.; Perna, Frank M.] NCI, Behav Res Program, Rockville, MD USA. [Phillips, Siobhan M.; Alfano, Catherine] NCI, Off Canc Survivorship, Rockville, MD USA. RP Ottenbacher, A (reprint author), NCI, Sci Res & Technol Branch, Rockville, MD 20892 USA. EM allio34218@aol.com OI Ottenbacher, Allison/0000-0002-8974-5580 NR 24 TC 2 Z9 2 U1 0 U2 1 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 MAY PY 2015 VL 12 IS 5 BP 675 EP 679 DI 10.1123/jpah.2014-0003 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CO5DD UT WOS:000359178900012 PM 24834485 ER PT J AU Belcher, BR Moser, RP Dodd, KW Atienza, A Ballard-Barbash, R Berrigan, D AF Belcher, Britni R. Moser, Richard P. Dodd, Kevin W. Atienza, Audie Ballard-Barbash, Rachel Berrigan, David TI Self-Reported Versus Accelerometer-Measured Physical Activity and Biomarkers Among NHANES Youth SO JOURNAL OF PHYSICAL ACTIVITY & HEALTH LA English DT Article DE adolescent; measurement; metabolic health; physical activity assessment; survey research; cardiovascular health ID SEDENTARY BEHAVIOR; BODY-COMPOSITION; VISCERAL ADIPOSITY; CHILDREN; ADOLESCENTS; FITNESS; HEALTH; INTENSITY; EXERCISE; ASSOCIATIONS AB Background: Discrepancies in self-report and accelerometer-measured moderate-to-vigorous physical activity (MVPA) may influence relationships with obesity-related biomarkers in youth. Methods: Data came from 2003-2006 National Health and Nutrition Examination Surveys (NHANES) for 2174 youth ages 12 to 19. Biomarkers were: body mass index (BMI, kg/m(2)), BMI percentile, height and waist circumference (WC, cm), triceps and subscapular skinfolds (mm), systolic & diastolic blood pressure (BP, mmHg), high-density lipoprotein (HDL, mg/dL), total cholesterol (mg/dL), triglycerides (mg/dL), insulin (mu U/ml), C-reactive protein (mg/dL), and glycohemoglobin (%). In separate sex-stratified models, each biomarker was regressed on accelerometer variables [mean MVPA (min/day), nonsedentary counts, and MVPA bouts (mean min/day)] and self-reported MVPA. Covariates were age, race/ethnicity, SES, physical limitations, and asthma. Results: In boys, correlations between self-report and accelerometer MVPA were stronger (boys: r = 0.14-0.21; girls: r = 0.07-0.11; P < .010) and there were significant associations with BMI, WC, triceps skinfold, and SBP and accelerometer MVPA (P < .01). In girls, there were no significant associations between biomarkers and any measures of physical activity. Conclusions: Physical activity measures should be selected based on the outcome of interest and study population; however, associations between PA and these biomarkers appear to be weak regardless of the measure used. C1 [Belcher, Britni R.] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, Hlth Behav Res Branch,Behav Res Program, Bethesda, MD 20892 USA. [Moser, Richard P.; Atienza, Audie] NCI, Sci Res & Technol Branch, Behav Res Program, Bethesda, MD 20892 USA. [Dodd, Kevin W.] NCI, Biometry Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. [Ballard-Barbash, Rachel] NIH, Off Dis Prevent, Bethesda, MD 20892 USA. [Berrigan, David] NCI, Hlth Behav Res Branch, Behav Res Program, Bethesda, MD 20892 USA. RP Belcher, BR (reprint author), NCI, Canc Prevent Fellowship Program, Canc Prevent Div, Hlth Behav Res Branch,Behav Res Program, Bethesda, MD 20892 USA. EM belcherbr@mail.nih.gov FU Cancer Prevention Fellowship Program, Office of the Director, National Cancer Institute, National Institutes of Health FX The authors wish to thank Dr. James McClain for guidance on the accelerometer variables and Dr. Rick Troiano for his insight into the use of multiple measurement modalities in studies with biomarker outcomes. BRB and DB are responsible for the project concept. BRB and KWD conducted the main statistical analyses. RPM, AA and RB-B contributed to the statistical analyses and manuscript preparation. All authors were involved in writing the paper and had final approval of the submitted and published versions. The authors report no conflict of interest. The National Cancer Institute reviewed and approved this article before submission. The views and opinions expressed in this paper are those of the authors and not necessarily those of the National Institutes of Health, or the National Cancer Institute. Belcher was supported by the Cancer Prevention Fellowship Program, Office of the Director, National Cancer Institute, National Institutes of Health during the preparation of this paper. NR 46 TC 2 Z9 2 U1 2 U2 7 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 MAY PY 2015 VL 12 IS 5 BP 708 EP 716 DI 10.1123/jpah.2013-0193 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CO5DD UT WOS:000359178900017 PM 24909801 ER PT J AU Gennuso, KR Matthews, CE Colbert, LH AF Gennuso, Keith R. Matthews, Charles E. Colbert, Lisa H. TI Reliability and Validity of 2 Self-Report Measures to Assess Sedentary Behavior in Older Adults SO JOURNAL OF PHYSICAL ACTIVITY & HEALTH LA English DT Article DE aging; physical activity; sitting/standing ID PHYSICAL-ACTIVITY SURVEY; TYPE-2 DIABETES-MELLITUS; TELEVISION VIEWING TIME; PROSPECTIVE COHORT; DAY RECALL; US ADULTS; RISK; MORTALITY; HEALTH; CANCER AB Background: The purpose of this study was to examine the reliability and validity of 2 currently available physical activity surveys for assessing time spent in sedentary behavior (SB) in older adults. Methods: Fifty-eight adults (>= 65 years) completed the Yale Physical Activity Survey for Older Adults (YPAS) and Community Health Activities Model Program for Seniors (CHAMPS) before and after a 10-day period during which they wore an ActiGraph accelerometer (ACC). Intraclass correlation coefficients (ICC) examined test-retest reliability. Overall percent agreement and a kappa statistic examined YPAS validity. Lin's concordance correlation, Pearson correlation, and Bland-Altman analysis examined CHAMPS validity. Results: Both surveys had moderate test-retest reliability (ICC: YPAS = 0.59 (P < .001), CHAMPS = 0.64 (P < .001)) and significantly underestimated SB time. Agreement between YPAS and ACC was low (kappa = 0.0003); however, there was a linear increase (P < .01) in ACC-derived SB time across YPAS response categories. There was poor agreement between ACC-derived SB and CHAMPS (Lin's r = .005; 95% CI, -0.010 to 0.020), and no linear trend across CHAMPS quartiles (P = .53). Conclusions: Neither of the surveys should be used as the sole measure of SB in a study; though the YPAS has the ability to rank individuals, providing it with some merit for use in correlational SB research. C1 [Gennuso, Keith R.] Univ Wisconsin, Dept Populat Hlth Sci, Madison, WI 53706 USA. [Matthews, Charles E.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Colbert, Lisa H.] Univ Wisconsin, Dept Kinesiol, Madison, WI USA. RP Gennuso, KR (reprint author), Univ Wisconsin, Dept Populat Hlth Sci, Madison, WI 53706 USA. EM gennuso@wisc.edu FU National Institutes of Health [R21AG025839]; Graduate School, University of Wisconsin-Madison; Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS) [UL1TR000427] FX The present work benefited from the input of Dr. Ronald E. Gangnon who provided valuable assistance to the statistical analysis of the research summarized here, and from Heidi Walaski, Jeanne Stublaski, Barbara Woodhouse, Linda Harris, Howard Bailey, Brad Julius, Brent Johnson, Jaclyn Krupsky, and Aimee Mastrangelo, for assistance with the data collection and management. The project described was supported by R21AG025839 from the National Institutes of Health; the Graduate School, University of Wisconsin-Madison, and by the Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS), grant UL1TR000427. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. NR 48 TC 3 Z9 4 U1 3 U2 8 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 MAY PY 2015 VL 12 IS 5 BP 727 EP 732 DI 10.1123/jpah.2013-0546 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CO5DD UT WOS:000359178900019 PM 25110344 ER PT J AU Deter, RL Lee, W Sangi-Haghpeykar, H Tarca, AL Yeo, L Romero, R AF Deter, Russell L. Lee, Wesley Sangi-Haghpeykar, Haleh Tarca, Adi L. Yeo, Lami Romero, Roberto TI A modified prenatal growth assessment score for the evaluation of fetal growth in the third trimester using single and composite biometric parameters SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE Individualized growth assessment; pregnancy; Rossavik models; size standards ID FOR-GESTATIONAL-AGE; CUSTOMIZED BIRTH-WEIGHT; PERINATAL OUTCOMES; CURVE STANDARDS; FEMUR LENGTH; 3-DIMENSIONAL ULTRASONOGRAPHY; SONOGRAPHIC MEASUREMENTS; ULTRASOUND ESTIMATION; 3RD-TRIMESTER GROWTH; CONVENTIONAL METHODS AB Objective: To define modified Prenatal Growth Assessment Scores (mPGAS) for single and composite biometric parameters and determine their reference ranges in normal fetuses. Methods: Nine anatomical parameters (ap) were measured and the weight estimated (EWTa, EWTb) in a longitudinal study of 119 fetuses with normal neonatal growth outcomes. Expected third trimester size trajectories, obtained from second trimester Rossavik size models, were used in calculating Percent Deviations (% Dev's) and their age-specific reference ranges in each fetus. The components of individual % Dev's values outside their reference ranges, designated +iapPGAS, -iapPGAS, were averaged to give +apPGAS and -apPGAS values for the 3rd trimester. The +iapPGAS and -iapPGAS values for different combinations of ap (c1a (HC, AC, FDL, ThC, EWTa), c1b (NC, AC, FDL, ThC, EWTb), c2 (ThC, ArmC, AVol, TVol), c3 (NC, AC, FDL, EWTa)) were then averaged to give +icPGAS and -icPGAS values at different time points or at the end of the third trimester (+cPGAS, -cPGAS). Values for iapPGAS, ic1bPGAS, and ic2PGAS were compared to their respective apPGAS or cPGAS reference ranges. Results: All mPGAS values had one 95% range boundary at 0.0%. Upper boundaries of 1D +apPGAS values ranged from 0.0% (HC) to +0.49% (ThC) and were +0.06%, +2.3% and +1.8% for EWT, AVol and TVol, respectively. Comparable values for apPGAS were 0.0% (BPD, FDL, HDL), to -0.58% (ArmC), -0.13% (EWT), -0.8% (AVol), and 0.0% (TVol). The +cPGAS, 95% reference range upper boundaries varied from +0.36% (c1b) to +0.89% (c2). Comparable values for cPGAS lower boundaries were -0.17% (c1b) to -0.43% (c2). Conclusions: The original PGAS concept has now been extended to individual biometric parameters and their combinations. With the standards provided, mPGAS values can now be tested to see if detection of different types of third trimester growth problems is improved. C1 [Deter, Russell L.; Lee, Wesley; Sangi-Haghpeykar, Haleh] Baylor Coll Med, Dept Obstet & Gynecol, Houston, TX 77030 USA. [Lee, Wesley] Oakland Univ, Dept Obstet & Gynecol, William Beaumont Sch Med, Rochester, MI 48063 USA. [Lee, Wesley; Tarca, Adi L.; Yeo, Lami; Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Lee, Wesley; Tarca, Adi L.; Yeo, Lami] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Lee, Wesley; Tarca, Adi L.; Yeo, Lami] Wayne State Univ, Hutzel Hosp, Dept Obstet & Gynecol, Detroit, MI USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. RP Deter, RL (reprint author), Baylor Coll Med, Dept Obstet & Gynecol, One Baylor Plaza, Houston, TX 77030 USA. EM russelld@bcm.edu FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NH, DHHS FX This research was supported (in part) by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NH, DHHS. NR 133 TC 1 Z9 1 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1476-7058 EI 1476-4954 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD MAY PY 2015 VL 28 IS 7-8 BP 745 EP 754 DI 10.3109/14767058.2014.934218 PG 10 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CN8OT UT WOS:000358701200002 PM 24993892 ER PT J AU Deter, RL Lee, W Sangi-Haghpeykar, H Tarca, AL Yeo, L Romero, R AF Deter, Russell L. Lee, Wesley Sangi-Haghpeykar, Haleh Tarca, Adi L. Yeo, Lami Romero, Roberto TI Fetal growth cessation in late pregnancy: its impact on predicted size parameters used to classify small for gestational age neonates SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE Birth characteristic predictions; SGA subgroups; ultrasound ID UMBILICAL ARTERY DOPPLER; BIRTH-WEIGHT PREDICTION; CROWN-HEEL LENGTH; PERINATAL OUTCOMES; ASSESSMENT SCORE; CUSTOMIZED ASSESSMENT; CURVE STANDARDS; 3RD TRIMESTER; TERM; FETUSES AB Objective: To evaluate the impact of late 3rd trimester fetal growth cessation on anatomical birth characteristic predictions used in classifying SGA neonates. Methods: A prospective longitudinal study was performed in 119 pregnancies with normal neonatal growth outcomes. Seven biometric parameters were measured at 3-4 weeks intervals using 3D ultrasonography. Rossavik size models were determined to predict birth characteristics at different ages. Percent Differences (% Diff) were calculated from predicted and measured birth characteristics. Growth Cessation Ages (GCA) were identified when no systematic change in % Diff values occurred after specified prediction ages. Systematic and random prediction errors were compared using different assumptions about the GCA. Predicted and measured size parameters were used to determine six new Growth Potential Realization Index (GPRI) reference ranges. Five were used to sub-classify 34 SGA neonates (weight <10th percentile) based on the number of abnormal GPRI values. Results: Growth cessation ages were 38 weeks for HC, AC, mid-thigh circumference, estimated weight and mid-arm circumference. Crown-heel length GCA was 38.5 weeks. At GCA, birth characteristics had prediction errors that varied from 0.08 +/- 3.4% to 15.7 +/- 9.1% and zero % Diff slopes after 38 weeks. Assuming growth to delivery gave increased systematic and random prediction errors as well as positive % Diff slopes after 38 weeks, MA. Seventeen of the SGA neonates had 0 or 1 abnormal GPRI values [Subgroup 1] and 17 others had 2 or more abnormal values [Subgroup 2]. In Subgroup 1,4/85 (4.7%) of GPRI's were abnormal while in Subgroup 2, 43/85 (50.6%) were abnormal. Use of only one type of GPRI for SGA subclassification resulted in substantial false negative and some false positive rates when compared to subclassification based on all five GPRI values. Conclusions: Growth cessation occurred at approximately 38 weeks for all six birth characteristics studied. SGA neonates can be separated into normal and growth restricted subgroups based on the frequency of abnormal GPRI values (GPRI Profile Classification). C1 [Deter, Russell L.; Lee, Wesley; Sangi-Haghpeykar, Haleh] Baylor Coll Med, Dept Obstet & Gynecol, Houston, TX 77030 USA. [Lee, Wesley] Oakland Univ, William Beaumont Sch Med, Dept Obstet & Gynecol, Rochester, MI 48063 USA. [Lee, Wesley; Tarca, Adi L.; Yeo, Lami; Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Lee, Wesley; Tarca, Adi L.; Yeo, Lami; Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Lee, Wesley; Yeo, Lami] Wayne State Univ, Hutzel Hosp, Dept Obstet & Gynecol, Detroit, MI USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. RP Deter, RL (reprint author), Baylor Coll Med, Dept Obstet & Gynecol, One Baylor Plaza, Houston, TX 77030 USA. EM russelld@bcm.edu FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS FX This research was supported (in part) by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS. NR 67 TC 5 Z9 5 U1 0 U2 5 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1476-7058 EI 1476-4954 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD MAY PY 2015 VL 28 IS 7-8 BP 755 EP 765 DI 10.3109/14767058.2014.934219 PG 11 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CN8OT UT WOS:000358701200003 PM 24936858 ER PT J AU Asiedu, K Koyasu, S Szajek, L Choyke, P Sato, N AF Asiedu, Kingsley Koyasu, Sho Szajek, Lawrence Choyke, Pete Sato, Noriko TI Zr-89-oxine complex positron emission tomography (PET) visualizes trafficking of bone marrow (BM) cells in a mouse transplant model. SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract CT Annual Meeting of the Society-of-Nuclear-Medicine-and-Molecular-Imaging CY JUN 06-10, 2015 CL Baltimore, MD SP Soc Nucl Med & Mol Imaging C1 [Asiedu, Kingsley; Koyasu, Sho; Choyke, Pete; Sato, Noriko] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Szajek, Lawrence] NIH, PET Dept, CC, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD MAY 1 PY 2015 VL 56 IS 3 SU 3 MA 278 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CN9AU UT WOS:000358738800278 ER PT J AU Cortes, M Singh, P Morse, C Shrestha, S Jenko, K Kowalski, A Zoghbi, S Fujita, M Innis, R Pike, V AF Cortes, Michelle Singh, Prachi Morse, Cheryl Shrestha, Saurav Jenko, Kimberly Kowalski, Aneta Zoghbi, Sami Fujita, Masahiro Innis, Robert Pike, Victor TI Synthesis of PET radioligands as potential probes for imaging COX-2 in neuroinflammation SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract CT Annual Meeting of the Society-of-Nuclear-Medicine-and-Molecular-Imaging CY JUN 06-10, 2015 CL Baltimore, MD SP Soc Nucl Med & Mol Imaging C1 [Cortes, Michelle; Singh, Prachi; Morse, Cheryl; Shrestha, Saurav; Jenko, Kimberly; Kowalski, Aneta; Zoghbi, Sami; Fujita, Masahiro; Innis, Robert; Pike, Victor] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD MAY 1 PY 2015 VL 56 IS 3 SU 3 MA 1092 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CN9AU UT WOS:000358738802062 ER PT J AU Feng, T Ahlman, M Kolbitsch, C Guo, LH Tsui, B Bluemke, D AF Feng, Tao Ahlman, Mark Kolbitsch, Christoph Guo, Liheng Tsui, Benjamin Bluemke, David TI Comparison of MR and PET derived respiratory motion estimates for dual respiratory and cardiac motion correction in cardiac PET SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract CT Annual Meeting of the Society-of-Nuclear-Medicine-and-Molecular-Imaging CY JUN 06-10, 2015 CL Baltimore, MD SP Soc Nucl Med & Mol Imaging C1 [Feng, Tao; Guo, Liheng; Tsui, Benjamin] Johns Hopkins, Baltimore, MD USA. [Ahlman, Mark; Bluemke, David] NIH, Bethesda, MD 20892 USA. [Kolbitsch, Christoph] Kings Coll London, London WC2R 2LS, England. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD MAY 1 PY 2015 VL 56 IS 3 SU 3 MA 204 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CN9AU UT WOS:000358738800205 ER PT J AU Fujita, M Turtzo, LC Shenouda, C Fennell, E Rallis-Frutos, D Zoghbi, S Pike, V Innis, R Diaz-Arrastia, R Latour, L AF Fujita, Masahiro Turtzo, L. Christine Shenouda, Christian Fennell, Emily Rallis-Frutos, Denise Zoghbi, Sami Pike, Victor Innis, Robert Diaz-Arrastia, Ramon Latour, Lawrence TI Inflammation in brain parenchyma detected by PET imaging of translocator protein but not by MRI after traumatic brain injury and massive subdural hematoma SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract CT Annual Meeting of the Society-of-Nuclear-Medicine-and-Molecular-Imaging CY JUN 06-10, 2015 CL Baltimore, MD SP Soc Nucl Med & Mol Imaging C1 [Fujita, Masahiro; Fennell, Emily; Rallis-Frutos, Denise; Zoghbi, Sami; Pike, Victor; Innis, Robert] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. [Turtzo, L. Christine] NIH CC, Diagnost Radil, Bethesda, MD USA. [Shenouda, Christian] NIH CC, Phys Med Sect, Bethesda, MD USA. [Diaz-Arrastia, Ramon] Ctr Neurosci & Regenerat Med, Rockville, MD USA. [Latour, Lawrence] NINDS, Acute Stroke Res Sect, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD MAY 1 PY 2015 VL 56 IS 3 SU 3 MA 1611 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CN9AU UT WOS:000358738803231 ER PT J AU Giesel, F Fiedler, H Sterzing, F Flechsig, P Moltz, J Afshar-Oromieh, A Kopka, K Choyke, P Haberkorn, U Kratochwil, C AF Giesel, Frederik Fiedler, Hannah Sterzing, Florian Flechsig, Paul Moltz, Jan Afshar-Oromieh, Ali Kopka, Klaus Choyke, Pete Haberkorn, Uwe Kratochwil, Clemens TI 3D Volumetric lymph node assessment based on CT versus PSMA-PET/CT in recurrent prostate cancer SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract CT Annual Meeting of the Society-of-Nuclear-Medicine-and-Molecular-Imaging CY JUN 06-10, 2015 CL Baltimore, MD SP Soc Nucl Med & Mol Imaging C1 [Giesel, Frederik; Fiedler, Hannah; Afshar-Oromieh, Ali; Haberkorn, Uwe; Kratochwil, Clemens] Heidelberg Univ, Dept Nucl Med, Heidelberg, Germany. [Sterzing, Florian] Univ Heidelberg Hosp, Radiat Oncol, Heidelberg, Germany. [Flechsig, Paul] Univ Heidelberg Hosp, Diagnost & Intervent Radiol, Heidelberg, Germany. [Moltz, Jan] Fraunhofer MEVIS, Bremen, Germany. [Choyke, Pete] NIH, Bethesda, MD 20892 USA. [Kopka, Klaus] German Canc Res Ctr, Radiopharmaceut Chem, Heidelberg, Germany. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD MAY 1 PY 2015 VL 56 IS 3 SU 3 MA 1438 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CN9AU UT WOS:000358738803058 ER PT J AU Guo, N Zheng, K Wang, MD El Fakhri, G Li, F Chen, XY Zhu, ZH Li, QZ AF Guo, Ning Zheng, Kun Wang, Mengdie El Fakhri, Georges Li, Fang Chen, Xiaoyuan Zhu, Zhaohui Li, Quanzheng TI Whole-body Parametric Imaging of Lung Cancer Patients with Ga-68-PRGD2 SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract CT Annual Meeting of the Society-of-Nuclear-Medicine-and-Molecular-Imaging CY JUN 06-10, 2015 CL Baltimore, MD SP Soc Nucl Med & Mol Imaging C1 [Guo, Ning; Wang, Mengdie; El Fakhri, Georges; Li, Quanzheng] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Adv Med Imaging Sci,Radiol, Boston, MA USA. [Zheng, Kun; Li, Fang; Zhu, Zhaohui] Beijing Union Med Coll Hosp, Dept Nucl Med, Beijing, Peoples R China. [Chen, Xiaoyuan] NIBIB, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD MAY 1 PY 2015 VL 56 IS 3 SU 3 MA 122 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CN9AU UT WOS:000358738800123 ER PT J AU Huang, SY Liu, JM Yao, J Summers, R Seo, Y Lee, C AF Huang, Shih-ying Liu, Jiamin Yao, Jack Summers, Ronald Seo, Youngho Lee, Choonsik TI Internal Dosimetry Comparison between Computational Voxelized Human Phantoms and Patient-Specific CT images SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract CT Annual Meeting of the Society-of-Nuclear-Medicine-and-Molecular-Imaging CY JUN 06-10, 2015 CL Baltimore, MD SP Soc Nucl Med & Mol Imaging C1 [Huang, Shih-ying] Univ Calif San Francisco, Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Liu, Jiamin; Yao, Jack; Summers, Ronald; Seo, Youngho; Lee, Choonsik] NCI, Radiol & Imaging Sci, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 3 U2 3 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD MAY 1 PY 2015 VL 56 IS 3 SU 3 MA 106 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CN9AU UT WOS:000358738800107 ER PT J AU Ikawa, M Lohith, T Jenko, K Shrestha, S Telu, S Zoghbi, S Fujita, M Pike, V Innis, R AF Ikawa, Masamichi Lohith, Talakad Jenko, Kimberly Shrestha, Stal Telu, Sanjay Zoghbi, Sami Fujita, Masahiro Pike, Victor Innis, Robert TI Differential in vitro and in vivo sensitivity of [C-11]ER176 to a genetic polymorphism in the gene for translocator protein SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract CT Annual Meeting of the Society-of-Nuclear-Medicine-and-Molecular-Imaging CY JUN 06-10, 2015 CL Baltimore, MD SP Soc Nucl Med & Mol Imaging C1 [Ikawa, Masamichi; Lohith, Talakad; Jenko, Kimberly; Shrestha, Stal; Telu, Sanjay; Zoghbi, Sami; Fujita, Masahiro; Pike, Victor; Innis, Robert] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD MAY 1 PY 2015 VL 56 IS 3 SU 3 MA 489 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CN9AU UT WOS:000358738801140 ER PT J AU Jagoda, E Kuo, F Basuli, F Williams, M Wong, K Green, M Seidel, J Adler, S Xu, BY Choyke, P AF Jagoda, Elaine Kuo, Frank Basuli, Falguni Williams, Mark Wong, Karen Green, Michael Seidel, Jurgen Adler, Stephen Xu, Biying Choyke, Pete TI F-18-Albumin, a potential PET imaging agent to quantify tumor angiogenesis SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract CT Annual Meeting of the Society-of-Nuclear-Medicine-and-Molecular-Imaging CY JUN 06-10, 2015 CL Baltimore, MD SP Soc Nucl Med & Mol Imaging C1 [Jagoda, Elaine; Kuo, Frank; Williams, Mark; Wong, Karen; Green, Michael; Seidel, Jurgen; Adler, Stephen; Choyke, Pete] NCI, MIP, Bethesda, MD 20892 USA. [Basuli, Falguni; Xu, Biying] NHLBI, IPDC, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD MAY 1 PY 2015 VL 56 IS 3 SU 3 MA 1110 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CN9AU UT WOS:000358738802080 ER PT J AU Janssen, I Blanchet, E Chen, C Millo, C Herscovitch, P Taieb, D Kebebew, E Lehnert, H Fojo, A Pacak, K AF Janssen, Ingo Blanchet, Elise Chen, Clara Millo, Corina Herscovitch, Peter Taieb, David Kebebew, Electron Lehnert, Hendrik Fojo, Antonio Pacak, Karel TI Superiority of [Ga-68]-DOTATATE PET/CT to other functional imaging modalities in the localization of SDHB-associated metastatic pheochromocytoma and paraganglioma SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract CT Annual Meeting of the Society-of-Nuclear-Medicine-and-Molecular-Imaging CY JUN 06-10, 2015 CL Baltimore, MD SP Soc Nucl Med & Mol Imaging C1 [Janssen, Ingo; Pacak, Karel] NICHD, NIH, Bethesda, MD USA. [Blanchet, Elise] Hop Xavier Bichat, Dept Nucl Med, Paris, France. [Millo, Corina; Herscovitch, Peter] NIH, PET Dept, Bethesda, MD 20892 USA. [Taieb, David] La Timone Univ Hosp, Dept Nucl Med, Marseille, France. [Kebebew, Electron] NCI, Endocrine Oncol Branch, Bethesda, MD 20892 USA. [Lehnert, Hendrik] Univ Hosp Schleswig Holstein, Dept Internal Med 1, Lubeck, Germany. [Fojo, Antonio] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Chen, Clara] NIH, Div Nucl Med, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD MAY 1 PY 2015 VL 56 IS 3 SU 3 MA 265 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CN9AU UT WOS:000358738800265 ER PT J AU Kim, H Lee, SJ Davies-Venn, C Kim, JS Dejene, E Yao, ZS Kim, I Paik, C Bluemke, D AF Kim, Heejung Lee, Sung-Jin Davies-Venn, Cynthia Kim, Jin Su Dejene, Eden Yao, Zhengsheng Kim, Insook Paik, Chang Bluemke, David TI Cu-64-DOTA as a surrogate positron analog of Gd-DOTA for cardiac fibrosis detection in a rat model of chronic MI. SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract CT Annual Meeting of the Society-of-Nuclear-Medicine-and-Molecular-Imaging CY JUN 06-10, 2015 CL Baltimore, MD SP Soc Nucl Med & Mol Imaging C1 [Kim, Heejung; Lee, Sung-Jin; Davies-Venn, Cynthia; Kim, Jin Su; Dejene, Eden; Yao, Zhengsheng; Paik, Chang; Bluemke, David] NIH, RAD&IS Clin Ctr, Bethesda, MD 20892 USA. [Kim, Insook] Leidos Biomed Res Inc, ADRD, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD MAY 1 PY 2015 VL 56 IS 3 SU 3 MA 1472 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CN9AU UT WOS:000358738803092 ER PT J AU Kobayashi, M Jenko, K Zoghbi, S Lohith, T Rallis-Frutos, D Page, E Ikawa, M Pike, V Innis, R Fujita, M AF Kobayashi, Masato Jenko, Kimberly Zoghbi, Sami Lohith, Talakad Rallis-Frutos, Denise Page, Emily Ikawa, Masamichi Pike, Victor Innis, Robert Fujita, Masahiro TI Blockade of translocator protein (TSPO) to measure specific binding of C-11-(R)-PK 11195 in human brain SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract CT Annual Meeting of the Society-of-Nuclear-Medicine-and-Molecular-Imaging CY JUN 06-10, 2015 CL Baltimore, MD SP Soc Nucl Med & Mol Imaging C1 [Kobayashi, Masato; Jenko, Kimberly; Zoghbi, Sami; Lohith, Talakad; Rallis-Frutos, Denise; Page, Emily; Ikawa, Masamichi; Pike, Victor; Innis, Robert; Fujita, Masahiro] NIMH, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD MAY 1 PY 2015 VL 56 IS 3 SU 3 MA 467 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CN9AU UT WOS:000358738801118 ER PT J AU Kreisl, W Lyoo, CH Wei, M Snow, J Jenko, K Morse, C Zoghbi, S Pike, V Turner, R Innis, R AF Kreisl, William Lyoo, Chul Hyoung Wei, Monica Snow, Joseph Jenko, Kimberly Morse, Cheryl Zoghbi, Sami Pike, Victor Turner, Raymond Innis, Robert TI Radioligand binding to translocator protein increases with Alzheimer's disease progression but not healthy aging SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract CT Annual Meeting of the Society-of-Nuclear-Medicine-and-Molecular-Imaging CY JUN 06-10, 2015 CL Baltimore, MD SP Soc Nucl Med & Mol Imaging C1 [Kreisl, William; Lyoo, Chul Hyoung; Wei, Monica; Jenko, Kimberly; Morse, Cheryl; Zoghbi, Sami; Pike, Victor; Innis, Robert] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. [Snow, Joseph] NIMH, Off Clin Director, Bethesda, MD 20892 USA. [Turner, Raymond] Georgetown Univ, Memory Disorders Program, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD MAY 1 PY 2015 VL 56 IS 3 SU 3 MA 246 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CN9AU UT WOS:000358738800246 ER PT J AU Kreisl, W Lyoo, CH Ikawa, M Liow, JS Zoghbi, S Morse, C Pike, V Fujita, M Innis, R AF Kreisl, William Lyoo, Chul Hyoung Ikawa, Masamichi Liow, Jeih-San Zoghbi, Sami Morse, Cheryl Pike, Victor Fujita, Masahiro Innis, Robert TI Ratio method for C-11-PBR28 detects increase in translocator protein binding in Alzheimer's disease SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract CT Annual Meeting of the Society-of-Nuclear-Medicine-and-Molecular-Imaging CY JUN 06-10, 2015 CL Baltimore, MD SP Soc Nucl Med & Mol Imaging C1 [Kreisl, William; Lyoo, Chul Hyoung; Ikawa, Masamichi; Liow, Jeih-San; Zoghbi, Sami; Morse, Cheryl; Pike, Victor; Fujita, Masahiro; Innis, Robert] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD MAY 1 PY 2015 VL 56 IS 3 SU 3 MA 250 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CN9AU UT WOS:000358738800250 ER PT J AU Lee, D Hammoud, D Muthusamy, S Di Mascio, M Matsuda, K AF Lee, Dianne Hammoud, Dima Muthusamy, Siva Di Mascio, Michele Matsuda, Kenta TI Dynamic changes of serotonin transporter expression in SIV Infected macaques before and after treatment SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract CT Annual Meeting of the Society-of-Nuclear-Medicine-and-Molecular-Imaging CY JUN 06-10, 2015 CL Baltimore, MD SP Soc Nucl Med & Mol Imaging C1 [Lee, Dianne; Hammoud, Dima; Muthusamy, Siva; Di Mascio, Michele; Matsuda, Kenta] NIH, Radiol & Imaging Sci, Bethesda, MD 20892 USA. 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SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract CT Annual Meeting of the Society-of-Nuclear-Medicine-and-Molecular-Imaging CY JUN 06-10, 2015 CL Baltimore, MD SP Soc Nucl Med & Mol Imaging C1 [Sato, Noriko; Choyke, Pete] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Hoyt, Robert] NCI, LASP, Biomed Res, FNLCR, Frederick, MD 21701 USA. [Davidson-Moncada, Jan] NHLBI, Ctr Human Immunol, NIH, Bethesda, MD 20892 USA. [Reger, Robert; Clevenger, Randy; Childs, Richard] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Szajek, Lawrence] NIH, PET Dept, CC, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD MAY 1 PY 2015 VL 56 IS 3 SU 3 MA 225 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CN9AU UT WOS:000358738800225 ER PT J AU Singh, P Cortes, M Morse, C Jenko, K Shrestha, S Zoghbi, S Gladding, R Fujita, M Innis, R Pike, V AF Singh, Prachi Cortes, Michelle Morse, Cheryl Jenko, Kimberly Shrestha, Saurav Zoghbi, Sami Gladding, Robert Fujita, Masahiro Innis, Robert Pike, Victor TI [F-18]PS-2 as a candidate radioligand for imaging COX-1 expression in brain: radiosynthesis and monkey PET imaging SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract CT Annual Meeting of the Society-of-Nuclear-Medicine-and-Molecular-Imaging CY JUN 06-10, 2015 CL Baltimore, MD SP Soc Nucl Med & Mol Imaging C1 [Singh, Prachi; Cortes, Michelle; Morse, Cheryl; Jenko, Kimberly; Shrestha, Saurav; Zoghbi, Sami; Gladding, Robert; Fujita, Masahiro; Innis, Robert; Pike, Victor] NIMH, NIH, Bethesda, MD 20892 USA. 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NR 0 TC 0 Z9 0 U1 0 U2 0 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD MAY 1 PY 2015 VL 56 IS 3 SU 3 MA 477 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CN9AU UT WOS:000358738801128 ER PT J AU Dummer, PD Limou, S Rosenberg, AZ Heymann, J Nelson, G Winkler, CA Kopp, JB AF Dummer, Patrick D. Limou, Sophie Rosenberg, Avi Z. Heymann, Jurgen Nelson, George Winkler, Cheryl A. Kopp, Jeffrey B. TI APOL1 Kidney Disease Risk Variants: An Evolving Landscape SO SEMINARS IN NEPHROLOGY LA English DT Review DE Health disparities; chronic kidney disease; focal segmental glomerulosclerosis; innate immunity; APOL1 ID TRYPANOSOME LYTIC FACTOR; APOLIPOPROTEIN-L GENE; HIV-ASSOCIATED NEPHROPATHY; PROTEIN FAMILIES DATABASE; TRYPANOLYTIC FACTOR APOL1; HIGH-DENSITY-LIPOPROTEIN; LIPID-BINDING PROTEIN; AUTOPHAGIC CELL-DEATH; STAGE RENAL-DISEASE; AFRICAN-AMERICANS AB Apolipoprotein L1 (APOL1) genetic variants account for much of the excess risk of chronic and end-stage kidney disease, which results in a significant global health disparity for persons of African ancestry. We estimate the lifetime risk of kidney disease in APOL1 dual-risk allele individuals to be at least 15%. Experimental evidence suggests a direct role of APOL1 in pore formation, cellular injury, and programmed cell death in renal injury. The APOL1 BH3 motif, often associated with cell death, is unlikely to play a role in APOL1-induced cytotoxicity because it is not conserved within the APOL family and is dispensable for cell death in vitro. We discuss two models for APOL1 trypanolytic activity: one involving lysosome permeabilization and another involving colloidosmotic swelling of the cell body, as well as their relevance to human pathophysiology. Experimental evidence from human cell culture models suggests that both mechanisms may be operative. A systems biology approach whereby APOL1-associated perturbations in gene and protein expression in affected individuals are correlated with molecular pathways may be productive to elucidate APOL1 function in vivo. Published by Elsevier Inc. C1 [Dummer, Patrick D.; Rosenberg, Avi Z.; Heymann, Jurgen; Kopp, Jeffrey B.] NIDDK, NIH, Kidney Dis Branch, Bethesda, MD USA. [Limou, Sophie; Nelson, George; Winkler, Cheryl A.] NCI, Ctr Canc Res, Mol Epidemiol Genet Sect, Frederick, MD 21701 USA. [Rosenberg, Avi Z.] Johns Hopkins Univ, Dept Pathol, Baltimore, MD USA. RP Kopp, JB (reprint author), NIH, 10 Ctr Dr,3NI16, Bethesda, MD 20892 USA. EM jeffreyk@intra.niddk.nih.gov OI Rosenberg, Avi/0000-0003-2356-950X FU National Cancer Institute, National Institutes of Health [HHSN26120080001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; Intramural Research Programs of the NIDDK, NIH 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 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 U.S. Government. This work was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This work was supported in part by the Intramural Research Programs of the NIDDK, NIH. NR 110 TC 10 Z9 10 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0270-9295 EI 1558-4488 J9 SEMIN NEPHROL JI Semin. Nephrol. PD MAY PY 2015 VL 35 IS 3 BP 222 EP 236 DI 10.1016/j.semnephrol.2015.04.008 PG 15 WC Urology & Nephrology SC Urology & Nephrology GA CO0AV UT WOS:000358813400003 PM 26215860 ER PT J AU Nast, CC Lemley, KV Hodgin, JB Bagnasco, S Avila-Casado, C Hewitt, SM Barisoni, L AF Nast, Cynthia C. Lemley, Kevin V. Hodgin, Jeffrey B. Bagnasco, Serena Avila-Casado, Carmen Hewitt, Stephen M. Barisoni, Laura TI Morphology in the Digital Age: Integrating High-Resolution Description of Structural Alterations With Phenotypes and Genotypes SO SEMINARS IN NEPHROLOGY LA English DT Review DE Digital pathology; whole slide imaging; virtual slide; virtual microscopy; NEPTUNE; renal pathology; glomerulus ID CONGENITAL NEPHROTIC SYNDROME; VIRTUAL MICROSCOPY; SEGMENTAL GLOMERULOSCLEROSIS; STEROID-RESISTANT; NETWORK NEPTUNE; PATHOLOGY; CLASSIFICATION; GLOMERULONEPHRITIS; NEPHROPATHY; MUTATIONS AB Conventional light microscopy has been used to characterize and classify renal diseases, evaluate histopathology in studies and trials, and educate renal pathologists and nephrologists. The advent of digital pathology, in which a glass slide can be scanned to create whole slide images (WSIs) for viewing and manipulating on a computer monitor, provides real and potential advantages compared with conventional light microscopy. Software tools such as annotation, morphometry, and image analysis can be applied to WSIs for studies or educational purposes, and the digital images are available globally to clinicians, pathologists, and investigators. New ways of assessing renal pathology with observational data collection may allow better morphologic correlations and integration with molecular and genetic signatures, refinements of classification schema, and understanding of disease pathogenesis. In multicenter studies, WSIs, which require additional quality assurance steps, provide efficiency by reducing slide shipping and consensus conference costs, and they allow slide viewing anytime and anywhere. Although validation studies for the routine diagnostic use of digital pathology still are needed, this is a powerful tool currently available for translational research, clinical trials, and education in renal pathology. (C) 2015 Elsevier Inc. All rights reserved. C1 [Nast, Cynthia C.] Cedars Sinai Med Ctr, Dept Pathol, Los Angeles, CA 90048 USA. [Lemley, Kevin V.] Childrens Hosp Los Angeles, Div Nephrol, Los Angeles, CA 90027 USA. [Hodgin, Jeffrey B.] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Bagnasco, Serena] Johns Hopkins Univ, Med Ctr, Dept Pathol, Baltimore, MD 21218 USA. [Avila-Casado, Carmen] Univ Toronto, Dept Pathol, Toronto, ON, Canada. [Hewitt, Stephen M.] NCI, Expt Pathol Lab, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Barisoni, Laura] Univ Miami, Dept Pathol, Miami, FL USA. RP Barisoni, L (reprint author), Univ Miami Hlth Syst, Dept Pathol, 1611 NW 12th Ave, Miami, FL 33136 USA. EM LBarisoni@med.miami.edu OI Hewitt, Stephen/0000-0001-8283-1788 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; Nephrotic Syndrome Study Network Consortium (NEPTUNE), National Institutes of Health Rare Disease Clinical Research Network [U54-DK-083912]; Office of Rare Diseases Research; National Center for Advancing Translational Science; National Institute of Diabetes and Digestive and Kidney Diseases FX Supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and by the Nephrotic Syndrome Study Network Consortium (NEPTUNE; U54-DK-083912), which is part of the National Institutes of Health Rare Disease Clinical Research Network, which is supported through a collaboration between the Office of Rare Diseases Research, National Center for Advancing Translational Science, and the National Institute of Diabetes and Digestive and Kidney Diseases. NR 46 TC 4 Z9 4 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0270-9295 EI 1558-4488 J9 SEMIN NEPHROL JI Semin. Nephrol. PD MAY PY 2015 VL 35 IS 3 BP 266 EP 278 DI 10.1016/j.semnephrol.2015.04.006 PG 13 WC Urology & Nephrology SC Urology & Nephrology GA CO0AV UT WOS:000358813400007 PM 26215864 ER PT J AU Wexler, L Chandler, M Gone, JP Cwik, M Kirmayer, LJ LaFromboise, T Brockie, T O'Keefe, V Walkup, J Allen, J AF Wexler, Lisa Chandler, Michael Gone, Joseph P. Cwik, Mary Kirmayer, Laurence J. LaFromboise, Teresa Brockie, Teresa O'Keefe, Victoria Walkup, John Allen, James TI Advancing Suicide Prevention Research With Rural American Indian and Alaska Native Populations SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID INUPIAT YOUTH SUICIDE; MENTAL-HEALTH; PROTECTIVE-FACTORS; INDIGENOUS COMMUNITIES; SUBSTANCE-ABUSE; PUBLIC-HEALTH; ALCOHOL-ABUSE; HELP-SEEKING; ADOLESCENTS; RISK AB As part of the National Action Alliance for Suicide Prevention's American Indian and Alaska Native (AI/AN) Task Force, a multidisciplinary group of AI/AN suicide research experts convened to outline pressing issues related to this subfield of suicidology. Suicide disproportionately affects Indigenous peoples, and remote Indigenous communities can offer vital and unique insights with relevance to other rural and marginalized groups. Outcomes from this meeting include identifying the central challenges impeding progress in this subfield and a description of promising research directions to yield practical results. These proposed directions expand the alliance's prioritized research agenda and offer pathways to advance the field of suicide research in Indigenous communities and beyond. C1 [Wexler, Lisa] Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Dept Hlth Promot & Policy Community Hlth Educ, Amherst, MA 01003 USA. [Chandler, Michael] Univ British Columbia, Dept Psychol, Vancouver, BC V5Z 1M9, Canada. [Gone, Joseph P.] Univ Michigan, Dept Psychol, Ann Arbor, MI USA. [Gone, Joseph P.] Univ Michigan, Dept Amer Culture, Ann Arbor, MI USA. [Cwik, Mary] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Div Social & Behav Intervent, Baltimore, MD USA. [Kirmayer, Laurence J.] McGill Univ, Dept Psychiat, Div Social & Transcultural Psychiat, Montreal, PQ, Canada. [LaFromboise, Teresa] Stanford Grad Sch Educ, Stanford, CA USA. [Brockie, Teresa] NIH, Ctr Clin, Nursing Res & Translat Sci, Bethesda, MD 20892 USA. [O'Keefe, Victoria] Oklahoma State Univ, Dept Clin Psychol, Stillwater, OK 74078 USA. [Walkup, John] Weill Cornell Med Coll, Dept Psychiat, New York, NY USA. [Allen, James] Univ Minnesota, Sch Med, Dept Biobehav Hlth & Populat Sci, Minneapolis, MN 55455 USA. RP Wexler, L (reprint author), Univ Massachusetts, 715 North Pleasant St, Amherst, MA 01003 USA. EM lwexler@schoolph.umass.edu OI Kirmayer, Laurence/0000-0002-6228-1739 FU NIAAA NIH HHS [R01 AA023754] NR 105 TC 11 Z9 11 U1 3 U2 30 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD MAY PY 2015 VL 105 IS 5 BP 891 EP 899 DI 10.2105/AJPH.2014.302517 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CN3AN UT WOS:000358295600031 PM 25790403 ER PT J AU Mensah, GA Kiley, J Mockrin, SC Lauer, M Hoots, WK Patel, Y Cook, NL Patterson, AP Gibbons, GH AF Mensah, George A. Kiley, James Mockrin, Stephen C. Lauer, Michael Hoots, W. Keith Patel, Yasin Cook, Nakela L. Patterson, Amy P. Gibbons, Gary H. TI National Heart, Lung, and Blood Institute Strategic Visioning: Setting an Agenda Together for the NHLBI of 2025 SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material ID DISEASE C1 [Mensah, George A.; Kiley, James; Mockrin, Stephen C.; Lauer, Michael; Hoots, W. Keith; Patel, Yasin; Cook, Nakela L.; Patterson, Amy P.; Gibbons, Gary H.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Mensah, GA (reprint author), NHLBI, Ctr Translat Res & Implementat Sci, NIH, One Rockledge Ctr,Room 6070,6705 Rockledge Dr, Bethesda, MD 20892 USA. EM george.mensah@nih.gov NR 15 TC 5 Z9 5 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD MAY PY 2015 VL 105 IS 5 BP E25 EP E28 DI 10.2105/AJPH.2015.302605 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CN3AN UT WOS:000358295600011 PM 25723452 ER PT J AU Sharma, S Kho, AT Chhabra, D Qiu, WL Gaedigk, R Vyhlidal, CA Leeder, JS Barraza-Villarreal, A London, SJ Gilliland, F Raby, BA Weiss, ST Tantisira, KG AF Sharma, Sunita Kho, Alvin T. Chhabra, Divya Qiu, Weiliang Gaedigk, Roger Vyhlidal, Carrie A. Leeder, J. Steven Barraza-Villarreal, Albino London, Stephanie J. Gilliland, Frank Raby, Benjamin A. Weiss, Scott T. Tantisira, Kelan G. TI Glucocorticoid Genes and the Developmental Origins of Asthma Susceptibility and Treatment Response SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article DE glucocorticoid genes; lung development; asthma; asthma treatment ID HUMAN-FETAL LUNG; ANTENATAL STEROID-THERAPY; SMOOTH-MUSCLE-CELLS; IN-VITRO; II CELLS; INHALED CORTICOSTEROIDS; PRETERM DELIVERY; CHILDHOOD ASTHMA; EXPRESSION; MATURATION AB Antenatal corticosteroids enhance lung maturation. However, the importance of glucocorticoid genes on early lung development, asthma susceptibility, and treatment response remains unknown. We investigated whether glucocorticoid genes are important during lung development and their role in asthma susceptibility and treatment response. We identified genes that were differentially expressed by corticosteroids in two of three genomic datasets: lymphoblastoid cell lines of participants in the Childhood Asthma Management Program, a glucocorticoid chromatin immunoprecipitation/RNA sequencing experiment, or a murine model; these genes made up the glucocorticoid gene set (GCGS). Using gene expression profiles from 38 human fetal lungs and C57BL/6J murine fetal lungs, we identified developmental genes that were in the top 5% of genes contributing to the top three principal components (PCs) most highly associated with post-conceptional age. Glucocorticoid genes that were enriched in this set of developmental genes were then included in the developmental glucocorticoid gene set (DGGS). We then investigated whether glucocorticoid genes are important during lung development, and their role in asthma susceptibility and treatment response. A total of 232 genes were included in the GCGS. Analysis of gene expression demonstrated that glucocorticoid genes were enriched in lung development (P = 7.02 x 10(-26)). The developmental GCGS was enriched for genes that were differentially expressed between subjects with asthma and control subjects (P = 4.26 x 10(-3)) and were enriched after treatment of subjects with asthma with inhaled corticosteroids (P < 2.72 x 10(-4)). Our results show that glucocorticoid genes are overrepresented among genes implicated in fetal lung development. These genes influence asthma susceptibility and treatment response, suggesting their involvement in the early ontogeny of asthma. C1 [Sharma, Sunita; Kho, Alvin T.; Chhabra, Divya; Qiu, Weiliang; Raby, Benjamin A.; Weiss, Scott T.; Tantisira, Kelan G.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Sharma, Sunita; Raby, Benjamin A.; Tantisira, Kelan G.] Brigham & Womens Hosp, Div Pulm & Crit Care Med, Boston, MA 02115 USA. [Gaedigk, Roger; Vyhlidal, Carrie A.; Leeder, J. Steven] Childrens Mercy Hosp & Clin, Kansas City, MO USA. [Barraza-Villarreal, Albino] Natl Inst Publ Hlth, Cuernavaca, Morelos, Mexico. [London, Stephanie J.] NIEHS, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Gilliland, Frank] Univ So Calif, Keck Sch Med, Preventat Med, Los Angeles, CA 90033 USA. RP Sharma, S (reprint author), Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. EM sunita.sharma@channing.harvard.edu OI London, Stephanie/0000-0003-4911-5290 FU National Heart, Lung, and Blood Institute, National Institutes of Health (NIH/NHLBI) [R01 HL097144, R01 HL092197, U01 HL065899, R01 HL086601, RC2 HL101543]; NIH/NHLBI [K08 HL096833]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [ZIA ES049019]; [K25 HL091124] FX This work is supported by grant R01 HL097144, R01 HL092197, U01 HL065899 from the National Heart, Lung, and Blood Institute, National Institutes of Health (NIH/NHLBI). The Asthma BRIDGE work was supported by R01 HL086601 and RC2 HL101543 from the National Heart, Lung, and Blood Institute, National Institutes of Health (NIH/NHLBI). S.S. receives additional support from K08 HL096833 from NIH/NHLBI. A.T.K. receives support from support from K25 HL091124. S.J.L. is supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (ZIA ES049019). NR 47 TC 4 Z9 4 U1 0 U2 10 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 MAY PY 2015 VL 52 IS 5 BP 543 EP 553 DI 10.1165/rcmb.2014-0109OC PG 11 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA CN2DH UT WOS:000358230200003 PM 25192440 ER PT J AU Gordon, EB Hart, GT Tran, TM Waisberg, M Akkaya, M Skinner, J Zinocker, S Pena, M Yazew, T Qi, CF Miller, LH Pierce, SK AF Gordon, Emile B. Hart, Geoffrey T. Tran, Tuan M. Waisberg, Michael Akkaya, Munir Skinner, Jeff Zinoecker, Severin Pena, Mirna Yazew, Takele Qi, Chen-Feng Miller, Louis H. Pierce, Susan K. TI Inhibiting the Mammalian Target of Rapamycin Blocks the Development of Experimental Cerebral Malaria SO MBIO LA English DT Article ID BLOOD-BRAIN-BARRIER; CD8(+) T-CELLS; AFRICAN CHILDREN; PARASITE SEQUESTRATION; FALCIPARUM-MALARIA; HEME OXYGENASE-1; PATHOGENESIS; EXPRESSION; ACCUMULATION; INDUCTION AB Malaria is an infectious disease caused by parasites of several Plasmodium spp. Cerebral malaria (CM) is a common form of severe malaria resulting in nearly 700,000 deaths each year in Africa alone. At present, there is no adjunctive therapy for CM. Although the mechanisms underlying the pathogenesis of CM are incompletely understood, it is likely that both intrinsic features of the parasite and the human host's immune response contribute to disease. The kinase mammalian target of rapamycin (mTOR) is a central regulator of immune responses, and drugs that inhibit the mTOR pathway have been shown to be antiparasitic. In a mouse model of CM, experimental CM (ECM), we show that the mTOR inhibitor rapamycin protects against ECM when administered within the first 4 days of infection. Treatment with rapamycin increased survival, blocked breakdown of the blood-brain barrier and brain hemorrhaging, decreased the influx of both CD4(+) and CD8(+) T cells into the brain and the accumulation of parasitized red blood cells in the brain. Rapamycin induced marked transcriptional changes in the brains of infected mice, and analysis of transcription profiles predicted that rapamycin blocked leukocyte trafficking to and proliferation in the brain. Remarkably, animals were protected against ECM even though rapamycin treatment significantly increased the inflammatory response induced by infection in both the brain and spleen. These results open a new avenue for the development of highly selective adjunctive therapies for CM by targeting pathways that regulate host and parasite metabolism. IMPORTANCE Malaria is a highly prevalent infectious disease caused by parasites of several Plasmodium spp. Malaria is usually uncomplicated and resolves with time; however, in about 1% of cases, almost exclusively among young children, malaria becomes severe and life threatening, resulting in nearly 700,000 deaths each year in Africa alone. Among the most severe complications of Plasmodium falciparum infection is cerebral malaria with a fatality rate of 15 to 20%, despite treatment with antimalarial drugs. Cerebral malaria takes a second toll on African children, leaving survivors at high risk of debilitating neurological defects. At present, we have no effective adjunctive therapies for cerebral malaria, and developing such therapies would have a large impact on saving young lives in Africa. Here we report results that open a new avenue for the development of highly selective adjunctive therapies for cerebral malaria by targeting pathways that regulate host and parasite metabolism. C1 [Gordon, Emile B.; Hart, Geoffrey T.; Tran, Tuan M.; Waisberg, Michael; Akkaya, Munir; Skinner, Jeff; Zinoecker, Severin; Pena, Mirna; Yazew, Takele; Qi, Chen-Feng; Pierce, Susan K.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Miller, Louis H.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. RP Pierce, SK (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM spierce@nih.gov OI Skinner, Jeff/0000-0001-5697-0442; AKKAYA, Munir/0000-0002-9949-9424 FU National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This study was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 46 TC 4 Z9 4 U1 2 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD MAY-JUN PY 2015 VL 6 IS 3 AR e00725-15 DI 10.1128/mBio.00725-15 PG 17 WC Microbiology SC Microbiology GA CM7JH UT WOS:000357867400075 PM 26037126 ER PT J AU He, SS Hickman, AB Varani, AM Siguier, P Chandler, M Dekker, JP Dyda, F AF He, Susu Hickman, Alison Burgess Varani, Alessandro M. Siguier, Patricia Chandler, Michael Dekker, John P. Dyda, Fred TI Insertion Sequence IS26 Reorganizes Plasmids in Clinically Isolated Multidrug-Resistant Bacteria by Replicative Transposition SO MBIO LA English DT Article ID COMPLETE NUCLEOTIDE-SEQUENCE; SPECTRUM BETA-LACTAMASE; MOBILE GENETIC ELEMENT; NEW-YORK HOSPITALS; ESCHERICHIA-COLI; KLEBSIELLA-PNEUMONIAE; BLA(KPC) GENE; FUNCTIONAL-CHARACTERIZATION; ACINETOBACTER-BAUMANNII; PROKARYOTIC GENOMES AB Carbapenemase-producing Enterobacteriaceae (CPE), which are resistant to most or all known antibiotics, constitute a global threat to public health. Transposable elements are often associated with antibiotic resistance determinants, suggesting a role in the emergence of resistance. One insertion sequence, IS26, is frequently associated with resistance determinants, but its role remains unclear. We have analyzed the genomic contexts of 70 IS26 copies in several clinical and surveillance CPE isolates from the National Institutes of Health Clinical Center. We used target site duplications and their patterns as guides and found that a large fraction of plasmid reorganizations result from IS26 replicative transpositions, including replicon fusions, DNA inversions, and deletions. Replicative transposition could also be inferred for transposon Tn4401, which harbors the carbapenemase bla(KPC) gene. Thus, replicative transposition is important in the ongoing reorganization of plasmids carrying multidrug-resistant determinants, an observation that carries substantial clinical and epidemiological implications for understanding how such extreme drug resistance phenotypes evolve. IMPORTANCE Although IS26 is frequently reported to reside in resistance plasmids of clinical isolates, the characteristic hallmark of transposition, target site duplication (TSD), is generally not observed, raising questions about the mode of transposition for IS26. The previous observation of cointegrate formation during transposition implies that IS26 transposes via a replicative mechanism. The other possible outcome of replicative transposition is DNA inversion or deletion, when transposition occurs intramolecularly, and this would also generate a specific TSD pattern that might also serve as supporting evidence for the transposition mechanism. The numerous examples we present here demonstrate that replicative transposition, used by many mobile elements (including IS26 and Tn4401), is prevalent in the plasmids of clinical isolates and results in significant plasmid reorganization. This study also provides a method to trace the evolution of resistance plasmids based on TSD patterns. C1 [He, Susu; Hickman, Alison Burgess; Dyda, Fred] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Varani, Alessandro M.] Univ Estadual Paulista, Fac Ciencias Agr & Vet Jaboticabal, Dept Tecnol, Sao Paulo, Brazil. [Siguier, Patricia; Chandler, Michael] CNRS, Lab Microbiol & Genet Mol, Toulouse, France. [Dekker, John P.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Dyda, F (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM fred.dyda@nih.gov OI Chandler, Michael/0000-0002-0292-6662 FU National Institute of Diabetes and Digestive and Kidney Diseases; NIH Clinical Center FX This work was partially supported by the Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases (S.H., A.B.H., and F.D.) and the NIH Clinical Center (J.P.D.). NR 66 TC 10 Z9 10 U1 2 U2 13 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD MAY-JUN PY 2015 VL 6 IS 3 AR e00762-15 DI 10.1128/mBio.00762-15 PG 14 WC Microbiology SC Microbiology GA CM7JH UT WOS:000357867400076 PM 26060276 ER PT J AU Mlera, L Offerdahl, DK Martens, C Porcella, SF Melik, W Bloom, ME AF Mlera, Luwanika Offerdahl, Danielle K. Martens, Craig Porcella, Stephen F. Melik, Wessam Bloom, Marshall E. TI Development of a Model System for Tick-Borne Flavivirus Persistence in HEK 293T Cells SO MBIO LA English DT Article ID WEST-NILE-VIRUS; DEFECTIVE INTERFERING PARTICLES; INTEGRATIVE GENOMICS VIEWER; NONSTRUCTURAL PROTEINS NS1; ENCEPHALITIS-VIRUS; FOLLOW-UP; INFECTION; REPLICATION; RNA; IDENTIFICATION AB We devised a model system to study persistent infection by the tick-borne flavivirus Langat virus (LGTV) in 293T cells. Infection with a molecularly cloned LGTV strain produced an acute lytic crisis that left few surviving cells. The culture was repopulated by cells that were similar to 90% positive for LGTV E protein, thus initiating a persistent infection that was maintained for at least 35 weeks without additional lytic crises. Staining of cells for viral proteins and ultrastructural analysis revealed only minor differences from the acute phase of infection. Infectious LGTV decreased markedly over the study period, but the number of viral genomes remained relatively constant, suggesting the development of defective interfering particles (DIPs). Viral genome changes were investigated by RNA deep sequencing. At the initiation of persistent infection, levels of DIPs were below the limit of detection at a coverage depth of 11,288-fold, implying that DIPs are not required for initiation of persistence. However, after 15 passages, DIPs constituted approximately 34% of the total LGTV population (coverage of 1,293-fold). Furthermore, at this point, one specific DIP population predominated in which nucleotides 1058 to 2881 had been deleted. This defective genome specified an intact polyprotein that coded for a truncated fusion protein containing 28 N-terminal residues of E and 134 C-terminal residues of NS1. Such a fusion protein has not previously been described, and a possible function in persistent infection is uncertain. DIPs are not required for the initiation of persistent LGTV infection but may play a role in the maintenance of viral persistence. IMPORTANCE Tick-borne flaviviruses are significant infectious agents that cause serious disease and death in humans worldwide. Infections are characterized by severe neurological symptoms, such as meningitis and encephalitis. A high percentage of people who get infected and recuperate from the acute phase of infection continue to suffer from chronic debilitating neurological sequelae, most likely as a result of nervous tissue damage, viral persistence, or both. However, little is known about mechanisms of viral persistence. Therefore, we undertook studies to investigate the persistence of Langat virus, a member of the tick-borne flavivirus group, in a mammalian cell line. Using next-generation sequencing, we determined that defective viral genomes do not play a role in the initiation of persistence, but their occurrence seems to be nonstochastic and could play a role in the maintenance of viral persistence via the expression of a novel envelope-NS1 fusion protein. C1 [Mlera, Luwanika; Offerdahl, Danielle K.; Melik, Wessam; Bloom, Marshall E.] NIAID, Virol Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Martens, Craig; Porcella, Stephen F.] NIAID, Genom Unit, Res Technol Sect, Rocky Mt Labs, Hamilton, MT USA. RP Bloom, ME (reprint author), NIAID, Virol Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM mbloom@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 49 TC 6 Z9 6 U1 1 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD MAY-JUN PY 2015 VL 6 IS 3 AR e00614-15 DI 10.1128/mBio.00614-15 PG 11 WC Microbiology SC Microbiology GA CM7JH UT WOS:000357867400061 PM 26045539 ER PT J AU Schisterman, EF Mumford, SL Schliep, KC Sjaarda, LA Stanford, JB Lesher, LL Wactawski-Wende, J Lynch, AM Townsend, JM Perkins, NJ Zarek, SM Tsai, MY Chen, Z Faraggi, D Galai, N Silver, RM AF Schisterman, Enrique F. Mumford, Sunni L. Schliep, Karen C. Sjaarda, Lindsey A. Stanford, Joseph B. Lesher, Laurie L. Wactawski-Wende, Jean Lynch, Anne M. Townsend, Janet M. Perkins, Neil J. Zarek, Shvetha M. Tsai, Michael Y. Chen, Zhen Faraggi, David Galai, Noya Silver, Robert M. TI Preconception Low Dose Aspirin and Time to Pregnancy: Findings From the Effects of Aspirin in Gestation and Reproduction Randomized Trial SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID IN-VITRO FERTILIZATION; RECURRENT MISCARRIAGE; ANTIPHOSPHOLIPID ANTIBODY; HUMAN-FERTILITY; WOMEN; PROSTACYCLIN; IMPLANTATION; THROMBOXANE; PREVENTION; EXPOSURE AB Objective: The objective was to determine the effect of preconception-initiated daily low-dose aspirin (LDA; 81 mg/day) treatment on time to pregnancy in women with a history of pregnancy loss. Design: This was a multicenter, block-randomized, double-blind, placebo-controlled trial. Participants were block-randomized by center and eligibility stratum. Setting: The study was conducted at four U.S.A. medical centers (2007-2012). Participants: Participants women aged 18-40 years actively attempting pregnancy, stratified by eligibility criteria: the "original" stratum, women with one loss <20 weeks' gestation during the previous year; and the "expanded" stratum, women with one or two previous losses of any gestational age regardless of time since loss. Intervention: Daily LDA was compared with matching placebo for up to six menstrual cycles of attempting pregnancy. Main Outcome Measure: Time to hCG detected pregnancy and clinically confirmed pregnancy, analyzed by intention-to-treat, was measured. Results: Of the 1228 women randomly assigned to LDA (n = 615) or placebo (n = 613), 410 (67%) women receiving LDA achieved pregnancy compared to 382 (63%) receiving placebo, corresponding to a fecundability odds ratio (FOR) of 1.14 (95% CI: 0.97, 1.33). Among women in the original stratum (n = 541), LDA was associated with increased fecundability compared to placebo (FOR: 1.28; 95% CI: 1.02, 1.62). Conclusions: Preconception-initiated LDA treatment resulted in a nonsignificant increase in fecundability of 14% in women with a history of 1-2 pregnancy losses, and a significant increase of 28% in women with a history of only one pregnancy loss of <20 weeks' gestation in the preceding year. Preconception-initiated LDA may increase fecundability in certain women with a recent early pregnancy loss. C1 [Schisterman, Enrique F.; Mumford, Sunni L.; Schliep, Karen C.; Sjaarda, Lindsey A.; Perkins, Neil J.; Zarek, Shvetha M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Epidemiol Branch, Bethesda, MD 20892 USA. [Chen, Zhen] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Biostat & Bioinformat Branch, Bethesda, MD 20892 USA. [Stanford, Joseph B.] Univ Utah, Dept Family & Prevent Med, Salt Lake City, UT 84112 USA. [Lesher, Laurie L.; Silver, Robert M.] Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT 84111 USA. [Lesher, Laurie L.; Silver, Robert M.] Intermt Healthcare, Salt Lake City, UT 84111 USA. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Epidemiol & Environm Hlth, Buffalo, NY 14260 USA. [Lynch, Anne M.] Univ Colorado, Dept Obstet & Gynecol, Denver, CO 80045 USA. [Townsend, Janet M.] Commonwealth Med Coll, Dept Family Community & Rural Hlth, Scranton, PA 18509 USA. [Tsai, Michael Y.] Univ Minnesota, Sch Med, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Faraggi, David; Galai, Noya] Univ Haifa, Dept Stat, IL-3498838 Haifa, Israel. RP Schisterman, EF (reprint author), 6100 Execut Blvd,7B03, Rockville, MD 20854 USA. EM schistee@mail.nih.gov OI Perkins, Neil/0000-0002-6802-4733; Sjaarda, Lindsey/0000-0003-0539-8110; Schisterman, Enrique/0000-0003-3757-641X FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland [HHSN267200603423, HHSN267200603424, HHSN267200603426] FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (Contract Nos. HHSN267200603423, HHSN267200603424, HHSN267200603426). NR 24 TC 4 Z9 4 U1 0 U2 3 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAY PY 2015 VL 100 IS 5 BP 1785 EP 1791 DI 10.1210/jc.2014-4179 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CM4QG UT WOS:000357669000029 PM 25710565 ER PT J AU Diker-Cohen, T Cochran, E Gorden, P Brown, RJ AF Diker-Cohen, Talia Cochran, Elaine Gorden, Phillip Brown, Rebecca J. TI Partial and Generalized Lipodystrophy: Comparison of Baseline Characteristics and Response to Metreleptin SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID LEPTIN-REPLACEMENT THERAPY; FAMILIAL PARTIAL LIPODYSTROPHY; LONG-TERM EFFICACY; INSULIN-RESISTANCE; HYPERANDROGENISM; GROWTH; SAFETY AB Context: Lipodystrophies are extreme forms of metabolic syndrome. Metreleptin was approved in the United States for generalized lipodystrophy (GLD) but not partial lipodystrophy (PLD). Objective: The objective of the study was to test metreleptin's efficacy in PLD vs GLD and find predictors for treatment response. Design: This was a prospective, single-arm, open- label study since 2000 with continuous enrollment. Current analysis included metreleptin treatment for 6 months or longer as of January 2014. Setting: The study was conducted at the National Institutes of Health (Bethesda, Maryland). Participants: Patients clinically diagnosed with lipodystrophy, leptin less than 8 ng/mL (males) or less than 12 (females), age older than 6 months, and one or more metabolic abnormalities (diabetes, insulin resistance, or hypertriglyceridemia) participated in the study. Intervention: The interventions included sc metreleptin injections (0.06-0.24 mg/kg.d). Main Outcomes and Measures: Changes in glycated hemoglobin A1c (HbA1c) and triglycerides after 6 and 12 months of metreleptin were measured. Results: Baseline metabolic parameters were similar in 55 GLD [HbA1c 8.4% +/- 2.3%; triglycerides, geometric mean (25th, 75th percentile), 467 mg/dL (200, 847)] and 31 PLD patients [HbA1c 8.1% +/- 2.2%, triglycerides 483 mg/dL (232, 856)] despite different body fat and endogenous leptin. At 12 months, metreleptin decreased HbA1c (to 6.4% +/- 1.5%, GLD, P < .001; 7.3% +/- 1.6%, PLD, P = .004) and triglycerides [to 180 mg/dL (106, 312), GLD, P < .001; 326 mg/dL (175, 478), PLD, P = .02]. HbA1c and triglyceride changes over time significantly differed between GLD and PLD. In subgroup analyses, metreleptin improved HbA1c and triglycerides in all GLD subgroups except those with baseline triglycerides less than 300 mg/dL and all PLD subgroups except baseline triglycerides less than 500 mg/dL, HbA1c less than 8%, or endogenous leptin greater than 4 ng/mL. Conclusions: In addition to its proven efficacy in GLD, metreleptin is effective in selected PLD patients with severe metabolic derangements or low leptin. C1 [Diker-Cohen, Talia; Cochran, Elaine; Gorden, Phillip; Brown, Rebecca J.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. RP Brown, RJ (reprint author), 10 Ctr Dr,MSC 1612,Room CRC 6-5942, Bethesda, MD 20892 USA. EM brownrebecca@niddk.nih.gov FU Intramural Research Program of the National Institutes of Health, the National Institute of Diabetes and Digestive and Kidney Diseases; Inter-Institute Endocrinology Fellowship Program at the National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by the Intramural Research Program of the National Institutes of Health, the National Institute of Diabetes and Digestive and Kidney Diseases, and by the Inter-Institute Endocrinology Fellowship Program at the National Institute of Diabetes and Digestive and Kidney Diseases. NR 29 TC 21 Z9 24 U1 0 U2 7 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAY PY 2015 VL 100 IS 5 BP 1802 EP 1810 DI 10.1210/jc.2014-4491 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CM4QG UT WOS:000357669000031 PM 25734254 ER PT J AU Xekouki, P Szarek, E Bullova, P Giubellino, A Quezado, M Mastroyannis, SA Mastorakos, P Wassif, CA Raygada, M Rentia, N Dye, L Cougnoux, A Koziol, D Sierra, MD Lyssikatos, C Belyavskaya, E Malchoff, C Moline, J Eng, C Maher, LJ Pacak, K Lodish, M Stratakis, CA AF Xekouki, Paraskevi Szarek, Eva Bullova, Petra Giubellino, Alessio Quezado, Martha Mastroyannis, Spyridon A. Mastorakos, Panagiotis Wassif, Christopher A. Raygada, Margarita Rentia, Nadia Dye, Louis Cougnoux, Antony Koziol, Deloris Sierra, Maria de la Luz Lyssikatos, Charalampos Belyavskaya, Elena Malchoff, Carl Moline, Jessica Eng, Charis Maher, Louis James, III Pacak, Karel Lodish, Maya Stratakis, Constantine A. TI Pituitary Adenoma With Paraganglioma/Pheochromocytoma (3PAs) and Succinate Dehydrogenase Defects in Humans and Mice SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID HORMONE-RELEASING-HORMONE; TUMOR TRANSFORMING GENE; COMPLEX-II DEFICIENCY; AGE-RELATED-CHANGES; CAROTID-BODY; SDHD GENE; GH CELLS; PARAGANGLIOMA; MUTATIONS; GROWTH AB Context: Germline mutations in genes coding succinate dehydrogenase (SDH) subunits A, B, C, and D have been identified in familial paragangliomas (PGLs)/pheochromocytomas (PHEOs) and other tumors. We described a GH-secreting pituitary adenoma (PA) caused by SDHD mutation in a patient with familial PGLs. Additional patients with PAs and SDHx defects have since been reported. Design: We studied 168 patients with unselected sporadic PA and with the association of PAs, PGLs, and/or pheochromocytomas, a condition we named the 3P association (3PAs) for SDHx germline mutations. We also studied the pituitary gland and hormonal profile of Sdhb(+/-) mice and their wild-type littermates at different ages. Results: No SDHx mutations were detected among sporadic PA, whereas three of four familial cases were positive for a mutation (75%). Most of the SDHx-deficient PAs were either prolactinomas or somatotropinomas. Pituitaries of Sdhb(+/-) mice older than 12 months had an increased number mainly of prolactin-secreting cells and several ultrastructural abnormalities such as intranuclear inclusions, altered chromatin nuclear pattern, and abnormal mitochondria. Igf-1 levels of mutant mice tended to be higher across age groups, whereas Prl and Gh levels varied according to age and sex. Conclusion: The present study confirms the existence of a new association that we termed 3PAs. It is due mostly to germline SDHx defects, although sporadic cases of 3PAs without SDHx defects also exist. Using Sdhb(+/-) mice, we provide evidence that pituitary hyperplasia in SDHx-deficient cells may be the initial abnormality in the cascade of events leading to PA formation. C1 [Xekouki, Paraskevi; Szarek, Eva; Mastroyannis, Spyridon A.; Mastorakos, Panagiotis; Rentia, Nadia; Sierra, Maria de la Luz; Lyssikatos, Charalampos; Belyavskaya, Elena; Lodish, Maya; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Bethesda, MD 20892 USA. [Xekouki, Paraskevi; Giubellino, Alessio] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, Sect Med Neuroendocrinol, Bethesda, MD 20892 USA. [Wassif, Christopher A.; Cougnoux, Antony] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Sect Mol Dysmorphol, Bethesda, MD 20892 USA. [Dye, Louis] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, Microscopy & Imaging Core, Bethesda, MD 20892 USA. [Giubellino, Alessio; Quezado, Martha; Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Pathol Lab, Bethesda, MD 20892 USA. [Koziol, Deloris] NCI, Bethesda, MD 20892 USA. [Koziol, Deloris] NIH, Biostat & Clin Epidemiol Serv, Ctr Clin, Bethesda, MD 20892 USA. [Malchoff, Carl] Univ Connecticut, Ctr Hlth, Dept Endocrinol, Farmington, CT 06030 USA. [Moline, Jessica; Eng, Charis] Cleveland Clin, Genom Med Inst, Cleveland, OH 44195 USA. [Maher, Louis James, III] Mayo Clin, Coll Med, Dept Biochem & Mol Biol, Rochester, MN 55905 USA. [Bullova, Petra] Slovak Acad Sci, Inst Virol, Dept Mol Med, Bratislava 83306, Slovakia. RP Stratakis, CA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, Bldg 10,CRC,Room 1-3330,10 Ctr Dr,MSC1103, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov OI Wassif, Christopher/0000-0002-2524-1420 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [Z01 HD000642-04]; Alpha Omega Alpha Carolyn L. Kuckein Student Research Fellowship; Arthur Blank Foundation, Atlanta, Georgia FX This work was supported by the intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (Project Z01 HD000642-04; principal investigator, C.A.S.); an Alpha Omega Alpha Carolyn L. Kuckein Student Research Fellowship (to S.A.M.); and the Arthur Blank Foundation, Atlanta, Georgia (to C.E.). NR 56 TC 14 Z9 14 U1 0 U2 3 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAY PY 2015 VL 100 IS 5 BP E710 EP E719 DI 10.1210/jc.2014-4297 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CM4QG UT WOS:000357669000005 PM 25695889 ER PT J AU Panna, A Gomella, AA Harmon, KJ Chen, P Miao, H Bennett, EE Wen, H AF Panna, A. Gomella, A. A. Harmon, K. J. Chen, P. Miao, H. Bennett, E. E. Wen, H. TI Performance of low-cost X-ray area detectors with consumer digital cameras SO JOURNAL OF INSTRUMENTATION LA English DT Article DE X-ray detectors; Instrumental noise; Image processing AB We constructed X-ray detectors using consumer-grade digital cameras coupled to commercial X-ray phosphors. Several detector configurations were tested against the Varian PaxScan 3024M (Varian 3024M) digital flat panel detector. These include consumer cameras (Nikon D800, Nikon D700, and Nikon D3X) coupled to a green emission phosphor in a back-lit, normal incidence geometry, and in a front-lit, oblique incidence geometry. We used the photon transfer method to evaluate detector sensitivity and dark noise, and the edge test method to evaluate their spatial resolution. The essential specifications provided by our evaluation include discrete charge events captured per mm(2) per unit exposure surface dose, dark noise in equivalents of charge events per pixel, and spatial resolution in terms of the full width at half maximum (FWHM) of the detector`s line spread function (LSF). Measurements were performed using a tungsten anode X-ray tube at 50 kVp. The results show that the home-built detectors provide better sensitivity and lower noise than the commercial flat panel detector, and some have better spatial resolution. The trade-off is substantially smaller imaging areas. Given their much lower costs, these home-built detectors are attractive options for prototype development of low-dose imaging applications. C1 [Panna, A.; Gomella, A. A.; Harmon, K. J.; Chen, P.; Miao, H.; Bennett, E. E.; Wen, H.] NHLBI, Imaging Phys Lab, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. RP Wen, H (reprint author), NHLBI, Imaging Phys Lab, Biochem & Biophys Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM wenh@nhlbi.nih.gov RI Wen, Han/G-3081-2010 OI Wen, Han/0000-0001-6844-2997 NR 7 TC 2 Z9 2 U1 4 U2 8 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 1748-0221 J9 J INSTRUM JI J. Instrum. PD MAY PY 2015 VL 10 AR T05005 DI 10.1088/1748-0221/10/05/T05005 PG 9 WC Instruments & Instrumentation SC Instruments & Instrumentation GA CM8ZI UT WOS:000357993300051 ER PT J AU Maachani, UB Kramp, T Hanson, R Zhao, SP Celiku, O Shankavaram, U Colombo, R Caplen, NJ Camphausen, K Tandle, A AF Maachani, Uday Bhanu Kramp, Tamalee Hanson, Ryan Zhao, Shuping Celiku, Orieta Shankavaram, Uma Colombo, Riccardo Caplen, Natasha J. Camphausen, Kevin Tandle, Anita TI Targeting MPS1 Enhances Radiosensitization of Human Glioblastoma by Modulating DNA Repair Proteins SO MOLECULAR CANCER RESEARCH LA English DT Article ID DOUBLE-STRAND BREAKS; MITOTIC CHECKPOINT; GENOMIC INSTABILITY; CANCER CELLS; KINASE; EXPRESSION; INHIBITOR; ANEUPLOIDY; DAMAGE; AUTOPHOSPHORYLATION AB To ensure faithful chromosome segregation, cells use the spindle assembly checkpoint (SAC), which can be activated in aneuploid cancer cells. Targeting the components of SAC machinery required for the growth of aneuploid cells may offer a cancer cell-specific therapeutic approach. In this study, the effects of inhibiting Monopolar spindle 1, MPS1 (TTK), an essential SAC kinase, on the radiosensitization of glioblastoma (GBM) cells were analyzed. Clonogenic survival was used to determine the effects of the MPS1 inhibitor NMS-P715 on radiosensitivity in multiple model systems, including GBM cell lines, a normal astrocyte, and a normal fibroblast cell line. DNA double-strand breaks (DSB) were evaluated using gamma H2AX foci, and cell death was measured by mitotic catastrophe evaluation. Transcriptome analysis was performed via unbiased microarray expression profiling. Tumor xenografts grown from GBM cells were used in tumor growth delay studies. Inhibition of MPS1 activity resulted in reduced GBM cell proliferation. Further-more, NMS-P715 enhanced the radiosensitivity of GBM cells by decreased repair of DSBs and induction of postradiation mitotic catastrophe. NMS-P715 in combination with fractionated doses of radiation significantly enhanced the tumor growth delay. Molecular profiling of MPS1-silenced GBM cells showed an altered expression of transcripts associated with DNA damage, repair, and replication, including the DNA-dependent protein kinase (PRKDC/DNAPK). Next, inhibition of MPS1 blocked two important DNA repair pathways. In conclusion, these results not only highlight a role for MPS1 kinase in DNA repair and as prognostic marker but also indicate it as a viable option in glioblastoma therapy. (C)2015 AACR. C1 [Maachani, Uday Bhanu; Kramp, Tamalee; Hanson, Ryan; Zhao, Shuping; Celiku, Orieta; Shankavaram, Uma; Camphausen, Kevin; Tandle, Anita] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Colombo, Riccardo] Nerviano Med Sci Srl, Oncol, Nerviano, Italy. [Caplen, Natasha J.] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. RP Tandle, A (reprint author), NCI, Radiat Oncol Branch, NIH, Bldg 10,Room B3B100, Bethesda, MD 20892 USA. EM tandlea@mail.nih.gov RI Caplen, Natasha/H-2768-2016 OI Caplen, Natasha/0000-0002-0001-9460 FU Intramural Research Program of the NIH, National Cancer Institute FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute. NR 39 TC 8 Z9 9 U1 1 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 EI 1557-3125 J9 MOL CANCER RES JI Mol. Cancer Res. PD MAY PY 2015 VL 13 IS 5 BP 852 EP 862 DI 10.1158/1541-7786.MCR-14-0462-T PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CM9VN UT WOS:000358057500005 PM 25722303 ER PT J AU Song, LN Silva, J Koller, A Rosenthal, A Chen, EI Gelmann, EP AF Song, Liang-Nian Silva, Jose Koller, Antonius Rosenthal, Andrew Chen, Emily I. Gelmann, Edward P. TI The Tumor Suppressor NKX3.1 Is Targeted for Degradation by DYRK1B Kinase SO MOLECULAR CANCER RESEARCH LA English DT Article ID PANCREATIC-CANCER CELLS; MIRK/DYRK1B KINASE; PROSTATE-CANCER; PROTEIN-KINASES; PHOSPHORYLATION; CARCINOGENESIS; SPECIFICITY; PROGRESSION; EXPRESSION; INHIBITORS AB NKX3.1 is a prostate-specific homeodomain protein and tumor suppressor whose expression is reduced in the earliest phases of prostatic neoplasia. NKX3.1 expression is not only diminished by genetic loss and methylation, but the protein itself is a target for accelerated degradation caused by inflammation that is common in the aging prostate gland. NKX3.1 degradation is activated by phosphorylation at C-terminal serine residues that mediate ubiquitination and protein turnover. Because NKX3.1 is haploinsufficient, strategies to increase its protein stability could lead to new therapies. Here, a high-throughput screen was developed using an siRNA library for kinases that mediate NKX3.1 degradation. This approach identified several candidates, of which DYRK1B, a kinase that is subject to gene amplification and overexpression in other cancers, had the greatest impact on NKX3.1 half-life. Mechanistically, NKX3.1 and DYRK1B were shown to interact via the DYRK1B kinase domain. In addition, an in vitro kinase assay showed that DYRK1B phosphorylated NKX3.1 at serine185, a residue critical for NKX3.1 steady-state turnover. Lastly, small-molecule inhibitors of DYRK1B prolonged NKX3.1 half-life. Thus, DYRK1B is a target for enzymatic inhibition in order to increase cellular NKX3.1. (C)2015 AACR. C1 [Song, Liang-Nian; Gelmann, Edward P.] Columbia Univ, Herbert Irving Comprehens Canc Ctr, Med Ctr, Dept Med, New York, NY 10032 USA. [Song, Liang-Nian; Gelmann, Edward P.] Columbia Univ, Herbert Irving Comprehens Canc Ctr, Med Ctr, Dept Pathol, New York, NY 10032 USA. [Silva, Jose] Icahn, New York, NY USA. [Koller, Antonius; Chen, Emily I.] Columbia Univ, Herbert Irving Comprehens Canc Ctr, Prote Shared Resource Herbert Irving Ctr Comprehe, Med Ctr, New York, NY 10032 USA. [Rosenthal, Andrew] NIH, Chem Genom Ctr, Bethesda, MD 20892 USA. [Chen, Emily I.] Columbia Univ, Herbert Irving Comprehens Canc Ctr, Med Ctr, Dept Pharmacol, New York, NY 10032 USA. RP Gelmann, EP (reprint author), Columbia Univ, Herbert Irving Comprehens Canc Ctr, 6N-435,177 Ft Washington Ave, New York, NY 10032 USA. EM gelmanne@columbia.edu FU Department of Defense Prostate Cancer Research Program [W81XWH-11-1-0177]; NCI grant via the Bioinformatics Shared Resource [P01 CA154293, CCSG P30 CA013696-36]; [5 P30 CA013696-39S3] FX This study was supported in part by Department of Defense Prostate Cancer Research Program W81XWH-11-1-0177, NCI grant P01 CA154293, and CCSG P30 CA013696-36 via the Bioinformatics Shared Resource and 5 P30 CA013696-39S3 to the Proteomics Shared Resource. NR 32 TC 3 Z9 3 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 EI 1557-3125 J9 MOL CANCER RES JI Mol. Cancer Res. PD MAY PY 2015 VL 13 IS 5 BP 913 EP 922 DI 10.1158/1541-7786.MCR-14-0680 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CM9VN UT WOS:000358057500011 PM 25777618 ER PT J AU Pelosi, E Simonsick, E Forabosco, A Garcia-Ortiz, JE Schlessinger, D AF Pelosi, Emanuele Simonsick, Eleanor Forabosco, Antonino Elias Garcia-Ortiz, Jose Schlessinger, David TI Dynamics of the Ovarian Reserve and Impact of Genetic and Epidemiological Factors on Age of Menopause SO BIOLOGY OF REPRODUCTION LA English DT Review DE female infertility; gonadal function; menopause; ovary; primary ovarian insufficiency ID FOLLICLE-STIMULATING-HORMONE; GENOME-WIDE ASSOCIATION; BRITISH BIRTH COHORT; FRAGILE-X-SYNDROME; LINE STEM-CELLS; NATURAL MENOPAUSE; GERM-CELLS; MOUSE OVARY; PRIMORDIAL FOLLICLES; TURNER SYNDROME AB The narrow standard age range of menopause, similar to 50 yr, belies the complex balance of forces that govern the underlying formation and progressive loss of ovarian follicles (the "ovarian reserve'' whose size determines the age of menopause). We show here the first quantitative graph of follicle numbers, distinguished from oocyte counts, across the reproductive lifespan, and review the current state of information about genetic and epidemiological risk factors in relation to possible preservation of reproductive capacity. In addition to structural X-chromosome changes, several genes involved in the process of follicle formation and/or maintenance are implicated in Mendelian inherited primary ovarian insufficiency (POI), with menopause before age 40. Furthermore, variants in a largely distinct cohort of reported genes-notably involved in pathways relevant to atresia, including DNA repair and cell death-have shown smaller but additive effects on the variation in timing of menopause in the normal range, early menopause (age <45), and POI. Epidemiological factors show effect sizes comparable to those of genetic factors, with smoking accounting for about 5% of the risk of early menopause, equivalent to the summed effect of the top 17 genetic variants. The identified genetic and epidemiological factors underline the importance of early detection of reproductive problems to enhance possible interventions. C1 [Pelosi, Emanuele; Simonsick, Eleanor; Schlessinger, David] NIA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Forabosco, Antonino] Cante Monteveccio Assoc, Genom Res Ctr, Fano, Italy. [Elias Garcia-Ortiz, Jose] IMSS, Ctr Invest Biomed Occidente, Div Genet, Guadalajara, Jalisco, Mexico. RP Pelosi, E (reprint author), NIA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM pelosie@mail.nih.gov OI Pelosi, Emanuele/0000-0003-1890-9821 FU Intramural Research Program of the National Institute on Aging, NIH FX Supported by the Intramural Research Program of the National Institute on Aging, NIH. NR 148 TC 7 Z9 8 U1 2 U2 8 PU SOC STUDY REPRODUCTION PI MADISON PA 1691 MONROE ST,SUITE # 3, MADISON, WI 53711-2021 USA SN 0006-3363 EI 1529-7268 J9 BIOL REPROD JI Biol. Reprod. PD MAY 1 PY 2015 VL 92 IS 5 AR 130 DI 10.1095/biolreprod.114.127381 PG 9 WC Reproductive Biology SC Reproductive Biology GA CM5RX UT WOS:000357747400008 PM 25904009 ER PT J AU Zhang, L Zhang, W Wang, YF Liu, B Zhang, WF Zhao, YF Kulkarni, AB Sun, ZJ AF Zhang, L. Zhang, W. Wang, Y-F Liu, B. Zhang, W-F Zhao, Y-F Kulkarni, A. B. Sun, Z-J TI Dual induction of apoptotic and autophagic cell death by targeting survivin in head neck squamous cell carcinoma SO CELL DEATH & DISEASE LA English DT Article ID ADENOID CYSTIC CARCINOMA; NEGATIVE BREAST-CANCER; SIGNALING PATHWAY; MAMMALIAN TARGET; PROSTATE-CANCER; MOUSE MODEL; YM155; SUPPRESSANT; COMBINATION; STATISTICS AB Survivin is ubiquitously expressed in patients with head neck squamous cell carcinoma (HNSCC) and is associated with poor survival and chemotherapy resistance. Sepantronium bromide (YM155) is a selective survivin suppressant that exhibits potent antitumor activities by inducing apoptosis and autophagy in various types of cancer. However, the curative effects and underlying mechanisms of YM155 in HNSCC remain unclear. This study showed that survivin overexpression positively correlated with p-S6, p-Rb and LAMP2 but negatively correlated with the autophagic marker LC3 in human HNSCC tissues. In vitro studies revealed that YM155 triggered apoptosis of HNSCC cells in mitochondria and death receptor-dependent manner. The treatment also significantly enhanced autophagy by upregulating Beclin1, which led to cell death. YM155 not only downregulated the expression of survivin but also remarkably suppressed the activation of the mTOR signaling pathway in vitro and in vivo. YM155 displayed potent antitumor activities in both CAL27 xenograft and transgenic HNSCC mice models by delaying tumor onset and suppressing tumor growth. Furthermore, YM155 combined with docetaxel promoted tumor regression better than either treatment alone without causing considerable body weight loss in the HNSCC xenograft models. Overall, targeting survivin by YM155 can benefit HNSCC therapy by increasing apoptotic and autophagic cell death, and suppressing prosurvival pathways. C1 [Zhang, L.; Zhang, W.; Wang, Y-F; Zhao, Y-F; Sun, Z-J] Wuhan Univ, Sch & Hosp Stomatol, Minist Educ, State Key Lab Breeding Base Basic Sci Stomatol, Wuhan 430079, Hubei, Peoples R China. [Zhang, L.; Zhang, W.; Wang, Y-F; Zhao, Y-F; Sun, Z-J] Wuhan Univ, Sch & Hosp Stomatol, Minist Educ, Key Lab Oral Biomed, Wuhan 430079, Hubei, Peoples R China. [Liu, B.; Zhang, W-F; Zhao, Y-F; Sun, Z-J] Wuhan Univ, Sch & Hosp Stomatol, Dept Oral & Maxillofacial Head & Neck Oncol, Wuhan 430079, Hubei, Peoples R China. [Kulkarni, A. B.] Natl Inst Dent & Craniofacial Res, Funct Genom Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD USA. RP Sun, ZJ (reprint author), Wuhan Univ, Sch & Hosp Stomatol, Dept Oral & Maxillofacial Head & Neck Oncol, Minist Educ,State Key Lab Breeding Base Basic Sci, Wuhan 430079, Hubei, Peoples R China. EM zhijundejia@163.com FU National Natural Science Foundation of China [81072203, 81272963, 81472528, 81371106, 81272946, 81170977, 81371159]; program for new century excellent talents in university, Ministry of Education of China [NCET-13-0439] FX We thank ABK of LCDB, National Institute of Dental and Craniofacial Research, NIH, USA for gift of Tgfbr1/Pten 2cKO mice. This study was supported by National Natural Science Foundation of China (81072203, 81272963, 81472528) to ZJS, (81371106) to LZ, (81272946, 81472528) to WFZ and (81170977, 81371159) to YFZ. ZJS was supported by program for new century excellent talents in university (NCET-13-0439), Ministry of Education of China. NR 48 TC 12 Z9 13 U1 4 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-4889 J9 CELL DEATH DIS JI Cell Death Dis. PD MAY PY 2015 VL 6 AR e1771 DI 10.1038/cddis.2015.139 PG 11 WC Cell Biology SC Cell Biology GA CM2MA UT WOS:000357513200036 PM 26018732 ER PT J AU Mentz, RJ Babyak, MA Bittner, V Fleg, JL Keteyian, SJ Swank, AM Pina, IL Kraus, WE Whellan, DJ O'Connor, CM Blumenthal, JA AF Mentz, Robert J. Babyak, Michael A. Bittner, Vera Fleg, Jerome L. Keteyian, Steven J. Swank, Ann M. Pina, Ileana L. Kraus, William E. Whellan, David J. O'Connor, Christopher M. Blumenthal, James A. CA HF-ACTION Investigators TI Prognostic Significance of Depression in Blacks With Heart Failure Insights From Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training SO CIRCULATION-HEART FAILURE LA English DT Article DE blacks; depression; heart failure; outcome assessment ID RANDOMIZED CONTROLLED-TRIAL; HF-ACTION; RACIAL-DIFFERENCES; CLINICAL-OUTCOMES; SYMPTOMS; MORTALITY; DISEASE; RISK; RACE; SERTRALINE AB Background Although studies have shown that depression is associated with worse outcomes in patients with heart failure, most studies have been in white patients. The impact of depression on outcomes in blacks with heart failure has not been studied. Methods and Results We analyzed 747 blacks and 1420 whites enrolled in Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training, which randomized 2331 patients with ejection fraction 35% to usual care with or without exercise training. We examined the association between depressive symptoms assessed by the Beck Depression Inventory-II (BDI-II) at baseline and after 3 months with all-cause mortality/hospitalization. A race by baseline BDI-II interaction was observed (P=0.003) in which elevated baseline scores were associated with worse outcomes in blacks versus whites. In blacks, the association was nonlinear with a hazard ratio of 1.44 (95% confidence interval, 1.24-1.68) when comparing the 75th and 25th percentile of BDI-II (score of 15 and 5, respectively). No race interaction was observed for mortality (P=0.34). There was no differential association between BDI-II change and outcomes in blacks versus whites. In blacks, an increase in BDI-II score from baseline to 3 months was associated with increased mortality/hospitalization (hazard ratio, 1.33; 95% confidence interval, 1.12-1.57 per 10 point increase), whereas a decrease was not related to outcomes. Conclusions In blacks with heart failure, baseline symptoms of depression and worsening of symptoms over time are associated with increased all-cause mortality/hospitalization. Routine assessment of depressive symptoms in blacks with heart failure may help guide management. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00047437. C1 [Mentz, Robert J.; Babyak, Michael A.; Kraus, William E.; O'Connor, Christopher M.; Blumenthal, James A.] Duke Univ, Med Ctr, Durham, NC 27710 USA. [Bittner, Vera] Univ Alabama Birmingham, Birmingham, AL USA. [Fleg, Jerome L.] NHLBI, Bethesda, MD 20892 USA. [Keteyian, Steven J.] Henry Ford Hosp, Detroit, MI 48202 USA. [Swank, Ann M.] Univ Louisville, Louisville, KY 40292 USA. [Pina, Ileana L.] Montefiore Einstein Med Ctr, New York, NY USA. [Whellan, David J.] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. RP Mentz, RJ (reprint author), Duke Univ, Med Ctr, 2301 Erwin Rd, Durham, NC 27710 USA. EM robert.mentz@duke.edu FU National Heart, Lung and Blood Institute [HL063747, HL093374]; National Institute of General Medical Sciences [T32GM086330] FX Supported by grants HL063747 and HL093374 from the National Heart, Lung and Blood Institute and by grant no. T32GM086330 to Dr Mentz from the National Institute of General Medical Sciences. NR 34 TC 3 Z9 4 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1941-3289 EI 1941-3297 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD MAY PY 2015 VL 8 IS 3 BP 497 EP 503 DI 10.1161/CIRCHEARTFAILURE.114.001995 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CL6LX UT WOS:000357079700013 PM 25901047 ER PT J AU Matito, A Carter, M AF Matito, A. Carter, M. TI Cutaneous and Systemic Mastocytosis in Children: A Risk Factor for Anaphylaxis? SO CURRENT ALLERGY AND ASTHMA REPORTS LA English DT Review DE Anaphylaxis; Mastocytosis; Pediatric ID MAST-CELL ACTIVATION; PEDIATRIC EMERGENCY-DEPARTMENT; SERUM BASAL TRYPTASE; C-KIT MUTATIONS; URTICARIA-PIGMENTOSA; CLINICAL-FEATURES; PLASMA HISTAMINE; HYPERSENSITIVITY REACTIONS; ONSET MASTOCYTOSIS; SPANISH NETWORK AB Childhood mastocytosis is usually a clonal mast cell disease related to activating mutations in KIT. The symptoms in childhood mastocytosis are typically cutaneous in nature although systemic symptoms including anaphylaxis due to the release of mast cells (MC) mediators can also manifest. The prevalence of anaphylaxis reported in childhood mastocytosis is higher than the rates reported in the pediatric general population, but lower than the prevalence of anaphylaxis described in adult mastocytosis. An extensive cutaneous involvement was reported as a risk factor for anaphylaxis, and patients with diffuse cutaneous mastocytosis have been documented to have more severe anaphylaxis symptoms. Anaphylaxis due to unknown causes or idiopathic anaphylaxis was the primary etiology in pediatric mastocytosis, followed by foods as the most relevant identified trigger; however, hymenoptera stings are not a frequent trigger of anaphylaxis in children with mastocytosis in contrast to the adult patients. C1 [Matito, A.] Hosp Virgen del Valle, Spanish Network Mastocytosis REMA, Inst Estudios Mastocitosis Castilla La Mancha, Toledo 45071, Spain. [Carter, M.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Matito, A (reprint author), Hosp Virgen del Valle, Spanish Network Mastocytosis REMA, Inst Estudios Mastocitosis Castilla La Mancha, Carretera Cobisa S-N, Toledo 45071, Spain. EM amatito@sescam.jccm.es; mcarter@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 103 TC 3 Z9 3 U1 0 U2 0 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1529-7322 EI 1534-6315 J9 CURR ALLERGY ASTHM R JI Curr. Allergy Asthma Rep. PD MAY PY 2015 VL 15 IS 5 AR 22 DI 10.1007/s11882-015-0525-1 PG 9 WC Allergy; Immunology SC Allergy; Immunology GA CM1GA UT WOS:000357428100006 PM 26139333 ER PT J AU McDermott, MM Guralnik, JM Criqui, MH Ferrucci, L Liu, K Spring, B Tian, L Domanchuk, K Kibbe, M Zhao, LH Jones, DL Liao, YH Gao, Y Rejeski, WJ AF McDermott, Mary M. Guralnik, Jack M. Criqui, Michael H. Ferrucci, Luigi Liu, Kiang Spring, Bonnie Tian, Lu Domanchuk, Kathryn Kibbe, Melina Zhao, Lihui Jones, Donald Lloyd Liao, Yihua Gao, Ying Rejeski, W. Jack TI Unsupervised Exercise and Mobility Loss in Peripheral Artery Disease: A Randomized Controlled Trial SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE exercise; mobility; peripheral artery disease; randomized controlled trial ID PHYSICAL PERFORMANCE BATTERY; LOWER-EXTREMITY FUNCTION; ANKLE BRACHIAL INDEX; INTERMITTENT CLAUDICATION; SUBSEQUENT DISABILITY; FUNCTIONAL PERFORMANCE; LEG SYMPTOMS; WALKING; HEALTH; MORTALITY AB Background-Few medical therapies improve lower extremity functioning in people with lower extremity peripheral artery disease (PAD). Among people with PAD, we studied whether a group-mediated cognitive behavioral intervention promoting home-based unsupervised exercise prevented mobility loss and improved functional performance compared to control. Methods and Results-One hundred ninety-four PAD participants were randomized. During months 1 to 6, the intervention group met weekly with other PAD participants and a facilitator. Group support and self-regulatory skills were used to help participants adhere to walking exercise. Ninety-percent of exercise was conducted at or near home. The control group attended weekly lectures. During months 6 to 12, each group received telephone contact only. Primary outcomes have been reported. Here we compare changes in exploratory outcomes of mobility loss (the inability to climb a flight of stairs or walk one-quarter mile without assistance), walking velocity, and the Short Physical Performance Battery. Compared to controls, fewer participants randomized to the intervention experienced mobility loss at 6-month follow-up: 6.3% versus 26.5%, P=0.002, odds ratio=0.19 (95% CI=0.06 to 0.58) and at 12-month follow-up: 5.2% versus 18.5%, P=0.029, odds ratio=0.24 (95% CI=0.06 to 0.97). The intervention improved fast-paced 4-m walking velocity at 6-month follow-up (P=0.005) and the Short Physical Performance Battery at 12-month follow-up (P=0.027), compared to controls. Conclusions-In exploratory analyses, a group-mediated cognitive behavioral intervention promoting unsupervised walking exercise prevented mobility loss and improved functioning at 6- and 12-month follow-up in PAD patients. C1 [McDermott, Mary M.; Domanchuk, Kathryn; Jones, Donald Lloyd] Northwestern Univ, Dept Med, Feinberg Sch Med, Chicago, IL 60611 USA. [McDermott, Mary M.; Liu, Kiang; Spring, Bonnie; Tian, Lu; Jones, Donald Lloyd; Liao, Yihua; Gao, Ying] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Kibbe, Melina] Northwestern Univ, Dept Surg, Feinberg Sch Med, Chicago, IL 60611 USA. [Guralnik, Jack M.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Criqui, Michael H.] Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [Ferrucci, Luigi] NIA, Bethesda, MD 20892 USA. [Tian, Lu] Stanford Univ, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Kibbe, Melina] Jesse Brown Vet Affairs Med Ctr, Chicago, IL USA. [Rejeski, W. Jack] Wake Forest Univ, Dept Hlth & Exercise Sci, Winston Salem, NC 27109 USA. RP McDermott, MM (reprint author), 750 North Lake Shore Dr,10th Floor, Chicago, IL 60611 USA. EM mdm608@northwestern.edu FU National Heart, Lung, and Blood Institute (NHLBI) [R01-HL088589, R01-HL107510]; National Institutes on Aging (NIA); National Institutes of Health (NIH) FX Supported by R01-HL088589 and R01-HL107510 from the National Heart, Lung, and Blood Institute (NHLBI). Supported in part by the Intramural Research Program, National Institutes on Aging (NIA), and National Institutes of Health (NIH). NR 39 TC 1 Z9 1 U1 7 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD MAY PY 2015 VL 4 IS 5 AR e001659 DI 10.1161/JAHA.114.001659 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CK6OO UT WOS:000356347600005 ER PT J AU Behl, M Hsieh, JH Shafer, TJ Mundy, WR Rice, J Boyd, W Freedman, J Hunter, ES Jarema, K Padilla, S Tice, R AF Behl, Mamta Hsieh, Jui-Hua Shafer, Timothy J. Mundy, William R. Rice, Julie Boyd, Windy Freedman, Jonathan Hunter, E. Sidney, III Jarema, Kimberly Padilla, Stephanie Tice, Raymond TI Use of alternative assays to identify and prioritize potential developmental and neurotoxicity of emerging organophosphorous flame retardants SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Meeting Abstract CT 39th Annual Meeting of the Neurobehavioral-Teratology-Society (NBTS) / 15th Biennial Meeting of the International-Neurotoxicology-Association (INA) Held in Conjunction with the 55th Annual Meeting of the Teratology-Society CY JUN 27-JUL 01, 2015 CL Montreal, CANADA SP Neurobehavioral Teratol Soc, Int Neurotoxicol Assoc, Teratol Soc C1 [Behl, Mamta; Hsieh, Jui-Hua; Rice, Julie; Boyd, Windy; Freedman, Jonathan; Tice, Raymond] NIEHS, Res Triangle Pk, NC 27709 USA. [Shafer, Timothy J.; Mundy, William R.; Hunter, E. Sidney, III; Jarema, Kimberly; Padilla, Stephanie] S Environm Protect Agcy, Res Triangle Pk, NC USA. NR 0 TC 2 Z9 2 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0892-0362 EI 1872-9738 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD MAY-JUN PY 2015 VL 49 MA NTX26 BP 108 EP 109 DI 10.1016/j.ntt.2015.04.032 PG 2 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA CL7HI UT WOS:000357142700036 ER PT J AU Amano, M Tojo, Y Salcedo-Gomez, PM Parham, GL Nyalapatla, PR Das, D Ghosh, AK Mitsuya, H AF Amano, Masayuki Tojo, Yasushi Salcedo-Gomez, Pedro Miguel Parham, Garth L. Nyalapatla, Prasanth R. Das, Debananda Ghosh, Arun K. Mitsuya, Hiroaki TI A Novel Tricyclic Ligand-Containing Nonpeptidic HIV-1 Protease Inhibitor, GRL-0739, Effectively Inhibits the Replication of Multidrug-Resistant HIV-1 Variants and Has a Desirable Central Nervous System Penetration Property In Vitro SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; ANTIRETROVIRAL THERAPY; POTENT; PI; DESIGN; P-2-LIGANDS; DISCOVERY; INFECTION; PATTERNS; SURVIVAL AB We report here that GRL-0739, a novel nonpeptidic HIV-1 protease inhibitor containing a tricycle (cyclohexyl-bis-tetrahydrofuranylurethane [THF]) and a sulfonamide isostere, is highly active against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC50], 0.0019 to 0.0036 mu M), with minimal cytotoxicity (50% cytotoxic concentration [CC50], 21.0 mu M). GRL-0739 blocked the infectivity and replication of HIV-1(NL4-3) variants selected by concentrations of up to 5 mu M ritonavir or atazanavir (EC50, 0.035 to 0.058 mu M). GRL-0739 was also highly active against multidrug-resistant clinical HIV-1 variants isolated from patients who no longer responded to existing antiviral regimens after long-term antiretroviral therapy, as well as against the HIV-2(ROD) variant. The development of resistance against GRL-0739 was substantially delayed compared to that of amprenavir (APV). The effects of the nonspecific binding of human serum proteins on the anti-HIV-1 activity of GRL-0739 were insignificant. In addition, GRL-0739 showed a desirable central nervous system (CNS) penetration property, as assessed using a novel in vitro blood-brain barrier model. Molecular modeling demonstrated that the tricyclic ring and methoxybenzene of GRL-0739 have a larger surface and make greater van der Waals contacts with protease than in the case of darunavir. The present data demonstrate that GRL-0739 has desirable features as a compound with good CNS-penetrating capability for treating patients infected with wild-type and/or multidrug-resistant HIV-1 variants and that the newly generated cyclohexyl-bis-THF moiety with methoxybenzene confers highly desirable anti-HIV-1 potency in the design of novel protease inhibitors with greater CNS penetration profiles. C1 [Amano, Masayuki; Tojo, Yasushi; Salcedo-Gomez, Pedro Miguel; Mitsuya, Hiroaki] Kumamoto Univ, Sch Med, Dept Infect Dis, Kumamoto 860, Japan. [Amano, Masayuki; Tojo, Yasushi; Salcedo-Gomez, Pedro Miguel; Mitsuya, Hiroaki] Kumamoto Univ, Sch Med, Dept Hematol, Kumamoto 860, Japan. [Parham, Garth L.; Nyalapatla, Prasanth R.; Ghosh, Arun K.] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. [Parham, Garth L.; Nyalapatla, Prasanth R.; Ghosh, Arun K.] Purdue Univ, Dept Med Chem, W Lafayette, IN 47907 USA. [Das, Debananda; Mitsuya, Hiroaki] NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Mitsuya, Hiroaki] Natl Ctr Global Hlth & Med, Ctr Clin Sci, Tokyo, Japan. RP Mitsuya, H (reprint author), Kumamoto Univ, Sch Med, Dept Infect Dis, Kumamoto 860, Japan. EM hm21q@nih.gov RI Amano, Masayuki/N-7407-2016 OI Amano, Masayuki/0000-0003-0516-9502 FU global education and a research center aimed at the control of AIDS; Monbu-Kagakusho; Ministry of Health, Welfare, and Labor of Japan; grant to the Cooperative Research Project on Clinical and Epidemiological Studies of Emerging and Reemerging Infectious Diseases of Monbu-Kagakusho [78]; Intramural Research Program of Center for Cancer Research; National Cancer Institute; National Institutes of Health; National Center for Global Health and Medicine FX This work was supported in part by a grant for global education and a research center aimed at the control of AIDS (Global Center of Excellence supported by Monbu-Kagakusho), the promotion of AIDS research from the Ministry of Health, Welfare, and Labor of Japan, the grant to the Cooperative Research Project on Clinical and Epidemiological Studies of Emerging and Reemerging Infectious Diseases (Renkei Jigyo: no. 78, Kumamoto University) of Monbu-Kagakusho (to H.M.), the Intramural Research Program of Center for Cancer Research, the National Cancer Institute, the National Institutes of Health (to H.M.), a grant from the National Center for Global Health and Medicine (to H.M.), and a grant from the National Institutes of Health (grant GM53386 to A.K.G.). NR 38 TC 1 Z9 1 U1 0 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD MAY PY 2015 VL 59 IS 5 BP 2625 EP 2635 DI 10.1128/AAC.04757-14 PG 11 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA CL4DH UT WOS:000356902300019 PM 25691652 ER PT J AU Adelson, KB Ramaswamy, B Sparano, JA Christos, PJ Wright, JJ Raptis, G Villalona, MC Ma, CX Hershman, D Baar, J Klein, P Cigler, T Budd, GT Novik, Y Tan, AR Tannenbaum, S Goel, A Levine, E Shapiro, CL Andreopoulou, E Naughton, M Kalinsky, K Waxman, S Germain, D AF Adelson, Kerin B. Ramaswamy, Bhuvaneswari Sparano, Joseph A. Christos, Paul J. Wright, John J. Raptis, George Villalona, Miguel C. Ma, Cynthia X. Hershman, Dawn Baar, Joseph Klein, Paula Cigler, Tessa Budd, G. Thomas Novik, Yelena Tan, Antoinette R. Tannenbaum, Susan Goel, Anupama Levine, Ellis Shapiro, Charles L. Andreopoulou, Eleni Naughton, Michael Kalinsky, Kevin Waxman, Samuel Germain, Doris TI Randomized phase II trial of fulvestrant alone or in combination with bortezomib in hormone receptor-positive metastatic breast cancer resistant to aromatase inhibitors: A New York cancer consortium trial SO CANCER RESEARCH LA English DT Meeting Abstract CT 37th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 09-13, 2014 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 [Adelson, Kerin B.] Yale Univ, Sch Med, Yale Canc Inst, New Haven, CT 06520 USA. [Ramaswamy, Bhuvaneswari; Shapiro, Charles L.] Ohio State Univ, Columbus, OH 43210 USA. [Sparano, Joseph A.; Cigler, Tessa] Montefiore Med Ctr, Bronx, NY USA. [Christos, Paul J.; Andreopoulou, Eleni] Weill Cornell Med Ctr, New York, NY USA. [Wright, John J.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Raptis, George; Villalona, Miguel C.] North Shore LIJ Canc Inst, New York, NY USA. [Ma, Cynthia X.; Naughton, Michael] Washington Univ, Sch Med, St Louis, MO 63130 USA. [Hershman, Dawn; Kalinsky, Kevin] Columbia Univ, Med Ctr, New York, NY 10027 USA. [Baar, Joseph] Univ Hosp Cleveland, Cleveland, OH 44106 USA. [Klein, Paula] Mt Sinai Med Ctr Beth Israel, New York, NY USA. [Budd, G. Thomas] Cleveland Clin, Taussig Canc Inst, Cleveland, OH USA. [Novik, Yelena] NYU, Sch Med, New York, NY 10003 USA. [Tan, Antoinette R.] Rutgers Canc Inst New Jersey, New Brunswick, NJ USA. [Tannenbaum, Susan] Univ Connecticut, Ctr Hlth, Storrs, CT USA. [Goel, Anupama] Mt Sinai Med Ctr Roosevelt, New York, NY USA. [Levine, Ellis] Roswell Pk Canc Inst, Buffalo, NY USA. [Waxman, Samuel; Germain, Doris] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD MAY 1 PY 2015 VL 75 SU 9 MA S6-03 DI 10.1158/1538-7445.SABCS14-S6-03 PG 2 WC Oncology SC Oncology GA CL1UK UT WOS:000356730200041 ER PT J AU Anderson, KS Pepe, M Marks, J Engstrom, P Patriotis, C Zangar, R Skates, S Lampe, P LaBaer, J Li, CI AF Anderson, Karen S. Pepe, Margaret Marks, Jeffrey Engstrom, Paul Patriotis, Christos Zangar, Richard Skates, Steven Lampe, Paul LaBaer, Joshua Li, Christopher I. TI A blinded multicenter phase II study of a panel of plasma biomarkers for the detection of triple negative breast cancer SO CANCER RESEARCH LA English DT Meeting Abstract CT 37th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 09-13, 2014 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 [Anderson, Karen S.; LaBaer, Joshua] Arizona State Univ, Biodesign Inst, Tempe, AZ 85287 USA. [Pepe, Margaret; Lampe, Paul; Li, Christopher I.] Fred Hutchinson Canc Res Ctr, Seattle, WA USA. [Marks, Jeffrey] Duke Univ, Med Ctr, Durham, NC 27706 USA. [Engstrom, Paul] Fox Chase Canc Ctr, Philadelphia, PA USA. [Patriotis, Christos] Natl Canc Inst, Bethesda, MD USA. [Zangar, Richard] Pacific NW Natl Lab, Richland, WA USA. [Skates, Steven] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD MAY 1 PY 2015 VL 75 SU 9 MA P4-02-05 PG 2 WC Oncology SC Oncology GA CL1UK UT WOS:000356730202156 ER PT J AU Cittelly, DM Cruz, H Serkova, NJ Virginia, BF Peter, K Patricia, SS Carol, SA AF Cittelly, Diana M. Cruz, Hazel Serkova, Natalie J. Virginia, Borges F. Peter, Kabos Patricia, Steeg S. Carol, Sartorius A. TI Estrogen signaling through astrocytes promotes migration and invasion of ER-negative brain metastatic breast cancer cells SO CANCER RESEARCH LA English DT Meeting Abstract CT 37th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 09-13, 2014 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 [Cittelly, Diana M.; Cruz, Hazel; Serkova, Natalie J.; Virginia, Borges F.; Peter, Kabos; Carol, Sartorius A.] Univ Colorado, Boulder, CO 80309 USA. [Patricia, Steeg S.] NIH, Womens Malignancies Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD MAY 1 PY 2015 VL 75 SU 9 MA P4-04-04 PG 2 WC Oncology SC Oncology GA CL1UK UT WOS:000356730202164 ER PT J AU Giltnane, JM Balko, JM Stricker, TL Young, C Estrada, MV Wagle, N van Allen, E Mu, XJ Sanchez, V Farley, J Fitzgerald, K Graber, A Pinto, JA Doimi, F Gomez, H Rizzo, M Julian, TB Abramson, V Mayer, I Kelley, M Yenamandra, A Wheeler, FC Sanders, M Garraway, L Meszoely, I Arteaga, CL AF Giltnane, Jennifer M. Balko, Justin M. Stricker, Thomas L. Young, Christian Estrada, M. Valeria Wagle, Nikhil van Allen, Eliezer Mu, X. Jasmine Sanchez, Violeta Farley, Jaime Fitzgerald, Kerry Graber, Armin Pinto, Joseph A. Doimi, Franco Gomez, Henry Rizzo, Monica Julian, Thomas B. Abramson, Vandana Mayer, Ingrid Kelley, Mark Yenamandra, Ashwini Wheeler, Ferrin C. Sanders, Melinda Garraway, Levi Meszoely, Ingrid Arteaga, Carlos L. TI Recurrent ESR1 fusion transcripts are associated with endocrine resistance in estrogen receptor positive, HER2 negative breast cancer SO CANCER RESEARCH LA English DT Meeting Abstract CT 37th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 09-13, 2014 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 [Giltnane, Jennifer M.; Balko, Justin M.; Stricker, Thomas L.; Young, Christian; Estrada, M. Valeria; Sanchez, Violeta; Farley, Jaime; Abramson, Vandana; Mayer, Ingrid; Kelley, Mark; Yenamandra, Ashwini; Wheeler, Ferrin C.; Sanders, Melinda; Meszoely, Ingrid; Arteaga, Carlos L.] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Wagle, Nikhil; van Allen, Eliezer; Mu, X. Jasmine; Garraway, Levi] Broad Inst Harvard & MIT, Cambridge, MA USA. [Fitzgerald, Kerry; Graber, Armin] Genoptix, Carlsbad, CA USA. [Doimi, Franco; Gomez, Henry] Inst Nacl Enfermedades Neoplas, Lima, Peru. [Rizzo, Monica] Emory Univ, Atlanta, GA 30322 USA. [Julian, Thomas B.] Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. [Julian, Thomas B.] NSABP, Redwood City, CA USA. [Pinto, Joseph A.] Oncosalud AUNA, San Borja, Peru. NR 0 TC 1 Z9 1 U1 1 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD MAY 1 PY 2015 VL 75 SU 9 MA PD6-3 DI 10.1158/1538-7445.SABCS14-PD6-3 PG 2 WC Oncology SC Oncology GA CL1UK UT WOS:000356730200174 ER PT J AU Jerusalem, G Mariani, G Ciruelos, EM Martin, M Tjan-Heijnen, VCG Neven, P Gregori, JG Michelotti, A Montemurro, F Lang, I Mardiak, J Naume, B Camozzi, M Lorizzo, K Brenski, D Conte, P AF Jerusalem, Guy Mariani, Gabriella Ciruelos, Eva M. Martin, Miguel Tjan-Heijnen, Vivianne C. G. Neven, Patrick Gregori, Joaquin Gavila Michelotti, Andrea Montemurro, Filippo Lang, Istvan Mardiak, Josef Naume, Bjoem Camozzi, Maura Lorizzo, Katia Brenski, Dariusz Conte, Pierfranco TI Everolimus in combination with exemestane in hormone receptor-positive locally advanced or metastatic breast cancer (BC) patients progressing on prior nonsteroidal AI (NSAIs): Ballet study (CRAD001YIC04) SO CANCER RESEARCH LA English DT Meeting Abstract CT 37th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 09-13, 2014 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 [Jerusalem, Guy] CHU Sart Tilman Liege, Liege, Belgium. [Jerusalem, Guy] Univ Liege, B-4000 Liege, Belgium. [Mariani, Gabriella] Fdn IRCCS Inst Nazl Tumori, Milan, Italy. [Ciruelos, Eva M.] Univ Hosp 12 Octubre, Madrid, Spain. [Martin, Miguel] Hosp Gen Univ Gregorio Maranon, Madrid, Spain. [Tjan-Heijnen, Vivianne C. G.] Maastricht Univ, Med Ctr, NL-6200 MD Maastricht, Netherlands. [Neven, Patrick] Katholieke Univ Leuven, Louvain, Belgium. [Neven, Patrick] Univ Hosp Leuven, Louvain, Belgium. [Gregori, Joaquin Gavila] Fdn Inst Valenciano Oncol, Valencia, Spain. [Michelotti, Andrea] Univ Pisana, Santa Chiara Hosp, Azienda Osped, Pisa, Italy. [Montemurro, Filippo] Inst Candiolo Canc Ctr IRCCs, Fdn Piemonte Oncol, Candiolo, Italy. [Lang, Istvan] Natl Inst Oncol, New York, NY USA. [Mardiak, Josef] Natl Canc Inst, Bethesda, MD USA. [Naume, Bjoem] Oslo Univ Hosp, N-0450 Oslo, Norway. [Naume, Bjoem] Univ Oslo, Norwa & KG Jebsen Ctr Breast Canc Res, Inst Clin Med, N-0316 Oslo, Norway. [Camozzi, Maura; Lorizzo, Katia; Brenski, Dariusz] Novartis Farma SpA, Saronno, Italy. [Conte, Pierfranco] Ist Oncol Veneto IRCCS, Padua, Italy. [Conte, Pierfranco] Univ Padua, I-35100 Padua, Italy. RI Conte, PierFranco/F-7418-2014 OI Conte, PierFranco/0000-0002-5210-5344 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD MAY 1 PY 2015 VL 75 SU 9 MA P5-19-02 DI 10.1158/1538-7445.SABCS14-P5-19-02 PG 2 WC Oncology SC Oncology GA CL1UK UT WOS:000356730203155 ER PT J AU Paik, S Pogue-Geile, KL Song, N Gavin, PG Kim, SR AF Paik, Soonmyung Pogue-Geile, Katherine L. Song, Nan Gavin, Patrick G. Kim, Seong-Rim TI Intrinsic subtypes, PIK3CA mutation, and the degree of benefit from adjuvant trastuzumab in NSABP trial B-31 SO CANCER RESEARCH LA English DT Meeting Abstract CT 37th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 09-13, 2014 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 [Paik, Soonmyung; Pogue-Geile, Katherine L.; Song, Nan; Gavin, Patrick G.; Kim, Seong-Rim] NSABP, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD MAY 1 PY 2015 VL 75 SU 9 MA S3-05 DI 10.1158/1538-7445.SABCS14-S3-05 PG 2 WC Oncology SC Oncology GA CL1UK UT WOS:000356730200022 ER PT J AU Ru, YB Mural, RJ Steeg, PS Rui, H Shriver, CD Hu, H AF Ru, Yuanbin Mural, Richard J. Steeg, Patricia S. Rui, Hallgeir Shriver, Craig D. Hu, Hai TI Age independently predicts worse disease-specific survival in patients diagnosed with invasive breast cancers at 50 years of age or older but not younger SO CANCER RESEARCH LA English DT Meeting Abstract CT 37th Annual CTRC-AACR San Antonio Breast Cancer Symposium CY DEC 09-13, 2014 CL San Antonio, TX SP Canc Therapy Res Ctr, Amer Assoc Canc Res C1 [Ru, Yuanbin; Mural, Richard J.; Hu, Hai] Windber Res Inst, Windber, PA USA. [Steeg, Patricia S.] Natl Canc Inst, Bethesda, MD USA. [Rui, Hallgeir] Thomas Jefferson Univ, Philadelphia, PA USA. [Shriver, Craig D.] Walter Reed Natl Mil Med Ctr, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD MAY 1 PY 2015 VL 75 SU 9 MA P6-08-24 DI 10.1158/1538-7445.SABCS14-P6-08-24 PG 2 WC Oncology SC Oncology GA CL1UK UT WOS:000356730203269 ER PT J AU Roshanravan, B Patel, KV Robinson-Cohen, C de Boer, IH O'Hare, AM Ferrucci, L Himmelfarb, J Kestenbaum, B AF Roshanravan, Baback Patel, Kushang V. Robinson-Cohen, Cassianne de Boer, Ian H. O'Hare, Ann M. Ferrucci, Luigi Himmelfarb, Jonathan Kestenbaum, Bryan TI Creatinine Clearance, Walking Speed, and Muscle Atrophy: A Cohort Study SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Physical performance; skeletal muscle composition; muscle strength; mobility impairment; muscle atrophy; longitudinal trajectory; creatinine clearance (Clcr); renal function; chronic kidney disease (CKD) ID CHRONIC KIDNEY-DISEASE; OLDER-ADULTS; BODY-COMPOSITION; CYSTATIN-C; GAIT-SPEED; PHYSICAL PERFORMANCE; GLUCOSE-INTOLERANCE; MOBILITY DISABILITY; PROTEIN-DEGRADATION; METABOLIC-ACIDOSIS AB Background: Chronic kidney disease is associated with malnutrition and inflammation. These processes may lead to loss of skeletal muscle and reduced physical performance. Associations of kidney function with muscle composition and longitudinal measures of physical performance are unknown. Study Design: Prospective cohort study. Setting & Participants: We evaluated 826 community-dwelling older adults enrolled in the Invecchiare in Chianti (InCHIANTI) Study who were free of baseline stroke or activities of daily living disability. Predictor: Baseline creatinine clearance (Clcr) based on 24-hour urine collection. Outcomes: Cross-sectional and longitudinal trajectories of physical performance measured by 7-m usual gait speed, 400-m fast gait speed, and knee extension strength using isometric dynamometry. Calf muscle composition assessed by quantitative computed tomography. Results: Mean age of participants was 74 +/- 7 (SD) years, with 183 having Clcr < 60 mL/min/1.73 m(2). After adjustment, each 10-mL/min/1.73 m(2) decrement in Clcr was associated with 0.01 (95% CI, 0.004-0.017) m/s slower 7-m usual walking speed and 0.008 (95% CI, 0.002-0.014) m/s slower 400-m walking speed. Each 10-mL/min/1.73 m(2) decrement in Clcr was associated with 28 (95% CI, 0.8-55) mm(2) lower muscle area and 0.15 (95% CI, 0.04-0.26) mg/cm(3) lower muscle density. After adjustment, lower Clcr was associated with slower mean 7-m (P = 0.005) and 400-m (P = 0.02) walk and knee extension strength (P = 0.001) during the course of follow-up. During a mean follow-up of 7.1 +/- 2.5 years, each 10-mL/min/1.73 m(2) lower baseline Clcr was associated with 0.024 (95% CI, 0.01-0.037) kg/y greater decline in knee strength. Limitations: Single baseline measurement of Clcr and 3-year interval between follow-up visits may lead to nondifferential misclassification and attenuation of estimates. Conclusions: Among older adults, lower Clcr is associated with muscle atrophy, reduced walking speed, and more rapid declines in lower-extremity strength over time. (C) 2015 by the National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. C1 [Roshanravan, Baback; Robinson-Cohen, Cassianne; de Boer, Ian H.; Himmelfarb, Jonathan; Kestenbaum, Bryan] Univ Washington, Div Nephrol, Kidney Res Inst, Dept Med, Seattle, WA 98104 USA. [Patel, Kushang V.] Univ Washington, Dept Anesthesiol & Pain Med, Seattle, WA 98104 USA. [O'Hare, Ann M.] Univ Washington, Vet Affairs Puget Sound Healthcare Syst, Seattle, WA 98104 USA. [Ferrucci, Luigi] NIA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Roshanravan, B (reprint author), Univ Washington, Div Nephrol, Kidney Res Inst, Box 359606,325 9th Ave, Seattle, WA 98104 USA. EM broshanr@u.washington.edu OI Robinson-Cohen, Cassianne/0000-0003-4783-7046 FU Italian Ministry of Health [ICS110.1/RF97.71]; National Institute on Aging (NIA), National Institutes of Health (NIH); NIA [N.1-AG-1-1, N.1-AG-1-2111, N01-AG-5-0002, 1 Z01 AG001050-01]; NIH [1K23DK099442-01] FX The InCHIANTI Study baseline (1998-2000) was supported as a "targeted project" by the Italian Ministry of Health (ICS110.1/RF97.71) and in part by the Intramural Research Program of the National Institute on Aging (NIA), National Institutes of Health (NIH); the InCHIANTI follow-ups were supported by the NIA (N.1-AG-1-1, N.1-AG-1-2111, N01-AG-5-0002, and 1 Z01 AG001050-01). This work was also supported by NIH 1K23DK099442-01 (Dr Rashanravan). NR 37 TC 7 Z9 7 U1 4 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 EI 1523-6838 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD MAY PY 2015 VL 65 IS 5 BP 737 EP 747 DI 10.1053/j.ajkd.2014.10.016 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA CL1SA UT WOS:000356723300016 PM 25542415 ER PT J AU Ribeiro, JMC Schwarz, A Francischetti, IMB AF Ribeiro, Jose M. C. Schwarz, Alexandra Francischetti, Ivo M. B. TI A Deep Insight Into the Sialotranscriptome of the Chagas Disease Vector, Panstrongylus megistus (Hemiptera: Heteroptera) SO JOURNAL OF MEDICAL ENTOMOLOGY LA English DT Article DE Chagas disease; vector biology; salivary gland; transcriptome; medical entomology ID TRIATOMA-INFESTANS; PLATELET-AGGREGATION; BOOPHILUS-MICROPLUS; SEQUENCE ALIGNMENT; SALIVARY PROTEIN; CATTLE TICK; TRANSCRIPTOME; EXPRESSION; FAMILY; PREDICTION AB Saliva of blood-sucking arthropods contains a complex cocktail of pharmacologically active compounds that assists feeding by counteracting their hosts' hemostatic and inflammatory reactions. Panstrongylus megistus (Burmeister) is an important vector of Chagas disease in South America, but despite its importance there is only one salivary protein sequence publicly deposited in GenBank. In the present work, we used Illumina technology to disclose and publicly deposit 3,703 coding sequences obtained from the assembly of >70 million reads. These sequences should assist proteomic experiments aimed at identifying pharmacologically active proteins and immunological markers of vector exposure. C1 [Ribeiro, Jose M. C.; Francischetti, Ivo M. B.] NIAAA, Lab Malaria & Vector Res, Rockville, MD 20852 USA. [Schwarz, Alexandra] Acad Sci Czech Republic, Inst Parasitol, Ctr Biol, CZ-37005 Ceske Budejovice, Czech Republic. RP Ribeiro, JMC (reprint author), NIAAA, Lab Malaria & Vector Res, 12735 Twinbrook Pkwy, Rockville, MD 20852 USA. EM jribeiro@niaid.nih.gov OI Ribeiro, Jose/0000-0002-9107-0818 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA [Z01 AI000810-16]; Grant Agency of the Czech Republic [P302/11/P798]; Ministry of Education, Youth and Sports of the Czech Republic (KONTAKT II) [LH12002]; Academy of Sciences of the Czech Republic [Z60220518] FX We are thankful to Dr. John Andersen for critical review of the manuscript. This work was partially supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA, (project Z01 AI000810-16: Vector-Borne Diseases: Biology Of Vector Host Relationship) and by a grant from the Grant Agency of the Czech Republic (Grant P302/11/P798), the Ministry of Education, Youth and Sports of the Czech Republic (KONTAKT II grant LH12002), and the Academy of Sciences of the Czech Republic (grant Z60220518). NR 60 TC 8 Z9 8 U1 1 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-2585 EI 1938-2928 J9 J MED ENTOMOL JI J. Med. Entomol. PD MAY PY 2015 VL 52 IS 3 BP 351 EP 358 DI 10.1093/jme/tjv023 PG 8 WC Entomology; Veterinary Sciences SC Entomology; Veterinary Sciences GA CL1RC UT WOS:000356720600008 PM 26334808 ER PT J AU Ochs, C Geller, J Perl, Y Chen, Y Xu, JC Min, H Case, JT Wei, Z AF Ochs, Christopher Geller, James Perl, Yehoshua Chen, Yan Xu, Junchuan Min, Hua Case, James T. Wei, Zhi TI Scalable quality assurance for large SNOMED CT hierarchies using subject-based subtaxonomies SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article DE SNOMED CT; terminology quality assurance; standards quality assurance; abstraction network; scalable quality assurance; subject-based terminology quality assurance ID COMPLEX CONCEPTS; TERMINOLOGY; REPRESENTATION; ABSTRACTION; DISEASES; EHEALTH AB Objective Standards terminologies may be large and complex, making their quality assurance challenging. Some terminology quality assurance (TQA) methodologies are based on abstraction networks (AbNs), compact terminology summaries. We have tested AbNs and the performance of related TQA methodologies on small terminology hierarchies. However, some standards terminologies, for example, SNOMED, are composed of very large hierarchies. Scaling AbN TQA techniques to such hierarchies poses a significant challenge. We present a scalable subject-based approach for AbN TQA. Methods An innovative technique is presented for scaling TQA by creating a new kind of subject-based AbN called a subtaxonomy for large hierarchies. New hypotheses about concentrations of erroneous concepts within the AbN are introduced to guide scalable TQA. Results We test the TQA methodology for a subject-based subtaxonomy for the Bleeding subhierarchy in SNOMED's large Clinical finding hierarchy. To test the error concentration hypotheses, three domain experts reviewed a sample of 300 concepts. A consensus-based evaluation identified 87 erroneous concepts. The subtaxonomy-based TQA methodology was shown to uncover statistically significantly more erroneous concepts when compared to a control sample. Discussion The scalability of TQA methodologies is a challenge for large standards systems like SNOMED. We demonstrated innovative subject-based TQA techniques by identifying groups of concepts with a higher likelihood of having errors within the subtaxonomy. Scalability is achieved by reviewing a large hierarchy by subject. Conclusions An innovative methodology for scaling the derivation of AbNs and a TQA methodology was shown to perform successfully for the largest hierarchy of SNOMED. C1 [Ochs, Christopher; Geller, James; Perl, Yehoshua; Wei, Zhi] New Jersey Inst Technol, Dept Comp Sci, Newark, NJ 07102 USA. [Chen, Yan] CUNY, BMCC, Comp Informat Syst Dept, New York, NY 10021 USA. [Xu, Junchuan] NYU, Div Knowledge Informat, New York, NY USA. [Min, Hua] George Mason Univ, Dept Hlth Adm & Policy, Fairfax, VA 22030 USA. [Case, James T.] NIH, Natl Lib Med, Bethesda, MD 20892 USA. RP Ochs, C (reprint author), New Jersey Inst Technol, Dept Comp Sci, Newark, NJ 07102 USA. EM cro3@njit.edu FU NCI NIH HHS [R01 CA190779] NR 39 TC 6 Z9 6 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1067-5027 EI 1527-974X J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD MAY PY 2015 VL 22 IS 3 BP 507 EP 518 DI 10.1136/amiajnl-2014-003151 PG 12 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA CL1PV UT WOS:000356717100004 PM 25336594 ER PT J AU Deckard, J McDonald, CJ Vreeman, DJ AF Deckard, Jamalynne McDonald, Clement J. Vreeman, Daniel J. TI Supporting interoperability of genetic data with LOINC SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article DE Genetics; LOINC; Medical records systems; Clinical laboratory information systems; Vocabulary; controlled ID ELECTRONIC HEALTH RECORD; CLINICAL DOCUMENT NAMES; ALLELE NOMENCLATURE; SUGGESTIONS; ONTOLOGY; GENOMICS AB Electronic reporting of genetic testing results is increasing, but they are often represented in diverse formats and naming conventions. Logical Observation Identifiers Names and Codes (LOINC) is a vocabulary standard that provides universal identifiers for laboratory tests and clinical observations. In genetics, LOINC provides codes to improve interoperability in the midst of reporting style transition, including codes for cytogenetic or mutation analysis tests, specific chromosomal alteration or mutation testing, and fully structured discrete genetic test reporting. LOINC terms follow the recommendations and nomenclature of other standards such as the Human Genome Organization Gene Nomenclature Committee's terminology for gene names. In addition to the narrative text they report now, we recommend that laboratories always report as discrete variables chromosome analysis results, genetic variation(s) found, and genetic variation(s) tested for. By adopting and implementing data standards like LOINC, information systems can help care providers and researchers unlock the potential of genetic information for delivering more personalized care. C1 [Deckard, Jamalynne; Vreeman, Daniel J.] Regenstrief Inst Inc, Indianapolis, IN 46202 USA. [McDonald, Clement J.] NIH, Lister Hill Natl Ctr Biomed Commun, Natl Lib Med, Bethesda, MD 20892 USA. [Vreeman, Daniel J.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. RP Deckard, J (reprint author), Regenstrief Inst Inc, 410 W 10th St,Suite 2000, Indianapolis, IN 46202 USA. EM jkdeckar@regenstrief.org FU National Library of Medicine [HSN2762008000006C, HHSN276201400138P, HHSN276201400239P] FX This work was supported by the National Library of Medicine grant numbers HSN2762008000006C, HHSN276201400138P, and HHSN276201400239P. NR 36 TC 3 Z9 3 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1067-5027 EI 1527-974X J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD MAY PY 2015 VL 22 IS 3 BP 621 EP 627 DI 10.1093/jamia/ocu012 PG 7 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA CL1PV UT WOS:000356717100016 PM 25656513 ER PT J AU Ochs, C Geller, J Perl, Y Chen, Y Agrawal, A Case, JT Hripcsak, G AF Ochs, Christopher Geller, James Perl, Yehoshua Chen, Yan Agrawal, Ankur Case, James T. Hripcsak, George TI A tribal abstraction network for SNOMED CT target hierarchies without attribute relationships SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article DE SNOMED CT; terminology quality assurance; abstraction network; terminology without lateral relationships; hierarchical abstraction network; terminology summarization ID OBJECT-ORIENTED DATABASE; COMPLEX CONCEPTS; NCI THESAURUS; UMLS; TERMINOLOGY; REPRESENTATION; DISEASES; DESIGN AB Objective Large and complex terminologies, such as Systematized Nomenclature of Medicine-Clinical Terms (SNOMED CT), are prone to errors and inconsistencies. Abstraction networks are compact summarizations of the content and structure of a terminology. Abstraction networks have been shown to support terminology quality assurance. In this paper, we introduce an abstraction network derivation methodology which can be applied to SNOMED CT target hierarchies whose classes are defined using only hierarchical relationships (ie, without attribute relationships) and similar description-logic-based terminologies. Methods We introduce the tribal abstraction network (TAN), based on the notion of a tribe-a subhierarchy rooted at a child of a hierarchy root, assuming only the existence of concepts with multiple parents. The TAN summarizes a hierarchy that does not have attribute relationships using sets of concepts, called tribal units that belong to exactly the same multiple tribes. Tribal units are further divided into refined tribal units which contain closely related concepts. A quality assurance methodology that utilizes TAN summarizations is introduced. Results A TAN is derived for the Observable entity hierarchy of SNOMED CT, summarizing its content. A TAN-based quality assurance review of the concepts of the hierarchy is performed, and erroneous concepts are shown to appear more frequently in large refined tribal units than in small refined tribal units. Furthermore, more erroneous concepts appear in large refined tribal units of more tribes than of fewer tribes. Conclusions In this paper we introduce the TAN for summarizing SNOMED CT target hierarchies. A TAN was derived for the Observable entity hierarchy of SNOMED CT. A quality assurance methodology utilizing the TAN was introduced and demonstrated. C1 [Ochs, Christopher; Geller, James; Perl, Yehoshua] New Jersey Inst Technol, Dept Comp Sci, Newark, NJ 07102 USA. [Chen, Yan] CUNY, BMCC, Comp Informat Syst Dept, New York, NY 10021 USA. [Agrawal, Ankur] Manhattan Coll, Dept Comp Sci, Riverdale, NY USA. [Case, James T.] NIH, Natl Lib Med, Bethesda, MD 20892 USA. [Hripcsak, George] Columbia Univ, Dept Biomed Informat, New York, NY USA. RP Ochs, C (reprint author), New Jersey Inst Technol, Dept Comp Sci, Newark, NJ 07102 USA. EM cro3@njit.edu FU NCI NIH HHS [R01 CA190779] NR 43 TC 6 Z9 6 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1067-5027 EI 1527-974X J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD MAY PY 2015 VL 22 IS 3 BP 628 EP 639 DI 10.1136/amiajnl-2014-003173 PG 12 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA CL1PV UT WOS:000356717100017 PM 25332354 ER PT J AU Fung, KW Xu, JL AF Fung, Kin Wah Xu, Julia TI An exploration of the properties of the CORE problem list subset and how it facilitates the implementation of SNOMED CT SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article DE problem-oriented medical record; problem list; electronic health record; SNOMED Clinical Terms; controlled medical terminology; medical vocabulary ID ELECTRONIC HEALTH RECORDS; MEANINGFUL USE; CLASSIFICATION; TERMINOLOGIES; SYSTEM AB Objective Systematized Nomenclature of Medicine Clinical Terms (SNOMED CT) is the emergent international health terminology standard for encoding clinical information in electronic health records. The CORE Problem List Subset was created to facilitate the terminology's implementation. This study evaluates the CORE Subset's coverage and examines its growth pattern as source datasets are being incorporated. Methods Coverage of frequently used terms and the corresponding usage of the covered terms were assessed by "leave-one-out" analysis of the eight datasets constituting the current CORE Subset. The growth pattern was studied using a retrospective experiment, growing the Subset one dataset at a time and examining the relationship between the size of the starting subset and the coverage of frequently used terms in the incoming dataset. Linear regression was used to model that relationship. Results On average, the CORE Subset covered 80.3% of the frequently used terms of the left-out dataset, and the covered terms accounted for 83.7% of term usage. There was a significant positive correlation between the CORE Subset's size and the coverage of the frequently used terms in an incoming dataset. This implies that the CORE Subset will grow at a progressively slower pace as it gets bigger. Conclusion The CORE Problem List Subset is a useful resource for the implementation of Systematized Nomenclature of Medicine Clinical Terms in electronic health records. It offers good coverage of frequently used terms, which account for a high proportion of term usage. If future datasets are incorporated into the CORE Subset, it is likely that its size will remain small and manageable. C1 [Fung, Kin Wah; Xu, Julia] Natl Lib Med, Bethesda, MD 20894 USA. RP Fung, KW (reprint author), Natl Lib Med, Bldg 38A,Rm9S914,MSC 3826,8600 Rockville Pike, Bethesda, MD 20894 USA. EM kwfung@nlm.nih.gov FU Intramural Research Program of the National Institutes of Health, National Library of Medicine FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 35 TC 0 Z9 0 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1067-5027 EI 1527-974X J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD MAY PY 2015 VL 22 IS 3 BP 649 EP 658 DI 10.1093/jamia/ocu022 PG 10 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA CL1PV UT WOS:000356717100019 PM 25725003 ER PT J AU Boehm, EWA Marson, G Mathiassen, GH Gardiennet, A Schoch, CL AF Boehm, Eric W. A. Marson, Guy Mathiassen, Geir H. Gardiennet, Alain Schoch, Conrad L. TI An overview of the genus Glyphium and its phylogenetic placement in Patellariales SO MYCOLOGIA LA English DT Article DE Bayesian; maximum likelihood; multigene phylogeny; Patellariaceae ID RIBOSOMAL DNA-SEQUENCES; NUCLEAR; ASCOMYCOTA; ALIGNMENT; PLEOSPOROMYCETIDAE; MYTILINIDIACEAE; HYSTERIACEAE; SYSTEMATICS; EVOLUTION; FAMILY AB Glyphium encompasses species with erect, carbonaceous ligulate to dolabrate ascomata that are strongly laterally compressed and dehisce along a longitudinal slit. The five currently recognized members of the genus are separated primarily by whether the ascospores disassociate into part-spores within the ascus. Glyphium has traditionally been placed in Mytilinidiaceae (Mytilinidiales, Pleosporomycetidae, Dothideomycetes). The present study, based on freshly collected material of G. elatum and G. grisonense, was initiated to determine the phylogenetic placement of Glyphium. Phylogenies inferred from the analysis of sequences of six gene regions (nuLSU, nuSSU, mtSSU, TEF1, RPB1, RPB2) derived from six accessions indicate that Glyphium belongs to Patellariales (Pleosporomycetidae, Dothideomycetes). Our phylogenies also support the phylogenetic relationship of Patellaria and Hysteropatella within this order. The nomenclatural history of Glyphium is summarized and a key to species is provided. C1 [Marson, Guy] Museum Nat Hist, Div Mycol, L-2160 Luxembourg, Luxembourg. [Mathiassen, Geir H.] Arctic Univ Norway, Tromso Univ Museum, Dept Nat Sci, NO-9037 Tromso, Norway. [Schoch, Conrad L.] NIH, Natl Ctr Biotechnol NCBI, Natl Lib Med, Bethesda, MD 20892 USA. RP Schoch, CL (reprint author), NIH, Natl Ctr Biotechnol NCBI, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM schoch2@ncbi.nlm.nih.gov FU Intramural Research Program of the National Institutes of Health, National Library of Medicine FX We thank Teppo Rama (University of Tromso) for a critical reading of the manuscript. CLS acknowledges support from the Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 56 TC 2 Z9 2 U1 0 U2 0 PU ALLEN PRESS INC PI LAWRENCE PA 810 E 10TH ST, LAWRENCE, KS 66044 USA SN 0027-5514 EI 1557-2536 J9 MYCOLOGIA JI Mycologia PD MAY-JUN PY 2015 VL 107 IS 3 BP 607 EP 618 DI 10.3852/14-191 PG 12 WC Mycology SC Mycology GA CL4EX UT WOS:000356906500012 PM 25661715 ER PT J AU Lavender, CA Gorelick, RJ Weeks, KM AF Lavender, Christopher A. Gorelick, Robert J. Weeks, Kevin M. TI Structure-Based Alignment and Consensus Secondary Structures for Three HIV-Related RNA Genomes SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; MULTIPLE SEQUENCE ALIGNMENT; REVERSE-TRANSCRIPTASE; NUCLEOTIDE-SEQUENCE; MUTATIONAL ANALYSIS; MOLECULAR CLONE; DNA-SYNTHESIS; IN-VIVO; SHAPE; PROTEIN AB HIV and related primate lentiviruses possess single-stranded RNA genomes. Multiple regions of these genomes participate in critical steps in the viral replication cycle, and the functions of many RNA elements are dependent on the formation of defined structures. The structures of these elements are still not fully understood, and additional functional elements likely exist that have not been identified. In this work, we compared three full-length HIV-related viral genomes: HIV-1(NL4-3), SIVcpz, and SIVmac (the latter two strains are progenitors for all HIV-1 and HIV-2 strains, respectively). Model-free RNA structure comparisons were performed using whole-genome structure information experimentally derived from nucleotide-resolution SHAPE reactivities. Consensus secondary structures were constructed for strongly correlated regions by taking into account both SHAPE probing structural data and nucleotide covariation information from structure-based alignments. In these consensus models, all known functional RNA elements were recapitulated with high accuracy. In addition, we identified multiple previously unannotated structural elements in the HIV-1 genome likely to function in translation, splicing and other replication cycle processes; these are compelling targets for future functional analyses. The structure-informed alignment strategy developed here will be broadly useful for efficient RNA motif discovery. C1 [Lavender, Christopher A.; Weeks, Kevin M.] Univ N Carolina, Dept Chem, Chapel Hill, NC 27514 USA. [Gorelick, Robert J.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, Frederick, MD USA. RP Lavender, CA (reprint author), Univ N Carolina, Dept Chem, Chapel Hill, NC 27514 USA. EM weeks@unc.edu FU National Institutes of Health [AI068462]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Leidos Biomedical Research FX This work was supported by the National Institutes of Health (grant AI068462 to KMW) and with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E with Leidos Biomedical Research (RJG). 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 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD MAY PY 2015 VL 11 IS 5 AR UNSP e1004230 DI 10.1371/journal.pcbi.1004230 PG 19 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA CL1KA UT WOS:000356700200019 PM 25992893 ER PT J AU Luna, A McFadden, GB Aladjem, MI Kohn, KW AF Luna, Augustin McFadden, Geoffrey B. Aladjem, Mirit I. Kohn, Kurt W. TI Predicted Role of NAD Utilization in the Control of Circadian Rhythms during DNA Damage Response SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID CLOCK GENE; SALVAGE PATHWAY; REGULATOR CLOCK; CANCER; SIRT1; MODEL; DEACETYLATION; OSCILLATIONS; ACETYLATION; EPSILON AB The circadian clock is a set of regulatory steps that oscillate with a period of approximately 24 hours influencing many biological processes. These oscillations are robust to external stresses, and in the case of genotoxic stress (i.e. DNA damage), the circadian clock responds through phase shifting with primarily phase advancements. The effect of DNA damage on the circadian clock and the mechanism through which this effect operates remains to be thoroughly investigated. Here we build an in silico model to examine damage-induced circadian phase shifts by investigating a possible mechanism linking circadian rhythms to metabolism. The proposed model involves two DNA damage response proteins, SIRT1 and PARP1, that are each consumers of nicotinamide adenine dinucleotide (NAD), a metabolite involved in oxidation-reduction reactions and in ATP synthesis. This model builds on two key findings: 1) that SIRT1 (a protein deacetylase) is involved in both the positive (i.e. transcriptional activation) and negative (i.e. transcriptional repression) arms of the circadian regulation and 2) that PARP1 is a major consumer of NAD during the DNA damage response. In our simulations, we observe that increased PARP1 activity may be able to trigger SIRT1-induced circadian phase advancements by decreasing SIRT1 activity through competition for NAD supplies. We show how this competitive inhibition may operate through protein acetylation in conjunction with phosphorylation, consistent with reported observations. These findings suggest a possible mechanism through which multiple perturbations, each dominant during different points of the circadian cycle, may result in the phase advancement of the circadian clock seen during DNA damage. C1 [Luna, Augustin; Aladjem, Mirit I.; Kohn, Kurt W.] NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA. [Luna, Augustin] Boston Univ, Dept Bioinformat, Boston, MA 02215 USA. [McFadden, Geoffrey B.] NIST, Appl & Computat Math Div, Gaithersburg, MD 20899 USA. RP Luna, A (reprint author), NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA. EM augustin@mail.nih.gov RI Aladjem, Mirit/G-2169-2010; McFadden, Geoffrey/A-7920-2008 OI Aladjem, Mirit/0000-0002-1875-3110; McFadden, Geoffrey/0000-0001-6723-2103 FU NIH, National Cancer Institute, Center for Cancer Research FX This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 2 Z9 3 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD MAY PY 2015 VL 11 IS 5 AR e1004144 DI 10.1371/journal.pcbi.1004144 PG 23 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA CL1KA UT WOS:000356700200005 PM 26020938 ER PT J AU Berger, VW AF Berger, Vance W. TI A NOTE ON NON-INFERIORITY MARGINS RE: CRITICALLY APPRAISING NONINFERIORITY RANDOMIZED CONTROLLED TRIALS: A PRIMER FOR EMERGENCY PHYSICIANS SO CANADIAN JOURNAL OF EMERGENCY MEDICINE LA English DT Letter C1 [Berger, Vance W.] NCI, Rockville, MD 20852 USA. [Berger, Vance W.] Univ Maryland Baltimore Cty, Baltimore, MD 21228 USA. RP Berger, VW (reprint author), NCI, Rockville, MD 20852 USA. NR 3 TC 1 Z9 1 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1481-8035 EI 1481-8043 J9 CAN J EMERG MED JI Can. J. Emerg. Med. PD MAY PY 2015 VL 17 IS 3 BP 237 EP 238 DI 10.1017/cem.2015.40 PG 2 WC Emergency Medicine SC Emergency Medicine GA CK2RY UT WOS:000356060800003 PM 26034907 ER PT J AU Sun, JH Nguyen, T Aponte, AM Menazza, S Kohr, MJ Roth, DM Patel, HH Murphy, E Steenbergen, C AF Sun, Junhui Nguyen, Tiffany Aponte, Angel M. Menazza, Sara Kohr, Mark J. Roth, David M. Patel, Hemal H. Murphy, Elizabeth Steenbergen, Charles TI Ischaemic preconditioning preferentially increases protein S-nitrosylation in subsarcolemmal mitochondria SO CARDIOVASCULAR RESEARCH LA English DT Article DE Protein S-nitrosylation; Ischaemic preconditioning; Caveolae; Subsarcolemmal and interfibrillar mitochondria ID NITRIC-OXIDE SYNTHASE; ISCHEMIA/REPERFUSION INJURY; CARDIOMYOCYTE MITOCHONDRIA; CARDIAC PROTECTION; ENDOTHELIAL-CELLS; CAVEOLAE; HEART; CARDIOPROTECTION; INTERNALIZATION; TRAFFICKING AB Nitric oxide (NO) and protein S-nitrosylation (SNO) have been shown to play important roles in ischaemic preconditioning (IPC)-induced acute cardioprotection. The majority of proteins that show increased SNO following IPC are localized to the mitochondria, and our recent studies suggest that caveolae transduce acute NO/SNO cardioprotective signalling in IPC hearts. Due to the close association between subsarcolemmal mitochondria (SSM) and the sarcolemma/caveolae, we tested the hypothesis that SSM, rather than the interfibrillar mitochondria (IFM), are major targets for NO/SNO signalling derived from caveolae-associated eNOS. Following either control perfusion or IPC, SSM and IFM were isolated from Langendorff perfused mouse hearts, and SNO was analysed using a modified biotin switch method with fluorescent maleimide fluors. In perfusion control hearts, the SNO content was higher in SSM compared with IFM (1.33 +/- 0.19, ratio of SNO content Perf-SSM vs. Perf-IFM), and following IPC SNO content significantly increased preferentially in SSM, but not in IFM (1.72 +/- 0.17 and 1.07 +/- 0.04, ratio of SNO content IPC-SSM vs. Perf-IFM, and IPC-IFM vs. Perf-IFM, respectively). Consistent with these findings, eNOS, caveolin-3, and connexin-43 were detected in SSM, but not in IFM, and IPC resulted in a further significant increase in eNOS/caveolin-3 levels in SSM. Interestingly, we did not observe an IPC-induced increase in SNO or eNOS/caveolin-3 in SSM isolated from caveolin-3(-/-) mouse hearts, which could not be protected with IPC. In conclusion, these results suggest that SSM may be the preferential target of sarcolemmal signalling-derived post-translational protein modification (caveolae-derived eNOS/NO/SNO), thus providing an important role in IPC-induced cardioprotection. C1 [Sun, Junhui; Nguyen, Tiffany; Aponte, Angel M.; Menazza, Sara; Kohr, Mark J.; Murphy, Elizabeth] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. [Aponte, Angel M.] NHLBI, Prote Core Facil, NIH, Bethesda, MD 20892 USA. [Kohr, Mark J.; Steenbergen, Charles] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. [Roth, David M.; Patel, Hemal H.] VA San Diego Healthcare Syst, Dept Anesthesiol, La Jolla, CA 92093 USA. [Roth, David M.; Patel, Hemal H.] Univ Calif San Diego, La Jolla, CA 92093 USA. RP Sun, JH (reprint author), NHLBI, Syst Biol Ctr, NIH, 10 Ctr Dr,Bldg10 Rm8N206, Bethesda, MD 20892 USA. EM sun1@mail.nih.gov FU NIH [1K99HL114721, 5R01HL039752, HL091071, HL107200, HL066941]; VA Merit [BX001963, BX000783] FX This work was supported by the NIH Intramural Program (J.S., T.N., A. A., S.M., and E.M.), 1K99HL114721 (M.K.), 5R01HL039752 (C.S.), HL091071 (H.H.P.), HL107200 (H.H.P. and D.M.R.), HL066941 (D.M.R. and H.H.P.), VA Merit BX001963 (H.H.P.), and VA Merit BX000783 (D.M.R.). NR 50 TC 20 Z9 21 U1 1 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0008-6363 EI 1755-3245 J9 CARDIOVASC RES JI Cardiovasc. Res. PD MAY 1 PY 2015 VL 106 IS 2 BP 227 EP 236 DI 10.1093/cvr/cvv044 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CK4GT UT WOS:000356182900009 PM 25694588 ER PT J AU Zhang, NN Park, YD Williamson, PR AF Zhang, Nannan Park, Yoon-Dong Williamson, Peter R. TI New technology and resources for cryptococcal research SO FUNGAL GENETICS AND BIOLOGY LA English DT Article DE Cryptococcus neoformans; Cryptococcus gattii; Cryptococcosis; Pathogenic fungus; RNAi; Yeast ID SIGNATURE-TAGGED MUTAGENESIS; NEOFORMANS GENE-EXPRESSION; CELL-WALL INTEGRITY; WHEAT-GERM LECTIN; VIRULENCE FACTORS; RNA INTERFERENCE; INSERTIONAL MUTAGENESIS; MACROPHAGE INFECTION; NEGATIVE SELECTION; VANCOUVER-ISLAND AB Rapid advances in molecular biology and genome sequencing have enabled the generation of new technology and resources for cryptococcal research. RNAi-mediated specific gene knock down has become routine and more efficient by utilizing modified shRNA plasmids and convergent promoter RNAi constructs. This system was recently applied in a high-throughput screen to identify genes involved in host-pathogen interactions. Gene deletion efficiencies have also been improved by increasing rates of homologous recombination through a number of approaches, including a combination of double-joint PCR with split-marker transformation, the use of dominant selectable markers and the introduction of Cre-Loxp systems into Cryptococcus. Moreover, visualization of cryptococcal proteins has become more facile using fusions with codon-optimized fluorescent tags, such as green or red fluorescent proteins or, mCherry. Using recent genome-wide analytical tools, new transcriptional factors and regulatory proteins have been identified in novel virulence-related signaling pathways by employing microarray analysis, RNA-sequencing and proteomic analysis. Published by Elsevier Inc. C1 [Zhang, Nannan; Park, Yoon-Dong; Williamson, Peter R.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Williamson, PR (reprint author), NIAID, Translat Mycol Unit, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM williamsonpr@mail.nih.gov FU NIH, NIAID FX This work was supported by the intramural research program of the NIH, NIAID. NR 132 TC 1 Z9 1 U1 3 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1087-1845 EI 1096-0937 J9 FUNGAL GENET BIOL JI Fungal Genet. Biol. PD MAY PY 2015 VL 78 SI SI BP 99 EP 107 DI 10.1016/j.fgb.2014.11.001 PG 9 WC Genetics & Heredity; Mycology SC Genetics & Heredity; Mycology GA CK7FK UT WOS:000356398000011 PM 25460849 ER PT J AU Scher, AS Scher, AI VerasdeAndrade, VR Merikangas, K Metti, AL Peterlin, B AF Scher, A. S. Scher, A., I VerasdeAndrade, Vieira R. Merikangas, K. Metti, A. L. Peterlin, B. TI The Individual and Combined Burden of Migraine and PTSD in a Population Based Cohort SO HEADACHE LA English DT Meeting Abstract CT 57th Annual Scientific Meeting of the American-Headache-Society CY JUN 18-21, 2015 CL Washington, DC SP Amer Headache Soc C1 [Scher, A. S.; Peterlin, B.] Johns Hopkins Sch Med, Baltimore, MD 21205 USA. [Scher, A., I] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [VerasdeAndrade, Vieira R.] Univ Fed Rio Grande do Sul, Porto Alegre, RS, Brazil. [Merikangas, K.] NIMH, 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 0017-8748 EI 1526-4610 J9 HEADACHE JI Headache PD MAY PY 2015 VL 55 SU 3 SI SI MA PF55 BP 156 EP 157 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA CK7RT UT WOS:000356430500073 ER PT J AU Lateef, TM He, J Calkins, M Gur, R Merikangas, K AF Lateef, T. M. He, J. Calkins, M. Gur, R. Merikangas, K. TI Physical and Mental Comorbidity of Pediatric Migraine in the Philadelphia Neurodevelopmental Cohort SO HEADACHE LA English DT Meeting Abstract CT 57th Annual Scientific Meeting of the American-Headache-Society CY JUN 18-21, 2015 CL Washington, DC SP Amer Headache Soc C1 [Lateef, T. M.] George Washington Univ, Sch Med, Manassas, VA USA. [He, J.] NIMH, Bethesda, MD USA. [Calkins, M.; Gur, R.] Univ Penn, Perelman Sch Med, Neuropsychiat Sect, Philadelphia, PA 19104 USA. [Calkins, M.; Gur, R.] Univ Penn, Perelman Sch Med, Brain Behav Lab, Philadelphia, PA 19104 USA. [Merikangas, K.] NIMH, NIH, Bethesda, MD 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 0017-8748 EI 1526-4610 J9 HEADACHE JI Headache PD MAY PY 2015 VL 55 SU 3 SI SI MA PS11 BP 165 EP 165 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA CK7RT UT WOS:000356430500094 ER PT J AU Fried, NT Oshinsky, ML Daugherty, BL Lederman, S Elliott, MB AF Fried, N. T. Oshinsky, M. L. Daugherty, B. L. Lederman, S. Elliott, M. B. TI The (R)- isomer of Isometheptene*, decreases Trigeminal Sensitivity in a Rat Model of Primary Headache SO HEADACHE LA English DT Meeting Abstract CT 57th Annual Scientific Meeting of the American-Headache-Society CY JUN 18-21, 2015 CL Washington, DC SP Amer Headache Soc C1 [Fried, N. T.; Elliott, M. B.] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. [Oshinsky, M. L.] NINDS, NIH, Bethesda, MD 20892 USA. [Daugherty, B. L.; Lederman, S.] Tonix Pharmaceut, New York, NY 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 0017-8748 EI 1526-4610 J9 HEADACHE JI Headache PD MAY PY 2015 VL 55 SU 3 SI SI MA PS58 BP 184 EP 184 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA CK7RT UT WOS:000356430500141 ER PT J AU Lee, SY Chen, SL Chang, YH Chu, CH Chen, SH Chen, PS Huang, SY Tzeng, NS Wang, LJ Lee, IH Wang, TY Chen, KC Yang, YK Hong, JS Lu, RB AF Lee, Sheng-Yu Chen, Shiou-Lan Chang, Yun-Hsuan Chu, Chun-Hsien Chen, Shih-Heng Chen, Po See Huang, San-Yuan Tzeng, Nian-Sheng Wang, Liang-Jen Lee, I. Hui Wang, Tzu-Yun Chen, Kao Chin Yang, Yen Kuang Hong, Jau-Shyong Lu, Ru-Band TI A Placebo-Controlled Trial of Dextromethorphan as an Adjunct in Opioid-Dependent Patients Undergoing Methadone Maintenance Treatment SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article DE cytokine; dextromethorphan; methadone maintenance therapy; opioid dependence Dextromethorphan; Heroin; Cytokines ID DOPAMINERGIC-NEURONS; OXIDATIVE STRESS; OPIUM TARYAK; DOUBLE-BLIND; TNF-ALPHA; IN-VITRO; MORPHINE; ABUSE; DRUG; 3-HYDROXYMORPHINAN AB Background: Low-dose dextromethorphan (DM) might have anti-inflammatory and neurotrophic effects mechanistically remote from an NMDA receptor. In a randomized, double-blind, controlled 12 week study, we investigated whether add-on dextromethorphan reduced cytokine levels and benefitted opioid-dependent patients undergoing methadone maintenance therapy (MMT). Methods: Patients were randomly assigned to a group: DM60 (60 mg/day dextromethorphan; n = 65), DM120 (120 mg/day dextromethorphan; n = 65), or placebo (n = 66). Primary outcomes were the methadone dose required, plasma morphine level, and retention in treatment. Plasma tumor necrosis factor (TNF)-alpha, C-reactive protein, interleukin (IL)-6, IL-8, transforming growth factor-beta 1, and brain-derived neurotrophic factor (BDNF) levels were examined during weeks 0, 1, 4, 8, and 12. Multiple linear regressions with generalized estimating equation methods were used to examine the therapeutic effect. Results: After 12 weeks, the DM60 group had significantly longer treatment retention and lower plasma morphine levels than did the placebo group. Plasma TNF-alpha was significantly decreased in the DM60 group compared to the placebo group. However, changes in plasma cytokine levels, BDNF levels, and the methadone dose required in the three groups were not significantly different. Conclusions: We provide evidence-decreased concomitant heroin use-of low-dose add-on DM's efficacy for treating opioid-dependent patients undergoing MMT. C1 [Lee, Sheng-Yu] Kaohsiung Vet Gen Hosp, Dept Psychiat, Kaohsiung, Taiwan. [Lee, Sheng-Yu; Chen, Po See; Lee, I. Hui; Wang, Tzu-Yun; Chen, Kao Chin; Yang, Yen Kuang; Lu, Ru-Band] Natl Cheng Kung Univ, Dept Psychiat, Tainan 70428, Taiwan. [Chen, Shiou-Lan] Kaohsiung Med Univ, Dept Neurol, Sch Med, Kaohsiung, Taiwan. [Chang, Yun-Hsuan; Lu, Ru-Band] Natl Cheng Kung Univ, Inst Allied Hlth Sci, Tainan 70428, Taiwan. [Chu, Chun-Hsien; Chen, Shih-Heng] NIEHS, Neurobiol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Huang, San-Yuan; Tzeng, Nian-Sheng] Triserv Gen Hosp, Natl Def Med Ctr, Dept Psychiat, Taipei, Taiwan. [Wang, Liang-Jen; Wang, Tzu-Yun; Hong, Jau-Shyong] Kaohsiung Chang Gung Mem Hosp, Dept Child & Adolescent Psychiat, Kaohsiung, Taiwan. [Wang, Liang-Jen; Wang, Tzu-Yun; Hong, Jau-Shyong] Chang Gung Univ, Coll Med, Kaohsiung, Taiwan. [Lu, Ru-Band] Natl Cheng Kung Univ, Coll Med & Hosp, Inst Behav Med, Tainan 70428, Taiwan. [Lu, Ru-Band] Natl Cheng Kung Univ, Addict Res Ctr, Tainan 70428, Taiwan. [Lu, Ru-Band] Natl Hlth Res Inst, Ctr Neuropsychiatr Res, Miaoli, Taiwan. RP Lu, RB (reprint author), Natl Cheng Kung Univ, Coll Med & Hosp, Addict Ctr, Inst Behav Med,Dept Psychiat, 138 Sheng Li Rd, Tainan 70428, Taiwan. EM rblu@mail.ncku.edu.tw FU Taiwan National Science Council [NSC98-2314-B-006-022-MY3]; Taiwan Department of Health [DOH 95-TD-M-113-055]; Taiwan National Health Research Institute [NHRI-EX-97-9738NI]; National Cheng Kung University Project for Promoting Academic Excellence and Developing World Class Research Centers FX Trial registration is NCT01189097. The trial ran from April 2008 to March 2011 at National Cheng Kung University Hospital. This work was supported in part by grant NSC98-2314-B-006-022-MY3 (Dr Lu) from the Taiwan National Science Council, grant DOH 95-TD-M-113-055 (Dr Lu) from the Taiwan Department of Health, grant NHRI-EX-97-9738NI (Dr Lu) from the Taiwan National Health Research Institute, and by a grant from the National Cheng Kung University Project for Promoting Academic Excellence and Developing World Class Research Centers. NR 40 TC 2 Z9 2 U1 2 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1461-1457 EI 1469-5111 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD MAY PY 2015 VL 18 IS 7 DI 10.1093/ijnp/pyv008 PG 8 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CL1KV UT WOS:000356702800013 ER PT J AU N'Gouemo, P Akinfiresoye, LR Allard, JS Lovinger, DM AF N'Gouemo, Prosper Akinfiresoye, Luli R. Allard, Joanne S. Lovinger, David M. TI Alcohol Withdrawal-Induced Seizure Susceptibility is Associated with an Upregulation of Ca(V)1.3 Channels in the Rat Inferior Colliculus SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article DE alcohol withdrawal seizures; Cacna1d mRNA; Cacna1c mRNA; Ca(V)1.2 alpha 1 subunit; Ca(V)1.3 alpha 1 subunit ID ETHANOL WITHDRAWAL; CALCIUM-CHANNELS; AUDIOGENIC-SEIZURES; PYRAMIDAL NEURONS; DOWN-REGULATION; DECREASED GABA; IN-VITRO; EXPRESSION; MICROINJECTION; ANTAGONISTS AB Background: We previously reported increased current density through L-type voltage-gated Ca2+ (Ca(V)1) channels in inferior colliculus (IC) neurons during alcohol withdrawal. However, the molecular correlate of this increased Ca(V)1 current is currently unknown. Methods: Rats received three daily doses of ethanol every 8 hours for 4 consecutive days; control rats received vehicle. The IC was dissected at various time intervals following alcohol withdrawal, and the mRNA and protein levels of the Ca(V)1.3 and Ca(V)1.2 alpha 1 subunits were measured. In separate experiments, rats were tested for their susceptibility to alcohol withdrawal-induced seizures (AWS) 3, 24, and 48 hours after alcohol withdrawal. Results: In the alcohol-treated group, AWS were observed 24 hours after withdrawal; no seizures were observed at 3 or 48 hours. No seizures were observed at any time in the control-treated rats. Compared to control-treated rats, the mRNA level of the Ca(V)1.3 a1 subunit was increased 1.4-fold, 1.9-fold, and 1.3-fold at 3, 24, and 48 hours, respectively. In contrast, the mRNA level of the Ca(V)1.2 alpha 1 subunit increased 1.5-fold and 1.4-fold at 24 and 48 hours, respectively. At 24 hours, Western blot analyses revealed that the levels of the Ca(V)1.3 and Ca(V)1.2 a1 subunits increased by 52% and 32%, respectively, 24 hours after alcohol withdrawal. In contrast, the Ca(V)1.2 and Ca(V)1.3 a1 subunits were not altered at either 3 or 48 hours during alcohol withdrawal. Conclusions: Expression of the Ca(V)1.3 alpha 1 subunit increased in parallel with AWS development, suggesting that altered L-type Ca(V)1.3 channel expression is an important feature of AWS pathogenesis. C1 [N'Gouemo, Prosper; Akinfiresoye, Luli R.] Georgetown Univ, Med Ctr, Dept Pediat, Washington, DC 20057 USA. [Allard, Joanne S.] Howard Univ, Coll Med, Dept Physiol & Biophys, Washington, DC 20059 USA. [Lovinger, David M.] NIAAA, Lab Integrat Neurosci, Rockville, MD 20852 USA. RP N'Gouemo, P (reprint author), Georgetown Univ, Med Ctr, Dept Pediat, Bldg D,Room 285,4000 Reservoir Rd NW, Washington, DC 20057 USA. EM pn@georgetown.edu FU National Institutes of Health Public Health Service [AA020073, AA020073-03S1]; NIAAA Division of Intramural Clinical and Biological Research FX This work was supported by National Institutes of Health Public Health Service Grants (AA020073 and AA020073-03S1, to Dr N'Gouemo) and the NIAAA Division of Intramural Clinical and Biological Research (to Dr Lovinger). The authors would like to thank Dr Katherine Conant and Guoxiang Luo for technical assistance in the early stages of this project and Dr George Luta for help with statistics. NR 37 TC 2 Z9 2 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1461-1457 EI 1469-5111 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD MAY PY 2015 VL 18 IS 7 DI 10.1093/ijnp/pyu123 PG 7 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CL1KV UT WOS:000356702800008 ER PT J AU Kutner, JS Blatchford, PJ Taylor, DH Ritchie, CS Bull, JH Fairclough, DL Hanson, LC LeBlanc, TW Samsa, GP Wolf, S Aziz, NM Currow, DC Ferrell, B Wagner-Johnston, N Zafar, SY Cleary, JF Dev, S Goode, PS Kamal, AH Kassner, C Kvale, EA McCallum, JG Ogunseitan, AB Pantilat, SZ Portenoy, RK Prince-Paul, M Sloan, JA Swetz, KM Von Gunten, CF Abernethy, AP AF Kutner, Jean S. Blatchford, Patrick J. Taylor, Donald H., Jr. Ritchie, Christine S. Bull, Janet H. Fairclough, Diane L. Hanson, Laura C. LeBlanc, Thomas W. Samsa, Greg P. Wolf, Steven Aziz, Noreen M. Currow, David C. Ferrell, Betty Wagner-Johnston, Nina Zafar, S. Yousuf Cleary, James F. Dev, Sandesh Goode, Patricia S. Kamal, Arif H. Kassner, Cordt Kvale, Elizabeth A. McCallum, Janelle G. Ogunseitan, Adeboye B. Pantilat, Steven Z. Portenoy, Russell K. Prince-Paul, Maryjo Sloan, Jeff A. Swetz, Keith M. Von Gunten, Charles F. Abernethy, Amy P. TI Safety and Benefit of Discontinuing Statin Therapy in the Setting of Advanced, Life-Limiting Illness A Randomized Clinical Trial SO JAMA INTERNAL MEDICINE LA English DT Article ID SHARED DECISION-MAKING; PALLIATIVE CARE; SURPRISE QUESTION; OLDER PATIENTS; HEART-FAILURE; RISK; MEDICATIONS; DISEASE; METAANALYSIS; MEDICINE AB IMPORTANCE For patients with limited prognosis, some medication risks may outweigh the benefits, particularly when benefits take years to accrue; statins are one example. Data are lacking regarding the risks and benefits of discontinuing statin therapy for patients with limited life expectancy. OBJECTIVE To evaluate the safety, clinical, and cost impact of discontinuing statin medications for patients in the palliative care setting. DESIGN, SETTING, AND PARTICIPANTS This was a multicenter, parallel-group, unblinded, pragmatic clinical trial. Eligibility included adults with an estimated life expectancy of between 1 month and 1 year, statin therapy for 3 months or more for primary or secondary prevention of cardiovascular disease, recent deterioration in functional status, and no recent active cardiovascular disease. Participants were randomized to either discontinue or continue statin therapy and were monitored monthly for up to 1 year. The study was conducted from June 3, 2011, to May 2, 2013. All analyses were performed using an intent-to-treat approach. INTERVENTIONS Statin therapy was withdrawn from eligible patients who were randomized to the discontinuation group. Patients in the continuation group continued to receive statins. MAIN OUTCOMES AND MEASURES Outcomes included death within 60 days (primary outcome), survival, cardiovascular events, performance status, quality of life (QOL), symptoms, number of nonstatin medications, and cost savings. RESULTS A total of 381 patients were enrolled; 189 of these were randomized to discontinue statins, and 192 were randomized to continue therapy. Mean (SD) age was 74.1 (11.6) years, 22.0% of the participants were cognitively impaired, and 48.8% had cancer. The proportion of participants in the discontinuation vs continuation groups who died within 60 days was not significantly different (23.8% vs 20.3%; 90% CI, -3.5% to 10.5%; P =.36) and did not meet the noninferiority end point. Total QOL was better for the group discontinuing statin therapy (mean McGill QOL score, 7.11 vs 6.85; P =.04). Few participants experienced cardiovascular events (13 in the discontinuation group vs 11 in the continuation group). Mean cost savings were $3.37 per day and $716 per patient. CONCLUSIONS AND RELEVANCE This pragmatic trial suggests that stopping statin medication therapy is safe and may be associated with benefits including improved QOL, use of fewer nonstatin medications, and a corresponding reduction in medication costs. Thoughtful patient-provider discussions regarding the uncertain benefit and potential decrement in QOL associated with statin continuation in this setting are warranted. C1 [Kutner, Jean S.] Univ Colorado, Sch Med, Dept Med, Aurora, CO USA. [Blatchford, Patrick J.; Fairclough, Diane L.] Colorado Sch Publ Hlth, Dept Biostat & Informat, Denver, CO USA. [Taylor, Donald H., Jr.] Duke Univ, Sanford Sch Publ Policy, Durham, NC 27710 USA. [Ritchie, Christine S.] San Francisco VA Med Ctr, Ctr Res Aging, Jewish Home San Francisco, San Francisco, CA USA. [Ritchie, Christine S.] Univ Calif San Francisco, Dept Med, Div Geriatr, San Francisco, CA USA. [Bull, Janet H.] Four Seasons Compass Life, Flat Rock, NC USA. [Hanson, Laura C.] Univ N Carolina, Div Geriatr Med, Chapel Hill, NC USA. [LeBlanc, Thomas W.; Zafar, S. Yousuf; Kamal, Arif H.; Abernethy, Amy P.] Duke Univ, Sch Med, Duke Clin Res Inst, Ctr Learning Hlth Care, Durham, NC 27710 USA. [Samsa, Greg P.; Wolf, Steven] Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Durham, NC 27710 USA. [Aziz, Noreen M.] NINR, NIH, Bethesda, MD 20892 USA. [Currow, David C.] Flinders Univ S Australia, Discipline, Palliat Serv, Adelaide, SA 5001, Australia. [Currow, David C.] Flinders Univ S Australia, Discipline, Support Serv, Adelaide, SA 5001, Australia. [Ferrell, Betty] City Hope Natl Med Ctr, City Hope Med Ctr, Dept Nursing Res, Duarte, CA USA. [Wagner-Johnston, Nina] Washington Univ, Dept Med, St Louis, MO USA. [Cleary, James F.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Div Hematol Oncol, Madison, WI 53706 USA. [Dev, Sandesh] Phoenix Vet Affairs Hlth Care Syst, Dept Med, Phoenix, AZ USA. [Goode, Patricia S.; Kvale, Elizabeth A.] Birmingham Vet Affairs Med Ctr, Vet Affairs Geriatr Res Educ & Clin Ctr, Birmingham, AL USA. [Goode, Patricia S.; Kvale, Elizabeth A.] Univ Alabama Birmingham, Div Gerontol Geriatr & Palliat Care, Birmingham, AL USA. [Kassner, Cordt] Hosp Analyt, Denver, CO USA. [McCallum, Janelle G.] Denver Hosp, Denver, CO USA. [Ogunseitan, Adeboye B.] Northwestern Univ, Feinberg Sch Med, Dept Med, Chicago, IL 60611 USA. [Pantilat, Steven Z.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Portenoy, Russell K.] Metropolitan Jewish Hlth Syst, Hosp & Palliat Care, New York, NY USA. [Prince-Paul, Maryjo] Case Western Reserve Univ, Frances Payne Bolton Sch Nursing, Cleveland, OH 44106 USA. [Sloan, Jeff A.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Swetz, Keith M.] Mayo Clin, Dept Med, Rochester, MN USA. [Von Gunten, Charles F.] OhioHealth, Dept Hosp & Palliat Med, Columbus, OH USA. RP Abernethy, AP (reprint author), Duke Univ, Sch Med, Duke Clin Res Inst, Ctr Learning Hlth Care, Durham, NC 27710 USA. EM amy.abernethy@duke.edu OI LeBlanc, Thomas/0000-0002-0546-7895; Currow, David/0000-0003-1988-1250 FU National Institute of Nursing Research [UC4-NR012584, U24-NR014637] FX This study received funding from the National Institute of Nursing Research (grants UC4-NR012584 and U24-NR014637). Furthermore, this work included the support of resources and facilities within the Veterans Affairs Health Care System (eg, Phoenix, Arizona, and Birmingham, Alabama). NR 45 TC 67 Z9 68 U1 1 U2 10 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD MAY PY 2015 VL 175 IS 5 BP 691 EP 700 DI 10.1001/jamainternmed.2015.0289 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA CK4FQ UT WOS:000356178400004 PM 25798575 ER PT J AU Pinsky, PF Schoen, RE AF Pinsky, Paul F. Schoen, Robert E. TI Colorectal Cancer Incidence by Age Among Patients Undergoing Surveillance Colonoscopy SO JAMA INTERNAL MEDICINE LA English DT Letter C1 [Pinsky, Paul F.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Schoen, Robert E.] Univ Pittsburgh, Sch Med, Dept Gastroenterol, Pittsburgh, PA USA. RP Pinsky, PF (reprint author), NCI, Canc Prevent Div, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM pp4f@nih.gov NR 4 TC 1 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD MAY PY 2015 VL 175 IS 5 BP 858 EP 860 DI 10.1001/jamainternmed.2015.0344 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA CK4FQ UT WOS:000356178400038 PM 25822077 ER PT J AU Li, JW Minami, H Steward, E Ma, T Mohar, D Robertson, C Shung, K Zhou, QF Patel, P Chen, ZP AF Li, Jiawen Minami, Hataka Steward, Earl Ma, Teng Mohar, Dilbahar Robertson, Claire Shung, Kirk Zhou, Qifa Patel, Pranav Chen, Zhongping TI Optimal flushing agents for integrated optical and acoustic imaging systems SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Article DE imaging system; optical coherence tomography; attenuation; ultrasound ID COHERENCE TOMOGRAPHY; REFRACTIVE-INDEX; CONTRAST-MEDIA; BLOOD; AGGREGATION; VISCOSITY; DEXTRAN; MICROSCOPY; DYNAMICS; IVUS AB An increasing number of integrated optical and acoustic intravascular imaging systems have been developed and hold great promise for accurately diagnosing vulnerable plaques and guiding atherosclerosis treatment. However, in any intravascular environment, the vascular lumen is filled with blood, a high-scattering source for optical and high-frequency ultrasound signals. Blood must be flushed away to provide clearer images. To our knowledge, no research has been performed to find the ideal flushing agent for combined optical and acoustic imaging techniques. We selected three solutions as potential flushing agents for their image-enhancing effects: mannitol, dextran, and iohexol. Testing of these flushing agents was performed in a closed-loop circulation model and in vivo on rabbits. We found that a high concentration of dextran was the most useful for simultaneous intravascular ultrasound and optical coherence tomography imaging. (C) 2015 Society of Photo-Optical Instrumentation Engineers (SPIE) C1 [Li, Jiawen; Chen, Zhongping] Univ Calif Irvine, Beckman Laser Inst, Irvine, CA 92617 USA. [Li, Jiawen; Minami, Hataka; Robertson, Claire; Chen, Zhongping] Univ Calif Irvine, Dept Biomed Engn, Irvine, CA 92697 USA. [Steward, Earl; Mohar, Dilbahar; Patel, Pranav] Univ Calif Irvine, Orange, CA 92868 USA. [Ma, Teng; Shung, Kirk; Zhou, Qifa] Univ So Calif, NIH, Ultrason Transducer Resource Ctr, Los Angeles, CA 90089 USA. RP Chen, ZP (reprint author), Univ Calif Irvine, Beckman Laser Inst, 1002 Hlth Sci Rd, Irvine, CA 92617 USA. EM z2chen@uci.edu FU National Institutes of Health [R01-HL-125084, R01-HL-12727, R01-HL-105215, R01-EY-021529, P41-EB002182, P41-EB015890]; University of California, Irvine's Undergraduate Research Opportunities Program FX This work was supported by the National Institutes of Health under Grant Nos. R01-HL-125084, R01-HL-12727, R01-HL-105215, R01-EY-021529, P41-EB002182, and P41-EB015890. We also received financial support from the University of California, Irvine's Undergraduate Research Opportunities Program. We would like to thank Dr. Matthew Brenner for his suggestion regarding the selection of flushing agents. Dr. Claire Robertson is currently working at Lawrence Berkeley National Lab. NR 48 TC 1 Z9 2 U1 2 U2 5 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 1083-3668 EI 1560-2281 J9 J BIOMED OPT JI J. Biomed. Opt. PD MAY PY 2015 VL 20 IS 5 AR 056005 DI 10.1117/1.JBO.20.5.056005 PG 8 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA CK5DH UT WOS:000356241900060 PM 25985096 ER PT J AU Sato, N Wu, HT Asiedu, KO Szajek, LP Griffiths, GL Choyke, PL AF Sato, Noriko Wu, Haitao Asiedu, Kingsley O. Szajek, Lawrence P. Griffiths, Gary L. Choyke, Peter L. TI Zr-89-Oxine Complex PET Cell Imaging in Monitoring Cell-based Therapies SO RADIOLOGY LA English DT Article ID LABELING LEUKOCYTES; DENDRITIC CELLS; T-CELLS; TRACKING; CANCER; IMMUNOTHERAPY; TC-99M-HMPAO; INFLAMMATION; LEUKEMIA; SAFETY AB Purpose: To develop a clinically translatable method of cell labeling with zirconium 89 (Zr-89) and oxine to track cells with positron emission tomography (PET) in mouse models of cell-based therapy. Materials and Methods: This study was approved by the institutional animal care committee. Zr-89-oxine complex was synthesized in an aqueous solution. Cell labeling conditions were optimized by using EL4 mouse lymphoma cells, and labeling efficiency was examined by using dendritic cells (DCs) (n = 4), naive (n = 3) and activated (n = 3) cytotoxic T cells (CTLs), and natural killer (NK) (n = 4), bone marrow (n = 4), and EL4 (n = 4) cells. The effect of Zr-89 labeling on cell survival, proliferation, and function were evaluated by using DCs (n = 3) and CTLs (n = 3). Labeled DCs (444-555 kBq/[5 x 10 (6)] cells, n = 5) and CTLs (185 kBq/[5 x 10 (6)] cells, n = 3) transferred to mice were tracked with microPET/CT. In a melanoma immunotherapy model, tumor targeting and cytotoxic function of labeled CTLs were evaluated with imaging (248.5 kBq/[7.7 x 10 (6)] cells, n = 4) and by measuring the tumor size (n = 6). Two-way analysis of variance was used to compare labeling conditions, the Wilcoxon test was used to assess cell survival and proliferation, and Holm-Sidak multiple tests were used to assess tumor growth and perform biodistribution analyses. Results: Zr-89-oxine complex was synthesized at a mean yield of 97.3% +/- 2.8 (standard deviation). It readily labeled cells at room temperature or 4 degrees C in phosphate-buffered saline (labeling efficiency range, 13.0%-43.9%) and was stably retained (83.5% +/- 1.8 retention on day 5 in DCs). Labeling did not affect the viability of DCs and CTLs when compared with nonlabeled control mice (P > .05), nor did it affect functionality. Zr-89-oxine complex enabled extended cell tracking for 7 days. Labeled tumor-specific CTLs accumulated in the tumor (4.6% on day 7) and induced tumor regression (P < .05 on day 7). Conclusion: We have developed a Zr-89-oxine complex cell tracking technique for use with PET that is applicable to a broad range of cell types and could be a valuable tool with which to evaluate various cell-based therapies. (C)RSNA, 2015 C1 [Sato, Noriko; Asiedu, Kingsley O.; Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Wu, Haitao] NHLBI, Imaging Probe Dev Ctr, NIH, Bethesda, MD 20892 USA. [Szajek, Lawrence P.] NIH, Positron Emiss Tomog Dept, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Griffiths, Gary L.] Frederick Natl Lab Canc Res, Leidos Biomed Res, Clin Res Directorate, Clin Monitoring Res Program, Frederick, MD USA. RP Sato, N (reprint author), NCI, Mol Imaging Program, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM saton@mail.nih.gov FU National Institutes of Health [ZIA BC 010657, HHSN261200800001E] FX This research was supported by the National Institutes of Health (grants ZIA BC 010657 and HHSN261200800001E). NR 36 TC 4 Z9 4 U1 5 U2 14 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD MAY PY 2015 VL 275 IS 2 BP 490 EP 500 DI 10.1148/radiol.15142849 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CK1SN UT WOS:000355987700021 PM 25706654 ER PT J AU Mollura, DJ Palmore, TN Folio, LR Bluemke, DA AF Mollura, Daniel J. Palmore, Tara N. Folio, Les R. Bluemke, David A. TI Radiology Preparedness in Ebola Virus Disease: Guidelines and Challenges for Disinfection of Medical Imaging Equipment for the Protection of Staff and Patients SO RADIOLOGY LA English DT Article AB The overlap of early Ebola virus disease (EVD) symptoms (eg, fever, headache, abdominal pain, diarrhea, emesis, and fatigue) with symptoms of other more common travel-related diseases (eg, malaria, typhoid fever, pneumonia, and meningococcemia) may result in delayed diagnosis of EVD before isolation of infected patients. Radiology departments should consider policies for and approaches to decontamination of expensive and potentially easily damaged radiology equipment. In addition, the protection of radiology personnel must be considered during the work-up phase of undiagnosed EVD patients presenting to emergency departments. The purpose of this article is to consider the effect of EVD on radiology departments and imaging equipment, with particular consideration of guidelines currently available from the Centers for Disease Control and Prevention that may be applicable to radiology. C1 [Mollura, Daniel J.; Bluemke, David A.] NIH, Ctr Infect Dis Imaging, Bethesda, MD 20892 USA. [Mollura, Daniel J.; Folio, Les R.; Bluemke, David A.] NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Palmore, Tara N.] NIH, Clin Ctr Hosp Epidemiol Serv, Bethesda, MD 20892 USA. RP Mollura, DJ (reprint author), NIH, Ctr Infect Dis Imaging, 10 Ctr Dr,Bldg 10,Room 1C349,Mailstop 1182, Bethesda, MD 20892 USA. EM Daniel.Mollura@nih.gov OI Bluemke, David/0000-0002-8323-8086 FU National Instititue of Allergy and Infectious Diseases, National Institutes of Health Clinical Center; NIH Center for Infectious Disease Imaging FX This research was funded by the intramural research programs of the National Instititue of Allergy and Infectious Diseases, National Institutes of Health Clinical Center, and NIH Center for Infectious Disease Imaging. NR 13 TC 3 Z9 3 U1 2 U2 4 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD MAY PY 2015 VL 275 IS 2 BP 538 EP 544 DI 10.1148/radiol.15142670 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CK1SN UT WOS:000355987700026 PM 25654616 ER PT J AU George, RT Mehra, VC Chen, MY Kitagawa, K Arbab-Zadeh, A Miller, JM Matheson, MB Vavere, AL Kofoed, KF Rochitte, CE Dewey, M Yaw, TS Niinuma, H Brenner, W Cox, C Clouse, ME Lima, JAC Di Carli, M AF George, Richard T. Mehra, Vishal C. Chen, Marcus Y. Kitagawa, Kakuya Arbab-Zadeh, Armin Miller, Julie M. Matheson, Matthew B. Vavere, Andrea L. Kofoed, Klaus F. Rochitte, Carlos E. Dewey, Marc Yaw, Tan S. Niinuma, Hiroyuki Brenner, Winfried Cox, Christopher Clouse, Melvin E. Lima, Joao A. C. Di Carli, Marcelo TI Comparing Apples and Oranges: High- End Cardiac 320-Detector Row CT vs Archaic SPECT Protocols Response SO RADIOLOGY LA English DT Letter ID CORONARY-ARTERY-DISEASE; EMISSION COMPUTED-TOMOGRAPHY; DIAGNOSTIC PERFORMANCE; CORE320 MULTICENTER; PERFUSION; ANGIOGRAPHY C1 [George, Richard T.; Mehra, Vishal C.; Arbab-Zadeh, Armin; Miller, Julie M.; Vavere, Andrea L.; Lima, Joao A. C.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21287 USA. [Matheson, Matthew B.; Cox, Christopher] Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Di Carli, Marcelo] Brigham & Womens Hosp, Dept Nucl Med & Cardiovasc Imaging, Boston, MA 02115 USA. [Rochitte, Carlos E.] Univ Sao Paulo, Sch Med, Dept Cardiol, Heart Inst InCor, Sao Paulo, Brazil. [Mehra, Vishal C.; Chen, Marcus Y.] NHLBI, NIH, Bethesda, MD 20892 USA. [Niinuma, Hiroyuki] Iwate Med Univ, Dept Radiol, Morioka, Iwate 020, Japan. [Niinuma, Hiroyuki] St Lukes Int Hosp, Dept Radiol, Tokyo, Japan. [Kitagawa, Kakuya] Mie Univ Hosp, Dept Radiol, Tsu, Mie, Japan. [Clouse, Melvin E.] Harvard Univ, Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA 02215 USA. [Kofoed, Klaus F.] Univ Copenhagen, Dept Radiol, Rigshosp, DK-1168 Copenhagen, Denmark. [Yaw, Tan S.] Natl Heart Ctr, Dept Radiol, Singapore, Singapore. [Brenner, Winfried] Charite, D-13353 Berlin, Germany. RP George, RT (reprint author), Johns Hopkins Univ, Sch Med, 600 N Wolfe St,Blalock 524D2, Baltimore, MD 21287 USA. EM rgeorge3@jhmi.edu NR 9 TC 0 Z9 0 U1 1 U2 1 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD MAY PY 2015 VL 275 IS 2 BP 621 EP 622 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CK1SN UT WOS:000355987700042 ER PT J AU Zheng, G Li, ZH Geller, NL AF Zheng, Gang Li, Zhaohai Geller, Nancy L. TI A Conversation with Robert C. Elston SO STATISTICAL SCIENCE LA English DT Article DE British statisticians; family studies; genetic epidemiology; history of statistical genetics; pedigree data; SAGE software; statistical genetics; statistics biographies ID HOSPITAL BLOOD BANK; INVENTORY LEVELS AB Robert C. Elston was born on February 4, 1932, in London, England. He went to Cambridge University to study natural science from 1952-1956 and obtained B.A., M.A. and Diploma in Agriculture (Dip Ag). He came to the US at age 24 to study animal breeding at Cornell University and received his Ph.D. in 1959. From 1959-1960, he was a post-doctoral fellow in biostatistics at University of North Carolina (UNC), Chapel Hill, where he studied mathematical statistics. He then rose through the academic ranks in the department of biostatistics at UNC, becoming a full professor in 1969. From 1979-1995, he was a professor and head of the Department of Biometry and Genetics at Louisiana State University Medical Center in New Orleans. In 1995, he moved to Case Western Reserve University where he is a professor of epidemiology and biostatistics and served as chairman from 2008 to 2014. Between 1966 and 2013, he directed 42 Ph.D. students and mentored over 40 post-doctoral fellows. If one regards him as a founder of a pedigree in research in genetic epidemiology, it was estimated in 2007 that there were more than 500 progeny. Among his many honors are a NIH Research Career Development Award (1966-1976), the Leadership Award from International Society of Human Genetics (1995), William Allan Award from American Society of Human Genetics (1996), NIH MERIT Award (1998) and the Marvin Zelen Leadership Award, Harvard University (2004). He is a Fellow of the American Statistical Association and the Institute of Mathematical Statistics as well as a Fellow of the Ohio Academy of Science. A leader in research in genetic epidemiology for over 40 years, he has published over 600 research articles in biostatistics, genetic epidemiology and applications. He has also coauthored and edited 9 books in biostatistics, population genetics and methods for the analysis of genetic data. The original conversation took place on August 4, 2009, during the Joint Statistical Meetings (JSM) in Washington, DC by GZ and ZL. NLG had dinner with RCE during the 2013 JSM in Montreal, Canada, and added supplementary material and edited the conversation. RCE updated and clarified certain points. C1 [Zheng, Gang; Geller, Nancy L.] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Li, Zhaohai] George Washington Univ, Stat & Biostat, Washington, DC 20052 USA. [Li, Zhaohai] George Washington Univ, Dept Stat, Washington, DC 20052 USA. EM zli@gwu.edu; gellern@nhlbi.nih.gov NR 14 TC 0 Z9 0 U1 1 U2 1 PU INST MATHEMATICAL STATISTICS PI CLEVELAND PA 3163 SOMERSET DR, CLEVELAND, OH 44122 USA SN 0883-4237 J9 STAT SCI JI Stat. Sci. PD MAY PY 2015 VL 30 IS 2 BP 258 EP 267 DI 10.1214/14-STS497 PG 10 WC Statistics & Probability SC Mathematics GA CL0PH UT WOS:000356644100012 ER PT J AU Garside, P Arizpe, J Lau, CI Goh, C Walsh, V AF Garside, Peter Arizpe, Joseph Lau, Chi-Ieong Goh, Crystal Walsh, Vincent TI Cross-hemispheric Alternating Current Stimulation During a Nap Disrupts Slow Wave Activity and Associated Memory Consolidation SO BRAIN STIMULATION LA English DT Article DE Memory consolidation; Declarative memory; tACS; Sleep; Nap; Montage; Slow wave sleep; Delta wave; Oscillations ID MOTOR CORTICAL EXCITABILITY; DECLARATIVE MEMORY; HUMAN SLEEP; PROCEDURAL MEMORY; MECHANISMS; HUMANS; BRAIN; ELECTROENCEPHALOGRAM; OSCILLATIONS; PERFORMANCE AB Background: Slow Wave Activity (SWA), the low frequency (<4 Hz) oscillations that characterize Slow Wave Sleep (SWS) are thought to relate causally to declarative memory consolidation during nocturnal sleep. Evidence is conflicting relating SWA to memory consolidation during nap however. Objective/hypothesis: We applied transcranial alternating current stimulation (tACS) - which, with a cross-hemispheric electrode montage (F3 and F4 - International 10:20 EEG system), is able to disrupt brain oscillations-to determine if disruption of low frequency oscillation generation during afternoon nap is causally related to disruption in declarative memory consolidation. Methods: Eight human subjects each participated in stimulation and sham nap sessions. A verbal paired associate learning (PAL) task measured memory changes. During each nap period, five 5-min stimulation (0.75 Hz cross-hemispheric frontal tACS) or sham intervals were applied with 1-min post-stimulation intervals (PSI's). Spectral EEG power for Slow (0.7-0.8 Hz), Delta (1.0-4.0 Hz), Theta (4.0-8.0 Hz), Alpha (8.0-12.0 Hz), and Spindle-range (12.0-14.0) frequencies was analyzed during the 1-min preceding the onset of stimulation and the 1-min PSI's. Results: As hypothesized, power reduction due to stimulation positively correlated with reduction in word-pair recall post-nap specifically for Slow (P < 0.0022) and Delta (P < 0.037) frequency bands. Conclusions: These results provide preliminary evidence suggesting a causal and specific role of SWA in declarative memory consolidation during nap. (C) 2015 Elsevier Inc. C1 [Garside, Peter; Arizpe, Joseph; Lau, Chi-Ieong; Goh, Crystal; Walsh, Vincent] UCL, Inst Cognit Neurosci, London WC1N 3AR, England. [Garside, Peter] UCL, Sch Med, London WC1E 6BT, England. [Arizpe, Joseph] NIMH, NIH, Bethesda, MD 20892 USA. [Lau, Chi-Ieong] Shin Kong Wu Ho Su Mem Hosp, Dept Neurol, Taipei, Taiwan. RP Arizpe, J (reprint author), UCL, Inst Cognit Neurosci, 17 Queen Sq, London WC1N 3AR, England. EM Joseph.Arizpe.10@ucl.ac.uk RI Arizpe, Joseph/N-1399-2014 OI Arizpe, Joseph/0000-0001-8958-7757 FU UCL Medical School; Royal Society (Industry Research Fellowship award); Medical Research Council grant [G0700929]; Intramural Research Training Award from the US National Institute of Mental Health [NCT00001360]; CL-NIMH Graduate Partnership Program scholarship FX This research was funded by UCL Medical School, The Royal Society (Industry Research Fellowship award to VW), a Medical Research Council grant (G0700929) awarded to VW, and the Intramural Research Training Award from the US National Institute of Mental Health (NCT00001360; CL-NIMH Graduate Partnership Program scholarship awarded to JA). NR 54 TC 7 Z9 7 U1 0 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1935-861X EI 1876-4754 J9 BRAIN STIMUL JI Brain Stimul. PD MAY-JUN PY 2015 VL 8 IS 3 BP 520 EP 527 DI 10.1016/j.brs.2014.12.010 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CJ8RX UT WOS:000355772300012 PM 25697588 ER PT J AU Davis, JL Chan, CC Goldstein, DA AF Davis, Janet L. Chan, Chi-Chao Goldstein, Debra A. TI Women in Print SO JAMA OPHTHALMOLOGY LA English DT Letter C1 [Davis, Janet L.] Univ Miami, Sch Med, Bascom Palmer Eye Inst, Dept Ophthalmol, Miami, FL 33136 USA. [Chan, Chi-Chao] NEI, Histol Core, NIH, Bethesda, MD 20892 USA. [Chan, Chi-Chao] NEI, Immunopathol Sect, NIH, Bethesda, MD 20892 USA. [Goldstein, Debra A.] Northwestern Univ, Feinberg Sch Med, Dept Ophthalmol, Chicago, IL 60611 USA. RP Davis, JL (reprint author), Univ Miami, Sch Med, Bascom Palmer Eye Inst, 900 NW 17th St,Ste 265, Miami, FL 33136 USA. EM jdavis@med.miami.edu NR 5 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6165 EI 2168-6173 J9 JAMA OPHTHALMOL JI JAMA Ophthalmol. PD MAY PY 2015 VL 133 IS 5 BP 620 EP 621 DI 10.1001/jamaophthalmol.2015.221 PG 5 WC Ophthalmology SC Ophthalmology GA CK2NF UT WOS:000356046700029 PM 25763927 ER PT J AU Irinyi, L Serena, C Garcia-Hermoso, D Arabatzis, M Desnos-Ollivier, M Vu, D Cardinali, G Arthur, I Normand, AC Giraldo, A da Cunha, KC Sandoval-Denis, M Hendrickx, M Nishikaku, AS Melo, ASD Merseguel, KB Khan, A Parente Rocha, JA Sampaio, P Briones, MRD Ferreira, RCE Muniz, MD Castanon-Olivares, LR Estrada-Barcenas, D Cassagne, C Mary, C Duan, SY Kong, FR Sun, AY Zeng, XY Zhao, ZT Gantois, N Botterel, F Robbertse, B Schoch, C Gams, W Ellis, D Halliday, C Chen, S Sorrell, TC Piarroux, R Colombo, AL Pais, C de Hoog, S Zancope-Oliveira, RM Taylor, ML Toriello, C Soares, CMD Delhaes, L Stubbe, D Dromer, F Ranque, S Guarro, J Cano-Lira, JF Robert, V Velegraki, A Meyer, W AF Irinyi, Laszlo Serena, Carolina Garcia-Hermoso, Dea Arabatzis, Michael Desnos-Ollivier, Marie Vu, Duong Cardinali, Gianluigi Arthur, Ian Normand, Anne-Cecile Giraldo, Alejandra Cassia da Cunha, Keith Sandoval-Denis, Marcelo Hendrickx, Marijke Nishikaku, Angela Satie de Azevedo Melo, Analy Salles Merseguel, Karina Bellinghausen Khan, Aziza Parente Rocha, Juliana Alves Sampaio, Paula da Silva Briones, Marcelo Ribeiro Carmona e Ferreira, Renata de Medeiros Muniz, Mauro Castanon-Olivares, Laura Rosio Estrada-Barcenas, Daniel Cassagne, Carole Mary, Charles Duan, Shu Yao Kong, Fanrong Sun, Annie Ying Zeng, Xianyu Zhao, Zuotao Gantois, Nausicaa Botterel, Francoise Robbertse, Barbara Schoch, Conrad Gams, Walter Ellis, David Halliday, Catriona Chen, Sharon Sorrell, Tania C. Piarroux, Renaud Colombo, Arnaldo L. Pais, Celia de Hoog, Sybren Zancope-Oliveira, Rosely Maria Taylor, Maria Lucia Toriello, Conchita de Almeida Soares, Celia Maria Delhaes, Laurence Stubbe, Dirk Dromer, Francoise Ranque, Stephane Guarro, Josep Cano-Lira, Jose F. Robert, Vincent Velegraki, Aristea Meyer, Wieland TI International Society of Human and Animal Mycology (ISHAM)-ITS reference DNA barcoding database-the quality controlled standard tool for routine identification of human and animal pathogenic fungi SO MEDICAL MYCOLOGY LA English DT Review DE fungal identification; DNA barcoding; ITS region; reference ITS database; intraspecies; interspecies genetic diversity ID SEQUENCE-BASED IDENTIFICATION; SOLANI SPECIES COMPLEX; CRYPTOCOCCUS-NEOFORMANS; RIBOSOMAL DNA; TRANSCRIBED SPACER; SCEDOSPORIUM-APIOSPERMUM; GEOTRICHUM-CANDIDUM; MOLECULAR TAXONOMY; GENETIC DIVERSITY; TRICHOPHYTON-MENTAGROPHYTES AB Human and animal fungal pathogens are a growing threat worldwide leading to emerging infections and creating new risks for established ones. There is a growing need for a rapid and accurate identification of pathogens to enable early diagnosis and targeted antifungal therapy. Morphological and biochemical identification methods are time-consuming and require trained experts. Alternatively, molecular methods, such as DNA barcoding, a powerful and easy tool for rapid monophasic identification, offer a practical approach for species identification and less demanding in terms of taxonomical expertise. However, its wide-spread use is still limited by a lack of quality-controlled reference databases and the evolving recognition and definition of new fungal species/complexes. An international consortium of medical mycology laboratories was formed aiming to establish a quality controlled ITS database under the umbrella of the ISHAM working group on "DNA barcoding of human and animal pathogenic fungi." A new database, containing 2800 ITS sequences representing 421 fungal species, providing the medical community with a freely accessible tool at http://www.isham.org and http://its.mycologylab.org/ to rapidly and reliably identify most agents of mycoses, was established. The generated sequences included in the new database were used to evaluate the variation and overall utility of the ITS region for the identification of pathogenic fungi at intra-and interspecies level. The average intraspecies variation ranged from 0 to 2.25%. This highlighted selected pathogenic fungal species, such as the dermatophytes and emerging yeast, for which additional molecular methods/genetic markers are required for their reliable identification from clinical and veterinary specimens. C1 [Irinyi, Laszlo; Serena, Carolina; Khan, Aziza; Duan, Shu Yao; Chen, Sharon; Sorrell, Tania C.; Meyer, Wieland] Univ Sydney, Marie Bashir Inst Infect Dis & Bioscur, Ctr Infect Dis & Microbiol,Westmead Hosp, Mol Mycol Res Lab,Sydney Med Sch,Westmead Millenn, Sydney, NSW 2006, Australia. [Garcia-Hermoso, Dea; Desnos-Ollivier, Marie; Dromer, Francoise] CNRS, Inst Pasteur, Natl Reference Ctr Invas Mycoses & Antifungals, Mol Mycol Unit,URA3012, Paris, France. [Arabatzis, Michael; Velegraki, Aristea] Univ Athens, Univ Athens Hellen Collect Pathogen Fungi UOA HCP, Sch Med, Mycol Res Lab,Dept Microbiol, Athens 11528, Greece. [Vu, Duong; Gams, Walter; de Hoog, Sybren; Robert, Vincent] CBS KNAW, Fungal Biodivers Ctr, Utrecht, Netherlands. [Cardinali, Gianluigi] Univ Perugia, Dept Pharmaceut Sci, I-06100 Perugia, Italy. [Arthur, Ian] QEII Med Ctr, PathWest Lab Med WA, Dept Microbiol & Infect Dis, Mycol Lab, Nedlands, WA, Australia. [Normand, Anne-Cecile; Cassagne, Carole; Mary, Charles; Piarroux, Renaud; Ranque, Stephane] CHU Timone Adultes, APHM, Parasitol Mycol, Marseille, France. [Normand, Anne-Cecile; Cassagne, Carole; Mary, Charles; Piarroux, Renaud; Ranque, Stephane] Aix Marseille Univ, UMR MD3 IP TPT, Marseille, France. [Giraldo, Alejandra; Cassia da Cunha, Keith; Sandoval-Denis, Marcelo; Guarro, Josep; Cano-Lira, Jose F.] Univ Rovira & Virgili, IISPV, Fac Med & Ciencies Salut, Unitat Microbiol, E-43201 Reus, Spain. [Hendrickx, Marijke; Stubbe, Dirk] Sci Inst Publ Hlth, Biomed Fungi & Yeasts Collect, BCCM IHEM, Brussels, Belgium. [Nishikaku, Angela Satie; de Azevedo Melo, Analy Salles; Merseguel, Karina Bellinghausen; Colombo, Arnaldo L.] Univ Fed Sao Paulo, Escola Paulista Med, Lab Especial Micol, Sao Paulo, Brazil. [Parente Rocha, Juliana Alves; de Almeida Soares, Celia Maria] Univ Fed Goias, Inst Ciencias Biol, Lab Biol Mol, Goiania, Go, Brazil. [Sampaio, Paula; Pais, Celia] Univ Minho, Sch Sci, Dept Biol, Ctr Mol & Environm Biol CBMA, Braga, Portugal. [da Silva Briones, Marcelo Ribeiro; Carmona e Ferreira, Renata] Univ Fed Sao Paulo, Escola Paulista Med, Lab Genom & Biocomplexidade Evolut, Sao Paulo, Brazil. [de Medeiros Muniz, Mauro; Zancope-Oliveira, Rosely Maria] Fundacao Oswald Cruz Fiocruz, Inst Pesquisa Clin Evandro Chagas IPEC, Rio De Janeiro, Brazil. [Castanon-Olivares, Laura Rosio; Estrada-Barcenas, Daniel; Taylor, Maria Lucia; Toriello, Conchita] Univ Nacl Autonoma Mexico, Dept Microbiol & Parasitol, Fac Med, Unidad Micol, Ciudad Mexico, Mexico. [Kong, Fanrong; Zeng, Xianyu; Zhao, Zuotao; Halliday, Catriona; Chen, Sharon] Westmead Hosp, Ctr Infect Dis & Microbiol, Westmead, NSW 2145, Australia. [Sun, Annie Ying] Univ Adelaide, Sch Paediat & Reprod Hlth, Adelaide, SA, Australia. [Sun, Annie Ying] Univ Adelaide, Robinson Inst, Adelaide, SA, Australia. [Gantois, Nausicaa; Delhaes, Laurence] Univ Lille 2, Inst Pasteur Lille, CHU Lille, BDEEP EA4547,CIIL, Lille, France. [Botterel, Francoise] CHU Henri Mondor, AP HP, Unite Parasitol Mycol, Dynamyc Team, F-94010 Creteil, France. [Robbertse, Barbara; Schoch, Conrad] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Ellis, David] Univ Adelaide, SA Pathol, Mycol & Infect Dis, Adelaide, SA, Australia. [Serena, Carolina] Univ Rovira & Virgili, Inst Invest Sanitaria Rovira & Virgili IISPV, Hosp Joan XXIII, Unitat Recerca, E-43007 Tarragona, Spain. RP Meyer, W (reprint author), CIDM, Mol Mycol Res Lab, MBI, Level 4,Room 0 4 04,176 Hawkesbury Rd, Westmead, NSW 2145, Australia. EM wieland.meyer@sydney.edu.au RI Ranque, Stephane/K-2317-2015; CBMA, CBMA/J-1937-2016; OI Ranque, Stephane/0000-0003-3293-5276; CBMA, CBMA/0000-0002-2841-2678; Sampaio, Paula/0000-0002-1415-4428; Cano-Lira, Jose F./0000-0003-4495-4394; Serena, Carolina/0000-0003-2251-0856; Pais, Celia/0000-0001-5959-290X FU National Health and Medical Research Council of Australia (NHMRC) [APP1031952]; CNPq [350338/2000-0, 308011/2010-4]; FAPERJ [E-26/103.157/2011, 2007/08575-1]; Fundacao de Amparo Pesquisa do Estado de So Paulo (FAPESP); Fundacao para a Ciencia e Tecnologia (FCT) [PEst-OE/BIA/UI4050/2014]; Belgian Science Policy Office (Belspo); MEXBOL program of CONACyT-Mexico [1228961, 122481]; Institut Pasteur and Institut de Veil le Sanitaire; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq); Fundacao de Amparo a Pesquisa do Estado de Goias (FAPEG); NIH, National Library of Medicine; NH&MRC of Australia FX This study was supported by an National Health and Medical Research Council of Australia (NH&MRC) grant [#APP1031952] to W Meyer, S Chen, V Robert, and D Ellis; CNPq [350338/2000-0] and FAPERJ [E-26/103.157/2011] grants to RM Zancope-Oliveira; CNPq [308011/2010-4] and FAPESP [2007/08575-1] Fundacao de Amparo Pesquisa do Estado de So Paulo (FAPESP) grants to AL Colombo; PEst-OE/BIA/UI4050/2014 from Fundacao para a Ciencia e Tecnologia (FCT) to C Pais; the Belgian Science Policy Office (Belspo) to BCCM/IHEM; the MEXBOL program of CONACyT-Mexico, [ref. number: 1228961 to ML Taylor and [122481] to C Toriello; the Institut Pasteur and Institut de Veil le Sanitaire to F Dromer and D Garcia-Hermoso; and the grants from the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) and the Fundacao de Amparo a Pesquisa do Estado de Goias (FAPEG) to CM de Almeida Soares and JA Parente Rocha. I Arthur would like to thank G Cherian, A Higgins and the staff of the Molecular Diagnostics Laboratory, Division of Microbiology and Infectious Diseases, Path West, QEII Medial Centre. Dromer would like to thank for the technical help of the sequencing facility and specifically that of I, Diancourt, A-S Delannoy-Vieillard, J-M Thiberge (Genotyping of Pathogens and Public Health, Institut Pasteur). RM Zancope-Oliveira would like to thank the Genomic/DNA Sequencing Platform at Fundacao Oswaldo Cruz-PDTIS/FIOCRUZ [RPT01A], Brazil for the sequencing. B Robbertse and CL Schoch acknowledge support from the Intramural Research Program of the NIH, National Library of Medicine. T Sorrell's work is funded by the NH&MRC of Australia; she is a Sydney Medical School Foundation Fellow. NR 141 TC 38 Z9 39 U1 7 U2 31 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1369-3786 EI 1460-2709 J9 MED MYCOL JI Med. Mycol. PD MAY PY 2015 VL 53 IS 4 BP 313 EP 337 DI 10.1093/mmy/myv008 PG 25 WC Infectious Diseases; Mycology; Veterinary Sciences SC Infectious Diseases; Mycology; Veterinary Sciences GA CK5FV UT WOS:000356249200001 PM 25802363 ER PT J AU Steeves, JA Liu, BM Willis, G Lee, R Smith, AW AF Steeves, Jeremy A. Liu, Benmei Willis, Gordon Lee, Richard Smith, Ashley Wilder TI Physicians' personal beliefs about weight-related care and their associations with care delivery: The US National Survey of Energy Balance Related Care among Primary Care Physicians SO OBESITY RESEARCH & CLINICAL PRACTICE LA English DT Article DE Energy balance; Primary care practices; Attitudes; Weight-related care ID CHILDHOOD OBESITY; PRACTICE PATTERNS; TREATING OBESITY; SELF-EFFICACY; UNITED-STATES; ATTITUDES; BARRIERS; PEDIATRICIANS; PREVALENCE; KNOWLEDGE AB Background: Overweight and obesity are major health risks in the United States (US) and primary care physicians (PCPs) are uniquely positioned to address them. However, their personal beliefs about weight-related care may influence their delivery of care. Methods: A nationally representative sample of 2022 physicians completed the National Survey of Energy Balance-Related Care among Primary Care Physicians. Physicians responded to questions regarding their beliefs and clinical practices associated with weight control including assessment, counselling, referral and follow-up for diet, physical activity, and weight. Multivariate logistic regression was used to examine associations between physician characteristics and personal beliefs, and associations between personal beliefs and care delivery, adjusting for specialty, age, gender, race, region, urban/rural location, and patient population. Results: Most physicians feel a responsibility (97%) to promote weight-related care, but over half (53%) have concerns about their effectiveness and almost two-thirds feel they lack effective strategies to help patients (63%). Demographics and medical specialty were associated with beliefs (female, Asian-American, Midwest and Southern location, and internal medicine physicians were more likely to have stronger positive beliefs about weight-related care). Personal beliefs about weight-related care were associated with the likelihood of its delivery. However, two practices, regular BMI assessment and referring patients for further evaluation and management, were less related to PCP beliefs than were other care practices. Conclusions: PCPs' beliefs may be important to their practice of weight-related care. Training in behavioural counselling, and providing physician's tools and resources may help to address their concerns about helping patients with weight-related care. Published by Elsevier Ltd on behalf of Asia Oceania Assoc. for the Study of Obesity. C1 [Steeves, Jeremy A.; Liu, Benmei; Willis, Gordon; Lee, Richard; Smith, Ashley Wilder] NCI, Div Canc Control & Populat Sci, Rockville, MD 20892 USA. RP Steeves, JA (reprint author), NCI, Canc Prevent Fellowship Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,MSC 9762, Rockville, MD 20892 USA. EM steevesja@mail.nih.gov FU National Cancer Institute's [N02-PC-61301] FX Data collection for this survey was supported by the National Cancer Institute's Contract No. N02-PC-61301. NR 55 TC 4 Z9 4 U1 2 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1871-403X EI 1878-0318 J9 OBES RES CLIN PRACT JI Obes. Res. Clin. Pract. PD MAY-JUN PY 2015 VL 9 IS 3 BP 243 EP 255 DI 10.1016/j.orcp.2014.08.002 PG 13 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA CK2RN UT WOS:000356059400007 PM 25175671 ER PT J AU Zhang, FQ Xu, Y Shugart, YY Yue, WH Qi, GY Yuan, GZ Cheng, ZH Yao, JJ Wang, JD Wang, GQ Cao, HB Guo, W Zhou, ZH Wang, ZQ Tian, L Jin, CH Yuan, JM Liu, CX Zhang, D AF Zhang, Fuquan Xu, Yong Shugart, Yin Yao Yue, Weihua Qi, Guoyang Yuan, Guozhen Cheng, Zaohuo Yao, Jianjun Wang, Jidong Wang, Guoqiang Cao, Hongbao Guo, Wei Zhou, Zhenhe Wang, Zhiqiang Tian, Lin Jin, Chunhui Yuan, Jianmin Liu, Chenxing Zhang, Dai TI Converging Evidence Implicates the Abnormal MicroRNA System in Schizophrenia SO SCHIZOPHRENIA BULLETIN LA English DT Article DE schizophrenia; microRNA; mRNA; rare variants; early-onset ID DORSOLATERAL PREFRONTAL CORTEX; GENOME-WIDE ASSOCIATION; GENE-EXPRESSION; RARE VARIANTS; MOUSE MODEL; BIOGENESIS; BRAIN; DELETION; NETWORKS; DEFICITS AB Background: Previous findings are inconsistent; yet, converging evidence suggests an association between schizophrenia (SZ) and the impairment of posttranscriptional regulation of brain development through microRNA (miRNA) systems. Methods: This study aims to (1) compare the overall frequency of 121 rare variants (RVs) in 59 genes associated with the miRNA system in genome-wide association studies (GWAS)-derived data including 768 SZ cases and 1348 healthy controls and validated in an independent GWAS data including 1802 SZ cases and 1447 controls; (2) profile genome-wide miRNA expression in blood collected from 15 early-onset SZ (EOS) cases and 15 healthy controls; and (3) construct a miRNA-messenger RNA (mRNA) regulatory network using our previous genome-wide mRNA expression data generated from a separate sample of 18 EOS cases and 12 healthy controls. Results: Our findings indicate that: (1) In genes associated with the control of miRNAs, there are approximately 50% more RVs in SZ cases than in controls (P <= 2.62E-10); (2) The observed lower miRNA activity in EOS patients compared with the healthy controls suggests that miRNAs are abnormally downregulated; (3) There exists a predicted regulatory network among some downregulated miRNAs and some upregulated mRNAs. Conclusions: Collectively, results from all 3 lines of evidence, suggest that the genetically based dysregulation of miRNA systems undermines miRNAs' inhibitory effects, resulting in the abnormal upregulation of genome transcription in the development of SZ. C1 [Zhang, Fuquan; Qi, Guoyang; Yuan, Guozhen; Cheng, Zaohuo; Yao, Jianjun; Wang, Jidong; Wang, Guoqiang; Zhou, Zhenhe; Wang, Zhiqiang; Tian, Lin; Jin, Chunhui; Yuan, Jianmin] Nanjing Med Univ, Wuxi Mental Hlth Ctr, Dept Clin Psychol, Wuxi, Peoples R China. [Zhang, Fuquan; Yue, Weihua; Liu, Chenxing; Zhang, Dai] Peking Univ, Key Lab Mental Hlth, Minist Hlth, Dept Psychiat,Affiliated Hosp 6, Beijing 100191, Peoples R China. [Zhang, Fuquan; Yue, Weihua; Liu, Chenxing; Zhang, Dai] Peking Univ, Inst Mental Hlth, Beijing 100191, Peoples R China. [Zhang, Fuquan; Shugart, Yin Yao; Cao, Hongbao; Guo, Wei] NIMH, Div Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Xu, Yong] Shanxi Med Univ, Hosp 1, Dept Psychiat, Taiyuan, Peoples R China. [Shugart, Yin Yao] Johns Hopkins Univ, Sch Med, Dept Gastroenterol, Baltimore, MD USA. [Zhang, Dai] Peking Univ, Peking Tsinghua Ctr Life Sci, PKU IDG, McGovern Inst Brain Res, Beijing 100191, Peoples R China. RP Zhang, D (reprint author), Peking Univ, Inst Mental Hlth, 51 Hua Yuan Bei Rd, Beijing 100191, Peoples R China. EM daizhang@bjmu.edu.cn NR 70 TC 7 Z9 7 U1 1 U2 13 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAY PY 2015 VL 41 IS 3 BP 728 EP 735 DI 10.1093/schbul/sbu148 PG 8 WC Psychiatry SC Psychiatry GA CK1UT UT WOS:000355993800023 PM 25429046 ER PT J AU Brown, LA Cox, C Baptiste, J Summers, H Button, R Bahlow, K Spurrier, V Kyser, J Luttge, BG Kuo, L Freed, EO Summers, MF AF Brown, Lola A. Cox, Cassiah Baptiste, Janae Summers, Holly Button, Ryan Bahlow, Kennedy Spurrier, Vaughn Kyser, Jenna Luttge, Benjamin G. Kuo, Lillian Freed, Eric O. Summers, Michael F. TI NMR Structure of the Myristylated Feline Immunodeficiency Virus Matrix Protein SO VIRUSES-BASEL LA English DT Article ID HIV-1 GAG; PLASMA-MEMBRANE; LIPID RAFTS; HETERONUCLEAR NMR; ANIMAL-MODELS; TYPE-1; CATS; FIV; PHOSPHATIDYLINOSITOL-(4,5)-BISPHOSPHATE; ELECTROSTATICS AB Membrane targeting by the Gag proteins of the human immunodeficiency viruses (HIV types-1 and -2) is mediated by Gag's N-terminally myristylated matrix (MA) domain and is dependent on cellular phosphatidylinositol-4,5-bisphosphate [PI(4,5)P-2]. To determine if other lentiviruses employ a similar membrane targeting mechanism, we initiated studies of the feline immunodeficiency virus (FIV), a widespread feline pathogen with potential utility for development of human therapeutics. Bacterial co-translational myristylation was facilitated by mutation of two amino acids near the amino-terminus of the protein (Q5A/G6S; myrMA(Q5A/G6S)). These substitutions did not affect virus assembly or release from transfected cells. NMR studies revealed that the myristyl group is buried within a hydrophobic pocket in a manner that is structurally similar to that observed for the myristylated HIV-1 protein. Comparisons with a recent crystal structure of the unmyristylated FIV protein [myr(-)MA] indicate that only small changes in helix orientation are required to accommodate the sequestered myr group. Depletion of PI(4,5)P-2 from the plasma membrane of FIV-infected CRFK cells inhibited production of FIV particles, indicating that, like HIV, FIV hijacks the PI(4,5)P-2 cellular signaling system to direct intracellular Gag trafficking during virus assembly. C1 [Brown, Lola A.; Cox, Cassiah; Baptiste, Janae; Summers, Holly; Button, Ryan; Bahlow, Kennedy; Spurrier, Vaughn; Kyser, Jenna; Summers, Michael F.] Univ Maryland Baltimore Cty, Howard Hughes Med Inst, Baltimore, MD 21250 USA. [Luttge, Benjamin G.; Kuo, Lillian; Freed, Eric O.] NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Freed, EO (reprint author), NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. EM lola.brown@yale.edu; cassiah.cox@nih.gov; janaeb@umbc.edu; hsummers@umbc.edu; ryan.button@umaryland.edu; kennedy.bahlow@temple.edu; vspurrier@uchicago.edu; jmk216@lehigh.edu; bxl244@case.edu; kuols@mail.nih.gov; efreed@mail.nih.gov; summers@hhmi.umbc.edu FU NIH [R37 AI30917, R25 GM-055036-18]; NSF [DGE-1144243]; Temple University MARC program (NIH) [T34 GM-087239-06]; Center for Cancer Research, National Cancer Institute, NIH; Intramural AIDS Targeted Antiviral Program FX This work was supported by NIH grant R37 AI30917 (to MFS). LB was supported by an NSF pre-doctoral grant DGE-1144243, and LB, CC, and JB were supported by an NIH grant that promotes doctoral diversity (IMSD R25 GM-055036-18). VS was supported through the Temple University MARC program (NIH grant T34 GM-087239-06). Work in the Freed lab was 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 71 TC 4 Z9 4 U1 2 U2 7 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD MAY PY 2015 VL 7 IS 5 BP 2210 EP 2229 DI 10.3390/v7052210 PG 20 WC Virology SC Virology GA CK4YG UT WOS:000356228700002 PM 25941825 ER PT J AU McKinney, CC Hussmann, KL McBride, AA AF McKinney, Caleb C. Hussmann, Katherine L. McBride, Alison A. TI The Role of the DNA Damage Response throughout the Papillomavirus Life Cycle SO VIRUSES-BASEL LA English DT Review ID BROMODOMAIN PROTEIN BRD4; BOVINE PAPILLOMAVIRUS; E2 PROTEIN; VIRAL-DNA; MITOTIC CHROMOSOMES; GENOMIC INSTABILITY; HUMAN KERATINOCYTES; TRANSCRIPTION ACTIVATION; PRODUCTIVE REPLICATION; EPISOMAL MAINTENANCE AB The DNA damage response (DDR) maintains genomic integrity through an elaborate network of signaling pathways that sense DNA damage and recruit effector factors to repair damaged DNA. DDR signaling pathways are usurped and manipulated by the replication programs of many viruses. Here, we review the papillomavirus (PV) life cycle, highlighting current knowledge of how PVs recruit and engage the DDR to facilitate productive infection. C1 [McKinney, Caleb C.; Hussmann, Katherine L.; McBride, Alison A.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP McBride, AA (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM caleb.mckinney@nih.gov; katherine.hussmann@nih.gov; amcbride@nih.gov OI McBride, Alison/0000-0001-5607-5157 FU National Institute of Allergy and Infectious Disease of the National Institutes of Health FX The authors' research is funded by the Intramural Research Program of the National Institute of Allergy and Infectious Disease of the National Institutes of Health. NR 120 TC 18 Z9 18 U1 3 U2 9 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD MAY PY 2015 VL 7 IS 5 BP 2450 EP 2469 DI 10.3390/v7052450 PG 20 WC Virology SC Virology GA CK4YG UT WOS:000356228700013 PM 26008695 ER PT J AU Ko, SU Simonsick, E Deshpande, N Ferrucci, L AF Ko, Seung-Uk Simonsick, Eleanor Deshpande, Nandini Ferrucci, Luigi TI Sex-specific age associations of ankle proprioception test performance in older adults: results from the Baltimore Longitudinal Study of Aging SO AGE AND AGEING LA English DT Article DE proprioception; ageing; gait; older people ID FUNCTIONAL PERFORMANCE; KNEE OSTEOARTHRITIS; MOVEMENT PERCEPTION; NEUROPATHY; WALKING AB Objectives: this study was aimed to test the hypothesis that ankle proprioception assessed by custom-designed proprioception testing equipment changes with ageing in men and women. Methods: ankle proprioception was assessed in 289 participants (131 women) of the Baltimore Longitudinal Study of Aging (BLSA); the participants aged 51-95 years and were blinded during testing. Results: the average minimum perceived ankle rotation was 1.11 degrees (SE = 0.07) in women and 1.00 degrees (SE = 0.06) in men, and it increased with ageing in both sexes (P < 0.001, for both). Ankle tracking performance, which is the ability to closely follow with the left ankle, a rotational movement induced on the right ankle by a torque motor, declines with ageing in both men and women (P = 0.018 and P = 0.011, respectively). Conclusions: a simple, standardised method for assessing ankle proprioception was introduced in this study using a customized test instrument, software and test protocol. Age-associated reduction in ankle proprioception was confirmed from two subtests of threshold and tracking separately for women and men. Findings in this study prompt future studies to determine whether these age-associated differences in the threshold for passive motion detection and movement tracking are evident in longitudinal study and how these specific deficits in ankle proprioception are related to age-associated chronic conditions such as knee or hip osteoarthritis and type II diabetes and affect daily activities such as gait. C1 [Ko, Seung-Uk] Chonnam Natl Univ, Dept Mech Engn, Yeosu 550749, Jeonnam, South Korea. [Simonsick, Eleanor; Ferrucci, Luigi] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA. [Deshpande, Nandini] Queens Univ, Sch Rehabil Therapy, Kingston, ON, Canada. RP Ko, SU (reprint author), Chonnam Natl Univ, Dept Mech Engn, 50 Daehak Ro, Yeosu 550749, Jeonnam, South Korea. EM seunguk.ko@gmail.com FU NIH, National Institute on Aging; Chonnam National University FX This paper was supported by the Intramural Research Program of the NIH, National Institute on Aging and Chonnam National University. Data for these analyses were obtained from the Baltimore Longitudinal Study of Aging, a study performed by the National Institute on Aging. NR 20 TC 6 Z9 6 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0002-0729 EI 1468-2834 J9 AGE AGEING JI Age Ageing PD MAY PY 2015 VL 44 IS 3 BP 485 EP 490 DI 10.1093/ageing/afv005 PG 6 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA CJ6SE UT WOS:000355623100024 PM 25637144 ER PT J AU Friesen, MC Shortreed, SM Wheeler, DC Burstyn, I Vermeulen, R Pronk, A Colt, JS Baris, D Karagas, MR Schwenn, M Johnson, A Armenti, KR Silverman, DT Yu, K AF Friesen, Melissa C. Shortreed, Susan M. Wheeler, David C. Burstyn, Igor Vermeulen, Roel Pronk, Anjoeka Colt, Joanne S. Baris, Dalsu Karagas, Margaret R. Schwenn, Molly Johnson, Alison Armenti, Karla R. Silverman, Debra T. Yu, Kai TI Using Hierarchical Cluster Models to Systematically Identify Groups of Jobs With Similar Occupational Questionnaire Response Patterns to Assist Rule-Based Expert Exposure Assessment in Population-Based Studies SO ANNALS OF OCCUPATIONAL HYGIENE LA English DT Article DE case-control studies; diesel exhaust; hierarchical clusters; occupational exposures ID DIESEL EXHAUST EXPOSURE; BLADDER-CANCER; DECISION RULES AB Objectives: Rule-based expert exposure assessment based on questionnaire response patterns in population-based studies improves the transparency of the decisions. The number of unique response patterns, however, can be nearly equal to the number of jobs. An expert may reduce the number of patterns that need assessment using expert opinion, but each expert may identify different patterns of responses that identify an exposure scenario. Here, hierarchical clustering methods are proposed as a systematic data reduction step to reproducibly identify similar questionnaire response patterns prior to obtaining expert estimates. As a proof-of-concept, we used hierarchical clustering methods to identify groups of jobs (clusters) with similar responses to diesel exhaust-related questions and then evaluated whether the jobs within a cluster had similar (previously assessed) estimates of occupational diesel exhaust exposure. Methods: Using the New England Bladder Cancer Study as a case study, we applied hierarchical cluster models to the diesel-related variables extracted from the occupational history and job-and industry-specific questionnaires (modules). Cluster models were separately developed for two subsets: (i) 5395 jobs with >= 1 variable extracted from the occupational history indicating a potential diesel exposure scenario, but without a module with diesel-related questions; and (ii) 5929 jobs with both occupational history and module responses to diesel-relevant questions. For each subset, we varied the numbers of clusters extracted from the cluster tree developed for each model from 100 to 1000 groups of jobs. Using previously made estimates of the probability (ordinal), intensity (mu g m(-3) respirable elemental carbon), and frequency (hours per week) of occupational exposure to diesel exhaust, we examined the similarity of the exposure estimates for jobs within the same cluster in two ways. First, the clusters' homogeneity (defined as >75% with the same estimate) was examined compared to a dichotomized probability estimate (<5 versus >= 5%; <50 versus >= 50%). Second, for the ordinal probability metric and continuous intensity and frequency metrics, we calculated the intraclass correlation coefficients (ICCs) between each job's estimate and the mean estimate for all jobs within the cluster. Results: Within-cluster homogeneity increased when more clusters were used. For example, >= 80% of the clusters were homogeneous when 500 clusters were used. Similarly, ICCs were generally above 0.7 when >= 200 clusters were used, indicating minimal within-cluster variability. The most within-cluster variability was observed for the frequency metric (ICCs from 0.4 to 0.8). We estimated that using an expert to assign exposure at the cluster-level assignment and then to review each job in non-homogeneous clusters would require similar to 2000 decisions per expert, in contrast to evaluating 4255 unique questionnaire patterns or 14 983 individual jobs. Conclusions: This proof-of-concept shows that using cluster models as a data reduction step to identify jobs with similar response patterns prior to obtaining expert ratings has the potential to aid rule-based assessment by systematically reducing the number of exposure decisions needed. While promising, additional research is needed to quantify the actual reduction in exposure decisions and the resulting homogeneity of exposure estimates within clusters for an exposure assessment effort that obtains cluster-level expert assessments as part of the assessment process. C1 [Friesen, Melissa C.; Wheeler, David C.; Colt, Joanne S.; Baris, Dalsu; Silverman, Debra T.] NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, Bethesda, MD 20892 USA. [Shortreed, Susan M.] Grp Hlth Res Inst, Biostat, Seattle, WA 98101 USA. [Wheeler, David C.] Virginia Commonwealth Univ, Dept Biostat, Richmond, VA 23298 USA. [Burstyn, Igor] Drexel Univ, Dept Environm & Occupat Hlth, Philadelphia, PA 19104 USA. [Vermeulen, Roel] Univ Utrecht, Utrecht, Netherlands. [Pronk, Anjoeka] TNO, Utrecht, Netherlands. [Karagas, Margaret R.] Geisel Sch Med Dartmouth, Hanover, NH 03756 USA. [Schwenn, Molly] Maine Canc Registry, Augusta, ME 04333 USA. [Johnson, Alison] Vermont Canc Registry, Burlington, VT 05402 USA. [Armenti, Karla R.] New Hampshire Dept Hlth & Human Serv, Div Publ Hlth Serv, Bur Publ Hlth Stat & Informat, Concord, NH 03301 USA. [Yu, Kai] NCI, Div Canc Epidemiol & Genet, Biostat, Bethesda, MD 20892 USA. RP Friesen, MC (reprint author), NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, Bethesda, MD 20892 USA. EM friesenmc@mail.nih.gov RI Friesen, Melissa/A-5362-2009; Vermeulen, Roel/F-8037-2011 OI Vermeulen, Roel/0000-0003-4082-8163 FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health [Z01 CP10122-19] FX Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (Z01 CP10122-19). NR 23 TC 1 Z9 1 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0003-4878 EI 1475-3162 J9 ANN OCCUP HYG JI Ann. Occup. Hyg. PD MAY PY 2015 VL 59 IS 4 BP 455 EP 466 DI 10.1093/annhyg/meu101 PG 12 WC Public, Environmental & Occupational Health; Toxicology SC Public, Environmental & Occupational Health; Toxicology GA CJ6TE UT WOS:000355625800005 PM 25477475 ER PT J AU Duarte, HA Harris, DR Tassiopoulos, K Leister, E Negrini, SFBD Ferreira, FF Cruz, MLS Pinto, J Allison, S Hazra, R AF Duarte, Horacio A. Harris, Donald Robert Tassiopoulos, Katherine Leister, Erin Biason de Moura Negrini, Silvia Fabiana Ferreira, Flavia Faleiro Santos Cruz, Maria Leticia Pinto, Jorge Allison, Susannah Hazra, Rohan CA NISDI PLACES Study Grp TI Relationship between viral load and behavioral measures of adherence to antiretroviral therapy in children living with human immunodeficiency virus in Latin America SO BRAZILIAN JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Pediatric; ART; Adherence; Latin America ID HIV-INFECTED CHILDREN; SELF-REPORT MEASURES; HIV-1-INFECTED CHILDREN; MEDICATION ADHERENCE; REPORTED ADHERENCE; CLINICAL MANAGEMENT; VIROLOGICAL FAILURE; DRUG-RESISTANCE; SOUTH-AFRICA; ADOLESCENTS AB Few studies have examined antiretroviral therapy adherence in Latin American children. Standardized behavioral measures were applied to a large cohort of human immunodeficiency virus-infected children in Brazil, Mexico, and Peru to assess adherence to prescribed antiretroviral therapy doses during the three days prior to study visits, assess timing of last missed dose, and evaluate the ability of the adherence measures to predict viral suppression. Time trends in adherence were modeled using a generalized estimating equations approach to account for possible correlations in outcomes measured repeatedly in the same participants. Associations of adherence with human immunodeficiency virus viral load were examined using linear regression. Mean enrollment age of the 380 participants was 5 years; 57.6% had undetectable' viral load (<400 copies/mL). At enrollment, 90.8% of participants were perfectly (100%) adherent, compared to 87.6% at the 6-month and 92.0% at the 12-month visit; the proportion with perfect adherence did not differ over time (p = 0.1). Perfect adherence was associated with a higher probability of undetectable viral load at the 12-month visit (odds ratio = 4.1, 95% confidence interval: 1.8-9.1; p < 0.001), but not at enrollment or the 6-month visit (p > 0.3). Last time missed any antiretroviral therapy dose was reported as "never" for 52.0% at enrollment, increasing to 60.7% and 65.9% at the 6- and 12-month visits, respectively (p < 0.001 for test of trend). The proportion with undetectable viral load was higher among those who never missed a dose at enrollment and the 12-month visit (p <= 0.005), but not at the 6-month visit (p = 0.2). While antiretroviral therapy adherence measures utilized in this study showed some association with viral load for these Latin American children, they may not be adequate for reliably identifying non-adherence and consequently children at risk for viral resistance. Other strategies are needed to improve the evaluation of adherence in this population. (C) 2015 Elsevier Editora Ltda. All rights reserved. C1 [Duarte, Horacio A.] Univ Washington, Sch Med, Dept Pediat, Seattle, WA USA. [Harris, Donald Robert] Westat Corp, Rockville, MD 20850 USA. [Tassiopoulos, Katherine] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Leister, Erin] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Biason de Moura Negrini, Silvia Fabiana] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pediat, Sao Paulo, SP, Brazil. [Ferreira, Flavia Faleiro; Pinto, Jorge] Univ Fed Minas Gerais, Fac Med, Belo Horizonte, MG, Brazil. [Santos Cruz, Maria Leticia] Hosp Fed Serv Estado, Rio De Janeiro, RJ, Brazil. [Allison, Susannah] NIMH, Div AIDS Res, NIH, Bethesda, MD 20892 USA. [Hazra, Rohan] NICHD, Maternal & Pediat Infect Dis Branch, NIH, Bethesda, MD USA. RP Harris, DR (reprint author), Westat Corp, 1600 Res Blvd, Rockville, MD 20850 USA. EM bobharris@westat.com OI Harris, Donald/0000-0002-8262-3716; Alarcon, Jorge/0000-0002-0800-2380 FU NICHD [N01-HD-3-3345, HHSN267200800001C, HHSN275201300003C] FX Supported by NICHD Contracts N01-HD-3-3345 (2002-2007), HHSN267200800001C (2007-2012), and HHSN275201300003C (2012-2017). NR 41 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER BRAZIL PI RIO DE JANEIRO PA R SETE SETEMBRO, 111-16, RIO DE JANEIRO, RJ 20050-006, BRAZIL SN 1413-8670 EI 1678-4391 J9 BRAZ J INFECT DIS JI Braz. J. Infect. Dis. PD MAY-JUN PY 2015 VL 19 IS 3 BP 263 EP 271 DI 10.1016/j.bjid.2015.01.004 PG 9 WC Infectious Diseases SC Infectious Diseases GA CJ3JF UT WOS:000355378500005 PM 25743569 ER PT J AU Wylie, LA Hardwick, LJA Papkovskaia, TD Thiele, CJ Philpott, A AF Wylie, Luke A. Hardwick, Laura J. A. Papkovskaia, Tatiana D. Thiele, Carol J. Philpott, Anna TI Ascl1 phospho-status regulates neuronal differentiation in a Xenopus developmental model of neuroblastoma SO DISEASE MODELS & MECHANISMS LA English DT Article DE Ascl1; Xenopus; Cell cycle; Development; Differentiation; Neuroblastoma ID UBIQUITIN-MEDIATED PROTEOLYSIS; TRANSCRIPTION FACTOR SOX10; HIGH-RISK NEUROBLASTOMA; NEURAL CREST; N-MYC; AUTONOMIC NEURONS; GROWTH ARREST; CELL-LINES; STEM-CELLS; EXPRESSION AB Neuroblastoma (NB), although rare, accounts for 15% of all paediatric cancer mortality. Unusual among cancers, NBs lack a consistent set of gene mutations and, excluding large-scale chromosomal rearrangements, the genome seems to be largely intact. Indeed, many interesting features of NB suggest that it has little in common with adult solid tumours but instead has characteristics of a developmental disorder. NB arises overwhelmingly in infants under 2 years of age during a specific window of development and, histologically, NB bears striking similarity to undifferentiated neuroblasts of the sympathetic nervous system, its likely cells of origin. Hence, NB could be considered a disease of development arising when neuroblasts of the sympathetic nervous system fail to undergo proper differentiation, but instead are maintained precociously as progenitors with the potential for acquiring further mutations eventually resulting in tumour formation. To explore this possibility, we require a robust and flexible developmental model to investigate the differentiation of NB's presumptive cell of origin. Here, we use Xenopus frog embryos to characterise the differentiation of anteroventral noradrenergic (AVNA) cells, cells derived from the neural crest. We find that these cells share many characteristics with their mammalian developmental counterparts, and also with NB cells. We find that the transcriptional regulator Ascl1 is expressed transiently in normal AVNA cell differentiation but its expression is aberrantly maintained in NB cells, where it is largely phosphorylated on multiple sites. We show that Ascl1's ability to induce differentiation of AVNA cells is inhibited by its multi-site phosphorylation at serine-proline motifs, whereas overexpression of cyclin-dependent kinases (CDKs) and MYCN inhibit wild-type Ascl1-driven AVNA differentiation, but not differentiation driven by a phospho-mutant form of Ascl1. This suggests that the maintenance of ASCL1 in its multiply phosphorylated state might prevent terminal differentiation in NB, which could offer new approaches for differentiation therapy in NB. C1 [Wylie, Luke A.; Hardwick, Laura J. A.; Papkovskaia, Tatiana D.; Philpott, Anna] Univ Cambridge, Hutchison MRC Res Ctr, Dept Oncol, Cambridge CB2 0XZ, England. [Wylie, Luke A.; Thiele, Carol J.] NCI, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Philpott, A (reprint author), Univ Cambridge, Hutchison MRC Res Ctr, Dept Oncol, Cambridge Biomed Campus, Cambridge CB2 0XZ, England. EM ap113@cam.ac.uk FU UK Neuroblastoma Society; National Cancer Institute, National Institutes of Health; UK Medical Research Council Doctoral Training Award FX This work was supported by a grant from the UK Neuroblastoma Society (A.P., L.A.W. and T.D.P.). C.J.T. and L.A.W. are supported by the intramural research program of the National Cancer Institute, National Institutes of Health. L.A.W. is an NIH-OxCam Scholar. L.J.A.H. is supported by a UK Medical Research Council Doctoral Training Award. NR 53 TC 7 Z9 7 U1 1 U2 3 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 1754-8403 EI 1754-8411 J9 DIS MODEL MECH JI Dis. Model. Mech. PD MAY PY 2015 VL 8 IS 5 BP 429 EP 441 DI 10.1242/dmm.018630 PG 13 WC Cell Biology; Pathology SC Cell Biology; Pathology GA CJ5UW UT WOS:000355558000003 PM 25786414 ER PT J AU Updegrove, TB Shabalina, SA Storz, G AF Updegrove, Taylor B. Shabalina, Svetlana A. Storz, Gisela TI How do base-pairing small RNAs evolve? SO FEMS MICROBIOLOGY REVIEWS LA English DT Review DE sRNAs; Hfq; evolution; mosaic pattern of selective pressure ID REGULATORY SMALL RNAS; TARGET MESSENGER-RNA; BACTERIAL SMALL RNAS; DEPENDENT SMALL RNA; BINDING SMALL RNAS; ESCHERICHIA-COLI; SOLUBLE-RNAS; VIBRIO-CHOLERAE; STAPHYLOCOCCUS-AUREUS; BIOFILM FORMATION AB The increasing numbers of characterized base-pairing small RNAs (sRNAs) and the identification of these regulators in a broad range of bacteria are allowing comparisons between species and explorations of sRNA evolution. In this review, we describe some examples of trans-encoded base-pairing sRNAs that are species-specific and others that are more broadly distributed. We also describe examples of sRNA orthologs where different features are conserved. These examples provide the background for a discussion of mechanisms of sRNA evolution and selective pressures on the sRNAs and their mRNA target(s). C1 [Updegrove, Taylor B.; Storz, Gisela] Eunice Kennedy Shriver Natl Inst Hlth, Cell Biol & Metab Program, Bethesda, MD 20892 USA. [Shabalina, Svetlana A.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Storz, G (reprint author), Eunice Kennedy Shriver Natl Inst Hlth, Cell Biol & Metab Program, Bethesda, MD 20892 USA. EM storz@helix.nih.gov FU Intramural Research Programs of the National Library of Medicine; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This work was supported by the Intramural Research Programs of the National Library of Medicine (S.A.S.) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (G.S.). NR 111 TC 16 Z9 16 U1 0 U2 14 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0168-6445 EI 1574-6976 J9 FEMS MICROBIOL REV JI Fems Microbiol. Rev. PD MAY PY 2015 VL 39 IS 3 BP 379 EP 391 DI 10.1093/femsre/fuv014 PG 13 WC Microbiology SC Microbiology GA CJ9RY UT WOS:000355841200008 PM 25934120 ER PT J AU Buonfiglio, DC Ramos-Lobo, AM Silveira, MA Furigo, IC Hennighausen, L Frazao, R Donato, J AF Buonfiglio, Daniella C. Ramos-Lobo, Angela M. Silveira, Marina A. Furigo, Isadora C. Hennighausen, Lothar Frazao, Renata Donato, Jose, Jr. TI Neuronal STAT5 signaling is required for maintaining lactation but not for postpartum maternal behaviors in mice SO HORMONES AND BEHAVIOR LA English DT Article DE Prolactin; Hypothalamus; Signaling pathways; Preoptic region ID NULLIPAROUS FEMALE RATS; ESTROGEN-RECEPTOR-ALPHA; MEDIAL PREOPTIC AREA; PLACENTAL-LACTOGEN; ENERGY-BALANCE; CYTOKINE SIGNALING-3; TRANSCRIPTION 5B; FOOD RESTRICTION; SOCS3 DEFICIENCY; NEUROPEPTIDE-Y AB Prolactin and placental lactogens control mammary development and lactation as well as play an important role in maternal behaviors. However, the molecular mechanisms in the brain responsible for this regulation remain largely unknown. Therefore, the present study investigated whether Signal Transducer and Activator of Transcription 5 (STAT5) signaling in the brain, the key transcriptional factor recruited by prolactin receptor and other hormones, is required for postpartum maternal behavior, maintenance of lactation and offspring growth. Neuronal ablation of STAT5 impaired the control of prolactin secretion and reduced the hypothalamic expression of suppressors of cytokine signaling (i.e., SOCS3 and CISH). In addition, neuronal STAT5 deletion attenuated the hyperphagia commonly observed during lactation by decreasing the hypothalamic expression of orexigenic neurotransmitters such as the neuropeptide Y and agouti-related protein. The lower food intake of lactating neuron-specific STAT5 knockout females resulted in reduced milk production and offspring growth. Unexpectedly, postpartum maternal behavior expression was not impaired in neuron-specific STAT5 knockout females. On the contrary, the latency to retrieve and group the pups into the nest was reduced in mutant dams. Finally, we demonstrated that approximately 30% of recorded neurons in the medial preoptic area were acutely depolarized by prolactin suggesting that fast STAT5-independent signaling pathways may be involved in the regulation of maternal behaviors. Overall, our results revealed important information about the molecular mechanisms recruited by hormones to orchestrate the activation of neural circuitries engaged in the induction of maternal care. (C) 2015 Elsevier Inc. All rights reserved. C1 [Buonfiglio, Daniella C.; Ramos-Lobo, Angela M.; Furigo, Isadora C.; Donato, Jose, Jr.] Univ Sao Paulo, Dept Physiol & Biophys, Inst Biomed Sci, BR-05508000 Sao Paulo, SP, Brazil. [Silveira, Marina A.; Frazao, Renata] Univ Sao Paulo, Dept Anat, Inst Biomed Sci, BR-05508900 Sao Paulo, SP, Brazil. [Hennighausen, Lothar] NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. RP Donato, J (reprint author), Ave Prof Lineu Prestes 1524, BR-05508000 Sao Paulo, SP, Brazil. EM jdonato@icb.usp.br RI Donato, Jose Jr./A-9662-2010; Furigo, Isadora/G-3575-2016; FrazAo, Renata/D-1374-2012; Buonfiglio, Daniella /C-2321-2017 OI Donato, Jose Jr./0000-0002-6183-3861; Furigo, Isadora/0000-0002-4387-3878; Buonfiglio, Daniella /0000-0002-9503-4363 FU Sao Paulo Research Foundation (FAPESP-Brazil) [10/18086, 12/12202-4, 13/21722-4, 14/11752-6]; CAPES (Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior); Intramural Research Program of the NIH, The National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) FX We thank Ana M.P. Campos for the technical assistance and the Sao Paulo Research Foundation (FAPESP-Brazil, 10/18086, 12/12202-4, 13/21722-4 and 14/11752-6) and CAPES (Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior) for the financial support and fellowships. LH was supported by the Intramural Research Program of the NIH, The National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK). NR 56 TC 7 Z9 7 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0018-506X EI 1095-6867 J9 HORM BEHAV JI Horm. Behav. PD MAY PY 2015 VL 71 BP 60 EP 68 DI 10.1016/j.yhbeh.2015.04.004 PG 9 WC Behavioral Sciences; Endocrinology & Metabolism SC Behavioral Sciences; Endocrinology & Metabolism GA CJ5ZT UT WOS:000355573500008 PM 25896118 ER PT J AU Yi, L Kaler, SG AF Yi, Ling Kaler, Stephen G. TI Direct interactions of adaptor protein complexes 1 and 2 with the copper transporter ATP7A mediate its anterograde and retrograde trafficking SO HUMAN MOLECULAR GENETICS LA English DT Article ID POLARIZED EPITHELIAL-CELLS; TRANS-GOLGI NETWORK; P-TYPE ATPASE; PLASMA-MEMBRANE; MENKES PROTEIN; AMPA RECEPTORS; INTRACELLULAR-LOCALIZATION; SOMATODENDRITIC DOMAIN; REGULATED TRAFFICKING; MDCK CELLS AB ATP7A is a P-type ATPase in which diverse mutations lead to X-linked recessive Menkes disease or occipital horn syndrome. Recently, two previously unknown ATP7A missense mutations, T994I and P1386S, were shown to cause an isolated distal motor neuropathy without clinical or biochemical features of other ATP7A disorders. These mutant alleles cause subtle defects in ATP7A intracellular trafficking, resulting in preferential plasma membrane localization compared with wild-type ATP7A. We reported previously that ATP7A(P1386S) causes unstable insertion of the eighth and final transmembrane segment, preventing proper position of the carboxyl-terminal tail in a proportion of mutant molecules. Here, we utilize this and other naturally occurring and engineered mutant ATP7A alleles to identify mechanisms of normal ATP7A trafficking. We show that adaptor protein (AP) complexes 1 and 2 physically interact with ATP7A and that binding is mediated in part by a carboxyl-terminal di-leucine motif. In contrast to other ATP7A missense mutations, ATP7A(P1386S) partially disturbs interactions with both APs, leading to abnormal axonal localization in transfected NSC-34 motor neurons and altered calcium-signaling following glutamate stimulation. Our results imply that AP-1 normally tethers ATP7A at the trans-Golgi network in the somatodendritic segments of motor neurons and that alterations affecting the ATP7A carboxyl-terminal tail induce release of the copper transporter to the axons or axonal membranes. The latter effects are intensified by diminished interaction with AP-2, impeding ATP7A retrograde trafficking. Taken together, these findings further illuminate the normal molecular mechanisms of ATP7A trafficking and suggest a pathophysiological basis for ATP7A-related distal motor neuropathy. C1 [Yi, Ling; Kaler, Stephen G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Translat Neurosci, Program Mol Med, NIH, Bethesda, MD 20892 USA. RP Kaler, SG (reprint author), NIH, Porter Neurosci Res Ctr 2, Bldg 35A,Room 2D-971,35A Convent Dr,MSC 3754, Bethesda, MD 20892 USA. EM kalers@mail.nih.gov FU NIH FX This research was supported by the NIH Intramural Research Program (IRP). NR 50 TC 8 Z9 8 U1 0 U2 7 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 MAY 1 PY 2015 VL 24 IS 9 BP 2411 EP 2425 DI 10.1093/hmg/ddv002 PG 15 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CJ2OX UT WOS:000355325400001 PM 25574028 ER PT J AU Michalsky, MP Inge, TH Simmons, M Jenkins, TM Buncher, R Helmrath, M Brandt, ML Harmon, CM Courcoulas, A Chen, M Horlick, M Daniels, SR Urbina, EM AF Michalsky, Marc P. Inge, Thomas H. Simmons, Mark Jenkins, Todd M. Buncher, Ralph Helmrath, Michael Brandt, Mary L. Harmon, Carroll M. Courcoulas, Anita Chen, Michael Horlick, Mary Daniels, Stephen R. Urbina, Elaine M. CA Teen-LABS Consortium TI Cardiovascular Risk Factors in Severely Obese Adolescents The Teen Longitudinal Assessment of Bariatric Surgery (Teen-LABS) Study SO JAMA PEDIATRICS LA English DT Article ID MODEL ASSESSMENT HOMA; WEIGHT-LOSS SURGERY; METABOLIC SYNDROME; PRACTICE GUIDELINES; DIABETES-MELLITUS; CHILDREN; OVERWEIGHT; DISEASE; METAANALYSIS; PREVALENCE AB IMPORTANCE Severe obesity is increasingly common in the adolescent population but, as of yet, very little information exists regarding cardiovascular disease (CVD) risks in this group. OBJECTIVE To assess the baseline prevalence and predictors of CVD risks among severely obese adolescents undergoing weight-loss surgery. DESIGN, SETTING, AND PARTICIPANTS A prospective cohort study was conducted from February 28, 2007, to December 30, 2011, at the following 5 adolescent weight-loss surgery centers in the United States: Nationwide Children's Hospital in Columbus, Ohio; Cincinnati Children's Hospital Medical Center in Cincinnati, Ohio; Texas Children's Hospital in Houston; University of Pittsburgh Medical Center in Pittsburgh, Pennsylvania; and Children's Hospital of Alabama in Birmingham. Consecutive patients aged 19 years or younger were offered enrollment in a long-term outcome study; the final analysis cohort consisted of 242 participants. MAIN OUTCOMES AND MEASURES This report examined the preoperative prevalence of CVD risk factors (ie, fasting hyperinsulinemia, elevated high-sensitivity C-reactive protein levels, impaired fasting glucose levels, dyslipidemia, elevated blood pressure, and diabetes mellitus) and associations between risk factors and body mass index (calculated as weight in kilograms divided by height in meters squared), age, sex, and race/ethnicity. Preoperative data were collected within 30 days preceding bariatric surgery. RESULTS The mean (SD) age was 17 (1.6) years and median body mass index was 50.5. Cardiovascular disease risk factor prevalence was fasting hyperinsulinemia (74%), elevated high-sensitivity C-reactive protein levels (75%), dyslipidemia (50%), elevated blood pressure (49%), impaired fasting glucose levels (26%), and diabetes mellitus (14%). The risk of impaired fasting glucose levels, elevated blood pressure, and elevated high-sensitivity C-reactive protein levels increased by 15%, 10%, and 6%, respectively, per 5-unit increase in body mass index (P < .01). Dyslipidemia (adjusted relative risk = 1.60 [95% CI, 1.26-2.03]; P < .01) and elevated blood pressure (adjusted relative risk = 1.48 [95% CI, 1.16-1.89]; P < .01) were more likely in adolescent boys compared with adolescent girls. White individuals were at greater risk of having elevated triglyceride levels (adjusted relative risk = 1.76 [95% CI, 1.14-2.72]; P = .01) but were less likely to have impaired fasting glucose levels (adjusted relative risk = 0.58 [95% CI, 0.38-0.89]; P = .01). CONCLUSIONS AND RELEVANCE Numerous CVD risk factors are apparent in adolescents undergoing weight-loss surgery. Increasing body mass index and male sex increase the relative risk of specific CVD risk factors. These data suggest that even among severely obese adolescents, recognition and treatment of CVD risk factors is important to help limit further progression of disease. C1 [Michalsky, Marc P.] Nationwide Childrens Hosp, Columbus, OH 43205 USA. [Inge, Thomas H.; Jenkins, Todd M.; Helmrath, Michael; Urbina, Elaine M.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Simmons, Mark; Buncher, Ralph] Univ Cincinnati, Cincinnati, OH USA. [Brandt, Mary L.] Texas Childrens Hosp, Baylor Coll Med, Houston, TX 77030 USA. [Harmon, Carroll M.] SUNY Buffalo, Buffalo, NY 14260 USA. [Courcoulas, Anita] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Chen, Michael] Univ Alabama Birmingham, Birmingham, AL USA. [Horlick, Mary] Natl Inst Diabet & Digest & Kidney Dis, NIH, Bethesda, MD USA. [Daniels, Stephen R.] Denver Childrens Hosp, Denver, CO USA. RP Michalsky, MP (reprint author), Nationwide Childrens Hosp, 700 Childrens Dr,ED 379, Columbus, OH 43205 USA. EM marc.michalsky@nationwidechildrens.org OI michalsky, marc/0000-0002-7119-3634 FU National Institutes of Health-National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Diabetes and Digestive and Kidney Diseases [U01DK072493, UM1DK072493, UM1DK095710]; Cincinnati Children's Hospital Medical Center [UL1 TR000077-04]; Nationwide Children's Hospital [UL1RR025755]; Texas Children's Hospital/Baylor College of Medicine [M01-RR00188]; University of Pittsburgh [UL1 RR024153, UL1TR000005]; University of Alabama, Birmingham [UL1 TR000165]; LABS Consortium [U01 DK066557] FX Dr Courcoulas received grants from the National Institutes of Health-National Institute of Diabetes and Digestive and Kidney Diseases. The Teen-LABS consortium was funded by cooperative agreements with the National Institute of Diabetes and Digestive and Kidney Diseases through grants U01DK072493, UM1DK072493, and UM1DK095710 (University of Cincinnati). The study was also supported by grants UL1 TR000077-04 (Cincinnati Children's Hospital Medical Center), UL1RR025755 (Nationwide Children's Hospital), M01-RR00188 (Texas Children's Hospital/Baylor College of Medicine), UL1 RR024153, UL1TR000005 (University of Pittsburgh), and UL1 TR000165 (University of Alabama, Birmingham). We gratefully acknowledge the significant contributions made by the Teen-LABS Consortium and grant U01 DK066557 from our parent study, LABS Consortium. NR 33 TC 8 Z9 8 U1 1 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6203 EI 2168-6211 J9 JAMA PEDIATR JI JAMA Pediatr. PD MAY PY 2015 VL 169 IS 5 BP 438 EP 444 DI 10.1001/jamapediatrics.2014.3690 PG 7 WC Pediatrics SC Pediatrics GA CJ8EX UT WOS:000355734000012 PM 25730293 ER PT J AU Lumeng, JC Taveras, EM Birch, L Yanovski, SZ AF Lumeng, Julie C. Taveras, Elsie M. Birch, Leann Yanovski, Susan Z. TI Prevention of Obesity in Infancy and Early Childhood A National Institutes of Health Workshop SO JAMA PEDIATRICS LA English DT Review ID INTERNET-BASED INTERVENTION; TODDLER SLEEP DISTURBANCES; WEIGHT-GAIN; MOTOR DEVELOPMENT; RANDOMIZED-TRIAL; BODY-COMPOSITION; YOUNG-CHILDREN; UNITED-STATES; LIFE-COURSE; BOTTLE USE AB Addressing the childhood obesity epidemic continues to be a challenge. Given that once obesity develops it is likely to persist, there has been an increasing focus on prevention at earlier stages of the life course. Research to develop and implement effective prevention and intervention strategies in the first 2 years after birth has been limited. In fall 2013, the National Institute of Diabetes and Digestive and Kidney Diseases convened a multidisciplinary workshop to summarize the current state of knowledge regarding the prevention of infant and early childhood obesity and to identify research gaps and opportunities. The questions addressed included (1) "What is known regarding risk for excess weight gain in infancy and early childhood?" (2) "What is known regarding interventions that are promising or have been shown to be efficacious?" and (3) "What are the challenges and opportunities in implementing and evaluating behavioral interventions for parents and other caregivers and their young children?" C1 [Lumeng, Julie C.] Univ Michigan, Dept Pediat, Div Child Behav Hlth, Ann Arbor, MI 48109 USA. [Lumeng, Julie C.] Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. [Lumeng, Julie C.] Univ Michigan, Ctr Human Growth & Dev, Ann Arbor, MI 48109 USA. [Taveras, Elsie M.] Massachusetts Gen Hosp Children, Div Gen Acad Pediat, Dept Pediat, Boston, MA USA. [Taveras, Elsie M.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Birch, Leann] Univ Georgia, Dept Foods & Nutr, Family & Consumer Sci, Athens, GA 30602 USA. [Yanovski, Susan Z.] Natl Inst Diabet & Digest & Kidney Dis, Div Digest Dis & Nutr, NIH, Bethesda, MD USA. RP Lumeng, JC (reprint author), Univ Michigan, Ctr Human Growth & Dev, 300 N Ingalls St,10th Floor, Ann Arbor, MI 48109 USA. EM jlumeng@umich.edu FU National Institute of Diabetes and Digestive and Kidney Diseases; National Heart Lung and Blood Institute; Office of Behavioral and Social Sciences Research of the National Institutes of Health FX Funding for the workshop was provided by the National Institute of Diabetes and Digestive and Kidney Diseases, National Heart Lung and Blood Institute, and Office of Behavioral and Social Sciences Research of the National Institutes of Health. NR 78 TC 16 Z9 16 U1 7 U2 25 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6203 EI 2168-6211 J9 JAMA PEDIATR JI JAMA Pediatr. PD MAY PY 2015 VL 169 IS 5 BP 484 EP 490 DI 10.1001/jamapediatrics.2014.3554 PG 7 WC Pediatrics SC Pediatrics GA CJ8EX UT WOS:000355734000018 PM 25775180 ER PT J AU Bernstock, JD Caples, CM Wagner, SC Kang, DG Lehman, RA AF Bernstock, Joshua D. Caples, Connor M. Wagner, Scott C. Kang, Daniel G. Lehman, Ronald A., Jr. TI Characteristics of Combat-Related Spine Injuries: A Review of Recent Literature SO MILITARY MEDICINE LA English DT Review ID OPERATION IRAQI FREEDOM; IMPROVISED EXPLOSIVE DEVICE; THORACOLUMBAR SPINE; BURST FRACTURES; SACRAL FRACTURE; BLAST TRAUMA; AFGHANISTAN; MANAGEMENT; WOUNDS; WAR AB Injuries to the spinal column in combat casualties sustained during the conflicts in Iraq and Afghanistan are common, and the highest in reported wartime history. High-energy blast mechanisms from improved explosive devices have resulted in complex polytrauma and injury patterns, which are often markedly different from those injuries encountered in civilian trauma. Herein, we review the most current literature with regard to the distinct types of combat-related spine injuries/concomitant comorbidities sustained in Operations Enduring Freedom, Iraqi Freedom and New Dawn. C1 [Bernstock, Joshua D.] NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. [Caples, Connor M.; Lehman, Ronald A., Jr.] Uniformed Serv Univ Hlth Sci, Dept Surg, Div Orthopaed, Bethesda, MD 20814 USA. [Caples, Connor M.; Wagner, Scott C.; Kang, Daniel G.; Lehman, Ronald A., Jr.] Walter Reed Natl Mil Med Ctr, Dept Orthopaed Surg, Bethesda, MD 20889 USA. RP Bernstock, JD (reprint author), NINDS, Stroke Branch, NIH, 10 Ctr Dr,Room B1D 733,MSC 1063, Bethesda, MD 20892 USA. NR 52 TC 0 Z9 0 U1 0 U2 3 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 MAY PY 2015 VL 180 IS 5 BP 503 EP 512 DI 10.7205/MILMED-D-14-00215 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA CJ5WF UT WOS:000355562600013 PM 25939103 ER PT J AU Gollapudi, BB Lynch, AM Heflich, RH Dertinger, SD Dobrovolsky, VN Froetschl, R Horibata, K Kenyon, MO Kimoto, T Lovell, DP Stankowski, LF White, PA Witt, KL Tanir, JY AF Gollapudi, B. Bhaskar Lynch, Anthony M. Heflich, Robert H. Dertinger, Stephen D. Dobrovolsky, Vasily N. Froetschl, Roland Horibata, Katsuyoshi Kenyon, Michelle O. Kimoto, Takafumi Lovell, David P. Stankowski, Leon F., Jr. White, Paul A. Witt, Kristine L. Tanir, Jennifer Y. TI The in vivo Pig-a assay: A report of the International Workshop On Genotoxicity Testing (IWGT) Workgroup SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Article; Proceedings Paper CT 6th International Workshop on Genotoxicity Testing (IWGT) CY OCT 31-NOV 01, 2013 CL Foz do Iguacu, BRAZIL DE Red blood cells; Reticulocytes; Glycosylphosphatidylinositol; Flow cytometry; CD59; Mutation ID GENE MUTATION ASSAY; ETHYL-N-NITROSOUREA; RED-BLOOD-CELLS; PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA; SPLEEN T-CELLS; FLOW-CYTOMETRIC DETECTION; BONE-MARROW ERYTHROIDS; LESCH-NYHAN-SYNDROME; END-POINTS; 1,3-PROPANE SULTONE AB The in vivo Pig-a assay uses flow cytometry to measure phenotypic variants for antibody binding to cell surface glycosylphosphatidylinositol (GPI)-anchored proteins. There is good evidence suggesting that the absence of antibody binding is the result of a mutation in the endogenous X-linked Pig-a gene, which forms the rationale for the assay. Although the assay has been performed with several types of hematopoietic cells and in a variety of mammalian species, including humans, currently it' is optimized only for measuring CD59-deficient (presumed Pig-a mutant) erythrocytes in the peripheral blood of rats. An expert workgroup formed by the International Workshop on Genotoxicity Testing considered the state of assay development and the potential of the assay for regulatory use. Consensus was reached on what is known about the Pig-a assay and how it should be conducted, and recommendations were made on additional data and refinements that would help to further enhance the assay for use in hazard identification and risk assessment. Published by Elsevier B.V. C1 [Gollapudi, B. Bhaskar] Exponent, Midland, MI USA. [Lynch, Anthony M.] GlaxoSmithKline, Stevenage, Herts, England. [Heflich, Robert H.; Dobrovolsky, Vasily N.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Dertinger, Stephen D.] Litron Labs, Rochester, NY USA. [Froetschl, Roland] Fed Inst Drugs & Med Devices, Bonn, Germany. [Horibata, Katsuyoshi] Natl Inst Hlth Sci, Tokyo, Japan. [Kenyon, Michelle O.] Pfizer Global Res & Dev, Groton, CT USA. [Kimoto, Takafumi] Teijin Pharma, Tokyo, Japan. [Lovell, David P.] Univ London, London WC1E 7HU, England. [Stankowski, Leon F., Jr.] BioReliance, Rockville, MD USA. [White, Paul A.] Hlth Canada, Environm Hlth Sci & Res Bur, Ottawa, ON K1A 0L2, Canada. [Witt, Kristine L.] NIEHS, NIH, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Tanir, Jennifer Y.] Hlth & Environm Sci Inst, Washington, DC USA. RP Heflich, RH (reprint author), US FDA, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM robert.heflich@fda.hhs.gov OI white, paul/0000-0001-5853-4759 FU National Institute of Health/National Institute of Environmental Health Sciences (NIEHS) [R44ES021973] FX The views expressed in this report are not necessarily shared by the institutions at which the workgroup members are employed. The information in these materials is not a formal dissemination of information by the U.S. Food and Drug Administration and does not represent agency position or policy. Data presented in this communication were partially funded by a grant from the National Institute of Health/National Institute of Environmental Health Sciences (NIEHS; grant no. R44ES021973). The contents of this report are solely the responsibility of the authors, and do not necessarily represent the official views of the NIEHS. NR 66 TC 34 Z9 34 U1 1 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5718 EI 1879-3592 J9 MUTAT RES-GEN TOX EN JI Mutat. Res. Genet. Toxicol. Environ. Mutagen. PD MAY 1 PY 2015 VL 783 SI SI BP 23 EP 35 DI 10.1016/j.mrgentox.2014.09.007 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA CJ2YX UT WOS:000355351700005 PM 25953398 ER PT J AU Yauk, CL Aardema, MJ van Benthem, J Bishop, JB Dearfield, KL DeMarini, DM Dubrova, YE Honma, M Lupski, JR Marchetti, F Meistrich, ML Pacchierotti, F Stewart, J Waters, MD Douglas, GR AF Yauk, Carole L. Aardema, Marilyn J. van Benthem, Jan Bishop, Jack B. Dearfield, Kerry L. DeMarini, David M. Dubrova, Yuri E. Honma, Masamitsu Lupski, James R. Marchetti, Francesco Meistrich, Marvin L. Pacchierotti, Francesca Stewart, Jane Waters, Michael D. Douglas, George R. TI Approaches for identifying germ cell mutagens: Report of the 2013 IWGT workshop on germ cell assays SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Article; Proceedings Paper CT 6th International Workshop on Genotoxicity Testing (IWGT) CY OCT 31-NOV 01, 2013 CL Foz do Iguacu, BRAZIL DE Germ cell mutation; Genetic disease; Reproductive health; Copy number variants; Gene; mutation; Chromosome aberrations ID COPY-NUMBER VARIANTS; BLOOD-TESTIS BARRIER; MARROW MICRONUCLEUS TEST; REPRODUCTIVE END-POINTS; DOMINANT LETHAL ASSAY; SPERM DNA-DAMAGE; RISK-ASSESSMENT; BONE-MARROW; HUMAN GENOME; IN-VIVO AB This workshop reviewed the current science to inform and recommend the best evidence-based approaches on the use of germ cell genotoxicity tests. The workshop questions and key outcomes were as follows. (1) Do genotoxicity and mutagenicity assays in somatic cells predict germ cell effects? Limited data suggest that somatic cell tests detect most germ cell mutagens, but there are strong concerns that dictate caution in drawing conclusions. (2) Should germ cell tests be done, and when? If there is evidence that a chemical or its metabolite(s) will not reach target germ cells or gonadal tissue, it is not necessary to conduct germ cell tests, notwithstanding somatic outcomes. However,,it was recommended that negative somatic cell mutagens with clear evidence for gonadal exposure and evidence of toxicity in germ cells could be considered for germ cell mutagenicity testing. For somatic mutagens that are known to reach the gonadal compartments and expose germ cells, the chemical could be assumed to be a germ cell mutagen without further testing. Nevertheless, germ cell mutagenicity testing would be needed for quantitative risk assessment. (3) What new assays should be implemented and how? There is an immediate need for research on the application of whole genome sequencing in heritable mutation analysis in humans and animals, and integration of germ cell assays with somatic cell genotoxicity tests. Focus should be on environmental exposures that can cause de novo mutations, particularly newly recognized types of genomic changes. Mutational events, which may occur by exposure of germ cells during embryonic development, should also be investigated. Finally, where there are indications of germ cell toxicity in repeat dose or reproductive toxicology tests, consideration should be given to leveraging those studies to inform of possible germ cell genotoxicity. Crown Copyright (C) 2015 Published by Elsevier B.V. C1 [Yauk, Carole L.; Marchetti, Francesco; Douglas, George R.] Hlth Canada, Environm Hlth Sci & Res Bur, Ottawa, ON K1A 0L2, Canada. [Aardema, Marilyn J.] Marilyn Aardema Consulting, Fairfield, OH USA. [van Benthem, Jan] Natl Inst Publ Hlth & Environm, NL-3720 BA Bilthoven, Netherlands. [Bishop, Jack B.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. [Dearfield, Kerry L.] USDA, Food Safety & Inspect Serv, Washington, DC 20250 USA. [DeMarini, David M.] Univ N Carolina, Chapel Hill, NC 27515 USA. [Dubrova, Yuri E.] Univ Leicester, Leicester LE1 7RH, Leics, England. [Honma, Masamitsu] Natl Inst Hlth Sci, Tokyo, Japan. [Lupski, James R.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Lupski, James R.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Meistrich, Marvin L.] Univ Texas MD Anderson Canc Ctr, Houston, TX USA. [Marchetti, Francesco] Italian Natl Agcy New Technol, ENEA, Energy & Sustainable Econ Dev, Milan, Italy. [Stewart, Jane] AstraZeneca, Bangalore, Karnataka, India. [Waters, Michael D.] Integrated Lab Syst Inc, Res Triangle Pk, NC USA. RP Yauk, CL (reprint author), Hlth Canada, Environm Hlth Sci & Res Bur, Ottawa, ON K1A 0L2, Canada. EM Carole.Yauk@hc-sc.gc.ca; George.Douglas@hc-sc.gc.ca OI Dubrova, Yuri/0000-0001-5281-7539; Marchetti, Francesco/0000-0002-9435-4867; Yauk, Carole/0000-0003-4919-876X FU IWGT FX Funding for this workshop was provided by the IWGT. NR 165 TC 14 Z9 14 U1 3 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5718 EI 1879-3592 J9 MUTAT RES-GEN TOX EN JI Mutat. Res. Genet. Toxicol. Environ. Mutagen. PD MAY 1 PY 2015 VL 783 SI SI BP 36 EP 54 DI 10.1016/j.mrgentox.2015.01.008 PG 19 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA CJ2YX UT WOS:000355351700006 PM 25953399 ER PT J AU Bartholdy, B Mukhopadhyay, R Lajugie, J Aladjem, MI Bouhassira, EE AF Bartholdy, Boris Mukhopadhyay, Rituparna Lajugie, Julien Aladjem, Mirit I. Bouhassira, Eric E. TI Allele-specific analysis of DNA replication origins in mammalian cells SO NATURE COMMUNICATIONS LA English DT Article ID IN-VIVO; GENOME; INITIATION; IDENTIFICATION; CHROMOSOME; SEQUENCES; FEATURES; REPEATS; MOTIFS; LOCUS AB The mechanisms that control the location and timing of firing of replication origins are poorly understood. Using a novel functional genomic approach based on the analysis of SNPs and indels in phased human genomes, we observe that replication asynchrony is associated with small cumulative variations in the initiation efficiency of multiple origins between the chromosome homologues, rather than with the activation of dormant origins. Allele-specific measurements demonstrate that the presence of G-quadruplex-forming sequences does not correlate with the efficiency of initiation. Sequence analysis reveals that the origins are highly enriched in sequences with profoundly asymmetric G/C and A/T nucleotide distributions and are almost completely depleted of antiparallel triplex-forming sequences. We therefore propose that although G4-forming sequences are abundant in replication origins, an asymmetry in nucleotide distribution, which increases the propensity of origins to unwind and adopt non-B DNA structure, rather than the ability to form G4, is directly associated with origin activity. C1 [Bartholdy, Boris; Mukhopadhyay, Rituparna; Lajugie, Julien; Bouhassira, Eric E.] Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10461 USA. [Aladjem, Mirit I.] NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Bouhassira, EE (reprint author), Albert Einstein Coll Med, Dept Cell Biol, 1300 Morris Pk Ave, Bronx, NY 10461 USA. EM Eric.bouhassira@einstein.yu.edu RI Aladjem, Mirit/G-2169-2010 OI Aladjem, Mirit/0000-0002-1875-3110 FU NYSTEM [C029154, C028113] FX This work was supported by NYSTEM grants C029154 and C028113. We thank Drs Carl Schildkraut, Karen Usdin and Michael Seidman for useful discussions. We thank Dr Barbara Birshtein for critical reading of the manuscript. NR 61 TC 9 Z9 9 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD MAY PY 2015 VL 6 AR 7051 DI 10.1038/ncomms8051 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ5ME UT WOS:000355530900002 PM 25987481 ER PT J AU Cortes, A Pulit, SL Leo, PJ Pointon, JJ Robinson, PC Weisman, MH Ward, M Gensler, LS Zhou, XD Garchon, HJ Chiocchia, G Nossent, J Lie, BA Forre, O Tuomilehto, J Laiho, K Bradbury, LA Elewaut, D Burgos-Vargas, R Stebbings, S Appleton, L Farrah, C Lau, J Haroon, N Mulero, J Blanco, FJ Gonzalez-Gay, MA Lopez-Larrea, C Bowness, P Gaffney, K Gaston, H Gladman, DD Rahman, P Maksymowych, WP Crusius, JBA van der Horst-Bruinsma, IE Valle-Onate, R Romero-Sanchez, C Hansen, IM Pimentel-Santos, FM Inman, RD Martin, J Breban, M Wordsworth, BP Reveille, JD Evans, DM de Bakker, PIW Brown, MA AF Cortes, Adrian Pulit, Sara L. Leo, Paul J. Pointon, Jenny J. Robinson, Philip C. Weisman, Michael H. Ward, Michael Gensler, Lianne S. Zhou, Xiaodong Garchon, Henri-Jean Chiocchia, Gilles Nossent, Johannes Lie, Benedicte A. Forre, Oystein Tuomilehto, Jaakko Laiho, Kari Bradbury, Linda A. Elewaut, Dirk Burgos-Vargas, Ruben Stebbings, Simon Appleton, Louise Farrah, Claire Lau, Jonathan Haroon, Nigil Mulero, Juan Blanco, Francisco J. Gonzalez-Gay, Miguel A. Lopez-Larrea, C. Bowness, Paul Gaffney, Karl Gaston, Hill Gladman, Dafna D. Rahman, Proton Maksymowych, Walter P. Crusius, J. Bart A. van der Horst-Bruinsma, Irene E. Valle-Onate, Raphael Romero-Sanchez, Consuelo Hansen, Inger Myrnes Pimentel-Santos, Fernando M. Inman, Robert D. Martin, Javier Breban, Maxime Wordsworth, Bryan Paul Reveille, John D. Evans, David M. de Bakker, Paul I. W. Brown, Matthew A. TI Major histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1 SO NATURE COMMUNICATIONS LA English DT Article ID UNFOLDED PROTEIN RESPONSE; GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; TRANSGENIC RATS; ENDOPLASMIC-RETICULUM; BEHCETS-DISEASE; HLA-B27; HLA; MHC; ANTIGEN AB Ankylosing spondylitis (AS) is a common, highly heritable, inflammatory arthritis for which HLA-B*27 is the major genetic risk factor, although its role in the aetiology of AS remains elusive. To better understand the genetic basis of the MHC susceptibility loci, we genotyped 7,264 MHC SNPs in 22,647 AS cases and controls of European descent. We impute SNPs, classical HLA alleles and amino-acid residues within HLA proteins, and tested these for association to AS status. Here we show that in addition to effects due to HLA-B*27 alleles, several other HLA-B alleles also affect susceptibility. After controlling for the associated haplotypes in HLA-B, we observe independent associations with variants in the HLA-A, HLA-DPB1 and HLA-DRB1 loci. We also demonstrate that the ERAP1 SNP rs30187 association is not restricted only to carriers of HLA-B*27 but also found in HLA-B*40:01 carriers independently of HLA-B*27 genotype. C1 [Cortes, Adrian; Leo, Paul J.; Robinson, Philip C.; Bradbury, Linda A.; Evans, David M.; Brown, Matthew A.] Univ Queensland, Diamantina Inst, Princess Alexandra Hosp, Brisbane, Qld 4102, Australia. [Pulit, Sara L.] Univ Med Ctr Utrecht, Ctr Mol Med, Dept Med Genet, NL-3584 Utrecht, Netherlands. [Pointon, Jenny J.; Bowness, Paul] Nuffield Orthopaed Ctr, NIHR Oxford Musculoskeletal Biomed Res Unit, Oxford OX3 7LD, England. [Weisman, Michael H.] Cedars Sinai Med Ctr, Dept Med Rheumatol, Los Angeles, CA 90048 USA. [Ward, Michael] NIAMSD, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Gensler, Lianne S.] Univ Calif San Francisco, Dept Med Rheumatol, San Francisco, CA 94143 USA. [Zhou, Xiaodong; Reveille, John D.] Univ Texas Hlth Sci Ctr Houston, Dept Rheumatol & Clin Immunogenet, Houston, TX 77030 USA. [Garchon, Henri-Jean; Chiocchia, Gilles; Breban, Maxime] Univ Versailles St Quentin En Yvelines, Lab Excellence Inflamex, INSERM, UMR 1173, F-78180 St Quentn En Yvelines, France. [Garchon, Henri-Jean] Hop Ambroise Pare, AP HP, Div Genet, F-78180 Boulogne, France. [Garchon, Henri-Jean] Univ Versailles St Quentin En Yvelines, F-78180 Boulogne, France. [Nossent, Johannes] Univ Western Australia, Sch Med, Perth, WA 6009, Australia. [Nossent, Johannes] Sir Charles Gairdner Hosp, Dept Rheumatol, Perth, WA 6009, Australia. [Lie, Benedicte A.] Univ Oslo, Dept Med Genet, N-0310 Oslo, Norway. [Lie, Benedicte A.] Oslo Univ Hosp, N-0310 Oslo, Norway. [Lie, Benedicte A.] Oslo Univ Hosp, Dept Immunol, N-0310 Oslo, Norway. [Forre, Oystein] Oslo Univ Hosp, Dept Rheumatol, N-0310 Oslo, Norway. [Forre, Oystein] Univ Oslo, N-0310 Oslo, Norway. [Tuomilehto, Jaakko] Natl Inst Hlth & Welfare, Dept Chron Dis Prevent, Helsinki 00271, Finland. [Tuomilehto, Jaakko] Danube Univ Krems, Ctr Vasc Prevent, A-3500 Krems, Austria. [Tuomilehto, Jaakko] King Abdulaziz Univ, Diabet Res Grp, Jeddah 21589, Saudi Arabia. [Laiho, Kari] Paijat Hame Cent Hosp, Dept Med, Lahti, Finland. [Elewaut, Dirk] Ghent Univ Hosp, Dept Rheumatol, B-9052 Ghent, Belgium. [Elewaut, Dirk] Univ Ghent, VIB Inflammat Res Ctr, B-9052 Ghent, Belgium. [Burgos-Vargas, Ruben] Hosp Gen Mexico City, Dept Rheumatol, Mexico City 06726, DF, Mexico. [Burgos-Vargas, Ruben] Univ Nacl Autonoma Mexico, Mexico City 06726, DF, Mexico. [Stebbings, Simon] Univ Otago, Dunedin Sch Med, Dept Med, Dunedin 9016, New Zealand. [Haroon, Nigil] Univ Toronto, Toronto Western Hosp, Div Rheumatol, Toronto, ON M5T 2S8, Canada. [Mulero, Juan] Hosp Puerta Hierro, Dept Rheumatol, Madrid 28222, Spain. [Blanco, Francisco J.] INIBIC, Complejo Hosp La Coruna, Dept Rheumatol, La Coruna 15006, Spain. [Gonzalez-Gay, Miguel A.] IFIMAV, Hosp Marques Valcecillas, Dept Rheumatol, Santander 39008, Spain. [Lopez-Larrea, C.] Hosp Univ Cent Asturias, Dept Immunol, Oviedo 33011, Spain. [Lopez-Larrea, C.] Fdn Renal Inigo Alvarez de Toledo, Madrid 33011, Spain. [Gaffney, Karl] Norfolk & Norwich Univ Hosp, Dept Rheumatol, Norwich NR4 7UY, Norfolk, England. [Gaston, Hill] Univ Cambridge, Addenbrookes Hosp, Dept Med, Cambridge CB2 0SP, England. [Gladman, Dafna D.] Univ Toronto, Div Rheumatol, Toronto, ON M4N 3M5, Canada. [Gladman, Dafna D.] Toronto Western Res Inst, Toronto, ON M4N 3M5, Canada. [Gladman, Dafna D.] Univ Hlth Network, Psoriat Arthrit Program, Toronto, ON M4N 3M5, Canada. [Rahman, Proton] Mem Univ Newfoundland, St John, NF A1B 3X9, Canada. [Maksymowych, Walter P.] Univ Alberta, Dept Med, Edmonton, AB T6G 2R7, Canada. [Crusius, J. Bart A.] Vrije Univ Amsterdam, Med Ctr, Immunogenet Lab, Dept Med Microbiol & Infect Control, NL-1081 BT Amsterdam, Netherlands. [van der Horst-Bruinsma, Irene E.] Vrije Univ Amsterdam, Med Ctr, Dept Rheumatol, NL-1081 BT Amsterdam, Netherlands. [Valle-Onate, Raphael; Romero-Sanchez, Consuelo] Univ La Sabana, Hosp Militar Cent, Div Rheumatol, Spondyloarthropaty Grp, Bogota, NA, Colombia. [Hansen, Inger Myrnes] Helgelandssykehuset, N-8613 Mo I Rana, Norway. [Pimentel-Santos, Fernando M.] Univ Nova Lisboa, Fac Ciencias Med, Chron Dis Res Ctr CEDOC, P-1169056 Lisbon, Portugal. [Martin, Javier] CSIC, Inst Parasitol & Biomed Lopez Neyra, Granada 18100, Spain. [Breban, Maxime] Hop Ambroise Pare, AP HP, Div Rheumatol, F-92100 Boulogne, France. [Breban, Maxime] Univ Versailles St Quentin En Yvelines, F-92100 Boulogne, France. [Evans, David M.] Univ Bristol, MRC Integrat Epidemiol Unit, Bristol, Avon, England. [Evans, David M.] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Dept Epidemiol, Utrecht, Netherlands. RP Brown, MA (reprint author), Univ Queensland, Diamantina Inst, Princess Alexandra Hosp, Brisbane, Qld 4102, Australia. EM matt.brown@uq.edu.au RI Blanco, Francisco J/C-3192-2014; Gonzalez-Gay, Miguel/B-2306-2008; Robinson, Philip/B-8319-2011; Martin, Javier/B-8141-2008; chiocchia, gilles/F-6287-2013; Elewaut, Dirk/K-6831-2014; Faculdade de Ciencias Medicas, Nova Medical School/K-6209-2013; OI Blanco, Francisco J/0000-0001-9821-7635; Gonzalez-Gay, Miguel/0000-0002-7924-7406; Robinson, Philip/0000-0002-3156-3418; chiocchia, gilles/0000-0001-9973-0940; Evans, David/0000-0003-0663-4621; bowness, paul/0000-0003-4597-0484 FU Arthritis Research UK [19536, 18797]; NIHR Oxford comprehensive Biomedical Research Centre [A93081]; NIHR Thames Valley collaborative research network; National Ankylosing Spondylitis Society (UK); Arthritis Society of Canada; National Institutes of Health/National Institute of Allergy and Infectious Diseases grant [1U01 AI09090-01]; Inst. Carlos III, Spain [PI12/02587]; European Union 'Fondos FEDER'; Agence Nationale de la Recherche [ANR-11-IDEX-0005-02]; Societe Francaise de Rhumatologie (SFR); Arthritis Foundation; Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health; National Health and Medical Research Council (Australia); Australian Research Council [FT130101709]; Netherlands Organization for Scientific Research [016.126.354]; National Institutes of Health [1R01AR062886-1] FX We thank all participating subjects with AS and healthy individuals who provided the DNA and clinical information necessary for this study. This work was in part funded by grants from Arthritis Research UK (19536 and 18797), the NIHR Oxford comprehensive Biomedical Research Centre (immunity and inflammation theme A93081) and NIHR Thames Valley collaborative research network and National Ankylosing Spondylitis Society (UK). SPARCC was established through the support of the Arthritis Society of Canada. Support was received from National Institutes of Health/National Institute of Allergy and Infectious Diseases grant 1U01 AI09090-01. This work was supported in part by grant PI12/02587 (Inst. Carlos III, Spain) and by European Union 'Fondos FEDER'. Support was received from Agence Nationale de la Recherche (grant ANR 2010 GEMISA and Investissements d'Avenir programme ANR-11-IDEX-0005-02), the Societe Francaise de Rhumatologie (SFR) and the Arthritis Foundation. M.W. is funded by the Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health. M.A.B. is funded by a National Health and Medical Research Council (Australia) Senior Principal Research Fellowship. D.M.E. is funded by an Australian Research Council Future Fellowship (FT130101709). P.I.W.d.B. is funded in part by the Netherlands Organization for Scientific Research (VIDI Vernieuwingsimpuls project 016.126.354) and by the National Institutes of Health (1R01AR062886-1). NR 47 TC 24 Z9 24 U1 1 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD MAY PY 2015 VL 6 AR 7146 DI 10.1038/ncomms8146 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ5ND UT WOS:000355533700005 PM 25994336 ER PT J AU Salton, M Kasprzak, WK Voss, T Shapiro, BA Poulikakos, PI Misteli, T AF Salton, Maayan Kasprzak, Wojciech K. Voss, Ty Shapiro, Bruce A. Poulikakos, Poulikos I. Misteli, Tom TI Inhibition of vemurafenib-resistant melanoma by interference with pre-mRNA splicing SO NATURE COMMUNICATIONS LA English DT Article ID ACQUIRED-RESISTANCE; BRAF INHIBITION; B-RAF; THERAPY; PATHWAY; MECHANISM; BRAF(V600E); SPLICEOSOME; PREDICTION; MUTATIONS AB Mutations in the serine/threonine kinase BRAF are found in more than 60% of melanomas. The most prevalent melanoma mutation is BRAF(V600E), which constitutively activates downstream MAPK signalling. Vemurafenib is a potent RAF kinase inhibitor with remarkable clinical activity in BRAF(V600E)-positive melanoma tumours. However, patients rapidly develop resistance to vemurafenib treatment. One resistance mechanism is the emergence of BRAF alternative splicing isoforms leading to elimination of the RAS-binding domain. Here we identify interference with pre-mRNA splicing as a mechanism to combat vemurafenib resistance. We find that small-molecule pre-mRNA splicing modulators reduce BRAF3-9 production and limit in-vitro cell growth of vemurafenib-resistant cells. In xenograft models, interference with pre-mRNA splicing prevents tumour formation and slows growth of vemurafenib-resistant tumours. Our results identify an intronic mutation as the molecular basis for a RNA splicing-mediated RAF inhibitor resistance mechanism and we identify pre-mRNA splicing interference as a potential therapeutic strategy for drug resistance in BRAF melanoma. C1 [Salton, Maayan; Voss, Ty; Misteli, Tom] NCI, NIH, Cell Biol Genomes Grp, Bethesda, MD 20892 USA. [Kasprzak, Wojciech K.] Leidos Biomed Res Inc, Frederick Natl Lab, Basic Sci Program, Ft Detrick, MD 21702 USA. [Shapiro, Bruce A.] NCI, NIH, RNA Struct & Design Sect, Frederick, MD 21702 USA. [Poulikakos, Poulikos I.] Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA. [Poulikakos, Poulikos I.] Tisch Canc Inst, Dept Dermatol, New York, NY 10029 USA. RP Misteli, T (reprint author), NCI, NIH, Cell Biol Genomes Grp, Bethesda, MD 20892 USA. EM mistelit@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, NCI, Center for Cancer Research; Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E] FX We thank Paola Scaffidi and Travis Dittmer for advice and technical help, Antoni Ribas for the M397/M397AR cell lines, Meenhard Herlyn for 451Lu/451Lu BR and WM938B/WM983B BR cell lines, Minoru Yoshida for the kind gift of SSA, Plexxikon Inc for PLX4720, Kazunori Koide for MAMB and Liang Cao for the use of the Sector Imager. This work was in part performed at the NCI High-Throughput Imaging Facility. This research was supported by the Intramural Research Program of the National Institutes of Health, NCI, Center for Cancer Research and was funded in part with federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under Contract HHSN261200800001E to W.K.K. NR 36 TC 13 Z9 13 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD MAY PY 2015 VL 6 AR 7103 DI 10.1038/ncomms8103 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ5MO UT WOS:000355531900002 PM 25971842 ER PT J AU Kolanos, R Partilla, JS Baumann, MH Hutse, BA Banks, ML Negus, SS Glennon, RA AF Kolanos, R. Partilla, J. S. Baumann, M. H. Hutse, B. A. Banks, M. L. Negus, S. S. Glennon, R. A. TI Stereoselective Actions of Methylenedioxypyrovalerone (MDPV) To Inhibit Dopamine and Norepinephrine Transporters and Facilitate Intracranial Self-Stimulation in Rats SO ACS CHEMICAL NEUROSCIENCE LA English DT Article DE Synthetic cathinones; MDPV; DAT; NET; reuptake inhibition; ICSS (intracranial self-stimulation); psychomotor stimulants; cocaine; drug abuse ID PSYCHOACTIVE BATH SALTS; ALPHA-AMINO-ACIDS; MEPHEDRONE; COCAINE; ANALOGS; DRUGS AB The designer stimulant methylenedioxypyrovalerone (MDPV) is a potent reuptake inhibitor at transporters for dopamine (DAT) and norepinephrine (NET) that produces a constellation of abuse-related behavioral effects. MDPV possesses a chiral center, and the abused formulation of the drug is a racemic mixture, but no data are available on the pharmacology of its isomers. Here, the individual optical isomers of MDPV were prepared and examined with respect to their neurochemical actions on neurotransmitter reuptake and behavioral effects in an assay of intracranial self-stimulation (ICSS) in rats. In assays of DAT uptake inhibition, S(+)MDPV (EC50 = 2.13 nM) was more potent than either (+/-)MDPV (EC30 = 4.85 nM) or R(-)MDPV (EC50 = 382.80 nM); the three drugs were less potent at NET uptake inhibition, with the same rank order of potency. Neither racemic MDPV nor its optical isomers inhibited the reuptake of serotonin at concentrations up to 10 mu M. S(+)MDPV produced an abuse-related and dose-dependent facilitation of ICSS, and the potency of S(+)MDPV (significant facilitation at doses >= 0.1 mg/kg) was greater than that of the racemate (significant facilitation at doses >= 0.32 mg/kg). R(-)MDPV failed to alter ICSS at doses up to 100 times greater than the lowest effective dose of S(+)MDPV. The results indicate that abuse-related neurochemical and behavioral effects of racemic MDPV reside primarily with its S(+) isomer. C1 [Kolanos, R.; Glennon, R. A.] Virginia Commonwealth Univ, Sch Pharm, Dept Med Chem, Richmond, VA 23298 USA. [Partilla, J. S.; Baumann, M. H.] NIDA, Designer Drug Res Unit, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Hutse, B. A.; Banks, M. L.; Negus, S. S.] Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Richmond, VA 23298 USA. RP Glennon, RA (reprint author), Virginia Commonwealth Univ, Sch Pharm, Dept Med Chem, 800 E Leigh St,POB 980540, Richmond, VA 23298 USA. EM glennon@vcu.edu RI Banks, Matthew/K-4429-2014 OI Banks, Matthew/0000-0003-4949-5246 FU PHS [R01 DA033930, T32 DA007027] FX This work was supported in part by PHS grant R01 DA033930 and T32 DA007027. NR 17 TC 7 Z9 7 U1 1 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-7193 J9 ACS CHEM NEUROSCI JI ACS Chem. Neurosci. PD MAY PY 2015 VL 6 IS 5 BP 771 EP 777 DI 10.1021/acschemneuro.5b00006 PG 7 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Neurosciences SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Neurosciences & Neurology GA CI9CE UT WOS:000355067200010 PM 25688761 ER PT J AU Novelle, MG Wahl, D Dieguez, C Bernier, M de Cabo, R AF Novelle, Marta G. Wahl, Devin Dieguez, Carlos Bernier, Michel de Cabo, Rafael TI Resveratrol supplementation: Where are we now and where should we go? SO AGEING RESEARCH REVIEWS LA English DT Review DE Resveratrol; Bioavailability; Metabolism; Clinical trials; Translational research ID CORONARY-ARTERY-DISEASE; GENETICALLY HETEROGENEOUS MICE; RANDOMIZED CONTROLLED-TRIALS; ACTIVATED PROTEIN-KINASE; TYPE-2 DIABETES-MELLITUS; BLOOD MONONUCLEAR-CELLS; IN-VIVO EVIDENCE; KAPPA-B PATHWAY; TRANS-RESVERATROL; CALORIC RESTRICTION AB Pre-clinical findings have provided mounting evidence that resveratrol, a dietary polyphenol, may confer health benefits and protect against a variety of medical conditions and age-related complications. However, there is no consistent evidence of an increased protection against metabolic disorders and other ailments when comparing studies in laboratory animals and humans. A number of extraneous and potential confounding variables can affect the outcome of clinical research. To date, most of the studies that have investigated the effect of resveratrol administration on patient outcomes have been limited by their sample sizes. In this review, we will survey the latest advances regarding the timing, dosage, formulation, bioavailability, toxicity of resveratrol, and resveratrol-drug interactions in human studies. Moreover, the present report focuses on the actions of resveratrol treatment in combating diseases, such as cancer, diabetes, neurodegeneration, cardiovascular disease, and other age-related ailments. Published by Elsevier B.V. C1 [Novelle, Marta G.; Wahl, Devin; Bernier, Michel; de Cabo, Rafael] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Novelle, Marta G.; Dieguez, Carlos] Univ Santiago de Compostela, Inst Invest Sanitaria, Res Ctr Mol Med & Chron Dis CIMUS, Santiago De Compostela 15782, Spain. [Novelle, Marta G.; Dieguez, Carlos] CIBER Fisiopatol Obesidad & Nutr CIBERobn, Santiago De Compostela 15706, Spain. RP de Cabo, R (reprint author), NIA, Expt Gerontol Sect, TGB, NIH, 251 Bayview Blvd,Suite 100-Room 9C218, Baltimore, MD 21224 USA. EM decabora@grc.nia.nih.gov RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; Bernier, Michel/0000-0002-5948-368X; Wahl, Devin/0000-0003-2794-0185; NOVELLE, MARTA G/0000-0003-0285-7182; , rafael/0000-0003-2830-5693 FU Intramural Research Program of the National Institute on Aging, National Institutes of Health FX This work has been supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. CIBER de Fisiopatologia de la Obesidad y Nutricion is an initiative of ISCIII. The funding agencies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 164 TC 45 Z9 46 U1 9 U2 76 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1568-1637 EI 1872-9649 J9 AGEING RES REV JI Ageing Res. Rev. PD MAY PY 2015 VL 21 BP 1 EP 15 DI 10.1016/j.arr.2015.01.002 PG 15 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA CI8QX UT WOS:000355037900001 PM 25625901 ER PT J AU van Loon, B Woodgate, R Hubscher, U AF van Loon, Barbara Woodgate, Roger Huebscher, Ulrich TI DNA polymerases: Biology, diseases and biomedical applications SO DNA REPAIR LA English DT Editorial Material C1 [van Loon, Barbara; Huebscher, Ulrich] Univ Zurich Irchel, Inst Vet Biochem & Mol Biol, CH-8057 Zurich, Switzerland. [Woodgate, Roger] NICHHD, Lab Genom Integr, NIH, Bethesda, MD 20892 USA. RP van Loon, B (reprint author), Univ Zurich Irchel, Inst Vet Biochem & Mol Biol, Winterthurerstr 190, CH-8057 Zurich, Switzerland. NR 1 TC 3 Z9 3 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 EI 1568-7856 J9 DNA REPAIR JI DNA Repair PD MAY PY 2015 VL 29 SI SI BP 1 EP 3 DI 10.1016/j.dnarep.2015.04.001 PG 3 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA CJ2ZA UT WOS:000355352000001 PM 25951980 ER PT J AU Vaisman, A Woodgate, R AF Vaisman, Alexandra Woodgate, Roger TI Redundancy in ribonucleotide excision repair: Competition, compensation, and cooperation SO DNA REPAIR LA English DT Article DE Ribonucleotide excision repair; Nucleotide excision repair; Mismatch repair; Ribonuclease H; Flap endonuclease; DNA polymerase I ID DNA-POLYMERASE-BETA; OKAZAKI FRAGMENT MATURATION; AICARDI-GOUTIERES-SYNDROME; ESCHERICHIA-COLI; MISMATCH REPAIR; RNASE H2; SINGLE RIBONUCLEOTIDE; GENOME INTEGRITY; TOPOISOMERASE-I; STRAND DNA AB The survival of all living organisms is determined by their ability to reproduce, which in turn depends on accurate duplication of chromosomal DNA. In order to ensure the integrity of genome duplication, DNA polymerases are equipped with stringent mechanisms by which they select and insert correctly paired nucleotides with a deoxyribose sugar ring. However, this process is never 100% accurate. To fix occasional mistakes, cells have evolved highly sophisticated and often redundant mechanisms. A good example is mismatch repair (MMR), which corrects the majority of mispaired bases and which has been extensively studied for many years. On the contrary, pathways leading to the replacement of nucleotides with an incorrect sugar that is embedded in chromosomal DNA have only recently attracted significant attention. This review describes progress made during the last few years in understanding such pathways in both prokaryotes and eukaryotes. Genetic studies in Escherichia coli and Saccharomyces cerevisiae demonstrated that MMR has the capacity to replace errant ribonucleotides, but only when the base is mispaired. In contrast, the major evolutionarily conserved ribonucleotide repair pathway initiated by the ribonuclease activity of type 2 Rnase H has broad specificity. In yeast, this pathway also requires the concerted action of Fen1 and pol delta, while in bacteria it can be successfully completed by DNA polymerase I. Besides these main players, all organisms contain alternative enzymes able to accomplish the same tasks, although with differing efficiency and fidelity. Studies in bacteria have very recently demonstrated that isolated rNMPs can be removed from genomic DNA by error-free nucleotide excision repair (NER), while studies in yeast suggest the involvement of topoisomerase 1 in alternative mutagenic ribonucleotide processing. This review summarizes the most recent progress in understanding the ribonucleotide repair mechanisms in prokaryotes and eukaryotes. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). C1 [Vaisman, Alexandra; Woodgate, Roger] NICHHD, Lab Genom Integr, NIH, Bethesda, MD 20892 USA. RP Woodgate, R (reprint author), 9800 Med Ctr Dr,Bldg C,Room 320, Bethesda, MD 20892 USA. EM woodgate@nih.gov FU NIH/NICHD FX This study was made possible by funding from the NIH/NICHD Intramural Research Program. NR 63 TC 8 Z9 8 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 EI 1568-7856 J9 DNA REPAIR JI DNA Repair PD MAY PY 2015 VL 29 SI SI BP 74 EP 82 DI 10.1016/j.dnarep.2015.02.008 PG 9 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA CJ2ZA UT WOS:000355352000009 PM 25753809 ER PT J AU Martinez-Jimenez, MI Garcia-Gomez, S Bebenek, K Sastre-Moreno, G Calvo, PA Diaz-Talavera, A Kunkel, TA Blanco, L AF Martinez-Jimenez, Maria I. Garcia-Gomez, Sara Bebenek, Katarzyna Sastre-Moreno, Guillermo Calvo, Patricia A. Diaz-Talavera, Alberto Kunkel, Thomas A. Blanco, Luis TI Alternative solutions and new scenarios for translesion DNA synthesis by human PrimPol SO DNA REPAIR LA English DT Article DE PrimPol; DNA primase; DNA polymerase; 8oxoG; Lesion bypass; Translesion synthesis ID MITOCHONDRIAL RNA-POLYMERASE; HUMAN POL-MU; PRIMASE-POLYMERASE; STRAND SYNTHESIS; REPLICATION; PROTEINS; NHEJ; LAMBDA; MANGANESE; FIDELITY AB PrimPol is a recently described DNA polymerase that has the virtue of initiating DNA synthesis. In addition of being a sensu stricto DNA primase, PrimPol's polymerase activity has a large capacity to tolerate different kind of lesions. The different strategies used by PrimPol for DNA damage tolerance are based on its capacity to "read" certain lesions, to skip unreadable lesions, and as an ultimate solution, to restart DNA synthesis beyond the lesion thus acting as a TLS primase. This lesion bypass potential, revised in this article, is strengthened by the preferential use of moderate concentrations of manganese ions as the preferred metal activator. We show here that PrimPol is able to extend RNA primers with ribonucleotides, even when bypassing 8oxoG lesions, suggesting a potential new scenario for PrimPol as a TLS polymerase assisting transcription. We also show that PrimPol displays a high degree of versatility to accept or induce distortions of both primer and template strands, creating alternative alignments based on microhomology that would serve to skip unreadable lesions and to connect separate strands. In good agreement, PrimPol is highly prone to generate indels at short nucleotide repeats. Finally, an evolutionary view of the relationship between translesion synthesis and primase functions is briefly discussed. (C) 2015 Elsevier B.V. All rights reserved. C1 [Martinez-Jimenez, Maria I.; Garcia-Gomez, Sara; Sastre-Moreno, Guillermo; Calvo, Patricia A.; Diaz-Talavera, Alberto; Blanco, Luis] Ctr Biol Mol Severo Ochoa CSIC UAM, Madrid 28049, Spain. [Bebenek, Katarzyna; Kunkel, Thomas A.] NIH, Genome Integr & Struct Biol Lab, Res Triangle Pk, NC 27709 USA. RP Blanco, L (reprint author), Ctr Biol Mol Severo Ochoa CSIC UAM, Madrid 28049, Spain. EM lblanco@cbm.csic.es RI Blanco, Luis/I-1848-2015 FU Comunidad de Madrid [S2010/BMD-2361]; Spanish Ministry of Economy and Competitiveness [BFU2012-37969]; Division of Intramural Research of the US National Institutes of Health (NIH), National Institute of Environmental Health Sciences [Z01 ES065070]; Fundacion Ramon Areces; Spanish Council for Scientific Research; Spanish Ministry of Economy and Competitiveness FX We thank Ian J. Holt and Juan Mendez for helpful discussions, and Shigenore Iwai for the (6-4)pp oligonucleotide. This work was supported by Comunidad de Madrid (S2010/BMD-2361), Spanish Ministry of Economy and Competitiveness (BFU2012-37969) to L.B., by the Division of Intramural Research of the US National Institutes of Health (NIH), National Institute of Environmental Health Sciences project Z01 ES065070 to T.A.K., and by an Institutional grant to Centro de Biologia Molecular 'Severo Ochoa' from Fundacion Ramon Areces. G.S.-M. and P.C were recipients of a JAE-predoctoral fellowship from the Spanish Council for Scientific Research, and from the Spanish Ministry of Economy and Competitiveness, respectively. NR 59 TC 11 Z9 11 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 EI 1568-7856 J9 DNA REPAIR JI DNA Repair PD MAY PY 2015 VL 29 SI SI BP 127 EP 138 DI 10.1016/j.dnarep.2015.02.013 PG 12 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA CJ2ZA UT WOS:000355352000014 PM 25746449 ER PT J AU McIntyre, J Woodgate, R AF McIntyre, Justyna Woodgate, Roger TI Regulation of translesion DNA synthesis: Posttranslational modification of lysine residues in key proteins SO DNA REPAIR LA English DT Article DE Translesion synthesis; Ubiquitin; Y-family polymerase; PCNA ID CELL NUCLEAR ANTIGEN; E3 UBIQUITIN LIGASE; POLYMERASE-ETA; SACCHAROMYCES-CEREVISIAE; REPLICATION FORK; REV1 PROTEIN; POSTREPLICATION REPAIR; PROTEASOME PATHWAY; MASS-SPECTROMETRY; BINDING PROTEINS AB Posttranslational modification of proteins often controls various aspects of their cellular function. Indeed, over the past decade or so, it has been discovered that posttranslational modification of lysine residues plays a major role in regulating translesion DNA synthesis (TLS) and perhaps the most appreciated lysine modification is that of ubiquitination. Much of the recent interest in ubiquitination stems from the fact that proliferating cell nuclear antigen (PCNA) was previously shown to be specifically ubiquitinated at 1(164 and that such ubiquitination plays a key role in regulating TLS. In addition, TLS polymerases themselves are now known to be ubiquitinated. In the case of human polymerase eta, ubiquitination at four lysine residues in its C-terminus appears to regulate its ability to interact with PCNA and modulate TLS. Within the past few years, advances in global proteomic research have revealed that many proteins involved in TLS are, in fact, subject to a previously underappreciated number of lysine modifications. In this review, we will summarize the known lysine modifications of several key proteins involved in TLS; PCNA and Y-family polymerases eta, iota, kappa and Rev1 and we will discuss the potential regulatory effects of such modification in controlling TLS in vivo. (C) 2015 Published by Elsevier B.V. C1 [McIntyre, Justyna] Polish Acad Sci, Inst Biochem & Biophys, PL-02106 Warsaw, Poland. [Woodgate, Roger] NICHHD, Lab Genom Integr, NIH, Bethesda, MD 20892 USA. RP McIntyre, J (reprint author), Polish Acad Sci, Inst Biochem & Biophys, Ul Pawinskiego 5a, PL-02106 Warsaw, Poland. EM justyna@ibb.waw.pl RI McIntyre, Justyna/M-9186-2014 FU National Institutes of Health; Foundation for Polish Science [HOMING PLUS/2013-7/10] FX Funding for this review was provided by the National Institutes of Health Intramural Research Program (to R.W.) and the Foundation for Polish Science HOMING PLUS/2013-7/10 Regulation of human DNA polymerase iota by ubiquitination (to J.M.). We would like to thank Ewa Sledziewska-Gojska, Alexandra Vaisman and Mary McLenigan for critical comments on the manuscript and members of the Mass Spectrometry Lab from IBB PAS for help with analyzing some of the mass spectrometry data. NR 233 TC 8 Z9 9 U1 3 U2 18 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 EI 1568-7856 J9 DNA REPAIR JI DNA Repair PD MAY PY 2015 VL 29 SI SI BP 166 EP 179 DI 10.1016/j.dnarep.2015.02.011 PG 14 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA CJ2ZA UT WOS:000355352000018 PM 25743599 ER PT J AU Chew, EY AF Chew, Emily Y. TI There is level 1 evidence for intensive glycemic control for reducing the progression of diabetic retinopathy in persons with type 2 diabetes SO ENDOCRINE LA English DT Editorial Material ID GLUCOSE CONTROL; COMPLICATIONS C1 NEI, Div Epidemiol & Clin Applicat, NIH, CRC, Bethesda, MD 20892 USA. RP Chew, EY (reprint author), NEI, Div Epidemiol & Clin Applicat, NIH, CRC, Bldg 10,Room 3-2531,10 Ctr Dr,MSC 1204, Bethesda, MD 20892 USA. EM echew@nei.nih.gov NR 16 TC 0 Z9 0 U1 0 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1355-008X EI 1559-0100 J9 ENDOCRINE JI Endocrine PD MAY PY 2015 VL 49 IS 1 BP 1 EP 3 DI 10.1007/s12020-015-0553-6 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CJ1GM UT WOS:000355231900001 PM 25722012 ER PT J AU Janssen, EM McGinty, EE Azrin, ST Juliano-Bult, D Daumit, GL AF Janssen, Ellen M. McGinty, Emma E. Azrin, Susan T. Juliano-Bult, Denise Daumit, Gail L. TI Review of the evidence: prevalence of medical conditions in the United States population with serious mental illness SO GENERAL HOSPITAL PSYCHIATRY LA English DT Review DE Schizophrenia; Bipolar disorder; Medical co-morbidity; Prevalence ID SUBSTANCE USE DISORDERS; METABOLIC RISK-FACTORS; BIPOLAR I DISORDER; HEPATITIS-C; CARDIOVASCULAR-DISEASE; HEART-DISEASE; 2ND-GENERATION ANTIPSYCHOTICS; CATIE SCHIZOPHRENIA; ACCOUNTABLE CARE; HEALTH BEHAVIORS AB Objective: Persons with serious mental illness (SMI) have high rates of premature mortality from preventable medical conditions, but this group is underrepresented in epidemiologic surveys and we lack national estimates of the prevalence of conditions such as obesity and diabetes in this group. We performed a comprehensive review to synthesize estimates of the prevalence of 15 medical conditions among the population with SMI. Method: We reviewed studies published in the peer-reviewed literature from January 2000 to August 2012. Studies were included if they assessed prevalence in a sample of 100 or more United States (US) adults with schizophrenia or bipolar disorder. Results: A total of 57 studies were included in the review. For most medical conditions, the prevalence estimates varied considerably. For example, estimates of obesity prevalence ranged from 26% to 55%. This variation appeared to be due to differences in measurement (e.g., self-report versus clinical measures) and underlying differences in study populations. Few studies assessed prevalence in representative, community samples of persons with SMI. Conclusions: In many studies, the prevalence of medical conditions among the population with SMI was higher than among the overall US population. Screening for and monitoring of these conditions should be common practice in clinical settings serving persons with SMI. (C) 2015 Elsevier Inc. All rights reserved. C1 [Janssen, Ellen M.; McGinty, Emma E.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD 21205 USA. [Azrin, Susan T.; Juliano-Bult, Denise] NIMH, Rockville, MD 20852 USA. [Daumit, Gail L.] Johns Hopkins Sch Med, Div Gen Internal Med, Baltimore, MD 21205 USA. RP McGinty, EE (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, 624 North Broadway,Room 359, Baltimore, MD 21205 USA. EM ejansse1@jhu.edu; bmcginty@jhu.edu; Susan.Azrin@nih.gov; Djuliano@mail.nih.gov; gdaumit@jhmi.edu OI Janssen, Ellen/0000-0003-0405-4252 FU NIMH FX This study was commissioned and supported by the NIMH. NR 116 TC 8 Z9 8 U1 5 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0163-8343 EI 1873-7714 J9 GEN HOSP PSYCHIAT JI Gen. Hosp. Psych. PD MAY-JUN PY 2015 VL 37 IS 3 BP 199 EP 222 DI 10.1016/j.genhosppsych.2015.03.004 PG 24 WC Psychiatry SC Psychiatry GA CI9VN UT WOS:000355118300003 PM 25881768 ER PT J AU te Riele, ASJM Tandri, H Sanborn, DM Bluemke, DA AF te Riele, Anneline S. J. M. Tandri, Harikrishna Sanborn, Danita M. Bluemke, David A. TI Noninvasive Multimodality Imaging in ARVD/C SO JACC-CARDIOVASCULAR IMAGING LA English DT Article DE arrhythmogenic right ventricular dysplasia/cardiomyopathy; cardiac magnetic resonance; computed tomography; echocardiography; imaging ID RIGHT-VENTRICULAR DYSPLASIA; CARDIOVASCULAR MAGNETIC-RESONANCE; TASK-FORCE CRITERIA; MYOCARDIAL PERFORMANCE INDEX; IN-VIVO VALIDATION; COMPUTED-TOMOGRAPHY; 3-DIMENSIONAL ECHOCARDIOGRAPHY; AMERICAN-SOCIETY; SUDDEN-DEATH; EUROPEAN-ASSOCIATION AB Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a familial cardiomyopathy resulting in progressive right ventricular (RV) dysfunction and malignant ventricular arrhythmias. Although ARVD/C is generally considered an inherited cardiomyopathy, the arrhythmogenic nature of the disease is striking. Affected individuals typically present in the second to fourth decade of Life with arrhythmias originating from the right ventricle. Over the past decade, pathogenic ARVD/C-causing mutations have been identified in 5 genes encoding the cardiac desmosome. Disruption of the desmosomal connection system between cardiomyocytes may be represented structurally by ventricular enlargement, global or regional contraction abnormalities; RV-aneurysms, or fibrofatty replacement. These abnormalities are typically observed in predilection areas, including the subtricuspid region, basal RV free wall, and Left ventricular posterolateral wall. As such, structural and functional abnormalities on cardiac imaging constitute an important diagnostic criterion for the disease. This paper discusses the current status and role of echocardiography, cardiac magnetic resonance imaging, and computed tomography for suspected ARVD/C. (C) 2015 by the American College of Cardiology Foundation. C1 [te Riele, Anneline S. J. M.; Tandri, Harikrishna] Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. [te Riele, Anneline S. J. M.] Univ Med Ctr Utrecht, Dept Med, Div Cardiol, Utrecht, Netherlands. [Sanborn, Danita M.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med,Div Cardiol, Boston, MA USA. [Bluemke, David A.] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. [Bluemke, David A.] NIH, Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. RP Bluemke, DA (reprint author), NIH, Radiol & Imaging Sci, Ctr Clin, 10 Ctr Dr, Bethesda, MD 20892 USA. EM david.bluemke@nih.gov RI 刘, 李陆/H-8469-2015; OI Bluemke, David/0000-0002-8323-8086 FU Dr. Francis P. Chiaramonte Private Foundation; St. Jude Medical, Inc.; Medtronic, Inc.; Leyla Erkan Family Fund for ARVD research; Dr. Satish, Rupal, and Robin Shah ARVD Fund at Johns Hopkins; Bogle Foundation; Healing Hearts Foundation; Campanella family; Patrick J. Harrison Family; Peter French Memorial Foundation; Wilmerding Endowments FX This work was performed during Dr. te Riele's tenure as the Mark Josephson and Hein Wellens Research Fellow of the Heart Rhythm Society. Funding was received from the Dr. Francis P. Chiaramonte Private Foundation, St. Jude Medical, Inc., and Medtronic, Inc. The Johns Hopkins ARVD/C Program is supported by the Leyla Erkan Family Fund for ARVD research, the Dr. Satish, Rupal, and Robin Shah ARVD Fund at Johns Hopkins, the Bogle Foundation, the Healing Hearts Foundation, the Campanella family, the Patrick J. Harrison Family, the Peter French Memorial Foundation, and the Wilmerding Endowments. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 82 TC 6 Z9 6 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-878X EI 1876-7591 J9 JACC-CARDIOVASC IMAG JI JACC-Cardiovasc. Imag. PD MAY PY 2015 VL 8 IS 5 BP 597 EP 611 DI 10.1016/j.jcmg.2015.02.007 PG 15 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA CI9CR UT WOS:000355068500014 PM 25937197 ER PT J AU Baker, SG AF Baker, Stuart G. TI RE: A Cancer Theory Kerfuffle Can Lead to New Lines of Research RESPONSE SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter ID IDENTIFYING DRIVER MUTATIONS; GENOMES C1 [Baker, Stuart G.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Baker, SG (reprint author), NCI, 9609 Med Ctr Dr 5E638 MSC 9789, Bethesda, MD 20892 USA. EM sb16i@nih.gov NR 6 TC 0 Z9 0 U1 2 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD MAY PY 2015 VL 107 IS 5 AR UNSP djv061 DI 10.1093/jnci/djv061 PG 1 WC Oncology SC Oncology GA CI9KJ UT WOS:000355088600021 ER PT J AU Gail, MH AF Gail, Mitchell H. TI Twenty-five Years of Breast Cancer Risk Models and Their Applications SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID SCREENING MAMMOGRAPHY; AMERICAN WOMEN; FAMILY-HISTORY; OVARIAN-CANCER; DISEASE; TAMOXIFEN; DENSITY; PREDICTION; BENEFITS; AGE C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. RP Gail, MH (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 7E138, Rockville, MD 20850 USA. EM gailm@mail.nih.gov NR 51 TC 1 Z9 1 U1 0 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD MAY PY 2015 VL 107 IS 5 AR djv042 DI 10.1093/jnci/djv042 PG 6 WC Oncology SC Oncology GA CI9KJ UT WOS:000355088600013 ER PT J AU Guo, Q Schmidt, MK Kraft, P Canisius, S Chen, C Khan, S Tyrer, J Bolla, MK Wang, Q Dennis, J Michailidou, K Lush, M Kar, S Beesley, J Dunning, AM Shah, M Czene, K Darabi, H Eriksson, M Lambrechts, D Weltens, C Leunen, K Bojesen, SE Nordestgaard, BG Nielsen, SF Flyger, H Chang-Claude, J Rudolph, A Seibold, P Flesch-Janys, D Blomqvist, C Aittomaki, K Fagerholm, R Muranen, TA Couch, FJ Olson, JE Vachon, C Andrulis, IL Knight, JA Glendon, G Mulligan, AM Broeks, A Hogervorst, FB Haiman, CA Henderson, BE Schumacher, F Le Marchand, L Hopper, JL Tsimiklis, H Apicella, C Southey, MC Cox, A Cross, SS Reed, MWR Giles, GG Milne, RL McLean, C Winqvist, R Pylkas, K Jukkola-Vuorinen, A Grip, M Hooning, MJ Hollestelle, A Martens, JWM Van den Ouweland, AMW Marme, F Schneeweiss, A Yang, RX Burwinkel, B Figueroa, J Chanock, SJ Lissowska, J Sawyer, EJ Tomlinson, I Kerin, MJ Miller, N Brenner, H Dieffenbach, AK Arndt, V Holleczek, B Mannermaa, A Kataja, V Kosma, VM Hartikainen, JM Li, JM Brand, JS Humphreys, K Devilee, P Tollenaar, RAEM Seynaeve, C Radice, P Peterlongo, P Bonanni, B Mariani, P Fasching, PA Beckmann, MW Hein, A Ekici, AB Chenevix-Trench, G Balleine, R Phillips, KA Benitez, J Zamora, MP Perez, JIA Menendez, P Jakubowska, A Lubinski, J Jaworska-Bieniek, K Durda, K Hamann, U Kabisch, M Ulmer, HU Rudiger, T Margolin, S Kristensen, V Nord, S Evans, DG Abraham, JE Earl, HM Hiller, L Dunn, JA Bowden, S Berg, C Campa, D Diver, WR Gapstur, SM Gaudet, MM Hankinson, SE Hoover, RN Husing, A Kaaks, R Machiela, MJ Willett, W Barrdahl, M Canzian, F Chin, SF Caldas, C Hunter, DJ Lindstrom, S Garcia-Closas, M Hall, P Easton, DF Eccles, DM Rahman, N Nevanlinna, H Pharoah, PDP AF Guo, Qi Schmidt, Marjanka K. Kraft, Peter Canisius, Sander Chen, Constance Khan, Sofia Tyrer, Jonathan Bolla, Manjeet K. Wang, Qin Dennis, Joe Michailidou, Kyriaki Lush, Michael Kar, Siddhartha Beesley, Jonathan Dunning, Alison M. Shah, Mitul Czene, Kamila Darabi, Hatef Eriksson, Mikael Lambrechts, Diether Weltens, Caroline Leunen, Karin Bojesen, Stig E. Nordestgaard, Borge G. Nielsen, Sune F. Flyger, Henrik Chang-Claude, Jenny Rudolph, Anja Seibold, Petra Flesch-Janys, Dieter Blomqvist, Carl Aittomaeki, Kristiina Fagerholm, Rainer Muranen, Taru A. Couch, Fergus J. Olson, Janet E. Vachon, Celine Andrulis, Irene L. Knight, Julia A. Glendon, Gord Mulligan, Anna Marie Broeks, Annegien Hogervorst, Frans B. Haiman, Christopher A. Henderson, Brian E. Schumacher, Fredrick Le Marchand, Loic Hopper, John L. Tsimiklis, Helen Apicella, Carmel Southey, Melissa C. Cox, Angela Cross, Simon S. Reed, Malcolm W. R. Giles, Graham G. Milne, Roger L. McLean, Catriona Winqvist, Robert Pylkaes, Katri Jukkola-Vuorinen, Arja Grip, Mervi Hooning, Maartje J. Hollestelle, Antoinette Martens, John W. M. Van den Ouweland, Ans M. W. Marme, Federik Schneeweiss, Andreas Yang, Rongxi Burwinkel, Barbara Figueroa, Jonine Chanock, Stephen J. Lissowska, Jolanta Sawyer, Elinor J. Tomlinson, Ian Kerin, Michael J. Miller, Nicola Brenner, Hermann Dieffenbach, Aida Karina Arndt, Volker Holleczek, Bernd Mannermaa, Arto Kataja, Vesa Kosma, Veli-Matti Hartikainen, Jaana M. Li, Jingmei Brand, Judith S. Humphreys, Keith Devilee, Peter Tollenaar, Rob A. E. M. Seynaeve, Caroline Radice, Paolo Peterlongo, Paolo Bonanni, Bernardo Mariani, Paolo Fasching, Peter A. Beckmann, Matthias W. Hein, Alexander Ekici, Arif B. Chenevix-Trench, Georgia Balleine, Rosemary Phillips, Kelly-Anne Benitez, Javier Zamora, M. Pilar Perez, Jose Ignacio Arias Menendez, Primitiva Jakubowska, Anna Lubinski, Jan Jaworska-Bieniek, Katarzyna Durda, Katarzyna Hamann, Ute Kabisch, Maria Ulmer, Hans Ulrich Ruediger, Thomas Margolin, Sara Kristensen, Vessela Nord, Silje Evans, D. Gareth Abraham, Jean E. Earl, Helena M. Hiller, Louise Dunn, Janet A. Bowden, Sarah Berg, Christine Campa, Daniele Diver, W. Ryan Gapstur, Susan M. Gaudet, Mia M. Hankinson, Susan E. Hoover, Robert N. Huesing, Anika Kaaks, Rudolf Machiela, Mitchell J. Willett, Walter Barrdahl, Myrto Canzian, Federico Chin, Suet-Feung Caldas, Carlos Hunter, David J. Lindstrom, Sara Garcia-Closas, Montserrat Hall, Per Easton, Douglas F. Eccles, Diana M. Rahman, Nazneen Nevanlinna, Heli Pharoah, Paul D. P. CA kConFab Investigators TI Identification of Novel Genetic Markers of Breast Cancer Survival SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID GENOME-WIDE ASSOCIATION; SINGLE-NUCLEOTIDE POLYMORPHISMS; GENOTYPE IMPUTATION; PROGNOSIS; RISK; LOCI; CYCLOPHOSPHAMIDE; METAANALYSIS; PROGRESSION; EPIRUBICIN AB Background: Survival after a diagnosis of breast cancer varies considerably between patients, and some of this variation may be because of germline genetic variation. We aimed to identify genetic markers associated with breast cancer-specific survival. Methods: We conducted a large meta-analysis of studies in populations of European ancestry, including 37 954 patients with 2900 deaths from breast cancer. Each study had been genotyped for between 200 000 and 900 000 single nucleotide polymorphisms (SNPs) across the genome; genotypes for nine million common variants were imputed using a common reference panel from the 1000 Genomes Project. We also carried out subtype-specific analyses based on 6881 estrogen receptor (ER)-negative patients (920 events) and 23 059 ER-positive patients (1333 events). All statistical tests were two-sided. Results: We identified one new locus (rs2059614 at 11q24.2) associated with survival in ER-negative breast cancer cases (hazard ratio [HR] = 1.95, 95% confidence interval [CI] = 1.55 to 2.47, P = 1.91 x 10(-8)). Genotyping a subset of 2113 case patients, of which 300 were ER negative, provided supporting evidence for the quality of the imputation. The association in this set of case patients was stronger for the observed genotypes than for the imputed genotypes. A second locus (rs148760487 at 2q24.2) was associated at genome-wide statistical significance in initial analyses; the association was similar in ER-positive and ER-negative case patients. Here the results of genotyping suggested that the finding was less robust. Conclusions: This is currently the largest study investigating genetic variation associated with breast cancer survival. Our results have potential clinical implications, as they confirm that germline genotype can provide prognostic information in addition to standard tumor prognostic factors. C1 [Guo, Qi; Tyrer, Jonathan; Dunning, Alison M.; Shah, Mitul; Abraham, Jean E.; Easton, Douglas F.; Pharoah, Paul D. P.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England. [Schmidt, Marjanka K.; Canisius, Sander; Broeks, Annegien; Hogervorst, Frans B.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands. [Kraft, Peter; Hankinson, Susan E.; Hunter, David J.; Lindstrom, Sara] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Kraft, Peter; Chen, Constance; Hunter, David J.; Lindstrom, Sara] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA. [Kar, Siddhartha; Fagerholm, Rainer; Muranen, Taru A.; Nevanlinna, Heli] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland. [Khan, Sofia; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Michailidou, Kyriaki; Lush, Michael; Easton, Douglas F.; Pharoah, Paul D. P.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England. [Beesley, Jonathan; Chenevix-Trench, Georgia] QIMR Berghofer Med Res Inst, Dept Genet, Brisbane, Qld, Australia. [Czene, Kamila; Darabi, Hatef; Eriksson, Mikael; Li, Jingmei; Brand, Judith S.; Humphreys, Keith; Hall, Per] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. [Lambrechts, Diether] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium. [Lambrechts, Diether] VIB, Vesalius Res Ctr, Leuven, Belgium. [Weltens, Caroline; Leunen, Karin] Univ Hosp Gasthuisberg, Dept Oncol, Leuven, Belgium. [Bojesen, Stig E.; Nordestgaard, Borge G.; Nielsen, Sune F.] Herlev Hosp, Copenhagen Gen Populat Study, Copenhagen, Denmark. [Bojesen, Stig E.; Nordestgaard, Borge G.; Nielsen, Sune F.] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Copenhagen, Denmark. [Bojesen, Stig E.; Nordestgaard, Borge G.] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark. [Flyger, Henrik] Copenhagen Univ Hosp, Herlev Hosp, Dept Breast Surg, Copenhagen, Denmark. [Chang-Claude, Jenny; Rudolph, Anja; Seibold, Petra; Campa, Daniele; Huesing, Anika; Kaaks, Rudolf; Barrdahl, Myrto] German Canc Res Ctr, Div Canc Epidemiol, Deutsch Krebsforschungszentrum, Heidelberg, Germany. [Flesch-Janys, Dieter] Univ Clin Hamburg Eppendorf, Clin Canc Registry, Dept Canc Epidemiol, Hamburg, Germany. [Flesch-Janys, Dieter] Univ Clin Hamburg Eppendorf, Inst Med Biometr & Epidemiol, Hamburg, Germany. [Blomqvist, Carl] Univ Helsinki, Cent Hosp, Dept Oncol, Helsinki, Finland. [Aittomaeki, Kristiina] Univ Helsinki, Cent Hosp, Dept Clin Genet, Helsinki, Finland. [Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Olson, Janet E.; Vachon, Celine] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Andrulis, Irene L.; Glendon, Gord] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Ontario Canc Genet Network, Toronto, ON M5G 1X5, Canada. [Knight, Julia A.] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Epidemiol, Toronto, ON, Canada. [Knight, Julia A.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada. [Mulligan, Anna Marie] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada. [Mulligan, Anna Marie] Univ Hlth Network, Lab Med Program, Toronto, ON, Canada. [Haiman, Christopher A.; Henderson, Brian E.; Schumacher, Fredrick] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Hopper, John L.; Apicella, Carmel; Giles, Graham G.; Milne, Roger L.] Univ Melbourne, Melbourne Sch Populat Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia. [Tsimiklis, Helen; Southey, Melissa C.] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Melbourne, Vic, Australia. [Cox, Angela; Reed, Malcolm W. R.] Univ Sheffield, Sheffield Canc Res Ctr, Dept Oncol, Sheffield, S Yorkshire, England. [Cross, Simon S.] Univ Sheffield, Dept Neurosci, Acad Unit Pathol, Sheffield, S Yorkshire, England. [Giles, Graham G.; Milne, Roger L.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [McLean, Catriona] Alfred Hosp, Anat Pathol, Melbourne, Vic, Australia. [Winqvist, Robert] Univ Oulu, Dept Clin Chem, Lab Canc Genet & Tumor Biol, Oulu, Finland. [Winqvist, Robert] Univ Oulu, Bioctr Oulu, Oulu, Finland. [Pylkaes, Katri] Northern Finland Lab Ctr NordLab, Lab Canc Genet & Tumor Biol, Oulu, Finland. [Jukkola-Vuorinen, Arja] Univ Oulu, Oulu Univ Hosp, Dept Oncol, Oulu, Finland. [Grip, Mervi] Univ Oulu, Dept Surg, Oulu Univ Hosp, Oulu, Finland. [Hooning, Maartje J.; Hollestelle, Antoinette; Martens, John W. M.; Van den Ouweland, Ans M. W.] Erasmus MC Canc Inst, Family Canc Clin, Dept Med Oncol, Rotterdam, Netherlands. [Marme, Federik; Schneeweiss, Andreas; Yang, Rongxi; Burwinkel, Barbara] Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany. [Marme, Federik; Schneeweiss, Andreas] Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany. [Burwinkel, Barbara] German Canc Res Ctr, Mol Epidemiol Grp, Heidelberg, Germany. [Figueroa, Jonine; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Figueroa, Jonine] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Chanock, Stephen J.] Frederick Natl Lab Canc Res, Core Genotyping Facil, Gaithersburg, MD USA. [Hopper, John L.] M Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Sawyer, Elinor J.] Kings Coll London, Guys & St Thomas NHS Fdn Trust, Comprehens Biomed Res Ctr, Div Canc Studies,NIHR, London WC2R 2LS, England. [Tomlinson, Ian] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX1 2JD, England. [Tomlinson, Ian] Univ Oxford, Oxford NIHR Biomed Res Ctr, Oxford OX1 2JD, England. [Kerin, Michael J.; Miller, Nicola] Univ Hosp Galway, Inst Clin Sci, Galway, Ireland. [Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Brenner, Hermann; Dieffenbach, Aida Karina] German Canc Consortium DKTK, Heidelberg, Germany. [Holleczek, Bernd] Saarland Canc Registry, Saarbrucken, Germany. [Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M.] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, SF-70210 Kuopio, Finland. [Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M.] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Sch Med, Kuopio, Finland. [Kataja, Vesa] Kuopio Univ Hosp, Canc Ctr Eastern Finland, Bioctr Kuopio, SF-70210 Kuopio, Finland. [Kataja, Vesa] Univ Eastern Finland, Inst Clin Med, Sch Med, Oncol, Kuopio, Finland. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Human Genet, NL-2300 RC Leiden, Netherlands. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Pathol, NL-2300 RC Leiden, Netherlands. [Tollenaar, Rob A. E. M.] Leiden Univ, Med Ctr, Dept Surg Oncol, NL-2300 RC Leiden, Netherlands. [Seynaeve, Caroline] Erasmus MC Daniel den Hoed Canc Ctr, Dept Med Oncol, Family Canc Clin, Rotterdam, Netherlands. [Radice, Paolo] Fdn IRCCS Ist Nazl Tumori, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, Milan, Italy. [Peterlongo, Paolo; Mariani, Paolo] Fdn Ist FIRC Oncol Mol, IFOM, Milan, Italy. [Burwinkel, Barbara] Ist Europeo Oncol, Div Canc Prevent & Genet, Milan, Italy. [Mariani, Paolo] Cogentech Canc Genet Test Lab, Milan, Italy. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Fasching, Peter A.; Beckmann, Matthias W.; Hein, Alexander] Univ Erlangen Nurnberg, Comprehens Canc Ctr Erlangen EMN, Univ Hosp Erlangen, Dept Gynecol & Obstet, D-91054 Erlangen, Germany. [Ekici, Arif B.] Univ Erlangen Nurnberg, Comprehens Canc Ctr Erlangen EMN, Univ Hosp Erlangen, Inst Human Genet, D-91054 Erlangen, Germany. [Balleine, Rosemary] Univ Sydney, Westmead Millennium Inst Med Res, Western Sydney & Nepean Blue Mt Local Hlth Dist, Sydney, NSW 2006, Australia. [kConFab Investigators] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Phillips, Kelly-Anne] Univ Melbourne, Melbourne, Vic, Australia. [Phillips, Kelly-Anne] Peter MacCallum Canc Ctr, Div Canc Med, Melbourne, Australia. [Benitez, Javier] Ctr Invest Red Enfermedades Raras, Valencia, Spain. [Benitez, Javier] Spanish Natl Canc Res Ctr, Human Canc Genet Program, Human Genet Grp, Madrid, Spain. [Zamora, M. Pilar] Hosp Univ La Paz, Serv Oncol Med, Madrid, Spain. [Perez, Jose Ignacio Arias] Hosp Monte Naranco, Serv Cirugia Gen & Especialidades, Oviedo, Spain. [Mariani, Paolo] Hosp Monte Naranco, Serv Anat Patol, Oviedo, Spain. [Jakubowska, Anna; Lubinski, Jan; Jaworska-Bieniek, Katarzyna; Durda, Katarzyna] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland. [Hamann, Ute; Kabisch, Maria] German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany. [Ulmer, Hans Ulrich] Frauenklin Stadtklin Baden Baden, Baden Baden, Germany. [Ruediger, Thomas] Stadt Klinikum Karlsruhe, Inst Pathol, Karlsruhe, Germany. [Margolin, Sara] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. [Kristensen, Vessela; Nord, Silje] Oslo Univ Hosp, Radiumhosp, Inst Canc Res, Dept Genet, Oslo, Norway. [Kristensen, Vessela; Nord, Silje] Univ Oslo, Fac Div Ahus, Fac Med, N-0316 Oslo, Norway. [Evans, D. Gareth] Univ Manchester, St Marys Hosp, Cent Manchester Fdn Trust, Genom Med,Manchester Acad Hlth Sci Ctr, Manchester M13 0JH, Lancs, England. [Abraham, Jean E.; Earl, Helena M.; Caldas, Carlos] Univ Cambridge, Dept Oncol, Cambridge Breast Res Unit, Cambridge, England. [Abraham, Jean E.; Earl, Helena M.; Caldas, Carlos] Univ Cambridge, Dept Oncol, NIHR Cambridge Biomed Res Ctr, Cambridge, England. [Abraham, Jean E.; Earl, Helena M.; Caldas, Carlos] Cambridge Expt Canc Med Ctr, Cambridge, England. [Hiller, Louise; Dunn, Janet A.] Univ Warwick, Warwick Clin Trials Unit, Coventry CV4 7AL, W Midlands, England. [Bowden, Sarah] Univ Birmingham, Inst Canc Studies, Canc Res UK Clin Trials Unit, Birmingham, W Midlands, England. [Berg, Christine] NCI, Early Detect Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. [Campa, Daniele] Univ Pisa, Dept Biol, Pisa, Italy. [Diver, W. Ryan; Gapstur, Susan M.; Gaudet, Mia M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Hankinson, Susan E.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Hankinson, Susan E.] Univ Massachusetts, Amherst Sch Publ Hlth & Hlth Sci, Div Biostat & Epidemiol, Amherst, MA 01003 USA. [Hoover, Robert N.; Machiela, Mitchell J.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Willett, Walter] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Couch, Fergus J.] German Canc Res Ctr, Genom Epidemiol Grp, Heidelberg, Germany. [Chin, Suet-Feung; Caldas, Carlos] Univ Cambridge, Li Ka Shing Ctr, Canc Res UK Cambridge Inst, Breast Canc Funct Genom Lab, Cambridge CB1 8RN, England. [Garcia-Closas, Montserrat] Inst Canc Res, Div Breast Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England. [Garcia-Closas, Montserrat; Rahman, Nazneen] Inst Canc Res, Div Genet & Epidemiol, Sutton, Surrey, England. [Eccles, Diana M.] Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England. RP Guo, Q (reprint author), Univ Cambridge, Dept Oncol, Strangeways Res Lab, Worts Causeway, Cambridge CB1 8RN, England. EM qg209@medschl.cam.ac.uk; mk.schmidt@nki.nl RI Benitez ortiz, Javier/H-5232-2015; Knight, Julia/A-6843-2012; Hein, Alexander/F-6999-2010; Brenner, Hermann/B-4627-2017; Rahman, Nazneen/D-2802-2013; Li, Jingmei/I-2904-2012; Hartikainen, Jaana/E-6256-2015; Andrulis, Irene/E-7267-2013; Campa, Daniele/K-1617-2016; Nord, Silje/R-5212-2016; OI Benitez ortiz, Javier/0000-0002-0923-7202; Hein, Alexander/0000-0003-2601-3398; Brenner, Hermann/0000-0002-6129-1572; Rahman, Nazneen/0000-0003-4376-0440; Bowden, Sarah/0000-0001-7506-1340; chin, suet-feung/0000-0001-5697-1082; Li, Jingmei/0000-0001-8587-7511; Campa, Daniele/0000-0003-3220-9944; Nord, Silje/0000-0002-3271-5356; Cross, Simon/0000-0003-2044-1754; Phillips, Kelly-Anne/0000-0002-0475-1771; Earl, Helena/0000-0003-1549-8094; Dunning, Alison Margaret/0000-0001-6651-7166; Khan, Sofia/0000-0003-4185-8882; Muranen, Taru/0000-0002-5895-1808; Cox, Angela/0000-0002-5138-1099; Machiela, Mitchell/0000-0001-6538-9705; Giles, Graham/0000-0003-4946-9099; Evans, Gareth/0000-0002-8482-5784 FU European Commission [223175 - HEALTH-F2-2009-223175]; Cancer Research-UK [C1287/A10118, C1287/A12014]; European Union COST programme [BM0606]; FWO; Academy of Finland [266528]; Addenbrookes Charitable Trust; Agency for Science, Technology and Research of Singapore; Asociacion Espanola Contra el Cancer; Fondo de Investigacion Sanitario [PI11/00923, PI08/1120]; Baden Wurttemberg Ministry of Science, Research and Arts; Breast Cancer Campaign [2009PR42]; Breast Cancer Research Foundation; Canadian Institutes of Health Research (CIHR Team in Familial Risks of Breast Cancer program); Cancer Australia; Cancer Council of New South Wales; Cancer Council of Victoria; Cancer Council of Tasmania; Cancer Council of South Australia; Cancer Foundation of Western Australia; Cancer Fund of North Savo; Cancer Research UK [C1287/A10118, C1287/A12014, A7572, A10124, A11699, A16561, C507/A6306, C10097/A7484, C1275/A11699]; Chief Physician Johan Boserup and Lise Boserup Fund; Danish Breast Cancer Group; Danish Medical Research Council; Deutsche Krebshilfe [70-2892-BR I, PBZ_KBN_122/P05/2004]; Dietmar-Hopp Foundation; Dutch Cancer Society [1997-1505, 2004-3124, NKI2007-3839, 2009-4318, NKI2009-4363]; Dutch government [NWO 184.021.007]; Dutch National Genomics Initiative; ELAN-Fond of the University Hospital of Erlangen; European Community [HEALTH-F2-2009-223175]; Federal Ministry of Education and Research, Germany [01KH0402]; Finnish Cancer Society; Fondazione IRCCS Istituto Nazionale Tumori; Genome Spain Foundation; German Cancer Research Center (DKFZ); Hamburg Cancer Society; Helmholtz Society; Helsinki University Central Hospital Research Fund; Italian Association for Cancer Research (AIRC); Kuopio University Hospital special Government Funding; National Health and Medical Research Council of Australia [209057, 251553, 504711]; National Breast Cancer Foundation (Australia); National Institute for Health Research, Cambridge Biomedical Research Centre; Nordic Cancer Union; Marit and Hans Rausings Initiative Against Breast Cancer; Polish Foundation of Science [PBZ_KBN_122/P05/2004]; Queensland Cancer Fund; Red Tematica de Investigacion Cooperativa en Cancer; Sigrid Juselius Foundation; Susan G. Komen Breast Cancer Foundation; Stichting tegen Kanker [232-2008, 196-2010]; United States National Institutes of Health [BBMRI-NL-CP16, CA69638, CA69417, CA06503, CA116201, CA122340, CA128978, CA63464, CA54281, CA098758, CA132839, CA164920, CA98216, CA098233, CA148065, CA98710, CA98758]; United States National Institutes of Health (Intramural Research Program of the National Institutes of Health and the National Cancer Institute); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge, Guy's & St. Thomas' NHS Foundation Trust in partnership with King's College London; University of Oxford; University of Eastern Finland strategic funding; Victorian Health Promotion Foundation; Victorian Breast Cancer Research Consortium; Yorkshire Cancer Research [S295, S299, S305PA]; [KULPFV/10/016-SymBioSysII] FX Higher-level funding: The COGS project was funded through a European Commission's Seventh Framework Programme grant (agreement number 223175 - HEALTH-F2-2009-223175). The Breast Cancer Association Consortium (BCAC) is funded by Cancer Research-UK (C1287/A10118 and C1287/A12014). Meetings of the BCAC have been funded by the European Union COST programme (BM0606). ELAN Program of the University Hospital Erlangen (BBCC).; Personal support: DFE is a Principal Research Fellow of Cancer Research UK. JLH is a National Health and Medical Research Council (NHMRC) Australia Fellow. MCS is an NHMRC Senior Research Fellow. GCT is an NHMRC Senior Principal Research Fellow. DL is supported by the FWO and the KULPFV/10/016-SymBioSysII. JL is a UNESCO-L'Oreal International Fellow. RB was a Cancer Institute NSW Fellow. KAP is a National Breast Cancer Foundation Fellow (Australia).; Funding of constituent studies (these are listed by funding agency, with each grant number in parentheses): Academy of Finland (266528); Addenbrookes Charitable Trust; Agency for Science, Technology and Research of Singapore; Asociacion Espanola Contra el Cancer and the Fondo de Investigacion Sanitario (PI11/00923, PI08/1120); Baden Wurttemberg Ministry of Science, Research and Arts; Breast Cancer Campaign (2009PR42); Breast Cancer Research Foundation; Canadian Institutes of Health Research (CIHR Team in Familial Risks of Breast Cancer program); Cancer Australia; Cancer Councils of New South Wales, Victoria, Tasmania and South Australia; Cancer Foundation of Western Australia; Cancer Fund of North Savo; Cancer Research UK (C1287/A10118, C1287/A12014, A7572, A10124, A11699, A16561, C507/A6306, C10097/A7484, C1275/A11699); Chief Physician Johan Boserup and Lise Boserup Fund; Danish Breast Cancer Group; Danish Medical Research Council; Deutsche Krebshilfe (70-2892-BR I, PBZ_KBN_122/P05/2004); Dietmar-Hopp Foundation; Dutch Cancer Society (1997-1505, 2004-3124, NKI2007-3839, 2009-4318, NKI2009-4363); Dutch government (NWO 184.021.007); Dutch National Genomics Initiative; ELAN-Fond of the University Hospital of Erlangen; European Community's Seventh Framework Programme (HEALTH-F2-2009-223175); Federal Ministry of Education and Research, Germany (01KH0402); Finnish Cancer Society; Fondazione IRCCS Istituto Nazionale Tumori; Genome Spain Foundation; German Cancer Research Center (DKFZ); Hamburg Cancer Society; Helmholtz Society; Helsinki University Central Hospital Research Fund; Italian Association for Cancer Research (AIRC); Kuopio University Hospital special Government Funding; National Health and Medical Research Council of Australia (209057, 251553 and 504711); National Breast Cancer Foundation (Australia); National Institute for Health Research, Cambridge Biomedical Research Centre; Nordic Cancer Union; Marit and Hans Rausings Initiative Against Breast Cancer; Nordic Cancer Union; Polish Foundation of Science (PBZ_KBN_122/P05/2004); Queensland Cancer Fund; Red Tematica de Investigacion Cooperativa en Cancer; Sigrid Juselius Foundation; Susan G. Komen Breast Cancer Foundation; Stichting tegen Kanker (232-2008 and 196-2010); United States National Institutes of Health (BBMRI-NL-CP16, CA69638, CA69417, CA06503, CA116201, CA122340, CA128978, CA63464, CA54281, CA098758, CA132839, CA164920, CA98216, CA098233, CA148065, CA98710, CA98758, and the Intramural Research Program of the National Institutes of Health and the National Cancer Institute); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge, Guy's & St. Thomas' NHS Foundation Trust in partnership with King's College London, and University of Oxford; University of Eastern Finland strategic funding; Victorian Health Promotion Foundation; Victorian Breast Cancer Research Consortium; Yorkshire Cancer Research (S295, S299, S305PA). NR 41 TC 4 Z9 4 U1 0 U2 12 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD MAY PY 2015 VL 107 IS 5 AR djv081 DI 10.1093/jnci/djv081 PG 9 WC Oncology SC Oncology GA CI9KJ UT WOS:000355088600026 ER PT J AU Mavaddat, N Pharoah, PDP Michailidou, K Tyrer, J Brook, MN Bolla, MK Wang, Q Dennis, J Dunning, AM Shah, M Luben, R Brown, J Bojesen, SE Nordestgaard, BG Nielsen, SF Flyger, H Czene, K Darabi, H Eriksson, M Peto, J dos-Santos-Silva, I Dudbridge, F Johnson, N Schmidt, MK Broeks, A Verhoef, S Rutgers, EJ Swerdlow, A Ashworth, A Orr, N Schoemaker, MJ Figueroa, J Chanock, SJ Brinton, L Lissowska, J Couch, FJ Olson, JE Vachon, C Pankratz, VS Lambrechts, D Wildiers, H Van Ongeval, C Van Limbergen, E Kristensen, V Alnaes, GG Nord, S Borresen-Dale, AL Nevanlinna, H Muranen, TA Aittomaki, K Blomqvist, C Chang-Claude, J Rudolph, A Seibold, P Flesch-Janys, D Fasching, PA Haeberle, L Ekici, AB Beckmann, MW Burwinkel, B Marme, F Schneeweiss, A Sohn, C Trentham-Dietz, A Newcomb, P Titus, L Egan, KM Hunter, DJ Lindstrom, S Tamimi, RM Kraft, P Rahman, N Turnbull, C Renwick, A Seal, S Li, JM Liu, JJ Humphreys, K Benitez, J Zamora, MP Perez, JIA Menendez, P Jakubowska, A Lubinski, J Jaworska-Bieniek, K Durda, K Bogdanova, NV Antonenkova, NN Dork, T Anton-Culver, H Neuhausen, SL Ziogas, A Bernstein, L Devilee, P Tollenaar, RAEM Seynaeve, C van Asperen, CJ Cox, A Cross, SS Reed, MWR Khusnutdinova, E Bermisheva, M Prokofyeva, D Takhirova, Z Meindl, A Schmutzler, RK Sutter, C Yang, RX Schurmann, P Bremer, M Christiansen, H Park-Simon, TW Hillemanns, P Guenel, P Truong, T Menegaux, F Sanchez, M Radice, P Peterlongo, P Manoukian, S Pensotti, V Hopper, JL Tsimiklis, H Apicella, C Southey, MC Brauch, H Bruning, T Ko, YD Sigurdson, AJ Doody, MM Hamann, U Torres, D Ulmer, HU Forsti, A Sawyer, EJ Tomlinson, I Kerin, MJ Miller, N Andrulis, IL Knight, JA Glendon, G Mulligan, AM Chenevix-Trench, G Balleine, R Giles, GG Milne, RL McLean, C Lindblom, A Margolin, S Haiman, CA Henderson, BE Schumacher, F Le Marchand, L Eilber, U Wang-Gohrke, S Hooning, MJ Hollestelle, A van den Ouweland, AMW Koppert, LB Carpenter, J Clarke, C Scott, R Mannermaa, A Kataja, V Kosma, VM Hartikainen, JM Brenner, H Arndt, V Stegmaier, C Dieffenbach, AK Winqvist, R Pylkas, K Jukkola-Vuorinen, A Grip, M Offit, K Vijai, J Robson, M Rau-Murthy, R Dwek, M Swann, R Perkins, KA Goldberg, MS Labreche, F Dumont, M Eccles, DM Tapper, WJ Rafiq, S John, EM Whittemore, AS Slager, S Yannoukakos, D Toland, AE Yao, S Zheng, W Halverson, SL Gonzalez-Neira, A Pita, G Alonso, MR Alvarez, N Herrero, D Tessier, DC Vincent, D Bacot, F Luccarini, C Baynes, C Ahmed, S Maranian, M Healey, CS Simard, J Hall, P Easton, DF Garcia-Closas, M AF Mavaddat, Nasim Pharoah, Paul D. P. Michailidou, Kyriaki Tyrer, Jonathan Brook, Mark N. Bolla, Manjeet K. Wang, Qin Dennis, Joe Dunning, Alison M. Shah, Mitul Luben, Robert Brown, Judith Bojesen, Stig E. Nordestgaard, Borge G. Nielsen, Sune F. Flyger, Henrik Czene, Kamila Darabi, Hatef Eriksson, Mikael Peto, Julian dos-Santos-Silva, Isabel Dudbridge, Frank Johnson, Nichola Schmidt, Marjanka K. Broeks, Annegien Verhoef, Senno Rutgers, Emiel J. Swerdlow, Anthony Ashworth, Alan Orr, Nick Schoemaker, Minouk J. Figueroa, Jonine Chanock, Stephen J. Brinton, Louise Lissowska, Jolanta Couch, Fergus J. Olson, Janet E. Vachon, Celine Pankratz, Vernon S. Lambrechts, Diether Wildiers, Hans Van Ongeval, Chantal Van Limbergen, Erik Kristensen, Vessela Alnaes, Grethe Grenaker Nord, Silje Borresen-Dale, Anne-Lise Nevanlinna, Heli Muranen, Taru A. Aittomaeki, Kristiina Blomqvist, Carl Chang-Claude, Jenny Rudolph, Anja Seibold, Petra Flesch-Janys, Dieter Fasching, Peter A. Haeberle, Lothar Ekici, Arif B. Beckmann, Matthias W. Burwinkel, Barbara Marme, Frederik Schneeweiss, Andreas Sohn, Christof Trentham-Dietz, Amy Newcomb, Polly Titus, Linda Egan, Kathleen M. Hunter, David J. Lindstrom, Sara Tamimi, Rulla M. Kraft, Peter Rahman, Nazneen Turnbull, Clare Renwick, Anthony Seal, Sheila Li, Jingmei Liu, Jianjun Humphreys, Keith Benitez, Javier Zamora, M. Pilar Perez, Jose Ignacio Arias Menendez, Primitiva Jakubowska, Anna Lubinski, Jan Jaworska-Bieniek, Katarzyna Durda, Katarzyna Bogdanova, Natalia V. Antonenkova, Natalia N. Doerk, Thilo Anton-Culver, Hoda Neuhausen, Susan L. Ziogas, Argyrios Bernstein, Leslie Devilee, Peter Tollenaar, Robert A. E. M. Seynaeve, Caroline van Asperen, Christi J. Cox, Angela Cross, Simon S. Reed, Malcolm W. R. Khusnutdinova, Elza Bermisheva, Marina Prokofyeva, Darya Takhirova, Zalina Meindl, Alfons Schmutzler, Rita K. Sutter, Christian Yang, Rongxi Schuermann, Peter Bremer, Michael Christiansen, Hans Park-Simon, Tjoung-Won Hillemanns, Peter Guenel, Pascal Truong, Therese Menegaux, Florence Sanchez, Marie Radice, Paolo Peterlongo, Paolo Manoukian, Siranoush Pensotti, Valeria Hopper, John L. Tsimiklis, Helen Apicella, Carmel Southey, Melissa C. Brauch, Hiltrud Bruening, Thomas Ko, Yon-Dschun Sigurdson, Alice J. Doody, Michele M. Hamann, Ute Torres, Diana Ulmer, Hans-Ulrich Foersti, Asta Sawyer, Elinor J. Tomlinson, Ian Kerin, Michael J. Miller, Nicola Andrulis, Irene L. Knight, Julia A. Glendon, Gord Mulligan, Anna Marie Chenevix-Trench, Georgia Balleine, Rosemary Giles, Graham G. Milne, Roger L. McLean, Catriona Lindblom, Annika Margolin, Sara Haiman, Christopher A. Henderson, Brian E. Schumacher, Fredrick Le Marchand, Loic Eilber, Ursula Wang-Gohrke, Shan Hooning, Maartje J. Hollestelle, Antoinette van den Ouweland, Ans M. W. Koppert, Linetta B. Carpenter, Jane Clarke, Christine Scott, Rodney Mannermaa, Arto Kataja, Vesa Kosma, Veli-Matti Hartikainen, Jaana M. Brenner, Hermann Arndt, Volker Stegmaier, Christa Dieffenbach, Aida Karina Winqvist, Robert Pylkaes, Katri Jukkola-Vuorinen, Arja Grip, Mervi Offit, Kenneth Vijai, Joseph Robson, Mark Rau-Murthy, Rohini Dwek, Miriam Swann, Ruth Perkins, Katherine Annie Goldberg, Mark S. Labreche, France Dumont, Martine Eccles, Diana M. Tapper, William J. Rafiq, Sajjad John, Esther M. Whittemore, Alice S. Slager, Susan Yannoukakos, Drakoulis Toland, Amanda E. Yao, Song Zheng, Wei Halverson, Sandra L. Gonzalez-Neira, Anna Pita, Guillermo Alonso, M. Rosario Alvarez, Nuria Herrero, Daniel Tessier, Daniel C. Vincent, Daniel Bacot, Francois Luccarini, Craig Baynes, Caroline Ahmed, Shahana Maranian, Mel Healey, Catherine S. Simard, Jacques Hall, Per Easton, Douglas F. Garcia-Closas, Montserrat TI Prediction of Breast Cancer Risk Based on Profiling With Common Genetic Variants SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; FAMILY-HISTORY; PREVENTION; CONSORTIUM; PROSTATE; SUBTYPES; WOMEN AB Background: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking. Methods: We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates. Results: There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer. Conclusions: The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report. C1 [Pharoah, Paul D. P.; Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Luben, Robert; Brown, Judith; Easton, Douglas F.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England. [Pharoah, Paul D. P.; Tyrer, Jonathan; Dunning, Alison M.; Luccarini, Craig; Ahmed, Shahana; Maranian, Mel; Healey, Catherine S.; Easton, Douglas F.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England. [Brook, Mark N.; Swerdlow, Anthony; Schoemaker, Minouk J.] Inst Canc Res, Div Genet & Epidemiol, London SW3 6JB, England. [Bojesen, Stig E.; Nordestgaard, Borge G.; Nielsen, Sune F.] Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, Copenhagen, Denmark. [Bojesen, Stig E.; Nordestgaard, Borge G.; Nielsen, Sune F.] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Herlev, Denmark. [Bojesen, Stig E.; Nordestgaard, Borge G.] Copenhagen Univ Hosp, Fac Hlth & Med Sci, Herlev, Denmark. [Flyger, Henrik] Copenhagen Univ Hosp, Herlev Hosp, Dept Breast Surg, Herlev, Denmark. [Czene, Kamila; Darabi, Hatef; Eriksson, Mikael; Hall, Per] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Peto, Julian; dos-Santos-Silva, Isabel; Dudbridge, Frank] London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London WC1, England. [Johnson, Nichola; Ashworth, Alan; Orr, Nick; Garcia-Closas, Montserrat] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England. [Schmidt, Marjanka K.; Broeks, Annegien; Verhoef, Senno; Rutgers, Emiel J.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands. [Swerdlow, Anthony] Inst Canc Res, Div Breast Canc Res, London SW3 6JB, England. [Figueroa, Jonine; Chanock, Stephen J.; Schneeweiss, Andreas] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Olson, Janet E.; Vachon, Celine; Pankratz, Vernon S.; Seal, Sheila] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Lambrechts, Diether] VIB, Vesalius Res Ctr, Leuven, Belgium. [Lambrechts, Diether] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium. [Wildiers, Hans] Univ Hosp Leuven, Dept Gen Med Oncol, Leuven, Belgium. [Wildiers, Hans] Katholieke Univ Leuven, Dept Oncol, Leuven, Belgium. [Van Limbergen, Erik] Univ Hosp Gasthuisberg, Dept Radiat Oncol, Leuven, Belgium. [Van Ongeval, Chantal] Univ Hosp Gasthuisberg, Dept Radiol, Leuven, Belgium. [Alnaes, Grethe Grenaker; Nord, Silje; Borresen-Dale, Anne-Lise; Kataja, Vesa] Radiumhospitalet, Oslo Univ Hosp, Inst Canc Res, Dept Genet, Oslo, Norway. [Borresen-Dale, Anne-Lise; Kataja, Vesa] Univ Oslo, Inst Clin Med, Oslo, Norway. [Kataja, Vesa] Univ Oslo, Dept Clin Mol Biol, Oslo, Norway. [Nevanlinna, Heli; Muranen, Taru A.] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Hus, Finland. [Nevanlinna, Heli; Muranen, Taru A.] Univ Helsinki, Cent Hosp, Helsinki, Hus, Finland. [Aittomaeki, Kristiina] Univ Helsinki, Dept Clin Genet, Helsinki, Hus, Finland. Univ Helsinki, Dept Oncol, Helsinki, Hus, Finland. [Chang-Claude, Jenny; Rudolph, Anja; Seibold, Petra; Eilber, Ursula] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Flesch-Janys, Dieter] Univ Clin Hamburg Eppendorf, Clin Canc Registry, Dept Canc Epidemiol, Hamburg, Germany. 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[Hooning, Maartje J.; Hollestelle, Antoinette] Erasmus MC Canc Inst, Family Canc Clin, Dept Med Oncol, Rotterdam, Netherlands. [van den Ouweland, Ans M. W.] Erasmus Univ, Med Ctr, Dept Clin Genet, Rotterdam, Netherlands. [Koppert, Linetta B.] Erasmus MC Canc Inst, Dept Surg Oncol, Family Canc Clin, Rotterdam, Netherlands. [Carpenter, Jane] Univ Sydney, Australian Breast Canc Tissue Bank, Westmead Millennium Inst, Sydney, NSW 2006, Australia. [Scott, Rodney] Hunter Area Pathol Serv, Div Genet, Callaghan, NSW, Australia. [Scott, Rodney] Univ Newcastle, Callaghan, NSW 2308, Australia. [Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M.] Inst Clin Med Pathol & Forens Med, Sch Med, Kuopio, Finland. [Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M.] Univ Eastern Finland, Canc Ctr Eastern Finland, Kuopio, Finland. [Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M.] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, SF-70210 Kuopio, Finland. 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EM nm274@medschl.cam.ac.uk RI Khusnutdinova, Elza/A-4810-2013; Nord, Silje/R-5212-2016; Brenner, Hermann/B-4627-2017; manoukian, siranoush/E-7132-2017; Rahman, Nazneen/D-2802-2013; Brinton, Louise/G-7486-2015; Knight, Julia/A-6843-2012; Li, Jingmei/I-2904-2012; Hartikainen, Jaana/E-6256-2015; Dork, Thilo/J-8620-2012; Bruning, Thomas/G-8120-2015; Andrulis, Irene/E-7267-2013; OI Nord, Silje/0000-0002-3271-5356; Brenner, Hermann/0000-0002-6129-1572; manoukian, siranoush/0000-0002-6034-7562; Rahman, Nazneen/0000-0003-4376-0440; Robson, Mark/0000-0002-3109-1692; Brinton, Louise/0000-0003-3853-8562; Li, Jingmei/0000-0001-8587-7511; Bruning, Thomas/0000-0001-9560-5464; Schoemaker, Minouk/0000-0001-8403-2234; Cross, Simon/0000-0003-2044-1754; Rafiq, Sajjad/0000-0003-4873-4540; Luben, Robert/0000-0002-5088-6343; Dunning, Alison Margaret/0000-0001-6651-7166; Brook, Mark/0000-0002-8969-2378; Muranen, Taru/0000-0002-5895-1808; dos Santos Silva, Isabel/0000-0002-6596-8798; Cox, Angela/0000-0002-5138-1099; Joseph, Vijai/0000-0002-7933-151X; Yannoukakos, Drakoulis/0000-0001-7509-3510; Giles, Graham/0000-0003-4946-9099 FU Cancer Research-UK [C1287/A10118, C1287/A12014, C1287/A10710, C8197/A10123, C8620/A8372, C8620/A8857, A7572, A11699, C22524, C490/A10124]; European Community [223175 [HEALTH-F2-2009-223175]]; European Union [HEALTH-F2-2009-223175]; Canadian Institutes of Health Research (CIHR); Ministry of Economic Development, Innovation and Export Trade of Quebec [PSR-SIIRI-701]; Breakthrough Breast Cancer; National Institutes of Health Post-Genome Wide Association initiative [1U19CA148065, 1U19CA148537]; Government of Canada through Genome Canada; Canadian Institutes of Health Research; Ministere de l'enseignement superieur, de la recherche, de la science et de la technologie du Quebec through Genome Quebec; European Union European Cooperation in Science and Technology (COST) programme [BM0606]; US National Cancer Institute [UM1 CA164920]; National Health and Medical Research Council of Australia; New South Wales Cancer Council; Victorian Health Promotion Foundation (Australia); Victorian Breast Cancer Research Consortium; Dutch Cancer Society [NKI 2007-3839, 2009 4363, RUL 1997-1505, DDHK 2004-3124, DDHK 2009-4318]; BBMRI-NL - Dutch government [NWO 184.021.007]; Cancer Institute New South Wales; National Breast Cancer Foundation; ELAN-Fond of the University Hospital of Erlangen; National Health Service; National Cancer Research Network (NCRN); Institut National de Cancer; National Institutes for Health Research Comprehensive Biomedical Research Centre; Guy's & St. Thomas' NHS Foundation Trust; King's College London, United Kingdom; Oxford Biomedical Research Centre; Dietmar-Hopp Foundation; Helmholtz Society; German Cancer Research Center (DKFZ); Fondation de France; Institut National du Cancer (INCa); Ligue Nationale contre le Cancer; Ligue contre le Cancer Grand Ouest; Agence Nationale de Securite Sanitaire (ANSES); Agence Nationale de la Recherche (ANR); Lise Boserup Fund; Danish Medical Research Council; Herlev Hospital; Genome Spain Foundation; Red Tematica de Investigacion Cooperativa en Cancer; Asociacion Espanola Contra el Cancer; Fondo de Investigacion Sanitario [PI11/00923, PI081120]; California Breast Cancer; California Breast Cancer Research Fund [97-10500]; National Institutes of Health [R01 CA77398, CA63464, CA54281, CA098758, CA132839, R01CA100374, PO1 CA87969, R01 CA092447, CA128978, P30 CA016056]; Lon V. Smith Foundation [LVS39420]; California Department of Public Health as part of the statewide cancer reporting program; Against Breast Cancer Registered Charity [1121258]; charity Against Breast Cancer [1121258]; Baden Wurttemberg Ministry of Science, Research and Arts; German Cancer Aid (Deutsche Krebshilfe); US Military Acquisition (ACQ) Activity, an Era of Hope Award [W81XWH-05-1-0204]; Institute of Cancer Research UK; Medical Research Council (UK) Clinical Research Fellowship; FBCS acknowledges National Health Service (NHS); Deutsche Krebshilfe [107 352]; Federal Ministry of Education and Research (BMBF) Germany [01KW9975/5, 01KW9976/8, 01KW9977/0, 01KW0114, 01KH0402]; Robert Bosch Foundation, Stuttgart; Deutsches Krebsforschungszentrum (DKFZ), Heidelberg; Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), Bochum; Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany; Deutsche Krebshilfe e. V. [70492]; Hannover Medical School; Helsinki University Central Hospital Research Fund; Academy of Finland [266528]; Finnish Cancer Society; Nordic Cancer Union; Sigrid Juselius Foundation; Friends of Hannover Medical School; Rudolf Bartling Foundation; German Federal Ministry of Research and Education [RUS08/017]; Ministry of Education and Science of the Russian Federation [14.574.21.0026, RFMEFI57414X0026]; Russian Foundation for Basic Research [14-04-31169 mol_a]; State task of the Ministry of Education and Science of the Russian Federation [310-14]; Stockholm County Council; Karolinska Institutet; Swedish Cancer Society; Gustav V. Jubilee foundation; Bert von Kantzows foundation; special Government Funding (EVO) of Kuopio University Hospital grants; Cancer Fund of North Savo; Finnish Cancer Organizations; University of Eastern Finland; National Health and Medical Research Council [145684, 288704, 454508, 199600]; Queensland Cancer Fund; Cancer Council of New South Wales; Cancer Council of Victoria; Cancer Council of Tasmania; Cancer Council of South Australia; Cancer Foundation of Western Australia; United States Army Medical Research and Materiel Command [DAMD17-01-1-0729]; Stichting tegen Kanker [232-2008, 196-2010]; FWO; Deutsche Krebshilfe e.V. [70-2892-BR I, 106332, 108253, 108419]; Hamburg Cancer Society; Italian Association for Cancer Research (AIRC); Italian citizens of the Fondazione IRCCS Istituto Nazionale Tumori [5x1000]; National Institutes of Health, a National Institutes of Health Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA128978, CA122340, CA116201]; Breast Cancer Research Foundation; Komen Race for the Cure; VicHealth; Cancer Council Victoria; Australian National Health and Medical Research Council [209057, 251553, 504711]; Robert and Kate Niehaus Clinical Cancer Genetics Initiative; Quebec Breast Cancer Foundation; Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program [CRN-87521]; Ministry of Economic Development, Innovation and Export Trade [PSR-SIIRI-701]; CIHR; Health Scholar Award from the Fonds de la recherche en sante du Quebec; Norwegian Research council [155218/V40, 175240/S10, FUGE-NFR 181600/V11]; Swizz Bridge Award; Genetic Associations and Mechanisms in Oncology (GAME-ON) Network [U19 CA148065]; Finnish Cancer Foundation; Academy of Finland; University of Oulu; Oulu University Hospital; Biobanking and Biomolecular Resources Research Infrastructure [BBMRI-NL CP16]; Intramural Research Program of the Division of Cancer Epidemiology and Genetics; Intramural Research Program of the Center for Cancer Research of the National Cancer Institute; Marit and Hans Rausings Initiative Against Breast Cancer; Cancer Risk Prediction Center, a Linneus Centre - Swedish Research Council [70867902]; Agency for Science, Technology and Research of Singapore (A*STAR); Susan G. Komen Breast Cancer Foundation; Yorkshire Cancer Research [S295, S299, S305PA]; Sheffield Experimental Cancer Medicine Centre; National Program of Cancer Registries, Centers for Disease Control and Prevention (CDC); UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge; Deutsches Krebsforschungszentrum (DKFZ); National Institutes of Health Specialized Program of Research Excellence in Breast Cancer [CA116201]; European Union (European Social Fund - ESF); Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF); Program of the General Secretariat for Research & Technology: ARISTEIA; Hellenic Cooperative Oncology Group [HR R_BG/04]; Greek General Secretary for Research and Technology (GSRT) Program, Research Excellence II - European Union; Stefanie Spielman fund; OSU Comprehensive Cancer Center; RPCI DataBank and BioRepository (DBBR), a Cancer Center Support Grant Shared Resource [P30 CA016056-32]; National Institutes of Health, National Cancer Institute [CA-58860]; Lon V Smith Foundation [LVS-39420]; Institute of Cancer Research (ICR); NHS; Massachusetts center [R01CA47305]; Wisconsin center [R01 CA47147]; New Hampshire center [R01CA69664]; Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services; Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, US Department of Health and Human Services; Vanderbilt-Ingram Cancer Center [P30 CA68485]; [KULPFV/10/016-SymBioSysII]; [PBZ_KBN_122/P05/2004] FX This work was supported by Cancer Research-UK (grant numbers C1287/A10118, C1287/A12014) and the European Community's Seventh Framework Programme (223175 [HEALTH-F2-2009-223175]) (COGS). Genotyping of the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710), the Canadian Institutes of Health Research (CIHR) for the "CIHR Team in Familial Risks of Breast Cancer" program, and the Ministry of Economic Development, Innovation and Export Trade of Quebec (PSR-SIIRI-701). This work was also supported by Breakthrough Breast Cancer funding (to MGC). Analysis was supported in part by the National Institutes of Health Post-Genome Wide Association initiative (1U19CA148065 (DRIVE) and 1U19CA148537 (ELLIPSE)). Laboratory infrastructure was funded by Cancer Research UK (C8197/A10123). This work was also supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research and the Ministere de l'enseignement superieur, de la recherche, de la science et de la technologie du Quebec through Genome Quebec for the PERSPECTIVE project. Breast Cancer Association Consortium meetings were funded by the European Union European Cooperation in Science and Technology (COST) programme (BM0606).; The Australian Breast Cancer Family Study (ABCFS), Northern California Breast Cancer Family Registry (NC-BCFR) and Ontario Familial Breast Cancer Registry (OFBCR) studies were supported by the US National Cancer Institute (UM1 CA164920). The ABCFS was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia), and the Victorian Breast Cancer Research Consortium. JLH is a National Health and Medical Research Council (NHMRC) Australia Fellow and a Victorian Breast Cancer Research Consortium Group Leader. MCS is an NHMRC Senior Research Fellow and a Victorian Breast Cancer Research Consortium Group Leader. JLH and MCS are both group leaders of the Victoria Breast Cancer Research Consortium. The content of this manuscript does not necessarily reflect the views or policies of the US National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the BCFR.; The Amsterdam Breast Cancer Study (ABCS) was supported by the Dutch Cancer Society (NKI 2007-3839; 2009 4363) and BBMRI-NL, which is a Research Infrastructure financed by the Dutch government (NWO 184.021.007).; The Australian Breast Cancer Tissue Bank (ABCTB) study was supported by the National Health and Medical Research Council of Australia, The Cancer Institute New South Wales and the National Breast Cancer Foundation.; The Bavarian Breast Cancer Cases and Controls (BBCC) study was partly funded by ELAN-Fond of the University Hospital of Erlangen.; The British Breast Cancer Study (BBCS) was funded by Cancer Research UK and Breakthrough Breast Cancer and acknowledges National Health Service funding to the National Institutes for Health Research Biomedical Research Centre, and the National Cancer Research Network (NCRN). The BBCS GWAS received funding from The Institut National de Cancer.; The Breast Cancer In Galway Genetic Study (BIGGS) was supported by National Institutes for Health Research Comprehensive Biomedical Research Centre, Guy's & St. Thomas' NHS Foundation Trust in partnership with King's College London, United Kingdom (ES), and the Oxford Biomedical Research Centre (IT).; The Breast Cancer Study of the University Clinic Heidelberg (BSUCH) was supported by the Dietmar-Hopp Foundation, the Helmholtz Society, and the German Cancer Research Center (DKFZ).; The CECILE Breast Cancer Study (CECILE) was funded by Fondation de France, Institut National du Cancer (INCa), Ligue Nationale contre le Cancer, Ligue contre le Cancer Grand Ouest, Agence Nationale de Securite Sanitaire (ANSES), Agence Nationale de la Recherche (ANR).; The Copenhagen General Population Study (CGPS) was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council, and Herlev Hospital.; The Spanish National Cancer Centre Breast Cancer Study (CNIO-BCS) was supported by the Genome Spain Foundation, the Red Tematica de Investigacion Cooperativa en Cancer, and by grants from the Asociacion Espanola Contra el Cancer and the Fondo de Investigacion Sanitario (PI11/00923, PI081120).; The California Teachers Study (CTS) was initially supported by the California Breast Cancer Act of 1993 and the California Breast Cancer Research Fund (contract 97-10500) and is currently funded through the National Institutes of Health (R01 CA77398). The CTS study was also funded by the Lon V. Smith Foundation (LVS39420) to HAC. Collection of cancer incidence data was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885.; For the DietCompLyf Breast Cancer Survival Study (DBCSS) the University of Westminster curated the DietCompLyf database, created by and funded by Against Breast Cancer Registered Charity No. 1121258. The University of Westminster's Against Breast Cancer Research Unit acknowledges funding from the charity Against Breast Cancer (Registered Charity Number 1121258).; The Esther Breast Cancer Study (ESTHER) was supported by a grant from the Baden Wurttemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe).; The Familial Breast Cancer Study (FBCS) study was supported by funds from Cancer Research UK (C8620/A8372, C8620/A8857), a US Military Acquisition (ACQ) Activity, an Era of Hope Award (W81XWH-05-1-0204), and the Institute of Cancer Research UK. CT is funded by a Medical Research Council (UK) Clinical Research Fellowship. The FBCS acknowledges National Health Service (NHS) funding to the Royal Marsden / Institute of Cancer Research National Institutes for Health Research (NIHR) Specialist Cancer Biomedical Research Centre.; The German Consortium for Hereditary Breast & Ovarian Cancer (GC-HBOC) was supported by Deutsche Krebshilfe (107 352).; Gene Environment Interaction and Breast Cancer in Germany (GENICA) was funded by the Federal Ministry of Education and Research (BMBF) Germany (01KW9975/5, 01KW9976/8, 01KW9977/0, 01KW0114), the Robert Bosch Foundation, Stuttgart, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), Bochum, and the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany.; The Genetic Epidemiology Study of Breast Cancer by Age 50 (GESBC) study was supported by the Deutsche Krebshilfe e. V. (70492) and the German Cancer Research Center (DKFZ).; The Hannover Breast Cancer Study (HABCS) was supported by an intramural grant from Hannover Medical School.; The Helsinki Breast Cancer Study (HEBCS) was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (grant number 266528), the Finnish Cancer Society, the Nordic Cancer Union, and the Sigrid Juselius Foundation.; The Hannover-Minsk Breast Cancer Study (HMBCS) was supported by a grant from the Friends of Hannover Medical School and by the Rudolf Bartling Foundation.; The Hannover-Ufa Breast Cancer Study (HUBCS) was supported by a grant from the German Federal Ministry of Research and Education (RUS08/017) and by the Ministry of Education and Science of the Russian Federation (number 14.574.21.0026, agreement dated June 17, 2014, a unique identifier agreement RFMEFI57414X0026), the Russian Foundation for Basic Research (14-04-31169 mol_a) and State task of the Ministry of Education and Science of the Russian Federation (310-14).; The Karolinska Breast Cancer Study (KARBAC) was supported by the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, the Swedish Cancer Society, the Gustav V. Jubilee foundation, and the Bert von Kantzows foundation.; The Kuopio Breast Cancer Project (KBCP) was supported by the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, the Academy of Finland, and by the strategic funding of the University of Eastern Finland.; The kConFab study was supported by the National Breast Cancer Foundation and previously by the National Health and Medical Research Council, the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia, and the Cancer Foundation of Western Australia. The kConFab Clinical Follow Up Study was funded by the National Health and Medical Research Council (145684, 288704, 454508). RB was a Cancer Institute NSW Fellow.; The AOCS study was supported by the United States Army Medical Research and Materiel Command (DAMD17-01-1-0729), the Cancer Council of Tasmania, the Cancer Foundation of Western Australia and the National Health and Medical Research Council (199600), and a National Health and Medical Research Council grant to GCT.; The Leuven Multidisciplinary Breast Centre (LMBC) study is supported by the "Stichting tegen Kanker" (232-2008, 196-2010) and by the FWO and the KULPFV/10/016-SymBioSysII to DL.; The Mammary Carcinoma Risk Factor Investigation (MARIE) study was supported by the Deutsche Krebshilfe e.V. (70-2892-BR I, 106332, 108253, 108419), the Hamburg Cancer Society, the German Cancer Research Center (DKFZ), and the Federal Ministry of Education and Research (BMBF) Germany (01KH0402).; The Milan Breast Cancer Study Group (MBCSG) was supported by grants from the Italian Association for Cancer Research (AIRC) and by funds from the Italian citizens who allocated the 5/1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects "5x1000").; The Mayo Clinic Breast Cancer Study (MCBCS) was supported by the National Institutes of Health (CA122340, CA128978), a National Institutes of Health Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), the Breast Cancer Research Foundation, the Komen Race for the Cure, and by a generous gift from the David F. and Margaret T. Grohne Family Foundation and the Ting Tsung and Wei Fong Chao Foundation.; The Melbourne Collaborative Cohort Study (MCCS) cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian National Health and Medical Research Council (209057, 251553, 504711) and by infrastructure provided by Cancer Council Victoria.; The Multi-ethnic Cohort (MEC) was supported by the National Institutes of Health (CA63464, CA54281, CA098758, and CA132839).; The Memorial Sloan-Kettering Cancer Center (MSKCC) was supported by grants from the Breast Cancer Research Foundation and the Robert and Kate Niehaus Clinical Cancer Genetics Initiative.; The work of Montreal Gene-Environment Breast Cancer Study (MTLGEBCS) was supported by the Quebec Breast Cancer Foundation, the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program (CRN-87521), and the Ministry of Economic Development, Innovation and Export Trade (PSR-SIIRI-701). MG received an Investigator Award from the CIHR and a Health Scholar Award from the Fonds de la recherche en sante du Quebec. J Simard is chairholder of the Canada Research Chair in Oncogenetics.; The Norwegian Breast Cancer Study (NBCS) was supported by grants from the Norwegian Research council (155218/V40, 175240/S10 to ALBD, FUGE-NFR 181600/V11) to VNK and a Swizz Bridge Award to ALBD.; The Nashville Breast Health Study (NBHS) was supported by National Institutes of Health (grant R01CA100374).; The Nurses Health Study (NHS) was funded by National Institutes of Health (PO1 CA87969), and this project was (in part) supported by the Genetic Associations and Mechanisms in Oncology (GAME-ON) Network (U19 CA148065).; The Oulu Breast Cancer Study (OBCS) was supported by research grants from the Finnish Cancer Foundation, the Academy of Finland, the University of Oulu, and the Oulu University Hospital.; The Leiden University Medical Centre Breast Cancer Study (ORIGO) was supported by the Dutch Cancer Society (RUL 1997-1505) and the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL CP16).; The NCI Polish Breast Cancer Study (PBCS) was supported by the Intramural Research Programs of the Division of Cancer Epidemiology and Genetics and the Center for Cancer Research of the National Cancer Institute.; The Karolinska Mammography Project for Risk Prediction of Breast Cancer (pKARMA) study was supported by Marit and Hans Rausings Initiative Against Breast Cancer and Cancer Risk Prediction Center, a Linneus Centre (contract 70867902) financed by the Swedish Research Council.; The Prospective Study of Outcomes in Sporadic Versus Hereditary Breast Cancer (POSH) study was supported by Cancer Research UK (A7572, A11699, C22524).; The Rotterdam Breast Cancer Study (RBCS) was funded by the Dutch Cancer Society (DDHK 2004-3124, DDHK 2009-4318).; The Singapore and Sweden Breast Cancer Study (SASBAC) was supported by the Agency for Science, Technology and Research of Singapore (A*STAR), the National Institutes of Health, and the Susan G. Komen Breast Cancer Foundation.; The Sheffield Breast Cancer Study (SBCS) was supported by Yorkshire Cancer Research (S295, S299, S305PA) and the Sheffield Experimental Cancer Medicine Centre.; The Southern Community Cohort Study (SCCS) is funded by National Institutes of Health (R01 CA092447). The Arkansas Central Cancer Registry is fully funded by a grant from the National Program of Cancer Registries, Centers for Disease Control and Prevention (CDC).; Study of Epidemiology and Risk factors in Cancer Heredity (SEARCH) was funded by a programme grant from Cancer Research UK (C490/A10124), the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge, and a Cancer Research UK grant (C8197/A10123) to AMD.; The Stadtisches Klinikum Karlsruhe Deutsches Krebsforschungszentrum Study (SKKDKFZS) was supported by the Deutsches Krebsforschungszentrum (DKFZ).; The IHCC-Szczecin Breast Cancer Study (SZBCS) was supported by grant (PBZ_KBN_122/P05/2004).; The Triple Negative Breast Cancer Consortium Study (TNBCC) was supported by the National Institutes of Health (CA128978) and the National Institutes of Health Specialized Program of Research Excellence in Breast Cancer (CA116201), the Breast Cancer Research Foundation, a generous gift from the David F. and Margaret T. Grohne Family Foundation and the Ting Tsung and Wei Fong Chao Foundation, the Stefanie Spielman Breast Cancer fund and the Ohio State University (OSU) Comprehensive Cancer Center, DBBR (a CCSG Share Resource by National Institutes of Health Grant P30 CA016056), the European Union (European Social Fund - ESF) and Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF) - Research Funding Program of the General Secretariat for Research & Technology: ARISTEIA.; The DEMOKRITOS study was supported by a Hellenic Cooperative Oncology Group research grant (HR R_BG/04) and the Greek General Secretary for Research and Technology (GSRT) Program, Research Excellence II, funded at 75% by the European Union.; The OSU study was funded by the Stefanie Spielman fund and the OSU Comprehensive Cancer Center.; The Roswell Park Cancer Institute (RPCI) study was supported by RPCI DataBank and BioRepository (DBBR), a Cancer Center Support Grant Shared Resource (P30 CA016056-32).; The UCIBCS was supported by the National Institutes of Health, National Cancer Institute grant CA-58860 and the Lon V Smith Foundation grant LVS-39420.; The UK Breakthrough Generations Study (UKBGS) was funded by Breakthrough Breast Cancer and the Institute of Cancer Research (ICR). ICR acknowledges NHS funding to the Royal Marsden Hospital/ICR National Institutes for Health Research Biomedical Research Centre.; The US Three State Study (US3SS) was supported by Massachusetts (R01CA47305 to KME), Wisconsin (R01 CA47147 to PAN), and New Hampshire (R01CA69664 to LTE) centers and Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services.; The US Radiologic Technologists Study (USRT) was funded by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, US Department of Health and Human Services.; Biological sample preparation for several studies was conducted at the Epidemiology Biospecimen Core Lab, supported in part by the Vanderbilt-Ingram Cancer Center (P30 CA68485). NR 31 TC 37 Z9 37 U1 7 U2 39 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD MAY PY 2015 VL 107 IS 5 AR djv036 DI 10.1093/jnci/djv036 PG 15 WC Oncology SC Oncology GA CI9KJ UT WOS:000355088600009 ER PT J AU Marfeo, EE Ni, PS Chan, L Rasch, EK McDonough, CM Brandt, DE Bogusz, K Jette, AM AF Marfeo, Elizabeth E. Ni, Pengsheng Chan, Leighton Rasch, Elizabeth K. McDonough, Christine M. Brandt, Diane E. Bogusz, Kara Jette, Alan M. TI INTERPRETING PHYSICAL AND BEHAVIORAL HEALTH SCORES FROM NEW WORK DISABILITY INSTRUMENTS SO JOURNAL OF REHABILITATION MEDICINE LA English DT Article DE outcome assessment (healthcare); disability evaluation; work ID COMPUTERIZED ADAPTIVE TEST; ITEM POOL CONSTRUCTION; RETURN-TO-WORK; SOCIAL-SECURITY; OUTCOME MEASURES; REHABILITATION; MUSCULOSKELETAL; REFINEMENT; DISORDERS; SCALES AB Objective: To develop a system to guide interpretation of scores generated from 2 new instruments measuring work-related physical and behavioral health functioning (Work Disability Physical Function (WD-PF) and WD - Behavioral Function (WD-BH)). Design: Cross-sectional, secondary data from 3 independent samples to develop and validate the functional levels for physical and behavioral health functioning. Subjects: Physical group: 999 general adult subjects, 1,017 disability applicants and 497 work-disabled subjects. Behavioral health group: 1,000 general adult subjects, 1,015 disability applicants and 476 work-disabled subjects. Methods: Three-phase analytic approach including item mapping, a modified-Delphi technique, and known-groups validation analysis were used to develop and validate cut-points for functional levels within each of the WD-PF and WD-BH instrument's scales. Results: Four and 5 functional levels were developed for each of the scales in the WD-PF and WD-BH instruments. Distribution of the comparative samples was in the expected direction: the general adult samples consistently demonstrated scores at higher functional levels compared with the claimant and work-disabled samples. Conclusion: Using an item-response theory-based methodology paired with a qualitative process appears to be a feasible and valid approach for translating the WD-BH and WD-PF scores into meaningful levels useful for interpreting a person's work-related physical and behavioral health functioning. C1 [Marfeo, Elizabeth E.; Ni, Pengsheng; McDonough, Christine M.; Bogusz, Kara; Jette, Alan M.] Boston Univ, Sch Publ Hlth, Hlth & Disabil Res Inst, Boston, MA 02118 USA. [Chan, Leighton; Rasch, Elizabeth K.; Brandt, Diane E.] NIH, Dept Rehabil Med, Mark O Hatfield Clin Res Ctr, Bethesda, MD USA. RP Marfeo, EE (reprint author), Boston Univ, Sch Publ Hlth, Hlth & Disabil Res Inst, 715 Albany Streeet,T5W, Boston, MA 02118 USA. EM emarfeo@bu.edu FU Social Security Administration [HHSN269200900004C, HHSN269201000011C, HH-SN269201100009I]; National Institutes of Health [HHSN269200900004C, HHSN269201000011C, HH-SN269201100009I]; NIH intramural research program FX This research was supported by Social Security Administration and National Institutes of Health (SSA-NIH) Interagency Agreements (NIH contract nos. HHSN269200900004C, HHSN269201000011C, HH-SN269201100009I) and by the NIH intramural research program. The authors and co-authors have no financial or other conflicts of interest to disclose that may bias the reporting of the results presented in this study. NR 45 TC 0 Z9 0 U1 2 U2 5 PU FOUNDATION REHABILITATION INFORMATION PI UPPSALA PA TRADGARDSGATAN 14, UPPSALA, SE-753 09, SWEDEN SN 1650-1977 EI 1651-2081 J9 J REHABIL MED JI J. Rehabil. Med. PD MAY PY 2015 VL 47 IS 5 BP 394 EP 402 DI 10.2340/16501977-1947 PG 9 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA CJ3GO UT WOS:000355371600002 PM 25729901 ER PT J AU Ben Mortenson, W Demers, L Fuhrer, MJ Jutai, JW Lenker, J DeRuyter, F AF Ben Mortenson, W. Demers, Louise Fuhrer, Marcus J. Jutai, Jeffrey W. Lenker, James DeRuyter, Frank TI DEVELOPMENT AND PRELIMINARY EVALUATION OF THE CAREGIVER ASSISTIVE TECHNOLOGY OUTCOME MEASURE SO JOURNAL OF REHABILITATION MEDICINE LA English DT Article DE instrument development; assistive technology; informal caregivers; caregiver burden; self-help devices; caregivers; instrumentation ID LONG-TERM-CARE; OLDER-ADULTS; BURDEN; RELIABILITY; INDEX; HOME; QUESTIONNAIRES; PARTICIPATION; DISABILITY; CRITERIA AB Introduction: Assistive technology is often recommended with the aim of increasing user independence and reducing the burden on informal caregivers. However, until now, there has been no tool to measure the outcomes of this process for caregivers. Objectives: To describe the development of the Caregiver Assistive Technology Outcome Measure (CATOM), a tool developed to measure the impact of assistive technology interventions on the burden experienced by informal caregivers, and to undertake preliminary evaluation of its psychometric properties. Methods: Based on an existing conceptual framework, existing measures were reviewed to identify potential items in a preliminary version of the measure. Cognitive interviewing was used to identify items needing clarification. A revised CATOM and manual were then reviewed by clinicians. After revising some items based on the interview findings, the measure was piloted as part of an intervention study examining the impact of assistive technology on the users' informal caregivers (n=44). Results: Based on a review of 12 existing measures, a 3-part measure was developed and questions were refined based on cognitive interviews with informal caregivers and feedback experienced assistive technology practitioners. For the activity-specific and overall portions of the measure, the 6-week, test-retest intraclass correlations coefficients were 0.88 (95% CI 0.64-0.96) and 0.86 (95% CI 0.60-0.95), respectively. The CATOM data correlated as hypothesized with other measures. Conclusion: The CATOM is a promising measure with good content validity and encouraging psychometric properties. C1 [Ben Mortenson, W.] Univ British Columbia, Dept Occupat Sci & Occupat Therapy, Vancouver, BC V5Z 1M9, Canada. [Ben Mortenson, W.] GF Strong Rehabil Res Program, Vancouver, BC, Canada. [Ben Mortenson, W.] Int Collaborat Repair Discovery, Vancouver, BC, Canada. [Demers, Louise] Univ Montreal, Ctr Rech, Inst Univ Geriatrie Montreal, Ecole Readaptat, Montreal, PQ H3C 3J7, Canada. [Fuhrer, Marcus J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Jutai, Jeffrey W.] Univ Ottawa, Interdisciplinary Sch Hlth Sci, Ottawa, ON, Canada. [Jutai, Jeffrey W.] Bruyere Res Inst, Ottawa, ON, Canada. [Lenker, James] SUNY Buffalo, Dept Rehabil Sci, Buffalo, NY 14260 USA. [DeRuyter, Frank] Duke Univ, Dept Surg Speech Pathol & Audiol, Durham, NC USA. RP Demers, L (reprint author), Univ Montreal, Sch Rehabil, CP 6128,Succursale Ctr Ville, Montreal, PQ H3C 3J7, Canada. EM Louise.demers@umontreal.ca RI Mortenson, William/L-7441-2013; OI Mortenson, William/0000-0002-0183-6163; Jutai, Jeffrey/0000-0002-7294-1323 FU National Institute on Disability and Rehabilitation Research [H133A060062]; Banting post-doctoral fellowship FX This study was funded by the National Institute on Disability and Rehabilitation Research (grant #H133A060062). Personal financial support was provided for Dr Mortenson by a Banting post-doctoral fellowship. NR 43 TC 0 Z9 0 U1 2 U2 6 PU FOUNDATION REHABILITATION INFORMATION PI UPPSALA PA TRADGARDSGATAN 14, UPPSALA, SE-753 09, SWEDEN SN 1650-1977 EI 1651-2081 J9 J REHABIL MED JI J. Rehabil. Med. PD MAY PY 2015 VL 47 IS 5 BP 412 EP 418 DI 10.2340/16501977-1952 PG 7 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA CJ3GO UT WOS:000355371600004 ER PT J AU White, WB Galis, ZS Henegar, J Kandzari, DE Victor, R Sica, D Townsend, RR Turner, JR Virmani, R Mauri, L AF White, William B. Galis, Zorina S. Henegar, Jeffrey Kandzari, David E. Victor, Ronald Sica, Domenic Townsend, Raymond R. Turner, J. Rick Virmani, Renu Mauri, Laura TI Renal denervation therapy for hypertension: pathways for moving development forward SO JOURNAL OF THE AMERICAN SOCIETY OF HYPERTENSION LA English DT Article DE American Society of Hypertension; clinical trials; device therapy for hypertension; renal denervation ID TREATMENT-RESISTANT HYPERTENSION; SYMPLICITY HTN-3 TRIAL; BLOOD-PRESSURE; SYMPATHETIC DENERVATION; ACTIVATION; DISEASE; MODEL AB This scientific statement provides a summary of presentations and discussions at a cardiovascular Think Tank co-sponsored by the American Society of Hypertension (ASH), the United States Food and Drug Administration (FDA), and the National Heart, Lung, and Blood Institute (NHLBI) held in North Bethesda, Maryland, on June 26, 2014. Studies of device therapies for the treatment of hypertension are requested by regulators to evaluate their safety and efficacy during their development programs. Think Tank participants thought that important considerations in undertaking such studies were: (1) Preclinical assessment: how likely it is that both efficacy and safety data indicating benefit in humans will be obtained, and/or whether a plausible mechanism of action for efficacy can be identified; (2) Early human trial(s): the ability to determine that the device has an acceptable benefit-to-risk balance for its use in the intended patient population and without the influence of drug therapy during a short-term follow-up period; and (3) Pivotal Phase III trial(s): the ability to prove the effectiveness of the device in a broad population in which the trial can be made as non-confounded as possible while still allowing for the determination for benefits when added to antihypertensive therapies. (C) 2015 American Society of Hypertension. All rights reserved. C1 [White, William B.] Univ Connecticut, Calhoun Cardiol Ctr, Sch Med, Div Hypertens & Clin Pharmacol, Farmington, CT 06030 USA. [Galis, Zorina S.] NHLBI, NIH, Bethesda, MD 20892 USA. [Henegar, Jeffrey] Univ Missouri, Columbia, MO USA. [Kandzari, David E.] Piedmont Heart Inst, Atlanta, GA USA. [Victor, Ronald] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Sica, Domenic] Virginia Commonwealth Univ, Med Ctr, Richmond, VA USA. [Townsend, Raymond R.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Turner, J. Rick] Quintiles, Clin Commun, Durham, NC USA. [Virmani, Renu] CVPath Inst, Gaithersburg, MD USA. [Mauri, Laura] Harvard Clin Res Inst, Boston, MA USA. [Mauri, Laura] Brigham & Womens Hosp, Boston, MA 02115 USA. RP White, WB (reprint author), Univ Connecticut, Calhoun Cardiol Ctr, Sch Med, Med, Farmington, CT 06030 USA. EM wwhite@uchc.edu FU Boston Scientific; Medtronic, Inc; ReCor Medical; St. Jude Medical; National Institutes of Health (National Institute on Aging, National Institute on Drug Abuse); St. Jude Medical, Inc.; Medtronic CardioVascular; Boston Scientific Corporation; 480 Biomedical; Abbott Vascular; Atrium; Biosensors International; Biotronik; Cordis Johnson Johnson; GSK; Kona; Medtronic; Microport Medical; OrbusNeich Medical; ReCor; SINO Medical Technology; Terumo Corporation; Abbot Vascular; Cordis; Eli Lilly; Daiichi-Sankyo; Bristol-Myers Squibb; Sanofi-Aventis FX The forum described within this article was supported by grants from Boston Scientific, Medtronic, Inc, ReCor Medical, and St. Jude Medical.; Dr White receives research funding from the National Institutes of Health (National Institute on Aging, National Institute on Drug Abuse). Dr White has been a safety consultant (member of DSMB, CV end point committee, or advisory board) to Ardea Biosciences; Astra-Zeneca; Celgene, Forest Research Institute; Roche, Inc; Takeda Global Research and Development; and Teva Pharmaceutical Industries. Dr White was the president of the American Society of Hypertension (2012-2014) at the time of this forum. Dr Galls is an employee of the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, the opinions expressed do not necessarily represent those of NHLBI. She has no disclosures. Dr Heneger has received research support from St. Jude Medical, Inc. Dr Kandzari receives research grant support and consulting honoraria from Medtronic CardioVascular and Boston Scientific Corporation. Dr Victor has been a consultant to Medtronic CardioVascular and Northwinds, Inc. Dr Sica received research grant support to his institution from Medtronic CardioVascular. Dr Sica is the president of the American Society of Hypertension, 2014-2016. Dr Townsend declares consulting for Medtronic, Inc. In addition, he serves as consultant to Janssen Pharma. Dr Townsend is the vice president of the American Society of Hypertension, 2012-2015. Dr Turner is an employee and shareholder of Quintiles. He has no other disclosures. Dr Virmani receives research support to her institution from 480 Biomedical, Abbott Vascular, Atrium, Biosensors International, Biotronik, Boston Scientific, Cordis Johnson & Johnson, GSK, Kona, Medtronic, Microport Medical, OrbusNeich Medical, ReCor, SINO Medical Technology, Terumo Corporation. Dr Mauri receives grants to her institution from Abbot Vascular, Biotronik, Cordis, Boston Scientific, Medtronic, Eli Lilly, Daiichi-Sankyo, Bristol-Myers Squibb, and Sanofi-Aventis. She has served as a consultant to Biotronik, ReCor Medical, and St. Jude Medical. NR 36 TC 12 Z9 12 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1933-1711 EI 1878-7436 J9 J AM SOC HYPERTENS JI J. Am. Soc. Hypertens. PD MAY PY 2015 VL 9 IS 5 BP 341 EP 350 DI 10.1016/j.jash.2015.02.012 PG 10 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CI9DJ UT WOS:000355070300005 PM 25979410 ER PT J AU Silva, JC Egan, A Arze, C Spouge, JL Harris, DG AF Silva, Joana C. Egan, Amy Arze, Cesar Spouge, John L. Harris, David G. TI A New Method for Estimating Species Age Supports the Coexistence of Malaria Parasites and Their Mammalian Hosts SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article DE Plasmodium; molecular clock; speciation dates; total least squares; regression; malaria; Drosophila ID PLASMODIUM-FALCIPARUM; MITOCHONDRIAL GENOME; SUBSTITUTION RATES; DIVERGENCE DATES; MOLECULAR CLOCK; DROSOPHILA PHYLOGENY; EVOLUTIONARY ORIGIN; NUCLEAR GENES; VIVAX; SEQUENCES AB Species in the genus Plasmodium cause malaria in humans and infect a variety of mammals and other vertebrates. Currently, estimated ages for several mammalian Plasmodium parasites differ by as much as one order of magnitude, an inaccuracy that frustrates reliable estimation of evolutionary rates of disease-related traits. We developed a novel statistical approach to dating the relative age of evolutionary lineages, based on Total Least Squares regression. We validated this lineage dating approach by applying it to the genus Drosophila. Using data from the Drosophila 12 Genomes project, our approach accurately reconstructs the age of well-established Drosophila clades, including the speciation event that led to the subgenera Drosophila and Sophophora, and age of the melanogaster species subgroup. We applied this approach to hundreds of loci from seven mammalian Plasmodium species. We demonstrate the existence of a molecular clock specific to individual Plasmodium proteins, and estimate the relative age of mammalian-infecting Plasmodium. These analyses indicate that: 1) the split between the human parasite Plasmodium vivax and P. knowlesi, from Old World monkeys, occurred 6.1 times earlier than that between P. falciparum and P. reichenowi, parasites of humans and chimpanzees, respectively; and 2) mammalian Plasmodium parasites originated 22 times earlier than the split between P. falciparum and P. reichenowi. Calibrating the absolute divergence times for Plasmodium with eukaryotic substitution rates, we show that the split between P. falciparum and P. reichenowi occurred 3.0-5.5 Ma, and that mammalian Plasmodium parasites originated over 64 Ma. Our results indicate that mammalian-infecting Plasmodium evolved contemporaneously with their hosts, with little evidence for parasite host-switching on an evolutionary scale, and provide a solid timeframe within which to place the evolution of new Plasmodium species. C1 [Silva, Joana C.; Egan, Amy; Arze, Cesar] Univ Maryland, Sch Med, Inst Genome Sci, College Pk, MD 20742 USA. [Silva, Joana C.] Univ Maryland, Sch Med, Dept Microbiol & Immunol, College Pk, MD 20742 USA. [Spouge, John L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Harris, David G.] Univ Maryland, Dept Appl Math & Stat, College Pk, MD 20742 USA. RP Silva, JC (reprint author), Univ Maryland, Sch Med, Inst Genome Sci, College Pk, MD 20742 USA. EM jcsilva@som.umaryland.edu FU National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Department of Health and Human Services [HHSN272200900009C]; National Institutes of Health, National Library of Medicine FX The authors thank Austin Hughes for stimulating discussions, and J. Crabtree, A. Ganapathy, and D. Riley for technical support. This project was funded in part with federal funds from the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Department of Health and Human Services under contract number HHSN272200900009C and by startup funds to J.C.S., and by the Intramural Research Program of the National Institutes of Health, National Library of Medicine (J.L.S.). NR 71 TC 6 Z9 6 U1 6 U2 19 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0737-4038 EI 1537-1719 J9 MOL BIOL EVOL JI Mol. Biol. Evol. PD MAY PY 2015 VL 32 IS 5 BP 1354 EP 1364 DI 10.1093/molbev/msv005 PG 11 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA CJ2MH UT WOS:000355318400020 PM 25589738 ER PT J AU Berndt, SI Wang, ZM Yeager, M Alavanja, MC Albanes, D Amundadottir, L Andriole, G Freeman, LB Campa, D Cancel-Tassin, G Canzian, F Cornu, JN Cussenot, O Diver, WR Gapstur, SM Gronberg, H Haiman, CA Henderson, B Hutchinson, A Hunter, DJ Key, TJ Kolb, S Koutros, S Kraft, P Le Marchand, L Lindstrom, S Machiela, MJ Ostrander, EA Riboli, E Schumacher, F Siddiq, A Stanford, JL Stevens, VL Travis, RC Tsilidis, KK Virtamo, J Weinstein, S Wilkund, F Xu, JF Zheng, SL Yu, K Wheeler, W Zhang, H Consortium, AAPCG Sampson, J Black, A Jacobs, K Hoover, RN Tucker, M Chanock, SJ AF Berndt, Sonja I. Wang, Zhaoming Yeager, Meredith Alavanja, Michael C. Albanes, Demetrius Amundadottir, Laufey Andriole, Gerald Freeman, Laura Beane Campa, Daniele Cancel-Tassin, Geraldine Canzian, Federico Cornu, Jean-Nicolas Cussenot, Olivier Diver, W. Ryan Gapstur, Susan M. Gronberg, Henrik Haiman, Christopher A. Henderson, Brian Hutchinson, Amy Hunter, David J. Key, Timothy J. Kolb, Suzanne Koutros, Stella Kraft, Peter Le Marchand, Loic Lindstroem, Sara Machiela, Mitchell J. Ostrander, Elaine A. Riboli, Elio Schumacher, Fred Siddiq, Afshan Stanford, Janet L. Stevens, Victoria L. Travis, Ruth C. Tsilidis, Konstantinos K. Virtamo, Jarmo Weinstein, Stephanie Wilkund, Fredrik Xu, Jianfeng Zheng, S. Lilly Yu, Kai Wheeler, William Zhang, Han Consortium, African Ancestry Prostate Canc G. W. A. S. Sampson, Joshua Black, Amanda Jacobs, Kevin Hoover, Robert N. Tucker, Margaret Chanock, Stephen J. TI Two susceptibility loci identified for prostate cancer aggressiveness SO NATURE COMMUNICATIONS LA English DT Article ID GENOME-WIDE ASSOCIATION; GTPASE-ACTIVATING PROTEIN; BASE-LINE CHARACTERISTICS; LINKAGE SCAN; SEQUENCE VARIANTS; GLEASON SCORE; RISK; POPULATION; COHORT; METAANALYSIS AB Most men diagnosed with prostate cancer will experience indolent disease; hence, discovering genetic variants that distinguish aggressive from nonaggressive prostate cancer is of critical clinical importance for disease prevention and treatment. In a multistage, case-only genome-wide association study of 12,518 prostate cancer cases, we identify two loci associated with Gleason score, a pathological measure of disease aggressiveness: rs35148638 at 5q14.3 (RASA1, P = 6.49 x 10(-9)) and rs78943174 at 3q26.31 (NAALADL2, P = 4.18 x 10(-8)). In a stratified case-control analysis, the SNP at 5q14.3 appears specific for aggressive prostate cancer (P = 8.85 x 10(-5)) with no association for nonaggressive prostate cancer compared with controls (P = 0.57). The proximity of these loci to genes involved in vascular disease suggests potential biological mechanisms worthy of further investigation. C1 [Berndt, Sonja I.; Wang, Zhaoming; Yeager, Meredith; Alavanja, Michael C.; Albanes, Demetrius; Amundadottir, Laufey; Freeman, Laura Beane; Cornu, Jean-Nicolas; Koutros, Stella; Machiela, Mitchell J.; Weinstein, Stephanie; Yu, Kai; Zhang, Han; Sampson, Joshua; Black, Amanda; Jacobs, Kevin; Hoover, Robert N.; Tucker, Margaret; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Wang, Zhaoming; Yeager, Meredith; Hutchinson, Amy] NCI, Canc Genom Res Lab, Div Canc Epidemiol & Genet, Leidos Biomed Res Inc,Frederick Natl Lab Canc Res, Frederick, MD 21701 USA. [Andriole, Gerald] Washington Univ, Sch Med, Div Urol Surg, St Louis, MO 63110 USA. [Campa, Daniele] German Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Germany. [Cancel-Tassin, Geraldine; Cussenot, Olivier] Univ Paris 06, AP HP, CeRePP, Paris, France. [Canzian, Federico] German Canc Res Ctr, Genom Epidemiol Grp, D-69120 Heidelberg, Germany. [Diver, W. Ryan; Gapstur, Susan M.; Stevens, Victoria L.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30303 USA. [Gronberg, Henrik; Wilkund, Fredrik] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. [Haiman, Christopher A.; Henderson, Brian; Schumacher, Fred] Univ So Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Dept Preventat Med, Los Angeles, CA 90033 USA. [Hunter, David J.; Kraft, Peter; Lindstroem, Sara] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Key, Timothy J.; Travis, Ruth C.] Univ Oxford, Nuffield Dept Clin Med, Canc Epidemiol Unit, Oxford OX3 7BN, England. [Kolb, Suzanne; Stanford, Janet L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96813 USA. [Ostrander, Elaine A.] NHGRI, NIH, Bethesda, MD 20892 USA. [Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London SW7 2AZ, England. [Siddiq, Afshan] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Genom Common Dis, London SW7 2AZ, England. [Stanford, Janet L.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Tsilidis, Konstantinos K.] Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, GR-45110 Ioannina, Greece. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, FI-00271 Helsinki, Finland. [Xu, Jianfeng; Zheng, S. Lilly] Wake Forest Univ, Bowman Gray Sch Med, Ctr Canc Gen, Winston Salem, NC 27157 USA. [Wheeler, William] Informat Management Serv Inc, Rockville, MD 20852 USA. RP Berndt, SI (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM berndts@mail.nih.gov RI Campa, Daniele/K-1617-2016; Zhang, Han/K-2118-2016; Beane Freeman, Laura/C-4468-2015; OI Campa, Daniele/0000-0003-3220-9944; Zhang, Han/0000-0001-7977-9616; Beane Freeman, Laura/0000-0003-1294-4124; Machiela, Mitchell/0000-0001-6538-9705; Ostrander, Elaine/0000-0001-6075-9738; Cancel-Tassin, Geraldine/0000-0002-9583-6382 FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH [Z01-CP010119, ZIA-CP010152-11]; National Institute of Environmental Health Sciences [Z01-ES049030] FX This work was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH (Z01-CP010119, ZIA-CP010152-11) and in part by the National Institute of Environmental Health Sciences (Z01-ES049030). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services nor does mention of trade names, commercial products or organization indicate endorsement by the US Government. We thank Drs Christine Berg and Philip Prorok, Division of Cancer Prevention, NCI, the screening center investigators and staff of the PLCO Cancer Screening Trial, Mr Thomas Riley and staff at Information Management Services Inc. and Ms Barbara O'Brien and staff at Westat Inc. for their contributions to the PLCO. Finally, we are grateful to the study participants for donating their time and making this study possible. NR 66 TC 19 Z9 20 U1 0 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD MAY PY 2015 VL 6 AR 6889 DI 10.1038/ncomms7889 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ5KN UT WOS:000355526400001 PM 25939597 ER PT J AU Huang, JY Chen, J Esparza, J Ding, J Elder, JT Abecasis, GR Lee, YA Lathrop, GM Moffatt, MF Cookson, WOC Liang, LM AF Huang, Jinyan Chen, Jun Esparza, Jorge Ding, Jun Elder, James T. Abecasis, Goncalo R. Lee, Young-Ae Lathrop, G. Mark Moffatt, Miriam F. Cookson, William O. C. Liang, Liming TI eQTL mapping identifies insertion- and deletion-specific eQTLs in multiple tissues SO NATURE COMMUNICATIONS LA English DT Article ID GENOME-WIDE ASSOCIATION; GLOBAL GENE-EXPRESSION; TYPE-2 DIABETES RISK; FALSE DISCOVERY RATE; SUSCEPTIBILITY LOCI; PROSTATE-CANCER; CROHNS-DISEASE; CELL; VARIANTS; MAP AB Genome-wide gene expression quantitative trait loci (eQTL) mapping have been focused on single-nucleotide polymorphisms and have helped interpret findings from diseases mapping studies. The functional effect of structure variants, especially short insertions and deletions (indel) has not been well investigated. Here we impute 1,380,133 indels based on the latest 1,000 Genomes Project panel into three eQTL data sets from multiple tissues. Imputation of indels increased 9.9% power and identifies indel-specific eQTLs for 325 genes. We find introns and vicinities of UTRs are more enriched of indel eQTLs and 3.6 (single-tissue)-9.2%(multi-tissue) of previous identified eSNPs were taggers of eindels. Functional analyses identifies epigenetics marks, gene ontology categories and disease GWAS loci affected by SNPs and indels eQTLs showing tissue-consistent or tissue-specific effects. This study provides new insights into the underlying genetic architecture of gene expression across tissues and new resource to interpret function of diseases and traits associated structure variants. C1 [Huang, Jinyan] Shanghai Jiao Tong Univ, Sch Med, Rui Jin Hosp, Shanghai Inst Hematol,State Key Lab Med Genom, Shanghai 200025, Peoples R China. [Huang, Jinyan; Liang, Liming] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Chen, Jun; Liang, Liming] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Chen, Jun] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN 55905 USA. [Esparza, Jorge; Lee, Young-Ae] Max Delbruck Ctr Mol Med, D-13092 Berlin, Germany. [Ding, Jun] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. [Elder, James T.] Univ Michigan, Sch Med, Dept Dermatol, Ann Arbor, MI 48109 USA. [Elder, James T.] Ann Arbor Vet Affairs Hosp, Ann Arbor, MI 48105 USA. [Abecasis, Goncalo R.] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Lathrop, G. Mark] McGill Univ, Dept Human & Med Genet, Montreal, PQ H3A 0G1, Canada. [Lathrop, G. Mark] Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada. [Moffatt, Miriam F.; Cookson, William O. C.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London SW3 6LY, England. RP Liang, LM (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. EM lliang@hsph.harvard.edu FU Chinese National Key Basic Research Project 973 [2013CB966800]; Ministry of Health Grant [201202003]; Mega-projects of Scientific Research [2013ZX09303302]; State Key Laboratories Project of Excellence [81123005]; NIH [R01GM104411]; Samuel Waxman Cancer Research Foundation Co-PI Program; Intramural Research Program of the NIH, National Institute on Aging FX This work was supported by the Chinese National Key Basic Research Project 973 (NO.2013CB966800), Ministry of Health Grant (NO. 201202003), the Mega-projects of Scientific Research for the 12th Five-Year Plan Grant (NO.2013ZX09303302), the State Key Laboratories Project of Excellence Grant (NO.81123005), NIH Grant (R01GM104411) and Samuel Waxman Cancer Research Foundation Co-PI Program. This research was also supported in part by the Intramural Research Program of the NIH, National Institute on Aging. NR 59 TC 4 Z9 4 U1 2 U2 15 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD MAY PY 2015 VL 6 AR 6821 DI 10.1038/ncomms7821 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ5KF UT WOS:000355525600001 PM 25951796 ER PT J AU Hwang, S Palin, AC Li, LQ Song, KD Lee, J Herz, J Tubo, N Chu, H Pepper, M Lesourne, R Zvezdova, E Pinkhasov, J Jenkins, MK McGavern, D Love, PE AF Hwang, SuJin Palin, Amy C. Li, LiQi Song, Ki-Duk Lee, Jan Herz, Jasmin Tubo, Noah Chu, Hamlet Pepper, Marion Lesourne, Renaud Zvezdova, Ekaterina Pinkhasov, Julia Jenkins, Marc K. McGavern, Dorian Love, Paul E. TI TCR ITAM multiplicity is required for the generation of follicular helper T-cells SO NATURE COMMUNICATIONS LA English DT Article ID CHAIN SIGNALING MOTIFS; NEGATIVE SELECTION; ANTIGEN RECEPTOR; ZETA-CHAIN; TRANSCRIPTION FACTOR; ACTIVATION MOTIFS; NKT CELLS; REPERTOIRE; THYMOCYTES; STRENGTH AB The T-cell antigen receptor (TCR) complex contains 10 copies of a di-tyrosine Immunoreceptor-Tyrosine-based-Activation-Motif (ITAM) that initiates TCR signalling by recruiting protein tyrosine kinases. ITAM multiplicity amplifies TCR signals, but the importance of this capability for T-cell responses remains undefined. Most TCR ITAMs (6 of 10) are contributed by the CD3z subunits. We generated 'knock-in' mice that express non-signalling CD3z chains in lieu of wild-type CD3z. Here we demonstrate that ITAM multiplicity is important for the development of innate-like T-cells and follicular helper T-cells, events that are known to require strong/sustained TCR-ligand interactions, but is not essential for 'general' T-cell responses including proliferation and cytokine production or for the generation of a diverse antigen-reactive TCR repertoire. C1 [Hwang, SuJin; Palin, Amy C.; Li, LiQi; Song, Ki-Duk; Lee, Jan; Lesourne, Renaud; Zvezdova, Ekaterina; Pinkhasov, Julia; Love, Paul E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Herz, Jasmin; McGavern, Dorian] NINDS, Viral Immunol & Intravital Imaging Sect, NIH, Bethesda, MD 20892 USA. [Tubo, Noah; Chu, Hamlet; Pepper, Marion; Jenkins, Marc K.] Univ Minnesota, Sch Med, Ctr Immunol, Dept Microbiol, Minneapolis, MN 55455 USA. RP Love, PE (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Room 2B-210,Bldg 6B, Bethesda, MD 20892 USA. EM lovep@mail.nih.gov RI Zvezdova, Ekaterina/N-7860-2015; Lesourne, Renaud/M-1855-2014; OI Song, Ki-Duk/0000-0003-2827-0873; Jenkins, Marc/0000-0001-8009-7655 FU Intramural Research Program of the Eunice Kennedy Shriver, NICHD (PEL) [1ZIAHD001803 19] FX This work was funded by the Intramural Research Program of the Eunice Kennedy Shriver, NICHD (PEL: Project number: 1ZIAHD001803 19). NR 40 TC 3 Z9 5 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD MAY PY 2015 VL 6 AR 6982 DI 10.1038/ncomms7982 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CJ5LF UT WOS:000355528200001 PM 25959494 ER PT J AU Gartrell, K Storr, CL Trinkoff, AM Wilson, ML Guises, AP AF Gartrell, Kyungsook Storr, Carla L. Trinkoff, Alison M. Wilson, Marisa L. Guises, Ayse P. TI Electronic personal health record use among registered nurses SO NURSING OUTLOOK LA English DT Article DE Personal health record; Nurse; Health care provider; Electronic health record; Chronic condition and medication use ID RANDOMIZED-TRIAL; PRIMARY-CARE; ATTITUDES; INFORMATION; MANAGEMENT; NEEDS AB Introduction: Nurses promote self-care and active participation of individuals in managing their health care, yet little is known about their own use of electronic personal health records (ePHRs). The purpose of this study was to examine factors associated with ePHR use by nurses for their own health management. Methods: A total of 664 registered nurses working in 12 hospitals in the Maryland and Washington DC area participated in an online survey from December 2013 to January 2014. Multiple logistic regression models identified factors associated with ePHR use. Results: More than a third (41%; 95% confidence interval [CI], 0.37-0.44) of the respondents were ePHR users. There was no variation between ePHR users and nonusers by demographic or job-related information. However, ePHR users were more likely to be active health care consumers (i.e., have a chronic medical condition and take prescribed medications; odds ratio [OR] = 1.64; 95% CI, 1.06-2.53) and have health care providers who used electronic health records for care (OR = 3.62; 95% CI, 2.45-5.36). Conclusions: Nurses were proactive in managing their chronic medical conditions and prescribed medication use with ePHRs. ePHR use by nurses can be facilitated by increasing use of electronic health records. C1 [Gartrell, Kyungsook] NIH, Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD 20892 USA. [Storr, Carla L.; Trinkoff, Alison M.] Univ Maryland, Sch Nursing, Baltimore, MD 21201 USA. [Wilson, Marisa L.] Johns Hopkins Univ, Sch Nursing, Baltimore, MD USA. [Guises, Ayse P.] Johns Hopkins Med, Dept Anesthesiol, Crit Care Med, Armstrong Inst Patient Safety & Qual, Baltimore, MD USA. RP Gartrell, K (reprint author), NIH, Bldg 10,Room 6-2551,10 Ctr Dr,MSC 1504, Bethesda, MD 20892 USA. EM kyungsook.gartrell@nih.gov OI Gartrell, Kyungsook/0000-0002-0716-2497 FU American Nursing Informatics Association Scholarship Award; University of Maryland School of Nursing FX Supported by the American Nursing Informatics Association Scholarship Award and by the Graduate Assistance in Areas of National Need fellowship from the University of Maryland School of Nursing. NR 52 TC 0 Z9 0 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0029-6554 EI 1528-3968 J9 NURS OUTLOOK JI Nurs. Outlook PD MAY-JUN PY 2015 VL 63 IS 3 BP 278 EP 287 DI 10.1016/j.outlook.2014.11.013 PG 10 WC Nursing SC Nursing GA CJ1KN UT WOS:000355242600007 PM 25982768 ER PT J AU Wroblewski, EE Norman, PJ Guethlein, LA Rudicell, RS Ramirez, MA Li, YY Hahn, BH Pusey, AE Parham, P AF Wroblewski, Emily E. Norman, Paul J. Guethlein, Lisbeth A. Rudicell, Rebecca S. Ramirez, Miguel A. Li, Yingying Hahn, Beatrice H. Pusey, Anne E. Parham, Peter TI Signature Patterns of MHC Diversity in Three Gombe Communities of Wild Chimpanzees Reflect Fitness in Reproduction and Immune Defense against SIVcpz SO PLOS BIOLOGY LA English DT Article ID MAJOR HISTOCOMPATIBILITY COMPLEX; IMMUNODEFICIENCY-VIRUS TYPE-1; PAN-TROGLODYTES-SCHWEINFURTHII; ACUTE HIV-1 INFECTION; ANTIGEN-BINDING SITE; NATURAL-KILLER-CELLS; CLASS-I MOLECULES; HLA-B ALLELES; NATIONAL-PARK; GENETIC DIVERSITY AB Major histocompatibility complex (MHC) class I molecules determine immune responses to viral infections. These polymorphic cell-surface glycoproteins bind peptide antigens, forming ligands for cytotoxic T and natural killer cell receptors. Under pressure from rapidly evolving viruses, hominoid MHC class I molecules also evolve rapidly, becoming diverse and species-specific. Little is known of the impact of infectious disease epidemics on MHC class I variant distributions in human populations, a context in which the chimpanzee is the superior animal model. Population dynamics of the chimpanzees inhabiting Gombe National Park, Tanzania have been studied for over 50 years. This population is infected with SIVcpz, the precursor of human HIV-1. Because HLA-B is the most polymorphic human MHC class I molecule and correlates strongly with HIV-1 progression, we determined sequences for its ortholog, Patr-B, in 125 Gombe chimpanzees. Eleven Patr-B variants were defined, as were their frequencies in Gombe's three communities, changes in frequency with time, and effect of SIVcpz infection. The growing populations of the northern and central communities, where SIVcpz is less prevalent, have stable distributions comprising a majority of low-frequency Patr-B variants and a few high-frequency variants. Driving the latter to high frequency has been the fecundity of immigrants to the northern community, whereas in the central community, it has been the fecundity of socially dominant individuals. In the declining population of the southern community, where greater SIVcpz prevalence is associated with mortality and emigration, Patr-B variant distributions have been changing. Enriched in this community are Patr-B variants that engage with natural killer cell receptors. Elevated among SIVcpz-infected chimpanzees, the Patr-B*06:03 variant has striking structural and functional similarities to HLA-B*57, the human allotype most strongly associated with delayed HIV-1 progression. Like HLA-B*57, Patr-B*06:03 correlates with reduced viral load, as assessed by detection of SIVcpz RNA in feces. C1 [Wroblewski, Emily E.; Norman, Paul J.; Guethlein, Lisbeth A.; Parham, Peter] Stanford Univ, Sch Med, Dept Biol Struct, Stanford, CA 94305 USA. [Wroblewski, Emily E.; Norman, Paul J.; Guethlein, Lisbeth A.; Parham, Peter] Stanford Univ, Sch Med, Dept Microbiol & Immunol, Stanford, CA 94305 USA. [Rudicell, Rebecca S.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Rudicell, Rebecca S.] Sanofi, Cambridge, MA USA. [Ramirez, Miguel A.; Li, Yingying; Hahn, Beatrice H.] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Ramirez, Miguel A.; Li, Yingying; Hahn, Beatrice H.] Univ Penn, Perelman Sch Med, Dept Microbiol, Philadelphia, PA 19104 USA. [Pusey, Anne E.] Duke Univ, Dept Evolutionary Anthropol, Durham, NC USA. RP Wroblewski, EE (reprint author), Stanford Univ, Sch Med, Dept Biol Struct, Stanford, CA 94305 USA. EM eewro1@stanford.edu; peropa@stanford.edu FU National Institutes of Health [R01 AI 24258, R01 AI 31168, R01 AI 058715]; NIH/NIAID, Ruth L. Kirschstein National Research Service Award (NRSA) [F32 AI085959]; ORIP/OD [P51 OD011132]; National Science Foundation [LTREB-1052693, DBS-9021946, SBR-9319909, BCS-0452315, BCS-0648481]; University of Minnesota; Harris Steel Group; Windibrow Foundation; Jane Goodall Institute; Carnegie Corporation; Duke University FX The Gombe chimpanzee MHC genetic data generation and analysis was funded by the National Institutes of Health (R01 AI 24258 and R01 AI 31168) and EEW was funded by an NIH/NIAID, Ruth L. Kirschstein National Research Service Award (NRSA) (F32 AI085959). Samples received from Yerkes National Primate Research Center were collected with funding from ORIP/OD P51 OD011132. All other Gombe population data collection was primarily supported by the Jane Goodall Institute (JGI) and with additional support from the National Science Foundation (LTREB-1052693) and the National Institutes of Health (R01 AI 058715). Digitization and analysis of population, SIVcpz, and microsatellite genetic data were supported by grants from the National Science Foundation (DBS-9021946, SBR-9319909, BCS-0452315, BCS-0648481, LTREB-1052693), the National Institutes of Health (R01 AI 058715), the University of Minnesota, the Harris Steel Group, the Windibrow Foundation, the Jane Goodall Institute, the Carnegie Corporation and Duke University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 91 TC 3 Z9 3 U1 2 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1545-7885 J9 PLOS BIOL JI PLoS. Biol. PD MAY PY 2015 VL 13 IS 5 AR e1002144 DI 10.1371/journal.pbio.1002144 PG 36 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA CJ2HU UT WOS:000355305600004 PM 26020813 ER PT J AU Lada, AG Kliver, SF Dhar, A Polev, DE Masharsky, AE Rogozin, IB Pavlov, YI AF Lada, Artem G. Kliver, Sergei F. Dhar, Alok Polev, Dmitrii E. Masharsky, Alexey E. Rogozin, Igor B. Pavlov, Youri I. TI Disruption of Transcriptional Coactivator Sub1 Leads to Genome-Wide Re-distribution of Clustered Mutations Induced by APOBEC in Active Yeast Genes SO PLOS GENETICS LA English DT Article ID INDUCED CYTIDINE DEAMINASE; REPLICATION PROTEIN-A; RNA-POLYMERASE-II; EDITING ENZYME APOBEC1; SOMATIC HYPERMUTATION; HUMAN CANCERS; CYTOSINE DEAMINASE; ESCHERICHIA-COLI; DNA-POLYMERASES; AID AB Mutations in genomes of species are frequently distributed non-randomly, resulting in mutation clusters, including recently discovered kataegis in tumors. DNA editing deaminases play the prominent role in the etiology of these mutations. To gain insight into the enigmatic mechanisms of localized hypermutagenesis that lead to cluster formation, we analyzed the mutational single nucleotide variations (SNV) data obtained by whole-genome sequencing of drug-resistant mutants induced in yeast diploids by AID/APOBEC deaminase and base analog 6-HAP. Deaminase from sea lamprey, PmCDA1, induced robust clusters, while 6-HAP induced a few weak ones. We found that PmCDA1, AID, and APOBEC1 deaminases preferentially mutate the beginning of the actively transcribed genes. Inactivation of transcription initiation factor Sub1 strongly reduced deaminase-induced can1 mutation frequency, but, surprisingly, did not decrease the total SNV load in genomes. However, the SNVs in the genomes of the sub1 clones were re-distributed, and the effect of mutation clustering in the regions of transcription initiation was even more pronounced. At the same time, the mutation density in the protein-coding regions was reduced, resulting in the decrease of phenotypically detected mutants. We propose that the induction of clustered mutations by deaminases involves: a) the exposure of ssDNA strands during transcription and loss of protection of ssDNA due to the depletion of ssDNA-binding proteins, such as Sub1, and b) attainment of conditions favorable for APOBEC action in subpopulation of cells, leading to enzymatic deamination within the currently expressed genes. This model is applicable to both the initial and the later stages of oncogenic transformation and explains variations in the distribution of mutations and kataegis events in different tumor cells. C1 [Lada, Artem G.; Pavlov, Youri I.] Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA. [Kliver, Sergei F.] St Petersburg State Univ, Dept Genet & Biotechnol, St Petersburg 199034, Russia. [Dhar, Alok] Univ Nebraska Med Ctr, Dept Genet Cell Biol & Anat, Omaha, NE USA. [Dhar, Alok] Univ Nebraska Med Ctr, Munroe Meyer Inst, Omaha, NE USA. [Polev, Dmitrii E.; Masharsky, Alexey E.] St Petersburg State Univ, Res Resource Ctr Mol & Cell Technol, St Petersburg 199034, Russia. [Rogozin, Igor B.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Rogozin, Igor B.] Russian Acad Sci, Inst Cytol & Genet, Novosibirsk 630090, Russia. [Rogozin, Igor B.] Novosibirsk State Univ, Novosibirsk 630090, Russia. RP Lada, AG (reprint author), Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA. EM artem.g.lada@gmail.com; ypavlo@unmc.edu FU Eppley Pilot Project; Russian Foundation for Basic Research [15-04-08625]; St. Petersburg State University [1.38.426.2015] FX This work was supported by Eppley Pilot Project Grants (2014, 2015), Russian Foundation for Basic Research #15-04-08625, and Research Grant of St. Petersburg State University #1.38.426.2015 to YIP. Whole-genome sequencing was partially supported by Research Resource Center for Molecular and Cell Technologies, St. Petersburg State University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 82 TC 9 Z9 9 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD MAY PY 2015 VL 11 IS 5 AR e1005217 DI 10.1371/journal.pgen.1005217 PG 27 WC Genetics & Heredity SC Genetics & Heredity GA CJ2HQ UT WOS:000355305200033 PM 25941824 ER PT J AU Liu, ZY Shi, HR Szymczak, LC Aydin, T Yun, SJ Constas, K Schaeffer, A Ranjan, S Kubba, S Alam, E McMahon, DE He, JP Shwartz, N Tian, CX Plavskin, Y Lindy, A Dad, NA Sheth, S Amin, NM Zimmerman, S Liu, D Schwarz, EM Smith, H Krause, MW Liu, J AF Liu, Zhiyu Shi, Herong Szymczak, Lindsey C. Aydin, Taner Yun, Sijung Constas, Katharine Schaeffer, Arielle Ranjan, Sinthu Kubba, Saad Alam, Emad McMahon, Devin E. He, Jingpeng Shwartz, Neta Tian, Chenxi Plavskin, Yevgeniy Lindy, Amanda Dad, Nimra Amir Sheth, Sunny Amin, Nirav M. Zimmerman, Stephanie Liu, Dennis Schwarz, Erich M. Smith, Harold Krause, Michael W. Liu, Jun TI Promotion of Bone Morphogenetic Protein Signaling by Tetraspanins and Glycosphingolipids SO PLOS GENETICS LA English DT Article ID BETA PATHWAY COMPONENTS; SCHNURRI HOMOLOG SMA-9; ELEGANS TGF-BETA; CAENORHABDITIS-ELEGANS; C-ELEGANS; BODY-SIZE; IN-VIVO; MEMBRANE-PROTEIN; SPLIT-UBIQUITIN; GENE ENCODES AB Bone morphogenetic proteins (BMPs) belong to the transforming growth factor beta (TGF beta) superfamily of secreted molecules. BMPs play essential roles in multiple developmental and homeostatic processes in metazoans. Malfunction of the BMP pathway can cause a variety of diseases in humans, including cancer, skeletal disorders and cardiovascular diseases. Identification of factors that ensure proper spatiotemporal control of BMP signaling is critical for understanding how this pathway is regulated. We have used a unique and sensitive genetic screen to identify the plasma membrane-localized tetraspanin TSP-21 as a key new factor in the C. elegans BMP-like "Sma/Mab" signaling pathway that controls body size and postembryonic M lineage development. We showed that TSP-21 acts in the signal-receiving cells and genetically functions at the ligand-receptor level. We further showed that TSP-21 can associate with itself and with two additional tetraspanins, TSP-12 and TSP-14, which also promote Sma/Mab signaling. TSP-12 and TSP-14 can also associate with SMA-6, the type I receptor of the Sma/Mab pathway. Finally, we found that glycosphingolipids, major components of the tetraspanin-enriched microdomains, are required for Sma/Mab signaling. Our findings suggest that the tetraspanin-enriched membrane microdomains are important for proper BMP signaling. As tetraspanins have emerged as diagnostic and prognostic markers for tumor progression, and TSP-21, TSP-12 and TSP-14 are all conserved in humans, we speculate that abnormal BMP signaling due to altered expression or function of certain tetraspanins may be a contributing factor to cancer development. C1 [Liu, Zhiyu; Shi, Herong; Szymczak, Lindsey C.; Aydin, Taner; Constas, Katharine; Schaeffer, Arielle; Ranjan, Sinthu; Kubba, Saad; Alam, Emad; McMahon, Devin E.; He, Jingpeng; Shwartz, Neta; Tian, Chenxi; Plavskin, Yevgeniy; Lindy, Amanda; Dad, Nimra Amir; Sheth, Sunny; Amin, Nirav M.; Zimmerman, Stephanie; Liu, Dennis; Schwarz, Erich M.; Liu, Jun] Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY 14850 USA. [Yun, Sijung; Smith, Harold; Krause, Michael W.] NIDDK, Mol Biol Lab, Bethesda, MD 20892 USA. RP Liu, ZY (reprint author), Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY 14850 USA. EM JL53@cornell.edu OI Krause, Michael/0000-0001-6127-3940; Schwarz, Erich/0000-0003-3151-4381 FU National Institutes of Health [R01 GM066953, R01 GM103869]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health; Cornell CALS Charitable Trust Undergraduate Research Grant; Weill Cornell Medical College in Qatar; Empire State Stem Cell Fund through New York State Department of Health [C026075]; Office of the Associate Vice Provost for Research, Weill Institute of Cell and Molecular Biology, Cornell Graduate School, Center for Vertebrate Genomics, Division of Nutritional Sciences; Department of Molecular Biology and Genetics; Cornell University FX This work was supported by R01 GM066953 and R01 GM103869 from the National Institutes of Health (to JL), and by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (to MWK). YP and AL were Cornell Howard Hughes Undergraduate Research Scholars. YP was a recipient of the Cornell CALS Charitable Trust Undergraduate Research Grant. SK, EA and NAD were supported by the Summer Research Fellowship from Weill Cornell Medical College in Qatar. DEM was a Cornell Stem Cell Undergraduate Research Scholar, with funds provided by the Empire State Stem Cell Fund through New York State Department of Health contract #C026075. DL and TA were Hunter R. Rawlings III Presidential Research Scholars at Cornell University. NS was a student in the MBG REU program, which was supported in part by the following Cornell sources: Office of the Associate Vice Provost for Research, Weill Institute of Cell and Molecular Biology, Cornell Graduate School, Center for Vertebrate Genomics, Division of Nutritional Sciences, and Department of Molecular Biology and Genetics. EMS was supported by Cornell University salary and start-up funds. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 105 TC 3 Z9 3 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7390 EI 1553-7404 J9 PLOS GENET JI PLoS Genet. PD MAY PY 2015 VL 11 IS 5 AR UNSP e1005221 DI 10.1371/journal.pgen.1005221 PG 33 WC Genetics & Heredity SC Genetics & Heredity GA CJ2HQ UT WOS:000355305200035 PM 25978409 ER PT J AU Westra, HJ Arends, D Esko, T Peters, MJ Schurmann, C Schramm, K Kettunen, J Yaghootkar, H Fairfax, BP Andiappan, AK Li, Y Fu, JY Karjalainen, J Platteel, M Visschedijk, M Weersma, RK Kasela, S Milani, L Tserel, L Peterson, P Reinmaa, E Hofman, A Uitterlinden, AG Rivadeneira, F Homuth, G Petersmann, A Lorbeer, R Prokisch, H Meitinger, T Herder, C Roden, M Grallert, H Ripatti, S Perola, M Wood, AR Melzer, D Ferrucci, L Singleton, AB Hernandez, DG Knight, JC Melchiotti, R Lee, B Poidinger, M Zolezzi, F Larbi, A Wang, DY van den Berg, LH Veldink, JH Rotzschke, O Makino, S Salomaa, V Strauch, K Volker, U van Meurs, JBJ Metspalu, A Wijmenga, C Jansen, RC Franke, L AF Westra, Harm-Jan Arends, Danny Esko, Tonu Peters, Marjolein J. Schurmann, Claudia Schramm, Katharina Kettunen, Johannes Yaghootkar, Hanieh Fairfax, Benjamin P. Andiappan, Anand Kumar Li, Yang Fu, Jingyuan Karjalainen, Juha Platteel, Mathieu Visschedijk, Marijn Weersma, Rinse K. Kasela, Silva Milani, Lili Tserel, Liina Peterson, Part Reinmaa, Eva Hofman, Albert Uitterlinden, Andre G. Rivadeneira, Fernando Homuth, Georg Petersmann, Astrid Lorbeer, Roberto Prokisch, Holger Meitinger, Thomas Herder, Christian Roden, Michael Grallert, Harald Ripatti, Samuli Perola, Markus Wood, Andrew R. Melzer, David Ferrucci, Luigi Singleton, Andrew B. Hernandez, Dena G. Knight, Julian C. Melchiotti, Rossella Lee, Bernett Poidinger, Michael Zolezzi, Francesca Larbi, Anis Wang, De Yun van den Berg, Leonard H. Veldink, Jan H. Rotzschke, Olaf Makino, Seiko Salomaa, Veikko Strauch, Konstantin Voelker, Uwe van Meurs, Joyce B. J. Metspalu, Andres Wijmenga, Cisca Jansen, Ritsert C. Franke, Lude TI Cell Specific eQTL Analysis without Sorting Cells SO PLOS GENETICS LA English DT Article ID ACTIVE CROHNS-DISEASE; GENE-EXPRESSION; WIDE ASSOCIATION; DNA METHYLATION; VARIANTS; HETEROGENEITY; BLOOD AB The functional consequences of trait associated SNPs are often investigated using expression quantitative trait locus (eQTL) mapping. While trait-associated variants may operate in a cell-type specific manner, eQTL datasets for such cell-types may not always be available. We performed a genome-environment interaction (GxE) meta-analysis on data from 5,683 samples to infer the cell type specificity of whole blood cis-eQTLs. We demonstrate that this method is able to predict neutrophil and lymphocyte specific cis-eQTLs and replicate these predictions in independent cell-type specific datasets. Finally, we show that SNPs associated with Crohn's disease preferentially affect gene expression within neutrophils, including the archetypal NOD2 locus. C1 [Westra, Harm-Jan; Fu, Jingyuan; Karjalainen, Juha; Platteel, Mathieu; Visschedijk, Marijn; Wijmenga, Cisca; Franke, Lude] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands. [Arends, Danny; Li, Yang; Jansen, Ritsert C.] Univ Groningen, Groningen Bioinformat Ctr, Groningen, Netherlands. [Esko, Tonu; Kasela, Silva; Milani, Lili; Reinmaa, Eva; Metspalu, Andres] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia. [Esko, Tonu] Boston Childrens Hosp, Div Endocrinol, Boston, MA USA. [Esko, Tonu] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Esko, Tonu] Broad Inst, Cambridge, MA USA. [Peters, Marjolein J.; Uitterlinden, Andre G.; Rivadeneira, Fernando; van Meurs, Joyce B. J.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Peters, Marjolein J.; Hofman, Albert; Uitterlinden, Andre G.; Rivadeneira, Fernando; van Meurs, Joyce B. J.] Netherlands Genom Initiat Sponsored Netherlands C, Leiden, Netherlands. [Schurmann, Claudia; Homuth, Georg; Voelker, Uwe] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany. [Schurmann, Claudia] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA. [Schramm, Katharina; Prokisch, Holger; Meitinger, Thomas] German Res Ctr Environm Hlth, Inst Human Genet, Helmholtz Zentrum Munchen, Neuherberg, Germany. [Schramm, Katharina; Meitinger, Thomas] Tech Univ Munich, Inst Humangenet, D-80290 Munich, Germany. [Kettunen, Johannes] Univ Oulu, Computat Med, Fac Med, Inst Hlth Sci, Oulu, Finland. [Kettunen, Johannes; Ripatti, Samuli] Univ Helsinki, FIMM, Helsinki, Finland. [Kettunen, Johannes; Ripatti, Samuli; Perola, Markus; Salomaa, Veikko] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Yaghootkar, Hanieh; Wood, Andrew R.] Univ Exeter, Sch Med, Genet Complex Traits, Exeter, Devon, England. [Fairfax, Benjamin P.; Knight, Julian C.; Makino, Seiko] Wellcome Trust Ctr Human Genet, Oxford, England. [Fairfax, Benjamin P.] Churchill Hosp, Dept Oncol, Canc & Haematol Ctr, Oxford OX3 7LJ, England. [Andiappan, Anand Kumar; Melchiotti, Rossella; Lee, Bernett; Poidinger, Michael; Zolezzi, Francesca; Larbi, Anis; Rotzschke, Olaf] ASTAR, Singapore Immunol Network SIgN, Singapore, Singapore. [Visschedijk, Marijn; Weersma, Rinse K.] Univ Groningen, Univ Med Ctr Groningen, Dept Gastroenterol & Hepatol, Groningen, Netherlands. [Kasela, Silva] Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia. [Tserel, Liina; Peterson, Part] Univ Tartu, Mol Pathol, Inst Biomed & Translat Med, EE-50090 Tartu, Estonia. [Hofman, Albert; Uitterlinden, Andre G.; Rivadeneira, Fernando] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Petersmann, Astrid] Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany. [Lorbeer, Roberto] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Meitinger, Thomas] Munich Heart Alliance, Munich, Germany. [Meitinger, Thomas] German Ctr Cardiovasc Res DZHK, Munich, Germany. [Herder, Christian; Roden, Michael] Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Clin Diabetol, Dusseldorf, Germany. [Herder, Christian; Roden, Michael] German Ctr Diabet Res DZD, Dusseldorf, Germany. [Roden, Michael] Univ Dusseldorf, Univ Hosp Dusseldorf, Dept Diabetol & Endocrinol, Dusseldorf, Germany. [Grallert, Harald] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany. [Ripatti, Samuli] Wellcome Trust Sanger Inst, Cambridge, England. [Ripatti, Samuli] Univ Helsinki, Dept Publ Hlth, Hjelt Inst, Helsinki, Finland. [Melzer, David] Univ Exeter, Sch Med, Inst Biomed & Clin Sci, Exeter, Devon, England. [Ferrucci, Luigi] NIA, Clin Res Branch, ASTRA Unit, Harbor Hosp, Baltimore, MD 21224 USA. [Singleton, Andrew B.; Hernandez, Dena G.] NIA, Neurogenet Lab, NIH, Baltimore, MD 21224 USA. [Hernandez, Dena G.] UCL, Inst Neurol, Dept Mol Neurosci, London, England. [Hernandez, Dena G.] UCL, Inst Neurol, Reta Lila Labs, London, England. [Melchiotti, Rossella] Univ Milano Bicocca, Doctoral Sch Translat & Mol Med DIMET, Milan, Italy. [Wang, De Yun] Natl Univ Singapore, Dept Otolaryngol, Singapore 117548, Singapore. [van den Berg, Leonard H.] Univ Med Ctr Utrecht, Rudolf Magnus Inst Neurosci, Dept Neurol, Utrecht, Netherlands. [Strauch, Konstantin] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany. [Strauch, Konstantin] Univ Munich, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, Neuherberg, Germany. RP Westra, HJ (reprint author), Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands. EM lude@ludesign.nl RI Knight, Julian/C-7242-2009; Grallert, Harald/B-3424-2013; Rivadeneira, Fernando/O-5385-2015; Peterson, Part/A-5788-2009; Schurmann, Claudia/L-1204-2016; Franke, Lude/P-7036-2016; Karjalainen, Juha/P-8624-2016; Arends, Danny/C-5368-2012; Ripatti, Samuli/H-9446-2014; Singleton, Andrew/C-3010-2009; Meitinger, Thomas/O-1318-2015; OI Peters, Marjolein/0000-0003-3167-9063; Melzer, David/0000-0002-0170-3838; Poidinger, Michael/0000-0002-1047-2277; Knight, Julian/0000-0002-0377-5536; Rivadeneira, Fernando/0000-0001-9435-9441; Peterson, Part/0000-0001-6755-791X; Schurmann, Claudia/0000-0003-4158-9192; Franke, Lude/0000-0002-5159-8802; Arends, Danny/0000-0001-8738-0162; Ripatti, Samuli/0000-0002-0504-1202; Esko, Tonu/0000-0003-1982-6569 FU European Community [261433, HEALTH-F4-2007-201413, 259867]; Academy of Finland Center of Excellence in Complex Disease Genetics [213506, 129680]; Academy of Finland [251217, 139635]; Finnish foundation for Cardiovascular Research; Sigrid Juselius Foundation; Finnish Academy SALVE program "Pubgensense'' [129322]; Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012]; Deutsche Forschungsgemeinschaft [DFG GRK840D2]; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg West Pomerania; network 'Greifswald Approach to Individualized Medicine (GANI_MED)' - Federal Ministry of Education and Research [03IS2061A]; Siemens Healthcare, Erlangen, Germany; Federal State of Mecklenburg, West Pomerania; FP7 [201413, 245536]; Estonian Government [SF0180142s08]; Ministry of Research and Science; Ministry of Social Affairs; University of Tartu; European Union through the European Regional Development Fund; German Bundesministerium fuer Forschung und Technology [01 AK 803 A-H, 01 IG 07015 G]; European Commission [HEALTH-F2-2008-201865, HEALTH-F2-2008 35627, TREAT-OA 200800]; Netherlands Organization of Scientific Research NWO Investments [175.010.2005.011, 911-03012]; Research Institute for Diseases in the Elderly [014-93-015]; Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) [050-060-810]; NWO VIDI [917103521]; Erasmus Medical Center; Erasmus University, Rotterdam; Netherlands Organization for Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam; Celiac Disease Consortium; Dutch Government [BSIK03009]; Netherlands Organization for Scientific Research (NWO-VICI) [918.66.620]; Netherlands Organization for Scientific Research (NWO-VENI) [916.10.135]; Dutch Digestive Disease Foundation [MLDS WO11-30]; Horizon Breakthrough grant from the Netherlands Genomics Initiative [92519031]; Prinses Beatrix Fonds; VSB fonds; Kersten Foundation; Netherlands ALS Foundation; Adessium Foundation; BBMRI NL Functional Genomics Project; Netherlands Organization for Scientific Research [184021007]; Centre for BioSystems Genomics (CBSG) part of the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research; Netherlands Consortium of Systems Biology (NCSB) part of the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research; Wellcome Trust [083270/Z/07/Z, 074318, 088891, 075491/Z/04]; U.S. National Institute on Aging (NIA); Intramural Research Program, NIA; National Institute of Health (NIH); Peninsula NIHR Clinical Research Facility; Helmholtz Zentrum Munchen; German Research Center for Environmental Health - BMBF; State of Bavaria; German Federal Ministry of Health; Ministry of School, Science and Research of the State of North-Rhine-Westphalia; German Research Foundation (DFG) [RA 459/2-1]; BMBF [0315494A]; DZHK (Deutsches Zentrum fur Herz-Kreislauf-Forschung - German Centre for Cardiovascular Research); BMBF (National Genome Research Network NGFNplus Atherogenomics) [01GS0834]; Leibniz Association (WGL Pakt fur Forschung und Innovation); European Research Council under the European Union [281824]; NIHR Oxford Biomedical Research Centre; A*STAR/SIgN [SIgN-06-006, SIgN-08-020, SIgN-10-029] FX DILGOM: JKe and SR were supported by funds from The European Community's Seventh Framework Programme (FP7/2007-2013) BioSHaRE, grant agreement 261433, SR was supported by funds from The European Community's Seventh Framework Programme (FP7/2007-2013) ENGAGE Consortium, grant agreement HEALTH-F4-2007-201413", the Academy of Finland Center of Excellence in Complex Disease Genetics (grants 213506 and 129680), Academy of Finland (grant 251217), the Finnish foundation for Cardiovascular Research and the Sigrid Juselius Foundation. VS was supported by the Academy of Finland, grant number 139635 and Finnish Foundation for Cardiovascular Research. MPe was partly financially supported for this work by the Finnish Academy SALVE program "Pubgensense'' 129322 and by grants from the Finnish Foundation for Cardiovascular Research. The DILGOM-study was supported by the Academy of Finland, grant # 118065. SHIP-TREND: SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Deutsche Forschungsgemeinschaft (DFG GRK840D2), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg West Pomerania, and the network 'Greifswald Approach to Individualized Medicine (GANI_MED)' funded by the Federal Ministry of Education and Research (grant 03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg, West Pomerania. Whole-body MR imaging was supported by a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg West Pomerania. The University of Greifswald is a member of the 'Center of Knowledge Interchange' program of the Siemens AG and the Cache Campus program of the InterSystems GmbH. The SHIP authors thank Mario Stanke for the opportunity to use his Server Cluster for the SNP imputation. EGCUT: EGCUT received financing by FP7 grants (201413, 245536), also received targeted financing from the Estonian Government (SF0180142s08) and direct funding from the Ministries of Research and Science and Social Affairs. EGCUTstudies are funded by the University of Tartu in the framework of the Center of Translational Genomics and by the European Union through the European Regional Development Fund, in the framework of the Centre of Excellence in Genomics. Rotterdam Study: The Erasmus GRID Office, Erasmus MC Rotterdam, The Netherlands, and especially the national German MediGRID and Services@ MediGRID part of the German D-Grid, both funded by the German Bundesministerium fuer Forschung und Technology under grants #01 AK 803 A-H and # 01 IG 07015 G for access to their grid resources. The authors thank the study participants and staff from the Rotterdam Study, the participating general practitioners and the pharmacists. The Rotterdam Study was funded by the European Commission (HEALTH-F2-2008-201865, GEFOS; HEALTH-F2-2008 35627, TREAT-OA 200800), the Netherlands Organization of Scientific Research NWO Investments (nos 175.010.2005.011, 911-03012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) (project nr. 050-060-810), an NWO VIDI grant (# 917103521).; The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. Fehrmann: This study was supported by grants from the Celiac Disease Consortium (an innovative cluster approved by the Netherlands Genomics Initiative and partly funded by the Dutch Government (grant BSIK03009), the Netherlands Organization for Scientific Research (NWO-VICI grant 918.66.620, NWO-VENI grant 916.10.135 to LF), the Dutch Digestive Disease Foundation (MLDS WO11-30), and a Horizon Breakthrough grant from the Netherlands Genomics Initiative (grant 92519031 to LFr). This project was supported by the Prinses Beatrix Fonds, VSB fonds, H. Kersten and M. Kersten (Kersten Foundation), The Netherlands ALS Foundation, and J. R. van Dijk and the Adessium Foundation. The research leading to these results has received funding from the European Community's Health Seventh Framework Programme (FP7/2007-2013) under grant agreement 259867. This study was supported by the BBMRI NL Functional Genomics Project. Funding for the project was provided by the Netherlands Organization for Scientific Research under award number 184021007, dated July 9, 2009 and made available as a Rainbow Project of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL). DA was supported by the Centre for BioSystems Genomics (CBSG) and the Netherlands Consortium of Systems Biology (NCSB), both of which are part of the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research. InCHIANTI: InCHIANTI was supported by the Wellcome Trust 083270/Z/07/Z. The InCHIANTI study was supported by contract funding from the U.S. National Institute on Aging (NIA), and the research was supported in part by the Intramural Research Program, NIA, and National Institute of Health (NIH). ARW was supported by the Peninsula NIHR Clinical Research Facility. Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust. KORA F4: The KORA research platform and the KORA Augsburg studies are financed by the Helmholtz Zentrum Munchen, German Research Center for Environmental Health, which is funded by the BMBF and by the State of Bavaria. We thank the field staff in Augsburg who were involved in the studies. The German Diabetes Center is funded by the German Federal Ministry of Health and the Ministry of School, Science and Research of the State of North-Rhine-Westphalia. The Diabetes Cohort Study was funded by a German Research Foundation project grant (DFG; RA 459/2-1). This study was supported in part by a grant from the BMBF to the German Center for Diabetes Research (DZD e.V.), by the DZHK (Deutsches Zentrum fur Herz-Kreislauf-Forschung - German Centre for Cardiovascular Research) and by the BMBF funded Systems Biology of Metabotypes grant (SysMBo#0315494A). Additional support was given by the BMBF (National Genome Research Network NGFNplus Atherogenomics, 01GS0834) and the Leibniz Association (WGL Pakt fur Forschung und Innovation). Oxford: This work was supported by the Wellcome Trust (Grants 074318 [JCK], 088891 [BPF], and 075491/Z/04 [core facilities Wellcome Trust Centre for Human Genetics]), the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013) / ERC Grant agreement no.; 281824 (JCK) and the NIHR Oxford Biomedical Research Centre. Singapore Chinese functional genomics cohort: These studies were supported by A*STAR/SIgN core funding, and grants SIgN-06-006, SIgN-08-020 and SIgN-10-029. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 8 Z9 8 U1 1 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7390 EI 1553-7404 J9 PLOS GENET JI PLoS Genet. PD MAY PY 2015 VL 11 IS 5 AR UNSP e1005223 DI 10.1371/journal.pgen.1005223 PG 17 WC Genetics & Heredity SC Genetics & Heredity GA CJ2HQ UT WOS:000355305200036 PM 25955312 ER PT J AU Wickner, RB Edskes, HK AF Wickner, Reed B. Edskes, Herman K. TI Yeast Killer Elements Hold Their Hosts Hostage SO PLOS GENETICS LA English DT Editorial Material ID LINEAR DNA PLASMIDS; DOUBLE-STRANDED-RNA; SACCHAROMYCES-CEREVISIAE; KLUYVEROMYCES-LACTIS; WINGEA-ROBERTSIAE; PICHIA-ACACIAE; CHARACTER; PRIONS; SYSTEM C1 [Wickner, Reed B.; Edskes, Herman K.] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Wickner, RB (reprint author), NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. EM wickner@helix.nih.gov FU Intramural NIH HHS NR 13 TC 1 Z9 1 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7390 EI 1553-7404 J9 PLOS GENET JI PLoS Genet. PD MAY PY 2015 VL 11 IS 5 AR e1005139 DI 10.1371/journal.pgen.1005139 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA CJ2HQ UT WOS:000355305200010 PM 25973796 ER PT J AU Achee, NL Gould, F Perkins, TA Reiner, RC Morrison, AC Ritchie, SA Gubler, DJ Teyssou, R Scott, TW AF Achee, Nicole L. Gould, Fred Perkins, T. Alex Reiner, Robert C., Jr. Morrison, Amy C. Ritchie, Scott A. Gubler, Duane J. Teyssou, Remy Scott, Thomas W. TI A Critical Assessment of Vector Control for Dengue Prevention SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Review ID AEDES-AEGYPTI DIPTERA; CLUSTER-RANDOMIZED-TRIAL; BANCROFTIAN FILARIASIS; DEVELOPING-COUNTRIES; MOSQUITO POPULATION; SUSTAINED-RELEASE; RNA INTERFERENCE; FIELD-EVALUATION; LETHAL OVITRAP; KEY CONTAINER AB Recently, the Vaccines to Vaccinate (v2V) initiative was reconfigured into the Partnership for Dengue Control (PDC), a multi-sponsored and independent initiative. This redirection is consistent with the growing consensus among the dengue-prevention community that no single intervention will be sufficient to control dengue disease. The PDC's expectation is that when an effective dengue virus (DENV) vaccine is commercially available, the public health community will continue to rely on vector control because the two strategies complement and enhance one another. Although the concept of integrated intervention for dengue prevention is gaining increasingly broader acceptance, to date, no consensus has been reached regarding the details of how and what combination of approaches can be most effectively implemented to manage disease. To fill that gap, the PDC proposed a three step process: (1) a critical assessment of current vector control tools and those under development, (2) outlining a research agenda for determining, in a definitive way, what existing tools work best, and (3) determining how to combine the best vector control options, which have systematically been defined in this process, with DENV vaccines. To address the first step, the PDC convened a meeting of international experts during November 2013 in Washington, DC, to critically assess existing vector control interventions and tools under development. This report summarizes those deliberations. C1 [Achee, Nicole L.; Perkins, T. Alex] Univ Notre Dame, Dept Biol Sci, Notre Dame, IN 46556 USA. [Achee, Nicole L.; Perkins, T. Alex] Univ Notre Dame, Eck Inst Global Hlth, Notre Dame, IN 46556 USA. [Gould, Fred] N Carolina State Univ, Dept Entomol, Raleigh, NC 27695 USA. [Perkins, T. Alex; Reiner, Robert C., Jr.; Scott, Thomas W.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Reiner, Robert C., Jr.] Indiana Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Bloomington, IN USA. [Morrison, Amy C.; Scott, Thomas W.] Univ Calif Davis, Dept Entomol & Nematol, Davis, CA 95616 USA. [Morrison, Amy C.] US Naval Med Res Unit, Iquitos, Peru. [Ritchie, Scott A.] James Cook Univ, Coll Publ Hlth Med & Vet Sci, Cairns, Australia. [Gubler, Duane J.] Duke NUS Grad Med Sch, Emerging Infect Dis Program, Singapore, Singapore. [Gubler, Duane J.; Teyssou, Remy; Scott, Thomas W.] Fdn Merieux, Partnership Dengue Control, Lyon, France. RP Achee, NL (reprint author), Univ Notre Dame, Dept Biol Sci, Notre Dame, IN 46556 USA. EM nachee@nd.edu FU Partnership for Dengue Control (PDC); Bill & Melinda Gates Foundation [OPP1081737]; Research and Policy for Infectious Disease Dynamics program of the Science and Technology Directory, Department of Homeland Security; Fogarty International Center, National Institutes of Health; National Institutes of Health (NIH) [R01AI091980-01A1] FX This review was supported by the Partnership for Dengue Control (PDC). NLA, RCR, ACM, and TWS acknowledge support from the Bill & Melinda Gates Foundation award OPP1081737. TAP, RCR, and TWS received support from the Research and Policy for Infectious Disease Dynamics program of the Science and Technology Directory, Department of Homeland Security, and Fogarty International Center, National Institutes of Health. FG, ACM, and TWS received support from National Institutes of Health (NIH) grant R01AI091980-01A1. The PDC had no role in study design, data collection and analysis. RT participated in the decision to publish and preparation of the manuscript. NR 126 TC 39 Z9 40 U1 7 U2 43 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD MAY PY 2015 VL 9 IS 5 AR UNSP e0003655 DI 10.1371/journal.pntd.0003655 PG 19 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA CJ2HA UT WOS:000355303600007 PM 25951103 ER PT J AU Kotsyfakis, M Kopacek, P Franta, Z Pedra, JHF Ribeiro, JMC AF Kotsyfakis, Michalis Kopacek, Petr Franta, Zdenek Pedra, Joao H. F. Ribeiro, Jose M. C. TI Deep Sequencing Analysis of the Ixodes ricinus Haemocytome SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID RHIPICEPHALUS BOOPHILUS MICROPLUS; DROSOPHILA IMD PATHWAY; INNATE IMMUNITY; ANTIMICROBIAL PEPTIDES; CATTLE TICK; HARD TICK; ANOPHELES-GAMBIAE; SALIVARY-GLANDS; BABESIA-BOVIS; SOFT TICK AB Background Ixodes ricinus is the main tick vector of the microbes that cause Lyme disease and tick-borne encephalitis in Europe. Pathogens transmitted by ticks have to overcome innate immunity barriers present in tick tissues, including midgut, salivary glands epithelia and the hemocoel. Molecularly, invertebrate immunity is initiated when pathogen recognition molecules trigger serum or cellular signalling cascades leading to the production of antimicrobials, pathogen opsonization and phagocytosis. We presently aimed at identifying hemocyte transcripts from semi-engorged female I. ricinus ticks by mass sequencing a hemocyte cDNA library and annotating immune-related transcripts based on their hemocyte abundance as well as their ubiquitous distribution. Methodology/principal findings De novo assembly of 926,596 pyrosequence reads plus 49,328,982 Illumina reads (148 nt length) from a hemocyte library, together with over 189 million Illumina reads from salivary gland and midgut libraries, generated 15,716 extracted coding sequences (CDS); these are displayed in an annotated hyperlinked spreadsheet format. Read mapping allowed the identification and annotation of tissue-enriched transcripts. A total of 327 transcripts were found significantly over expressed in the hemocyte libraries, including those coding for scavenger receptors, antimicrobial peptides, pathogen recognition proteins, proteases and protease inhibitors. Vitellogenin and lipid metabolism transcription enrichment suggests fat body components. We additionally annotated ubiquitously distributed transcripts associated with immune function, including immune-associated signal transduction proteins and transcription factors, including the STAT transcription factor. Conclusions/significance This is the first systems biology approach to describe the genes expressed in the haemocytes of this neglected disease vector. A total of 2,860 coding sequences were deposited to GenBank, increasing to 27,547 the number so far deposited by our previous transcriptome studies that serves as a discovery platform for studies with I. ricinus biochemistry and physiology. C1 [Kotsyfakis, Michalis; Kopacek, Petr; Franta, Zdenek] Acad Sci Czech Republic, Ctr Biol, Inst Parasitol, Budweis, Czech Republic. [Pedra, Joao H. F.] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. [Ribeiro, Jose M. C.] NIAID, Vector Biol Sect, Lab Malaria & Vector Res, NIH, Rockville, MD USA. RP Kotsyfakis, M (reprint author), Acad Sci Czech Republic, Ctr Biol, Inst Parasitol, Budweis, Czech Republic. EM mich_kotsyfakis@yahoo.com RI Kotsyfakis, Michail/G-9525-2014; Kopacek, Petr/G-8414-2014; OI Kotsyfakis, Michail/0000-0002-7526-1876; Ribeiro, Jose/0000-0002-9107-0818 FU Grant Agency of the Czech Republic [P506/10/2136, 13-11043S, P502/12/2409]; EU-FP7 project TRANSVAC [FP7-INFRASTRUCTURES-2008-228403]; EU-FP-7 Marie Curie Reintegration grant [PIRG07-GA-2010-268177]; Jan Evangelista Purkyne Fellowship from the Academy of Sciences of the Czech Republic; Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA; National Institutes of Health [R01 AI093653]; University of Maryland, Baltimore School of Medicine FX This work was supported by the Grant Agency of the Czech Republic, Project Nos: P506/10/2136, 13-11043S to PK and P502/12/2409 to MK. MK was further supported by the EU-FP7 project TRANSVAC (FP7-INFRASTRUCTURES-2008-228403), EU-FP-7 Marie Curie Reintegration grant PIRG07-GA-2010-268177, and a Jan Evangelista Purkyne Fellowship from the Academy of Sciences of the Czech Republic. The institutional support of the Institute of Parasitology BC ASCR is covered by RVO 60077344. JMCR was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA. MK and JHFP were supported by the National Institutes of Health (R01 AI093653) and JHFP was supported by start-up funds provided by the University of Maryland, Baltimore School of Medicine. Because JMCR is a government employee and this is government work, the work is in the public domain in the United States. Notwithstanding any other agreements, the NIH reserves the right to provide the work to PubMedCentral for display and use by the public, and PubMedCentral may tag or modify the work consistent with its customary practices. Rights can be established outside of the United States subject to a government use license. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 75 TC 5 Z9 5 U1 2 U2 17 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD MAY PY 2015 VL 9 IS 5 AR e0003754 DI 10.1371/journal.pntd.0003754 PG 22 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA CJ2HA UT WOS:000355303600024 PM 25970599 ER PT J AU Crooks, ET Tong, T Chakrabarti, B Narayan, K Georgiev, IS Menis, S Huang, XX Kulp, D Osawa, K Muranaka, J Stewart-Jones, G Destefano, J O'Dell, S LaBranche, C Robinson, JE Montefiori, DC McKee, K Du, SX Doria-Rose, N Kwong, PD Mascola, JR Zhu, P Schief, WR Wyatt, RT Whalen, RG Binley, JM AF Crooks, Ema T. Tong, Tommy Chakrabarti, Bimal Narayan, Kristin Georgiev, Ivelin S. Menis, Sergey Huang, Xiaoxing Kulp, Daniel Osawa, Keiko Muranaka, Janelle Stewart-Jones, Guillaume Destefano, Joanne O'Dell, Sijy LaBranche, Celia Robinson, James E. Montefiori, David C. McKee, Krisha Du, Sean X. Doria-Rose, Nicole Kwong, Peter D. Mascola, John R. Zhu, Ping Schief, William R. Wyatt, Richard T. Whalen, Robert G. Binley, James M. TI Vaccine-Elicited Tier 2 HIV-1 Neutralizing Antibodies Bind to Quaternary Epitopes Involving Glycan-Deficient Patches Proximal to the CD4 Binding Site SO PLOS PATHOGENS LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ENVELOPE GLYCOPROTEIN TRIMERS; MONOCLONAL-ANTIBODIES; ENV TRIMERS; COMPARATIVE IMMUNOGENICITY; CONFORMATIONAL EPITOPE; POTENT NEUTRALIZATION; BROAD NEUTRALIZATION; GP41-GP120 INTERFACE; DEPENDENT EPITOPE AB Eliciting broad tier 2 neutralizing antibodies (nAbs) is a major goal of HIV-1 vaccine research. Here we investigated the ability of native, membrane-expressed JR-FL Env trimers to elicit nAbs. Unusually potent nAb titers developed in 2 of 8 rabbits immunized with virus-like particles (VLPs) expressing trimers (trimer VLP sera) and in 1 of 20 rabbits immunized with DNA expressing native Env trimer, followed by a protein boost (DNA trimer sera). All 3 sera neutralized via quaternary epitopes and exploited natural gaps in the glycan defenses of the second conserved region of JR-FL gp120. Specifically, trimer VLP sera took advantage of the unusual absence of a glycan at residue 197 (present in 98.7% of Envs). Intriguingly, removing the N197 glycan (with no loss of tier 2 phenotype) rendered 50% or 16.7% (n = 18) of clade B tier 2 isolates sensitive to the two trimer VLP sera, showing broad neutralization via the surface masked by the N197 glycan. Neutralizing sera targeted epitopes that overlap with the CD4 binding site, consistent with the role of the N197 glycan in a putative "glycan fence" that limits access to this region. A bioinformatics analysis suggested shared features of one of the trimer VLP sera and monoclonal antibody PG9, consistent with its trimer-dependency. The neutralizing DNA trimer serum took advantage of the absence of a glycan at residue 230, also proximal to the CD4 binding site and suggesting an epitope similar to that of monoclonal antibody 8ANC195, albeit lacking tier 2 breadth. Taken together, our data show for the first time that strain-specific holes in the glycan fence can allow the development of tier 2 neutralizing antibodies to native spikes. Moreover, cross-neutralization can occur in the absence of protecting glycan. Overall, our observations provide new insights that may inform the future development of a neutralizing antibody vaccine. C1 [Chakrabarti, Bimal; Menis, Sergey; Kulp, Daniel; Schief, William R.; Wyatt, Richard T.] Scripps Res Inst, Int AIDS Vaccine Initiat IAVI Neutralizing Antibo, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Narayan, Kristin; Muranaka, Janelle; Du, Sean X.; Whalen, Robert G.] Altravax Inc, Sunnyvale, CA USA. [Georgiev, Ivelin S.; Stewart-Jones, Guillaume; O'Dell, Sijy; McKee, Krisha; Doria-Rose, Nicole; Kwong, Peter D.; Mascola, John R.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Menis, Sergey; Kulp, Daniel; Schief, William R.; Wyatt, Richard T.] Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA. [Huang, Xiaoxing; Zhu, Ping] Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing 100080, Peoples R China. [Stewart-Jones, Guillaume] Univ Oxford, John Radcliffe Hosp, MRC Human Immunol Unit, Weatherall Inst Mol Med, Oxford OX3 9DU, England. [Destefano, Joanne] Design & Dev Lab, Int AIDS Vaccine Initiat, Brooklyn, NY USA. [LaBranche, Celia; Montefiori, David C.] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Robinson, James E.] Tulane Natl Primate Res Ctr, Covington, LA USA. [Schief, William R.] Ragon Inst MGH MIT & Harvard, Cambridge, MA USA. EM jbinley@sdbri.org FU National Institutes of Health [RO1AI93278, RO1AI58763, R33AI84714, P01 AI056375]; Department of Defense [W9113M-08-1-0008]; International AIDS Vaccine Initiative; National Natural Science Foundation of China [81261120418]; National Institutes of Health Intramural Research Program; US-China Program in Biomedical Research Cooperation [AI58763] FX This work was supported by National Institutes of Health (www.nih.gov) grants RO1AI93278, RO1AI58763 and R33AI84714 (JMB); National Institutes of Health grant P01 AI056375 and Department of Defense grant W9113M-08-1-0008 (RGW); the International AIDS Vaccine Initiative (www.iavi.org) Intramural Research Program (RTW); supplements provided by the US-China Program in Biomedical Research Cooperation to National Institutes of Health grant AI58763 (JMB) and National Natural Science Foundation of China (http://www.nsfc.gov.cn/publish/portal1/) grant 81261120418 (PZ); and the National Institutes of Health Intramural Research Program (ISG, SO, GSJ, NDR, PDK, and JRM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 90 TC 36 Z9 36 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD MAY PY 2015 VL 11 IS 5 AR UNSP e1004932 DI 10.1371/journal.ppat.1004932 PG 34 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA CJ1UF UT WOS:000355269300058 PM 26023780 ER PT J AU Panackal, AA Wuest, SC Lin, YC Wu, TX Zhang, NN Kosa, P Komori, M Blake, A Browne, SK Rosen, LB Hagen, F Meis, J Levitz, SM Quezado, M Hammoud, D Bennett, JE Bielekova, B Williamson, PR AF Panackal, Anil A. Wuest, Simone C. Lin, Yen-Chih Wu, Tianxia Zhang, Nannan Kosa, Peter Komori, Mika Blake, Andrew Browne, Sarah K. Rosen, Lindsey B. Hagen, Ferry Meis, Jacques Levitz, Stuart M. Quezado, Martha Hammoud, Dima Bennett, John E. Bielekova, Bibi Williamson, Peter R. TI Paradoxical Immune Responses in Non-HIV Cryptococcal Meningitis SO PLOS PATHOGENS LA English DT Article ID RECONSTITUTION INFLAMMATORY SYNDROME; ALLERGIC BRONCHOPULMONARY-MYCOSIS; T-CELL RESPONSES; NEOFORMANS INFECTION; CEREBROSPINAL-FLUID; ANTIRETROVIRAL THERAPY; TRANSPLANT RECIPIENTS; ACTIVATED MACROPHAGES; ANTIFUNGAL THERAPY; IFN-GAMMA AB The fungus Cryptococcus is a major cause of meningoencephalitis in HIV-infected as well as HIV-uninfected individuals with mortalities in developed countries of 20% and 30%, respectively. In HIV-related disease, defects in T-cell immunity are paramount, whereas there is little understanding of mechanisms of susceptibility in non-HIV related disease, especially that occurring in previously healthy adults. The present description is the first detailed immunological study of non-HIV-infected patients including those with severe central nervous system (s-CNS) disease to 1) identify mechanisms of susceptibility as well as 2) understand mechanisms underlying severe disease. Despite the expectation that, as in HIV, T-cell immunity would be deficient in such patients, cerebrospinal fluid (CSF) immunophenotyping, T-cell activation studies, soluble cytokine mapping and tissue cellular phenotyping demonstrated that patients with s-CNS disease had effective microbiological control, but displayed strong intrathecal expansion and activation of cells of both the innate and adaptive immunity including HLA-DR+ CD4+ and CD8+ cells and NK cells. These expanded CSF T cells were enriched for cryptococcal-antigen specific CD4+ cells and expressed high levels of IFN-gamma as well as a lack of elevated CSF levels of typical T-cell specific Th2 cytokines -IL-4 and IL-13. This inflammatory response was accompanied by elevated levels of CSF NFL, a marker of axonal damage, consistent with ongoing neurological damage. However, while tissue macrophage recruitment to the site of infection was intact, polarization studies of brain biopsy and autopsy specimens demonstrated an M2 macrophage polarization and poor phagocytosis of fungal cells. These studies thus expand the paradigm for cryptococcal disease susceptibility to include a prominent role for macrophage activation defects and suggest a spectrum of disease whereby severe neurological disease is characterized by immune-mediated host cell damage. C1 [Panackal, Anil A.; Zhang, Nannan; Browne, Sarah K.; Rosen, Lindsey B.; Bennett, John E.; Williamson, Peter R.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Panackal, Anil A.] Uniformed Serv Univ Hlth Sci, Div Infect Dis, Dept Med, F Hebert Sch Med, Bethesda, MD 20814 USA. [Wuest, Simone C.; Lin, Yen-Chih; Wu, Tianxia; Kosa, Peter; Komori, Mika; Blake, Andrew; Bielekova, Bibi] NINDS, Neuroimmunol Dis Unit, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. [Hagen, Ferry; Meis, Jacques] Canisius Wilhelmina Hosp, Dept Med Microbiol & Infect Dis, Nijmegen, Netherlands. [Meis, Jacques] Radboudumc, Dept Med Microbiol, Nijmegen, Netherlands. [Levitz, Stuart M.] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA USA. [Quezado, Martha] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hammoud, Dima] NIH, Ctr Infect Dis Imaging Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. RP Panackal, AA (reprint author), NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM Bibi.Bielekova@nih.gov; williamsonpr@mail.nih.gov RI Hagen, Ferry/B-9044-2009; Meis, J.F.G.M./L-4518-2015 OI Hagen, Ferry/0000-0002-5622-1916; FU National Institute of Allergy and Infectious Diseases (NIAID) [AI001123-01, AI001124-01]; National Institute of Neurological Diseases and Stroke (NINDS) at the National Institutes of Health; extramural NIH support [RO1 AI026780] FX This research was supported by the Intramural Research Program (Grant # AI001123-01 and AI001124-01) of the National Institute of Allergy and Infectious Diseases (NIAID) and the National Institute of Neurological Diseases and Stroke (NINDS) at the National Institutes of Health as well as extramural NIH support RO1 AI026780. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 67 TC 14 Z9 14 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD MAY PY 2015 VL 11 IS 5 AR UNSP e1004884 DI 10.1371/journal.ppat.1004884 PG 27 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA CJ1UF UT WOS:000355269300031 PM 26020932 ER PT J AU Shingai, M Welbourn, S Brenchley, JM Acharya, P Miyagi, E Plishka, RJ Buckler-White, A Kwong, PD Nishimura, Y Strebel, K Martin, MA AF Shingai, Masashi Welbourn, Sarah Brenchley, Jason M. Acharya, Priyamvada Miyagi, Eri Plishka, Ronald J. Buckler-White, Alicia Kwong, Peter D. Nishimura, Yoshiaki Strebel, Klaus Martin, Malcolm A. TI The Expression of Functional Vpx during Pathogenic SIVmac Infections of Rhesus Macaques Suppresses SAMHD1 in CD4(+) Memory T Cells SO PLOS PATHOGENS LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HIV-1 INFECTION; GASTROINTESTINAL-TRACT; IMMUNE RECONSTITUTION; PIGTAIL MACAQUES; PROTEIN; RESTRICTION; PHOSPHORYLATION; DEPLETION; MONKEYS AB For nearly 20 years, the principal biological function of the HIV-2/SIV Vpx gene has been thought to be required for optimal virus replication in myeloid cells. Mechanistically, this Vpx activity was recently reported to involve the degradation of Sterile Alpha Motif and HD domain-containing protein 1 (SAMHD1) in this cell lineage. Here we show that when macaques were inoculated with either the T cell tropic SIVmac239 or the macrophage tropic SIVmac316 carrying a Vpx point mutation that abrogates the recruitment of DCAF1 and the ensuing degradation of endogenous SAMHD1 in cultured CD4(+) T cells, virus acquisition, progeny virion production in memory CD4(+) T cells during acute infection, and the maintenance of set-point viremia were greatly attenuated. Revertant viruses emerging in two animals exhibited an augmented replication phenotype in memory CD4(+) T lymphocytes both in vitro and in vivo, which was associated with reduced levels of endogenous SAMHD1. These results indicate that a critical role of Vpx in vivo is to promote the degradation of SAMHD1 in memory CD4(+) T lymphocytes, thereby generating high levels of plasma viremia and the induction of immunodeficiency. C1 [Shingai, Masashi; Welbourn, Sarah; Brenchley, Jason M.; Miyagi, Eri; Plishka, Ronald J.; Buckler-White, Alicia; Nishimura, Yoshiaki; Strebel, Klaus; Martin, Malcolm A.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Acharya, Priyamvada; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Martin, MA (reprint author), NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. EM malm@nih.gov FU Intramural Research Program; Vaccine Research Center of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program and the Vaccine Research Center of the 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 47 TC 7 Z9 7 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD MAY PY 2015 VL 11 IS 5 AR UNSP e1004928 DI 10.1371/journal.ppat.1004928 PG 23 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA CJ1UF UT WOS:000355269300056 PM 25996507 ER PT J AU Moorthy, B Chu, C Carlin, DJ AF Moorthy, Bhagavatula Chu, Chun Carlin, Danielle J. TI Polycyclic Aromatic Hydrocarbons: From Metabolism to Lung Cancer SO TOXICOLOGICAL SCIENCES LA English DT Review DE polycyclic aromatic hydrocarbons; PAH; lung cancer; Ah receptor; carcinogenesis; genetic susceptibility; metabolism; mixtures ID CYTOCHROMES P450 1A1; PERIPHERAL-BLOOD LYMPHOCYTES; ENVIRONMENTAL TOBACCO-SMOKE; DNA-ADDUCTS; IN-VIVO; TRANSCRIPTIONAL ACTIVATION; ADENOCARCINOMA CELLS; OXIDATIVE STRESS; GENE-REGULATION; KNOCKOUT MOUSE AB Excessive exposure to polycyclic aromatic hydrocarbons (PAHs) often results in lung cancer, a disease with the highest cancer mortality in the United States. After entry into the lung, PAHs induce phase I metabolic enzymes such as cytochrome P450 (CYP) monooxygenases, i.e. CYP1A1/2 and 1B1, and phase II enzymes such as glutathione S-transferases, UDP glucuronyl transferases, NADPH quinone oxidoreductases (NQOs), aldo-keto reductases (AKRs), and epoxide hydrolases (EHs), via the aryl hydrocarbon receptor (AhR)-dependent and independent pathways. Humans can also be exposed to PAHs through diet, via consumption of charcoal broiled foods. Metabolism of PAHs through the CYP1A1/1B1/EH pathway, CYP peroxidase pathway, and AKR pathway leads to the formation of the active carcinogens diol-epoxides, radical cations, and o-quinones. These reactive metabolites produce DNA adducts, resulting in DNA mutations, alteration of gene expression profiles, and tumorigenesis. Mutations in xenobiotic metabolic enzymes, as well as polymorphisms of tumor suppressor genes (e.g. p53) and/or genes involved in gene expression (e.g. X-ray repair cross-complementing proteins), are associated with lung cancer susceptibility in human populations from different ethnicities, gender, and age groups. Although various metabolic activation/inactivation pathways, AhR signaling, and genetic susceptibilities contribute to lung cancer, the precise points at which PAHs induce tumor initiation remain unknown. The goal of this review is to provide a current state-of-the-science of the mechanisms of human lung carcinogenesis mediated by PAHs, the experimental approaches used to study this complex class of compounds, and future directions for research of these compounds. C1 [Moorthy, Bhagavatula; Chu, Chun] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Carlin, Danielle J.] NIEHS, Div Extramural Res & Training, Res Triangle Pk, NC 27709 USA. RP Moorthy, B (reprint author), Baylor Coll Med, Dept Pediat, 1102 Bates Ave,Suite 530, Houston, TX 77030 USA. FU National Institute of Health [ES-009132, HL-112516, HL-087174, ES-019689] FX National Institute of Health (grants ES-009132, HL-112516, HL-087174, and ES-019689 to B.M.). NR 117 TC 18 Z9 18 U1 20 U2 99 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD MAY PY 2015 VL 145 IS 1 BP 5 EP 15 DI 10.1093/toxsci/kfv040 PG 11 WC Toxicology SC Toxicology GA CJ1YL UT WOS:000355280900002 PM 25911656 ER PT J AU Feldstein, LR Brownstein, JS Brady, OJ Hay, SI Johansson, MA AF Feldstein, Leora R. Brownstein, John S. Brady, Oliver J. Hay, Simon I. Johansson, Michael A. TI Dengue on islands: a Bayesian approach to understanding the global ecology of dengue viruses SO TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE LA English DT Article DE Dengue; Ecology; Epidemiology; Islands; Transmission dynamics ID TIME-SERIES ANALYSIS; AEDES-AEGYPTI; INFECTIOUS-DISEASES; CLIMATE VARIABILITY; TRANSMISSION; FEVER; VARIABLES; THAILAND; MEXICO; TEMPERATURE AB Background: Transmission of dengue viruses (DENV), the most common arboviral pathogens globally, is influenced by many climatic and socioeconomic factors. However, the relative contributions of these factors on a global scale are unclear. Methods: We randomly selected 94 islands stratified by socioeconomic and geographic characteristics. With a Bayesian model, we assessed factors contributing to the probability of islands having a history of any dengue outbreaks and of having frequent outbreaks. Results: Minimum temperature was strongly associated with suitability for DENV transmission. Islands with a minimum monthly temperature of greater than 14.8A degrees C (95% CI: 12.4-16.6A degrees C) were predicted to be suitable for DENV transmission. Increased population size and precipitation were associated with increased outbreak frequency, but did not capture all of the variability. Predictions for 48 testing islands verified these findings. Conclusions: This analysis clarified two key components of DENV ecology: minimum temperature was the most important determinant of suitability; and endemicity was more likely in areas with high precipitation and large, but not necessarily dense, populations. Wealth and connectivity, in contrast, had no discernable effects. This model adds to our knowledge of global determinants of dengue risk and provides a basis for understanding the ecology of dengue endemicity. C1 [Feldstein, Leora R.; Brownstein, John S.] Boston Childrens Hosp, Childrens Hosp Informat Program, Boston, MA 02215 USA. [Feldstein, Leora R.] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Ctr Stat & Quantitat Infect Dis, Seattle, WA 98104 USA. [Brownstein, John S.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02215 USA. [Brady, Oliver J.; Hay, Simon I.] Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Oxford OX1 3PS, England. [Hay, Simon I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Johansson, Michael A.] CDC, Dengue Branch, Div Vector Borne Dis, San Juan, PR 00920 USA. RP Johansson, MA (reprint author), CDC, Dengue Branch, Div Vector Borne Dis, 1324 Calle Canada, San Juan, PR 00920 USA. EM mjohansson@cdc.gov RI Hay, Simon/F-8967-2015; OI Hay, Simon/0000-0002-0611-7272; Brady, Oliver/0000-0002-3235-2129 FU National Institutes of Health, National Library of Medicine [R01LM010812]; Wellcome Trust [095066]; Bill & Melinda Gates Foundation [OPP1093011]; RAPIDD program of the Science & Technology Directorate; Department of Homeland Security, National Institutes of Health; Fogarty International Center; Biotechnology and Biological Sciences Research Council FX This work is supported by the National Institutes of Health, National Library of Medicine [R01LM010812 to JSB], the Wellcome Trust [#095066 to SIH], the Bill & Melinda Gates Foundation [#OPP1093011 to SIH and JSB], RAPIDD program of the Science & Technology Directorate (to SIH), the Department of Homeland Security, National Institutes of Health (to SIH), the Fogarty International Center (to SIH), and the Biotechnology and Biological Sciences Research Council (to OJB). NR 63 TC 3 Z9 3 U1 2 U2 17 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0035-9203 EI 1878-3503 J9 T ROY SOC TROP MED H JI Trans. Roy. Soc. Trop. Med. Hyg. PD MAY PY 2015 VL 109 IS 5 BP 303 EP 312 DI 10.1093/trstmh/trv012 PG 10 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA CJ1YB UT WOS:000355279900004 PM 25771261 ER PT J AU Craig, BM Mitchell, SA AF Craig, B. M. Mitchell, S. A. TI THE VALUE WOMEN PLACE ON MENOPAUSAL SYMPTOM RELIEF SO VALUE IN HEALTH LA English DT Meeting Abstract C1 [Craig, B. M.] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Mitchell, S. A.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-3015 EI 1524-4733 J9 VALUE HEALTH JI Value Health PD MAY PY 2015 VL 18 IS 3 MA PIH36 BP A109 EP A109 PG 1 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA CI1IZ UT WOS:000354498501305 ER PT J AU Dhankhar, P Isupov, T Araujo-Vilar, D Brown, R Garg, A Jae, DH Miller, VR Oral, E Stratton, A AF Dhankhar, P. Isupov, T. Araujo-Vilar, D. Brown, R. Garg, A. Jae, D. H. Miller, Rangel, V Oral, E. Stratton, A. TI ESTIMATING QUALITY OF LIFE OF PATIENTS WITH LIPODYSTROPHY SO VALUE IN HEALTH LA English DT Meeting Abstract C1 [Dhankhar, P.; Isupov, T.] AstraZeneca, Ft Washington, MD USA. [Araujo-Vilar, D.] Univ Santiago de Compostela, Santiago De Compostela, Spain. [Brown, R.] NIDDKD, Bethesda, MD USA. [Garg, A.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Jae, D. H.; Miller, Rangel, V] Patient Crossroads, La Jolla, CA USA. [Oral, E.] Univ Michigan, Ann Arbor, MI 48109 USA. [Stratton, A.] Lipodystrophy United, Los Lunas, NM USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-3015 EI 1524-4733 J9 VALUE HEALTH JI Value Health PD MAY PY 2015 VL 18 IS 3 MA PSY7 BP A292 EP A292 PG 1 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA CI1IZ UT WOS:000354498505059 ER PT J AU Guy, G Ekwueme, D Li, R Rim, SH Yabroff, KR AF Guy, G. Ekwueme, D. Li, R. Rim, S. H. Yabroff, K. R. TI THE IMPACT OF CHRONIC CONDITIONS ON THE ECONOMIC BURDEN OF CANCER SURVIVORSHIP IN THE UNITED STATES SO VALUE IN HEALTH LA English DT Meeting Abstract C1 [Guy, G.; Li, R.; Rim, S. H.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Ekwueme, D.] Ctr Dis Control & Prevent, Chamblee, GA USA. [Yabroff, K. R.] NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-3015 EI 1524-4733 J9 VALUE HEALTH JI Value Health PD MAY PY 2015 VL 18 IS 3 MA CN1 BP A5 EP A5 PG 1 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA CI1IZ UT WOS:000354498500022 ER PT J AU Howard, K Clifford, S Powers, JH Saretsky, T Hoffmann, SC Llorens, L Talbot, GH Cimms, TA AF Howard, K. Clifford, S. Powers, J. H. Saretsky, T. Hoffmann, S. C. Llorens, L. Talbot, G. H. Cimms, T. A. TI COMMUNITY-ACQUIRED BACTERIAL PNEUMONIA (CABP): DEVELOPMENT OF A NEW PATIENT-REPORTED OUTCOME (PRO) FNIH BIOMARKERS CONSORTIUM CABP ABSI PROJECT TEAM '3 SO VALUE IN HEALTH LA English DT Meeting Abstract C1 [Howard, K.; Clifford, S.; Saretsky, T.] ICON Clin Res LLC, San Francisco, CA USA. [Powers, J. H.] Leidos Biomed Res Inc, North Bethesda, MD USA. [Hoffmann, S. C.] Fdn Natl Inst Hlth, Bethesda, MD USA. [Llorens, L.] Llorens Consultants, Alameda, CA USA. [Talbot, G. H.] Talbot Advisors LLC, Anna Maria, FL USA. [Cimms, T. A.] AstraZeneca, Gaithersburg, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-3015 EI 1524-4733 J9 VALUE HEALTH JI Value Health PD MAY PY 2015 VL 18 IS 3 MA PIN84 BP A242 EP A242 PG 1 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA CI1IZ UT WOS:000354498504096 ER PT J AU Powers, JH Howard, K Saretsky, T Clifford, S Hoffmann, SC Talbot, GH Cimms, TA Llorens, L AF Powers, J. H. Howard, K. Saretsky, T. Clifford, S. Hoffmann, S. C. Talbot, G. H. Cimms, T. A. Llorens, L. TI DEVELOPMENT OF A PATIENT-REPORTED OUTCOME INSTRUMENT (SKINFECT-PRO) TO STANDARDIZE AND QUALIFY SYMPTOMS OF ACUTE BACTERIAL SKIN AND SKIN STRUCTURE INFECTION (ABSSSI) FNIH BIOMARKERS CONSORTIUM CABP ABSI PROJECT TEAM '3 SO VALUE IN HEALTH LA English DT Meeting Abstract C1 [Powers, J. H.] Leidos Biomed Res Inc, North Bethesda, MD USA. [Howard, K.; Saretsky, T.; Clifford, S.] ICON Clin Res LLC, San Francisco, CA USA. [Hoffmann, S. C.] Fdn Natl Inst Hlth, Bethesda, MD USA. [Talbot, G. H.] Talbot Advisors LLC, Anna Maria, FL USA. [Cimms, T. A.] AstraZeneca, Gaithersburg, MD USA. [Llorens, L.] Llorens Consultants, Alameda, CA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-3015 EI 1524-4733 J9 VALUE HEALTH JI Value Health PD MAY PY 2015 VL 18 IS 3 MA PIN83 BP A242 EP A242 PG 1 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA CI1IZ UT WOS:000354498504095 ER PT J AU Saretsky, T Clifford, S Hoffmann, SC Powers, JH Talbot, GH Howard, K AF Saretsky, T. Clifford, S. Hoffmann, S. C. Powers, J. H. Talbot, G. H. Howard, K. TI SIGNS, SYMPTOMS, AND EXISTING PATIENT-REPORTED OUTCOME (PRO) MEASURES IN HOSPITAL-ACQUIRED BACTERIAL PNEUMONIA (HABP): A COMPREHENSIVE LITERATURE REVIEW SO VALUE IN HEALTH LA English DT Meeting Abstract C1 [Saretsky, T.; Clifford, S.; Howard, K.] ICON Clin Res LLC, San Francisco, CA USA. [Hoffmann, S. C.] Fdn Natl Inst Hlth, Bethesda, MD USA. [Powers, J. H.] Leidos Biomed Res Inc, North Bethesda, MD USA. [Talbot, G. H.] Talbot Advisors LLC, Anna Maria, FL USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-3015 EI 1524-4733 J9 VALUE HEALTH JI Value Health PD MAY PY 2015 VL 18 IS 3 MA PIN86 BP A242 EP A242 PG 1 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA CI1IZ UT WOS:000354498504098 ER PT J AU Hasson, SA Fogel, AI Wang, CX MacArthur, R Guha, R Heman-Ackah, S Martin, S Youle, RJ Inglese, J AF Hasson, Samuel A. Fogel, Adam I. Wang, Chunxin MacArthur, Ryan Guha, Rajarshi Heman-Ackah, Sabrina Martin, Scott Youle, Richard J. Inglese, James TI Chemogenomic Profiling of Endogenous PARK2 Expression Using a Genome-Edited Coincidence Reporter SO ACS CHEMICAL BIOLOGY LA English DT Article ID PARKINSONS-DISEASE; DRUG DISCOVERY; GENE ASSAYS; MITOCHONDRIA; INHIBITORS; NEURONS; PROTEIN; CELLS; PINK1; JNK AB Parkin, an E3 ubiquitin ligase, is a central mediator of mitochondrial quality control and is linked to familial forms of Parkinson's disease (PD). Removal of dysfunctional mitochondria from the cell by Parkin is thought to be neuroprotective, and pharmacologically increasing Parkin levels may be a novel therapeutic approach. We used genome-editing to integrate a coincidence reporter into the PARK2 gene locus of a neuroblastoma-derived cell line and developed a quantitative high-throughput screening (qHTS) assay capable of accurately detecting subtle compound-mediated increases in endogenous PARK2 expression. Interrogation of a chemogenomic library revealed diverse chemical classes that up-regulate the PARK2 transcript, including epigenetic agents, drugs controlling cholesterol biosynthesis, and JNK inhibitors. Use of the coincidence reporter eliminated wasted time pursuing reporter-biased false positives accounting for similar to 2/3 of the actives and, coupled with titration-based screening, greatly improves the efficiency of compound selection. This approach represents a strategy to revitalize reporter-gene assays for drug discovery. C1 [Hasson, Samuel A.; Fogel, Adam I.; Wang, Chunxin; Youle, Richard J.] NINDS, Bethesda, MD 20892 USA. [MacArthur, Ryan; Guha, Rajarshi; Martin, Scott; Inglese, James] Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Heman-Ackah, Sabrina] NIAMSD, NIH, Ctr Regenerat Med, Bethesda, MD 20892 USA. [Inglese, James] NHGRI, NIH, Bethesda, MD 20892 USA. RP Inglese, J (reprint author), Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. EM jinglese@mail.nih.gov RI Wang, Chunxin/B-9312-2016 OI Wang, Chunxin/0000-0001-6015-6806 FU NCATS; NINDS; Michael J. Fox Foundation [8966] FX We thank C. Eggers, B. Binkowski, and K. Kopish of Promega for development of the NanoDLR assay reagent used in this study; P. Dranchak, B. Wright, M. Mendez and the members of the NCATS engineering core for assistance with liquid handling systems; M. Rao's lab at NIH for assistance with iPS neuron cultures; and D. Leja for graphic abstract artwork. This work was supported by the NCATS (J.I.) and NINDS (R.J.Y.) intramural program and The Michael J. Fox Foundation (grant 8966 awarded to J.I. and R.J.Y.). NR 51 TC 8 Z9 8 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 EI 1554-8937 J9 ACS CHEM BIOL JI ACS Chem. Biol. PD MAY PY 2015 VL 10 IS 5 BP 1188 EP 1197 DI 10.1021/cb5010417 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CI6XL UT WOS:000354907400005 PM 25689131 ER PT J AU Willette, AA Johnson, SC Birdsill, AC Sager, MA Christian, B Baker, LD Craft, S Oh, J Statz, E Hermann, BP Jonaitis, EM Koscik, RL La Rue, A Asthana, S Bendlin, BB AF Willette, Auriel A. Johnson, Sterling C. Birdsill, Alex C. Sager, Mark A. Christian, Bradley Baker, Laura D. Craft, Suzanne Oh, Jennifer Statz, Eric Hermann, Bruce P. Jonaitis, Erin M. Koscik, Rebecca L. La Rue, Asenath Asthana, Sanjay Bendlin, Barbara B. TI Insulin resistance predicts brain amyloid deposition in late middle-aged adults SO ALZHEIMERS & DEMENTIA LA English DT Article DE Insulin resistance; Amyloid; PiB; Alzheimer's disease; Cognitively normal; Prefrontal ID PITTSBURGH COMPOUND-B; GRAY-MATTER VOLUME; ALZHEIMERS-DISEASE; DEGRADING ENZYME; IN-VIVO; RISK; PET; METABOLISM; COGNITION; DEMENTIA AB Background: Insulin resistance (IR) increases Alzheimer's disease (AD) risk. IR is related to greater amyloid burden post-mortem and increased deposition within areas affected by early AD. No studies have examined if IR is associated with an in vivo index of amyloid in the human brain in late middle-aged participants at risk for AD. Methods: Asymptomatic, late middle-aged adults (N = 186) from the Wisconsin Registry for Alzheimer's Prevention underwent [C-11]Pittsburgh compound B (PiB) positron emission tomography. The cross-sectional design tested the interaction between insulin resistance and glycemic status on PiB distribution volume ratio in three regions of interest (frontal, parietal, and temporal). Results: In participants with normoglycemia but not hyperglycemia, higher insulin resistance corresponded to higher PiB uptake in frontal and temporal areas, reflecting increased amyloirl deposition. Conclusions: This is the first human study to demonstrate that insulin resistance may contribute to amyloid deposition in brain regions affected by AD. (C) 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved. C1 [Willette, Auriel A.; Johnson, Sterling C.; Birdsill, Alex C.; Oh, Jennifer; Statz, Eric; Asthana, Sanjay; Bendlin, Barbara B.] William S Middleton Mem Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, Madison, WI 53705 USA. [Willette, Auriel A.; Johnson, Sterling C.; Birdsill, Alex C.; Sager, Mark A.; Oh, Jennifer; Statz, Eric; Hermann, Bruce P.; Asthana, Sanjay; Bendlin, Barbara B.] Univ Wisconsin, Sch Med & Publ Hlth, Wisconsin Alzheimers Dis Res Ctr, Madison, WI USA. [Willette, Auriel A.] NIA, Lab Neurosci, Baltimore, MD 21224 USA. [Johnson, Sterling C.] Univ Wisconsin, Waisman Lab Brain Imaging & Behav, Madison, WI USA. [Johnson, Sterling C.; Sager, Mark A.; Hermann, Bruce P.; Jonaitis, Erin M.; Koscik, Rebecca L.; La Rue, Asenath] Wisconsin Sch Med & Publ Hlth, Wisconsin Alzheimers Inst, Madison, WI USA. [Christian, Bradley] Wisconsin Sch Med & Publ Hlth, Dept Med Phys, Madison, WI USA. [Baker, Laura D.; Craft, Suzanne] Wake Forest Sch Med, Dept Internal Med, Winston Salem, NC USA. RP Bendlin, BB (reprint author), William S Middleton Mem Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, Madison, WI 53705 USA. EM bbb@medicine.wisc.edu OI Bendlin, Barbara/0000-0002-0580-9875 FU National Institute on Aging [R01 AG027161]; ADRC [P50 AG033514, R01 AG021155]; University of Wisconsin Institute for Clinical and Translational Research; National Center for Research Resources/National Institutes of Health Clinical and Translational Science Award [1UL1RR025011]; National Center for Research Resources, United States National Institutes of Health FX The authors gratefully acknowledge Nancy Davenport-Sis, Amy Hawley, Sandra Harding, Caitlin Cleary, Chuck Illingworth, and the support of researchers and staff at the Waisman Center, University of Wisconsin Madison, for their assistance in recruitment, data collection, and data analysis. Above all, we wish to thank our dedicated volunteers for their participation in this research. This project was supported by the National Institute on Aging (R01 AG027161 [M.A.S.], ADRC P50 AG033514 [S.A.], R01 AG021155 [S.C.J.], the University of Wisconsin Institute for Clinical and Translational Research, funded through a National Center for Research Resources/National Institutes of Health Clinical and Translational Science Award, 1UL1RR025011, a program of the National Center for Research Resources, United States National Institutes of Health), and by the facilities and resources at the Geriatric Research, Education, and Clinical Center (GRECC) of the William S. Middleton Memorial Veterans Hospital, Madison, WI. Barbara Bendlin had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. NR 40 TC 31 Z9 31 U1 6 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1552-5260 EI 1552-5279 J9 ALZHEIMERS DEMENT JI Alzheimers. Dement. PD MAY PY 2015 VL 11 IS 5 BP 504 EP 510 DI 10.1016/j.jalz.2014.03.011 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA CI8KN UT WOS:000355021300005 PM 25043908 ER PT J AU Kang, HS Kim, J Jang, SG Kwon, SY Park, YS Green, JE Kim, HK Ro, J AF Kang, Han Sung Kim, Joseph Jang, Sang-Geun Kwon, Sun Young Park, Young Soo Green, Jeffrey E. Kim, Hark Kyun Ro, Jungsil TI MicroRNA Signature for HER2-positive Breast and Gastric Cancer (vol 34, pg 3807, 2014) SO ANTICANCER RESEARCH LA English DT Correction C1 [Kang, Han Sung; Jang, Sang-Geun; Kim, Hark Kyun; Ro, Jungsil] Natl Canc Ctr, Goyang, South Korea. [Kim, Joseph] ROK Army, Seoul, South Korea. [Kwon, Sun Young] Keimyung Univ, Dongsan Med Ctr, Daegu, South Korea. [Park, Young Soo] Asan Med Ctr, Seoul, South Korea. [Green, Jeffrey E.] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. RP Kang, HS (reprint author), Natl Canc Ctr, Goyang, South Korea. NR 1 TC 0 Z9 0 U1 0 U2 0 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0250-7005 EI 1791-7530 J9 ANTICANCER RES JI Anticancer Res. PD MAY PY 2015 VL 35 IS 5 BP 3109 EP 3109 PG 1 WC Oncology SC Oncology GA CH8DU UT WOS:000354267200083 ER PT J AU Kang, HS Kim, J Jang, SG Kwon, SY Park, YS Green, JE Kim, HK Ro, J AF Kang, Han Sung Kim, Joseph Jang, Sang-Geun Kwon, Sun Young Park, Young Soo Green, Jeffrey E. Kim, Hark Kyun Ro, Jungsil TI Gene Expression Analysis for Evaluation of Potential Biomarkers in Hepatocellular Carcinoma (vol 35, pg 2021, 2015) SO ANTICANCER RESEARCH LA English DT Correction C1 [Kang, Han Sung; Jang, Sang-Geun; Kim, Hark Kyun; Ro, Jungsil] Natl Canc Ctr, Goyang, South Korea. [Kim, Joseph] ROK Army, Seoul, South Korea. [Kwon, Sun Young] Keimyung Univ, Dongsan Med Ctr, Daegu, South Korea. [Park, Young Soo] Asan Med Ctr, Seoul, South Korea. [Green, Jeffrey E.] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. RP Kang, HS (reprint author), Natl Canc Ctr, Goyang, South Korea. NR 1 TC 0 Z9 0 U1 1 U2 1 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0250-7005 EI 1791-7530 J9 ANTICANCER RES JI Anticancer Res. PD MAY PY 2015 VL 35 IS 5 BP 3109 EP 3109 PG 1 WC Oncology SC Oncology GA CH8DU UT WOS:000354267200085 ER PT J AU Kang, HS Kim, J Jang, SG Kwon, SY Park, YS Green, JE Kim, HK Ro, J AF Kang, Han Sung Kim, Joseph Jang, Sang-Geun Kwon, Sun Young Park, Young Soo Green, Jeffrey E. Kim, Hark Kyun Ro, Jungsil TI PSCA and MUC1 Gene Polymorphisms Are Linked with Gastric Cancer and Pre-malignant Gastric Conditions (vol 34, pg 7167, 2014) SO ANTICANCER RESEARCH LA English DT Correction C1 [Kang, Han Sung; Jang, Sang-Geun; Kim, Hark Kyun; Ro, Jungsil] Natl Canc Ctr, Goyang, South Korea. [Kim, Joseph] ROK Army, Seoul, South Korea. [Kwon, Sun Young] Keimyung Univ, Dongsan Med Ctr, Daegu, South Korea. [Park, Young Soo] Asan Med Ctr, Seoul, South Korea. [Green, Jeffrey E.] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. RP Kang, HS (reprint author), Natl Canc Ctr, Goyang, South Korea. NR 1 TC 0 Z9 0 U1 1 U2 1 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0250-7005 EI 1791-7530 J9 ANTICANCER RES JI Anticancer Res. PD MAY PY 2015 VL 35 IS 5 BP 3109 EP 3109 PG 1 WC Oncology SC Oncology GA CH8DU UT WOS:000354267200084 ER PT J AU Nelson, KB AF Nelson, K. B. TI Birth Defects and Cerebral Palsy SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Nelson, K. B.] NINDS, NIH, Bethesda, MD 20892 USA. [Nelson, K. B.] Childrens Natl Med Ctr, Washington, DC 20010 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 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2015 VL 103 IS 5 MA S32 BP 365 EP 365 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA CI4SD UT WOS:000354742400034 ER PT J AU Li, Q Kappil, M Li, A Dassanayke, PS Darrah, T Friedman, AE Friedman, M Lambertini, L Landrigan, P Stodgell, CJ Aagaard, K Schadt, E Murray, J Clark, EB Dole, N Culhane, J Swanson, J Varner, M Moye, J Kasten, C Miller, RK Chen, J AF Li, Q. Kappil, M. Li, A. Dassanayke, P. S. Darrah, T. Friedman, A. E. Friedman, M. Lambertini, L. Landrigan, P. Stodgell, C. J. Aagaard, K. Schadt, E. Murray, J. Clark, E. B. Dole, N. Culhane, J. Swanson, J. Varner, M. Moye, J. Kasten, C. Miller, R. K. Chen, J. CA Natl Childrens Study Consortium TI Exploring the Associations between microRNA Expression Profiles and Environmental Pollutants in Human Placenta from the National Children's Study (NCS) SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Li, Q.; Kappil, M.; Lambertini, L.; Landrigan, P.; Schadt, E.; Chen, J.] Mt Sinai, Ichan Sch Med, New York, NY USA. [Li, A.; Dassanayke, P. S.] Univ Illinois, Chicago, IL USA. [Darrah, T.] Ohio State Univ, Columbus, OH 43210 USA. [Friedman, A. E.; Friedman, M.; Stodgell, C. J.; Miller, R. K.] Univ Rochester, Sch Med & Dent, Rochester, NY USA. [Aagaard, K.] Baylor Sch Med, Houston, TX USA. [Murray, J.] Univ Iowa, Iowa City, IA USA. [Clark, E. B.; Varner, M.] Univ Utah, Salt Lake City, UT USA. [Dole, N.] Univ N Carolina, Chapel Hill, NC USA. [Culhane, J.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Swanson, J.] Univ Calif Irvine, Irvine, CA USA. [Moye, J.; Natl Childrens Study Consortium] NIH, Bethesda, MD 20892 USA. [Kasten, C.] US FDA, Silver Spring, MD USA. OI Li, An/0000-0002-8476-8783 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 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2015 VL 103 IS 5 MA 5 BP 378 EP 378 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA CI4SD UT WOS:000354742400055 ER PT J AU Tucker, D Chappell, V Rodriguez, K Yao, H Fenton, S AF Tucker, D. Chappell, V Rodriguez, K. Yao, H. Fenton, S. TI Altered Mammary Gland Development As a Result of In Utero Exposure to a High and Low Dose of Inorganic Arsenic (iAs) in the CD-1 Mouse SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Tucker, D.] Univ N Carolina, Chapel Hill, NC USA. [Tucker, D.; Chappell, V; Fenton, S.] NIEHS, Div NTP, NTPL, Res Triangle Pk, NC 27709 USA. [Rodriguez, K.; Yao, H.] NIEHS, Lab Reprod & Dev Toxicol, DIR, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2015 VL 103 IS 5 MA 9 BP 380 EP 380 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA CI4SD UT WOS:000354742400058 ER PT J AU Kleinstreuer, NC Allen, D Casey, WM AF Kleinstreuer, N. C. Allen, D. Casey, W. M. TI Using ToxCast/Tox21 HTS Assays to Assess Endocrine Disruption SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Kleinstreuer, N. C.; Allen, D.] NICEATM, ILS, Res Triangle Pk, NC USA. [Casey, W. M.] NIEHS, NIH, DNTP, NICEATM, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 2 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2015 VL 103 IS 5 MA 39 BP 395 EP 395 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA CI4SD UT WOS:000354742400088 ER PT J AU Hagen, EM Sicko, R Kay, DE Rigler, S Dimopoulos, A Warmerdam, B Ahmad, S Doleman, M Fan, R Romitti, P Browne, M Caggana, M Brody, L Shaw, G Jelliffe-Pawlowski, L Mills, JL AF Hagen, E. M. Sicko, R. Kay, D. E. Rigler, S. Dimopoulos, A. Warmerdam, B. Ahmad, S. Doleman, M. Fan, R. Romitti, P. Browne, M. Caggana, M. Brody, L. Shaw, G. Jelliffe-Pawlowski, L. Mills, J. L. TI Copy-Number Variant Analysis of Classic Heterotaxy Highlights the Importance of Body Patterning Pathways SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Hagen, E. M.; Dimopoulos, A.; Fan, R.; Mills, J. L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Sicko, R.; Kay, D. E.; Browne, M.; Caggana, M.] New York State Dept Hlth, Albany, NY USA. [Rigler, S.] Naval Med Ctr, Portsmouth, VA USA. [Warmerdam, B.; Ahmad, S.; Doleman, M.] Calif CBDMP, Sacramento, CA USA. [Romitti, P.] Univ Iowa, Iowa City, IA USA. [Brody, L.] NHGRI, Bethesda, MD 20892 USA. [Shaw, G.] Stanford Univ, Stanford, CA 94305 USA. [Jelliffe-Pawlowski, L.] Calif Genet Dis Screening Program, Sacramento, CA USA. [Jelliffe-Pawlowski, L.] Univ Calif San Francisco, San Francisco, CA 94143 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 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2015 VL 103 IS 5 MA 50 BP 400 EP 400 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA CI4SD UT WOS:000354742400099 ER PT J AU Dimopoulos, A Sicko, R Kay, DE Rigler, S Fan, R Romitti, P Browne, M Druschel, C Caggana, M Brody, L Mills, JL AF Dimopoulos, A. Sicko, R. Kay, D. E. Rigler, S. Fan, R. Romitti, P. Browne, M. Druschel, C. Caggana, M. Brody, L. Mills, J. L. TI Copy Number Variants in a Population-Based Investigation of Klippel Trenaunay Weber Syndrome SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Dimopoulos, A.; Fan, R.; Mills, J. L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Sicko, R.; Kay, D. E.; Browne, M.; Druschel, C.; Caggana, M.] New York State Dept Hlth, Albany, NY USA. [Rigler, S.] Naval Med Ctr Porthsmouth, Porthsmouth, VA USA. [Romitti, P.] Univ Iowa, Iowa City, IA USA. [Brody, L.] NHGRI, 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 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2015 VL 103 IS 5 MA 51 BP 401 EP 401 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA CI4SD UT WOS:000354742400100 ER PT J AU Dimopoulos, A Sicko, R Kay, DE Rigler, S Fan, R Romitti, P Browne, M Druschel, C Caggana, M Brody, L Mills, JL AF Dimopoulos, A. Sicko, R. Kay, D. E. Rigler, S. Fan, R. Romitti, P. Browne, M. Druschel, C. Caggana, M. Brody, L. Mills, J. L. TI Copy Number Variants in a Population-Based Investigation of Hypoplastic Right Heart Syndrome SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Dimopoulos, A.; Fan, R.; Mills, J. L.] NICHD, Bethesda, MD USA. [Sicko, R.; Kay, D. E.; Browne, M.; Druschel, C.; Caggana, M.] New York State Dept Hlth, Albany, NY USA. [Rigler, S.] Naval Med Ctr Portsmouth, Portsmouth, VA USA. [Romitti, P.] Univ Iowa, Iowa City, IA USA. [Brody, L.] NHGRI, 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 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2015 VL 103 IS 5 MA P11 BP 407 EP 407 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA CI4SD UT WOS:000354742400111 ER PT J AU Dimopoulos, A Sicko, R Kay, DE Boghossian, N Rigler, S Hagen, EM Fan, R Romitti, P Browne, M Druschel, C Caggana, M Brody, L Mills, JL AF Dimopoulos, A. Sicko, R. Kay, D. E. Boghossian, N. Rigler, S. Hagen, E. M. Fan, R. Romitti, P. Browne, M. Druschel, C. Caggana, M. Brody, L. Mills, J. L. TI Rare Copy Number Variants in a Population-Based Investigation of Isolated Tracheoesophageal Fistula and Esophageal Atresia SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Dimopoulos, A.; Hagen, E. M.; Fan, R.; Mills, J. L.] NICHD, Bethesda, MD USA. [Sicko, R.; Kay, D. E.; Browne, M.; Druschel, C.; Caggana, M.] New York State Dept Hlth, Albany, NY USA. [Boghossian, N.] Univ S Carolina, Columbia, SC 29208 USA. [Rigler, S.] Naval Med Ctr Portsmouth, Portsmouth, VA USA. [Romitti, P.] Univ Iowa, Iowa City, IA USA. [Brody, L.] NHGRI, 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 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2015 VL 103 IS 5 MA P12 BP 408 EP 408 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA CI4SD UT WOS:000354742400112 ER PT J AU Mcintyre, S Blair, E Badawi, N Nelson, KB AF Mcintyre, S. Blair, E. Badawi, N. Nelson, K. B. TI Birth Defects and Growth Restriction in Term and Late Preterm Singletons with Cerebral Palsy or Neonatal Death SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Mcintyre, S.; Badawi, N.] Cerebral Palsy Alliance, Sydney, NSW, Australia. [Badawi, N.] Univ Sydney, Sydney, NSW 2006, Australia. [Mcintyre, S.; Blair, E.] Telethon Kids Inst, Perth, WA, Australia. [Nelson, K. B.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Nelson, K. B.] NINDS, NIH, Bethesda, MD 20892 USA. RI Badawi, Nadia/A-3179-2014 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 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2015 VL 103 IS 5 MA P37 BP 420 EP 420 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA CI4SD UT WOS:000354742400137 ER PT J AU Nakamura, N Inselman, AL Han, T Fuscoe, JC Harrouk, W Mcintyre, B Foster, PM Hansen, DK AF Nakamura, N. Inselman, A. L. Han, T. Fuscoe, J. C. Harrouk, W. Mcintyre, B. Foster, P. M. Hansen, D. K. TI Gene Expression Changes in the Testes and Prostate from Postnatal Day 30 Sprague-Dawley Rats Dosed Perinatally with Oxybenzone-Preliminary Study SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Nakamura, N.; Inselman, A. L.; Han, T.; Fuscoe, J. C.; Hansen, D. K.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Harrouk, W.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Mcintyre, B.; Foster, P. M.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 1 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2015 VL 103 IS 5 MA P40 BP 422 EP 422 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA CI4SD UT WOS:000354742400140 ER PT J AU Lim, H Agopian, AJ Whitehead, LW Beasley, CW Langlois, PH Emery, RJ Waller, DK AF Lim, H. Agopian, A. J. Whitehead, L. W. Beasley, C. W. Langlois, P. H. Emery, R. J. Waller, D. K. TI Maternal Occupational Exposure to Ionizing Radiation and Major Structural Birth Defects SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Lim, H.] NCI, Bethesda, MD 20892 USA. [Agopian, A. J.; Whitehead, L. W.; Emery, R. J.; Waller, D. K.] Univ Texas Houston, Sch Publ Hlth, Houston, TX USA. [Beasley, C. W.] Univ Texas Houston, Sch Med, Houston, TX USA. [Langlois, P. H.] Texas Dept State Hlth Serv, Birth Defects Epidemiol & Surveillance Branch, Austin, TX 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 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2015 VL 103 IS 5 MA P53 BP 428 EP 428 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA CI4SD UT WOS:000354742400153 ER PT J AU Fried, NT Oshinsky, ML AF Fried, N. T. Oshinsky, M. L. TI Mitochondrial dysfunction in the development of trigeminal sensitivity in a rat model of chronic migraine and the spontaneous trigeminal allodynia rat model SO CEPHALALGIA LA English DT Meeting Abstract CT International Headache Congress of the International-Headache-Society CY MAY 14-17, 2015 CL Valencia, SPAIN SP Int Headache Soc C1 [Fried, N. T.] Thomas Jefferson Univ, Neurosci, Philadelphia, PA 19107 USA. [Oshinsky, M. L.] NIH, Neurosci, Philadelphia, PA 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 0333-1024 EI 1468-2982 J9 CEPHALALGIA JI Cephalalgia PD MAY PY 2015 VL 35 SU 6 MA PO488 BP 256 EP 256 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CI2FC UT WOS:000354559400502 ER PT J AU Chen, P Denniston, A Hannes, S Tucker, W Wei, L Liu, BY Xiao, TJ Hirani, S Li, ZY Jawad, S Si, H Lee, RWJ Sen, HN Nussenblatt, RB AF Chen, Ping Denniston, Alastair Hannes, Susan Tucker, William Wei, Lai Liu, Baoying Xiao, Tiaojiang Hirani, Sima Li, Zhiyu Jawad, Shaynna Si, Han Lee, Richard W. J. Sen, H. Nida Nussenblatt, Robert B. TI Increased CD1c(+) mDC1 with mature phenotype regulated by TNF alpha-p38 MAPK in autoimmune ocular inflammatory disease SO CLINICAL IMMUNOLOGY LA English DT Article DE CD1c(+) mDC1; CD1c(hi) mDC1 subpopulation; Antigen uptake; TNF alpha; p38 MAPK; Autoimmune uveitis ID AUTOREACTIVE T-CELLS; BLOOD DENDRITIC CELLS; AQUEOUS-HUMOR; NONINFECTIOUS UVEITIS; PERIPHERAL-BLOOD; ANTIGEN PRESENTATION; ACTIVATION; SERUM; MATURATION; TH17 AB In this study we investigated the role of blood CD1c(+) myeloid dendritic cells 1 (mDC1), a key mDC subtype, in patients with autoimmune uveitis. We observed a significant increase of blood CD1c(+) mDC1 in uveitis patients. The increased CD1c(+) mDC1 exhibited high HLADR expression and less antigen uptake. CD1c(+) mDC1 were divided into two subpopulations. CD1c(hi) mDC1 subpopulation showed less antigen uptake and higher HLADR expression compared to CD1c(lo) mDC1 subpopulation. Importantly, the CD1c(hi) mDC1 subpopulation was increased in uveitis patients. In vitro, mature monocyte-derived dendritic cells (MoDCs), characterized by lower levels of antigen uptake, induced more CD4(+)CD62L(-) T helper cell proliferation. The mature phenotype and function of CD1c(+) mDC1 were regulated by TNF alpha via a p38 MAPK-dependent pathway. These data show that alterations in the systemic immune response are involved in the pathogenesis of autoimmune uveitis and invite the therapeutic possibility of attenuating uveitis by manipulating blood CD1c(+) mDC1. Published by Elsevier Inc. C1 [Chen, Ping; Hannes, Susan; Tucker, William; Wei, Lai; Liu, Baoying; Hirani, Sima; Li, Zhiyu; Jawad, Shaynna; Si, Han; Sen, H. Nida; Nussenblatt, Robert B.] NEI, Immunol Lab, NIH, Rockville, MD 20892 USA. [Denniston, Alastair] Univ Hosp Birmingham NHSFT, Queen Elizabeth Hosp Birmingham, Dept Ophthalmol, Birmingham B15 2WB, W Midlands, England. [Denniston, Alastair] Univ Birmingham, Ctr Translat Inflammat Res, Birmingham B15 2TT, W Midlands, England. [Xiao, Tiaojiang] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Lee, Richard W. J.] Univ Bristol, Dept Clin Sci, Bristol, Avon, England. RP Nussenblatt, RB (reprint author), NEI, NIH, 9000 Rockville Pike,Bldg 10-10N109, Rockville, MD 20892 USA. EM nussenblattr@netnih.gov RI Lee, Richard/A-3116-2017 OI Lee, Richard/0000-0002-9480-6843 FU Intramural Research Program of the NIH, National Institute of Eye (NEI) FX This project was supported by the Intramural Research Program of the NIH, National Institute of Eye (NEI). We thank Rafael Villasmil and Julie Laux for assisting on flow cytometry. We thank Cheng-Rong Yu and Fan Pan for critical reading of the manuscript. NR 43 TC 2 Z9 3 U1 2 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 EI 1521-7035 J9 CLIN IMMUNOL JI Clin. Immunol. PD MAY PY 2015 VL 158 IS 1 BP 35 EP 46 DI 10.1016/j.clim.2015.03.002 PG 12 WC Immunology SC Immunology GA CI2QR UT WOS:000354592600005 PM 25784146 ER PT J AU Hsu, CY Ballard, S Batlle, D Bonventre, JV Bottinger, EP Feldman, HI Klein, JB Coresh, J Eckfeldt, JH Inker, LA Kimmel, PL Kusek, JW Liu, KD Mauer, M Mifflin, TE Molitch, ME Nelsestuen, GL Rebholz, CM Rovin, BH Sabbisetti, VS Van Eyk, JE Vasan, RS Waikar, SS Whitehead, KM Nelson, RG AF Hsu, Chi-Yuan Ballard, Shawn Batlle, Daniel Bonventre, Joseph V. Boettinger, Erwin P. Feldman, Harold I. Klein, Jon B. Coresh, Josef Eckfeldt, John H. Inker, Lesley A. Kimmel, Paul L. Kusek, John W. Liu, Kathleen D. Mauer, Michael Mifflin, Theodore E. Molitch, Mark E. Nelsestuen, Gary L. Rebholz, Casey M. Rovin, Brad H. Sabbisetti, Venkata S. Van Eyk, Jennifer E. Vasan, Ramachandran S. Waikar, Sushrut S. Whitehead, Krista M. Nelson, Robert G. CA CKD Biomarkers Consortium TI Cross-Disciplinary Biomarkers Research: Lessons Learned by the CKD Biomarkers Consortium SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article AB Significant advances are needed to improve the diagnosis, prognosis, and management of persons with CKD. Discovery of new biomarkers and improvements in currently available biomarkers for CKD hold great promise to achieve these necessary advances. Interest in identification and evaluation of biomarkers for CKD has increased substantially over the past decade. In 2009, the National Institute of Diabetes and Digestive and Kidney Diseases established the CKD Biomarkers Consortium (http://www.ckdbiomarkersconsortium.org/), a multidisciplinary, collaborative study group located at over a dozen academic medical centers. The main objective of the consortium was to evaluate new biomarkers for purposes related to CKD in established prospective cohorts, including those enriched for CKD. During the first 5 years of the consortium, many insights into collaborative biomarker research were gained that may be useful to other investigators involved in biomarkers research. These lessons learned are outlined in this Special Feature and include a wide range of issues related to biospecimen collection, storage, and retrieval, and the internal and external quality assessment of laboratories that performed the assays. The authors propose that investigations involving biomarker discovery and validation are greatly enhanced by establishing and following explicit quality control metrics, including the use of blind replicate and proficiency samples, by carefully considering the conditions under which specimens are collected, handled, and stored, and by conducting pilot and feasibility studies when there are concerns about the condition of the specimens or the accuracy or reproducibility of the assays. C1 [Hsu, Chi-Yuan; Liu, Kathleen D.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Ballard, Shawn; Feldman, Harold I.; Mifflin, Theodore E.; Whitehead, Krista M.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Batlle, Daniel; Molitch, Mark E.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Bonventre, Joseph V.; Sabbisetti, Venkata S.; Waikar, Sushrut S.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Boettinger, Erwin P.] Mt Sinai Hosp, New York, NY 10029 USA. [Klein, Jon B.] Univ Louisville, Louisville, KY 40292 USA. [Coresh, Josef; Rebholz, Casey M.; Van Eyk, Jennifer E.] Johns Hopkins Univ, Baltimore, MD USA. [Eckfeldt, John H.; Mauer, Michael; Nelsestuen, Gary L.] Univ Minnesota, Minneapolis, MN USA. [Inker, Lesley A.] Tufts Med Ctr, Boston, MA USA. [Kimmel, Paul L.; Kusek, John W.] NIDDK, NIH, Bethesda, MD 20892 USA. [Rovin, Brad H.] Ohio State Univ, Columbus, OH 43210 USA. [Van Eyk, Jennifer E.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Vasan, Ramachandran S.] Boston Univ, Boston, MA 02215 USA. [Nelson, Robert G.] NIDDK, NIH, Phoenix, AZ 85014 USA. RP Nelson, RG (reprint author), NIDDK, NIH, 1550 E Indian Sch Rd, Phoenix, AZ 85014 USA. EM rnelson@nih.gov OI Hewitt, Stephen/0000-0001-8283-1788; Ramachandran, Vasan/0000-0001-7357-5970; daehn, ilse/0000-0001-9915-5376 FU CKD Biomarkers Consortium - NIDDK [U01-DK85649, U01-DK085673, U01-DK085660, U01-DK085688, U01-DK085651, U01-DK085689]; NIDDK FX This work was supported by the CKD Biomarkers Consortium funded by the NIDDK (U01-DK85649, U01-DK085673, U01-DK085660, U01-DK085688, U01-DK085651 and U01-DK085689) and by the Intramural Research Program of the NIDDK. NR 6 TC 4 Z9 4 U1 4 U2 6 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 EI 1555-905X J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD MAY PY 2015 VL 10 IS 5 BP 894 EP 902 DI 10.2215/CJN.11541114 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA CH6KG UT WOS:000354144900022 PM 25739849 ER PT J AU Ghosh, A Dzeng, E Cheng, MJ AF Ghosh, Amrita Dzeng, Elizabeth Cheng, M. Jennifer TI Interaction of Palliative Care and Primary Care SO CLINICS IN GERIATRIC MEDICINE LA English DT Article DE Primary palliative care; Specialty palliative care; Referral ID METRICS CONSENSUS RECOMMENDATIONS; CELL LUNG-CANCER; OLDER-ADULTS; LIFE; CONSULTATION; PATIENT; INTEGRATION; DEPRESSION; ONCOLOGY; HOSPICE AB Primary care physicians are often the first medical providers patients seek out, and are in an excellent position to provide primary palliative care. Primary palliative care encompasses basic skills including basic evaluation and management of symptoms and discussions about goals of care and advance care planning. Specialty palliative care consultation complements primary care by assisting with complex psychosocial-spiritual patient and family situations. This article reviews primary palliative care skill sets and criteria for when to consider referring patients to specialty palliative care and hospice services. C1 [Ghosh, Amrita; Cheng, M. Jennifer] NIH, Pain & Palliat Care Serv, Ctr Clin, Bethesda, MD 20892 USA. [Dzeng, Elizabeth] Johns Hopkins Univ, Sch Med, Program Palliat Care, Div Gen Internal Med, Baltimore, MD 21287 USA. [Dzeng, Elizabeth] Univ Cambridge, Sch Clin Med, Cambridge CB2 0SR, England. RP Cheng, MJ (reprint author), NIH, Pain & Palliat Care Serv, Ctr Clin, 10 Ctr Dr, Bethesda, MD 20892 USA. EM mok-chung.cheng@nih.gov NR 67 TC 2 Z9 2 U1 2 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0749-0690 EI 1879-8853 J9 CLIN GERIATR MED JI Clin. Geriatr. Med. PD MAY PY 2015 VL 31 IS 2 BP 207 EP + DI 10.1016/j.cger.2015.01.001 PG 14 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA CI4WC UT WOS:000354753600005 PM 25920056 ER PT J AU McGlynn, KA Petrick, JL London, WT AF McGlynn, Katherine A. Petrick, Jessica L. London, W. Thomas TI Global Epidemiology of Hepatocellular Carcinoma An Emphasis on Demographic and Regional Variability SO CLINICS IN LIVER DISEASE LA English DT Article DE Incidence; Hepatitis B virus; Hepatitis C virus; Aflatoxin; Diabetes; Alcohol; Chemoprevention; Coffee ID HEPATITIS-C-VIRUS; CHRONIC LIVER-DISEASE; B-VIRUS; UNITED-STATES; FOLLOW-UP; DIABETES-MELLITUS; CANCER-RISK; ANTIDIABETIC MEDICATIONS; AFLATOXIN EXPOSURE; VIRAL-HEPATITIS AB Liver cancer is the second leading cause of global cancer mortality. The major risk factors for hepatocellular carcinoma (HOC) are being addressed with success by prevention efforts. Vaccination against hepatitis B virus has reduced incidence of HOC in Taiwan and is partly responsible for lower rates in China. New infections with hepatitis C virus are low in developed countries because of prevention of posttransfusion infections and reduced exposure to HCV by drug users. Aflatoxin exposure has been reduced by better grain storage and dietary changes. Obesity, metabolic syndrome, and diabetes are increasing in developed and developing countries and will lead to more cases of HCC. C1 [McGlynn, Katherine A.; Petrick, Jessica L.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [London, W. Thomas] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. RP McGlynn, KA (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM mcglynnk@mail.nih.gov FU National Institutes of Health Intramural Research Program FX This work was supported by funding of the National Institutes of Health Intramural Research Program. NR 114 TC 48 Z9 51 U1 5 U2 17 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1089-3261 EI 1557-8224 J9 CLIN LIVER DIS JI Clin. Liver Dis. PD MAY PY 2015 VL 19 IS 2 BP 223 EP + DI 10.1016/j.cld.2015.01.001 PG 17 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CI3RG UT WOS:000354664500002 PM 25921660 ER PT J AU Palmer, J Chai, XY Martin, PJ Weisdorf, D Inamoto, Y Pidala, J Jagasia, M Pavletic, S Cutler, C Vogelsang, G Arai, S Flowers, MED Lee, SJ AF Palmer, Jeanne Chai, Xiaoyu Martin, Paul J. Weisdorf, Daniel Inamoto, Yoshihiro Pidala, Joseph Jagasia, Madan Pavletic, Steven Cutler, Corey Vogelsang, Georgia Arai, Sally Flowers, Mary E. D. Lee, Stephanie J. TI Failure-free survival in a prospective cohort of patients with chronic graft-versus-host disease SO HAEMATOLOGICA LA English DT Article ID STEM-CELL TRANSPLANTATION; LONG-TERM SURVIVAL; CHRONIC GVHD; SYSTEMIC TREATMENT; LATE DEATHS; CONSORTIUM; PROGNOSIS; SEVERITY; CRITERIA; OUTCOMES AB Failure-free survival, defined as the absence of relapse, non-relapse mortality or addition of another systemic therapy, has been proposed as a potential endpoint for clinical trials, but its use has only been reported for single-center studies. We measured failure-free survival in a prospective observational cohort of patients (n= 575) with both newly diagnosed and existing chronic graft-versus-host disease from nine centers. Failure was observed in 389 (68%) patients during the observation period. The median follow up of all patients was 30.9 months, and the median failure-free survival was 9.8 months (63% at 6 months, 45% at 1 year, and 29% at 2 years). Of the variables measured at enrollment, ten were associated with shorter failure-free survival: higher National Institutes of Health 0-3 skin score, higher National Institutes of Health 0-3 gastrointestinal score, worse range of motion summary score, lower forced vital capacity (%), bronchiolitis obliterans syndrome, worse quality of life, moderate to severe hepatic dysfunction, absence of treatment for gastric acid, female donor for male recipient, and prior grade II-IV acute graft-versus-host disease. Addition of a new systemic treatment, the major cause of failure, was associated with an increased risk of subsequent non-relapse mortality (hazard ratio= 2.06, 95% confidence interval: 1.29-3.32; P< 0.003) and decreased survival (hazard ratio= 1.51, 95% confidence interval: 1.04-2.18; P< 0.03). These results show that fewer than half of patients on systemic treatment will be failure-free survivors at 1 year, and fewer than a third will reach 2 years without experiencing failure. Better treatments are needed for chronic graft-versus-host disease. C1 [Palmer, Jeanne] Mayo Clin Phoenix, Div Hematol Oncol, Phoenix, AZ 85054 USA. [Chai, Xiaoyu; Martin, Paul J.; Inamoto, Yoshihiro; Flowers, Mary E. D.; Lee, Stephanie J.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Weisdorf, Daniel] Univ Minnesota, Blood & Marrow Transplant Program, Minneapolis, MN USA. [Inamoto, Yoshihiro] Natl Canc Ctr, Div Hematopoiet Stem Cell Transplantat, Tokyo, Japan. [Pidala, Joseph] Univ S Florida, H Lee Moffitt Canc Ctr, Blood & Marrow Transplantat, Tampa, FL 33682 USA. [Jagasia, Madan] Vanderbilt Univ, Med Ctr, Hematol & Stem Cell Transplant Program, Nashville, TN USA. [Pavletic, Steven] NCI, NIH, Bethesda, MD 20892 USA. [Cutler, Corey] Dana Farber Canc Inst, Hematol Malignancies, Boston, MA 02115 USA. [Vogelsang, Georgia] Johns Hopkins Univ Hosp, Div Oncol, Baltimore, MD 21287 USA. [Arai, Sally] Stanford Univ, Med Ctr, Div Blood & Marrow Transplantat, Stanford, CA 94305 USA. RP Palmer, J (reprint author), Mayo Clin Phoenix, Div Hematol Oncol, Phoenix, AZ 85054 USA. EM palmer.jeanne@mayo.edu FU Chronic GVHD Consortium, National Institutes of Health Rare Disease Clinical Research Network [U54 CA163438]; [CA118953] FX The Chronic GVHD Consortium (U54 CA163438) is a part of the National Institutes of Health Rare Disease Clinical Research Network, supported through a collaboration between the Office of Rare Diseases Research, NCATS, and the National Cancer Institute. This work was also supported by CA118953 NR 23 TC 7 Z9 7 U1 0 U2 0 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD MAY PY 2015 VL 100 IS 5 BP 690 EP 695 DI 10.3324/haematol.2014.117283 PG 6 WC Hematology SC Hematology GA CI5IE UT WOS:000354788000035 PM 25715403 ER PT J AU Feng, XM Scheinberg, P Young, NS AF Feng, Xingmin Scheinberg, Phillip Young, Neal S. TI Answer to "Confounding effect of cyclosporine dosing when comparing horse and rabbit antithymocyte globulin in patients with severe aplastic anemia" SO HAEMATOLOGICA LA English DT Letter DE aplastic anemia; cyclosporine; pharmacokinetics; regulatory T cells C1 [Feng, Xingmin; Scheinberg, Phillip; Young, Neal S.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Feng, XM (reprint author), NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. EM fengx2@nhlbi.nih.gov NR 4 TC 0 Z9 0 U1 0 U2 2 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD MAY PY 2015 VL 100 IS 5 DI 10.3324/haematol.2015.124446 PG 1 WC Hematology SC Hematology GA CI5IE UT WOS:000354788000016 ER PT J AU Faucette, AN Gonik, B Chen, K AF Faucette, Azure N. Gonik, Bernard Chen, Kang TI Reply: Maternal vaccination: moving the science forward SO HUMAN REPRODUCTION UPDATE LA English DT Letter ID LYMPHOCYTE SUBSETS; NORMAL-PREGNANCY; B-LYMPHOPOIESIS; CELLS; WOMEN; IMMUNOGENICITY; IMMUNIZATION; POSTPARTUM; DIPHTHERIA; INCREASE C1 [Faucette, Azure N.; Gonik, Bernard; Chen, Kang] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Faucette, Azure N.; Chen, Kang] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Detroit, MI 48201 USA. [Chen, Kang] Barbara Ann Karmanos Canc Inst, Tumor Biol & Microenvironm Program, Detroit, MI 48201 USA. [Chen, Kang] Wayne State Univ, Sch Med, Dept Immunol & Microbiol, Detroit, MI 48201 USA. [Chen, Kang] Wayne State Univ, Dept Oncol, Detroit, MI 48201 USA. [Chen, Kang] NIAID, Mucosal Immunol Studies Team, NIH, Bethesda, MD 20892 USA. RP Chen, K (reprint author), Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48201 USA. EM kchen@med.wayne.edu NR 15 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1355-4786 EI 1460-2369 J9 HUM REPROD UPDATE JI Hum. Reprod. Update PD MAY-JUN PY 2015 VL 21 IS 3 BP 408 EP 409 DI 10.1093/humupd/dmv010 PG 3 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CI5JW UT WOS:000354792800012 PM 25712340 ER PT J AU Kant, AK Whitley, MI Graubard, BI AF Kant, A. K. Whitley, M. I. Graubard, B. I. TI Away from home meals: associations with biomarkers of chronic disease and dietary intake in American adults, NHANES 2005-2010 SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article ID FAST-FOOD CONSUMPTION; RESTAURANT MENUS; 14-YEAR TRENDS; WEIGHT STATUS; YOUNG-ADULTS; RISK-FACTORS; US ADULTS; OUTCOMES; OBESITY; QUALITY AB BACKGROUND: Away from home (AFH) meals are known to be energy-dense and of poor diet quality. Both direct and indirect exposure (for example, neighborhood restaurant density) to AFH meals have been implicated as contributors to higher body weight and adverse health outcomes. OBJECTIVE: To examine the association of frequency of eating AFH and fast-food meals with biomarkers of chronic disease and dietary intake. DESIGN: This cross-sectional study used frequency of AFH and fast-food meal and biomarker data from the NHANES 2005-2010. Information on weekly frequency of AFH and fast-food meals was collected via questionnaire during the household interview. The metabolic biomarkers examined included body mass index (BMI), serum cholesterol (total, high-density lipoprotein (HDL) and low-density lipoprotein (LDL)), triglycerides, glycohemoglobin and fasting glucose (n = 8314, age >= 20, National Health and Nutrition Examination Surveys (NHANES) 2007-2010). Biomarkers of dietary exposure included serum concentrations of vitamins A, D, E, C, B-6, B-12, folate and carotenoids (n = 4162; 2005-2006). Multiple linear and logistic regression methods adjusted for complex survey methodology and covariates. RESULTS: American adults reported a mean of 3.9 (95% confidence interval 3.7, 4.0) AFH and 1.8 (1.6, 1.9) fast-food meals/week. Over 50% of adults reported >= 3 AFH and > 35% reported >= 2 fast-food meals/week. The mean BMI of more frequent AFH or fast-food meal reporters was higher (P-trend <= 0.0004). Serum concentrations of total, LDL and HDL-cholesterol were related inversely with frequency of AFH meals (P < 0.05). Frequencies of fast-food meals and serum HDL-cholesterol were also related inversely (P = 0.0001). Serum concentrations of all examined micronutrients (except vitamin A and lycopene) declined with increasing frequency of AFH meals (P < 0.05); women and >= 50-year olds were at higher risk. CONCLUSIONS: Reporters of frequent AFH and fast-food meals had higher BMI and lower concentrations of HDL-cholesterol; however, profiles of other biomarkers did not indicate higher metabolic risk. However, the serum concentrations of nutrients with mostly plant foods as sources declined with increasing AFH meal frequency. C1 [Kant, A. K.; Whitley, M. I.] CUNY Queens Coll, Dept Family Nutr & Exercise Sci, Flushing, NY 11367 USA. [Graubard, B. I.] NCI, Div Canc Epidemiol & Genet, Biostat Branch, NIH, Bethesda, MD USA. RP Kant, AK (reprint author), CUNY Queens Coll, Dept Family Nutr & Exercise Sci, Remsen Hall,Room 306E, Flushing, NY 11367 USA. EM ashima.kant@qc.cuny.edu FU intramural research program of the Department of Health and Human Services, National Cancer Institute, NIH FX We thank Lisa L Kahle for expert SAS and SUDAAN programming support and David Check, NCI, NIH, for graphic support. This study was supported in part by the intramural research program of the Department of Health and Human Services, National Cancer Institute, NIH (BIG). NR 43 TC 8 Z9 8 U1 1 U2 13 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 EI 1476-5497 J9 INT J OBESITY JI Int. J. Obes. PD MAY PY 2015 VL 39 IS 5 BP 820 EP 827 DI 10.1038/ijo.2014.183 PG 8 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA CH5TJ UT WOS:000354097900014 PM 25319744 ER PT J AU Rinaldi, C Schmidt, T Situ, AJ Johnson, JO Lee, PR Chen, KL Bott, LC Fado, R Harmison, GH Parodi, S Grunseich, C Renvoise, B Biesecker, LG De Michele, G Santorelli, FM Filla, A Stevanin, G Durr, A Brice, A Casals, N Traynor, BJ Blackstone, C Ulmer, TS Fischbeck, KH AF Rinaldi, Carlo Schmidt, Thomas Situ, Alan J. Johnson, Janel O. Lee, Philip R. Chen, Ke-lian Bott, Laura C. Fado, Rut Harmison, George H. Parodi, Sara Grunseich, Christopher Renvoise, Benoit Biesecker, Leslie G. De Michele, Giuseppe Santorelli, Filippo M. Filla, Alessandro Stevanin, Giovanni Duerr, Alexandra Brice, Alexis Casals, Nuria Traynor, Bryan J. Blackstone, Craig Ulmer, Tobias S. Fischbeck, Kenneth H. TI Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia SO JAMA NEUROLOGY LA English DT Article ID CARNITINE PALMITOYLTRANSFERASE 1A; ENDOPLASMIC-RETICULUM; ISOFORM DEFICIENCY; TROYER-SYNDROME; PROTEIN; MECHANISMS; ATLASTIN; NEURONS; GTPASES; LETHAL AB IMPORTANCE The family of genes implicated in hereditary spastic paraplegias (HSPs) is quickly expanding, mostly owing to the widespread availability of next-generation DNA sequencing methods. Nevertheless, a genetic diagnosis remains unavailable for many patients. OBJECTIVE To identify the genetic cause for a novel form of pure autosomal dominant HSP. DESIGN, SETTING, AND PARTICIPANTS We examined and followed up with a family presenting to a tertiary referral center for evaluation of HSP for a decade until August 2014. Whole-exome sequencing was performed in 4 patients from the same family and was integrated with linkage analysis. Sanger sequencing was used to confirm the presence of the candidate variant in the remaining affected and unaffected members of the family and screen the additional patients with HSP. Five affected and 6 unaffected participants from a 3-generation family with pure adult-onset autosomal dominant HSP of unknown genetic origin were included. Additionally, 163 unrelated participants with pure HSP of unknown genetic cause were screened. MAIN OUTCOME AND MEASURE Mutation in the neuronal isoform of carnitine palmitoyl-transferase (CPT1C) gene. RESULTS We identified the nucleotide substitution c.109C>T in exon 3 of CPT1C, which determined the base substitution of an evolutionarily conserved Cys residue for an Arg in the gene product. This variant strictly cosegregated with the disease phenotype and was absent in online single-nucleotide polymorphism databases and in 712 additional exomes of control participants. We showed that CPT1C, which localizes to the endoplasmic reticulum, is expressed in motor neurons and interacts with atlastin-1, an endoplasmic reticulum protein encoded by the ATL1 gene known to be mutated in pure HSPs. The mutation, as indicated by nuclear magnetic resonance spectroscopy studies, alters the protein conformation and reduces the mean (SD) number (213.0 [46.99] vs 81.9 [14.2]; P < .01) and size (0.29 [0.01] vs 0.26 [0.01]; P < .05) of lipid droplets on overexpression in cells. We also observed a reduction of mean (SD) lipid droplets in primary cortical neurons isolated from Cpt1c(-/-) mice as compared with wild-type mice (1.0 [0.12] vs 0.44 [0.05]; P < .001), suggesting a dominant negative mechanism for the mutation. CONCLUSIONS AND RELEVANCE This study expands the genetics of autosomal dominant HSP and is the first, to our knowledge, to link mutation in CPT1C with a human disease. The association of the CPT1C mutation with changes in lipid droplet biogenesis supports a role for altered lipid-mediated signal transduction in HSP pathogenesis. C1 [Rinaldi, Carlo; Chen, Ke-lian; Bott, Laura C.; Harmison, George H.; Parodi, Sara; Grunseich, Christopher; Renvoise, Benoit; Blackstone, Craig; Fischbeck, Kenneth H.] NINDS, Porter Neurosci Res Ctr, Neurogenet Branch, Bethesda, MD 20892 USA. [Schmidt, Thomas; Situ, Alan J.; Ulmer, Tobias S.] Univ So Calif, Keck Sch Med, Zilkha Neurogenet Inst, Dept Biochem & Mol Biol, Los Angeles, CA 90033 USA. [Johnson, Janel O.; Traynor, Bryan J.] NIA, Neuromuscular Dis Res Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Lee, Philip R.] Eunice Kennedy Shriver Natl Inst Child & Human De, Sect Nervous Syst Dev & Plast, NIH, Bethesda, MD 20892 USA. [Bott, Laura C.] Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden. [Fado, Rut; Casals, Nuria] Univ Int Catalunya, Fac Med & Ciencies Salut, Dept Basic Sci, Sant Cugat Del Valles, Spain. [Fado, Rut; Casals, Nuria] CIBER Fisiopatol Obesidad & Nutr, Sant Cugat Del Valles, Spain. [Parodi, Sara] Ist Italiano Tecnol, Dept Neurosci & Brain Technol, Genoa, Italy. [Biesecker, Leslie G.] NHGRI, Genet Dis Res Branch, Bethesda, MD 20892 USA. [Biesecker, Leslie G.] Natl Inst Hlth Intramural Sequencing Ctr, NIH, Bethesda, MD USA. [De Michele, Giuseppe; Filla, Alessandro] Univ Naples Federico II, Dept Neurosci Reprod Sci & Odontostomatol, Naples, Italy. [Santorelli, Filippo M.] Ist Ricovero & Cura Carattere Sci Stella Maris, Neurogenet, Pisa, Italy. [Stevanin, Giovanni; Duerr, Alexandra; Brice, Alexis] Inst Cerveau & Moelle Epiniere, Paris, France. [Stevanin, Giovanni] Ecole Prat Hautes Etudes HeSam Univ, Inst Cerveau & Moelle Epiniere, Neurogenet Lab, Grp Hosp Pitie Salpetriere, Paris, France. [Stevanin, Giovanni; Duerr, Alexandra; Brice, Alexis] Univ Paris 06, Sorbonne Univ, Inst Cerveau & Moelle Epiniere, Paris, France. [Duerr, Alexandra; Brice, Alexis] AP HP, Dept Genet, Grp Hosp Pitie Salpetriere, Paris, France. RP Rinaldi, C (reprint author), NINDS, Porter Neurosci Res Ctr, Neurogenet Branch, 35 Convent Dr,MSC 3705,Bldg 35,Room 2A-1012, Bethesda, MD 20892 USA. EM rinaldic@ninds.nih.gov RI Stevanin, Giovanni/E-5038-2016; OI Casals, Nuria/0000-0002-6719-4300; Stevanin, Giovanni/0000-0001-9368-8657 FU National Institutes of Health, National Institute of Neurological Disorders and Stroke; National Institute on Aging [Z01-AG000949-02]; European Union; Investissements d'avenir [ANR-10-IAIHU-06]; French Agency for Research; Division of Intramural Research of the National Institute of Child Health and Human Development FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke, grant Z01-AG000949-02 from the National Institute on Aging (Drs Traynor and Johnson), the European Union's Seventh Framework Programme for Research (Dr Brice), grant ANR-10-IAIHU-06 from the Investissements d'avenir (Drs Brice and Durr), and the French Agency for Research (Dr Stevanin). Dr Lee is supported by funds from the Division of Intramural Research of the National Institute of Child Health and Human Development. NR 37 TC 7 Z9 8 U1 0 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6149 EI 2168-6157 J9 JAMA NEUROL JI JAMA Neurol. PD MAY PY 2015 VL 72 IS 5 BP 561 EP 570 DI 10.1001/jamaneurol.2014.4769 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA CH9MY UT WOS:000354361000014 PM 25751282 ER PT J AU Pandey, S Byler, DL Hallett, M AF Pandey, Sanjay Byler, Debra L. Hallett, Mark TI Defining the Eye-of-the-Tiger Sign Reply SO JAMA NEUROLOGY LA English DT Letter ID KINASE-ASSOCIATED NEURODEGENERATION C1 [Pandey, Sanjay; Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. [Pandey, Sanjay] Govind Ballabh Pant Hosp, New Delhi, India. [Byler, Debra L.] Penn State Coll Med, Dept Pediat, Hershey, PA USA. [Byler, Debra L.] Penn State Coll Med, Dept Neurol, Hershey, PA USA. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, NIH, 10 Ctr Dr,MSC1428,Bldg 10,Room 7D37, Bethesda, MD 20892 USA. EM hallettm@ninds.nih.gov NR 5 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6149 EI 2168-6157 J9 JAMA NEUROL JI JAMA Neurol. PD MAY PY 2015 VL 72 IS 5 BP 606 EP 607 DI 10.1001/jamaneurol.2015.0144 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA CH9MY UT WOS:000354361000024 PM 25961179 ER PT J AU Bresnahan, M Hornig, M Schultz, AF Gunnes, N Hirtz, D Lie, KK Magnus, P Reichborn-Kjennerud, T Roth, C Schjolberg, S Stoltenberg, C Suren, P Susser, E Lipkin, WI AF Bresnahan, Michaeline Hornig, Mady Schultz, Andrew F. Gunnes, Nina Hirtz, Deborah Lie, Kari Kveim Magnus, Per Reichborn-Kjennerud, Ted Roth, Christine Schjolberg, Synnve Stoltenberg, Camilla Suren, Pal Susser, Ezra Lipkin, W. Ian TI Association of Maternal Report of Infant and Toddler Gastrointestinal Symptoms With Autism Evidence From a Prospective Birth Cohort SO JAMA PSYCHIATRY LA English DT Article ID SPECTRUM DISORDER; YOUNG-CHILDREN; LANGUAGE DELAY; SEROTONIN; INDIVIDUALS; DYSFUNCTION; MET; DIAGNOSIS; PATTERNS; SYSTEM AB IMPORTANCE Gastrointestinal (GI) comorbidities are frequently described in association with autism spectrum disorder (ASD). However, the prevalence of GI disturbances and the age at which such problems first appear are unclear, and their specificity for ASD compared with other neurodevelopmental disorders is uncertain. OBJECTIVE To compare maternal report of GI symptoms during the first 3 years of life in children with ASD, developmental delay (DD), and typical development (TD). DESIGN, SETTING, AND PARTICIPANTS This large prospective cohort study consists of participants in the Norwegian Mother and Child Cohort Study. During a 10-year period (January 1, 1999, through December 31, 2008), women throughout Norway were recruited at the first prenatal ultrasonographic visit (approximately 18 weeks' gestation). The study enrolled 95 278 mothers, 75 248 fathers, and 114 516 children. Our analyses are based on MoBa data released through October 1, 2013, and NPR diagnoses registered through December 31, 2012, and include children born from January 1, 2002, through December 31, 2008, with completed age 18- and 36-month questionnaires. EXPOSURES We defined 3 groups of children: children with ASD (n = 195), children with DD and delayed language and/or motor development (n = 4636), and children with TD (n = 40 295). MAIN OUTCOMES AND MEASURES The GI symptoms were based on maternal report of constipation, diarrhea, and food allergy/intolerance. RESULTS Children with ASD were at significantly increased odds of maternally reported constipation (adjusted odds ratio [aOR], 2.7; 95% CI, 1.9-3.8; P < .001) and food allergy/intolerance (aOR, 1.7; 95% CI, 1.1-2.6; P = .01) in the 6- to 18-month-old age period and diarrhea (aOR, 2.3; 95% CI, 1.5-3.6; P < .001), constipation (aOR, 1.6; 95% CI, 1.2-2.3; P < .01), and food allergy/intolerance (aOR, 2.0; 95% CI, 1.3-3.1; P < .01) in the 18- to 36-month-old age period compared with children with TD. Similar results for these symptom categories were observed in comparisons with children with DD, but ORs were slightly lower. Mothers of children with ASD were significantly more likely to report 1 or more GI symptom in either the 6- to 18-month or the 18-to 36-month-old age period and more than twice as likely to report at least 1 GI symptom in both age periods compared with mothers of children with TD or DD. CONCLUSIONS AND RELEVANCE In this large prospective cohort, maternally reported GI symptoms are more common and more often persistent during the first 3 years of life in children with ASD than in children with TD or DD. C1 [Bresnahan, Michaeline; Hornig, Mady; Roth, Christine; Susser, Ezra; Lipkin, W. Ian] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA. [Bresnahan, Michaeline; Susser, Ezra] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Hornig, Mady; Schultz, Andrew F.; Lipkin, W. Ian] Columbia Univ, Mailman Sch Publ Hlth, Ctr Infect & Immun, New York, NY 10032 USA. [Gunnes, Nina; Lie, Kari Kveim; Magnus, Per; Reichborn-Kjennerud, Ted; Roth, Christine; Schjolberg, Synnve; Stoltenberg, Camilla; Suren, Pal] Norwegian Inst Publ Hlth, Oslo, Norway. [Hirtz, Deborah] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. [Reichborn-Kjennerud, Ted] Univ Oslo, Fac Med, Inst Clin Med, Oslo, Norway. RP Bresnahan, M (reprint author), Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, 622W168th St,Room 809, New York, NY 10032 USA. EM mab29@columbia.edu FU Norwegian Ministry of Health and Care Services; Norwegian Ministry of Education and Research; National Institutes of Health/National Institute of Neurological Disorders and Stroke [NS47537]; Research Council of Norway [189457, 190694, 196452] FX This research was supported by the Norwegian Ministry of Health and Care Services, the Norwegian Ministry of Education and Research, and grant NS47537 from the National Institutes of Health/National Institute of Neurological Disorders and Stroke (Dr Lipkin). The following grants from the Research Council of Norway have provided support to the ABC in general: 189457, 190694, and 196452. NR 42 TC 14 Z9 15 U1 4 U2 12 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-622X EI 2168-6238 J9 JAMA PSYCHIAT JI JAMA Psychiatry PD MAY PY 2015 VL 72 IS 5 BP 466 EP 474 DI 10.1001/jamapsychiatry.2014.3034 PG 9 WC Psychiatry SC Psychiatry GA CH6YC UT WOS:000354181400009 PM 25806498 ER PT J AU Desrosiers, NA Ramaekers, JG Chauchard, E Gorelick, DA Huestis, MA AF Desrosiers, Nathalie A. Ramaekers, Johannes G. Chauchard, Emeline Gorelick, David A. Huestis, Marilyn A. TI Smoked Cannabis' Psychomotor and Neurocognitive Effects in Occasional and Frequent Smokers SO JOURNAL OF ANALYTICAL TOXICOLOGY LA English DT Article ID RISK TASK BART; N-BACK TASK; WORKING-MEMORY; WHOLE-BLOOD; DRIVING PERFORMANCE; CONSTRUCT-VALIDITY; THC INTOXICATION; DECISION-MAKING; ACUTE MARIJUANA; ORAL FLUID AB Delta 9-Tetrahydrocannabinol (THC), the primary psychoactive constituent in cannabis, impairs psychomotor performance, cognition and driving ability; thus, driving under the influence of cannabis is a public safety concern. We documented cannabis' psychomotor, neurocognitive, subjective and physiological effects in occasional and frequent smokers to investigate potential differences between these smokers. Fourteen frequent (a parts per thousand yen4x/week) and 11 occasional (< 2x/week) cannabis smokers entered a secure research unit 19 h prior to smoking one 6.8% THC cigarette. Cognitive and psychomotor performance was evaluated with the critical tracking (CTT), divided attention (DAT), n-back (working memory) and Balloon Analog Risk (BART) (risk-taking) tasks at -1.75, 1.5, 3.5, 5.5 and 22.5 h after starting smoking. GLM (General Linear Model) repeated measures ANOVA was utilized to compare scores. Occasional smokers had significantly more difficulty compensating for CTT tracking error compared with frequent smokers 1.5 h after smoking. Divided attention performance declined significantly especially in occasional smokers, with session x group effects for tracking error, hits, false alarms and reaction time. Cannabis smoking did not elicit session x group effects on the n-back or BART. Controlled cannabis smoking impaired psychomotor function, more so in occasional smokers, suggesting some tolerance to psychomotor impairment in frequent users. These data have implications for cannabis-associated impairment in driving under the influence of cannabis cases. C1 [Desrosiers, Nathalie A.; Chauchard, Emeline; Gorelick, David A.; Huestis, Marilyn A.] NIDA IRP, Chem & Drug Metab Sect, Clin Pharmacol & Therapeut Res Branch, Baltimore, MD 21224 USA. [Desrosiers, Nathalie A.] Univ Maryland, Toxicol Program, Baltimore, MD 21201 USA. [Ramaekers, Johannes G.] Maastricht Univ, Fac Psychol & Neurosci, Dept Neuropsychol & Psychopharmacol, NL-6200 MD Maastricht, Netherlands. RP Huestis, MA (reprint author), NIDA IRP, Chem & Drug Metab Sect, Clin Pharmacol & Therapeut Res Branch, 251 Bayview Blvd,Suite 200 Room 05A-721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural Research Program, National Institute on Drug Abuse, NIH FX This research was funded by the Intramural Research Program, National Institute on Drug Abuse, NIH. NR 59 TC 11 Z9 11 U1 3 U2 21 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0146-4760 EI 1945-2403 J9 J ANAL TOXICOL JI J. Anal. Toxicol. PD MAY PY 2015 VL 39 IS 4 BP 251 EP 261 DI 10.1093/jat/bkv012 PG 11 WC Chemistry, Analytical; Toxicology SC Chemistry; Toxicology GA CI4DB UT WOS:000354695800001 PM 25745105 ER PT J AU Padmanabhan, R Taneyhill, LA AF Padmanabhan, Rangarajan Taneyhill, Lisa A. TI Cadherin-6B undergoes macropinocytosis and clathrin-mediated endocytosis during cranial neural crest cell EMT SO JOURNAL OF CELL SCIENCE LA English DT Article DE Cadherin; EMT; Neural crest; Macropinocytosis; Endocytosis ID EPITHELIAL-MESENCHYMAL TRANSITIONS; MICROVASCULAR ENDOTHELIAL-CELLS; P120 CATENIN; N-CADHERIN; BETA-CATENIN; VE-CADHERIN; DEPENDENT ENDOCYTOSIS; CONTACT INHIBITION; CYTOPLASMIC DOMAIN; ADHERENS JUNCTIONS AB The epithelial-to-mesenchymal transition (EMT) is important for the formation of migratory neural crest cells during development and is co-opted in human diseases such as cancer metastasis. Chick premigratory cranial neural crest cells lose intercellular contacts, mediated in part by Cadherin-6B (Cad6B), migrate extensively, and later form a variety of adult derivatives. Importantly, modulation of Cad6B is crucial for proper neural crest cell EMT. Although Cad6B possesses a long half-life, it is rapidly lost from premigratory neural crest cell membranes, suggesting the existence of post-translational mechanisms during EMT. We have identified a motif in the Cad6B cytoplasmic tail that enhances Cad6B internalization and reduces the stability of Cad6B upon its mutation. Furthermore, we demonstrate for the first time that Cad6B is removed from premigratory neural crest cells through cell surface internalization events that include clathrin-mediated endocytosis and macropinocytosis. Both of these processes are dependent upon the function of dynamin, and inhibition of Cad6B internalization abrogates neural crest cell EMT and migration. Collectively, our findings reveal the significance of post-translational events in controlling cadherins during neural crest cell EMT and migration. C1 [Padmanabhan, Rangarajan] NCI, NIH, Bethesda, MD 20892 USA. [Taneyhill, Lisa A.] Univ Maryland, Dept Anim & Avian Sci, College Pk, MD 20742 USA. RP Taneyhill, LA (reprint author), Univ Maryland, Dept Anim & Avian Sci, College Pk, MD 20742 USA. EM ltaney@umd.edu FU National Institutes of Health [R00HD055034]; Sigma Xi; University of Maryland FX This work was supported by the National Institutes of Health [grant number R00HD055034 to L.A.T.]; and a Sigma Xi Grants-In-Aid of Research and the University of Maryland Ann G. Wylie Dissertation Fellowship to R. P. Deposited in PMC for release after 12 months. NR 86 TC 5 Z9 5 U1 1 U2 4 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 MAY 1 PY 2015 VL 128 IS 9 BP 1773 EP 1786 DI 10.1242/jcs.164426 PG 14 WC Cell Biology SC Cell Biology GA CI6MI UT WOS:000354873100012 PM 25795298 ER PT J AU Niemela, J Kuehn, HS Kelly, C Zhang, MC Davies, J Melendez, J Dreiling, J Kleiner, D Calvo, K Oliveira, JB Rosenzweig, SD AF Niemela, Julie Kuehn, Hye Sun Kelly, Corin Zhang, Mingchang Davies, Joie Melendez, Jose Dreiling, Jennifer Kleiner, David Calvo, Katherine Oliveira, Joao B. Rosenzweig, Sergio D. TI Caspase-8 Deficiency Presenting as Late-Onset Multi-Organ Lymphocytic Infiltration with Granulomas in two Adult Siblings SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article DE Autoimmune lymphoproliferative syndrome (ALPS); lymphopenia; pulmonary hypertension; lung transplant; cranial palsy ID DNA-SEQUENCING DATA; ACTIVATION; FRAMEWORK; IMMUNITY AB Caspase-8 deficiency (CED) was originally described in 2002 in two pediatric patients presenting with clinical manifestations resembling autoimmune lymphoproliferative syndrome (ALPS) accompanied by infections, and T, B and NK cell defects. Since then, no new CED patients were published. Here we report two adult siblings (Pt1 and Pt2) presenting in their late thirties with pulmonary hypertension leading to lung transplant (Pt1), and a complex neurological disease leading to multiple cranial nerves palsies (Pt2) as their main manifestations. A thorough clinical and immunological evaluation was performed at the Primary Immunodeficiency Clinic at NIH, followed by whole exome sequencing. The patients had multiorgan lymphocytic infiltration and granulomas, as well as clinical signs of immune deficiency/ immune dysregulation. Both siblings carried homozygous mutations in CASP8, c.1096C > T, p.248R > W. This was the same mutation described on the previously published CED patients, to whom these new patients were likely distantly related. We report two new CED patients presenting during adulthood with life-threatening end-organ lymphocyte infiltrates affecting the lungs, liver, spleen, bone marrow and central nervous system. This phenotype broadens the clinical spectrum of manifestations associated with this disease and warrants the search of CASP8 mutations in other cohorts of patients. C1 [Niemela, Julie; Kuehn, Hye Sun; Zhang, Mingchang; Calvo, Katherine; Oliveira, Joao B.; Rosenzweig, Sergio D.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Kelly, Corin] NIAID, Lab Host Def, NIH, Bethesda, MD 20892 USA. [Davies, Joie] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Melendez, Jose] Baylor Sch Med, Houston, TX USA. [Dreiling, Jennifer; Kleiner, David] NCI, Dept Pathol, NIH, Bethesda, MD 20892 USA. [Rosenzweig, Sergio D.] NIAID, Primary Immunodeficiency Clin, NIH, Bethesda, MD 20892 USA. [Oliveira, Joao B.] Inst Med Integral Prof Fernando Figueira IMIP, Diretoria Pesquisa, BR-50070550 Recife, PE, Brazil. [Rosenzweig, Sergio D.] NIHCC, Serv Immunol, Dept Lab Med, Bethesda, MD 20892 USA. RP Oliveira, JB (reprint author), Inst Med Integral Prof Fernando Figueira IMIP, Diretoria Pesquisa, Rua Coelhos 300, BR-50070550 Recife, PE, Brazil. EM bosco.oliveira@imip.org.br; srosenzweig@cc.nih.gov OI Niemela, Julie/0000-0003-4197-3792 FU National Institutes of Health FX The content of this article 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. Supported by the Intramural Research Program of the National Institutes of Health. NR 16 TC 3 Z9 3 U1 1 U2 2 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD MAY PY 2015 VL 35 IS 4 BP 348 EP 355 DI 10.1007/s10875-015-0150-8 PG 8 WC Immunology SC Immunology GA CI5TW UT WOS:000354823700005 PM 25814141 ER PT J AU Otsu, M Yamada, M Nakajima, S Kida, M Maeyama, Y Hatano, N Toita, N Takezaki, S Okura, Y Kobayashi, R Matsumoto, Y Tatsuzawa, O Tsuchida, F Kato, S Kitagawa, M Mineno, J Hershfield, M Bali, P Candotti, F Onodera, M Kawamura, N Sakiyama, Y Ariga, T AF Otsu, Makoto Yamada, Masafumi Nakajima, Satoru Kida, Miyuki Maeyama, Yoshihiro Hatano, Norikazu Toita, Nariaki Takezaki, Shunichiro Okura, Yuka Kobayashi, Ryoji Matsumoto, Yoshinori Tatsuzawa, Osamu Tsuchida, Fumiko Kato, Shunichi Kitagawa, Masanari Mineno, Junichi Hershfield, Michael S. Bali, Pawan Candotti, Fabio Onodera, Masafumi Kawamura, Nobuaki Sakiyama, Yukio Ariga, Tadashi TI Outcomes in Two Japanese Adenosine Deaminase-Deficiency Patients Treated by Stem Cell Gene Therapy with No Cytoreductive Conditioning SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article DE Gene therapy; adenosine deaminase (ADA); severe combined immunodeficiency (SCID); primary immunodeficiency (PID); retroviral vector(s); hematopoietic stem cell(s) ID SEVERE COMBINED IMMUNODEFICIENCY; CHRONIC GRANULOMATOUS-DISEASE; ENZYME-REPLACEMENT THERAPY; PERIPHERAL-BLOOD LYMPHOCYTES; WISKOTT-ALDRICH-SYNDROME; BONE-MARROW-CELLS; HEMATOPOIETIC STEM; RETROVIRAL VECTORS; ADA DEFICIENCY; T-LYMPHOCYTES AB Objective We here describe treatment outcomes in two adenosine deaminase (ADA)-deficiency patients (pt) who received stem cell gene therapy (SCGT) with no cytoreductive conditioning. As this protocol has features distinct from those of other clinical trials, its results provide insights into SCGT for ADA deficiency. Patients and Methods Pt 1 was treated at age 4.7 years, whereas pt 2, who had previously received T-cell gene therapy, was treated at age 13 years. Bone marrow CD34(+) cells were harvested after enzyme replacement therapy (ERT) was withdrawn; following transduction of ADA cDNA by the gamma-retroviral vector GCsapM-ADA, they were administered intravenously. No cytoreductive conditioning, at present considered critical for therapeutic benefit, was given before cell infusion. Hematological/immunological reconstitution kinetics, levels of systemic detoxification, gene-marking levels, and proviral insertion sites in hematopoietic cells were assessed. Results Treatment was well tolerated, and no serious adverse events were observed. Engraftment of gene-modified repopulating cells was evidenced by the appearance and maintenance of peripheral lymphocytes expressing functional ADA. Systemic detoxification was moderately achieved, allowing temporary discontinuation of ERT for 6 and 10 years in pt 1 and pt 2, respectively. Recovery of immunity remained partial, with lymphocyte counts in pts 1 and 2, peaked at 408/mm(3) and 1248/mm(3), approximately 2 and 5 years after SCGT. Vector integration site analyses confirmed that hematopoiesis was reconstituted with a limited number of clones, some of which were shown to have myelo-lymphoid potential. Conclusions Outcomes in SCGT for ADA-SCID are described in the context of a unique protocol, which used neither ERT nor cytoreductive conditioning. Although proven safe, immune reconstitution was partial and temporary. Our results reiterate the importance of cytoreductive conditioning to ensure greater benefits from SCGT. C1 [Otsu, Makoto] Univ Tokyo, Inst Med Sci, Ctr Stem Cell Biol & Regenerat Med, Tokyo, Japan. [Yamada, Masafumi; Hatano, Norikazu; Toita, Nariaki; Takezaki, Shunichiro; Okura, Yuka; Kobayashi, Ryoji; Matsumoto, Yoshinori; Kawamura, Nobuaki; Sakiyama, Yukio; Ariga, Tadashi] Hokkaido Univ, Grad Sch Med, Dept Pediat, Kita Ku, Sapporo, Hokkaido 0608638, Japan. [Otsu, Makoto; Nakajima, Satoru; Kida, Miyuki; Maeyama, Yoshihiro; Sakiyama, Yukio; Ariga, Tadashi] Hokkaido Univ, Grad Sch Med, Res Grp Human Gene Therapy, Sapporo, Hokkaido 0608638, Japan. [Tatsuzawa, Osamu; Onodera, Masafumi] Natl Ctr Child Hlth & Dev, Dept Human Genet, Tokyo, Japan. [Tsuchida, Fumiko; Kato, Shunichi] Tokai Univ, Sch Med, Dept Cell Transplantat & Regenerat Med, Hiratsuka, Kanagawa 25912, Japan. [Kitagawa, Masanari; Mineno, Junichi] Takara Bio, Shiga, Japan. [Hershfield, Michael S.; Bali, Pawan] Duke Univ, Sch Med, Dept Biochem, Durham, NC USA. [Candotti, Fabio] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Ariga, T (reprint author), Hokkaido Univ, Grad Sch Med, Dept Pediat, Kita Ku, N-15,W-7, Sapporo, Hokkaido 0608638, Japan. EM tada-ari@med.hokudai.ac.jp OI Otsu, Makoto/0000-0002-9769-0217 FU Ministry of Health, Labor and Welfare FX We would like to thank both patients and both families for their cooperation. We are also grateful to the doctors, nurses, and other co-medical staff members who have supported them and this study in many ways. We thank W. Jay Ramsey, Laura Tuschong, G. Jayashree Jagadeesh, and Linda Muul in the Clinical Gene Therapy Branch of the National Human Genome Research Institute, NIH, for the production of clinical-grade GCsapM-ADA supernatant. This work was supported by grants from the Ministry of Health, Labor and Welfare. NR 47 TC 5 Z9 5 U1 3 U2 8 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD MAY PY 2015 VL 35 IS 4 BP 384 EP 398 DI 10.1007/s10875-015-0157-1 PG 15 WC Immunology SC Immunology GA CI5TW UT WOS:000354823700010 PM 25875699 ER PT J AU Knepper, MA AF Knepper, Mark A. TI Systems biology of diuretic resistance SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material ID COLLECTING DUCT CELLS; KIDNEY AB Diuretics are commonly used to treat hypertension and extracellular fluid volume expansion. However, the development of compensatory responses in the kidney limits the benefit of this class of drugs. In this issue of the JCI, Grimm and colleagues use a systems biology approach in mice lacking the kinase SPAK and unravel a complex mechanism that explains thiazide diuretic resistance. The overall process involves interactions among six different cell types in the kidney. C1 [Knepper, Mark A.] NHLBI, Epithelial Syst Biol Lab, NIH, Bethesda, MD 20892 USA. RP Knepper, MA (reprint author), NIH, 10 Ctr Dr,Bldg 10,Room 6N260, Bethesda, MD 20892 USA. EM knep@helix.nih.gov FU NHLBI NIH HHS [HL006128, Z01 HL001285, HL006129] NR 14 TC 4 Z9 4 U1 1 U2 3 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD MAY PY 2015 VL 125 IS 5 BP 1793 EP 1795 DI 10.1172/JCI81505 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CH5JK UT WOS:000354071700004 PM 25893597 ER PT J AU Pollizzi, KN Patel, CH Sun, IH Oh, MH Waickman, AT Wen, JY Delgoffe, GM Powell, JD AF Pollizzi, Kristen N. Patel, Chirag H. Sun, Im-Hong Oh, Min-Hee Waickman, Adam T. Wen, Jiayu Delgoffe, Greg M. Powell, Jonathan D. TI mTORC1 and mTORC2 selectively regulate CD8(+) T cell differentiation SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID TUBEROUS SCLEROSIS COMPLEX; TUMOR-SUPPRESSOR TSC1; TRANSCRIPTION FACTOR; MAMMALIAN TARGET; GENE-PRODUCTS; MEMORY DEVELOPMENT; GROWTH-CONTROL; CUTTING EDGE; EFFECTOR; ACTIVATION AB Activation of mTOR-dependent pathways regulates the specification and differentiation of CD4(+) T effector cell subsets. Herein, we show that mTOR complex 1 (mTORC1) and mTORC2 have distinct roles in the generation of CD8(+) T cell effector and memory populations. Evaluation of mice with a T cell-specific deletion of the gene encoding the negative regulator of mTORC1, tuberous sclerosis complex 2 (TSC2), resulted in the generation of highly glycolytic and potent effector CD8(+) T cells; however, due to constitutive mTORC1 activation, these cells retained a terminally differentiated effector phenotype and were incapable of transitioning into a memory state. In contrast, CD8(+) T cells deficient in mTORC1 activity due to loss of RAS homolog enriched in brain (RHEB) failed to differentiate into effector cells but retained memory characteristics, such as surface marker expression, a lower metabolic rate, and increased longevity. However, these RHEB-deficient memory-like T cells failed to generate recall responses as the result of metabolic defects. While mTORC1 influenced CD8(+)T cell effector responses, mTORC2 activity regulated CD8(+) T cell memory. mTORC2 inhibition resulted in metabolic reprogramming, which enhanced the generation of CD8(+) memory cells. Overall, these results define specific roles for mTORC1 and mTORC2 that link metabolism and CD8(+) T cell effector and memory generation and suggest that these functions have the potential to be targeted for enhancing vaccine efficacy and antitumor immunity. C1 [Pollizzi, Kristen N.; Patel, Chirag H.; Sun, Im-Hong; Oh, Min-Hee; Waickman, Adam T.; Wen, Jiayu; Delgoffe, Greg M.; Powell, Jonathan D.] Johns Hopkins Univ Sch Med, Dept Oncol, Sidney Kimmel Comprehens Canc Res Ctr, Baltimore, MD USA. [Waickman, Adam T.] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Delgoffe, Greg M.] Univ Pittsburgh, Dept Immunol, Pittsburgh, PA USA. RP Powell, JD (reprint author), 1650 Orleans St,CRB-1 Rm 443, Baltimore, MD 21287 USA. EM poweljo@jhmi.edu FU NIH [AI072677, AI77610, AI091481] FX We thank Drew Pardoll and members of the Powell lab for reviewing the manuscript. We thank Ada Tam and Lee Blosser for assistance with flow cytometry sorting and Brian Herb and Christopher Gamper for assistance with statistical analysis. This work was supported by NIH grants AI072677, AI77610, and AI091481. NR 62 TC 34 Z9 34 U1 3 U2 8 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD MAY PY 2015 VL 125 IS 5 BP 2090 EP 2108 DI 10.1172/JCI77746 PG 19 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CH5JK UT WOS:000354071700030 PM 25893604 ER PT J AU Lin, L Chien, LC Acquaye, AA Vera-Bolanos, E Gilbert, MR Armstrong, TS AF Lin, Lin Chien, Lung-Chang Acquaye, Alvina A. Vera-Bolanos, Elizabeth Gilbert, Mark R. Armstrong, Terri S. TI Significant predictors of patients' uncertainty in primary brain tumors SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE Brain tumors; MUIS-BT; Symptoms; Uncertainty; Structured additive regression ID ADDITIVE REGRESSION-MODELS; ILLNESS; PSEUDOPROGRESSION; VALIDATION; MANAGEMENT; BT AB Patients with primary brain tumors (PBT) face uncertainty related to prognosis, symptoms and treatment response and toxicity. Uncertainty is correlated to negative mood states and symptom severity and interference. This study identified predictors of uncertainty during different treatment stages (newly-diagnosed, on treatment, followed-up without active treatment). One hundred eighty six patients with PBT were accrued at various points in the illness trajectory. Data collection tools included: a clinical checklist/a demographic data sheet/the Mishel Uncertainty in Illness Scale-Brain Tumor Form. The structured additive regression model was used to identify significant demographic and clinical predictors of illness-related uncertainty. Participants were primarily white (80 %) males (53 %). They ranged in age from 19-80 (mean = 44.2 +/- A 12.6). Thirty-two of the 186 patients were newly-diagnosed, 64 were on treatment at the time of clinical visit with MRI evaluation, 21 were without MRI, and 69 were not on active treatment. Three subscales (ambiguity/inconsistency; unpredictability-disease prognoses; unpredictability-symptoms and other triggers) were different amongst the treatment groups (P < .01). However, patients' uncertainty during active treatment was as high as in newly-diagnosed period. Other than treatment stages, change of employment status due to the illness was the most significant predictor of illness-related uncertainty. The illness trajectory of PBT remains ambiguous, complex, and unpredictable, leading to a high incidence of uncertainty. There was variation in the subscales of uncertainty depending on treatment status. Although patients who are newly diagnosed reported the highest scores on most of the subscales, patients on treatment felt more uncertain about unpredictability of symptoms than other groups. Due to the complexity and impact of the disease, associated symptoms, and interference with functional status, comprehensive assessment of patients is necessary throughout the illness trajectory. C1 [Lin, Lin] Univ Calif San Francisco, Dept Family Hlth Care Nursing, San Francisco, CA 94143 USA. [Chien, Lung-Chang] Univ Texas San Antonio, Sch Publ Hlth, Dept Biostat, San Antonio, TX USA. [Chien, Lung-Chang] Univ Texas Hlth Sci Ctr San Antonio, Res Adv Community Hlth Ctr, San Antonio, TX 78229 USA. [Acquaye, Alvina A.; Vera-Bolanos, Elizabeth; Armstrong, Terri S.] Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, Houston, TX 77030 USA. [Gilbert, Mark R.] NCI, Neurooncol Branch, NIH, Bethesda, MD 20892 USA. [Armstrong, Terri S.] Univ Texas Hlth Sci Ctr Houston, Dept Family Hlth, Houston, TX 77030 USA. RP Lin, L (reprint author), Univ Calif San Francisco, Dept Family Hlth Care Nursing, 2 Koret Way,N405K,Campus Mail Box 0606, San Francisco, CA 94143 USA. EM Lin.Lin2@ucsf.edu RI Gilbert, Mark/J-7494-2016 OI Gilbert, Mark/0000-0003-2556-9722 FU UT-Houston; Collaborative Ependymoma Research Network (CERN Foundation) FX The authors would like to thank the research subjects for their participation. The authors would also like to thank the CERN Foundation for the support of research assistant for data collection. This study is supported by the Dean's Research Award from UT-Houston and the Collaborative Ependymoma Research Network (CERN Foundation). NR 19 TC 1 Z9 1 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X EI 1573-7373 J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD MAY PY 2015 VL 122 IS 3 BP 507 EP 515 DI 10.1007/s11060-015-1756-7 PG 9 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA CI4KP UT WOS:000354717800010 PM 25805495 ER PT J AU Wang, CY Carriquiry, AL Chen, TC Loria, CM Pfeiffer, CM Liu, K Sempos, CT Perrine, CG Cogswell, ME AF Wang, Chia-Yih Carriquiry, Alicia L. Chen, Te-Ching Loria, Catherine M. Pfeiffer, Christine M. Liu, Kiang Sempos, Christopher T. Perrine, Cria G. Cogswell, Mary E. TI Estimating the Population Distribution of Usual 24-Hour Sodium Excretion from Timed Urine Void Specimens Using a Statistical Approach Accounting for Correlated Measurement Errors SO JOURNAL OF NUTRITION LA English DT Article DE sodium; population distribution; nutrition survey; calibration; 24-hour urine collection; timed urine void; usual sodium intake ID DAILY SALT INTAKE; POTASSIUM EXCRETION; UNITED-STATES; ADULTS; SPOT; COLLECTION; SAMPLES AB Background: High US sodium intake and national reduction efforts necessitate developing a feasible and valid monitoring method across the distribution of low-to-high sodium intake. Objective: We examined a statistical approach using timed urine voids to estimate the population distribution of usual 24-h sodium excretion. Methods: A sample of 407 adults, aged 18-39 y (54% female, 48% black), collected each void in a separate container for 24 h; 133 repeated the procedure 4-11 d later. Four timed voids (morning, afternoon, evening, overnight) were selected from each 24-h collection. We developed gender-specific equations to calibrate total sodium excreted in each of the one-void (e.g., morning) and combined two-void (e.g., morning + afternoon) urines to 24-h sodium excretion. The calibrated sodium excretions were used to estimate the population distribution of usual 24-h sodium excretion. Participants were then randomly assigned to modeling (n = 160) or validation (n = 247) groups to examine the bias in estimated population percentiles. Results: Median bias in predicting selected percentiles (5th, 25th, 50th, 75th, 95th) of usual 24-h sodium excretion with one-void urines ranged from 367 to 284 mg (-7.7 to 12.2% of the observed usual excretions) for men and 604 to 486 mg (-14.6 to 23.7%) for women, and with two-void urines from 338 to 263 mg (-6.9 to 10.4%) and -166 to 153 mg (-4.1 to 8.1%), respectively. Four of the 6 two-void urine combinations produced no significant bias in predicting selected percentiles. Conclusions: Our approach to estimate the population usual 24-h sodium excretion, which uses calibrated timed-void sodium to account for day-to-day variation and covariance between measurement errors, produced percentile estimates with relatively low biases across low-to-high sodium excretions. This may provide a low-burden, low-cost alternative to 24-h collections in monitoring population sodium intake among healthy young adults and merits further investigation in other population subgroups. This study was registered at clinicaltrials.gov as NCT01631240. C1 [Wang, Chia-Yih; Chen, Te-Ching] CDC, Div Hlth & Nutr Examinat Surveys, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Carriquiry, Alicia L.] Iowa State Univ, Dept Stat, Ames, IA USA. [Loria, Catherine M.] NHLBI, Bethesda, MD 20892 USA. [Sempos, Christopher T.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Pfeiffer, Christine M.] CDC, Div Lab Sci, Natl Ctr Environm Hlth, Atlanta, GA 30333 USA. [Perrine, Cria G.] CDC, Div Nutr Phys Act & Obes, Atlanta, GA 30333 USA. [Cogswell, Mary E.] CDC, Div Heart Dis & Stroke Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. [Liu, Kiang] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. RP Wang, CY (reprint author), CDC, Div Hlth & Nutr Examinat Surveys, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. EM cwang@cdc.gov FU CDC FX The data collection and laboratory analyses of sodium and creatinine were funded by the CDC. NR 29 TC 2 Z9 2 U1 0 U2 3 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 EI 1541-6100 J9 J NUTR JI J. Nutr. PD MAY PY 2015 VL 145 IS 5 BP 1017 EP 1024 DI 10.3945/jn.114.206250 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CH4OO UT WOS:000354013000025 PM 25833885 ER PT J AU Peterson, CM Fischer, S Young-Hyman, D AF Peterson, Claire M. Fischer, Sarah Young-Hyman, Deborah TI Topical Review: A Comprehensive Risk Model for Disordered Eating in Youth With Type 1 Diabetes SO JOURNAL OF PEDIATRIC PSYCHOLOGY LA English DT Review DE eating disorders; Modified Dual Pathway; risk for disordered eating in T1D; Type 1 diabetes ID ADOLESCENT GIRLS; TEENAGE GIRLS; DUAL-PATHWAY; BEHAVIOR; MELLITUS; INDIVIDUALS; PATHOLOGY; WOMEN AB Objectives Provide an updated literature review on prevalence, measurement, and correlates of disordered eating in youth with Type 1 diabetes (T1D), present a novel theoretical risk model (i.e., The Modified Dual Pathway Model) for disordered eating in youth with T1D incorporating psychosocial and physiological risk factors, and discuss clinical implications. Methods Literature review of prevalence, correlates, risk factors, and outcomes of disordered eating behavior (DEB) in youth with T1D. Results Insulin treatment, subsequent weight gain, and disruptions to hunger and satiety regulation are hypothesized disease-related mechanisms through which the treatment of T1D may increase vulnerability to development of behavior characterized as DEB. The Modified Dual Pathway Model integrates these factors with a validated psychosocial risk (body dissatisfaction, depression, and abstinence violation) model for DEB in nondiabetic youth. Conclusions The Modified Dual Pathway model of DEB in youth with T1D is a comprehensive representation of both psychosocial and T1D-related risk factors with the potential to inform future interventions for this population. C1 [Peterson, Claire M.] Cincinnati Childrens Hosp Med Ctr, Div Behav Med & Clin Psychol, Cincinnati, OH 45229 USA. [Fischer, Sarah] George Mason Univ, Dept Psychol, Fairfax, VA 22030 USA. [Young-Hyman, Deborah] NIH, Off Behav & Social Sci Res, Off Director, Bethesda, MD USA. RP Peterson, CM (reprint author), Cincinnati Childrens Hosp Med Ctr, Div Behav Med & Clin Psychol, 3333 Burnet Ave, Cincinnati, OH 45229 USA. EM claire.peterson@cchmc.org NR 33 TC 4 Z9 4 U1 2 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0146-8693 EI 1465-735X J9 J PEDIATR PSYCHOL JI J. Pediatr. Psychol. PD MAY PY 2015 VL 40 IS 4 BP 385 EP 390 DI 10.1093/jpepsy/jsu106 PG 6 WC Psychology, Developmental SC Psychology GA CI4FL UT WOS:000354702900002 PM 25502449 ER PT J AU Lally, N Nugent, AC Luckenbaugh, DA Niciu, MJ Roiser, JP Zarate, CA AF Lally, Niall Nugent, Allison C. Luckenbaugh, David A. Niciu, Mark J. Roiser, Jonathan P. Zarate, Carlos A., Jr. TI Neural correlates of change in major depressive disorder anhedonia following open-label ketamine SO JOURNAL OF PSYCHOPHARMACOLOGY LA English DT Article DE Anti-anhedonic; dorsal anterior cingulate cortex; depression; (18)FDG-PET; glutamate; hippocampus; NMDA; orbitofrontal cortex; reward; riluzole; subiculum ID METHYL-D-ASPARTATE; RAPID ANTIDEPRESSANT RESPONSE; RECEPTOR ANTAGONIST RESPONSE; RESISTANT BIPOLAR DEPRESSION; ASTROCYTIC GLUTAMATE UPTAKE; HUMAN ORBITOFRONTAL CORTEX; ADD-ON TRIAL; ALCOHOL DEPENDENCE; NUCLEUS-ACCUMBENS; PREFRONTAL CORTEX AB Anhedonia is a cardinal symptom of major depression and is often refractory to standard treatment, yet no approved medication for this specific symptom exists. In this exploratory re-analysis, we assessed whether administration of rapid-acting antidepressant ketamine was associated specifically with reduced anhedonia in medication-free treatment-refractory patients with major depressive disorder in an open-label investigation. Additionally, participants received either oral riluzole or placebo daily beginning 4 hours post-infusion. A subgroup of patients underwent fluorodeoxyglucose positron emission tomography scans at baseline (1-3 days pre-infusion) and 2 hours post-ketamine infusion. Anhedonia rapidly decreased following a single ketamine infusion; this was sustained for up to three days, but was not altered by riluzole. Reduced anhedonia correlated with increased glucose metabolism in the hippocampus and dorsal anterior cingulate cortex (dACC) and decreased metabolism in the inferior frontal gyrus and orbitofrontal cortex (OFC). The tentative relationship between change in anhedonia and glucose metabolism remained significant in dACC and OFC, and at trend level in the hippocampus, a result not anticipated, when controlling for change in total depression score. Results, however, remain tenuous due to the lack of a placebo control for ketamine. In addition to alleviating overall depressive symptoms, ketamine could possess anti-anhedonic potential in major depressive disorder, which speculatively, may be mediated by alterations in metabolic activity in the hippocampus, dACC and OFC. C1 [Lally, Niall; Nugent, Allison C.; Luckenbaugh, David A.; Niciu, Mark J.; Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Bethesda, MD 20892 USA. [Lally, Niall; Roiser, Jonathan P.] UCL, Inst Cognit Neurosci, London, England. RP Lally, N (reprint author), NIH, CRC, 10 Ctr Dr,Room 7-5340, Bethesda, MD 20892 USA. EM lallynm@mail.nih.gov RI Niciu, Mark/J-1766-2014; OI Niciu, Mark/0000-0002-5612-3021; Nugent, Allison/0000-0003-2569-2480 FU Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) [04-M-0222] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH; grant number 04-M-0222). NR 70 TC 22 Z9 22 U1 6 U2 16 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0269-8811 EI 1461-7285 J9 J PSYCHOPHARMACOL JI J. Psychopharmacol. PD MAY PY 2015 VL 29 IS 5 BP 596 EP 607 DI 10.1177/0269881114568041 PG 12 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CI6WD UT WOS:000354903600009 PM 25691504 ER PT J AU Goldstein, RB Chou, SP Smith, SM Jung, J Zhang, HT Saha, TD Pickering, RP Ruan, WJ Huang, BJ Grant, BF AF Goldstein, Rise B. Chou, S. Patricia Smith, Sharon M. Jung, Jeesun Zhang, Haitao Saha, Tulshi D. Pickering, Roger P. Ruan, W. June Huang, Boji Grant, Bridget F. TI Nosologic Comparisons of DSM-IV and DSM-5 Alcohol and Drug Use Disorders: Results From the National Epidemiologic Survey on Alcohol and Related Conditions-III SO JOURNAL OF STUDIES ON ALCOHOL AND DRUGS LA English DT Article ID SUBSTANCE-USE DISORDERS; GENERAL-POPULATION SAMPLE; ITEM RESPONSE THEORY; CANNABIS WITHDRAWAL SYNDROME; UNITED-STATES 1988; DIAGNOSTIC-CRITERIA; DRINKING PATTERNS; NONRESPONSE BIAS; COMMUNITY-SAMPLE; PROPOSED CHANGES AB Objective: The purpose of this study was to examine prevalences and concordances between Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), and Fifth Edition (DSM-5) substance use disorders (SUDs) in a newly completed U.S. epidemiologic survey. Method: The National Epidemiologic Survey on Alcohol and Related Conditions-III surveyed 36,309 civilian, noninstitutionalized adults. SUDs were assessed using the Alcohol Use Disorder and Associated Disabilities Interview Schedule-5. Concordances between DSM-IV and DSM-5 disorders were assessed using kappa statistics. Results: Prevalences of past-year substance-specific DSM-5 disorders (2+ criteria) were modestly higher than those of DSM-IV dependence and abuse combined for alcohol, sedatives/tranquilizers, opioids, and heroin, but lower for cannabis, cocaine, and stimulants. Lifetime prevalences were lower under DSM-5. Prevalences were similar between moderate to severe (4+ criteria) DSM-5 disorders and dependence, whereas prevalences of DSM-5 disorders at 3+ criteria (DSM-5 [3+]) were higher, particularly for cannabis. Past-year concordances were excellent for DSM-IV dependence and abuse combined versus any DSM-5 and DSM-IV dependence versus DSM-5 moderate to severe disorders; lifetime concordances were fair to excellent. Past-year concordances between DSM-IV and DSM-5 (3+) were generally similar to or modestly higher than those with any DSM-5 disorder; lifetime concordances were mostly lower. Conclusions: Findings are consistent with those informing the development of DSM-5. Future research should examine differences in patterns between past-year and lifetime disorders, particularly for cannabis. Other questions warranting investigation include whether different combinations of the same numbers of criteria carry different clinical or nosologic implications, whether changes in nosology yield changes in treatment demand, and whether changes in characteristics of individuals with DSM-5 SUDs dictate modifications to screening and intervention. C1 [Goldstein, Rise B.; Chou, S. Patricia; Smith, Sharon M.; Jung, Jeesun; Zhang, Haitao; Saha, Tulshi D.; Pickering, Roger P.; Ruan, W. June; Huang, Boji; Grant, Bridget F.] NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, Bethesda, MD 20892 USA. RP Goldstein, RB (reprint author), NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, Room 3071,MS 9304,5635 Fishers Lane, Bethesda, MD 20892 USA. EM goldster@mail.nih.gov OI Goldstein, Rise/0000-0002-9603-9473 FU National Institute on Alcohol Abuse and Alcoholism (NIAAA); Intramural Program of the National Institutes of Health, NIAAA FX The National Epidemiologic Survey on Alcohol and Related Conditions-III (NESARC-III) is funded by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) with supplemental support from the National Institute on Drug Abuse. This research was supported in part by the Intramural Program of the National Institutes of Health, NIAAA. The views and opinions expressed in this report are those of the authors and should not be construed to represent the views of sponsoring organizations, agencies, or the US. government. NR 110 TC 14 Z9 14 U1 5 U2 9 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 1937-1888 EI 1938-4114 J9 J STUD ALCOHOL DRUGS JI J. Stud. Alcohol Drugs PD MAY PY 2015 VL 76 IS 3 BP 378 EP 388 PG 11 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA CI4WR UT WOS:000354755100005 PM 25978823 ER PT J AU He, ZY Zheng, F Ma, YL Kim, HH Zhou, QF Shung, KK AF He, Zhengyao Zheng, Fan Ma, Yuanliang Kim, Hyung Ham Zhou, Qifa Shung, K. Kirk TI A sidelobe suppressing near-field beamforming approach for ultrasound array imaging SO JOURNAL OF THE ACOUSTICAL SOCIETY OF AMERICA LA English DT Article ID OPTIMAL APODIZATION DESIGN; CONSTRAINED LEAST-SQUARES; INFINITE PLANAR BAFFLE; RADIATION; PISTONS AB A method is proposed to suppress sidelobe level for near-field beamforming in ultrasound array imaging. An optimization problem is established, and the second-order cone algorithm is used to solve the problem to obtain the weight vector based on the near-field response vector of a transducer array. The weight vector calculation results show that the proposed method can be used to suppress the sidelobe level of the near-field beam pattern of a transducer array. Ultrasound images following the application of weight vector to the array of a wire phantom are obtained by simulation with the Field II program, and the images of a wire phantom and anechoic sphere phantom are obtained experimentally with a 64-element 26MHz linear phased array. The experimental and simulation results agree well and show that the proposed method can achieve a much lower sidelobe level than the conventional delay and sum beamforming method. The wire phantom image is demonstrated to focus much better and the contrast of the anechoic sphere phantom image improved by applying the proposed beamforming method. (C) 2015 Acoustical Society of America. C1 [He, Zhengyao; Ma, Yuanliang] Northwestern Polytech Univ, Inst Acoust Engn, Xian 710072, Peoples R China. [Zheng, Fan; Kim, Hyung Ham; Zhou, Qifa; Shung, K. Kirk] Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. [Zheng, Fan; Kim, Hyung Ham; Zhou, Qifa; Shung, K. Kirk] Univ So Calif, NIH, Transducer Resource Ctr, Los Angeles, CA 90089 USA. RP He, ZY (reprint author), Northwestern Polytech Univ, Inst Acoust Engn, Xian 710072, Peoples R China. EM hezhengyao@163.com FU National Natural Science Foundation of China [60901076]; Fundamental Research Funds for the Central Universities [3102014JCQ01008]; Hovering Star Plan of Northwestern Polytechnical University FX This work was supported by the National Natural Science Foundation of China under Grant No. 60901076, the Fundamental Research Funds for the Central Universities under Grant No. 3102014JCQ01008, and the Hovering Star Plan of Northwestern Polytechnical University. NR 27 TC 0 Z9 0 U1 1 U2 12 PU ACOUSTICAL SOC AMER AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0001-4966 EI 1520-8524 J9 J ACOUST SOC AM JI J. Acoust. Soc. Am. PD MAY PY 2015 VL 137 IS 5 BP 2785 EP 2790 DI 10.1121/1.4919318 PG 6 WC Acoustics; Audiology & Speech-Language Pathology SC Acoustics; Audiology & Speech-Language Pathology GA CI7RU UT WOS:000354962900031 PM 25994706 ER PT J AU Rabassa, M Cherubini, A Zamora-Ros, R Urpi-Sarda, M Bandinelli, S Ferrucci, L Andres-Lacueva, C AF Rabassa, Montserrat Cherubini, Antonio Zamora-Ros, Raul Urpi-Sarda, Mireia Bandinelli, Stefania Ferrucci, Luigi Andres-Lacueva, Cristina TI Low Levels of a Urinary Biomarker of Dietary Polyphenol Are Associated with Substantial Cognitive Decline over a 3-Year Period in Older Adults: The Invecchiare in Chianti Study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE urinary polyphenols; dietary polyphenols; biomarker; cognitive decline; epidemiology ID MINI-MENTAL-STATE; ALZHEIMERS-DISEASE; FLAVONOID INTAKE; RISK; EPIDEMIOLOGY; ANTIOXIDANTS; IMPAIRMENT; MECHANISMS; CREATININE; MORTALITY AB ObjectivesTo investigate the association between total urinary polyphenols (TUPs) and total dietary polyphenols (TDPs) and cognitive decline in an older population. DesignThe Invecchiare in Chianti (InCHIANTI) study, a cohort study with 3years of follow-up. SettingTuscany, Italy. ParticipantsIndividuals without dementia aged 65 and older (N=652). MeasurementsTUP and TDP concentrations were analyzed at baseline using the Folin-Ciocalteu assay and a validated food frequency questionnaire, respectively. Cognition was assessed using the Mini-Mental State Examination (MMSE) and Trail-Making Test (TMT) at baseline and after 3years of follow-up. Substantial cognitive decline was defined as a reduction in MMSE score of three or more points and an increase of at least 29seconds on the TMT Part A (TMT-A) and 68seconds on the TMT Part B (TMT-B) (the worst 10% of the distribution of decline) or as test discontinued because of multiple mistakes on the TMT A and B at follow-up. ResultsHigher TUP levels were associated with lower risk of substantial cognitive decline on the MMSE (odds ratio (OR) comparing extreme tertiles=0.53, 95% confidence interval (CI)=0.34-0.85, P-trend=.008) and on the TMT-A (OR=0.52, 95% CI=0.28-0.96, P-trend=.03), but not on TMT-B in a logistic regression model that adjusted for baseline cognitive score and potential confounding factors. TDP did not affect the development of substantial cognitive decline in either test. ConclusionHigh concentrations of polyphenols, a nutritional biomarker of polyphenol intake, were associated with lower risk of substantial cognitive decline in an older population studied over a 3-year period, suggesting a protective effect against cognitive impairment. C1 [Rabassa, Montserrat; Urpi-Sarda, Mireia; Andres-Lacueva, Cristina] Univ Barcelona, Biomarkers & Nutrimetab Lab, Nutr & Food Sci Dept, XaRTA,INSA,Pharm Fac, E-08028 Barcelona, Spain. [Cherubini, Antonio] Italian Natl Res Ctr Aging, Geriatr & Emergency Care, Ancona, Italy. [Zamora-Ros, Raul] Int Agcy Res Canc, Nutr & Metab Sect, Biomarkers Grp, F-69372 Lyon, France. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Rehabil Unit, Florence, Italy. [Ferrucci, Luigi] NIA, Clin Res Branch, NIH, Baltimore, MD 21224 USA. RP Andres-Lacueva, C (reprint author), Univ Barcelona, Biomarkers & Nutrimetab Lab, Nutr & Food Sci Dept, XaRTA,INSA,Pharm Fac, Campus Torribera,Ave Joan 23 S-N, E-08028 Barcelona, Spain. EM candres@ub.edu RI Andres-Lacueva, Cristina/J-3377-2012; OI Andres-Lacueva, Cristina/0000-0002-8494-4978; Cherubini, Antonio/0000-0003-0261-9897; urpi, mireia/0000-0002-4064-5175 FU Italian Ministry of Health; U.S. National Institute on Aging (NIA); Spanish government grants from the Ministry of Economy and Competitiveness (MINECO); Fondo Europeo de Desarrollo Regional: the CONSOLIDER-INGENIO program, FUN-C-Food [CSD2007-063]; JPI HDHL FOODBALL [PCIN-2014-133]; Generalitat de Catalunya's Agency AGAUR [2014SGR1566]; International Nut and Dried Fruit Council Foundation; Bosch I Gimpera Foundation [FBG307906]; Ramon y Cajal program from MINECO [RYC-2011-09677]; Fondo Social Europeo FX The InCHIANTI study is supported in part by the Italian Ministry of Health and by the U.S. National Institute on Aging (NIA). The authors are grateful for the support granted by Spanish government grants from the Ministry of Economy and Competitiveness (MINECO) and cofunded by the Fondo Europeo de Desarrollo Regional: the CONSOLIDER-INGENIO 2010 program, FUN-C-Food (CSD2007-063), and the JPI HDHL FOODBALL (PCIN-2014-133). We are also grateful for the award of 2014SGR1566 from the Generalitat de Catalunya's Agency AGAUR. Partially funded by the International Nut and Dried Fruit Council Foundation in collaboration with the Bosch I Gimpera Foundation (FBG307906). M.R. thanks the training abroad MAPFRE Grant. A.C. thanks the PIE-BKC, Campus of International Excellence program of the Spanish Ministry of Education, Culture and Sport. MU-S. thanks the Ramon y Cajal program (RYC-2011-09677) from MINECO and the Fondo Social Europeo. NR 48 TC 6 Z9 6 U1 2 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAY PY 2015 VL 63 IS 5 BP 938 EP 946 DI 10.1111/jgs.13379 PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA CI4NH UT WOS:000354726400013 PM 25919574 ER PT J AU Einhorn, PT Whelton, PK Davis, BR Wright, JT Cushman, WC Zieman, SJ AF Einhorn, Paula T. Whelton, Paul K. Davis, Barry R. Wright, Jackson T., Jr. Cushman, William C. Zieman, Susan J. TI Real-World Evidence Supports Optimally Dosed Thiazide-Type Diuretics As Preferred in Treatment Regimens of Older Adults with Hypertension SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Letter ID LIPID-LOWERING TREATMENT; HEART-ATTACK TRIAL; ALLHAT; OUTCOMES; RISK C1 [Einhorn, Paula T.] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Whelton, Paul K.] Tulane Univ, Sch Publ Hlth & Trop Med, New Orleans, LA USA. [Davis, Barry R.] Univ Texas Houston, Sch Publ Hlth, Coordinating Ctr Clin Trials, Houston, TX USA. [Wright, Jackson T., Jr.] Univ Hosp Case Med Ctr, Clin Hypertens Program, Cleveland, OH USA. [Cushman, William C.] Univ Tennessee, Ctr Hlth Sci, Vet Affairs Med Ctr, Memphis, TN 38163 USA. [Zieman, Susan J.] NIA, Div Geriatr & Clin Gerontol, NIH, Bethesda, MD 20892 USA. RP Einhorn, PT (reprint author), NHLBI, Div Cardiovasc Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. FU National Heart, Lung, and Blood Institute of the National Institutes of Health [NO1-HC-35130, HHSN268201100036C] FX This work was supported in part by Contracts NO1-HC-35130 and HHSN268201100036C from the National Heart, Lung, and Blood Institute of the National Institutes of Health. NR 10 TC 2 Z9 2 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAY PY 2015 VL 63 IS 5 BP 1045 EP 1047 DI 10.1111/jgs.13415 PG 3 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA CI4NH UT WOS:000354726400039 PM 25989579 ER PT J AU Kwak, JT Xu, S Wood, BJ Turkbey, B Choyke, PL Pinto, PA Wang, SJ Summers, RM AF Kwak, Jin Tae Xu, Sheng Wood, Bradford J. Turkbey, Baris Choyke, Peter L. Pinto, Peter A. Wang, Shijun Summers, Ronald M. TI Automated prostate cancer detection using T2-weighted and high-b-value diffusion-weighted magnetic resonance imaging SO MEDICAL PHYSICS LA English DT Article DE prostate cancer; multiparametric MRI; CAD; texture analysis; feature selection ID COMPUTER-AIDED DIAGNOSIS; MULTIPARAMETRIC MRI; 3 T; LOCALIZATION; CONTRAST; BIOPSY; DIFFERENTIATION; SPECTROSCOPY; MALIGNANCY; IMPROVES AB Purpose: The authors propose a computer-aided diagnosis (CAD) system for prostate cancer to aid in improving the accuracy, reproducibility, and standardization of multiparametric magnetic resonance imaging (MRI). Methods: The proposed system utilizes two MRI sequences [T2-weighted MRI and high-b-value (b = 2000 s/mm(2)) diffusion-weighted imaging (DWI)] and texture features based on local binary patterns. A three-stage feature selection method is employed to provide the most discriminative features. The authors included a total of 244 patients. Training the CAD system on 108 patients (78 MR-positive prostate cancers and 105 benign MR-positive lesions), two validation studies were retrospectively performed on 136 patients (68 MR-positive prostate cancers, 111 benign MR-positive lesions, and 117 MR-negative benign lesions). Results: In distinguishing cancer from MR-positive benign lesions, an area under receiver operating characteristic curve (AUC) of 0.83 [95% confidence interval (CI): 0.76-0.89] was achieved. For cancer vs MR-positive or MR-negative benign lesions, the authors obtained an AUC of 0.89 AUC (95% CI: 0.84-0.93). The performance of the CAD system was not dependent on the specific regions of the prostate, e.g., a peripheral zone or transition zone. Moreover, the CAD system outperformed other combinations of MRI sequences: T2W MRI, high-b-value DWI, and the standard apparent diffusion coefficient (ADC) map of DWI. Conclusions: The novel CAD system is able to detect the discriminative texture features for cancer detection and localization and is a promising tool for improving the quality and efficiency of prostate cancer diagnosis. C1 [Kwak, Jin Tae; Xu, Sheng; Wood, Bradford J.] NIH, Ctr Intervent Oncol, Ctr Clin, Bethesda, MD 20892 USA. [Turkbey, Baris; Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Wang, Shijun; Summers, Ronald M.] NIH, Imaging Biomarkers & Comp Aided Diag Lab, Ctr Clin, Bethesda, MD 20892 USA. RP Summers, RM (reprint author), NIH, Imaging Biomarkers & Comp Aided Diag Lab, Ctr Clin, Bethesda, MD 20892 USA. EM rms@nih.gov FU Intramural Research Program of the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institutes of Health. This work utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD (http:/biowulf.nih.gov). NR 48 TC 8 Z9 8 U1 1 U2 13 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD MAY PY 2015 VL 42 IS 5 BP 2368 EP 2378 DI 10.1118/1.4918318 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CI5ER UT WOS:000354776800029 PM 25979032 ER PT J AU Nalls, MA Escott-Price, V Williams, NM Lubbe, S Keller, MF Morris, HR Singleton, AB AF Nalls, Mike A. Escott-Price, Valentina Williams, Nigel M. Lubbe, Steven Keller, Margaux F. Morris, Huw R. Singleton, Andrew B. CA IPDGC TI Genetic risk and age in Parkinson's disease: Continuum not stratum SO MOVEMENT DISORDERS LA English DT Article DE Parkinson's disease; genetics; age at onset; statistics ID GENOME-WIDE ASSOCIATION; METAANALYSIS AB BackgroundRecent genomewide association study meta-analyses have identified 28 loci associated with risk of Parkinson's disease (PD). We sought to investigate whether these genetic risk factors are associated with PD age at onset. MethodsGenetic risk scores from these loci were calculated for 6,249 cases. Linear regression tested associations between cumulative genetic risk and PD age at onset. ResultsIncreasing genetic risk scores were associated with earlier age at onset (beta=-0.10, P=2.92 x 10(-8), adjusted r(2)=0.27). Single standard deviation increase in genetic risk score is associated with 37.44 d earlier age at onset. Highest genetic risk was found at 31 to 60 y, onset slightly below average age at onset (AAO). ConclusionsCommon genetic risk factors have a small but consistent association with AAO in PD. (c) 2015 International Parkinson and Movement Disorder Society C1 [Nalls, Mike A.; Singleton, Andrew B.] NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA. [Escott-Price, Valentina; Williams, Nigel M.] Cardiff Univ, MRC Ctr Neuropsychiat Genet & Genom, Cardiff CF10 3AX, S Glam, Wales. [Lubbe, Steven; Morris, Huw R.] UCL Inst Neurol, Dept Clin Neurosci, London, England. [Keller, Margaux F.] Merck Res Labs, Cambridge, MA USA. RP Singleton, AB (reprint author), NIA, Lab Neurogenet, Bldg 35,Pod 1A, Bethesda, MD 20892 USA. EM singleta@mail.nih.gov RI Singleton, Andrew/C-3010-2009; Lubbe, Steven/L-8261-2013; Morris, Huw/B-8527-2008; OI Morris, Huw/0000-0002-5473-3774; Escott-Price, Valentina/0000-0003-1784-5483 FU Parkinson's UK [8047, J-1101]; Medical Research Council UK [G0700943, G1100643] FX HM and SL are funded by Parkinson's UK (Grants 8047 and J-1101) and the Medical Research Council UK (G0700943, G1100643); additional consortium related information is located in the supplemental materials. NR 10 TC 10 Z9 10 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 EI 1531-8257 J9 MOVEMENT DISORD JI Mov. Disord. PD MAY PY 2015 VL 30 IS 6 BP 850 EP 854 DI 10.1002/mds.26192 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA CI4OT UT WOS:000354731500018 PM 25778492 ER PT J AU Ferrer, RA Green, PA Barrett, LF AF Ferrer, Rebecca A. Green, Paige A. Barrett, Lisa Feldman TI Affective Science Perspectives on Cancer Control: Strategically Crafting a Mutually Beneficial Research Agenda SO PERSPECTIVES ON PSYCHOLOGICAL SCIENCE LA English DT Article DE affective science; cancer control; emotion ID SERVICES TASK-FORCE; QUALITY-OF-LIFE; BREAST-CANCER; RECOMMENDATION STATEMENT; EMOTION REGULATION; RISK PERCEPTIONS; BASIC EMOTIONS; PSYCHOLOGICAL CONSTRUCTION; PSYCHOSOCIAL INTERVENTION; FUNCTIONAL ARCHITECTURE AB Cancer control research involves the conduct of basic and applied behavioral and social sciences to reduce cancer incidence, morbidity, and mortality and improve quality of life. Given the importance of behavior in cancer control, fundamental research is necessary to identify psychological mechanisms underlying cancer risk, prevention, and management behaviors. Cancer prevention, diagnosis, and treatment are often emotionally laden. As such, affective science research to elucidate questions related to the basic phenomenological nature of emotion, stress, and mood is necessary to understand how cancer control can be hindered or facilitated by emotional experiences. To date, the intersection of basic affective science research and cancer control remains largely unexplored. The goal of this article is to outline key questions in the cancer control research domain that provide an ecologically valid context for new affective science discoveries. We also provide examples of ways in which basic affective discoveries could inform future cancer prevention and control research. These examples are not meant to be exhaustive or prescriptive but instead are offered to generate creative thought about the promise of a cancer research context for answering basic affective science questions. Together, these examples provide a compelling argument for fostering collaborations between affective and cancer control scientists. C1 [Ferrer, Rebecca A.; Green, Paige A.] NCI, Basic Biobehav & Psychol Sci Branch, Behav Res Program, Div Canc Control & Populat Sci, Rockville, MD 20850 USA. [Barrett, Lisa Feldman] Northeastern Univ, Dept Psychol, Boston, MA 02115 USA. [Barrett, Lisa Feldman] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Barrett, Lisa Feldman] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Martinos Ctr Biomed Imaging, Boston, MA USA. RP Ferrer, RA (reprint author), NCI, Basic Biobehav & Psychol Sci Branch, 9609 Med Ctr Dr,3E114, Rockville, MD 20850 USA. EM ferrerra@mail.nih.gov OI Green, Paige/0000-0001-7886-8924 FU Intramural NIH HHS [Z99 CA999999] NR 193 TC 0 Z9 0 U1 2 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1745-6916 EI 1745-6924 J9 PERSPECT PSYCHOL SCI JI Perspect. Psychol. Sci. PD MAY PY 2015 VL 10 IS 3 BP 328 EP 345 DI 10.1177/1745691615576755 PG 18 WC Psychology, Multidisciplinary SC Psychology GA CI5DY UT WOS:000354774400004 PM 25987511 ER PT J AU Gulyas, G Toth, JT Toth, DJ Kurucz, I Hunyady, L Balla, T Varnai, P AF Gulyas, Gergo Toth, Jozsef T. Toth, Daniel J. Kurucz, Istvan Hunyady, Laszlo Balla, Tamas Varnai, Peter TI Measurement of Inositol 1,4,5-Trisphosphate in Living Cells Using an Improved Set of Resonance Energy Transfer-Based Biosensors SO PLOS ONE LA English DT Article ID PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE LEVELS; PROTEIN-COUPLED RECEPTOR; CALCIUM-ENTRY; FLUORESCENT PROTEIN; BINDING; DOMAINS; LIGAND; FRET; IDENTIFICATION; INDICATORS AB Improved versions of inositol-1,4,5-trisphosphate (InsP(3)) sensors were created to follow intracellular InsP(3) changes in single living cells and in cell populations. Similar to previous InsP(3) sensors the new sensors are based on the ligand binding domain of the human type-I InsP(3) receptor (InsP(3)R-LBD), but contain a mutation of either R265K or R269K to lower their InsP(3) binding affinity. Tagging the InsP(3)R-LBD with N-terminal Cerulean and C-terminal Venus allowed measurement of InsP(3) in single-cell FRET experiments. Replacing Cerulean with a Luciferase enzyme allowed experiments in multi-cell format by measuring the change in the BRET signal upon stimulation. These sensors faithfully followed the agonist-induced increase in InsP(3) concentration in HEK 293T cells expressing the Gq-coupled AT1 angiotensin receptor detecting a response to agonist concentration as low as 10 pmol/L. Compared to the wild type InsP(3) sensor, the mutant sensors showed an improved off-rate, enabling a more rapid and complete return of the signal to the resting value of InsP(3) after termination of M3 muscarinic receptor stimulation by atropine. For parallel measurements of intracellular InsP(3) and Ca2+ levels in BRET experiments, the Cameleon D3 Ca2+ sensor was modified by replacing its CFP with luciferase. In these experiments depletion of plasma membrane Ptdlns(4,5)P-2 resulted in the fall of InsP(3) level, followed by the decrease of the Ca2+-signal evoked by the stimulation of the AT1 receptor. In contrast, when type-III PI 4-kinases were inhibited with a high concentration of wortmannin or a more specific inhibitor, A1, the decrease of the Ca2+-signal preceded the fall of InsP(3) level indicating an InsP(3)(-), independent, direct regulation of capacitative Ca2+ influx by plasma membrane inositol lipids. Taken together, our results indicate that the improved InsP(3) sensor can be used to monitor both the increase and decrease of InsP(3) levels in live cells suitable for high-throughput BRET applications. C1 [Gulyas, Gergo; Toth, Jozsef T.; Toth, Daniel J.; Hunyady, Laszlo; Varnai, Peter] Semmelweis Univ, Fac Med, Dept Physiol, H-1094 Budapest, Hungary. [Kurucz, Istvan; Balla, Tamas] NICHHD, Sect Mol Signal Transduct, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. RP Varnai, P (reprint author), Semmelweis Univ, Fac Med, Dept Physiol, H-1094 Budapest, Hungary. EM varnai.peter@med.semmelweis-univ.hu OI Gulyas, Gergo/0000-0002-5491-8699; Toth, Daniel/0000-0001-6670-3348; Balla, Tamas/0000-0002-9077-3335 FU Hungarian Scientific Research Fund (OTKA) [K105006] FX Funding provided by Hungarian Scientific Research Fund (OTKA) K105006: PV, http://www.otka.hu/en. NR 33 TC 3 Z9 3 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 MAY 1 PY 2015 VL 10 IS 5 AR e0125601 DI 10.1371/journal.pone.0125601 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CH2XA UT WOS:000353887100120 PM 25932648 ER PT J AU Ruchi, R Genovese, G Lee, J Charoonratana, VT Bernhardy, AJ Alper, SL Kopp, JB Thadhani, R Friedman, DJ Pollak, MR AF Ruchi, Rupam Genovese, Giulio Lee, Jessica Charoonratana, Victoria T. Bernhardy, Andrea J. Alper, Seth L. Kopp, Jeffrey B. Thadhani, Ravi Friedman, David J. Pollak, Martin R. TI Copy Number Variation at the APOL1 Locus SO PLOS ONE LA English DT Article ID APOLIPOPROTEIN-L GENE; SEGMENTAL DUPLICATIONS; HUMAN GENOME; KIDNEY-DISEASE; EVOLUTION; VARIANTS; AFRICAN; REARRANGEMENTS; ARCHITECTURE; INITIATION AB Two coding variants in the APOL1 gene (G1 and G2) explain most of the high rate of kidney disease in African Americans. APOL1-associated kidney disease risk inheritance follows an autosomal recessive pattern: The relative risk of kidney disease associated with inheritance of two high-risk variants is 7-30 fold, depending on the specific kidney phenotype. We wished to determine if the variability in phenotype might in part reflect structural differences in APOL1 gene. We analyzed sequence coverage from 1000 Genomes Project Phase 3 samples as well as exome sequencing data from African American kidney disease cases for copy number variation. 8 samples sequenced in the 1000 Genomes Project showed increased coverage over a similar to 100kb region that includes APOL2, APOL1 and part of MYH9, suggesting the presence of APOL1 copy number greater than 2. We reasoned that such duplications should be enriched in apparent G1 heterozygotes with kidney disease. Using a PCR-based assay, we observed the presence of this duplication in additional samples from apparent G0G1 or G0G2 individuals. The frequency of this APOL1 duplication was compared among cases (n = 123) and controls (n = 255) with apparent G0G1 heterozygosity. The presence of APOL1 duplication was observed in 4.06% of cases and 0.78% controls, preliminary evidence that this APOL1 duplication may alter susceptibility to kidney disease (p = 0.03). Taqman-based copy number assays confirmed the presence of 3 APOL1 copies in individuals positive for this specific duplication by PCR assay, but also identified a small number of individuals with additional APOL1 copies of presumably different structure. These observations motivate further studies to better assess the contribution of APOL1 copy number on kidney disease risk and on APOL1 function. Investigators and clinicians genotyping APOL1 should also consider whether the particular genotyping platform used is subject to technical errors when more than two copies of APOL1 are present. C1 [Ruchi, Rupam; Lee, Jessica; Charoonratana, Victoria T.; Bernhardy, Andrea J.; Alper, Seth L.; Friedman, David J.; Pollak, Martin R.] Beth Israel Deaconess Med Ctr, Dept Med, Div Nephrol, Boston, MA 02215 USA. [Ruchi, Rupam] Univ Florida, Dept Med, Div Nephrol, Gainesville, FL USA. [Ruchi, Rupam; Alper, Seth L.; Friedman, David J.; Pollak, Martin R.] Harvard Univ, Sch Med, Boston, MA USA. [Genovese, Giulio; Alper, Seth L.] Broad Inst Harvard & MIT, Stanley Ctr, Cambridge, MA USA. [Genovese, Giulio; Pollak, Martin R.] Broad Inst Harvard & MIT, Cambridge, MA USA. [Kopp, Jeffrey B.] NIH, Kidney Dis Branch, Bethesda, MD 20892 USA. [Thadhani, Ravi] Massachusetts Gen Hosp, Dept Med, Renal Unit, Boston, MA 02114 USA. [Friedman, David J.] Beth Israel Deaconess Med Ctr, Vasc Biol Res Ctr, Boston, MA 02215 USA. RP Pollak, MR (reprint author), Beth Israel Deaconess Med Ctr, Dept Med, Div Nephrol, Boston, MA 02215 USA. EM mpollak@bidmc.harvard.edu FU NIH [MD007092]; NephCure Foundation FX The work was supported by NIH MD007092 and NephCure Foundation. NR 26 TC 4 Z9 4 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 1 PY 2015 VL 10 IS 5 AR e0125410 DI 10.1371/journal.pone.0125410 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CH2XA UT WOS:000353887100108 PM 25933006 ER PT J AU Radtke, AJ Tse, SW Zavala, F AF Radtke, Andrea J. Tse, Sze-Wah Zavala, Fidel TI From the draining lymph node to the liver: the induction and effector mechanisms of malaria-specific CD8(+) T cells SO SEMINARS IN IMMUNOPATHOLOGY LA English DT Review DE Plasmodium; CD8(+) T cell responses; Dendritic cells (DCs); T cell memory; In vivo imaging; Vaccines ID CD8-ALPHA(+) DENDRITIC CELLS; ANTIGEN-PRESENTING CELLS; IN-VIVO; PLASMODIUM-BERGHEI; SKIN-RESIDENT; CIRCUMSPOROZOITE PROTEIN; LANGERHANS CELLS; GAMMA-INTERFERON; IMMUNITY; INFECTION AB Parasitic protozoa cause considerable disease in humans and, due to their intracellular life cycle, induce robust CD8(+) T cell responses. A greater understanding of the factors that promote and maintain CD8(+) T cell-mediated immunity against these pathogens is likely needed for the development of effective vaccines. Immunization with radiation-attenuated sporozoites, the infectious stage of the malaria parasite transmitted by mosquitoes, is an excellent model to study these questions as CD8(+) T cells specific for a single epitope can completely eliminate parasite infection in the liver. Furthermore, live, radiation-attenuated parasites represent the "gold standard" for malaria vaccination. Here, we will highlight recent studies aimed at understanding the factors required for the induction, recruitment, and maintenance of effector and memory CD8(+) T cells against malaria liver stages. C1 [Radtke, Andrea J.] NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Tse, Sze-Wah] Harvard Univ, Sch Med, Childrens Hosp Boston, Program Cellular & Mol Med, Boston, MA USA. [Zavala, Fidel] Johns Hopkins Bloomberg Sch Publ Hlth, Johns Hopkins Malaria Res Inst, Baltimore, MD 21205 USA. [Zavala, Fidel] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA. RP Zavala, F (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Johns Hopkins Malaria Res Inst, Baltimore, MD 21205 USA. EM fzavala@jhsph.edu FU NIAID, NIH; NIH [AI44375] FX This work was supported in part by the Intramural Research Program, NIAID, NIH; AJR was supported by the Intramural Research Program of NIAID, NIH. FZ is supported by NIH grant AI44375. NR 85 TC 4 Z9 4 U1 2 U2 4 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1863-2297 EI 1863-2300 J9 SEMIN IMMUNOPATHOL JI Semin. Immunopathol. PD MAY PY 2015 VL 37 IS 3 BP 211 EP 220 DI 10.1007/s00281-015-0479-3 PG 10 WC Immunology; Pathology SC Immunology; Pathology GA CI5NU UT WOS:000354804700002 PM 25917387 ER PT J AU Maccarrone, M Bab, R Biro, T Cabral, GA Dey, SK Di Marzo, V Konje, JC Kunos, G Mechoulam, R Pacher, P Sharkey, KA Zimmer, A AF Maccarrone, Mauro Bab, Rai Biro, Tamas Cabral, Guy A. Dey, Sudhansu K. Di Marzo, Vincenzo Konje, Justin C. Kunos, George Mechoulam, Raphael Pacher, Pal Sharkey, Keith A. Zimmer, Andreas TI Endocannabinoid signaling at the periphery: 50 years after THC SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review DE bone; cardiovascular system; gastrointestinal tract; immune system; liver; localization; muscle; female and male reproductive system; signaling pathways; skin ID ACID AMIDE HYDROLASE; ESOPHAGEAL SPHINCTER RELAXATIONS; SYMPATHETIC-NERVOUS-SYSTEM; CANNABINOID CB2 RECEPTOR; OBESE ZUCKER RATS; INDUCED BONE LOSS; SKELETAL-MUSCLE; MONOACYLGLYCEROL LIPASE; GASTROINTESTINAL MOTILITY; ENERGY-EXPENDITURE AB In 1964, the psychoactive ingredient of Cannabis sativa, Delta(9)-tetrahydrocannabinol (THC), was isolated. Nearly 30 years later the endogenous counterparts of THC, collectively termed endocannabinoids (eCBs), were discovered: N-arachidonoylethanolamine (anandamide) (AEA) in 1992 and 2-arachidonoylglycerol (2-AG) in 1995. Since then, considerable research has shed light on the impact of eCBs on human health and disease, identifying an ensemble of proteins that bind, synthesize, and degrade them and that together form the eCB system (ECS). eCBs control basic biological processes including cell choice between survival and death and progenitor/stem cell proliferation and differentiation. Unsurprisingly, in the past two decades eCBs have been recognized as key mediators of several aspects of human pathophysiology and thus have emerged to be among the most widespread and versatile signaling molecules ever discovered. Here some of the pioneers of this research field review the state of the art of critical eCB functions in peripheral organs. Our community effort is aimed at establishing consensus views on the relevance of the peripheral ECS for human health and disease pathogenesis, as well as highlighting emerging challenges and therapeutic hopes. C1 [Maccarrone, Mauro] Campus Biomed Univ, Ctr Integrated Res, Rome, Italy. [Maccarrone, Mauro] Santa Lucia Fdn IRCCS, Ctr Brain Res, Rome, Italy. [Bab, Rai] Hebrew Univ Jerusalem, Fac Med, Bone Lab, Jerusalem, Israel. [Bab, Rai; Mechoulam, Raphael] Hebrew Univ Jerusalem, Fac Med, Inst Drug Res, Jerusalem, Israel. [Biro, Tamas] Debrecen Univ Med, Fac Med, Dept Physiol, MTA Lendulet Cellular Physiol Res Grp, H-4012 Debrecen, Hungary. [Cabral, Guy A.] Virginia Commonwealth Univ, Dept Microbiol & Immunol, Richmond, VA 23298 USA. [Dey, Sudhansu K.] Cincinnati Childrens Res Fdn, Div Reprod Sci, Cincinnati, OH USA. [Di Marzo, Vincenzo] CNR, Inst Biomol Chem, Endocannabinoid Res Grp, Pozzuoli, Italy. [Konje, Justin C.] Sidra Med & Res Ctr, Dept Obstet & Gynaecol, Doha, Qatar. [Kunos, George; Pacher, Pal] NIAAA, Bethesda, MD USA. [Sharkey, Keith A.] Univ Calgary, Cumming Sch Med, Hotchkiss Brain Inst, Dept Physiol & Pharmacol, Calgary, AB T2N 1N4, Canada. [Zimmer, Andreas] Univ Bonn, Inst Mol Psychiat, Bonn, Germany. RP Maccarrone, M (reprint author), Campus Biomed Univ, Ctr Integrated Res, Rome, Italy. EM m.maccarrone@unicampus.it RI Pacher, Pal/B-6378-2008; OI Pacher, Pal/0000-0001-7036-8108; Di Marzo, Vincenzo/0000-0002-1490-3070 FU Italian Ministero dell'Istruzione, dell'Universita e della Ricerca (grant PRIN ); Canadian Institutes of Health Research; National Institutes of Health (NIH)/National Institute on Drug Abuse (NIDA) [DA06668]; Deutsche Forschungsgemeinschaft (Cluster of Excellence 'Immunosensation') [FOR926] FX M.M. thanks Professor Alessandro Finazzi Agro (Campus Bio-Medico University, Rome, Italy) for his continuing interest and support and Dr Monica Bath (University of Rome Tor Vergata, Rome, Italy) for the male fertility artwork. G.C. thanks Dr Melissa Jamerson (Virginia Commonwealth University, Richmond, VA, USA) for her help in writing the immune system section and T.B. thanks Dr Attila Olah (University of Debrecen, Debrecen, Hungary) for his help in organizing the skin section. M.M. was supported by the Italian Ministero dell'Istruzione, dell'Universita e della Ricerca (grant PRIN 2010-2011), K.A.S. by the Canadian Institutes of Health Research, S.K.D. by the National Institutes of Health (NIH)/National Institute on Drug Abuse (NIDA) (grant DA06668), and A.Z. by the Deutsche Forschungsgemeinschaft (Cluster of Excellence 'Immunosensation', FOR926). NR 179 TC 60 Z9 62 U1 8 U2 45 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD MAY PY 2015 VL 36 IS 5 BP 277 EP 296 DI 10.1016/j.tips.2015.02.008 PG 20 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CI8TS UT WOS:000355045200004 PM 25796370 ER PT J AU Premo, C Apolo, AB Agarwal, PK Citrin, DE AF Premo, Christopher Apolo, Andrea B. Agarwal, Piyush K. Citrin, Deborah E. TI Trimodality Therapy in Bladder Cancer Who, What, and When? SO UROLOGIC CLINICS OF NORTH AMERICA LA English DT Article ID TRANSITIONAL-CELL-CARCINOMA; COMBINED-MODALITY THERAPY; LONG-TERM OUTCOMES; SELECTIVE ORGAN PRESERVATION; GROWTH-FACTOR RECEPTOR; QUALITY-OF-LIFE; RADIATION-THERAPY; TRANSURETHRAL RESECTION; RADICAL RADIOTHERAPY; ONCOLOGY-GROUP AB Radical cystectomy is a standard treatment of nonmetastatic, muscle-invasive bladder cancer. Treatment with trimodality therapy consisting of maximal transurethral resection of the bladder tumor followed by concurrent chemotherapy and radiation has emerged as a method to preserve the native bladder in highly motivated patients. Several factors can affect the likelihood of long-term bladder preservation after trimodality therapy and therefore should be taken into account when selecting patients. New radiation techniques such as intensity modulated radiation therapy and image-guided radiation therapy may decrease the toxicity of radiotherapy in this setting. Novel chemotherapy regimens may improve response rates and minimize toxicity. C1 [Premo, Christopher; Citrin, Deborah E.] NIH, Radiat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Apolo, Andrea B.] NCI, Bladder Canc Sect, Genitourinary Malignancies Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Agarwal, Piyush K.] NCI, Bladder Canc Sect, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Citrin, DE (reprint author), NIH, Radiat Oncol Branch, Ctr Canc Res, 10 CRC,B2-3500, Bethesda, MD 20892 USA. EM citrind@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 55 TC 0 Z9 0 U1 2 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0094-0143 EI 1558-318X J9 UROL CLIN N AM JI Urol. Clin. N. Am. PD MAY PY 2015 VL 42 IS 2 BP 169 EP + DI 10.1016/j.ucl.2015.02.002 PG 13 WC Urology & Nephrology SC Urology & Nephrology GA CI2OZ UT WOS:000354588200005 PM 25882559 ER PT J AU Koonin, EV Dolja, VV Krupovic, M AF Koonin, Eugene V. Dolja, Valerian V. Krupovic, Mart TI Origins and evolution of viruses of eukaryotes: The ultimate modularity SO VIROLOGY LA English DT Review DE Evolution of viruses; Transposable elements; Polintons; Bacteriophages; Recombination; Functional gene modules ID SINGLE-STRANDED-DNA; GROUP-II INTRON; DEPENDENT RNA-POLYMERASES; MEMBRANE-FUSION PROTEINS; HORIZONTAL GENE-TRANSFER; ENCODED REVERSE-TRANSCRIPTASE; SOYBEAN CYST-NEMATODE; MOVEMENT PROTEINS; ARCHAEAL VIRUSES; PLANT-VIRUSES AB Viruses and other selfish genetic elements are dominant entities in the biosphere, with respect to both physical abundance and genetic diversity. Various selfish elements parasitize on all cellular life forms. The relative abundances of different classes of viruses are dramatically different between prokaryotes and eukaryotes. In prokaryotes, the great majority of viruses possess double-stranded (ds) DNA genomes, with a substantial minority of single-stranded (ss) DNA viruses and only limited presence of RNA viruses. In contrast, in eukaryotes, RNA viruses account for the majority of the virome diversity although ssDNA and dsDNA viruses are common as well. Phylogenomic analysis yields tangible clues for the origins of major classes of eukaryotic viruses and in particular their likely roots in prokaryotes. Specifically, the ancestral genome of positive-strand RNA viruses of eukaryotes might have been assembled de novo from genes derived from prokaryotic retroelements and bacteria although a primordial origin of this class of viruses cannot be ruled out. Different groups of double-stranded RNA viruses derive either from dsRNA bacteriophages or from positive-strand RNA viruses. The eukaryotic ssDNA viruses apparently evolved via a fusion of genes from prokaryotic rolling circle-replicating plasmids and positive-strand RNA viruses. Different families of eukaryotic dsDNA viruses appear to have originated from specific groups of bacteriophages on at least two independent occasions. Polintons, the largest known eukaryotic transposons, predicted to also form virus particles, most likely, were the evolutionary intermediates between bacterial tectiviruses and several groups of eukaryotic dsDNA viruses including the proposed order "Megavirales" that unites diverse families of large and giant viruses. Strikingly, evolution of all classes of eukaryotic viruses appears to have involved fusion between structural and replicative gene modules derived from different sources along with additional acquisitions of diverse genes. Published by Elsevier Inc. C1 [Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Dolja, Valerian V.] Oregon State Univ, Dept Bot & Plant Pathol, Corvallis, OR 97331 USA. [Krupovic, Mart] Inst Pasteur, Dept Microbiol, Unite Biol Mol Gene Chez Extremophiles, F-75015 Paris, France. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov; doljav@science.oregonstate.edu; krupovic@pasteur.fr RI Krupovic, Mart/I-4209-2012 OI Krupovic, Mart/0000-0001-5486-0098 FU US Department of Health and Human Services (National Library of Medicine) FX The authors thank David Karlin and Tero Ahola for the kind permission to cite the results of their work before publication. EVK is supported by the intramural funds of the US Department of Health and Human Services (National Library of Medicine). NR 279 TC 42 Z9 43 U1 14 U2 82 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAY PY 2015 VL 479 SI SI BP 2 EP 25 DI 10.1016/j.virol.2015.02.039 PG 24 WC Virology SC Virology GA CI6YG UT WOS:000354909500001 PM 25771806 ER PT J AU Morelli, M Ogden, KM Patton, JT AF Morelli, Marco Ogden, Kristen M. Patton, John T. TI Silencing the alarms: Innate immune antagonism by rotavirus NSP1 and VP3 SO VIROLOGY LA English DT Review DE Rotavirus; Innate immunity; Interferon signaling pathway; OAS/RNase L pathway; beta-TrCP; NE-kappa B; Viral E3 ubiquitin ligase; Viral phosphodiesterase ID HOST-RANGE RESTRICTION; DOUBLE-STRANDED-RNA; GROUP-A ROTAVIRUS; GROUP-B ROTAVIRUS; NF-KAPPA-B; INTERFERON-REGULATORY-FACTORS; SEQUENCE-ANALYSIS; BOVINE ROTAVIRUS; RIG-I; GUANYLYLTRANSFERASE ACTIVITY AB The innate immune response involves a broad array of pathogen sensors that stimulate the production of interferons (IFNs) to induce an antiviral state. Rotavirus, a significant cause of childhood gastroenteritis and a member of the Reoviridae family of segmented, double-stranded RNA viruses, encodes at least two direct antagonists of host innate immunity: NSP1 and VP3. NSP1, a putative E3 ubiquitin ligase, mediates the degradation of cellular factors involved in both IFN induction and downstream signaling. VP3, the viral capping enzyme, utilizes a 2H-phosphodiesterase domain to prevent activation of the cellular oligoadenylate synthase (OAS)/RNase L pathway. Computational, molecular, and biochemical studies have provided key insights into the structural and mechanistic basis of innate immune antagonism by NSPI and VP3 of group A rotaviruses (RVA). Future studies with non-RVA isolates will be essential to understand how other rotavirus species evade host innate immune responses. Published by Elsevier Inc. C1 [Morelli, Marco; Ogden, Kristen M.; Patton, John T.] NIAID, Rotavirus Mol Biol Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Patton, JT (reprint author), NIAID, Infect Dis Lab, NIH, 50 South Dr,Room 6308, Bethesda, MD 20892 USA. EM jpattn76@vt.edu FU National Institute of Allergy and Infectious Diseases at the National Institutes of Health [Z1A AI000754, Z1A AI000788] FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health (Z1A AI000754 and Z1A AI000788). NR 102 TC 5 Z9 6 U1 2 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAY PY 2015 VL 479 SI SI BP 75 EP 84 DI 10.1016/j.virol.2015.01.006 PG 10 WC Virology SC Virology GA CI6YG UT WOS:000354909500007 PM 25724417 ER PT J AU Sutton, TC Subbarao, K AF Sutton, Troy C. Subbarao, Kanta TI Development of animal models against emerging coronaviruses: From SARS to MERS coronavirus SO VIROLOGY LA English DT Review DE Coronaviruses; SARS-CoV; MERS-CoV; Animal models; Receptor ID ACUTE RESPIRATORY SYNDROME; GOLDEN-SYRIAN-HAMSTERS; DIPEPTIDYL PEPTIDASE 4; ANGIOTENSIN-CONVERTING ENZYME-2; HUMAN MONOCLONAL-ANTIBODY; MIDDLE-EAST; FUNCTIONAL RECEPTOR; DROMEDARY CAMELS; RHESUS MACAQUES; SAUDI-ARABIA AB Two novel coronaviruses have emerged to cause severe disease in humans. While bats may be the primary reservoir for both viruses, SARS coronavirus (SARS-CoV) likely crossed into humans from civets in China, and MERS coronavirus (MERS-CoV) has been transmitted from camels in the Middle East. Unlike SARS-CoV that resolved within a year, continued introductions of MERS-CoV present an on-going public health threat. Animal models are needed to evaluate countermeasures against emerging viruses. With SARS-CoV, several animal species were permissive to infection. In contrast, most laboratory animals are refractory or only semi-permissive to infection with MERS-CoV. This host-range restriction is largely determined by sequence heterogeneity in the MERS-CoV receptor. We describe animal models developed to study coronaviruses, with a focus on host-range restriction at the level of the viral receptor and discuss approaches to consider in developing a model to evaluate countermeasures against MERS-CoV. (C) 2015 Published by Elsevier Inc. C1 [Sutton, Troy C.; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20817 USA. RP Subbarao, K (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20817 USA. EM ksubbarao@niaid.nih.gov FU Division of Intramural Research, NIAID, NIH FX Research in the authors lab was supported by the Division of Intramural Research, NIAID, NIH. NR 114 TC 5 Z9 5 U1 2 U2 18 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAY PY 2015 VL 479 SI SI BP 247 EP 258 DI 10.1016/j.virol.2015.02.030 PG 12 WC Virology SC Virology GA CI6YG UT WOS:000354909500023 PM 25791336 ER PT J AU Kuhn, RJ Dowd, KA Post, CB Pierson, TC AF Kuhn, Richard J. Dowd, Kimberly A. Post, Carol Beth Pierson, Theodore C. TI Shake, rattle, and roll: Impact of the dynamics of flavivirus particles on their interactions with the host SO VIROLOGY LA English DT Review DE Flavivirus; West Nile virus; Dengue virus; Viral breathing; Structural dynamics; Antibody-mediated neutralization ID WEST-NILE-VIRUS; BORNE ENCEPHALITIS-VIRUS; INDUCED CONFORMATIONAL-CHANGE; RHINOVIRUS CAPSID DYNAMICS; COMMON COLD VIRUS; DENGUE VIRUS; ENVELOPE GLYCOPROTEIN; DOMAIN-III; NEUTRALIZING ANTIBODIES; MONOCLONAL-ANTIBODIES AB Remarkable progress in structural biology has equipped virologists with insight into structures of viral proteins and virions at increasingly high resolution. Structural information has been used extensively to address fundamental questions about virtually all aspects of how viruses replicate in cells, interact with the host, and in the design of antiviral compounds. However, many critical aspects of virology exist outside the snapshots captured by traditional methods used to generate high-resolution structures. Like all proteins, viral proteins are not static structures. The conformational flexibility and dynamics of proteins play a significant role in protein-protein interactions, and in the structure and biology of virus particles. This review will discuss the implications of the dynamics of viral proteins on the biology, antigenicity, and immunogenicity of flaviviruses. Published by Elsevier Inc. C1 [Kuhn, Richard J.] Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA. [Kuhn, Richard J.] Purdue Univ, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. [Dowd, Kimberly A.; Pierson, Theodore C.] NIAID, Viral Pathogenesis Sect, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Post, Carol Beth] Purdue Univ, Dept Med Chem, W Lafayette, IN 47907 USA. [Post, Carol Beth] Purdue Univ, Dept Mol Pharmacol, W Lafayette, IN 47907 USA. RP Pierson, TC (reprint author), NIH, Viral Pathogenesis Sect, Viral Dis Lab, 33 North Dr,Bldg 33,Room 2E19A-2, Bethesda, MD 20892 USA. EM kuhnr@purdue.edu; dowdka@mail.nih.gov; cbp@purdue.edu; piersontc@mail.nih.gov FU National Institute of Allergy and Infectious Disease [AI000957] FX We thank members of our laboratories for their comments on this manuscript. This work was supported by the intramural program of the National Institute of Allergy and Infectious Disease (AI000957). NR 125 TC 12 Z9 13 U1 2 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAY PY 2015 VL 479 SI SI BP 508 EP 517 DI 10.1016/j.virol.2015.03.025 PG 10 WC Virology SC Virology GA CI6YG UT WOS:000354909500045 PM 25835729 ER PT J AU Kristie, TM AF Kristie, Thomas M. TI Dynamic modulation of HSV chromatin drives initiation of infection and provides targets for epigenetic therapies SO VIROLOGY LA English DT Review DE Herpes simplex virus; Chromatin; Demethylase; LSD1; JMJD2; HCF-1; Latency ID HERPES-SIMPLEX-VIRUS; IMMEDIATE-EARLY PROMOTERS; REPRESSIVE HISTONE MARKS; ZINC-FINGER PROTEINS; HOST-CELL FACTOR; GENE-EXPRESSION; LYTIC INFECTION; UNSTABLE NUCLEOSOMES; COACTIVATOR HCF-1; LATENT INFECTION AB Upon infection, the genomes of herpesviruses undergo a striking transition from a non-nucleosomal structure to a chromatin structure. The rapid assembly and modulation of nucleosomes during the initial stage of infection results in an overlay of complex regulation that requires interactions of a plethora of chromatin modulation components. For herpes simplex virus, the initial chromatin dynamic is dependent on viral and host cell transcription factors and coactivators that mediate the balance between heterochromatic suppression of the viral genome and the euchromatin transition that allows and promotes the expression of viral immediate early genes. Strikingly similar to lytic infection, in sensory neurons this dynamic transition between heterochromatin and euchromatin governs the establishment, maintenance, and reactivation from the latent state. Chromatin dynamics in both the lytic infection and latency-reactivation cycles provides opportunities to shift the balance using small molecule epigenetic modulators to suppress viral infection, shedding, and reactivation from latency. Published by Elsevier Inc. C1 NIAID, Mol Genet Sect, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Kristie, TM (reprint author), NIAID, Mol Genet Sect, Viral Dis Lab, NIH, Bld 33,Rm 3W20B-7 33 North Dr, Bethesda, MD 20892 USA. EM tkristie@niaid.nih.gov FU Intramural Research Division of the National Institutes of Allergy and Infectious Diseases, National Institutes of Health FX Due to the focused nature of this review, it was not possible to cite all of the important primary contributions to this field. I thank J.H. Arbuckle and A.M. Turner for constructive comments on this manuscript. Studies of the Molecular Genetics Section and the preparation of this review were supported by the Intramural Research Division of the National Institutes of Allergy and Infectious Diseases, National Institutes of Health. NR 70 TC 9 Z9 9 U1 2 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAY PY 2015 VL 479 SI SI BP 555 EP 561 DI 10.1016/j.virol.2015.01.026 PG 7 WC Virology SC Virology GA CI6YG UT WOS:000354909500049 PM 25702087 ER PT J AU Liu, XQ Cohen, JI AF Liu, XueQiao Cohen, Jeffrey I. TI The role of PI3K/Akt in human herpesvirus infection: From the bench to the bedside SO VIROLOGY LA English DT Review DE PI3K; Akt; Herpesvirus; Herpes simplex; Varicella-zoster; Cytomegalovirus; Epstein-Barr virus; Kaposi's sarcoma associated herpesvirus ID EPSTEIN-BARR-VIRUS; SARCOMA-ASSOCIATED HERPESVIRUS; PROTEIN-COUPLED RECEPTOR; PHOSPHATIDYLINOSITOL 3-KINASE/AKT PATHWAY; B-CELL LYMPHOMAS; POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDERS; PROLIFERATION SIGNAL INHIBITORS; RENAL-TRANSPLANT RECIPIENTS; ENDOTHELIAL GROWTH-FACTOR; FOCAL ADHESION KINASE AB The phosphatidylinositol-3-kinase (PI3K)-Akt signaling pathway regulates several key cellular functions including protein synthesis, cell growth, glucose metabolism, and inflammation. Many viruses have evolved mechanisms to manipulate this signaling pathway to ensure successful virus replication. The human herpesviruses undergo both latent and lytic infection, but differ in cell tropism, growth kinetics, and disease manifestations. Herpesviruses express multiple proteins that target the PI3K/Akt cell signaling pathway during the course of their life cycle to facilitate viral infection, replication, latency, and reactivation. Rare human genetic disorders with mutations in either the catalytic or regulatory subunit of PI3K that result in constitutive activation of the protein predispose to severe herpesvirus infections as well as to virus-associated malignancies. Inhibiting the PI3K/Akt pathway or its downstream proteins using drugs already approved for other diseases can block herpesvirus lytic infection and may reduce malignancies associated with latent herpesvirus infections. Published by Elsevier Inc. C1 [Liu, XueQiao; Cohen, Jeffrey I.] NIAID, Med Virol Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Cohen, JI (reprint author), NIH, Infect Dis Lab, Bldg 50,Room 6134,50 South Dr,MSC8007, Bethesda, MD 20892 USA. EM jcohen@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases FX This work was supported by the intramural research program of the National Institute of Allergy and Infectious Diseases. NR 150 TC 8 Z9 8 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAY PY 2015 VL 479 SI SI BP 568 EP 577 DI 10.1016/j.virol.2015.02.040 PG 10 WC Virology SC Virology GA CI6YG UT WOS:000354909500051 PM 25798530 ER PT J AU Moss, B AF Moss, Bernard TI Poxvirus membrane biogenesis SO VIROLOGY LA English DT Review DE Vaccinia virus; Endoplasmic reticulum; Viral membrane proteins; Virus morphogenesis ID VACCINIA VIRUS MORPHOGENESIS; GOLGI INTERMEDIATE COMPARTMENT; NASCENT VIRAL MEMBRANES; A17L ENVELOPE PROTEIN; ENDOPLASMIC-RETICULUM; VIRION MEMBRANE; IMMATURE VIRIONS; MATURE VIRION; BREFELDIN-A; F10 KINASE AB Poxviruses differ from most DNA viruses by replicating entirely within the cytoplasm. The first discernible viral structures are crescents and spherical immature virions containing a single lipoprotein membrane bilayer with an external honeycomb lattice. Because this viral membrane displays no obvious continuity with a cellular organelle, a de novo origin was suggested. Nevertheless, transient connections between viral and cellular membranes could be difficult to resolve. Despite the absence of direct evidence, the intermediate compartment (ERGIC) between the endoplasmic reticulum (ER) and Golgi apparatus and the ER itself were considered possible sources of crescent membranes. A break-through in understanding poxvirus membrane biogenesis has come from recent studies of the abortive replication of several vaccinia virus null mutants. Novel images showing continuity between viral crescents and the ER and the accumulation of immature virions in the expanded ER lumen provide the first direct evidence for a cellular origin of this poxvirus membrane. Published by Elsevier Inc. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM bmoss@nih.gov OI Moss, Bernard/0000-0002-2154-8564 FU Division of Intramural Research, NIAID, NIH FX The author thanks A. Weisberg and L Maruri-Avidal for discussions during the course of the research that led to the model of poxvirus membrane biogenesis. A. Weisberg kindly provided the electron microscopy images. The work was supported by the Division of Intramural Research, NIAID, NIH. NR 93 TC 11 Z9 11 U1 3 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAY PY 2015 VL 479 SI SI BP 619 EP 626 DI 10.1016/j.virol.2015.02.003 PG 8 WC Virology SC Virology GA CI6YG UT WOS:000354909500056 PM 25728299 ER PT J AU Fassl, SK Holzinger, D Vogl, T Gattorno, M Omenetti, A Chae, JJ Aksentijevich, I Roth, J Austermann, J AF Fassl, S. K. Holzinger, D. Vogl, T. Gattorno, M. Omenetti, A. Chae, J. J. Aksentijevich, I. Roth, J. Austermann, J. TI Pyrin and PSTPIP1, mutated in FMF, PAPA-, and PAMI syndrome, are involved in the hypersecretion of alarmins MRP8/14 SO EUROPEAN JOURNAL OF CLINICAL INVESTIGATION LA English DT Meeting Abstract C1 [Fassl, S. K.; Holzinger, D.; Vogl, T.; Roth, J.; Austermann, J.] Univ Munster, Inst Immunol, D-48149 Munster, Germany. [Holzinger, D.] Univ Childrens Hosp Munster, Dept Paediat Rheumatol & Immunol, Munster, Germany. [Gattorno, M.; Omenetti, A.] G Gaslini Sci Inst, Div Pediat 2, Genoa, Italy. [Chae, J. J.; Aksentijevich, I.] NHGRI, 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 0014-2972 EI 1365-2362 J9 EUR J CLIN INVEST JI Eur. J. Clin. Invest. PD MAY PY 2015 VL 45 SU 2 SI SI MA 5.31 BP 56 EP 56 PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA CH6CZ UT WOS:000354124800155 ER PT J AU Fenster, CB Reynolds, RJ Williams, CW Makowsky, R Dudash, MR AF Fenster, Charles B. Reynolds, Richard J. Williams, Christopher W. Makowsky, Robert Dudash, Michele R. TI Quantifying hummingbird preference for floral trait combinations: The role of selection on trait interactions in the evolution of pollination syndromes SO EVOLUTION LA English DT Article DE Correlational selection; floral evolution; pollination syndromes; trait interaction ID SILENE-VIRGINICA CARYOPHYLLACEAE; RADISH RAPHANUS-RAPHANISTRUM; NORTH-AMERICAN SILENE; NATURAL-SELECTION; CORRELATIONAL SELECTION; MEDIATED SELECTION; SPUR LENGTH; MORPHOLOGICAL INTEGRATION; PHENOTYPIC VARIATION; GYMNADENIA-CONOPSEA AB Darwin recognized the flower's importance for the study of adaptation and emphasized that the flower's functionality reflects the coordinated action of multiple traits. Here we use a multitrait manipulative approach to quantify the potential role of selection acting on floral trait combinations underlying the divergence and maintenance of three related North American species of Silene (Caryophyllaceae). We artificially generated 48 plant phenotypes corresponding to all combinations of key attractive traits differing among the three Silene species (color, height, inflorescence architecture, flower orientation, and corolla-tube width). We quantified main and interaction effects of trait manipulation on hummingbird visitation preference using experimental arrays. The main effects of floral display height and floral orientation strongly influenced hummingbird visitation, with hummingbirds preferring flowers held high above the ground and vertically to the sky. Hummingbirds also prefer traits in a nonadditive manner as multiple two-way and higher order interaction effects were important predictors of hummingbird visitation. Contemporary trait combinations found in hummingbird pollinated S. virginica are mostly preferred. Our study demonstrates the likelihood of pollination syndromes evolving due to selection on trait combinations and highlights the importance of trait interactions in understanding the evolution of complex adaptations. C1 [Fenster, Charles B.; Reynolds, Richard J.; Dudash, Michele R.] Univ Maryland, Dept Biol, College Pk, MD 20742 USA. [Fenster, Charles B.; Reynolds, Richard J.; Williams, Christopher W.; Dudash, Michele R.] Mt Lake Biol Stn, Pembroke, VA 24136 USA. [Reynolds, Richard J.] Univ Alabama Birmingham, Dept Med, Div Clin Immunol & Rheumatol, Birmingham, AL USA. [Williams, Christopher W.] Frostburg State Univ, Frostburg, MD 21502 USA. [Williams, Christopher W.] NIDDK, NIH, Bethesda, MD 20892 USA. RP Fenster, CB (reprint author), Univ Maryland, Dept Biol, College Pk, MD 20742 USA. EM cfenster@umd.edu FU Mountain Lake Biological Station (University of Virginia); NSF REU-Sites award [DBI-0453380]; NSF [DEB-0108285] FX We thank H. Wilbur and E. Nagy for logistical assistance, M. Benton, K. Fenster, and T. Fenster for field assistance, F. Brewer for photographic assistance, J. Conner, K. Fenster, J. Recknor, and J. McGlothlin for comments on the manuscript, S. Arnold and B. Brodie for thoughtful discussion, and two anonymous reviewers and the AE, Dr. M. Streisfield, for their constructive criticism. Research was sponsored by the Mountain Lake Biological Station (University of Virginia) to R. Reynolds, M. Dudash, and C. Fenster and NSF REU-Sites award DBI-0453380 to C. Williams and NSF DEB-0108285 to C. Fenster and M. Dudash. Data Archival Location: 10.5061/dryad.754c6 NR 77 TC 11 Z9 11 U1 14 U2 96 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-3820 EI 1558-5646 J9 EVOLUTION JI Evolution PD MAY PY 2015 VL 69 IS 5 BP 1113 EP 1127 DI 10.1111/evo.12639 PG 15 WC Ecology; Evolutionary Biology; Genetics & Heredity SC Environmental Sciences & Ecology; Evolutionary Biology; Genetics & Heredity GA CI2FT UT WOS:000354561600002 PM 25765062 ER PT J AU Jaramillo-Lambert, A Fuchsman, AS Fabritius, AS Smith, HE Golden, A AF Jaramillo-Lambert, Aimee Fuchsman, Abigail S. Fabritius, Amy S. Smith, Harold E. Golden, Andy TI Rapid and Efficient Identification of Caenorhabditis elegans Legacy Mutations Using Hawaiian SNP-Based Mapping and Whole-Genome Sequencing SO G3-GENES GENOMES GENETICS LA English DT Article DE whole-genome sequencing; Hawaiian SNP mapping; CRISPR/Cas9; essential genes; cdc-25 ID EMBRYONIC ARREST MUTANTS; C. ELEGANS; DEVELOPMENTAL DEFECTS; BACTERIOPHAGE T4D; LETHAL MUTATIONS; GENETIC-ANALYSIS; DNA-REPLICATION; CELL DIVISIONS; EXPRESSION; EMBRYOGENESIS AB The production of viable embryos requires the coordination of many cellular processes, including protein synthesis, cytoskeletal reorganization, establishment of polarity, cell migration, cell division, and in Caenorhabditis elegans, eggshell formation. Defects in any of these processes can lead to embryonic lethality. We examined six temperature-sensitive mutants as well as one nonconditional mutant that were previously identified in genetic screens as either embryonic lethal (maternal-effect or zygotic lethal) or eggshell defective. The responsible molecular lesion for each had never been determined. After confirmation of temperature sensitivity and lethality, we performed whole-genome sequencing using a single-nucleotide polymorphism mapping strategy to pinpoint the molecular lesions. Gene candidates were confirmed by RNA interference phenocopy and/or complementation tests and one mutant was further validated by CRISPR (Clustered Regularly Interspaced Short Palidromic Repeats)/Cas9 gene editing. This approach identified new alleles of several genes that had only been previously studied by RNA interference depletion. Our identification of temperature-sensitive alleles for all of these essential genes provides an extremely useful tool for further investigation for the C. elegans community, such as the ability to address mutant phenotypes at various developmental stages and the ability to carry out suppressor/enhancer screens to identify other genes that function in a specific cellular process. C1 [Jaramillo-Lambert, Aimee; Fuchsman, Abigail S.; Fabritius, Amy S.; Smith, Harold E.; Golden, Andy] NIDDK, NIH, Bethesda, MD 20892 USA. RP Golden, A (reprint author), NIDDK, LBG, NIH, 8 Ctr Dr,Bldg 8,Room 323, Bethesda, MD 20892 USA. EM andyg@mail.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases; NIH Office of Research Infrastructure Programs [P40 OD010440] FX We thank S. Kim for generating and analyzing emb-14 recombinants and comments regarding the manuscript. We also thank A. Walters and K. O'Connell for their advice and comments on the manuscript. This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases. Some nematode strains used in this work were provided by the Caenorhabditis Genetics Center, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). Some deletion allele strains were provided by the National Bioresource Project in Japan lead by S. Mitani. NR 48 TC 4 Z9 4 U1 3 U2 7 PU GENETICS SOCIETY AMERICA PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 2160-1836 J9 G3-GENES GENOM GENET JI G3-Genes Genomes Genet. PD MAY 1 PY 2015 VL 5 IS 5 BP 1007 EP 1019 DI 10.1534/g3.115.017038 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA CH8BX UT WOS:000354262000027 PM 25740937 ER PT J AU Temkin, SM AF Temkin, Sarah M. TI "Less is more:" The harms of overtreatment in early ovarian cancer SO GYNECOLOGIC ONCOLOGY LA English DT Editorial Material ID CARE C1 NCI, Community Oncol & Prevent Trials Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. RP Temkin, SM (reprint author), NCI, Community Oncol & Prevent Trials Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. NR 8 TC 1 Z9 1 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAY PY 2015 VL 137 IS 2 BP 191 EP 192 DI 10.1016/j.ygyno.2015.04.007 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA CI1KW UT WOS:000354504100001 PM 25953509 ER PT J AU Diaz-Padilla, I Wilson, MK Clarke, BA Hirte, HW Welch, SA Mackay, HJ Biagi, JJ Reedijk, M Weberpals, JI Fleming, GF Wang, LS Liu, G Zhou, C Blattler, C Ivy, SP Oza, AM AF Diaz-Padilla, Ivan Wilson, Michelle K. Clarke, Blaise A. Hirte, Hal W. Welch, Stephen A. Mackay, Helen J. Biagi, Jim J. Reedijk, Michael Weberpals, Johanne I. Fleming, Gini F. Wang, Lisa Liu, Geoffrey Zhou, Chen Blattler, Chantale Ivy, S. Percy Oza, Arnit M. TI A phase II study of single-agent RO4929097, a gamma-secretase inhibitor of Notch signaling, in patients with recurrent platinum-resistant epithelial ovarian cancer: A study of the Princess Margaret, Chicago and California phase II consortia SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Ovarian cancer; Gamma-secretase inhibitor; RO4929097; Notch; Phase II clinical trial ID ADVANCED SOLID TUMORS; STEM-CELLS; TARGETING NOTCH; BREAST-CANCER; SEROUS CARCINOMA; PATHWAY; SURVIVAL; GROWTH; CHEMORESISTANCE; OVEREXPRESSION AB Purpose. A phase II study was performed to evaluate the efficacy and safety of single-agent RO4929097 (a gamma-secretase inhibitor) in patients with recurrent platinum-resistant ovarian cancer. Experimental design. Women with progressive platinum-resistant ovarian cancer treated with <= 2 chemotherapy regimens for recurrent disease were enrolled in this trial. Patients received oral RO4929097 at 20 mg once daily, 3 days on/4 days off each week in a three week cycle. The primary endpoint was progression-free survival (PFS) rate at the end of 4 cycles. Secondary objectives included assessment of the safety of RO4929097 and exploration of molecular correlates of outcome in archival tumor tissue and serum. Results. Of 45 patients enrolled, 40 were evaluable for response. Thirty-seven (82%) patients had high-grade ovarian cancer. No objective responses were observed. Fifteen patients (33%) had stable disease as their best response, with a median duration of 3.1 months. The median PFS for the whole group was 1.3 months (1.2-2.5). Treatment was generally well tolerated with 10% of patients discontinuing treatment due to an adverse event. In high grade serous ovarian cancer patients, the median PFS trended higher when the expression of intracellular Notch (NICD) protein by immunohistochemistry was high versus low (3.3 versus 13 months, p = 0.09). No clear relationship between circulating angiogenic factors and PFS was found despite a suggestion of an improved outcome with higher baseline VEGFA levels. Conclusions. RO4929097 has insufficient activity as a single-agent in platinum-resistant ovarian cancer to warrant further study as monotherapy. Future studies are needed to explore the potential for cohort enrichment using NICD expression. (C) 2015 Published by Elsevier Inc. C1 [Diaz-Padilla, Ivan; Wilson, Michelle K.; Mackay, Helen J.; Wang, Lisa; Liu, Geoffrey; Zhou, Chen; Blattler, Chantale; Oza, Arnit M.] Princess Margaret Canc Ctr, Div Med Oncol & Hematol, Toronto, ON M5G 2M9, Canada. [Clarke, Blaise A.] Univ Toronto, Dept Lab Med, Toronto, ON, Canada. [Hirte, Hal W.] Juravinski Canc Ctr, Div Med Oncol, Hamilton, ON, Canada. [Welch, Stephen A.] London Reg Canc Program, Div Med Oncol, London, ON, Canada. [Biagi, Jim J.] Canc Ctr Southeastem Ontario, Dept Oncol, Kingston, ON, Canada. [Reedijk, Michael] Ontario Canc Inst, Campbell Family Inst Breast Canc Res, Toronto, ON M4X 1K9, Canada. [Weberpals, Johanne I.] Ottawa Hosp, Div Gynecol Oncol, Ottawa, ON, Canada. [Fleming, Gini F.] Univ Chicago, Med Ctr, Chicago, IL 60637 USA. [Ivy, S. Percy] NCI, Div Canc Treatment & Diag, Canc Therapy Evaluat Program, Invest Drug Branch, Rockville, MD USA. RP Oza, AM (reprint author), Princess Margaret Canc Ctr, Div Med Oncol & Hematol, 610 Univ Ave,5-700, Toronto, ON M5G 2M9, Canada. EM amit.oza@uhn.ca RI Liu, Geoffrey/N-4421-2016 FU NCI [N01-CM-2011-00032]; Jan Vermorken grant - Grupo Espanol de Investigacion en Cancer de Ovario (GEICO) FX This study has been supported by the NCI Contract No. N01-CM-2011-00032. ID-P was partially funded by the Jan Vermorken grant supported by the Grupo Espanol de Investigacion en Cancer de Ovario (GEICO). NR 47 TC 9 Z9 9 U1 0 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAY PY 2015 VL 137 IS 2 BP 216 EP 222 DI 10.1016/j.ygyno.2015.03.005 PG 7 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA CI1KW UT WOS:000354504100005 PM 25769658 ER PT J AU Miller, FG Grady, C AF Miller, Franklin G. Grady, Christine TI In Memoriam: Alan Wertheimer SO HASTINGS CENTER REPORT LA English DT Biographical-Item C1 [Miller, Franklin G.; Grady, Christine] Natl Inst Hlth, Bethesda, MD 20892 USA. RP Miller, FG (reprint author), Natl Inst Hlth, 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 0093-0334 EI 1552-146X J9 HASTINGS CENT REP JI Hastings Cent. Rep. PD MAY-JUN PY 2015 VL 45 IS 3 BP 6 EP 6 DI 10.1002/hast.450 PG 1 WC Ethics; Health Care Sciences & Services; Medical Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Health Care Sciences & Services; Medical Ethics; Biomedical Social Sciences GA CH8DC UT WOS:000354265300008 PM 25944198 ER PT J AU Freund, LS Taymans, S Wehr, E Stratakis, CA AF Freund, L. S. Taymans, S. Wehr, E. Stratakis, C. A. TI Developmental Focus on Disorders of Sex Development: Special Issue Overview SO HORMONE AND METABOLIC RESEARCH LA English DT Editorial Material DE disorders of sex development (DSD); gender development; psychosocial development; clinical management ID CONGENITAL ADRENAL-HYPERPLASIA; REPRODUCTION; RAT C1 [Freund, L. S.; Taymans, S.; Wehr, E.; Stratakis, C. A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Freund, LS (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Child Dev & Behav Branch, 6100 Execut Blvd,Room 4B05H, Bethesda, MD 20892 USA. EM lisa.freund@nih.gov FU Intramural NIH HHS NR 29 TC 1 Z9 1 U1 1 U2 7 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0018-5043 EI 1439-4286 J9 HORM METAB RES JI Horm. Metab. Res. PD MAY PY 2015 VL 47 IS 5 BP 309 EP 311 DI 10.1055/s-0035-1549880 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CH9OX UT WOS:000354366500001 PM 25970708 ER PT J AU Lossie, AC Green, J AF Lossie, A. C. Green, J. TI Building Trust: The History and Ongoing Relationships Amongst DSD Clinicians, Researchers, and Patient Advocacy Groups SO HORMONE AND METABOLIC RESEARCH LA English DT Article; Proceedings Paper CT Scientific Workshop of the National-Institute-of-Child-Health-and-Human-Development (NICHD) on Growing up with DSD - Critical Developmental Issues for Children and Families Affected by Disorders of Sex Development CY MAR 26-27, 2014 CL Bethesda, MD SP Natl Inst Child Hlth Human Dev DE androgen; fertility; ovary; testes ID SEX DEVELOPMENT DSD; PEER-SUPPORT; INTERSEX DISORDERS; MANAGEMENT; CHILDREN; RECOMMENDATIONS; DISTRESS; OUTCOMES; PARENTS; SURGERY AB Individuals born with differences or disorders of sex development (DSD) have been marginalized by society and the health care system. Standards of care in the mid-20th century were based on fixing the child with a DSD, using hormonal and surgical interventions; these treatments and the diagnoses were almost never disclosed to the child, and sometimes they were not disclosed to the parents. This led to secrecy, shame, and stigma. When these children became adults and demanded access to their medical records, the realization of the depth of secrecy led to the formation of activism groups that shook the medical community. Despite precarious beginnings, advocates, health care professionals, and researchers were able to elicit changes in the standard of care. The 2006 Consensus Statement on Management of Intersex Disorders called for a multidisciplinary approach to care and questioned the evidence for many of the standard procedures. Standard of care moved from a concealment model to a patient-centered paradigm, and funding agencies put resources into determining the future paths of research on DSD. Recognition of the need to address patient priorities led to changing international standards for including patients in research design. Some challenges that remain include: the findings from the Institute of Medicine that sexual and gender minorities experience poor health outcomes; establishing trust across all parties; developing a common language and creating venues where individuals can participate in dialogue that addresses personal experiences, research design, clinical practices and intervention strategies. C1 [Lossie, A. C.] NIH, OBSSR, Div Program Coordinat Planning & Strateg Initiat, Off Director, Bethesda, MD 20892 USA. [Green, J.] Accord Alliance, Whitehouse Stn, NJ USA. RP Lossie, AC (reprint author), NIH, Off Behav & Social Sci Res, Off Director, 31 Ctr Dr,Bldg 31,Room B1-C19,MSC 2027, Bethesda, MD 20892 USA. EM amy.lossie@nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [R01 HD068138]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (DSD-Translational Research Network) FX We thank Dr. William T. Riley and Dr. William N. Elwood for critical review of this manuscript. We are indebted to the patients and advocates who support all who are affected by conditions that affect reproductive tract development and to the clinicians, psychologists, and researchers who are devoted to improving the care for all who are affected by DSD. This work was supported, in part, through a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01 HD068138; DSD-Translational Research Network) to the AAN (JG). NR 35 TC 2 Z9 2 U1 1 U2 11 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0018-5043 EI 1439-4286 J9 HORM METAB RES JI Horm. Metab. Res. PD MAY PY 2015 VL 47 IS 5 BP 344 EP 350 DI 10.1055/s-0035-1548793 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CH9OX UT WOS:000354366500007 PM 25868122 ER PT J AU Chiang, YJ Hodes, RJ AF Chiang, Y. Jeffrey Hodes, Richard J. TI Regulation of T cell development by c-Cbl: essential role of Lck SO INTERNATIONAL IMMUNOLOGY LA English DT Article DE Cbl; Lck; T cell receptor; thymic development; ZAP70 ID ZAP-70 TYROSINE KINASE; ACTIVATION; REQUIREMENT; FAMILY; MICE; DIFFERENTIATION; SUBSTRATE; SELECTION; PROTEINS; RECEPTOR AB A canonical pre-TCR/TCR signaling pathway critical for thymic T cell development involves sequential phosphorylation and signaling through Lck, Zap70, Lat and Slp76. However, we and others have previously reported that genomic deletion of c-Cbl deletion does not affect Lck deficiency but restores Zap70-deficient signaling.A canonical pre-TCR/TCR signaling pathway critical for thymic T cell development involves sequential phosphorylation and signaling through Lck, Zap70, Lat and Slp76. However, we and others have previously reported that genomic deletion of c-Cbl (Cbl) partially or completely reverses the defects in thymic development in mice deficient in Zap70, Slp76, Lat or Vav1, indicating the presence of alternative pathways normally suppressed by Cbl. To further elucidate pre-TCR/TCR signaling pathways involved in thymic development, we characterized the effect of Cbl inactivation on developmental and signaling defects in mice deficient in proximal signaling molecules Lck and Zap70. Inactivation of Cbl partially reversed defective T cell development in Zap70 (-/-) mice and reversed defects in phosphorylation of Erk, Plc-gamma 1, Vav1 and Akt, in TCR-stimulated Cbl (-/-) Zap70 (-/-) thymocytes. Recent reports identified an essential role of Lck in associating with CD4 and CD8 coreceptors and mediating the requirement for MHC restriction in TCR recognition. Since TCR recognition has been shown to be MHC-restricted in Cbl (-/-) mice, it was of interest to determine whether the requirement for Lck remained unmodified by Cbl deletion. Indeed, in contrast to the effect of Cbl inactivation in partially or fully bypassing requirements for other TCR signaling components, inactivation of Cbl did not reverse either defective T cell development or defective phosphorylation of TCR signaling molecules in Lck (-/-) mice. Thus, Lck, which plays a unique role in enforcing MHC restriction, is essential for thymic development in presence or absence of Cbl, ensuring MHC restriction of T cells derived from either pathway. C1 [Chiang, Y. Jeffrey; Hodes, Richard J.] NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. [Hodes, Richard J.] NIA, NIH, Bethesda, MD 20892 USA. RP Hodes, RJ (reprint author), NCI, Expt Immunol Branch, Bldg 10, Bethesda, MD 20892 USA. EM richard_hodes@nih.gov FU Intramural Research Program of the National Institutes of Health (NIH); National Cancer Institute FX Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute. NR 24 TC 3 Z9 3 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0953-8178 EI 1460-2377 J9 INT IMMUNOL JI Int. Immunol. PD MAY PY 2015 VL 27 IS 5 BP 245 EP 251 DI 10.1093/intimm/dxu105 PG 7 WC Immunology SC Immunology GA CI4AP UT WOS:000354689000004 PM 25477210 ER PT J AU Tsuji, G Okiyama, N Villarroel, VA Katz, SI AF Tsuji, Gaku Okiyama, Naoko Villarroel, Vadim A. Katz, Stephen I. TI Histone deacetylase 6 inhibition impairs effector CD8 T-cell functions during skin inflammation SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE CD8 T cell; histone deacetylase 6; contact hypersensitivity; graft-versus-host-disease ID VERSUS-HOST-DISEASE; SIGNALING PATHWAYS; LYMPHOCYTES; RECEPTOR; INDUCTION; MICE AB Background: Broad-spectrum histone deacetylase (HDAC) inhibitors are useful in the treatment of allergic and autoimmune diseases and malignancy. However, use of more specific HDAC inhibitors might limit the toxicities caused by HDAC inhibition. HDAC6, a member of the HDAC family, is highly expressed on CD8 T cells and has been shown to regulate immune responses through interactions between T cells and antigen-presenting cells. However, the mechanism by which HDAC6 inhibition affects the activation and functions of CD8 T cells is unclear. Objectives: We investigated the role or roles of HDAC6 in CD8 T-cell activation and functions during skin inflammation in vitro and in vivo and examined the mechanism by which HDAC6 inhibition modifies T-cell receptor signaling in vitro. Methods: We assessed the clinical and biological effects of ACY1215, an HDAC6-specific inhibitor, by using murine CD8 T cellrelated skin disease models, including contact hypersensitivity (CHS) and experimental graft-versus-host disease (GVHD)-like disease. Results: ACY-1215, an HDAC6 inhibitor, prevented the development of CHS and GVHD-like disease in vivo by modulating CD8 T-cell activation and functions; abrogated the induction of effector T cells from naive CD8 T cells by means of anti-CD3/CD28 antibody-or antigen-specific stimulation in vitro; and enhanced the binding of acetylated heat shock protein 90 to lymphocyte-specific protein tyrosine kinase in vitro, disrupting lymphocyte-specific protein tyrosine kinase phosphorylation and leading to impairment of the mitogenactivated protein kinase pathway. Conclusion: HDAC6, a key modifier of T-cell receptor signaling, might represent a novel target for the treatment of CD8 T cellrelated skin diseases, including CHS and GVHD. C1 [Tsuji, Gaku; Okiyama, Naoko; Villarroel, Vadim A.; Katz, Stephen I.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Katz, SI (reprint author), NCI, Dermatol Branch, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. EM katzs@od.niams.nih.gov FU Center for Cancer Research of the National Cancer Institute, National Institutes of Health FX Supported by the Center for Cancer Research of the National Cancer Institute, National Institutes of Health. NR 21 TC 3 Z9 3 U1 0 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD MAY PY 2015 VL 135 IS 5 BP 1228 EP 1239 DI 10.1016/j.jaci.2014.10.002 PG 12 WC Allergy; Immunology SC Allergy; Immunology GA CH4DA UT WOS:000353980700016 PM 25458911 ER PT J AU Burks, AW Wood, RA Jones, SM Sicherer, SH Fleischer, DM Scurlock, AM Vickery, BP Liu, AH Henning, AK Lindblad, R Dawson, P Plaut, M Sampson, HA AF Burks, A. Wesley Wood, Robert A. Jones, Stacie M. Sicherer, Scott H. Fleischer, David M. Scurlock, Amy M. Vickery, Brian P. Liu, Andrew H. Henning, Alice K. Lindblad, Robert Dawson, Peter Plaut, Marshall Sampson, Hugh A. CA Consortium Food Allergy Res CoFAR TI Sublingual immunotherapy for peanut allergy: Long-term follow-up of a randomized multicenter trial SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Peanut allergy; sublingual immunotherapy; desensitization; food allergy; follow-up ID ORAL IMMUNOTHERAPY; FOOD ALLERGY; ANAPHYLACTIC REACTIONS; DOUBLE-BLIND; KIWI FRUIT; FATALITIES; EFFICACY; EXTRACT; READY AB Background: We previously reported the initial results of the first multicenter, randomized, double-blind, placebo-controlled clinical trial of peanut sublingual immunotherapy (SLIT), observing a favorable safety profile associated with modest clinical and immunologic effects in the first year. Objective: We sought to provide long-term (3-year) clinical and immunologic outcomes for our peanut SLIT trial. Key end points were (1) percentage of responders at 2 years (ie, could consume 5 g of peanut powder or a 10-fold increase from baseline), (2) percentage reaching desensitization at 3 years, (3) percentage attaining sustained unresponsiveness after 3 years, (4) immunologic end points, and (5) assessment of safety parameters. Methods: Response to treatment was evaluated in 40 subjects aged 12 to 40 years by performing a 10-g peanut powder oral food challenge after 2 and 3 years of daily peanut SLIT therapy. At 3 years, SLIT was discontinued for 8 weeks, followed by another 10-g oral food challenge and an open feeding of peanut butter to assess sustained unresponsiveness. Results: Approximately 98% of the 18,165 doses were tolerated without adverse reactions beyond the oropharynx, with no severe symptoms or uses of epinephrine. A high rate (> 50%) discontinued therapy. By study's end, 4 (10.8%) of 37 SLITtreated participants were fully desensitized to 10 g of peanut powder, and all 4 achieved sustained unresponsiveness. Responders at 2 years showed a significant decrease in peanutspecific basophil activation and skin prick test titration compared with nonresponders. Conclusions: Peanut SLIT induced a modest level of desensitization, decreased immunologic activity over 3 years in responders, and had an excellent long-term safety profile. However, most patients discontinued therapy by the end of year 3, and only 10.8% of subjects achieved sustained unresponsiveness. C1 [Burks, A. Wesley; Vickery, Brian P.] Univ N Carolina, Dept Pediat, Chapel Hill, NC USA. [Wood, Robert A.] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. [Jones, Stacie M.; Scurlock, Amy M.] Univ Arkansas Med Sci, Dept Pediat, Little Rock, AR 72205 USA. [Jones, Stacie M.; Scurlock, Amy M.] Arkansas Childrens Hosp, Little Rock, AR 72202 USA. [Sicherer, Scott H.; Sampson, Hugh A.] Icahn Sch Med Mt Sinai, Dept Pediat, New York, NY 10029 USA. [Fleischer, David M.] Univ Colorado, Denver Sch Med, Dept Pediat, Denver, CO 80202 USA. [Fleischer, David M.] Childrens Hosp Colorado, Denver, CO USA. [Liu, Andrew H.] Natl Jewish Hlth, Dept Pediat, Denver, CO USA. [Henning, Alice K.; Lindblad, Robert; Dawson, Peter] EMMES Corp, Rockville, MD USA. [Plaut, Marshall] NIAID, NIH, Bethesda, MD 20892 USA. RP Burks, AW (reprint author), Dept Pediat, 260 Macnider Bldg,Box 7220, Chapel Hill, NC 27599 USA. EM wburks@email.unc.edu FU National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID) [U19AI066738, U01AI066560]; National Center for Research Resources (NCRR)/NIH [UL1 RR025780]; NIH/National Center for Advancing Translational Sciences [UL1 TR000154]; NCRR [UL1 TR000067, UL1 TR000039, UL 1 RR024128, UL1 RR 025005] FX Supported by National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID) grants U19AI066738 and U01AI066560. The project was also supported by grant no. UL1 RR025780 from the National Center for Research Resources (NCRR)/NIH and grant no. UL1 TR000154 from the NIH/National Center for Advancing Translational Sciences (National Jewish) and grant nos. UL1 TR000067 (Mount Sinai), UL1 TR000039 (Arkansas), UL 1 RR024128 (North Carolina), and UL1 RR 025005 (Johns Hopkins) from the NCRR. The article's contents are solely the responsibility of the authors and do not necessarily represent the official view of the NCRR or NIH. NR 30 TC 27 Z9 27 U1 2 U2 21 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD MAY PY 2015 VL 135 IS 5 BP 1240 EP U648 DI 10.1016/j.jaci.2014.12.1917 PG 12 WC Allergy; Immunology SC Allergy; Immunology GA CH4DA UT WOS:000353980700017 PM 25656999 ER PT J AU Gorelik, M Narisety, SD Guerrerio, AL Chichester, KL Keet, CA Bieneman, AP Hamilton, RG Wood, RA Schroeder, JT Frischmeyer-Guerrerio, PA AF Gorelik, Mark Narisety, Satya D. Guerrerio, Anthony L. Chichester, Kristin L. Keet, Corinne A. Bieneman, Anja P. Hamilton, Robert G. Wood, Robert A. Schroeder, John T. Frischmeyer-Guerrerio, Pamela A. TI Suppression of the immunologic response to peanut during immunotherapy is often transient SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Peanut allergy; oral immunotherapy; sublingual immunotherapy; sustained unresponsiveness; basophil activation; dendritic cells; food allergy ID ORAL IMMUNOTHERAPY; FOOD ALLERGY; DENDRITIC CELLS; HUMAN BASOPHILS; CHILDREN; MODULATION; RELEASE; CD80 AB Background: Studies suggest that oral immunotherapy (OIT) and sublingual immunotherapy (SLIT) for food allergy hold promise; however, the immunologic mechanisms underlying these therapies are not well understood. Objective: We sought to generate insights into the mechanisms and duration of suppression of immune responses to peanut during immunotherapy. Methods: Blood was obtained from subjects at baseline and at multiple time points during a placebo-controlled trial of peanut OIT and SLIT. Immunologic outcomes included measurement of spontaneous and stimulated basophil activity by using automated fluorometry (histamine) and flow cytometry (activation markers and IL-4), measurement of allergen-induced cytokine expression in dendritic cell (DC)-T-cell cocultures by using multiplexing technology, and measurement of MHC II and costimulatory molecule expression on DCs by using flow cytometry. Results: Spontaneous and allergen-induced basophil reactivity (histamine release, CD63 expression, and IL-4 production) were suppressed during dose escalation and after 6 months of maintenance dosing. Peanut-and dust mite-induced expression of T(H)2 cytokines was reduced in DC-T-cell cocultures during immunotherapy. This was associated with decreased levels of CD40, HLA-DR, and CD86 expression on DCs and increased expression of CD80. These effects were most striking in myeloid DC-T-cell cocultures from subjects receiving OIT. Many markers of immunologic suppression reversed after withdrawal from immunotherapy and in some cases during ongoing maintenance therapy. Conclusion: OITand SLIT for peanut allergy induce rapid suppression of basophil effector functions, DC activation, and TH2 cytokine responses during the initial phases of immunotherapy in an antigen-nonspecific manner. Although there was some interindividual variation, in many patients suppression appeared to be temporary. C1 [Gorelik, Mark; Chichester, Kristin L.; Keet, Corinne A.; Wood, Robert A.; Frischmeyer-Guerrerio, Pamela A.] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. [Bieneman, Anja P.; Hamilton, Robert G.; Schroeder, John T.] Johns Hopkins Univ, Sch Med, Dept Med, Div Allergy & Immunol, Baltimore, MD 21205 USA. [Guerrerio, Anthony L.] Johns Hopkins Univ, Sch Med, Dept Pediat, Div Gastroenterol & Nutr, Baltimore, MD 21205 USA. [Narisety, Satya D.] Univ Med & Dent New Jersey, Dept Pediat, Div Allergy Immunol & Infect Dis, Newark, NJ 07103 USA. RP Frischmeyer-Guerrerio, PA (reprint author), NIAID, Lab Allerg Dis, 4 Mem Dr,Bldg 4,Room 228, Bethesda, MD 20892 USA. EM pamela.guerrerio@nih.gov FU National Center for Advancing Translational Sciences (NCATS) [UL1TR001079]; NIH Roadmap for Medical Research; Research Training in Pediatric Allergy and Immunology [5T32AI007007]; NIH [K23AI091869, AI079853]; ARTrust Faculty Development Award; Johns Hopkins University Clinician Scientist Award; NIH Asthma and Allergic Diseases Cooperative Research Centers grant [U19AI070345-01]; Food Allergy Research and Education grant; Eudowood Foundation; Winkelstein fellowship; Division of Intramural Research, NIAID, NIH; National Center for Research Resources; National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health [101872] FX Supported by grant no. UL1TR001079 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH), and the NIH Roadmap for Medical Research; a Research Training in Pediatric Allergy and Immunology grant (no. 5T32AI007007 to R.A.W. and M.G.); an NIH K23 Mentored Research Development Award (K23AI091869 to P.A.F.-G.); an ARTrust Faculty Development Award (to P.A.F.-G.); a Johns Hopkins University Clinician Scientist Award (to P.A.F.-G.); an NIH R21 Research Award (AI079853 to J.T.S.); NIH Asthma and Allergic Diseases Cooperative Research Centers grant (U19AI070345-01 to J.T.S.); a Food Allergy Research and Education grant (to R.A.W.); the Eudowood Foundation; and a Winkelstein fellowship (to M.G.). This work was supported in part by the Division of Intramural Research, NIAID, NIH (to P.A.F.-G.).; We thank Dr Xuhang Li and the Johns Hopkins Digestive Diseases Basic and Translational Research Core Center for their assistance with cytokine multiplexing and Dr Mark Liu for providing dust mite extracts. Assistance with statistics was provided by Carol B. Thompson, Assistant Scientist, Johns Hopkins Biostatistics Center, who was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health through grant no. 101872. NR 33 TC 24 Z9 24 U1 0 U2 9 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD MAY PY 2015 VL 135 IS 5 BP 1283 EP 1292 DI 10.1016/j.jaci.2014.11.010 PG 10 WC Allergy; Immunology SC Allergy; Immunology GA CH4DA UT WOS:000353980700022 PM 25542883 ER PT J AU Sun, SJ Gill, M Li, YF Huang, M Byrd, RA AF Sun, Shangjin Gill, Michelle Li, Yifei Huang, Mitchell Byrd, R. Andrew TI Efficient and generalized processing of multidimensional NUS NMR data: the NESTA algorithm and comparison of regularization terms SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE Non-uniform sampling; Multidimensional NMR data processing; Compressed sensing; NESTA; NUS; gp78; ASAP1 ID MAXIMUM-ENTROPY RECONSTRUCTION; SENSITIVITY IMPROVEMENT; SIGNAL RECOVERY; SPECTROSCOPY; RESOLUTION; DECOMPOSITION; MINIMIZATION; ENHANCEMENT; UNCERTAINTY; STRATEGIES AB The advantages of non-uniform sampling (NUS) in offering time savings and resolution enhancement in NMR experiments have been increasingly recognized. The possibility of sensitivity gain by NUS has also been demonstrated. Application of NUS to multidimensional NMR experiments requires the selection of a sampling scheme and a reconstruction scheme to generate uniformly sampled time domain data. In this report, an efficient reconstruction scheme is presented and used to evaluate a range of regularization algorithms that collectively yield a generalized solution to processing NUS data in multidimensional NMR experiments. We compare l1-norm (L1), iterative re-weighted l1-norm (IRL1), and Gaussian smoothed l0-norm (Gaussian-SL0) regularization for processing multidimensional NUS NMR data. Based on the reconstruction of different multidimensional NUS NMR data sets, L1 is demonstrated to be a fast and accurate reconstruction method for both quantitative, high dynamic range applications (e.g. NOESY) and for all J-coupled correlation experiments. Compared to L1, both IRL1 and Gaussian-SL0 are shown to produce slightly higher quality reconstructions with improved linearity in peak intensities, albeit with a computational cost. Finally, a generalized processing system, NESTA-NMR, is described that utilizes a fast and accurate first-order gradient descent algorithm (NESTA) recently developed in the compressed sensing field. NESTA-NMR incorporates L1, IRL1, and Gaussian-SL0 regularization. NESTA-NMR is demonstrated to provide an efficient, streamlined approach to handling all types of multidimensional NMR data using proteins ranging in size from 8 to 32 kDa. C1 [Sun, Shangjin; Gill, Michelle; Li, Yifei; Huang, Mitchell; Byrd, R. Andrew] NCI, Struct Biol Lab, Frederick, MD 21702 USA. RP Byrd, RA (reprint author), NCI, Struct Biol Lab, Frederick, MD 21702 USA. EM byrdra@mail.nih.gov OI Gill, Michelle/0000-0002-2861-355X; Byrd, R. Andrew/0000-0003-3625-4232 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX We thank Dr. Aleksandras Gutmanas (EBI, Hinxton, UK), Dr. Jinfa Ying (NIDDK, NIH, Bethesda, MD) and Mr. William Hanisch for useful discussions. This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 47 TC 12 Z9 12 U1 1 U2 21 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 EI 1573-5001 J9 J BIOMOL NMR JI J. Biomol. NMR PD MAY PY 2015 VL 62 IS 1 BP 105 EP 117 DI 10.1007/s10858-015-9923-x PG 13 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA CI1FG UT WOS:000354487600012 PM 25808220 ER PT J AU Morens, DM Taubenberger, JK AF Morens, David M. Taubenberger, Jeffery K. TI How Low Is the Risk of Influenza A(H5N1) Infection? SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material DE H5N1; H7N9; influenza; pandemic; seroepidemiology; serology ID AVIAN INFLUENZA; SOUTHERN CHINA; H5N1 VIRUSES; HUMANS; A/H5N1; HOST C1 [Morens, David M.; Taubenberger, Jeffery K.] NIAID, NIH, Bethesda, MD 20892 USA. RP Morens, DM (reprint author), NIH, Bldg 31,Rm 7A-03,31 Ctr Dr,MSC 2520, Bethesda, MD 20892 USA. EM dmorens@niaid.nih.gov NR 28 TC 5 Z9 5 U1 1 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD MAY 1 PY 2015 VL 211 IS 9 BP 1364 EP 1366 DI 10.1093/infdis/jiu530 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CI4LZ UT WOS:000354722000002 PM 25355943 ER PT J AU Schiller, JT Lowy, DR AF Schiller, John T. Lowy, Douglas R. TI Raising Expectations For Subunit Vaccine SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE HPV; HBV; prophylactic vaccine; virus-like particle; antibody; plasma cell; memory B cell ID HEPATITIS-B-VACCINE; ANTIBODY-RESPONSES; HUMORAL IMMUNITY; PAPILLOMAVIRUS; DURATION; EFFICACY; ANTIGEN AB Multidose regimens are recommended for all prophylactic subunit vaccines. Recent findings from clinical trials of an human papillomavirus virus-like particle vaccine suggest that it may be possible to develop effective single-dose subunit vaccines. The broad implications of these findings are discussed, and the importance of antigen structure and adjuvant in achieving this goal is considered. In conclusion, we argue for the inclusion of single-dose arms in future trials of vaccines, especially if they are based on induction of antibodies by virus-like displayed antigens. C1 [Schiller, John T.; Lowy, Douglas R.] NCI, Cellular Oncol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Schiller, JT (reprint author), NCI, Cellular Oncol Lab, Bldg 37,Rm 4106,9000 Rockville Pike, Bethesda, MD 20892 USA. EM schillej@mail.nih.gov FU Center for Cancer Research, National Cancer Institute FX This work was supported by the Center for Cancer Research, National Cancer Institute. NR 21 TC 17 Z9 17 U1 3 U2 9 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD MAY 1 PY 2015 VL 211 IS 9 BP 1373 EP 1375 DI 10.1093/infdis/jiu648 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA CI4LZ UT WOS:000354722000004 PM 25420478 ER PT J AU Chou, JY Jun, HS Mansfield, BC AF Chou, Janice Y. Jun, Hyun Sik Mansfield, Brian C. TI Type I glycogen storage diseases: disorders of the glucose-6-phosphatase/glucose-6-phosphate transporter complexes SO JOURNAL OF INHERITED METABOLIC DISEASE LA English DT Article; Proceedings Paper CT GSD Conference CY NOV 28-30, 2013 CL Heidelberg, GERMANY ID PHOSPHOHISTIDINE-ENZYME INTERMEDIATE; CONGENITAL NEUTROPENIA SYNDROME; GLUCOSE-6-PHOSPHATE TRANSPORTER; GENE-THERAPY; TRANSMEMBRANE TOPOLOGY; CANINE MODEL; MICE LACKING; 1B; DEFICIENCY; MUTATIONS AB Disorders of the glucose-6-phosphatase (G6Pase)/glucose-6-phosphate transporter (G6PT) complexes consist of three subtypes: glycogen storage disease type Ia (GSD-Ia), deficient in the liver/kidney/intestine-restricted G6Pase-alpha (or G6PC); GSD-Ib, deficient in a ubiquitously expressed G6PT (or SLC37A4); and G6Pase-beta deficiency or severe congenital neutropenia syndrome type 4 (SCN4), deficient in the ubiquitously expressed G6Pase-beta (or G6PC3). G6Pase-alpha and G6Pase-beta are glucose-6-phosphate (G6P) hydrolases with active sites lying inside the endoplasmic reticulum (ER) lumen and as such are dependent upon the G6PT to translocate G6P from the cytoplasm into the lumen. The tissue expression profiles of the G6Pase enzymes dictate the disease's phenotype. A functional G6Pase-alpha/G6PT complex maintains interprandial glucose homeostasis, while a functional G6Pase-beta/G6PT complex maintains neutrophil/macrophage energy homeostasis and functionality. G6Pase-beta deficiency is not a glycogen storage disease but biochemically it is a GSD-I related syndrome (GSD-Irs). GSD-Ia and GSD-Ib patients manifest a common metabolic phenotype of impaired blood glucose homeostasis not shared by GSD-Irs. GSD-Ib and GSD-Irs patients manifest a common myeloid phenotype of neutropenia and neutrophil/macrophage dysfunction not shared by GSD-Ia. While a disruption of the activity of the G6Pase-alpha/G6PT complex readily explains why GSD-Ia and GSD-Ib patients exhibit impaired glucose homeostasis, the basis for neutropenia and myeloid dysfunction in GSD-Ib and GSD-Irs are only now starting to be understood. Animal models of all three disorders are now available and are being exploited to both delineate the disease more precisely and develop new treatment approaches, including gene therapy. C1 [Chou, Janice Y.; Jun, Hyun Sik; Mansfield, Brian C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Cellular Differentiat, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Mansfield, Brian C.] Fdn Fighting Blindness, Columbia, MD 21046 USA. [Chou, Janice Y.] NIH, Bethesda, MD 20892 USA. RP Chou, JY (reprint author), NIH, Bldg 10,Room 9D42,10 Ctr Dr, Bethesda, MD 20892 USA. EM chouja@mail.nih.gov OI Mansfield, Brian/0000-0002-8533-2789 FU Intramural NIH HHS NR 52 TC 2 Z9 4 U1 0 U2 11 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0141-8955 EI 1573-2665 J9 J INHERIT METAB DIS JI J. Inherit. Metab. Dis. PD MAY PY 2015 VL 38 IS 3 BP 511 EP 519 DI 10.1007/s10545-014-9772-x PG 9 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA CI1JJ UT WOS:000354500000016 PM 25288127 ER PT J AU Raiten, DJ Ashour, FAS Ross, AC Meydani, SN Dawson, HD Stephensen, CB Brabin, BJ Suchdev, PS van Ommen, B AF Raiten, Daniel J. Ashour, Fayrouz A. Sakr Ross, A. Catharine Meydani, Simin N. Dawson, Harry D. Stephensen, Charles B. Brabin, Bernard J. Suchdev, Parminder S. van Ommen, Ben CA INSPIRE Consultative Grp TI Inflammation and Nutritional Science for Programs/Policies and Interpretation of Research Evidence (INSPIRE) SO JOURNAL OF NUTRITION LA English DT Article; Proceedings Paper CT Inflammation and Nutritional Science for Programs/Policies and Interpretation of Research Evidence (INSPIRE) Meeting CY NOV 28-30, 2012 CL Natl Inst Hlth, Bethesda, MD HO Natl Inst Hlth DE nutrition biomarkers; inflammation and nutrition; immune function and nutrients; BOND and inflammation/infection; assessment of micronutrient biomarkers ID C-REACTIVE PROTEIN; VITAMIN-A SUPPLEMENTATION; ACUTE-PHASE RESPONSE; TUMOR-NECROSIS-FACTOR; OBSTRUCTIVE PULMONARY-DISEASE; PLACEBO-CONTROLLED TRIAL; HUMAN-IMMUNODEFICIENCY-VIRUS; REGULATORY T-CELLS; NF-KAPPA-B; RANDOMIZED CONTROLLED-TRIAL AB An increasing recognition has emerged of the complexities of the global health agenda specifically, the collision of infections and noncommunicable diseases and the dual burden of over- and undernutrition. Of particular practical concern are both 1) the need for a better understanding of the bidirectional relations between nutritional status and the development and function of the immune and inflammatory response and 2) the specific impact of the inflammatory response on the selection, use, and interpretation of nutrient biomarkers. The goal of the Inflammation and Nutritional Science for Programs/Policies and Interpretation of Research Evidence (INSPIRE) is to provide guidance for those users represented by the global food and nutrition enterprise. These include researchers (bench and clinical), clinicians providing care/treatment, those developing and evaluating programs/interventions at scale, and those responsible for generating evidence-based policy. The INSPIRE process included convening 5 thematic working groups (WGs) charged with developing summary reports around the following issues: 1) basic overview of the interactions between nutrition, immune function, and the inflammatory response; 2) examination of the evidence regarding the impact of nutrition on immune function and inflammation; a evaluation of the impact of inflammation and clinical conditions (acute and chronic) on nutrition; 4) examination of existing and potential new approaches to account for the impact of inflammation on biomarker interpretation and use, and 5) the presentation of new approaches to the study of these relations. Each WG was tasked with synthesizing a summary of the evidence for each of these topics and delineating the remaining gaps in our knowledge. This review consists of a summary of the INSPIRE workshop and the WG deliberations. C1 [Raiten, Daniel J.; Ashour, Fayrouz A. Sakr] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Ross, A. Catharine] Penn State Univ, Dept Nutr Sci, University Pk, PA 16802 USA. [Ross, A. Catharine] Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. [Ross, A. Catharine] Penn State Univ, Ctr Mol Immunol & Infect Dis, University Pk, PA 16802 USA. [Meydani, Simin N.] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Dawson, Harry D.] USDA ARS, Beltsville Human Nutr Res Ctr, Diet Genom & Immunol Lab, Beltsville, MD USA. [Stephensen, Charles B.] ARS, Western Human Nutr Res Ctr, USDA, Davis, CA USA. [Brabin, Bernard J.] Univ Liverpool, Liverpool Sch Trop Med, Child & Reprod Hlth Grp, Liverpool L3 5QA, Merseyside, England. [Brabin, Bernard J.] Univ Amsterdam, Acad Med Ctr, Global Child Hlth Grp, NL-1105 AZ Amsterdam, Netherlands. [Suchdev, Parminder S.] Emory Univ, Dept Pediat & Global Hlth, Atlanta, GA 30322 USA. [van Ommen, Ben] TNO, NL-3700 AJ Zeist, Netherlands. RP Raiten, DJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. EM raitend@mail.nih.gov RI Calder, Philip/E-9739-2013; Rink, Lothar/C-1055-2014; Friis, Henrik/N-2047-2014; OI Calder, Philip/0000-0002-6038-710X; Friis, Henrik/0000-0002-2848-2940; Suchdev, Parmi/0000-0002-0350-3469 FU NIAID NIH HHS [R56 AI114972]; NICHD NIH HHS [R01 HD066982]; NIDDK NIH HHS [R56 DK041479] NR 798 TC 31 Z9 31 U1 5 U2 29 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 EI 1541-6100 J9 J NUTR JI J. Nutr. PD MAY PY 2015 VL 145 IS 5 SU S BP 1039S EP 1108S DI 10.3945/jn.114.194571 PG 70 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CH4OP UT WOS:000354013100001 PM 25833893 ER PT J AU Duffy, LC Raiten, DJ Hubbard, VS Starke-Reed, P AF Duffy, Linda C. Raiten, Daniel J. Hubbard, Van S. Starke-Reed, Pamela TI Progress and Challenges in Developing Metabolic Footprints from Diet in Human Gut Microbial Cometabolism SO JOURNAL OF NUTRITION LA English DT Article; Proceedings Paper CT Inflammation and Nutritional Science for Programs/Policies and Interpretation of Research Evidence (INSPIRE) Meeting CY NOV 28-30, 2012 CL Natl Inst Hlth, Bethesda, MD HO Natl Inst Hlth DE diet; metagenomics; microbial-host co-metabolism; microbiome; probiotics/prebiotics ID HUMAN-MILK OLIGOSACCHARIDES; IMMUNE-SYSTEM; NUTRITIONAL MODULATION; INTESTINAL MICROBIOTA; HOST METABOLISM; DISEASE RISK; OBESITY; PROBIOTICS; EVOLUTION; HEALTH AB Homo sapiens harbor trillions of microbes, whose microbial metagenome (collective genome of a microbial community) using omic validation interrogation tools is estimated to be at least 100-fold that of human cells, which comprise 23,000 genes. This article highlights some of the current progress and open questions in nutrition-related areas of microbiome research. It also underscores the metabolic capabilities of microbial fermentation on nutritional substrates that require further mechanistic understanding and systems biology approaches of studying functional interactions between diet composition, gut microbiota, and host metabolism. Questions surrounding bacterial fermentation and degradation of dietary constituents (particularly by Firmicutes and Bacteroidetes) and deciphering how microbial encoding of enzymes and derived metabolites affect recovery of dietary energy by the host are more complex than previously thought. Moreover, it is essential to understand to what extent the intestinal microbiota is subject to dietary control and to integrate these data with functional metabolic signatures and biomarkers. Many lines of research have demonstrated the significant role of the gut microbiota in human physiology and disease. Probiotic and prebiotic products are proliferating in the market in response to consumer demand, and the science and technology around these products are progressing rapidly. With high-throughput molecular technologies driving the science, studying the bidirectional interactions of host-microbial cometabolism, epithelial cell maturation, shaping of innate immune development, normal vs. dysfunctional nutrient absorption and processing, and the complex signaling pathways involved is now possible. Substantiating the safety and mechanisms of action of probiotic/prebiotic formulations is critical. Beneficial modulation of the human microbiota by using these nutritional and biotherapeutic strategies holds considerable promise as next-generation drugs, vaccinomics, and metabolic agents and in novel food discovery. C1 [Duffy, Linda C.] Natl Ctr Complementary & Integrat Hlth, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Raiten, Daniel J.] Eunice Kennedy Shriner Natl Inst Child Hlth & Hum, NIH, US Dept HHS, Bethesda, MD USA. [Hubbard, Van S.] NIH, US Dept HHS, Div Nutr Res Coordinat, Bethesda, MD USA. [Starke-Reed, Pamela] ARS, USDA, Beltsville, MD USA. RP Duffy, LC (reprint author), Natl Ctr Complementary & Integrat Hlth, NIH, US Dept HHS, Bethesda, MD 20892 USA. EM duffyl@mail.nih.gov NR 81 TC 9 Z9 9 U1 5 U2 59 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 EI 1541-6100 J9 J NUTR JI J. Nutr. PD MAY PY 2015 VL 145 IS 5 SU S BP 1123S EP 1130S DI 10.3945/jn.114.194936 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CH4OP UT WOS:000354013100004 PM 25833886 ER PT J AU Wu, LT Swartz, MS Brady, KT Hoyle, RH AF Wu, Li-Tzy Swartz, Marvin S. Brady, Kathleen T. Hoyle, Rick H. CA NIDA AAPI Workgrp TI Perceived cannabis use norms and cannabis use among adolescents in the United States SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Asian-Americans; Blacks; Cannabis use disorder; Hispanics; Marijuana use; Mixed-race; Native Hawaiians; Native-Americans; Pacific Islanders ID NATIVE HAWAIIANS/PACIFIC ISLANDERS; SUBSTANCE-ABUSE TREATMENT; HIGH-SCHOOL SENIORS; AGE-OF-ONSET; MARIJUANA USE; DRUG-USE; MEDICAL MARIJUANA; INJUNCTIVE NORMS; ASIAN-AMERICANS; USE DISORDERS AB Due to changes in cannabis policies, concerns about cannabis use (CU) in adolescents have increased. The population of nonwhite groups is growing quickly in the United States. We examined perceived CU norms and their association with CU and CU disorder (CUD) for White, Black, Hispanic, Native-American, Asian-American, Native Hawaiian/Pacific Islander (NH/PI), and mixed-race adolescents. Data were from adolescents (12-17 years) in the 2004-2012 National Surveys on Drug Use and Health (N = 163,837). Substance use and CUD were assessed by computer-assisted, self-interviewing methods. Blacks, Hispanics, Native-Americans, and mixed-race adolescents had greater odds of past-year CU and CUD than Whites. Among past-year cannabis users (CUs), Hispanics and Native-Americans had greater odds of having a CUD than Whites. Asian-Americans had the highest prevalence of perceived parental or close friends' CU disapproval. Native-Americans and mixed-race adolescents had lower odds than Whites of perceiving CU disapproval from parents or close friends. In adjusted analyses, adolescent's disapproval of CU, as well as perceived disapproval by parents or close friends, were associated with a decreased odds of CU in each racial/ethnic group, except for NHs/PIs. Adolescent's disapproval of CU was associated with a decreased odds of CUD among CUs for Whites (personal, parental, and close friends' disapproval), Hispanics (personal, parental, and close friends' disapproval), and mixed-race adolescents (personal, close friends' disapproval). Racial/ethnic differences in adolescent CU prevalence were somewhat consistent with adolescents' reports of CU norm patterns. Longitudinal research on CU health effects should oversample nonwhite adolescents to assure an adequate sample for analysis and reporting. (C) 2015 The Authors. Published by Elsevier Ltd. C1 [Wu, Li-Tzy; Swartz, Marvin S.] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Sch Med, Durham, NC 27710 USA. [Brady, Kathleen T.] Med Univ S Carolina, South Carolina Clin & Translat Res Inst, Charleston, SC 29425 USA. [Hoyle, Rick H.] Duke Univ, Dept Psychol & Neurosci, Durham, NC USA. [NIDA AAPI Workgrp] NIDA, Asian Amer & Pacific Islander Researchers & Schol, Bethesda, MD 20892 USA. RP Wu, LT (reprint author), Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Sch Med, Box 3903, Durham, NC 27710 USA. EM litzy.wu@duke.edu FU U.S. National Institutes of Health [R01MD007658, API-AS.NET2013-01, API-AS.NET2013-02, R01DA019623, R01DA019901, R33DA027503, P30DA023026, U10DA013727]; Department of Psychiatry and Behavioral Sciences [4416016]; Duke University School of Medicine FX This work was made possible by research support from the U.S. National Institutes of Health (R01MD007658, API-AS.NET2013-01, API-AS.NET2013-02, R01DA019623, R01DA019901, R33DA027503 to Li-Tzy Wu; P30DA023026 to Rick Hoyle; U10DA013727 to Kathleen Brady) and Department of Psychiatry and Behavioral Sciences (4416016), Duke University School of Medicine. The sponsoring agency had no further role in the study design and analysis, the writing of the report, or the decision to submit the paper for publication. The opinions expressed in this paper are solely those of the authors. NR 71 TC 6 Z9 7 U1 0 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 EI 1879-1379 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD MAY PY 2015 VL 64 BP 79 EP 87 DI 10.1016/j.jpsychires.2015.02.022 PG 9 WC Psychiatry SC Psychiatry GA CH9FS UT WOS:000354342000011 PM 25795093 ER PT J AU Lorsch, JR AF Lorsch, Jon R. TI Maximizing the return on taxpayers' investments in fundamental biomedical research SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID CITATION IMPACT; SMALL SCIENCE; R01 GRANTS AB The National Institute of General Medical Sciences (NIGMS) at the U.S. National Institutes of Health has an annual budget of more than $2.3 billion. The institute uses these funds to support fundamental biomedical research and training at universities, medical schools, and other institutions across the country. My job as director of NIGMS is to work to maximize the scientific returns on the taxpayers' investments. I describe how we are optimizing our investment strategies and funding mechanisms, and how, in the process, we hope to create a more efficient and sustainable biomedical research enterprise. C1 NIGMS, NIH, Bethesda, MD 20892 USA. RP Lorsch, JR (reprint author), NIGMS, NIH, Bethesda, MD 20892 USA. EM Jon.lorsch@nih.gov OI Lorsch, Jon/0000-0002-4521-4999 NR 28 TC 4 Z9 4 U1 4 U2 11 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 MAY 1 PY 2015 VL 26 IS 9 BP 1578 EP 1582 DI 10.1091/mbc.E14-06-1163 PG 5 WC Cell Biology SC Cell Biology GA CI0FQ UT WOS:000354412500002 PM 25926703 ER PT J AU Cruse, G Beaven, MA Music, SC Bradding, P Gilfillan, AM Metcalfe, DD AF Cruse, Glenn Beaven, Michael A. Music, Stephen C. Bradding, Peter Gilfillan, Alasdair M. Metcalfe, Dean D. TI The CD20 homologue MS4A4 directs trafficking of KIT toward clathrin-independent endocytosis pathways and thus regulates receptor signaling and recycling SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID FC-EPSILON-RI; STEM-CELL FACTOR; K(CA)3.1 K+ CHANNELS; MAST-CELLS; TYROSINE KINASES; LIPID RAFTS; C-KIT; FUNCTIONAL ACTIVATION; SURFACE EXPRESSION; ALZHEIMERS-DISEASE AB MS4A family members differentially regulate the cell cycle, and aberrant, or loss of, expression of MS4A family proteins has been observed in colon and lung cancer. However, the precise functions of MS4A family proteins and their mechanistic interactions remain unsolved. Here we report that MS4A4 facilitates trafficking of the receptor tyrosine kinase KIT through endocytic recycling rather than degradation pathways by a mechanism that involves recruitment of KIT to caveolin-1-enriched microdomains. Silencing of MS4A4 in human mast cells altered ligand-induced KIT endocytosis pathways and reduced receptor recycling to the cell surface, thus promoting KIT signaling in the endosomes while reducing that in the plasma membrane, as exemplified by Akt and PLC gamma 1 phosphorylation, respectively. The altered endocytic trafficking of KIT also resulted in an increase in SCF-induced mast cell proliferation and migration, which may reflect altered signaling in these cells. Our data reveal a novel function for MS4A family proteins in regulating trafficking and signaling, which could have implications in both proliferative and immunological diseases. C1 [Cruse, Glenn; Music, Stephen C.; Gilfillan, Alasdair M.; Metcalfe, Dean D.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Beaven, Michael A.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Bradding, Peter] Univ Leicester, Inst Lung Hlth, Dept Infect Immun & Inflammat, Leicester LE3 9QP, Leics, England. RP Cruse, G (reprint author), NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. EM glenncruse@hotmail.com OI Bradding, Peter/0000-0001-8403-0319 FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute within the National Institutes of Health; National Institute for Health Research Leicester Respiratory Biomedical Research Unit FX We thank the Biological Imaging Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, for expert advice in the acquisition and analysis of the confocal imaging. We also thank E. C. Chan (Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health) for providing cDNA from maturing MC cultures. Financial support was provided by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases and National Heart, Lung, and Blood Institute within the National Institutes of Health. Work in Leicester was supported in part by the National Institute for Health Research Leicester Respiratory Biomedical Research Unit. The views expressed are those of the authors and not necessarily those of the National Health Service, National Institute for Health Research, or the Department of Health. NR 78 TC 5 Z9 5 U1 2 U2 4 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD MAY 1 PY 2015 VL 26 IS 9 BP 1711 EP 1727 DI 10.1091/mbc.E14-07-1221 PG 17 WC Cell Biology SC Cell Biology GA CI0FQ UT WOS:000354412500013 PM 25717186 ER PT J AU Gaynor, JW Stopp, C Wypij, D Andropoulos, DB Atallah, J Atz, AM Beca, J Donofrio, MT Duncan, K Ghanayem, NS Goldberg, CS Hovels-Gurich, H Ichida, F Jacobs, JP Justo, R Latal, B Li, JS Mahle, WT McQuillen, PS Menon, SC Pemberton, VL Pike, NA Pizarro, C Shekerdemian, LS Synnes, A Williams, I Bellinger, DC Newburger, JW AF Gaynor, J. William Stopp, Christian Wypij, David b Andropoulos, Dean B. Atallah, Joseph Atz, Andrew M. Beca, John Donofrio, Mary T. g Duncan, Kim Ghanayem, Nancy S. Goldberg, Caren S. Hovels-Gurich, Hedwig Ichida, Fukiko Jacobs, Jeffrey P. Justo, Robert n Latal, Beatrice Li, Jennifer S. Mahle, William T. McQuillen, Patrick S. Menon, Shaji C. Pemberton, Victoria L. Pike, Nancy A. Pizarro, Christian Shekerdemian, Lara S. Synnes, Anne Williams, Ismee Bellinger, David C. Newburger, Jane W. CA ICCON Investigators TI Neurodevelopmental Outcomes After Cardiac Surgery in Infancy SO PEDIATRICS LA English DT Article ID HYPOTHERMIC CARDIOPULMONARY BYPASS; CONGENITAL HEART-DISEASE; PARTICIPANT DATA METAANALYSIS; CIRCULATORY ARREST; SINGLE VENTRICLE; HEALTH OUTCOMES; D-TRANSPOSITION; GREAT-ARTERIES; CHILDREN; TRIAL AB BACKGROUND: Neurodevelopmental disability is the most common complication for survivors of surgery for congenital heart disease (CHD). METHODS: We analyzed individual participant data from studies of children evaluated with the Bayley Scales of Infant Development, second edition, after cardiac surgery between 1996 and 2009. The primary outcome was Psychomotor Development Index (PDI), and the secondary outcome was Mental Development Index (MDI). RESULTS: Among 1770 subjects from 22 institutions, assessed at age 14.5 +/- 3.7 months, PDIs and MDIs (77.6 +/- 18.8 and 88.2 +/- 16.7, respectively) were lower than normative means (each P < .001). Later calendar year of birth was associated with an increased proportion of high-risk infants (complexity of CHD and prevalence of genetic/extracardiac anomalies). After adjustment for center and type of CHD, later year of birth was not significantly associated with better PDI or MDI. Risk factors for lower PDI were lower birth weight, white race, and presence of a genetic/extracardiac anomaly (all P <= .01). After adjustment for these factors, PDIs improved over time (0.39 points/year, 95% confidence interval 0.01 to 0.78; P = .045). Risk factors for lower MDI were lower birth weight, male gender, less maternal education, and presence of a genetic/extracardiac anomaly (all P < .001). After adjustment for these factors, MDIs improved over time (0.38 points/year, 95% confidence interval 0.05 to 0.71; P = .02). CONCLUSIONS: Early neurodevelopmental outcomes for survivors of cardiac surgery in infancy have improved modestly over time, but only after adjustment for innate patient risk factors. As more high-risk CHD infants undergo cardiac surgery and survive, a growing population will require significant societal resources. C1 [Gaynor, J. William] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Stopp, Christian; Wypij, David b; Bellinger, David C.; Newburger, Jane W.] Boston Childrens Hosp, Boston, MA USA. [Andropoulos, Dean B.] Texas Childrens Hosp, Houston, TX 77030 USA. [Atallah, Joseph] Stollery Childrens Hosp, Edmonton, AB, Canada. [Atallah, Joseph] Western Canadian Complex Pediat Therapies Follow, Edmonton, AB, Canada. [Atz, Andrew M.] Med Univ S Carolina, Div Pediat Cardiol, Charleston, SC 29425 USA. [Beca, John] Starship Childrens Hosp, Auckland, New Zealand. [Donofrio, Mary T. g] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Duncan, Kim] Childrens Hosp & Med Ctr, Omaha, NE USA. [Ghanayem, Nancy S.] Childrens Hosp Wisconsin, Med Coll Wisconsin, Milwaukee, WI 53201 USA. [Goldberg, Caren S.] Motts Childrens Hosp, Ann Arbor, MI USA. [Hovels-Gurich, Hedwig] Univ Hosp Aachen, Aachen, Germany. [Ichida, Fukiko] Toyama Univ Hosp, Toyama, Japan. [Jacobs, Jeffrey P.] Johns Hopkins All Childrens Heart Inst, St Petersburg, FL USA. [Justo, Robert n] Univ Queensland, Brisbane, Qld, Australia. [Latal, Beatrice] Univ Childrens Hosp Zurich, Zurich, Switzerland. [Li, Jennifer S.] Duke Univ, Med Ctr, Durham, NC USA. [Mahle, William T.] Childrens Healthcare Atlanta, Atlanta, GA USA. [McQuillen, Patrick S.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Menon, Shaji C.] Primary Childrens Med Ctr, Salt Lake City, UT 84103 USA. [Pemberton, Victoria L.] NHLBI, Bethesda, MD 20892 USA. [Pike, Nancy A.] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Pizarro, Christian] Alfred I duPont Hosp Children, Wilmington, DE USA. [Shekerdemian, Lara S.] Royal Childrens Hosp, Melbourne, Vic, Australia. [Synnes, Anne] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Williams, Ismee] New York Presbyterian Morgan Stanley Childrens Ho, New York, NY USA. RP Gaynor, JW (reprint author), Childrens Hosp Philadelphia, Div Cardiothorac Surg, 34th & Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM gaynor@email.chop.edu RI Justo, Robert/D-4708-2011; Colditz, Paul/F-6772-2010 OI Colditz, Paul/0000-0002-6408-8238 FU Mend-a-Heart Foundation; Kostin Family Innovation Fund; American Heart Association [9950480N, 0365018Y]; Auckland Medical Research Fund, Australia; New Zealand Intensive Care Society; Canadian Institutes of Health Research [MOP93780]; CReFF (Clinical Research Feasibility Fund); Children's National Medical Center Board of Visitors Grant; Doris Duke Foundation; Ethel Brown Foerderer Fund for Excellence; Farb Family Fund; Food and Drug Administration's Office of Orphan Products Development; Green Lane Research and Education Fund; Heart Foundation of New Zealand; Internal Children's National Medical Center Grants; Larry L. Hillblom Foundation [2002/3E]; March of Dimes Foundation [5-FY2005-1231, 6-FY2009-303]; Mercator Foundation Switzerland; Murdoch Children's Research Institute; National Center for Research Resources [RR01271, RR02172]; National Heart Foundation of Australia; National Heart, Lung, and Blood Institute [HL41786, HL063411, HL068269, HL068270, HL068279, HL068281, HL068285, HL068288, HL068290, HL068292, HL085057]; National Institute of Child Health and Development [HD18655, HD055501]; National Institute of Neurologic Disorders and Stroke [NS35902, NS40117, NS063876]; Prince Charles Hospital Foundation FX This pooled data analysis project was funded by a grant from the Mend-a-Heart Foundation. The Kostin Family Innovation Fund supplied partial support for Mr Stopp. Individual studies that contributed data were funded by grants from the American Heart Association (9950480N, 0365018Y), Auckland Medical Research Fund, Australia and New Zealand Intensive Care Society, Canadian Institutes of Health Research (MOP93780), CReFF (Clinical Research Feasibility Fund) Grant, Children's National Medical Center Board of Visitors Grant, Doris Duke Foundation, Ethel Brown Foerderer Fund for Excellence, Farb Family Fund, Food and Drug Administration's Office of Orphan Products Development, Green Lane Research and Education Fund, Heart Foundation of New Zealand, Internal Children's National Medical Center Grants, Larry L. Hillblom Foundation (2002/3E), March of Dimes Foundation (5-FY2005-1231, 6-FY2009-303), Mercator Foundation Switzerland, Murdoch Children's Research Institute, National Center for Research Resources (RR01271, RR02172), National Heart Foundation of Australia, National Heart, Lung, and Blood Institute (HL41786, HL063411, HL068269, HL068270, HL068279, HL068281, HL068285, HL068288, HL068290, HL068292, HL085057), National Institute of Child Health and Development (HD18655, HD055501), National Institute of Neurologic Disorders and Stroke (NS35902, NS40117, NS063876), and Prince Charles Hospital Foundation. NR 43 TC 40 Z9 40 U1 1 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 MAY PY 2015 VL 135 IS 5 BP 816 EP 825 DI 10.1542/peds.2014-3825 PG 10 WC Pediatrics SC Pediatrics GA CH0QX UT WOS:000353728400043 PM 25917996 ER PT J AU Davis, KD Lawson, KM Almeida, DM Kelly, EL King, RB Hammer, L Casper, LM Okechukwu, CA Hanson, G McHale, SM AF Davis, Kelly D. Lawson, Katie M. Almeida, David M. Kelly, Erin L. King, Rosalind B. Hammer, Leslie Casper, Lynne M. Okechukwu, Cassandra A. Hanson, Ginger McHale, Susan M. TI Parents' Daily Time With Their Children: A Workplace Intervention SO PEDIATRICS LA English DT Article ID WORK-FAMILY CONFLICT; RELATIONSHIP QUALITY; HEALTH; ADOLESCENCE; INVOLVEMENT; PERSPECTIVE; VALIDATION; ADJUSTMENT; CHILDHOOD; BEHAVIOR AB OBJECTIVES: In the context of a group randomized field trial, we evaluated whether parents who participated in a workplace intervention, designed to increase supervisor support for personal and family life and schedule control, reported significantly more daily time with their children at the 12-month follow-up compared with parents assigned to the Usual Practice group. We also tested whether the intervention effect was moderated by parent gender, child gender, or child age. METHODS: The Support-Transform-Achieve-Results Intervention was delivered in an information technology division of a US Fortune 500 company. Participants included 93 parents (45% mothers) of a randomly selected focal child aged 9 to 17 years (49% daughters) who completed daily telephone diaries at baseline and 12 months after intervention. During evening telephone calls on 8 consecutive days, parents reported how much time they spent with their child that day. RESULTS: Parents in the intervention group exhibited a significant increase in parent-child shared time, 39 minutes per day on average, between baseline and the 12-month follow-up. By contrast, parents in the Usual Practice group averaged 24 fewer minutes with their child per day at the 12-month follow-up. Intervention effects were evident for mothers but not for fathers and for daughters but not sons. CONCLUSIONS: The hypothesis that the intervention would improve parents' daily time with their children was supported. Future studies should examine how redesigning work can change the quality of parent-child interactions and activities known to be important for youth health and development. C1 [Davis, Kelly D.] Penn State Univ, Clearinghouse Mil Family Readiness, University Pk, PA 16802 USA. [Almeida, David M.] Penn State Univ, Human Dev & Family Studies, University Pk, PA 16802 USA. [Lawson, Katie M.] Ball State Univ, Dept Psychol Sci, Muncie, IN 47306 USA. [Kelly, Erin L.] Univ Minnesota, Dept Sociol, Minneapolis, MN 55455 USA. [King, Rosalind B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Dev, Populat Dynam Branch, Bethesda, MD USA. [Hammer, Leslie] Portland State Univ, Dept Psychol, Portland, OR 97207 USA. [Casper, Lynne M.] Univ So Calif, Dept Sociol, Los Angeles, CA 90089 USA. [Okechukwu, Cassandra A.] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Hanson, Ginger] Kaiser Permanente Ctr Hlth Res, Portland, OR USA. RP Davis, KD (reprint author), Penn State Clearinghouse Mil Family Readiness, 135 E Nittany Ave,Ste 402, State Coll, PA 16801 USA. EM kdavis@psu.edu FU National Institutes of Health; Centers for Disease Control and Prevention: Eunice Kennedy Shriver National Institute of Child Health and Human Development [U01HD051217, U01HD051218, U01HD051256, U01HD051276]; National Institute on Aging [U01AG027669]; Office of Behavioral and Social Sciences Research; National Institute for Occupational Safety and Health [U01OH008788, U01HD059773]; National Heart, Lung, and Blood Institute [R01HL107240]; William T. Grant Foundation; Alfred P. Sloan Foundation; Administration for Children and Families FX This research was conducted as part of the Work, Family, and Health Network (www.WorkFamilyHealthNetwork.org), which is funded by a cooperative agreement through the National Institutes of Health and the Centers for Disease Control and Prevention: Eunice Kennedy Shriver National Institute of Child Health and Human Development (U01HD051217, U01HD051218, U01HD051256, U01HD051276), National Institute on Aging (U01AG027669), Office of Behavioral and Social Sciences Research, and National Institute for Occupational Safety and Health (U01OH008788, U01HD059773). Grants from the National Heart, Lung, and Blood Institute (R01HL107240), William T. Grant Foundation, Alfred P. Sloan Foundation, and the Administration for Children and Families have provided additional funding. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of these institutes and offices. Funded by the National Institutes of Health (NIH). NR 40 TC 6 Z9 6 U1 1 U2 12 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 MAY PY 2015 VL 135 IS 5 BP 875 EP 882 DI 10.1542/peds.2014-2057 PG 8 WC Pediatrics SC Pediatrics GA CH0QX UT WOS:000353728400050 PM 25869371 ER PT J AU Jo, H Schieve, LA Sharma, AJ Hinkle, SN Li, RW Lind, JN AF Jo, Heejoo Schieve, Laura A. Sharma, Andrea J. Hinkle, Stefanie N. Li, Ruowei Lind, Jennifer N. TI Maternal Prepregnancy Body Mass Index and Child Psychosocial Development at 6 Years of Age SO PEDIATRICS LA English DT Article ID DIFFICULTIES QUESTIONNAIRE; INTELLECTUAL DISABILITY; PSYCHOMETRIC PROPERTIES; COGNITIVE-DEVELOPMENT; WEIGHT-GAIN; PREGNANCY; OBESITY; ASSOCIATIONS; TRENDS; RISK AB BACKGROUND: Both obesity and developmental disabilities have increased in recent decades. Limited studies suggest associations between maternal prepregnancy obesity and child neurodevelopment. METHODS: The Infant Feeding Practices Study II, a US nationally distributed longitudinal study of maternal health and infant health and feeding practices, was conducted from 2005 to 2007. In 2012, mothers were recontacted for information on their children's health and development. We examined associations between maternal prepregnancy BMI and child psychosocial development in 1311 mother-child pairs included in this follow-up study. Children's development was assessed by maternal report of child psychosocial difficulties from the Strengths and Difficulties Questionnaire, past developmental diagnoses, and receipt of special needs services. RESULTS: Adjusting for sociodemographic factors, children of obese class II/III mothers (BMI > 35.0) had increased odds of emotional symptoms (adjusted odds ratio [aOR] 2.24; 95% confidence interval [CI], 1.27-3.98), peer problems (aOR 2.07; 95% CI, 1.26-3.40), total psychosocial difficulties (aOR 2.17; 95% CI, 1.24-3.77), attention-deficit/hyperactivity disorder diagnosis (aOR 4.55; 95% CI, 1.80-11.46), autism or developmental delay diagnosis (aOR 3.13; 95% CI, 1.10-8.94), receipt of speech language therapy (aOR 1.93; 95% CI, 1.18-3.15), receipt of psychological services (aOR 2.27; 95% CI, 1.09-4.73), and receipt of any special needs service (aOR 1.99; 95% CI, 1.33-2.97) compared with children of normal weight mothers (BMI 18.5-24.9). Adjustment for potential causal pathway factors including pregnancy weight gain, gestational diabetes, breastfeeding duration, postpartum depression, and child's birth weight did not substantially affect most estimates. CONCLUSIONS: Children whose mothers were severely obese before pregnancy had increased risk for adverse developmental outcomes. C1 [Jo, Heejoo; Schieve, Laura A.] Ctr Dis Control & Prevent, Div Birth Defects & Dev Disabil, Natl Ctr Birth Defects & Dev Disabil, Atlanta, GA 30333 USA. [Li, Ruowei; Lind, Jennifer N.] Ctr Dis Control & Prevent, Div Nutr Phys Act & Obes, Atlanta, GA 30333 USA. [Lind, Jennifer N.] Ctr Dis Control & Prevent, Epidem Intelligence Serv, Off Surveillance Epidemiol & Lab Serv, Atlanta, GA 30333 USA. [Jo, Heejoo] Oak Ridge Inst Sci & Educ, Oak Ridge, TN USA. [Sharma, Andrea J.] Ctr Dis Control, Natl Ctr Chron Dis Prevent & Hlth Promot, Div Reprod Hlth, Atlanta, GA 30333 USA. [Sharma, Andrea J.; Lind, Jennifer N.] US Publ Hlth Serv Commissioned Corps, Atlanta, GA USA. [Hinkle, Stefanie N.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Bethesda, MD USA. RP Jo, H (reprint author), Ctr Dis Control & Prevent, Div Birth Defects & Dev Disabil, Natl Ctr Birth Defects & Dev Disabil, 1600 Clifton Rd,MS-E86, Atlanta, GA 30333 USA. EM heejoojo@usc.edu RI Hinkle, Stefanie/F-8253-2013; OI Hinkle, Stefanie/0000-0003-4312-708X; Sharma, Andrea/0000-0003-0385-0011 FU intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; National Institutes of Health (NIH) FX Supported in part by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. Funded by the National Institutes of Health (NIH). NR 42 TC 12 Z9 12 U1 3 U2 21 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 MAY PY 2015 VL 135 IS 5 BP E1198 EP E1209 DI 10.1542/peds.2014-3058 PG 12 WC Pediatrics SC Pediatrics GA CH0QX UT WOS:000353728400011 PM 25917989 ER PT J AU Yang, HJ Ratnapriya, R Cogliati, T Kim, JW Swaroop, A AF Yang, Hyun-Jin Ratnapriya, Rinki Cogliati, Tiziana Kim, Jung-Woong Swaroop, Anand TI Vision from next generation sequencing: Multi-dimensional genome-wide analysis for producing gene regulatory networks underlying retinal development, aging and disease SO PROGRESS IN RETINAL AND EYE RESEARCH LA English DT Article DE Systems biology; High throughput genomics; Gene regulatory network; Retinal degeneration; Macular degeneration; Photoreceptor; Inherited blindness; Network medicine; Whole exome sequencing; RNA-seq; ChIP-seq; eQTL; Pathway-based drug discovery; Personalized medicine ID NUCLEAR RECEPTOR NR2E3; EMBRYONIC STEM-CELLS; COMPLEMENT FACTOR-H; AGE-RELATED MACULOPATHY; S-CONE SYNDROME; PHOTORECEPTOR-SPECIFIC EXPRESSION; TRANSCRIPTION FACTOR NETWORK; PIGMENT EPITHELIAL-CELLS; PROTEIN-DNA INTERACTIONS; DEVELOPING MOUSE RETINA AB Genomics and genetics have invaded all aspects of biology and medicine, opening uncharted territory for scientific exploration. The definition of "gene" itself has become ambiguous, and the central dogma is continuously being revised and expanded. Computational biology and computational medicine are no longer intellectual domains of the chosen few. Next generation sequencing (NGS) technology, together with novel methods of pattern recognition and network analyses, has revolutionized the way we think about fundamental biological mechanisms and cellular pathways. In this review, we discuss NGS-based genome-wide approaches that can provide deeper insights into retinal development, aging and disease pathogenesis. We first focus on gene regulatory networks (GRNs) that govern the differentiation of retinal photoreceptors and modulate adaptive response during aging. Then, we discuss NGS technology in the context of retinal disease and develop a vision for therapies based on network biology. We should emphasize that basic strategies for network construction and analyses can be transported to any tissue or cell type. We believe that specific and uniform guidelines are required for generation of genome, transcriptome and epigenome data to facilitate comparative analysis and integration of multi-dimensional data sets, and for constructing networks underlying complex biological processes. As cellular homeostasis and organismal survival are dependent on gene gene and gene environment interactions, we believe that network-based biology will provide the foundation for deciphering disease mechanisms and discovering novel drug targets for retinal neurodegenerative diseases. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license. C1 [Yang, Hyun-Jin; Ratnapriya, Rinki; Cogliati, Tiziana; Kim, Jung-Woong; Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. RP Swaroop, A (reprint author), N NRL, Bldg 6,Room 338,MSC0610,6 Ctr Dr, Bethesda, MD 20892 USA. EM swaroopa@nei.nih.gov OI Swaroop, Anand/0000-0002-1975-1141 FU National Eye Institute, National Institutes of Health [ZO1-EY000450, ZO1-EY000473, ZO1-EY000475] FX We are grateful to Vijender Chaitanker for designing one of the figures and thank N-NRL colleagues, especially Alexis Boleda, Matthew Brooks, Linn Gieser, Koray Kaya, and Soo-Young Kim for assistance and discussions. We thank Belinda Seto for comments on the manuscript. This research is supported by Intramural Research program (ZO1-EY000450; ZO1-EY000473, ZO1-EY000475) of the National Eye Institute, National Institutes of Health. NR 343 TC 17 Z9 17 U1 4 U2 26 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1350-9462 J9 PROG RETIN EYE RES JI Prog. Retin. Eye Res. PD MAY PY 2015 VL 46 BP 1 EP 30 DI 10.1016/j.preteyeres.2015.01.005 PG 30 WC Ophthalmology SC Ophthalmology GA CI2PZ UT WOS:000354590800001 PM 25668385 ER PT J AU Lek, A Rahimov, F Jones, PL Kunkel, LM AF Lek, Angela Rahimov, Fedik Jones, Peter L. Kunkel, Louis M. TI Emerging preclinical animal models for FSHD SO TRENDS IN MOLECULAR MEDICINE LA English DT Review DE facioscapulohumeral dystrophy; muscular dystrophy; DUX4 ID FACIOSCAPULOHUMERAL MUSCULAR-DYSTROPHY; GENE-EXPRESSION; CANDIDATE GENE; ASYMPTOMATIC CARRIERS; DUX4 EXPRESSION; D4Z4; MUSCLE; PROTEIN; PITX1; DNA AB Facioscapulohumeral dystrophy (FSHD) is a unique and complex genetic disease that is not entirely solved. Recent advances in the field have led to a consensus genetic premise for the disorder, enabling researchers to now pursue the design of preclinical models. In this review we explore all available FSHD models (DUX4-dependent and -independent) for their utility in therapeutic discovery and potential to yield novel disease insights. Owing to the complex nature of FSHD, there is currently no single model that accurately recapitulates the genetic and pathophysiological spectrum of the disorder. Existing models emphasize only specific aspects of the disease, highlighting the need for more collaborative research and novel paradigms to advance the translational research space of FSHD. C1 [Lek, Angela; Rahimov, Fedik; Kunkel, Louis M.] Childrens Hosp, Manton Ctr Orphan Dis Res, Div Genet & Genom, Boston, MA 02115 USA. [Lek, Angela; Rahimov, Fedik; Kunkel, Louis M.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Lek, Angela; Rahimov, Fedik; Jones, Peter L.; Kunkel, Louis M.] Univ Massachusetts, Med Sch UMMS, Wellstone Program, Dept Neurol, Worcester, MA 01655 USA. [Lek, Angela; Rahimov, Fedik; Jones, Peter L.; Kunkel, Louis M.] Univ Massachusetts, Med Sch UMMS, Dept Cell & Dev Biol, Worcester, MA 01655 USA. [Jones, Peter L.] Univ Massachusetts, Sch Med, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Senator Paul D Wellstone Muscular Dystrophy Coope, Worcester, MA 01655 USA. RP Lek, A (reprint author), Childrens Hosp, Manton Ctr Orphan Dis Res, Div Genet & Genom, 300 Longwood Ave, Boston, MA 02115 USA. EM alek@enders.tch.harvard.edu FU UMMS; NICHD Wellstone Center for FSHD [U54HD060848]; National Institute of Arthritis, Musculoskeletal, and Skin Diseases [1R01AR062587]; FSH Society; Chris Carrino Foundation for FSHD FX A.L., F.R., and L.M.K. are supported by the UMMS, NICHD Wellstone Center for FSHD grant U54HD060848. P.L.J. is supported by grant 24 #1R01AR062587 from the National Institute of Arthritis, Musculoskeletal, and Skin Diseases. The authors thank Daniel P. Perez, the FSH Society, and the Chris Carrino Foundation for FSHD for supporting our 25 research projects. NR 71 TC 8 Z9 8 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4914 EI 1471-499X J9 TRENDS MOL MED JI Trends Mol. Med PD MAY PY 2015 VL 21 IS 5 BP 295 EP 306 DI 10.1016/j.molmed.2015.02.011 PG 12 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA CI2NE UT WOS:000354583500005 PM 25801126 ER PT J AU Wohlfarth, A Castaneto, MS Zhu, MS Pang, SK Scheidweiler, KB Kronstrand, R Huestis, MA AF Wohlfarth, Ariane Castaneto, Marisol S. Zhu, Mingshe Pang, Shaokun Scheidweiler, Karl B. Kronstrand, Robert Huestis, Marilyn A. TI Pentylindole/Pentylindazole Synthetic Cannabinoids and Their 5-Fluoro Analogs Produce Different Primary Metabolites: Metabolite Profiling for AB-PINACA and 5F-AB-PINACA SO AAPS JOURNAL LA English DT Article DE 5-fluoro-AB-PINACA; AB-PINACA; in silico prediction; metabolism; synthetic cannabinoids ID RESOLUTION MASS-SPECTROMETRY; HUMAN HEPATOCYTES; IN-VITRO; URINARY METABOLITES; SMOKING MIXTURES; DESIGNER DRUG; IDENTIFICATION; MS/MS; FUBINACA; AM-2201 AB Whereas non-fluoropentylindole/indazole synthetic cannabinoids appear to be metabolized preferably at the pentyl chain though without clear preference for one specific position, their 5-fluoro analogs' major metabolites usually are 5-hydroxypentyl and pentanoic acid metabolites. We determined metabolic stability and metabolites of N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-pentyl-1H-indazole-3-carboxamide (AB-PINACA) and 5-fluoro-AB-PINACA (5F-AB-PINACA), two new synthetic cannabinoids, and investigated if results were similar. In silico prediction was performed with MetaSite (Molecular Discovery). For metabolic stability, 1 mu mol/L of each compound was incubated with human liver microsomes for up to 1 h, and for metabolite profiling, 10 mu mol/L was incubated with pooled human hepatocytes for up to 3 h. Also, authentic urine specimens from AB-PINACA cases were hydrolyzed and extracted. All samples were analyzed by liquid chromatography high-resolution mass spectrometry on a TripleTOF 5600+ (AB SCIEX) with gradient elution (0.1% formic acid in water and acetonitrile). High-resolution full-scan mass spectrometry (MS) and information-dependent acquisition MS/MS data were analyzed with MetabolitePilot (AB SCIEX) using different data processing algorithms. Both drugs had intermediate clearance. We identified 23 AB-PINACA metabolites, generated by carboxamide hydrolysis, hydroxylation, ketone formation, carboxylation, epoxide formation with subsequent hydrolysis, or reaction combinations. We identified 18 5F-AB-PINACA metabolites, generated by the same biotransformations and oxidative defluorination producing 5-hydroxypentyl and pentanoic acid metabolites shared with AB-PINACA. Authentic urine specimens documented presence of these metabolites. AB-PINACA and 5F-AB-PINACA produced suggested metabolite patterns. AB-PINACA was predominantly hydrolyzed to AB-PINACA carboxylic acid, carbonyl-AB-PINACA, and hydroxypentyl AB-PINACA, likely in 4-position. The most intense 5F-AB-PINACA metabolites were AB-PINACA pentanoic acid and 5-hydroxypentyl-AB-PINACA. C1 [Wohlfarth, Ariane; Castaneto, Marisol S.; Scheidweiler, Karl B.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Zhu, Mingshe] Bristol Myers Squibb Co, Res & Dev, Dept Biotransformat, Princeton, NJ 08543 USA. [Pang, Shaokun] AB SCIEX, Redwood City, CA 94404 USA. [Kronstrand, Robert] Natl Board Forens Med, Dept Forens Genet & Forens Toxicol, S-58758 Linkoping, Sweden. [Kronstrand, Robert] Linkoping Univ, Div Drug Res, S-58185 Linkoping, Sweden. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab, Intramural Res Program, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. AB-PINACA and 5F-AB-PINACA were generously donated by the Drug Enforcement Administration. Molecular Discovery kindly provided the MetaSite software. NR 34 TC 24 Z9 24 U1 3 U2 20 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD MAY PY 2015 VL 17 IS 3 BP 660 EP 677 DI 10.1208/s12248-015-9721-0 PG 18 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CG8LY UT WOS:000353560700015 PM 25721194 ER PT J AU Sharp, RR Taylor, HA Brinich, MA Boyle, MM Cho, M Coors, M Danis, M Havard, M Magnus, D Wilfond, B AF Sharp, Richard R. Taylor, Holly A. Brinich, Margaret A. Boyle, Mary M. Cho, Mildred Coors, Marilyn Danis, Marion Havard, Molly Magnus, David Wilfond, Benjamin TI Research Ethics Consultation: Ethical and Professional Practice Challenges and Recommendations SO ACADEMIC MEDICINE LA English DT Article ID STRANGERS; SERVICE; SCIENCE; HEALTH AB The complexity of biomedical research has increased considerably in the last decade, as has the pace of translational research. This complexity has generated a number of novel ethical issues for clinical investigators, institutional review boards (IRBs), and other oversight committees. In response, many academic medical centers have created formal research ethics consultation (REC) services to help clinical investigators and IRBs navigate ethical issues in biomedical research. Key functions of a REC service include assisting with research design and implementation, providing a forum for deliberative exploration of ethical issues, and supplementing regulatory oversight. As increasing numbers of academic research institutions establish REC services, there is a pressing need for consensus about the primary aims and policies that should guide these activities. Establishing clear expectations about the aims and policies of REC services is important if REC programs are to achieve their full potential. Drawing on the experiences of a Clinical and Translational Science Award Research Ethics Consultation Working Group, this article describes three major ethical and professional practice challenges associated with the provision of REC: (1) managing multiple institutional roles and responsibilities, (2) managing sensitive information, and (3) communicating with consultation requestors about how these issues are managed. The paper also presents several practical strategies for addressing these challenges and enhancing the quality of REC services. C1 [Sharp, Richard R.] Mayo Clin, Biomed Eth Program, Rochester, MN USA. [Taylor, Holly A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD 21205 USA. [Taylor, Holly A.] Johns Hopkins Berman Inst Bioeth, Core Fac, Baltimore, MD USA. [Brinich, Margaret A.] Lakewood Observer, Lakewood, OH USA. [Boyle, Mary M.] Fred Hutchinson Canc Res Ctr, MDS MPN Grp, Transplantat Biol Dept, Div Clin Res, Seattle, WA 98104 USA. [Cho, Mildred] Stanford Univ, Stanford Dept Pediat, Stanford, CA 94305 USA. [Cho, Mildred] Stanford Univ, Stanford Ctr Biomed Eth, Stanford, CA 94305 USA. [Coors, Marilyn] Ctr Bioeth & Human, Dept Psychiat, Aurora, CO USA. [Danis, Marion] Natl Inst Hlth Clin Ctr, Eth & Hlth Policy, Dept Bioeth, Bethesda, MD USA. [Havard, Molly] Univ Cincinnati, Coll Med, Cincinnati, OH USA. [Magnus, David] Stanford Univ, Med & Biomed Eth, Stanford, CA 94305 USA. [Magnus, David] Stanford Univ, Stanford Ctr Biomed Eth, Stanford, CA 94305 USA. [Wilfond, Benjamin] Treuman Katz Ctr Pediat Bioeth, Seattle Childrens Res Inst, Seattle, WA USA. [Wilfond, Benjamin] Univ Washington, Sch Med, Dept Pediat, Div Bioeth, Seattle, WA 98195 USA. RP Taylor, HA (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, 1809 Ashland Ave,Deering Hall 205, Baltimore, MD 21205 USA. EM htaylor@jhu.edu FU National Center for Research Resources; National Center for Advancing Translational Sciences of the National Institutes of Health [3UL1RR025014-04S1] FX This project was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences of the National Institutes of Health under award number 3UL1RR025014-04S1 (Research Bioethics Consultation Standardization and Data Sharing). NR 21 TC 0 Z9 0 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-2446 EI 1938-808X J9 ACAD MED JI Acad. Med. PD MAY PY 2015 VL 90 IS 5 BP 615 EP 620 DI 10.1097/ACM.0000000000000640 PG 6 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA CH2UH UT WOS:000353879700022 PM 25607942 ER PT J AU Needle, D Lountos, GT Waugh, DS AF Needle, Danielle Lountos, George T. Waugh, David S. TI Structures of the Middle East respiratory syndrome coronavirus 3C-like protease reveal insights into substrate specificity SO ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY LA English DT Article DE MERS-CoV; coronavirus; main protease; 3CL(pro) ID ANTIVIRAL DRUG DESIGN; AZA-PEPTIDE EPOXIDE; MAIN PROTEASE; CRYSTAL-STRUCTURES; EXTRA DOMAIN; SECONDARY-STRUCTURE; DIMER INTERFACE; MERS-COV; SARS; PROTEINASE AB Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly pathogenic virus that causes severe respiratory illness accompanied by multi-organ dysfunction, resulting in a case fatality rate of approximately 40%. As found in other coronaviruses, the majority of the positive-stranded RNA MERS-CoV genome is translated into two polyproteins, one created by a ribosomal frameshift, that are cleaved at three sites by a papain-like protease and at 11 sites by a 3C-like protease (3CL(pro)). Since 3CL(pro) is essential for viral replication, it is a leading candidate for therapeutic intervention. To accelerate the development of 3CL(pro) inhibitors, three crystal structures of a catalytically inactive variant (C148A) of the MERS-CoV 3CL(pro) enzyme were determined. The aim was to co-crystallize the inactive enzyme with a peptide substrate. Fortuitously, however, in two of the structures the C-terminus of one protomer is bound in the active site of a neighboring molecule, providing a snapshot of an enzyme-product complex. In the third structure, two of the three protomers in the asymmetric unit form a homodimer similar to that of SARS-CoV 3CL(pro); however, the third protomer adopts a radically different conformation that is likely to correspond to a crystallographic monomer, indicative of substantial structural plasticity in the enzyme. The results presented here provide a foundation for the structure-based design of small-molecule inhibitors of the MERS-CoV 3CL(pro) enzyme. C1 [Needle, Danielle; Lountos, George T.; Waugh, David S.] NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21701 USA. [Lountos, George T.] Leidos Biomed Res Inc, Basic Sci Program, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Waugh, DS (reprint author), NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21701 USA. EM waughd@mail.nih.gov FU Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; National Interagency Confederation for Biological Research Collaborative Project Award Program; US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] 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 and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products or organizations imply endorsement by the US Government. Additional funding came from a National Interagency Confederation for Biological Research Collaborative Project Award Program to DN. We are grateful to our collaborators at the United States Army Research Institute of Infectious Diseases (R. Ulrich and colleagues) for providing us with a MERS-CoV 3CLpro PCR amplicon. We thank the Biophysics Resource in the Structural Biophysics Laboratory, NCI at Frederick for use of the LC/ESMS and dynamic light-scattering instruments. X-ray diffraction data were collected at the Southeast Regional Collaborative Access Team (SER-CAT) beamline 22-BM of the Advanced Photon Source, Argonne National Laboratory. Supporting institutions may be found at http://www.ser-cat.org/members.html. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences under contract No. W-31-109-Eng-38. NR 54 TC 7 Z9 9 U1 2 U2 13 PU INT UNION CRYSTALLOGRAPHY PI CHESTER PA 2 ABBEY SQ, CHESTER, CH1 2HU, ENGLAND EI 2059-7983 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Struct. Biol. PD MAY PY 2015 VL 71 BP 1102 EP 1111 DI 10.1107/S1399004715003521 PN 5 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA CH9SN UT WOS:000354376700009 PM 25945576 ER PT J AU Narayan, AJ Chen, MZ Martinez, PP Gold, PW Klimes-Dougan, B AF Narayan, Angela J. Chen, Muzi Martinez, Pedro P. Gold, Philip W. Klimes-Dougan, Bonnie TI Interparental Violence and Maternal Mood Disorders as Predictors of Adolescent Physical Aggression Within the Family SO AGGRESSIVE BEHAVIOR LA English DT Article DE interparental violence; Bipolar Disorder; depression; adolescence; aggression ID NATIONAL COMORBIDITY SURVEY; MAJOR DEPRESSIVE DISORDER; PARENT-CHILD CONFLICT; BIPOLAR DISORDER; DOMESTIC VIOLENCE; MARITAL CONFLICT; SURVEY REPLICATION; DATING VIOLENCE; ADJUSTMENT; SYMPTOMS AB Although a wealth of research has examined the effects of parental mood disorders on offspring maladjustment, studies have not identified whether elevated interparental violence (IPV) may be an exacerbating influence in this pathway. This study examined levels of physical IPV perpetration and victimization in mothers with unipolar depression or Bipolar Disorder (BD) and the processes by which maternal physical IPV moderated adolescents' physical aggression in families with maternal mood disorders. Mothers with lifetime mood disorders were predicted to have elevated IPV compared to well mothers, and maternal IPV was expected to moderate the association between lifetime mood disorders and adolescent aggression. Participants included 61 intact families with maternal depression (n = 24), BD (n = 13), or well mothers (n = 24) and two siblings (ages 10 to 18 years). Using the Conflict Tactics Scale, mothers reported on IPV perpetration and victimization, and adolescents reported on physical aggression. Mothers with BD reported significantly higher IPV perpetration, but not victimization, than depressed or well mothers. An interaction between maternal BD and IPV perpetration was a significant predictor of adolescent aggression. Main effects of maternal IPV victimization and interaction effects of maternal depression and either type of IPV on adolescent aggression were not significant. Adolescents of mothers who have BD and perpetrate IPV may be particularly vulnerable to being aggressive. Prevention and policy efforts to deter transmission of aggression in high-risk families should target families with maternal BD and intervene at the level of conflict resolution within the family. (C) 2014 Wiley Periodicals, Inc. C1 [Narayan, Angela J.] Univ Minnesota, Inst Child Dev, St Paul, MN USA. [Chen, Muzi] Univ Minnesota, Dept Family Social Sci, St Paul, MN USA. [Martinez, Pedro P.; Gold, Philip W.] NIMH, Bethesda, MD 20892 USA. [Klimes-Dougan, Bonnie] Univ Minnesota, Dept Psychol, St Paul, MN USA. RP Narayan, AJ (reprint author), Univ Minnesota, Inst Child Dev, 51 E River Rd, Minneapolis, MN 55455 USA. EM naray076@umn.edu FU Graduate School Fellowship from the University of Minnesota; Intramural Program of the National Institute of Mental Health (NIMH); Catherine T. MacArthur Foundation FX Contract grant sponsor: Graduate School Fellowship from the University of Minnesota; The Intramural Program of the National Institute of Mental Health (NIMH); The Catherine T. MacArthur Foundation NR 81 TC 0 Z9 0 U1 0 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0096-140X EI 1098-2337 J9 AGGRESSIVE BEHAV JI Aggressive Behav. PD MAY-JUN PY 2015 VL 41 IS 3 BP 253 EP 266 DI 10.1002/ab.21569 PG 14 WC Behavioral Sciences; Psychology, Multidisciplinary SC Behavioral Sciences; Psychology GA CH4XK UT WOS:000354036600005 PM 27541378 ER PT J AU Kebaabetswe, PM Stirratt, MJ McLellan-Lemal, E Henderson, FL Gray, SC Rose, CE Williams, T Paxton, LA AF Kebaabetswe, Poloko M. Stirratt, Michael J. McLellan-Lemal, Eleanor Henderson, Faith L. Gray, Simone C. Rose, Charles E. Williams, Tiffany Paxton, Lynn A. TI Factors Associated with Adherence and Concordance Between Measurement Strategies in an HIV Daily Oral Tenofovir/Emtricitibine as Pre-exposure Prophylaxis (Prep) Clinical Trial, Botswana, 2007-2010 SO AIDS AND BEHAVIOR LA English DT Article DE Oral pre-exposure prophylaxis (PrEP); Adherence; HIV prevention ID ANTIRETROVIRAL MEDICATIONS; BEHAVIOR-CHANGE; DOUBLE-BLIND; PREVENTION; INFECTION; WOMEN; TENOFOVIR; CHEMOPROPHYLAXIS; ACCEPTABILITY; CHALLENGES AB This study examined study product adherence and its determinants in the Botswana oral pre-exposure prophylaxis efficacy trial. Among the 1,219 participants, the mean adherence by pill count and 3-day self-report was 94 % for each. In multivariable models, pill count adherence was significantly associated with adverse events (nausea, dizziness, vomiting) (RR 0.98 95 % CI 0.98-1.00; p = 0.03) and side effect concerns (RR 0.98 95 % CI 0.96-0.99; p = 0.01). Self-reported adherence was significantly associated with having an HIV-positive partner (RR 1.02 95 % CI 1.00-1.04; p = 0.02) and Francistown residence (RR 0.98 95 % CI 0.96, 0.99; p = 0.0001). Detectable drug concentrations showed modest associations with self-report and pill count adherence, and drug levels were higher among those self-reporting 100 % adherence than those reporting < 100 %. Most common adherence barriers involved refill delays and other logistic challenges; cellphone alarm reminder use was the most common facilitator. C1 [Kebaabetswe, Poloko M.] CDC Botswana, HIV Prevent Res Unit, Gaborone, Botswana. [Kebaabetswe, Poloko M.] Univ Botswana, Sch Med, Gaborone, Botswana. [Stirratt, Michael J.] NIMH, Div AIDS Res, Bethesda, MD 20892 USA. [McLellan-Lemal, Eleanor; Henderson, Faith L.; Gray, Simone C.; Rose, Charles E.; Williams, Tiffany; Paxton, Lynn A.] Ctr Dis Control & Prevent, Div HIV AIDS Prevent, Off Infect Dis, Natl Ctr HIV AIDS Viral Hepatitis STD & TB Preven, Atlanta, GA 30333 USA. [Williams, Tiffany] ICF Int, Atlanta, GA USA. RP McLellan-Lemal, E (reprint author), Ctr Dis Control & Prevent, Div HIV AIDS Prevent, Off Infect Dis, Natl Ctr HIV AIDS Viral Hepatitis STD & TB Preven, 1600 Clifton Rd,MS E-45, Atlanta, GA 30333 USA. EM poloko.kebaabetswe@mopipi.ub.bw; stirrattm@mail.nih.gov; emclellanlemal@cdc.gov; fhenderson@cdc.gov; simonegray@cdc.gov; crose@cdc.gov; twilliams13@cdc.gov; paxtonl@tz.cdc.gov FU Centers for Disease Control and Prevention National, Office of Infectious Diseases, Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Division of HIV/AIDS Prevention FX Funding for this study was provided by the Centers for Disease Control and Prevention National, Office of Infectious Diseases, Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Division of HIV/AIDS Prevention. TDF2 Clinical-Trials.gov number: NCT00448669. We are indebted to all TDF2 participants and the entire HIV Prevention Research Team, and appreciate the leadership of Drs. Michael Thigpen and Dawn Smith. NR 42 TC 2 Z9 2 U1 1 U2 2 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD MAY PY 2015 VL 19 IS 5 BP 758 EP 769 DI 10.1007/s10461-014-0891-z PG 12 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA CH2WU UT WOS:000353886500003 PM 25186785 ER PT J AU Montgomery, ET van der Straten, A Stadler, J Hartmann, M Magazi, B Mathebula, F Laborde, N Soto-Torres, L AF Montgomery, Elizabeth T. van der Straten, Ariane Stadler, Jonathan Hartmann, Miriam Magazi, Busisiwe Mathebula, Florence Laborde, Nicole Soto-Torres, Lydia TI Male Partner Influence on Women's HIV Prevention Trial Participation and Use of Pre-exposure Prophylaxis: the Importance of "Understanding" SO AIDS AND BEHAVIOR LA English DT Article DE HIV/AIDS; Microbicides; PrEP; Women; South Africa ID ADHERENCE; RISK AB There is widespread evidence that male partners influence women's ability and willingness to join HIV prevention trials and to use female-controlled prevention strategies such as microbicide gels. VOICE-C was an ancillary study to the Microbicide Trials Network's VOICE trial at the Johannesburg site that explored social and structural factors influencing women's use of study tablets and vaginal gel. Qualitative data were analyzed from 102 randomly-selected VOICE participants interviewed through in-depth interviews (IDI, n = 41); ethnographic interviews (n = 21) or focus group discussions (FGD, n = 40) and 22 male partners interviewed in 14 IDI and 2 FGD. Male partners' "understanding" pervaded as a central explanation for how male partners directly and indirectly influenced their female partners' trial participation and product use, irrespective of assignment to the gel or tablet study groups. The meaning behind "understanding" in this context was described by both men and women in two important and complementary ways: (1) "comprehension" of the study purpose including biological properties or effects of the products, and (2) "support/agreeability" for female partners being study participants or using products. During analysis a third dimension of "understanding" emerged as men's acceptance of larger shifts in gender roles and relationship power, and the potential implications of women's increased access to biomedical knowledge, services and prevention methods. Despite displays of some female agency to negotiate and use HIV prevention methods, male partners still have a critical influence on women's ability and willingness to do so. Efforts to increase their understanding of research goals, study design and products' mechanisms of action could ameliorate distrust, empower men to serve as product advocates, adherence buddies, and foster greater adherence support for women in situations where it is needed. Strategies to address gender norms and the broader implications these have for female-initiated HIV prevention should likewise be integrated into future research and program activities. C1 [Montgomery, Elizabeth T.; van der Straten, Ariane; Hartmann, Miriam; Laborde, Nicole] RTI Int, Womens Global Hlth Imperat, San Francisco, CA 94104 USA. [van der Straten, Ariane] UCSF, Dept Med, Ctr AIDS Prevent Studies, San Francisco, CA 94105 USA. [Stadler, Jonathan; Magazi, Busisiwe; Mathebula, Florence] Univ Witwatersrand, Fac Hlth Sci, Wits Reprod Hlth & HIV Inst, ZA-2001 Johannesburg, South Africa. [Soto-Torres, Lydia] NIAID, DAIDS, NIH, Bethesda, MD 20892 USA. RP Montgomery, ET (reprint author), RTI Int, Womens Global Hlth Imperat, 114 Sansome St,Suite 500, San Francisco, CA 94104 USA. EM emontgomery@rti.org FU Microbicide Trial Network (MTN) - NIAID of the U.S. National Institutes of Health [5UM1AI068633]; NICHD of the U.S. National Institutes of Health; NIMH of the U.S. National Institutes of Health FX We would like to pay tribute to the women and men who participated in this study, their dedication and commitment made this study possible. The contributions of the MTN Behavioral Research Working Group, the VOICE trial leadership, Katie Schwartz and Kat Richards of FHI360, Catie Magee and Helen Cheng at RTI International, Sello Seoka at WRHI and other Protocol study team members are acknowledged as critical in the development, implementation, and/or analysis of this study. The full MTN003-C study team can be viewed at http://www.mtnstopshiv.org/studies/1087. This study was supported through the Microbicide Trial Network (MTN) which is funded by NIAID (5UM1AI068633), NICHD and NIMH, and all of the U.S. National Institutes of Health. NR 20 TC 5 Z9 5 U1 2 U2 8 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD MAY PY 2015 VL 19 IS 5 BP 784 EP 793 DI 10.1007/s10461-014-0950-5 PG 10 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA CH2WU UT WOS:000353886500005 PM 25416076 ER PT J AU Fernandez, MI Huszti, HC Wilson, PA Kahana, S Nichols, S Gonin, R Xu, JH Kapogiannis, BG AF Fernandez, M. Isabel Huszti, Heather C. Wilson, Patrick A. Kahana, Shoshana Nichols, Sharon Gonin, Rene Xu, Jiahong Kapogiannis, Bill G. TI Profiles of Risk Among HIV-Infected Youth in Clinic Settings SO AIDS AND BEHAVIOR LA English DT Article DE HIV infected youth; Risk profiles; Latent class analysis ID HUMAN-IMMUNODEFICIENCY-VIRUS; SUBSTANCE USE; ANCILLARY SERVICES; CIGARETTE-SMOKING; MENTAL-DISORDERS; POSITIVE YOUTH; UNITED-STATES; PRIMARY-CARE; LUNG-CANCER; YOUNG MEN AB Despite the rising number of new HIV infections among youth, few tailored interventions for youth living with HIV (YLH) have been developed and rigorously tested. Developing tailored interventions necessitates identifying different profiles of YLH and understanding how risk and protective factors cluster together. Obtaining this critical information requires accessing a sufficiently large sample of YLH from diverse geographic settings such as those available through the Adolescent Trials Network for HIV Interventions (ATN). We recruited a cross-sectional sample of 1,712 YLH from ATN clinics; participants completed a survey on psychosocial and health factors. Using latent class analysis on nine composite variables representing risk factors, we identified five classes distinguished by substance use, sexual behavior, and pregnancy history and differing on health outcomes. Findings suggest a need for tailored interventions addressing multiple risky behaviors of HIV-infected youth and research to clarify how intervention effectiveness may differ by risk profile. C1 [Fernandez, M. Isabel] Nova SE Univ, Dept Prevent Med, Coll Osteopath Med, Davie, FL USA. [Fernandez, M. Isabel] Nova SE Univ, Dept Publ Hlth Program, Coll Osteopath Med, Davie, FL USA. [Huszti, Heather C.] Childrens Hosp Orange Cty, Dept Pediat Psychol, Orange, CA 92668 USA. [Wilson, Patrick A.] Columbia Univ, Dept Sociomed Sci, New York, NY USA. [Kahana, Shoshana] NIDA, NIH, Bethesda, MA USA. [Nichols, Sharon] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA. [Gonin, Rene; Xu, Jiahong] Westat Corp, Rockville, MD USA. [Kapogiannis, Bill G.] NICHHD, Maternal & Pediat Infect Dis Branch, Bethesda, MA USA. RP Fernandez, MI (reprint author), 2000 S Dixie Hwy Suite 108, Miami, FL 33133 USA. EM mariafer@nova.edu FU Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) from the National Institutes of Health through the National Institute of Child Health and Human Development [U01 HD 040533, U01 HD 040474]; National Institute on Drug Abuse; National Institute on Mental Health FX This work was supported by The Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) from the National Institutes of Health [U01 HD 040533 and U01 HD 040474] through the National Institute of Child Health and Human Development (B. Kapogiannis, S. Lee), with supplemental funding from the National Institutes on Drug Abuse (K. Davenny, S. Kahana) and Mental Health (P. Brouwers, S. Allison). The study was scientifically reviewed by the ATN's Behavioral Leadership Group. Network, scientific and logistical support was provided by the ATN Coordinating Center (C. Wilson, C. Partlow) at The University of Alabama at Birmingham. Network operations and data management support was provided by the ATN Data and Operations Center at Westat, Inc. (J. Korelitz, B. Driver). We acknowledge the contribution of the investigators and staff at the following sites that participated in this study: the following ATN sites participated in this study: University of South Florida, Tampa (Emmanuel, Lujan-Zilbermann, Julian), Children's Hospital of Los Angeles (Belzer, Flores, Tucker), Children's National Medical Center (D'Angelo, Hagler, Trexler), Children's Hospital of Philadelphia (Douglas, Tanney, DiBenedetto), John H. Stroger Jr. Hospital of Cook County and the Ruth M. Rothstein CORE Center (Martinez, Bojan, Jackson), University of Puerto Rico (Febo, Ayala-Flores, Fuentes-Gomez), Montefiore Medical Center (Futterman, Enriquez-Bruce, Campos), Mount Sinai Medical Center (Steever, Geiger), University of California-San Francisco (Moscicki, Auerswald, Irish), Tulane University Health Sciences Center (Abdalian, Kozina, Baker), University of Maryland (Peralta, Gorle), University of Miami School of Medicine (Friedman, Maturo, Major-Wilson), Children's Diagnostic and Treatment Center (Puga, Leonard, Inman), St. Jude's Children's Research Hospital (Flynn, Dillard), Children's Memorial Hospital (Garofalo, Brennan, Flanagan). The investigators are grateful to the members of the local youth Community Advisory Boards for their insight and counsel and are particularly indebted to the youth who participated in this study. The views and opinions expressed in this report are those of the authors and should not be construed to represent the views of NIDA or any of the sponsoring organizations, agencies, or the US government. NR 53 TC 4 Z9 4 U1 2 U2 4 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD MAY PY 2015 VL 19 IS 5 BP 918 EP 930 DI 10.1007/s10461-014-0876-y PG 13 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA CH2WU UT WOS:000353886500018 PM 25117556 ER PT J AU Pitcher, A Emberson, J Lacro, RV Sleeper, LA Stylianou, M Mahony, L Pearson, GD Groenink, M Mulder, BJ Zwinderman, AH De Backer, J De Paepe, AM Arbustini, E Erdem, G Jin, XY Flather, MD Mullen, MJ Child, AH Forteza, A Evangelista, A Chiu, HH Wu, MH Sandor, G Bhatt, AB Creager, MA Devereux, RB Loeys, B Forfar, JC Neubauer, S Watkins, H Boileau, C Jondeau, G Dietz, HC Baigent, C AF Pitcher, Alex Emberson, Jonathan Lacro, Ronald V. Sleeper, Lynn A. Stylianou, Mario Mahony, Lynn Pearson, Gail D. Groenink, Maarten Mulder, Barbara J. Zwinderman, Aeilko H. De Backer, Julie De Paepe, Anne M. Arbustini, Eloisa Erdem, Guliz Jin, Xu Yu Flather, Marcus D. Mullen, Michael J. Child, Anne H. Forteza, Alberto Evangelista, Arturo Chiu, Hsin-Hui Wu, Mei-Hwan Sandor, George Bhatt, Ami B. Creager, Mark A. Devereux, Richard B. Loeys, Bart Forfar, J. Colin Neubauer, Stefan Watkins, Hugh Boileau, Catherine Jondeau, Guillaume Dietz, Harry C. Baigent, Colin TI Design and rationale of a prospective, collaborative meta-analysis of all randomized controlled trials of angiotensin receptor antagonists in Marfan syndrome, based on individual patient data: A report from the Marfan Treatment Trialists' Collaboration SO AMERICAN HEART JOURNAL LA English DT Article ID AORTIC-ROOT DILATION; CLINICAL-TRIAL; YOUNG-ADULTS; BETA-BLOCKER; LOSARTAN; ATENOLOL; THERAPY; PROGRESSION; ANEURYSM; CHILDREN AB Rationale A number of randomized trials are underway, which will address the effects of angiotensin receptor blockers (ARBs) on aortic root enlargement and a range of other end points in patients with Marfan syndrome. If individual participant data from these trials were to be combined, a meta-analysis of the resulting data, totaling approximately 2,300 patients, would allow estimation across a number of trials of the treatment effects both of ARB therapy and of beta-blockade. Such an analysis would also allow estimation of treatment effects in particular subgroups of patients on a range of end points of interest and would allow a more powerful estimate of the effects of these treatments on a composite end point of several clinical outcomes than would be available from any individual trial. Design A prospective, collaborative meta-analysis based on individual patient data from all randomized trials in Marfan syndrome of (i) ARBs versus placebo (or open-label control) and (ii) ARBs versus beta-blockers will be performed. A prospective study design, in which the principal hypotheses, trial eligibility criteria, analyses, and methods are specified in advance of the unblinding of the component trials, will help to limit bias owing to data-dependent emphasis on the results of particular trials. The use of individual patient data will allow for analysis of the effects of ARBs in particular patient subgroups and for time-to-event analysis for clinical outcomes. The meta-analysis protocol summarized in this report was written on behalf of the Marfan Treatment Trialists' Collaboration and finalized in late 2012, without foreknowledge of the results of any component trial, and will bemade available online (http:// www.ctsu.ox.ac.uk/research/meta-trials). C1 [Pitcher, Alex] Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Oxford OX3 9DU, England. [Emberson, Jonathan; Baigent, Colin] Univ Oxford, Clin Trial Serv Unit, Oxford OX3 9DU, England. [Emberson, Jonathan; Baigent, Colin] Univ Oxford, Epidemiol Studies Unit, Oxford OX3 9DU, England. [Lacro, Ronald V.; Pearson, Gail D.] Childrens Hosp Boston, Boston, MA USA. [Lacro, Ronald V.; Pearson, Gail D.; Creager, Mark A.] Harvard Univ, Sch Med, Boston, MA USA. [Sleeper, Lynn A.] New England Res Inst, Watertown, MA 02172 USA. [Stylianou, Mario] NHLBI, NIH, Bethesda, MD 20892 USA. [Mahony, Lynn] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Groenink, Maarten; Mulder, Barbara J.; Zwinderman, Aeilko H.] Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. [De Backer, Julie; De Paepe, Anne M.] Univ Hosp Ghent, Ctr Med Genet, Ghent, Belgium. [De Backer, Julie] Univ Hosp Ghent, Dept Cardiol, Ghent, Belgium. [Arbustini, Eloisa] IRCCS Fdn, San Matteo Hosp, Ctr Inherited Cardiovasc Dis, Pavia, Italy. [Erdem, Guliz] Royal Brompton & Harefield NHS Trust, Clin Trials & Evaluat Unit, London, England. [Jin, Xu Yu; Forfar, J. Colin] John Radcliffe Hosp, Oxford OX3 9DU, England. [Flather, Marcus D.] Univ E Anglia, UCL Inst Cardiovasc Sci, Norwich NR4 7TJ, Norfolk, England. [Mullen, Michael J.; Child, Anne H.] Univ London, St Georges Hosp, Dept Cardiac & Vasc Sci, London, England. [Forteza, Alberto] Hosp Univ 12 de Octubre, Madrid, Spain. [Evangelista, Arturo] Hosp Valle De Hebron, Dept Cardiol, Marfan Sydrome Unit, Barcelona, Spain. [Chiu, Hsin-Hui] Taipei Med Univ Hosp, Dept Pediat, Taipei, Taiwan. [Chiu, Hsin-Hui] Taipei Med Univ Hosp, Adult Congenital Heart Ctr, Taipei, Taiwan. [Wu, Mei-Hwan] Natl Taiwan Univ Hosp, Dept Pediat, Taipei 10016, Taiwan. [Wu, Mei-Hwan] Natl Taiwan Univ Hosp, Adult Congenital Heart Ctr, Taipei, Taiwan. [Sandor, George] British Columbia Childrens Hosp, Childrens Heart Ctr, Vancouver, BC, Canada. [Bhatt, Ami B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Creager, Mark A.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Devereux, Richard B.] Weill Cornell Med Coll, New York, NY USA. [Devereux, Richard B.] New York Presbyterian Hosp, New York, NY USA. [Loeys, Bart] Univ Antwerp, Fac Med & Hlth Sci, Ctr Med Genet, B-2020 Antwerp, Belgium. [Loeys, Bart] Univ Antwerp Hosp, Antwerp, Belgium. [Neubauer, Stefan] Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Oxford Ctr Clin Magnet Resonance Res, Oxford OX3 9DU, England. [Watkins, Hugh] Univ Oxford, Radcliffe Dept Med, Oxford OX3 9DU, England. [Boileau, Catherine] Hop Xavier Bichat Claude Bernard, Dept Genet, Inserm LVTS U1148, Paris, France. [Jondeau, Guillaume] Hop Bichat Claude Bernard, AP HP, Ctr Natl Reference Syndrome Marfan & Apparentes, Serv Cardiol,INSERM LVTS U1148, F-75877 Paris, France. [Dietz, Harry C.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Dietz, Harry C.] Howard Hughes Med Inst, Baltimore, MD USA. RP Pitcher, A (reprint author), Univ Oxford, John Radcliffe Hosp, Radcliffe Dept Med, Div Cardiovasc Med, Oxford OX3 9DU, England. EM alex.pitcher@cardiov.ox.ac.uk FU Arthritis Research UK; British Heart Foundation [FS/08/077/26366, RE/13/1/30181]; Medical Research Council [, MC_U137686849]; Wellcome Trust NR 33 TC 12 Z9 13 U1 2 U2 10 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD MAY PY 2015 VL 169 IS 5 BP 605 EP 612 DI 10.1016/j.ahj.2015.01.011 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CH6US UT WOS:000354172400006 PM 25965707 ER PT J AU Harris, TB Song, XL Reinders, I Lang, TF Garcia, ME Siggeirsdottir, K Sigurdsson, S Gudnason, V Eiriksdottir, G Sigurdsson, G Steingrimsdottir, L Aspelund, T Brouwer, IA Murphy, RA AF Harris, Tamara B. Song, Xiaoling Reinders, Ilse Lang, Thomas F. Garcia, Melissa E. Siggeirsdottir, Kristin Sigurdsson, Sigurdur Gudnason, Vilmundur Eiriksdottir, Gudny Sigurdsson, Gunnar Steingrimsdottir, Laufey Aspelund, Thor Brouwer, Ingeborg A. Murphy, Rachel A. TI Plasma phospholipid fatty acids and fish-oil consumption in relation to osteoporotic fracture risk in older adults: the Age, Gene/Environment Susceptibility Study SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE fatty acids; fish oil; osteoporotic fracture; aging; omega-3; bone health ID BONE-MINERAL DENSITY; FOOD FREQUENCY QUESTIONNAIRE; HIP FRACTURE; POSTMENOPAUSAL WOMEN; LINOLENIC ACID; DIETARY-INTAKE; VITAMIN-D; HEALTH; N-3; REYKJAVIK AB Background: Polyunsaturated fatty acids (PUFAs) may play a role in fracture, but studies have been largely confined to estimates of dietary intake. Objective: We aimed to examine associations between fatty acids measured in late life and fish-oil consumption in early life, midlife, and late life with osteoporotic fracture risk. Design: Osteoporotic fractures were determined from medical records over 5-9 y of follow-up in men and women aged 66-96 y. Data were analyzed from 1438 participants including 898 participants who were randomly selected from the Age, Gene/Environment Susceptibility Study, which is an observational study, and 540 participants with incident fracture. Plasma phospholipid fatty acids were assessed by using gas chromatography. Fish-oil consumption was assessed by using validated questionnaires as never (referent), less than daily, or daily. HRs and 95% CIs adjusted for age, education, height, weight, diabetes, physical activity, and medications were estimated by using Cox regression. Results: In men, the highest tertile of PUFAs, n-3 (omega-3), and eicosapentaenoic acid were associated with decreased fracture risk [HRs (95% CIs): 0.60 (95% CI: 0.41, 0.89), 0.66 (0.45, 0.95), and 0.59 (0.41, 0.86), respectively]. In women, PUFAs tended to be inversely associated with fracture risk (P-trend = 0.06), but tertiles 2 and 3 were not independently associated with risk. Tertile 2 of n-6 and arachidonic acid was associated with fracture risk in women [HRs (95% CIs): 1.43 (1.10, 1.85) and 1.42 (1.09, 1.85), respectively]. Daily fish-oil consumption in late life was associated with lower fracture risk in men (HR: 0.64; 95% CI: 0.45, 0.91). Daily fish-oil consumption in midlife was associated with lower fracture risk in women (HR: 0.75; 95% CI: 0.58, 0.98). Conclusions: Greater PUFA concentrations may be associated with lower osteoporotic fracture risk in older adults, particularly in men. C1 [Harris, Tamara B.; Reinders, Ilse; Garcia, Melissa E.; Murphy, Rachel A.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20814 USA. [Song, Xiaoling] Fred Hutchinson Canc Res Ctr, Biomarker Lab, Seattle, WA 98104 USA. [Reinders, Ilse; Brouwer, Ingeborg A.] Vrije Univ Amsterdam, Dept Hlth Sci, Amsterdam, Netherlands. [Reinders, Ilse; Brouwer, Ingeborg A.] Vrije Univ Amsterdam, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. [Lang, Thomas F.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Siggeirsdottir, Kristin; Sigurdsson, Sigurdur; Gudnason, Vilmundur; Eiriksdottir, Gudny; Sigurdsson, Gunnar; Aspelund, Thor] Iceland Heart Assoc, Kopavogur, Iceland. [Gudnason, Vilmundur; Sigurdsson, Gunnar; Steingrimsdottir, Laufey] Univ Iceland, Reykjavik, Iceland. RP Murphy, RA (reprint author), NIA, Lab Populat Sci, 7201 Wisconsin Ave,3C-309, Bethesda, MD 20814 USA. EM rachel.murphy@nih.gov RI Lang, Thomas/B-2685-2012; Gudnason, Vilmundur/K-6885-2015; Aspelund, Thor/C-5983-2008 OI Lang, Thomas/0000-0002-3720-8038; Gudnason, Vilmundur/0000-0001-5696-0084; Aspelund, Thor/0000-0002-7998-5433 FU Office of Dietary Supplements, NIH [N01-AG012100]; NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); Banting Postdoctoral Fellowship FX Supported by The Office of Dietary Supplements, NIH contract N01-AG012100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), the Althingi (the Icelandic Parliament), and a Banting Postdoctoral Fellowship (to RAM). NR 40 TC 4 Z9 4 U1 1 U2 6 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD MAY PY 2015 VL 101 IS 5 BP 947 EP 955 DI 10.3945/ajcn.114.087502 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CH5KS UT WOS:000354075100010 PM 25787995 ER PT J AU Guertin, KA Loftfield, E Boca, SM Sampson, JN Moore, SC Xiao, Q Huang, WY Xiong, XQ Freedman, ND Cross, AJ Sinha, R AF Guertin, Kristin A. Loftfield, Erikka Boca, Simina M. Sampson, Joshua N. Moore, Steven C. Xiao, Qian Huang, Wen-Yi Xiong, Xiaoqin Freedman, Neal D. Cross, Amanda J. Sinha, Rashmi TI Serum biomarkers of habitual coffee consumption may provide insight into the mechanism underlying the association between coffee consumption and colorectal cancer SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE coffee; colorectal cancer; dietary intake; metabolomics; metabolites ID BASAL-CELL CARCINOMA; SCREENING TRIAL; PROSPECTIVE COHORT; PHENOLIC-ACIDS; CARDIOVASCULAR-DISEASE; DITERPENES CAFESTOL; CHLOROGENIC ACIDS; CAFFEINE INTAKE; LIVER-CANCER; REDUCED RISK AB Background: Coffee intake may be inversely associated with colorectal cancer; however, previous studies have been inconsistent. Serum coffee metabolites are integrated exposure measures that may clarify associations with cancer and elucidate underlying mechanisms. Objectives: Our aims were 2-fold as follows: 1) to identify serum metabolites associated with coffee intake and 2) to examine these metabolites in relation to colorectal cancer. Design: In a nested case-control study of 251 colorectal cancer cases and 247 matched control subjects from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, we conducted untargeted metabolomics analyses of baseline serum by using ultrahigh-performance liquid-phase chromatography tandem mass spectrometry and gas chromatography mass spectrometry. Usual coffee intake was self-reported in a food-frequency questionnaire. We used partial Pearson correlations and linear regression to identify serum metabolites associated with coffee intake and conditional logistic regression to evaluate associations between coffee metabolites and colorectal cancer. Results: After Bonferroni correction for multiple comparisons (P = 0.05 divided by 657 metabolites), 29 serum metabolites were positively correlated with coffee intake (partial correlation coefficients: 0.18-0.61; P < 7.61 x 10(-5)); serum metabolites most highly correlated with coffee intake (partial correlation coefficients >0.40) included trigonelline (N'-methylnicotinate), quinate, and 7 unknown metabolites. Of 29 serum metabolites, 8 metabolites were directly related to caffeine metabolism, and 3 of these metabolites, theophylline (OR for 90th compared with 10th percentiles: 0.44; 95% CI: 0.25, 0.79; P-linear trend = 0.006), caffeine (OR for 90th compared with 10th percentiles: 0.56; 95% CI: 0.35, 0.89; P-linear trend = 0.015), and paraxanthine (OR for 90th compared with 10th percentiles: 0.58; 95% CI: 0.36, 0.94; P-linear trend = 0.027), were inversely associated with colorectal cancer. Conclusions: Serum metabolites can distinguish coffee drinkers from nondrinkers; some caffeine-related metabolites were inversely associated with colorectal cancer and should be studied further to clarify the role of coffee in the cause of colorectal cancer. C1 [Guertin, Kristin A.; Loftfield, Erikka; Moore, Steven C.; Xiao, Qian; Freedman, Neal D.; Sinha, Rashmi] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Sampson, Joshua N.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Huang, Wen-Yi] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Boca, Simina M.] Georgetown Univ, Med Ctr, Innovat Ctr Biomed Informat, Washington, DC 20007 USA. [Boca, Simina M.] Georgetown Univ, Med Ctr, Dept Oncol, Washington, DC 20007 USA. [Xiong, Xiaoqin] Informat Management Serv Inc, Silver Spring, MD USA. [Cross, Amanda J.] Univ London Imperial Coll Sci Technol & Med, Fac Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. RP Guertin, KA (reprint author), NCI, NIH, 9609 Med Ctr Dr,Room 6E326,Mail Stop Code 9760, Bethesda, MD 20892 USA. EM kristin.guertin@nih.gov; erikka.loftfield@nih.gov RI Sinha, Rashmi/G-7446-2015; Freedman, Neal/B-9741-2015; Moore, Steven/D-8760-2016 OI Sinha, Rashmi/0000-0002-2466-7462; Freedman, Neal/0000-0003-0074-1098; Moore, Steven/0000-0002-8169-1661 FU Intramural Research Program of the National Cancer Institute, NIH FX Supported by the Intramural Research Program of the National Cancer Institute, NIH. NR 67 TC 14 Z9 14 U1 2 U2 26 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD MAY PY 2015 VL 101 IS 5 BP 1000 EP 1011 DI 10.3945/ajcn.114.096099 PG 12 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CH5KS UT WOS:000354075100015 PM 25762808 ER PT J AU Arem, H Keadle, SK Matthews, CE AF Arem, Hannah Keadle, Sarah Kozey Matthews, Charles E. TI Invited Commentary: Meta-Physical Activity and the Search for the Truth SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material DE accelerometer; exercise; measurement; physical activity; self-report ID ACCELEROMETER OUTPUT; VALIDATION; ACTIGRAPH; VALIDITY AB Measurement error in self-reported data from questionnaires is a well-recognized challenge in studies of physical activity and health. In this issue of the Journal, Lim et al. (Am J Epidemiol. 2015; 181(9): 648-655) used data from accelerometers in a small measurement study to correct self-reported physical activity data from a larger study of adults from New York City and to develop an error correction model. They showed that correction of measurement error in self-reported physical activity levels strengthened the associations of physical activity with both obesity and diabetes by 30%-50% compared with using the self-reported questionnaire data alone. Thus, Lim et al. demonstrated a method to improve potentially biased estimates of the association between self-reported physical activity and disease. However, as this field develops, we feel it is important to call attention to a sometimes overlooked problem that occurs when comparing these instruments: Questionnaires and accelerometers are often calibrated (i.e., designed) to measure different types of physical activity, and accelerometers are still subject to measurement error. Thus, physical activity estimates corrected with an imperfect accelerometer measurement might over-or undercorrect the strength of the associations. We take this opportunity to further comment on physical activity measurement in epidemiologic studies and the implications for research. C1 [Arem, Hannah; Keadle, Sarah Kozey; Matthews, Charles E.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Arem, H (reprint author), NCI Shady Grove, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 6E314,MSC 9768, Bethesda, MD 20892 USA. EM Aremhe2@mail.nih.gov OI Keadle, Sarah/0000-0002-9569-9306 NR 17 TC 4 Z9 4 U1 0 U2 4 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 MAY 1 PY 2015 VL 181 IS 9 BP 656 EP 658 DI 10.1093/aje/kwu472 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CH1XR UT WOS:000353817100003 PM 25855648 ER PT J AU Albanese, E Davis, B Jonsson, PV Chang, M Aspelund, T Garcia, M Harris, T Gudnason, V Launer, LJ AF Albanese, Emiliano Davis, Benjamin Jonsson, Palmi V. Chang, Milan Aspelund, Thor Garcia, Melissa Harris, Tamara Gudnason, Vilmundur Launer, Lenore J. TI Overweight and Obesity in Midlife and Brain Structure and Dementia 26 Years Later SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE brain MRI; brain vascular lesions; cohort study; dementia; epidemiology; mortality; obesity ID BODY-MASS INDEX; ALZHEIMERS-DISEASE; AGES-REYKJAVIK; LATE-LIFE; COGNITIVE-DECLINE; RISK-FACTORS; POPULATION; ADIPOSITY; PREVALENCE; COHORT AB High adiposity in midlife might increase risk for late-life brain pathology, including dementia. Using data from the prospective Age, Gene/Environment Susceptibility-Reykjavik Study of men and women (born 1907-1935), we studied the associations of overweight and obesity at midlife (mean age, 50 (standard deviation, 4.7) years) with 1.5-T brain magnetic resonance imaging measures of infarct-like brain lesions, cerebral microbleeds, total brain volume, and white matter lesions volume, as well as dementia, in late life (mean age, 76 (standard deviation, 5.2) years). We used linear and Poisson models to estimate associations in 3,864 persons after adjustment for sociodemographic, health, and lifestyle characteristics. In midlife, the prevalence of overweight was 39% and that of obesity was 8%. After a mean follow-up of 26.2 (standard deviation, 4.9) years, midlife overweight and obesity were not associated with infarct-like brain lesions (relative risk (RR) = 0.82, 95% confidence interval (CI): 0.61, 1.10), cerebral microbleeds (RR = 0.69, 95% CI: 0.37, 1.32), total brain volume (beta = 0.05, 95% CI: -0.34, 0.45), white matter lesions volume (beta = -0.10, 95% CI: -0.20, 0.01), or dementia (RR = 0.91, 95% CI: 0.49, 1.72) compared with normal weight. These findings do not support the hypothesis that high body mass index in midlife modulates the risk for dementia. C1 [Albanese, Emiliano; Davis, Benjamin; Garcia, Melissa; Harris, Tamara; Launer, Lenore J.] NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA. [Albanese, Emiliano] Univ Hosp Geneva, Dept Mental Hlth & Psychiat, Geneva, Switzerland. [Albanese, Emiliano] Univ Geneva, Fac Med, Geneva, Switzerland. [Jonsson, Palmi V.] Landspitali Univ Hosp, Landspitali Natl Univ Hosp, Dept Geriatr, Reykjavik, Iceland. [Jonsson, Palmi V.; Aspelund, Thor; Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Chang, Milan] Landspitali Univ Hosp, Geriatr Res Ctr, Reykjavik, Iceland. [Aspelund, Thor; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. RP Launer, LJ (reprint author), NIA, Lab Epidemiol & Populat Sci, NIH, 7201 Wisconsin Ave,Suite 3C-309, Bethesda, MD 20892 USA. EM launerl@nia.nih.gov RI Gudnason, Vilmundur/K-6885-2015; Aspelund, Thor/C-5983-2008 OI Gudnason, Vilmundur/0000-0001-5696-0084; Aspelund, Thor/0000-0002-7998-5433 FU National Institutes of Health [N01-AG-12100]; National Institute on Aging Intramural Research Program; Icelandic Heart Association; Icelandic Parliament FX This study was funded by the National Institutes of Health (contract N01-AG-12100), the National Institute on Aging Intramural Research Program, the Icelandic Heart Association, and the Icelandic Parliament. NR 41 TC 3 Z9 3 U1 2 U2 11 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 MAY 1 PY 2015 VL 181 IS 9 BP 672 EP 679 DI 10.1093/aje/kwu331 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CH1XR UT WOS:000353817100006 PM 25810457 ER PT J AU Beydoun, MA Kuczmarski, MTF Beydoun, HA Rostant, OS Evans, MK Zonderman, AB AF Beydoun, May A. Kuczmarski, Marie T. Fanelli Beydoun, Hind A. Rostant, Ola S. Evans, Michele K. Zonderman, Alan B. TI Associations of the Ratios of n-3 to n-6 Dietary Fatty Acids With Longitudinal Changes in Depressive Symptoms Among US Women SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE adults; depressive symptoms; diet; longitudinal studies; n-3 fatty acids ID MULTIPLE-PASS METHOD; RANDOMIZED CONTROLLED-TRIAL; ADENYLATE-CYCLASE ACTIVITY; PLACEBO-CONTROLLED TRIAL; PROSPECTIVE FOLLOW-UP; MAJOR DEPRESSION; DOUBLE-BLIND; DOCOSAHEXAENOIC ACID; EICOSAPENTAENOIC ACID; DHA SUPPLEMENTATION AB In the present study, we examined longitudinal changes in self-reported depressive symptoms (and related domains) in relation to baseline intakes of n-3 fatty acids (absolute and relative to n-6 fatty acids). Sex-specific associations were evaluated in a prospective cohort of adults (n = 2,053) from Baltimore, Maryland, who were 30-64 years of age at baseline and were followed for a mean of 4.65 (standard deviation, 0.93) years (2004-2013). Using mean intakes of n-3 and n-6 fatty acids reported on two 24-hour dietary recalls, we estimated the ratios of n-3 to n-6 fatty acids for both highly unsaturated fatty acids (>= 20 carbon atoms) (HUFAs) and polyunsaturated fatty acids (>= 18 carbon atoms) (PUFAs). Outcomes included total and domain-specific scores on the 20-item Center for Epidemiologic Studies-Depression scale. Based on mixed-effects regression models, among women, both higher n-3 HUFA: n-6 PUFA and n-3 PUFA: n-6 PUFA ratios were associated with a slower rate of increase in total Center for Epidemiologic Studies-Depression scores over time. Higher n-3 HUFA: n-6 HUFA ratios were associated with slower increases in somatic complaints in men, whereas among women, higher n-3 HUFA: n-6 PUFA and n-3 PUFA: n-6 PUFA ratios were both linked to putative longitudinal improvement in positive affect over time. Among US adults, n-3: n-6 dietary fatty acid ratio was associated with longitudinal changes in depressive symptoms, with a higher ratio linked to a slower increase in depressive symptoms over time, particularly among women. C1 [Beydoun, May A.; Rostant, Ola S.; Evans, Michele K.; Zonderman, Alan B.] NIA, Lab Epidemiol & Populat Sci, NIH, Intramural Res Program, Baltimore, MD 21224 USA. [Kuczmarski, Marie T. Fanelli] Univ Delaware, Dept Behav Hlth & Nutr, Newark, DE USA. [Beydoun, Hind A.] Eastern Virginia Med Sch, Grad Program Publ Hlth, Norfolk, VA 23501 USA. RP Beydoun, MA (reprint author), NIA, NIH, Biomed Res Ctr, IRP, 251 Bayview Blvd,Suite 100,Room 04B118, Baltimore, MD 21224 USA. EM baydounm@mail.nih.gov OI Zonderman, Alan B/0000-0002-6523-4778 FU Intramural Research Program of the National Institute on Aging of the National Institutes of Health FX This research was supported entirely by the Intramural Research Program of the National Institute on Aging of the National Institutes of Health. NR 86 TC 8 Z9 8 U1 4 U2 13 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 MAY 1 PY 2015 VL 181 IS 9 BP 691 EP 705 DI 10.1093/aje/kwu334 PG 15 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CH1XR UT WOS:000353817100008 PM 25855645 ER PT J AU Gouvea, MIS Teixeira, MLB Joao, EC Souza, CV Quintana, MB Cruz, MLS Read, JS AF Gouvea, Maria Isabel S. Teixeira, Maria Lourdes B. Joao, Esau C. Souza, Claudia V. Quintana, Marcel B. Cruz, Maria Leticia S. Read, Jennifer S. TI Correlation between viral loads performed at 34-36 weeks and in the immediate postpartum period in HIV-infected pregnant women using HAART SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Editorial Material ID TRANSMISSION C1 [Gouvea, Maria Isabel S.; Teixeira, Maria Lourdes B.; Joao, Esau C.; Cruz, Maria Leticia S.] Hosp Fed Servidores Estado, Dept Infect Dis, Rio De Janeiro, Brazil. [Gouvea, Maria Isabel S.; Teixeira, Maria Lourdes B.; Souza, Claudia V.; Quintana, Marcel B.] Fundacao Oswaldo Cruz, Rio De Janeiro, Brazil. [Read, Jennifer S.] NIAID, NIH, Bethesda, MD 20892 USA. RP Gouvea, MIS (reprint author), Hosp Fed Servidores Estado, Dept Infect Dis, Rio De Janeiro, Brazil. NR 3 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD MAY PY 2015 VL 212 IS 5 BP 683 EP 684 DI 10.1016/j.ajog.2015.01.024 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CG8XH UT WOS:000353598500042 PM 25617733 ER PT J AU Downes, KL Hinkle, SN Sjaarda, LA Albert, PS Grantz, KL AF Downes, Katheryne L. Hinkle, Stefanie N. Sjaarda, Lindsey A. Albert, Paul S. Grantz, Katherine L. TI Previous prelabor or intrapartum cesarean delivery and risk of placenta previa SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 34th Annual Scientific Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine (SMFM) CY FEB 03-08, 2014 CL New Orleans, LA SP Soc Maternal Fetal Med DE cesarean delivery; intrapartum; placenta previa; prelabor ID LOWER UTERINE SEGMENT; CAUSAL-DIAGRAMS; VASA PREVIA; TERM; ACCRETA; SECTION; LABOR; PARTURITION; POPULATION; DIAGNOSIS AB OBJECTIVE: The purpose of this study was to examine the association between previous cesarean delivery and subsequent placenta previa while distinguishing cesarean delivery before the onset of labor from intrapartum cesarean delivery. STUDY DESIGN: We conducted a retrospective cohort study of electronic medical records from 20 Utah hospitals (2002-2010) with restriction to the first 2 singleton deliveries of nulliparous women at study entry (n = 26,987). First pregnancy delivery mode was classified as (1) vaginal (reference), (2) cesarean delivery before labor onset (prelabor), or (3) cesarean delivery after labor onset (intrapartum). Risk of second delivery previa was estimated by previous delivery mode with the use of logistic regression and was adjusted for maternal age, insurance, smoking, comorbidities, previous pregnancy loss, and history of previa. RESULTS: Most first deliveries were vaginal (82%; n = 22,142), followed by intrapartum cesarean delivery (14.6%; n = 3931), or prelabor cesarean delivery (3.4%; n = 914). Incidence of second delivery previa was 0.29% (n = 78) and differed by previous delivery mode: vaginal, 0.24%; prelabor cesarean delivery, 0.98%; intrapartum cesarean delivery, 0.38% (P < .001). Relative to vaginal delivery, previous prelabor cesarean delivery was associated with an increased risk of second delivery previa (adjusted odds ratio, 2.62; 95% confidence interval, 1.24-5.56). There was no significant association between previous intrapartum cesarean delivery and previa (adjusted odds ratio, 1.22; 95% confidence interval, 0.68-2.19). CONCLUSION: Previous prelabor cesarean delivery was associated with a >2-fold significantly increased risk of previa in the second delivery, although the approximately 20% increased risk of previa that was associated with previous intrapartum cesarean delivery was not significant. Although rare, the increased risk of placenta previa after previous prelabor cesarean delivery may be important when considering nonmedically indicated prelabor cesarean delivery. C1 [Downes, Katheryne L.; Hinkle, Stefanie N.; Sjaarda, Lindsey A.; Grantz, Katherine L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD 20892 USA. [Albert, Paul S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD USA. [Downes, Katheryne L.] Univ Maryland, Dept Family Sci, Sch Publ Hlth, College Pk, MD 20742 USA. RP Downes, KL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD 20892 USA. EM Katherine.grantz@nih.gov RI Hinkle, Stefanie/F-8253-2013; OI Hinkle, Stefanie/0000-0003-4312-708X; Sjaarda, Lindsey/0000-0003-0539-8110; Grantz, Katherine/0000-0003-0276-8534 FU Intramural NIH HHS [Z99 HD999999]; NICHD NIH HHS [HHSN275200800002I, HHSN275200800002C]; PHS HHS [HHSN27500004, HHSN275200800002I] NR 27 TC 7 Z9 7 U1 2 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD MAY PY 2015 VL 212 IS 5 AR 669.e1 DI 10.1016/j.ajog.2015.01.004 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CG8XH UT WOS:000353598500035 PM 25576818 ER PT J AU Faupel-Badger, JM McElrath, TF Lauria, M Houghton, LC Lim, KH Parry, S Cantonwine, D Lai, G Karumanchi, SA Hoover, RN Troisi, R AF Faupel-Badger, Jessica M. McElrath, Thomas F. Lauria, Michele Houghton, Lauren C. Lim, Kee-Hak Parry, Samuel Cantonwine, David Lai, Gabriel Karumanchi, S. Ananth Hoover, Robert N. Troisi, Rebecca TI Maternal circulating angiogenic factors in twin and singleton pregnancies SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE angiogenic balance; endoglin; pregnancy; singletons; soluble fms-like tyrosine kinase-1; twins ID PLACENTAL GROWTH-FACTOR; ANTIANGIOGENIC FACTORS; TYROSINE KINASE-1; SOLUBLE ENDOGLIN; CARDIOVASCULAR-DISEASE; BREAST-CANCER; PREECLAMPSIA; RISK; SERUM; METAANALYSIS AB OBJECTIVE: The purpose of this study was to compare longitudinally sampled maternal angiogenic proteins between singleton and twin pregnancies. STUDY DESIGN: Placental growth factor (PlGF), soluble feline McDonough sarcoma (fms)-like tyrosine kinase (sFlt)-1, and soluble endoglin from healthy pregnant women were quantified at 10, 18, 26, and 35 weeks' gestation (n = 91), and during the third trimester (31-39 weeks) and at delivery (33-41 weeks; n = 41). Geometric means and 95% confidence intervals were calculated for gestational age-adjusted angiogenic protein concentrations and compared between matched twin and singleton pregnancies. RESULTS: Maternal sFlt-1 concentrations and the sFlt-1/PlGF ratio were higher in twins than singletons across pregnancy and at delivery, with the greatest differences at week 35 (sFlt-1: 36,916 vs 10,151 pg/mL; P < .0001; sFlt-1/PlGF: 168.4 vs 29.0; P < .0001). Maternal concentrations of soluble endoglin also were higher in the third trimester and delivery. Maternal PlGF concentrations were lower in twin than singleton pregnancies at week 35 only (219.2 vs 350.2 pg/mL; P < .0001). Placental weight appeared to be inversely correlated with maternal sFlt-1/PlGF ratio at the end of pregnancy in both twins and singletons. CONCLUSION: Higher maternal antiangiogenic proteins in twin than singleton pregnancies does not appear to be due to greater placental mass in the former, and may be one explanation for the increased risk of preeclampsia in women carrying multiple gestations. Determining whether women with a history of multiple gestations have an altered cardiovascular disease and breast cancer risk, like those with a history of preeclampsia, is warranted. C1 [Faupel-Badger, Jessica M.] NCI, Canc Prevent Div, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Faupel-Badger, Jessica M.; Houghton, Lauren C.; Lai, Gabriel; Hoover, Robert N.; Troisi, Rebecca] NCI, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [McElrath, Thomas F.; Cantonwine, David] Brigham & Womens Hosp, Div Maternal Fetal Med, Boston, MA 02115 USA. [Karumanchi, S. Ananth] Beth Israel Deaconess Med Ctr, Dept Obstet & Gynecol, Div Maternal Fetal Med, Boston, MA 02215 USA. [Lim, Kee-Hak] Harvard Univ, Sch Med, Obstet Gynecol & Reprod Biol, Boston, MA USA. [Lauria, Michele] Dartmouth Hitchcock Med Ctr, Geisel Sch Med, Lebanon, NH 03766 USA. [Parry, Samuel] Univ Penn, Med Ctr, Dept Obstet & Gynecol, Div Maternal Fetal Med, Philadelphia, PA 19104 USA. RP Troisi, R (reprint author), NCI, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM troisir@mail.nih.gov OI Houghton, Lauren/0000-0002-1432-1580 FU Division of Cancer Epidemiology and Genetics; Center for Cancer Training, Cancer Prevention Fellowship Program, National Cancer Institute; Abbott Laboratories [9MZ-04-06N03]; Abbott Diagnostics [9MZ-04-06N03]; Thermofisher FX This research was supported by federal funds from the Division of Cancer Epidemiology and Genetics and Center for Cancer Training, Cancer Prevention Fellowship Program, National Cancer Institute. The data from the BIRTH cohort were funded by a research grant (9MZ-04-06N03) from Abbott Laboratories.; T.F.M. received a research grant (9MZ-04-06N03) from Abbott Diagnostics to measure the angiogenic factors in the BIRTH cohort. A.K. is an investigator of the Howard Hughes Medical Institute, a coinventor on multiple patents for preeclampsia markers, and a consultant to Siemens Diagnostics, and has grant funding from Thermofisher and a financial interest in Aggamin LLC. The remaining authors report no conflict of interest. NR 33 TC 3 Z9 3 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD MAY PY 2015 VL 212 IS 5 AR 636.e1 DI 10.1016/j.ajog.2014.11.035 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CG8XH UT WOS:000353598500023 PM 25434840 ER PT J AU Brisson, BK Mauldin, EA Lei, WW Vogel, LK Power, AM Lo, A Dopkin, D Khanna, C Wells, RG Pure, E Volk, SW AF Brisson, Becky K. Mauldin, Elizabeth A. Lei, Weiwei Vogel, Laurie K. Power, Ashley M. Lo, Albert Dopkin, Derek Khanna, Chand Wells, Rebecca G. Pure, Ellen Volk, Susan W. TI Type III Collagen Directs Stromal Organization and Limits Metastasis in a Murine Model of Breast Cancer SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID EHLERS-DANLOS-SYNDROME; MOUSE MAMMARY-TUMOR; CARCINOMA IN-SITU; EXTRACELLULAR-MATRIX; V COLLAGEN; HUMAN SKIN; PROGRESSION; CELLS; EXPRESSION; LUNG AB Breast cancer metastasis is the leading cause of cancer-related deaths in women worldwide. Collagen in the tumor microenvironment plays a crucial role in regulating tumor progression. We have shown that type III collagen (Col3), a component of tumor stroma, regulates myofibroblast differentiation and scar formation after cutaneous injury. During the course of these wound-healing studies, we noted that tumors developed at a higher frequency in Col3(+/-) mice compared to wild-type littermate controls. We, therefore, examined the effect of Col3 deficiency on tumor behavior, using the murine mammary carcinoma cell Line 4T1. Notably, tumor volume and pulmonary metastatic burden after orthotopic injection of 4T1 cells were increased in Col3(+/-) mice compared to Col3(+/+) Littermates. By using murine (411) and human (MDA-MB-231) breast cancer cells grown in Col3-poor and Col3-enriched microenvironments in vitro, we found that several major events of the metastatic process were suppressed by Col3, including adhesion, invasion, and migration. In addition, Col3 deficiency increased proliferation and decreased apoptosis of 4T1 cells both in vitro and in primary tumors in vivo. Mechanistically, Col3 suppresses the procarcinogenic microenvironment by regulating stromaL organization, including density and alignment of fibrillar collagen and myofibroblasts. We propose that Col3 plays an important role in the tumor microenvironment by suppressing metastasis-promoting characteristics of the tumor-associated stroma. C1 [Brisson, Becky K.; Lei, Weiwei; Vogel, Laurie K.; Power, Ashley M.; Dopkin, Derek; Volk, Susan W.] Univ Penn, Sch Vet Med, Dept Clin Studies Philadelphia, Philadelphia, PA 19104 USA. [Mauldin, Elizabeth A.] Univ Penn, Sch Vet Med, Dept Pathobiol, Philadelphia, PA 19104 USA. [Lo, Albert; Pure, Ellen] Univ Penn, Sch Vet Med, Dept Anim Biol, Philadelphia, PA 19104 USA. [Wells, Rebecca G.] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Khanna, Chand] NCI, Tumor & Metastasis Biol Sect, Pediat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Volk, SW (reprint author), Univ Penn, Sch Vet Med, 312 Hill Pavil,380 S Univ Ave, Philadelphia, PA 19104 USA. EM swvolk@vet.upenn.edu FU National Institute of Arthritis and Musculoskeletal and Skin Diseases [K08AR053945]; Mari Lowe Center for Comparative Oncology at the University of Pennsylvania School of Veterinary Medicine; Jack Miller-Ebrahimi Foundation; NIH [DK058123, R01CA180070, RO1CA141144, S10RR027128] FX Supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases grant K08AR053945, the Mari Lowe Center for Comparative Oncology at the University of Pennsylvania School of Veterinary Medicine, a Jack Miller-Ebrahimi Foundation gift (S.W.V.), and NIH grants DK058123 (R.G.W.), R01CA180070, and RO1CA141144 (E.P.), and S10RR027128 (which funded Bruce D. Freedman for instrumentation in the Penn Vet Imaging Core facility). NR 71 TC 7 Z9 7 U1 3 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 EI 1525-2191 J9 AM J PATHOL JI Am. J. Pathol. PD MAY PY 2015 VL 185 IS 5 BP 1471 EP 1486 DI 10.1016/j.ajpath.2015.01.029 PG 16 WC Pathology SC Pathology GA CH4OL UT WOS:000354012700026 PM 25795282 ER PT J AU Olson, G Weiner, SJ Rouse, D Reddy, UM Mercer, BM Varner, MW Leveno, KJ Iams, JD Wapner, RJ Ramin, SM Malone, FD Carpenter, MW O'Sullivan, MJ Dinsmoor, MJ Hankins, GDV Caritis, SN AF Olson, Gayle Weiner, Steven J. Rouse, Dwight. Reddy, Uma M. Mercer, Brian M. Varner, Michael W. Leveno, Kenneth J. Iams, Jay D. Wapner, Ronald J. Ramin, Susan M. Malone, Fergal D. Carpenter, Marshall W. O'Sullivan, Mary J. Dinsmoor, Mara J. Hankins, Gary D. V. Caritis, Steve N. CA Eunice Kennedy Shriver Natl Inst TI Relation between Birth Weight and Weight and Height at the Age of 2 in Children Born Preterm SO AMERICAN JOURNAL OF PERINATOLOGY LA English DT Article DE preterm; fetal growth potential; customized birth weight ID FETAL-GROWTH; UNITED-STATES; GESTATIONAL-AGE; STANDARD; MORTALITY; INFANTS; CHARTS AB Objective The aim of the study was to evaluate associations between fetal growth and weight at 2 years in infants born preterm using a customized approach for birth weight. Study Design This is a secondary analysis of a multicenter trial that included a 2-year follow-up of children born prematurely. Customized birth weight percentiles were calculated using the Gardosi model for a U.S. population, and the relation between customized percentile and weight and height at 2 years (adjusted for gender using z-score) was determined using regression analysis and by comparing z-scores for children with birth weight <10th versus >= 10th percentile. Results Weight z-score at 2 years was significantly lower in the <10th than in the >= 10th percentile group (median [interquartile range, IQR]: -0.66 [-1.58, -0.01] vs. -0.23 [-1.05, 0.55]; p < 0.001), and remained after adjusting for maternal education (p < 0.001). A similar relationship was noted for height z-score between groups (median [IQR]: -0.56 [-1.29, 0.19] vs. -0.24 [-0.99, 0.37]; p < 0.001). Positive relationships between customized birth weight percentile and weight and height at 2 years were noted (p < 0.001 for both), but were not strong (R-2 = 0.04 and 0.02, respectively). Conclusion Customized birth weight percentile is a minor determinant of weight at 2 years among children born preterrn. C1 [Olson, Gayle; Hankins, Gary D. V.] Univ Texas Med Branch, Dept Obstet & Gynecol, Galveston, TX 77555 USA. [Weiner, Steven J.] George Washington Univ, Dept Obstet & Gynecol, Ctr Biostat, Washington, DC USA. [Rouse, Dwight.] Univ Alabama Birmingham, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. [Reddy, Uma M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Mercer, Brian M.] Case Western Reserve Univ, Metrohlth Med Ctr, Dept Obstet & Gynecol, Cleveland, OH USA. [Mercer, Brian M.] Univ Tennessee, Dept Obstet & Gynecol, Memphis, TN 38103 USA. [Varner, Michael W.] Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT USA. [Leveno, Kenneth J.] Univ Texas SW Med Ctr Dallas, Dept Obstet & Gynecol, Dallas, TX 75390 USA. [Iams, Jay D.] Ohio State Univ, Dept Obstet & Gynecol, Columbus, OH 43210 USA. [Wapner, Ronald J.] Thomas Jefferson Univ, Dept Obstet & Gynecol, Philadelphia, PA 19107 USA. [Wapner, Ronald J.] Drexel Univ, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. [Ramin, Susan M.] Univ Texas Hlth Sci Ctr Houston, Dept Obstet & Gynecol, Houston, TX 77030 USA. [Malone, Fergal D.] Columbia Univ, Dept Obstet & Gynecol, New York, NY USA. [Carpenter, Marshall W.] Brown Univ, Dept Obstet & Gynecol, Providence, RI 02912 USA. [O'Sullivan, Mary J.] Univ Miami, Dept Obstet & Gynecol, Miami, FL USA. [Dinsmoor, Mara J.] NorthShore Univ HealthSyst, Dept Obstet & Gynecol, Evanston, IL USA. [Caritis, Steve N.] Univ Pittsburgh, Dept Obstet & Gynecol, Pittsburgh, PA USA. RP Olson, G (reprint author), Univ Texas Med Branch, Dept Obstet & Gynecol, 301 Univ Blvd, Galveston, TX 77555 USA. EM golson@utmb.edu RI Varner, Michael/K-9890-2013 OI Varner, Michael/0000-0001-9455-3973 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HD27869, HD34208, HD34116, HD40544, HD27915, HD34136, HD21414, HD27917, HD27860, HD40560, HD40545, HD40485, HD40500, HD27905, HD27861, HD34122, HD40512, HD53907, HD34210, HD21410, HD36801, HD19897]; National Institute of Neurological Disorders and Stroke (NINDS); [M01-RR-000080] FX The project described was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (HD27869, HD34208, HD34116, HD40544, HD27915, HD34136, HD21414, HD27917, HD27860, HD40560, HD40545, HD40485, HD40500, HD27905, HD27861, HD34122, HD40512, HD53907, HD34210, HD21410, HD36801, HD19897); M01-RR-000080; and by the National Institute of Neurological Disorders and Stroke (NINDS). Comments and views of the authors do not necessarily represent views of the NICHD. NR 24 TC 0 Z9 0 U1 0 U2 1 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0735-1631 EI 1098-8785 J9 AM J PERINAT JI Am. J. Perinatol. PD MAY PY 2015 VL 32 IS 6 BP 591 EP 597 DI 10.1055/s-0035-1544947 PG 7 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA CH9FW UT WOS:000354342400012 PM 25730133 ER PT J AU Coddou, C Yan, ZH Stojilkovic, SS AF Coddou, Claudio Yan, Zonghe Stojilkovic, Stanko S. TI Role of domain calcium in purinergic P2X2 receptor channel desensitization SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE ATP; calcium; desensitization; pore dilation; purinergic receptors ID P2X(2) RECEPTOR; DIVALENT-CATIONS; PROTEIN-KINASE; ION CHANNELS; IDENTIFICATION; ECTODOMAIN; MODULATION; ACTIVATION; RESIDUES; PURINOCEPTORS AB Activation of P2X2 receptor channels (P2X2Rs) is characterized by a rapid current growth accompanied by a decay of current during sustained ATP application, a phenomenon known as receptor desensitization. Using rat, mouse, and human receptors, we show here that two processes contribute to receptor desensitization: bath calcium-independent desensitization and calcium-dependent desensitization. Calcium-independent desensitization is minor and comparable during repetitive agonist application in cells expressing the full size of the receptor but is pronounced in cells expressing shorter versions of receptors, indicating a role of the COOH terminus in control of receptor desensitization. Calcium-dependent desensitization is substantial during initial agonist application and progressively increases during repetitive agonist application in bath ATP and calcium concentration-dependent manners. Experiments with substitution of bath Na+ with N-methyl-D-glucamine (NMDG(+)), a large organic cation, indicate that receptor pore dilation is a calcium-independent process in contrast to receptor desensitization. A decrease in the driving force for calcium by changing the holding potential from -60 to +120 mV further indicates that calcium influx through the channel pores at least partially accounts for receptor desensitization. Experiments with various receptor chimeras also indicate that the transmembrane and/or intracellular domains of P2X2R are required for development of calcium-dependent desensitization and that a decrease in the amplitude of current slows receptor desensitization. Simultaneous calcium and current recording shows development of calcium-dependent desensitization without an increase in global intracellular calcium concentrations. Combined with experiments with clamping intrapipette concentrations of calcium at various levels, these experiments indicate that domain calcium is sufficient to establish calcium-dependent receptor desensitization in experiments with whole-cell recordings. C1 [Coddou, Claudio; Yan, Zonghe; Stojilkovic, Stanko S.] NICHHD, Sect Cellular Signaling, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. [Coddou, Claudio] Univ Catolica Norte, Fac Med, Dept Biomed Sci, Coquimbo, Chile. RP Coddou, C (reprint author), Univ Catolica Norte, Fac Med, Dept Biomed Sci, Larrondo 1281, Coquimbo, Chile. EM ccoddou@ucn.cl FU FONDECYT [11121302]; Eunice Kennedy Shiver National Institute of Child Health and Human Development, National Institutes of Health FX This work was funded by FONDECYT Initiation Grant no. 11121302 (C. Coddou) and Intramural Research Program of the Eunice Kennedy Shiver National Institute of Child Health and Human Development, National Institutes of Health (S. Stojilkovic, Z. Yan, and C. Coddou). NR 42 TC 3 Z9 3 U1 2 U2 3 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 MAY 1 PY 2015 VL 308 IS 9 BP C729 EP C736 DI 10.1152/ajpcell.00399.2014 PG 8 WC Cell Biology; Physiology SC Cell Biology; Physiology GA CH3WJ UT WOS:000353961200006 PM 25673774 ER PT J AU Lazrak, A Creighton, J Yu, ZH Komarova, S Doran, SF Aggarwal, S Emala, CW Stober, VP Trempus, CS Garantziotis, S Matalon, S AF Lazrak, Ahmed Creighton, Judy Yu, Zhihong Komarova, Svetlana Doran, Stephen F. Aggarwal, Saurabh Emala, Charles W., Sr. Stober, Vandy P. Trempus, Carol S. Garantziotis, Stavros Matalon, Sadis TI Hyaluronan mediates airway hyperresponsiveness in oxidative lung injury SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE calcium; chlorine; human airway smooth muscle; membrane potential; patch clamp ID ALPHA-TRYPSIN INHIBITOR; EPITHELIAL NA+ CHANNELS; SMOOTH-MUSCLE; CHLORINE GAS; EXTRACELLULAR-MATRIX; RESPIRATORY SYMPTOMS; SOUTH-CAROLINA; TRP CHANNELS; MICE; INFLAMMATION AB Chlorine (Cl-2) inhalation induces severe oxidative lung injury and airway hyperresponsiveness (AHR) that lead to asthmalike symptoms. When inhaled, Cl-2 reacts with epithelial lining fluid, forming by-products that damage hyaluronan, a constituent of the extracellular matrix, causing the release of low-molecular-weight fragments (L-HA, <300 kDa), which initiate a series of proinflammatory events. Cl-2 (400 ppm, 30 min) exposure to mice caused an increase of L-HA and its binding partner, inter-alpha-trypsin-inhibitor (I alpha I), in the bronchoalveolar lavage fluid. Airway resistance following methacholine challenge was increased 24 h post-Cl-2 exposure. Intratracheal administration of high-molecular-weight hyaluronan (H-HA) or an antibody against I alpha I post-Cl-2 exposure decreased AHR. Exposure of human airway smooth muscle (HASM) cells to Cl-2 (100 ppm, 10 min) or incubation with Cl-2-exposed H-HA (which fragments it to L-HA) increased membrane potential depolarization, intracellular Ca2+, and RhoA activation. Inhibition of RhoA, chelation of intracellular Ca2+, blockade of cation channels, as well as postexposure addition of H-HA, reversed membrane depolarization in HASM cells. We propose a paradigm in which oxidative lung injury generates reactive species and L-HA that activates RhoA and Ca2+ channels of airway smooth muscle cells, increasing their contractility and thus causing AHR. C1 [Lazrak, Ahmed; Creighton, Judy; Yu, Zhihong; Komarova, Svetlana; Doran, Stephen F.; Aggarwal, Saurabh; Matalon, Sadis] Univ Alabama Birmingham, Sch Med, Dept Anesthesiol, Birmingham, AL USA. [Emala, Charles W., Sr.] Columbia Univ, Dept Anesthesiol, New York, NY USA. [Stober, Vandy P.; Trempus, Carol S.; Garantziotis, Stavros] NIEHS, Lab Resp Biol, Res Triangle Pk, NC 27709 USA. RP Matalon, S (reprint author), BMR II 224,901 19th St S, Birmingham, AL 35205 USA. EM sadis@uab.edu RI Garantziotis, Stavros/A-6903-2009 OI Garantziotis, Stavros/0000-0003-4007-375X FU CounterACT Program, National Institutes of Health Office of the Director (NIH OD); National Institute of Neurological Disorders and Stroke (NINDS) [5U01ES015676-05, 5R21 ES024027 02, 1R21ES025423 01]; Division of Intramural Research, National Institute of Environmental Health Sciences, NIH FX This study was supported by the CounterACT Program, National Institutes of Health Office of the Director (NIH OD), and the National Institute of Neurological Disorders and Stroke (NINDS), Grants 5U01ES015676-05, 5R21 ES024027 02, and 1R21ES025423 01. This work was also supported in part by funding from the Division of Intramural Research, National Institute of Environmental Health Sciences, NIH. NR 81 TC 9 Z9 9 U1 1 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 EI 1522-1504 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD MAY 1 PY 2015 VL 308 IS 9 BP L891 EP L903 DI 10.1152/ajplung.00377.2014 PG 13 WC Physiology; Respiratory System SC Physiology; Respiratory System GA CH3JX UT WOS:000353928100004 PM 25747964 ER PT J AU Fessler, MB AF Fessler, Michael B. TI Revisiting "Good" and "Bad" Cholesterol The Battle over Flow through Arteries Now Shifts to Flow through Airways SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Editorial Material ID HIGH-DENSITY-LIPOPROTEINS; CARDIOVASCULAR-DISEASE; HDL; INFLAMMATION; LUNG; FUTURE; PLASMA C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Fessler, MB (reprint author), NIEHS, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. FU NIEHS NIH HHS [Z01 ES102005] NR 21 TC 1 Z9 1 U1 0 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD MAY 1 PY 2015 VL 191 IS 9 BP 969 EP 970 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA CH2FJ UT WOS:000353840800001 PM 25932757 ER PT J AU Barochia, AV Kaler, M Cuento, RA Gordon, EM Weir, NA Sampson, M Fontana, JR MacDonald, S Moss, J Manganiello, V Remaley, AT Levine, SJ AF Barochia, Amisha V. Kaler, Maryann Cuento, Rosemarie A. Gordon, Elizabeth M. Weir, Nargues A. Sampson, Maureen Fontana, Joseph R. MacDonald, Sandra Moss, Joel Manganiello, Vincent Remaley, Alan T. Levine, Stewart J. TI Serum Apolipoprotein A-I and Large High-Density Lipoprotein Particles Are Positively Correlated with FEV1 in Atopic Asthma SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE asthma; airflow obstruction; lipids; lipoprotein particles; apolipoproteins ID NEUTROPHILIC AIRWAY INFLAMMATION; APOE-DEFICIENT MICE; CARDIOVASCULAR-DISEASE; NONFASTING TRIGLYCERIDES; CHOLESTEROL EFFLUX; ALLERGIC RHINITIS; LDL CHOLESTEROL; HEART-DISEASE; HDL; RISK AB Rationale: Although lipids, apolipoproteins, and lipoprotein particles are important modulators of inflammation, varying relationships exist between these parameters and asthma. Objectives: To determine whether serum lipids and apolipoproteins correlate with the severity of airflow obstruction in subjects With atopy and asthma. Methods: Serum samples were obtained from 154 atopic and nonatopic subjects without asthma, and 159 subjects with atopy and asthma; Serum lipid and lipoprotein levels were quantified Using standard diagnostic assays and nuclear magnetic resonance (NMR) spectroscopy. Airflow obstruction was assessed by FEV1% predicted. Measurements and Main Results: Serum lipid levels correlated with FEV1 only in the subjects with atopy and asthma. Serum levels of high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I (apoA-I) were positively correlated with FEV1 in subjects with atopy and asthma, whereas a negative correlation existed between FEV1 and serum levels of triglycerides, low-density lipoprotein (LDL) cholesterol, apolipoprotein B (apoB), and the apoB/apoA-I ratio. NMR spectroscopy identified a positive correlation between FEV1 and HDLNMR particle size, as well as the concentrations of large HDLNMR particles and total IDLNMR (intermediate-density lipoprotein) particles in, subjects with atopy and asthma. In contrast, LDLNMR particle size and concentrations of LDLNMR and VLDLNMR (very-low-density lipoprotein) particles were negatively correlated with FEV1 in subjects with atopy and asthma. Conclusions: In subjects with atopy and asthma, serum levels of apoA-I and large HDLNMR particles are positively correlated with FEV1, whereas serum triglycerides, LDL cholesterol, and apoB are associated with more severe airflow obstruction. These results may facilitate future studies to assess whether apoA-I and large HDLNMR particles can reduce airflow obstruction and disease severity in asthma. C1 [Barochia, Amisha V.; Kaler, Maryann; Cuento, Rosemarie A.; Gordon, Elizabeth M.; Weir, Nargues A.; Levine, Stewart J.] NHLBI, Lab Asthma & Lung Inflammat, NIH, Bethesda, MD 20892 USA. [Barochia, Amisha V.; Kaler, Maryann; Cuento, Rosemarie A.; Gordon, Elizabeth M.; Weir, Nargues A.; Fontana, Joseph R.; MacDonald, Sandra; Moss, Joel; Manganiello, Vincent; Remaley, Alan T.; Levine, Stewart J.] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Sampson, Maureen] NIH, Natl Inst Hlth Clin Ctr, Bethesda, MD 20892 USA. RP Barochia, AV (reprint author), NHLBI, Lab Asthma & Lung Inflammat, Cardiovasc & Pulm Branch, NIH, 10 Ctr Dr,CRC Room 6-3152, Bethesda, MD 20892 USA. EM barochiaav@nhlbi.nih.gov FU Division of Intramural Research, NHLBI, National Institutes of Health FX Supported by the Division of Intramural Research, NHLBI, National Institutes of Health. NR 50 TC 11 Z9 11 U1 1 U2 3 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD MAY 1 PY 2015 VL 191 IS 9 BP 990 EP 1000 DI 10.1164/rccm.201411-1990OC PG 11 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA CH2FJ UT WOS:000353840800008 PM 25692941 ER PT J AU Barta, SK Samuel, MS Xue, X Wang, D Lee, JY Mounier, N Ribera, JM Spina, M Tirelli, U Weiss, R Galicier, L Boue, F Little, RF Dunleavy, K Wilson, WH Wyen, C Remick, SC Kaplan, LD Ratner, L Noy, A Sparano, JA AF Barta, S. K. Samuel, M. S. Xue, X. Wang, D. Lee, J. Y. Mounier, N. Ribera, J. -M. Spina, M. Tirelli, U. Weiss, R. Galicier, L. Boue, F. Little, R. F. Dunleavy, K. Wilson, W. H. Wyen, C. Remick, S. C. Kaplan, L. D. Ratner, L. Noy, A. Sparano, J. A. TI Changes in the influence of lymphoma- and HIV-specific factors on outcomes in AIDS-related non-Hodgkin lymphoma SO ANNALS OF ONCOLOGY LA English DT Article DE lymphoma; AIDS; HIV; diffuse large B-cell lymphoma; Burkitt lymphoma; IPI ID ACTIVE ANTIRETROVIRAL THERAPY; LARGE-CELL LYMPHOMA; BURKITTS-LYMPHOMA; INTENSIVE CHEMOTHERAPY; PROGNOSTIC-FACTORS; SURVIVAL; INFECTION; ERA; INDEX; CHOP AB Background: We undertook the present analysis to examine the shifting influence of prognostic factors in HIV-positive patients diagnosed with aggressive non-Hodgkin lymphoma (NHL) over the last two decades. Patients and methods: We carried out a pooled analysis from an existing database of patients with AIDS-related lymphoma. Individual patient data had been obtained prior from prospective phase II or III clinical trials carried out between 1990 until 2010 in North America and Europe that studied chemo(immuno) therapy in HIV-positive patients diagnosed with AIDS-related lymphomas. Studies had been identified by a systematic review. We analyzed patient-level data for 1546 patients with AIDS-related lymphomas using logistic regression and Cox proportional hazard models to identify the association of patient-, lymphoma-, and HIV-specific variables with the outcomes complete response (CR), progression- free survival, and overall survival (OS) in different eras: pre-cART (1989-1995), early cART (1996-2000), recent cART (2001-2004), and contemporary cART era (2005-2010). Results: Outcomes for patients with AIDS-related diffuse large B-cell lymphoma and Burkitt lymphoma improved significantly over time, irrespective of baseline CD4 count or age-adjusted International Prognostic Index (IPI) risk category. Two-year OS was best in the contemporary era: 67% and 75% compared with 24% and 37% in the pre-cART era (P < 0.001). While the age-adjusted IPI was a significant predictor of outcome in all time periods, the influence of other factors waxed and waned. Individual HIV-related factors such as low CD4 counts (<50/mm(3)) and prior history of AIDS were no longer associated with poor outcomes in the contemporary era. Conclusions: Our results demonstrate a significant improvement of CR rate and survival for all patients with AIDS-related lymphomas. Effective HIV-directed therapies reduce the impact of HIV-related prognostic factors on outcomes and allow curative antilymphoma therapy for the majority of patients with aggressive NHL. C1 [Barta, S. K.] Fox Chase Canc Ctr, Dept Med Oncol, Philadelphia, PA 19111 USA. [Samuel, M. S.; Sparano, J. A.] Montefiore Med Ctr, Dept Med Oncol, Bronx, NY 10467 USA. [Xue, X.; Wang, D.] Albert Einstein Canc Ctr, Dept Epidemiol & Populat Hlth, Bronx, NY USA. [Lee, J. Y.] Univ Arkansas, Dept Biostat, Little Rock, AR 72204 USA. [Mounier, N.] GELASicily, Bayonne, France. [Ribera, J. -M.] ICO Hosp Germans Trias & Pujol, Jose Carreras Res Inst, Badalona, Spain. [Ribera, J. -M.] PETHEMA Grp, Badalona, Spain. [Spina, M.; Tirelli, U.] Natl Canc Inst, Dept Med Oncol, Aviano, Italy. [Galicier, L.] Hop St Louis, AP HP, Dept Immunol, Paris, France. [Boue, F.] Hop Antoine Beclere, Dept Internal Med & Immunol, Clamart, France. [Little, R. F.] NCI, Clin Invest Branch, Bethesda, MD 20892 USA. [Dunleavy, K.; Wilson, W. H.] NCI, Dept Med Oncol, Bethesda, MD 20892 USA. [Wyen, C.] Univ Hosp Cologne, Dept Internal Med, Cologne, Germany. [Remick, S. C.] W Virginia Univ, Mary Babb Randolph Canc Ctr, Morgantown, WV 26506 USA. [Kaplan, L. D.] Univ Calif San Francisco, Dept Hematol & Oncol, San Francisco, CA 94143 USA. [Ratner, L.] Washington Univ, Sch Med, Div Oncol, St Louis, MO USA. [Noy, A.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Noy, A.] Weill Cornell, Lymphoma Serv, New York, NY USA. RP Barta, SK (reprint author), Fox Chase Canc Ctr, Dept Med Oncol, 333 Cottman Ave, Philadelphia, PA 19111 USA. EM stefan.barta@fccc.edu OI Noy, Ariela/0000-0002-3001-4898 FU AIDS Malignancy Consortium (AMC) [UO1CA232947]; Paul Calabresi Career Development Award for Clinical Oncology [K12CA132783-03]; ASCO Cancer Foundation Young Investigator Award; RTICC, Instituto de Salud Carlos III, Spain [RD12/0036/0029]; CTSA [UL1 RR025750, KL2 RR025749]; National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) [TL1 RR025748]; NIH roadmap for Medical Research FX This work was supported in parts by the AIDS Malignancy Consortium (AMC; grant UO1CA232947), the Paul Calabresi Career Development Award for Clinical Oncology (K12CA132783-03 Grant), the ASCO Cancer Foundation 2010 Young Investigator Award, grant RD12/0036/0029 from RTICC, Instituto de Salud Carlos III, Spain, and by the CTSA Grants UL1 RR025750 and KL2 RR025749 and TL1 RR025748 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH roadmap for Medical Research. NR 29 TC 12 Z9 13 U1 0 U2 4 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 MAY PY 2015 VL 26 IS 5 BP 958 EP 966 DI 10.1093/annonc/mdv036 PG 10 WC Oncology SC Oncology GA CH2BS UT WOS:000353830000019 PM 25632071 ER PT J AU Veronesi, G Lazzeroni, M Szabo, E Brown, PH DeCensi, A Guerrieri-Gonzaga, A Bellomi, M Radice, D Grimaldi, MC Spaggiari, L Bonanni, B AF Veronesi, G. Lazzeroni, M. Szabo, E. Brown, P. H. DeCensi, 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 Article DE budesonide; lung cancer; chemoprevention; low-dose computed tomography; screening ID ATYPICAL ADENOMATOUS HYPERPLASIA; DOSE COMPUTED-TOMOGRAPHY; GROUND-GLASS OPACITY; CANCER; CT; GROWTH; TUMORS AB Background: A previously carried out randomized phase IIb, placebo-controlled trial of 1 year of inhaled budesonide, which was nested in a lung cancer screening study, showed that non-solid and partially solid lung nodules detected by low-dose computed tomography (LDCT), and not immediately suspicious for lung cancer, tended to regress. Because some of these nodules may be slow-growing adenocarcinoma precursors, we evaluated long-term outcomes (after stopping the 1-year intervention) by annual LDCT. Patients and methods: We analyzed the evolution of target and non-target trial nodules detected by LDCT in the budesonide and placebo arms up to 5 years after randomization. The numbers and characteristics of lung cancers diagnosed during follow-up were also analyzed. Results: The mean maximum diameter of non-solid nodules reduced significantly (from 5.03 mm at baseline to 2.61 mm after 5 years) in the budesonide arm; there was no significant size change in the placebo arm. The mean diameter of partially solid lesions also decreased significantly, but only by 0.69 mm. The size of solid nodules did not change. Neither the number of new lesions nor the number of lung cancers differed in the two arms. Conclusions: Inhaled budesonide given for 1 year significantly decreased the size of non-solid nodules detected by screening LDCT after 5 years. This is of potential importance since some of these nodules may progress slowly to adenocarcinoma. However, further studies are required to assess clinical implications. C1 [Veronesi, G.; Spaggiari, L.] European Inst Oncol, Div Thorac Surg, I-20141 Milan, Italy. [Lazzeroni, M.; DeCensi, A.; Guerrieri-Gonzaga, A.; Bonanni, B.] European Inst Oncol, Div Cancer Prevent & Genet, I-20141 Milan, Italy. [Szabo, E.] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Brown, P. H.] Univ Texas MD Anderson Canc Ctr, Dept Clin Canc Prevent, Houston, TX 77030 USA. [DeCensi, A.] Osped Galliera, Div Med Oncol, Genoa, Italy. [Bellomi, M.; Grimaldi, M. C.] European Inst Oncol, Div Radiol, I-20141 Milan, Italy. [Bellomi, M.; Spaggiari, L.] Univ Milan, Milan, Italy. [Radice, D.] European Inst Oncol, Div Epidemiol & Biostat, I-20141 Milan, Italy. RP Veronesi, G (reprint author), European Inst Oncol, Div Thorac Surg, Via Ripamonti 435, I-20141 Milan, Italy. EM giulia.veronesi@ieo.it OI Lazzeroni, Matteo/0000-0002-2162-4002 FU National Cancer Institute Division of Cancer Prevention [N01-CN-035159] FX This trial was supported by the National Cancer Institute Division of Cancer Prevention, contract N01-CN-035159 to the UT MD Anderson Early Phase Chemoprevention Consortium. NR 22 TC 4 Z9 4 U1 1 U2 5 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 MAY PY 2015 VL 26 IS 5 BP 1025 EP 1030 DI 10.1093/annonc/mdv064 PG 7 WC Oncology SC Oncology GA CH2BS UT WOS:000353830000029 PM 25672894 ER PT J AU Koizumi, A Maniscalco, B Lau, H AF Koizumi, Ai Maniscalco, Brian Lau, Hakwan TI Does perceptual confidence facilitate cognitive control? SO ATTENTION PERCEPTION & PSYCHOPHYSICS LA English DT Article DE Perceptual confidence; Visual perception; Confidence; Cognitive control; Signal detection theory ID PREFRONTAL CORTEX; UNCONSCIOUS ACTIVATION; CONSCIOUS PERCEPTION; FRONTAL-CORTEX; DISSOCIATION; BLINDSIGHT; AWARENESS AB Our visual perception is typically accompanied by a sense of subjective confidence. Since perceptual confidence is related to prefrontal activity, higher perceptual confidence may enhance cognitive control functions. To examine this interaction, we developed a novel method to selectively manipulate perceptual confidence while keeping stimulus discrimination accuracy constant. In a behavioral experiment, grating stimuli with different orientations were presented as go/no-go signals. Surprisingly, the results showed that confidence in visual discrimination of the signals on its own did not facilitate response inhibition, since when participants were presented with stimuli that yielded higher confidence, they were no better at performing a go/no-go task. These results were replicated with different (dot motion) stimuli, ruling out alternative explanations based on stimulus idiosyncrasy. In a different experiment, when the grating stimuli were presented as cues for task set preparation, we found that higher perceptual confidence also did not enhance task set preparation efficiency. This result was again replicated with dot motion stimuli. Since confidence may relate to perceptual awareness (Peirce & Jastrow, 1885), our findings may put current dominant theories in question, since these theories often suppose the critical involvement of consciousness in cognitive control. As a proof of concept, our method may also provide a new and powerful way to examine other functions of consciousness in future studies. C1 [Koizumi, Ai; Maniscalco, Brian; Lau, Hakwan] Columbia Univ, Dept Psychol, New York, NY 10027 USA. [Koizumi, Ai] Univ Tokyo, Dept Psychol, Tokyo, Japan. [Koizumi, Ai] US Japan Brain Res Cooperat Program, Okazaki, Aichi, Japan. [Maniscalco, Brian] NINDS, NIH, Bethesda, MD 20892 USA. [Lau, Hakwan] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90024 USA. RP Koizumi, A (reprint author), Columbia Univ, Dept Psychol, 406 Schermerhorn Hall,1190 Amsterdam Ave MC 5501, New York, NY 10027 USA. EM bellkoizumi@gmail.com FU Templeton Foundation [21569] FX This work was supported by a grant from the Templeton Foundation (No. 21569). We thank Aaron Apple, Xiaoyu Yan, and Guy Gerard Graney for helping with the data collection. We thank Ka Yuet Liu for advice on the data analysis. NR 36 TC 6 Z9 6 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1943-3921 EI 1943-393X J9 ATTEN PERCEPT PSYCHO JI Atten. Percept. Psychophys. PD MAY PY 2015 VL 77 IS 4 BP 1295 EP 1306 DI 10.3758/s13414-015-0843-3 PG 12 WC Psychology; Psychology, Experimental SC Psychology GA CH1YL UT WOS:000353819500022 PM 25737256 ER PT J AU Dibrova, DV Galperin, MY Koonin, EV Mulkidjanian, AY AF Dibrova, D. V. Galperin, M. Y. Koonin, E. V. Mulkidjanian, A. Y. TI Ancient systems of sodium/potassium homeostasis as predecessors of membrane bioenergetics SO BIOCHEMISTRY-MOSCOW LA English DT Article DE ATP synthase; sodium-motive force; proton-motive force; sodium symporter; membrane efflux pumps; abiogenesis; anoxic geothermal fields ID ANOXIC GEOTHERMAL FIELDS; LARGE RIBOSOMAL-SUBUNIT; PRIMARY SODIUM-PUMP; P-TYPE ATPASE; METAL-IONS; OXIDATIVE-PHOSPHORYLATION; LIPID BIOSYNTHESIS; MAXIMUM-LIKELIHOOD; ENTEROCOCCUS-HIRAE; RESPIRATORY-CHAIN AB Cell cytoplasm of archaea, bacteria, and eukaryotes contains substantially more potassium than sodium, and potassium cations are specifically required for many key cellular processes, including protein synthesis. This distinct ionic composition and requirements have been attributed to the emergence of the first cells in potassium-rich habitats. Different, albeit complementary, scenarios have been proposed for the primordial potassium-rich environments based on experimental data and theoretical considerations. Specifically, building on the observation that potassium prevails over sodium in the vapor of inland geothermal systems, we have argued that the first cells could emerge in the pools and puddles at the periphery of primordial anoxic geothermal fields, where the elementary composition of the condensed vapor would resemble the internal milieu of modern cells. Marine and freshwater environments generally contain more sodium than potassium. Therefore, to invade such environments, while maintaining excess of potassium over sodium in the cytoplasm, primordial cells needed means to extrude sodium ions. The foray into new, sodium-rich habitats was the likely driving force behind the evolution of diverse redox-, light-, chemically-, or osmotically-dependent sodium export pumps and the increase of membrane tightness. Here we present a scenario that details how the interplay between several, initially independent sodium pumps might have triggered the evolution of sodium-dependent membrane bioenergetics, followed by the separate emergence of the proton-dependent bioenergetics in archaea and bacteria. We also discuss the development of systems that utilize the sodium/potassium gradient across the cell membranes. C1 [Dibrova, D. V.; Mulkidjanian, A. Y.] Moscow MV Lomonosov State Univ, Belozersky Inst Physicochem Biol, Moscow 119992, Russia. [Galperin, M. Y.; Koonin, E. V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Mulkidjanian, A. Y.] Osnabrueck Univ, Sch Phys, D-49069 Osnabruck, Germany. [Mulkidjanian, A. Y.] Moscow MV Lomonosov State Univ, Sch Bioengn & Bioinformat, Moscow 119992, Russia. RP Mulkidjanian, AY (reprint author), Moscow MV Lomonosov State Univ, Belozersky Inst Physicochem Biol, Moscow 119992, Russia. EM amulkid@uos.de RI Mulkidjanian, Armen/J-8086-2013 OI Mulkidjanian, Armen/0000-0001-5844-3064 FU Russian Science Foundation [14-50-00029, 14-14-00592]; National Institutes of Health at the National Library of Medicine, USA FX This work was supported in part by Grants of the Russian Science Foundation (14-50-00029, DVD, phylogenomic analysis of K+-binding sites in nucleoside triphosphatases; and 14-14-00592, AYM, reconstruction of evolutionary events that could lead to the emergence of membrane bioenergetics) and by the Intramural Research Program of the National Institutes of Health at the National Library of Medicine, USA (MYG and EVK). NR 164 TC 4 Z9 6 U1 3 U2 27 PU MAIK NAUKA/INTERPERIODICA/SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013-1578 USA SN 0006-2979 EI 0320-9725 J9 BIOCHEMISTRY-MOSCOW+ JI Biochem.-Moscow PD MAY PY 2015 VL 80 IS 5 BP 495 EP 516 DI 10.1134/S0006297915050016 PG 22 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CH7BP UT WOS:000354190900001 PM 26071768 ER PT J AU Barr, TL VanGilder, R Rellick, S Brooks, SD Doll, DN Lucke-Wold, AN Chen, DQ Denvir, J Warach, S Singleton, A Matarin, M AF Barr, Taura L. VanGilder, Reyna Rellick, Stephanie Brooks, Steven D. Doll, Danielle N. Lucke-Wold, Ann Noelle Chen, Dongquan Denvir, James Warach, Steven Singleton, Andrew Matarin, Mar TI A Genomic Profile of the Immune Response to Stroke With Implications for Stroke Recovery SO BIOLOGICAL RESEARCH FOR NURSING LA English DT Article DE gene expression; ischemic stroke; recovery ID TOLL-LIKE RECEPTORS; ISCHEMIC-STROKE; GENE-EXPRESSION; CEREBRAL-ISCHEMIA; PERIPHERAL-BLOOD; ALZHEIMERS-DISEASE; NEURONAL DEATH; T-CELLS; INJURY; INFLAMMATION AB Objectives: The objectives of this study were to determine the change in gene expression between two time points following stroke and to identify biomarkers of stroke recovery through gene expression profiling and pathway analysis. Methods: Peripheral blood was collected from 34 ischemic stroke patients (confirmed by magnetic resonance imaging) 18 years of age, within 24 hr of symptom onset and 24-48 hr later, and from healthy controls. The Modified Rankin Scale (MRS) was used to determine 30-day recovery. Total RNA was extracted from whole blood in Paxgene RNA tubes, amplified, and hybridized to Illumina HumanRef-8v2 bead chips. Gene expression was compared in a univariate manner between stroke patients at both time points and good versus bad outcome using t-test in GeneSpring. Inflation of Type 1 error was corrected by false discovery rate (FDR), and Ingenuity Systems Pathway analysis (IPA) was performed. A secondary validation cohort was recruited from a local hospital. Results: Three genes were significantly downregulated over time (LY96, IL8, and SDPR; FDR corrected p < .05). This finding was confirmed in a validation cohort of stroke patients (n = 8). IPA revealed cytotoxic T-lymphocyte antigen 4 (CTLA4) signaling was the most significant pathway present in the peripheral whole blood of stroke patients 24-48 hr after onset. When controlling for age and National Institutes of Health Stroke Scale score, high baseline expression of TLR2 and TLR4 significantly predicted worse scores on the MRS. Conclusion: CTLA4 signaling is a novel pathway for the study of stroke-induced immune suppression. Markers of immune dysfunction early after stroke may prove useful for identifying patients with increased risk of poor recovery. C1 [Barr, Taura L.; VanGilder, Reyna] W Virginia Univ, Morgantown Dept, Sch Nursing, Morgantown, WV 26506 USA. [Barr, Taura L.; VanGilder, Reyna; Rellick, Stephanie] W Virginia Univ, Ctr Basic & Translat Stroke Res, Sch Med, Morgantown, WV 26506 USA. [Brooks, Steven D.; Doll, Danielle N.] W Virginia Univ, Ctr Neurosci, Sch Med, Morgantown, WV 26506 USA. [Lucke-Wold, Ann Noelle] W Virginia Univ, Sch Nursing, Morgantown, WV 26506 USA. [Chen, Dongquan] Univ Alabama Birmingham, Div Prevent Med, Birmingham, AL USA. [Denvir, James] Marshall Univ, Dept Biochem & Microbiol, Huntington, WV USA. [Warach, Steven] Seton Univ Texas, Clin Res Inst, Austin, TX USA. [Singleton, Andrew; Matarin, Mar] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Matarin, Mar] UCL, Dept Mol Neurosci, London, England. [Matarin, Mar] UCL, Dept Clin & Expt Epilepsy, London, England. RP Barr, TL (reprint author), W Virginia Univ, Morgantown Dept, Sch Nursing, Morgantown, WV 26506 USA. EM tlbarr@hsc.wvu.edu RI Singleton, Andrew/C-3010-2009; Matarin, Mar/F-1771-2016 OI Matarin, Mar/0000-0002-4717-5735 FU Division of Intramural Research of the NIH/NINDS/NIA, an Intramural Research Training Award via the Graduate Partnerships Program through the National Institute of Nursing Research [Z01 AG000957-05]; NINR [HHSN263201100872P]; WVU Foundation; WV-INBRE grant from the NIH National Center for Research Resources [P20 RR016477] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by the Division of Intramural Research of the NIH/NINDS/NIA (Z01 AG000957-05), an Intramural Research Training Award via the Graduate Partnerships Program through the National Institute of Nursing Research, an NINR Contract # HHSN263201100872P, WVU Foundation funding, and a WV-INBRE grant P20 RR016477 from the NIH National Center for Research Resources, which supports the Appalachian Cardiovascular Research Network (to T.L.B.). NR 36 TC 3 Z9 3 U1 0 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1099-8004 EI 1552-4175 J9 BIOL RES NURS JI Biol. Res. Nurs. PD MAY PY 2015 VL 17 IS 3 BP 248 EP 256 DI 10.1177/1099800414546492 PG 9 WC Nursing SC Nursing GA CH4HJ UT WOS:000353994300002 PM 25124890 ER PT J AU Goswami, M McGowan, KS Lu, K Jain, N Candia, J Hensel, NF Tang, J Calvo, KR Battiwalla, M Barrett, AJ Hourigan, CS AF Goswami, M. McGowan, K. S. Lu, K. Jain, N. Candia, J. Hensel, N. F. Tang, J. Calvo, K. R. Battiwalla, M. Barrett, A. J. Hourigan, C. S. TI A multigene array for measurable residual disease detection in AML patients undergoing SCT SO BONE MARROW TRANSPLANTATION LA English DT Article ID ACUTE MYELOID-LEUKEMIA; STEM-CELL TRANSPLANTATION; ACUTE MYELOGENOUS LEUKEMIA; TIME QUANTITATIVE PCR; TUMOR GENE WT1; FLOW-CYTOMETRY; RISK STRATIFICATION; COMPLETE REMISSION; INTERNATIONAL WORKSHOP; MULTICENTER TRIAL AB AML is a diagnosis encompassing a diverse group of myeloid malignancies. Heterogeneous genetic etiology, together with the potential for oligoclonality within the individual patient, have made the identification of a single high-sensitivity marker of disease burden challenging. We developed a multiple gene measurable residual disease (MG-MRD) RQ-PCR array for the high-sensitivity detection of AML, retrospectively tested on 74 patients who underwent allo-SCT at the NHLBI in the period 1994-2012. MG-MRD testing on peripheral blood samples prior to transplantation demonstrated excellent concordance with traditional BM-based evaluation and improved risk stratification for post-transplant relapse and OS outcomes. Pre-SCT assessment by MG-MRD predicted all clinical relapses occurring in the first 100 days after allo-SCT compared with 57% sensitivity using WT1 RQ-PCR alone. Nine patients who were negative for WT1 prior to transplantation were correctly reclassified into a high-risk MG-MRD-positive group, associated with 100% post-transplant mortality. This study provides proof of principle that a multiple gene approach may be superior to the use of WT1 expression alone for AML residual disease detection. C1 [Goswami, M.; McGowan, K. S.; Tang, J.; Hourigan, C. S.] NHLBI, Myeloid Malignancies Sect, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Lu, K.; Jain, N.; Hensel, N. F.; Battiwalla, M.; Barrett, A. J.] NHLBI, Stem Cell Allogen Transplantat Sect, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Candia, J.] Univ Maryland, Dept Phys, College Pk, MD 20742 USA. [Candia, J.] Univ Maryland, Sch Med, College Pk, MD 20742 USA. [Calvo, K. R.] NIH, Ctr Clin, Dept Lab Med, Bethesda, MD 20892 USA. RP Hourigan, CS (reprint author), NHLBI, Hematol Branch, Myeloid Malignancies Sect, Room 6C-103C,10 Ctr Dr, Bethesda, MD 20892 USA. EM hourigan@nih.gov RI Hourigan, Christopher/S-2476-2016 OI Hourigan, Christopher/0000-0002-6189-8067 FU National Heart, Lung, Blood Institute of the National Institutes of Health; NIH from the National Cancer Institute [T32CA154274] FX We thank Alan Hoofring and Ethan Tyler of the NIH Medical Arts Service for assistance. This work was supported by the Intramural Research Program of the National Heart, Lung, Blood Institute of the National Institutes of Health. JC was supported by NIH Award Number T32CA154274 from the National Cancer Institute. NR 61 TC 10 Z9 10 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 EI 1476-5365 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD MAY PY 2015 VL 50 IS 5 BP 642 EP 651 DI 10.1038/bmt.2014.326 PG 10 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA CH4ZI UT WOS:000354042900005 PM 25665046 ER PT J AU Slota, C Shi, A Chen, GB Bevans, M Weng, NP AF Slota, Christina Shi, Alvin Chen, Guobing Bevans, Margaret Weng, Nan-ping TI Norepinephrine preferentially modulates memory CD8 T cell function inducing inflammatory cytokine production and reducing proliferation in response to activation SO BRAIN BEHAVIOR AND IMMUNITY LA English DT Article DE Norepinephrine; CD8 T cells; Stress; Inflammation ID BETA-ADRENERGIC-RECEPTORS; CHRONIC STRESS; BETA-2-ADRENERGIC RECEPTOR; IMMUNE-SYSTEM; SYMPATHETIC-NERVE; INTERFERON-GAMMA; GENE-EXPRESSION; OLDER-ADULTS; IN-VIVO; LYMPHOCYTE AB Background: Norepinephrine (NE) is one of the primary catecholamines of the sympathetic nervous system released during a stress response and plays an important role in modulating immune function. NE binds to the adrenergic receptors on immune cells, including T cells, resulting in either suppressed or enhanced function depending on the type of cell, activation status of the cell, duration of NE exposure and concentration of NE. Here, we aim to analyze the effects of NE on the functionality of naive (Tn), central memory (Tcm) and effector memory (Tem) CD8 T cells. Methods: We isolated CD8 T cell subsets from healthy human adults and treated cells in vitro with NE (1 x 10(-6) M) for 16 h; we then stimulated NE treated and untreated CD8 T cell subsets with antibodies for CD3 and CD28 for 24 and 72 h. We assessed the level of beta-2 adrenergic receptor (ADRB2) expression in these cells as well as global gene expression changes in NE treated Tcm cells by microarray analysis. Altered expressed genes after NE treatment were identified and further confirmed by RT-qPCR, and by ELISA for protein changes. We further determined whether the observed NE effects on memory CD8 T cells are mediated by ADRB2 using specific adrenergic receptor agonist and antagonists. Finally, we examined the levels of mRNA and protein of the NE-induced genes in healthy adults with high serum levels of NE (>150 pg/mL) compared to low levels (<150 pg/mL). Results: We found that memory (Tcm and Tem) CD8 T cells expressed a significantly higher level of ADRB2 compared to naive cells. Consequently, memory CD8 T cells were significantly more sensitive than naive cells to NE induced changes in gene expressions in vitro. Global gene expression analysis revealed that NE induced an elevated expression of inflammatory cytokines and chemokines in resting and activated memory CD8 T cells in addition to a reduced expression of growth-related cytokines. The effects of NE on memory CD8 T cells were primarily mediated by ADRB2 as confirmed by the adrenergic receptor agonist and antagonist assays. Finally, individuals with high serum levels of NE had similar elevated gene expressions observed in vitro compared to the low NE group. Conclusions: Our results demonstrate that NE preferentially modulates the functions of memory CD8 T cells by inducing inflammatory cytokine production and reducing activation-induced memory CD8 T cell expansion. Published by Elsevier Inc. C1 [Slota, Christina] Univ Penn, Sch Nursing, Philadelphia, PA 19104 USA. [Slota, Christina; Shi, Alvin; Chen, Guobing; Weng, Nan-ping] NIA, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. [Bevans, Margaret] Natl Inst Hlth, Dept Nursing, Ctr Clin, Bethesda, MD USA. RP Weng, NP (reprint author), NIA, Lab Mol Biol & Immunol, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM wengn@mail.nih.gov RI Chen, Guobing/D-9572-2012; OI Chen, Guobing/0000-0002-2401-6168; Shi, Alvin/0000-0002-6625-6792 FU Intramural Program at the National Institute on Aging; Graduate Partnership Program; National Institute on Nursing Research, United States of America; National Institutes of Health Clinical Center FX The Intramural Program at the National Institute on Aging and National Institutes of Health Clinical Center, and the Graduate Partnership Program with the National Institute on Nursing Research, United States of America. NR 46 TC 14 Z9 14 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0889-1591 EI 1090-2139 J9 BRAIN BEHAV IMMUN JI Brain Behav. Immun. PD MAY PY 2015 VL 46 BP 168 EP 179 DI 10.1016/j.bbi.2015.01.015 PG 12 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA CH0ZO UT WOS:000353751100021 PM 25653192 ER PT J AU Demark-Wahnefried, W Rogers, LQ Alfano, CM Thomson, CA Courneya, KS Meyerhardt, JA Stout, NL Kvale, E Ganzer, H Ligibel, JA AF Demark-Wahnefried, Wendy Rogers, Laura Q. Alfano, Catherine M. Thomson, Cynthia A. Courneya, Kerry S. Meyerhardt, Jeffrey A. Stout, Nicole L. Kvale, Elizabeth Ganzer, Heidi Ligibel, Jennifer A. TI Practical clinical interventions for diet, physical activity, and weight control in cancer survivors SO CA-A CANCER JOURNAL FOR CLINICIANS LA English DT Review DE diet; physical activity; exercise; weight control; cancer survivors; neoplasms; exercise; oncology; primary care ID RANDOMIZED CONTROLLED-TRIAL; QUALITY-OF-LIFE; RESEARCH FUND/AMERICAN INSTITUTE; POSTMENOPAUSAL BREAST-CANCER; PATIENTS RECEIVING CHEMOTHERAPY; BODY-MASS INDEX; HOME-BASED DIET; PROSTATE-CANCER; EXERCISE INTERVENTION; BEHAVIOR-CHANGE AB The importance of expanding cancer treatment to include the promotion of overall long-term health is emphasized in the Institute of Medicine report on delivering quality oncology care. Weight management, physical activity, and a healthy diet are key components of tertiary prevention but may be areas in which the oncologist and/or the oncology care team may be less familiar. This article reviews current diet and physical activity guidelines, the evidence supporting those recommendations, and provides an overview of practical interventions that have resulted in favorable improvements in lifestyle behavior change in cancer survivors. It also describes current lifestyle practices among cancer survivors and the role of the oncologist in helping cancer patients and survivors embark upon changes in lifestyle behaviors, and it calls for the development of partnerships between oncology providers, primary care providers, and experts in nutrition, exercise science, and behavior change to help positively orient cancer patients toward longer and healthier lives. CA Cancer J Clin 2015;65: 167-189. (c) 2015 American Cancer Society. C1 [Demark-Wahnefried, Wendy; Rogers, Laura Q.] Univ Alabama Birmingham, Dept Nutr Sci, Nutr Sci, Birmingham, AL 35294 USA. [Alfano, Catherine M.] Natl Canc Inst, Behav Res Program, Bethesda, MD USA. [Thomson, Cynthia A.] Univ Arizona, Dept Hlth Promot Sci, Hlth Promot Sci, Tucson, AZ USA. [Courneya, Kerry S.] Univ Alberta, Fac Phys Educ & Recreat, Edmonton, AB, Canada. [Meyerhardt, Jeffrey A.; Ligibel, Jennifer A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Stout, Nicole L.] NIH, Dept Rehabil Med, Bethesda, MD 20892 USA. [Kvale, Elizabeth] Univ Alabama Birmingham, Dept Med, Med, Birmingham, AL 35294 USA. [Ganzer, Heidi] MN Oncol, St Paul, MN USA. RP Demark-Wahnefried, W (reprint author), Wallace Tumor Inst, 1824 Sixth Ave,Room 310-D, Birmingham, AL 35295 USA. EM demark@uab.edu FU American Cancer Society [121093-CCCDA-11-191-01-CCCDA]; [CRP-14-111-01-CPPB] FX Dr. Demark-Wahnefried was supported by grant CRP-14-111-01-CPPB, and Dr. Kvale was supported by grant 121093-CCCDA-11-191-01-CCCDA from the American Cancer Society. NR 178 TC 19 Z9 19 U1 8 U2 39 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-9235 EI 1542-4863 J9 CA-CANCER J CLIN JI CA-Cancer J. Clin. PD MAY-JUN PY 2015 VL 65 IS 3 BP 167 EP 189 DI 10.3322/caac.21265 PG 23 WC Oncology SC Oncology GA CH8GM UT WOS:000354274400003 PM 25683894 ER PT J AU Berger, AM Mitchell, SA Jacobsen, PB Pirl, WF AF Berger, Ann M. Mitchell, Sandra A. Jacobsen, Paul B. Pirl, William F. TI Screening, evaluation, and management of cancer-related fatigue: Ready for implementation to practice? SO CA-A CANCER JOURNAL FOR CLINICIANS LA English DT Review DE cancer-related fatigue; evidence-based interventions; multidisciplinary management; patient-reported outcomes; screening ID RANDOMIZED CONTROLLED-TRIAL; QUALITY-OF-LIFE; L-CARNITINE SUPPLEMENTATION; COGNITIVE-BEHAVIOR THERAPY; STAGE BREAST-CANCER; PATIENTS RECEIVING CHEMOTHERAPY; III CLINICAL-TRIAL; METASTATIC COLORECTAL-CANCER; PATIENT-REPORTED OUTCOMES; STEM-CELL TRANSPLANTATION AB Evidence regarding cancer-related fatigue (fatigue) has accumulated sufficiently such that recommendations for screening, evaluation, and/or management have been released recently by 4 leading cancer organizations. These evidence-based fatigue recommendations are available for clinicians, and some have patient versions; but barriers at the patient, clinician, and system levels hinder dissemination and implementation into practice. The underlying biologic mechanisms for this debilitating symptom have not been elucidated completely, hindering the development of mechanistically driven interventions. However, significant progress has been made toward methods for screening and comprehensively evaluating fatigue and other common symptoms using reliable and valid self-report measures. Limited data exist to support the use of any pharmacologic agent; however, several nonpharmacologic interventions have been shown to be effective in reducing fatigue in adults. Never before have evidence-based recommendations for fatigue management been disseminated by 4 premier cancer organizations (the National Comprehensive Cancer, the Oncology Nursing Society, the Canadian Partnership Against Cancer/Canadian Association of Psychosocial Oncology, and the American Society of Clinical Oncology). Clinicians may ask: Are we ready for implementation into practice? The reply: A variety of approaches to screening, evaluation, and management are ready for implementation. To reduce fatigue severity and distress and its impact on functioning, intensified collaborations and close partnerships between clinicians and researchers are needed, with an emphasis on system-wide efforts to disseminate and implement these evidence-based recommendations. CA Cancer J Clin 2015;65: 190-211. (c) 2015 American Cancer Society. C1 [Berger, Ann M.] Univ Nebraska Med Ctr, Coll Nursing, Fred & Pamela Buffett Canc Ctr, Omaha, NE 68198 USA. [Mitchell, Sandra A.] NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Jacobsen, Paul B.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Div Populat Sci, Tampa, FL 33612 USA. [Pirl, William F.] Massachusetts Gen Hosp, Ctr Canc, Ctr Psychiat Oncol & Behav Sci, Boston, MA 02114 USA. [Pirl, William F.] Harvard Univ, Sch Med, Boston, MA USA. RP Berger, AM (reprint author), Univ Nebraska Med Ctr, 985330 Nebraska Med Ctr, Omaha, NE 68198 USA. EM aberger@unmc.edu NR 315 TC 21 Z9 21 U1 7 U2 41 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-9235 EI 1542-4863 J9 CA-CANCER J CLIN JI CA-Cancer J. Clin. PD MAY-JUN PY 2015 VL 65 IS 3 BP 190 EP 211 DI 10.3322/caac.21268 PG 22 WC Oncology SC Oncology GA CH8GM UT WOS:000354274400004 PM 25760293 ER PT J AU Baum, RP Kulkarni, HR Muller, D Satz, S Danthi, N Kim, YS Brechbiel, MW AF Baum, Richard P. Kulkarni, Harshad R. Mueller, Dirk Satz, Stanley Danthi, Narasimhan Kim, Young-Seung Brechbiel, Martin W. TI First-In-Human Study Demonstrating Tumor-Angiogenesis by PET/CT Imaging with Ga-68-NODAGA-THERANOST, a High-Affinity Peptidomimetic for alpha(v)beta(3) Integrin Receptor Targeting SO CANCER BIOTHERAPY AND RADIOPHARMACEUTICALS LA English DT Article DE alpha(v)beta(3) receptor targeting; positron emission tomography; Ga-68-NODAGA-THERANOST (TM) ID RADIOLABELED RGD PEPTIDES; EXPRESSION; RADIOPHARMACEUTICALS; THERANOSTICS; THERAPY; TRACERS; AGENT; ACID; MICE AB Ga-68-NODAGA-THERANOST (TM) is an alpha(v)beta(3) integrin antagonist and the first radiolabeled peptidomimetic to reach clinical development for targeting integrin receptors. In this first-in-human study, the feasibility of integrin receptor peptidomimetic positron emission tomography/computed tomography (PET/CT) imaging was confirmed in patients with non-small-cell lung cancer and breast cancer. Methods: Patients underwent PET/CT imaging with Ga-68 NODAGA-THERANOST. PET images were analyzed qualitatively and quantitatively and compared to 2-deoxy-2-(F-18) fluoro-d-glucose (F-18-FDG) findings. Images were obtained 60 minutes postinjection of 300-500 MBq of Ga-68-NODAGA-THERANOST. Results: Ga-68-NODAGA-THERANOST revealed high tumor-to-background ratios (SUVmax=4.8) and uptake at neoangiogenesis sites. Reconstructed fused images distinguished cancers with high malignancy potential and enabled enhanced bone metastasis detection. F-18-FDG-positive lung and lymph node metastases did not show uptake, indicating the absence of neovascularization. Conclusions: Ga-68-NODAGA-THERANOST was found to be safe and effective, exhibiting in this study rapid blood clearance, stability, rapid renal excretion, favorable biodistribution and PK/PD, low irradiation burden (mu Sv/MBq/mu g), and convenient radiolabeling. This radioligand might enable theranostics, that is, a combination of diagnostics followed by the appropriate therapeutics, namely antiangiogenic therapy, image-guided presurgical assessment, treatment response evaluation, prediction of pathologic response, neoadjuvant-peptidomimetic-radiochemotherapy, and personalized medicine strategies. Further clinical trials evaluating Ga-68-NODAGA-THERANOST are warranted. C1 [Baum, Richard P.; Kulkarni, Harshad R.; Mueller, Dirk] ENETS Ctr Excellence, Zent Klin Bad Berka, THERANOSTICS Ctr Mol Radiotherapy & Mol Imaging, Bad Berka, Germany. [Satz, Stanley] Adv Imaging Projects LLC, Boca Raton, FL 33431 USA. [Danthi, Narasimhan] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Kim, Young-Seung; Brechbiel, Martin W.] NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Satz, S (reprint author), Adv Imaging Projects LLC, 3651 FAU Blvd, Boca Raton, FL 33431 USA. EM stanley.satz@gmail.com FU Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer Research and Advanced Imaging Projects, LLC FX The authors thank Rosanne Satz for her logistical efforts and editing. This research was supported, in part, by the Intramural Research Program of the NIH, the National Cancer Institute, and the Center for Cancer Research and Advanced Imaging Projects, LLC. NR 32 TC 5 Z9 5 U1 1 U2 17 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1084-9785 EI 1557-8852 J9 CANCER BIOTHER RADIO JI Cancer Biother. Radiopharm. PD MAY 1 PY 2015 VL 30 IS 4 BP 152 EP 159 DI 10.1089/cbr.2014.1747 PG 8 WC Oncology; Medicine, Research & Experimental; Pharmacology & Pharmacy; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Research & Experimental Medicine; Pharmacology & Pharmacy; Radiology, Nuclear Medicine & Medical Imaging GA CH4AJ UT WOS:000353972400002 PM 25945808 ER PT J AU Cole, DE Lester-McCully, CM Widemann, BC Warren, KE AF Cole, Diane E. Lester-McCully, Cynthia M. Widemann, Brigitte C. Warren, Katherine E. TI Plasma and cerebrospinal fluid pharmacokinetics of the Akt inhibitor, perifosine, in a non-human primate model SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Pharmacology; Non-human primate; Perifosine; Pharmacokinetics; Glioma ID BONE-MARROW-CELLS; RHESUS-MONKEY; HUMAN CANCER; PHASE-I; ACTIVATION; GLIOMAS; ALKYLPHOSPHOCHOLINE; MICRODIALYSIS; TEMOZOLOMIDE; EVEROLIMUS AB Central nervous system tumors are histologically and biologically heterogeneous. Standard treatment for malignant tumors includes surgery, radiation and chemotherapy, yet surgical resection is not always an option and chemotherapeutic agents have limited benefit. Recent investigations have focused on molecularly targeted therapies aimed at critical tumorigenic pathways. Several tumor types, including high-grade gliomas and pediatric pontine gliomas, exhibit Akt activation. Perifosine, an orally bioavailable, synthetic alkylphospholipid and potent Akt inhibitor, has demonstrated activity in some preclinical models, but absent activity in a genetically engineered mouse model of pontine glioma. We evaluated the plasma and cerebrospinal fluid pharmacokinetics of orally administered perifosine in a non-human primate model to evaluate CNS penetration. Perifosine was administered orally to three adult rhesus monkeys as a single dose of 7.0 mg/kg perifosine. Serial paired plasma and CSF samples were collected for up to 64 days. Perifosine was quantified with a validated HPLC/tandem mass spectrometry assay. Pharmacokinetic parameters were estimated using non-compartmental methods. CSF penetration was calculated from the areas under the concentration-time curves. Peak plasma concentrations (C (max)) ranged from 11.7-19.3 A mu M, and remained > 1 A mu M for > 28 days. Time to C (max) (T (max)) was 19 h. The median (range) AUC(Pl) was 3148 (2502-4705) A mu M/h, with a median (range) terminal half-life (t (1/2)) of 193 (170-221) h. Plasma clearance was 494 (329-637) mL/h/kg. Peak CSF concentrations were 4.1-10.1 nM (T (max) 64-235 h). CSF AUCs and t (1/2) were 6358 (2266-7568) nM/h and 277 (146-350) h, respectively. Perifosine concentrations in the CSF remained over nM for > 35 days. The mean CSF penetration was 0.16 %. CNS penetration of perifosine after systemic administration is poor. However, levels were measurable in both plasma and CSF for an extended time (> 2 months) after a single oral dose. C1 [Cole, Diane E.; Widemann, Brigitte C.] NCI, Pharmacol & Expt Therapeut, POB, NIH, Bethesda, MD 20892 USA. [Lester-McCully, Cynthia M.; Warren, Katherine E.] NCI, Pediat Neurooncol Sect, POB, NIH, Bethesda, MD 20892 USA. RP Warren, KE (reprint author), NCI, Pediat Neurooncol Sect, POB, NIH, 10 Ctr Dr,Bldg 10-Rm 1 W-5750, Bethesda, MD 20892 USA. EM warrenk@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This work was presented in part at the 2012 International Society of Pediatric Neuro-Oncology Meeting in Toronto. This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. The views herein do not necessarily represent the official views of the National Cancer Institute, the National Institutes of Health, the U.S. Department of Health and Human Services, or any other agency of the U.S. Government. NR 25 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 EI 1432-0843 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD MAY PY 2015 VL 75 IS 5 BP 923 EP 928 DI 10.1007/s00280-015-2711-1 PG 6 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA CH5DU UT WOS:000354055800006 PM 25740692 ER PT J AU Nudelman, Z Findler, M Barasch, D Nemirovski, A Pikovsky, A Kirmayer, D Basheer, M Gutkind, JS Friedman, M Czerninski, R AF Nudelman, Zakhar Findler, Mordechai Barasch, Dinorah Nemirovski, Alina Pikovsky, Anna Kirmayer, David Basheer, Maamoun Gutkind, J. Silvio Friedman, Michael Czerninski, Rakefet TI Levels of sirolimus in saliva and blood following oral topical sustained-release varnish delivery system application SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Sirolimus; Rapalogs; Local sustained-release application; Oral cancer; Safety; Mucositis ID SQUAMOUS-CELL CARCINOMA; NECK-CANCER; STREPTOCOCCUS-MUTANS; MTOR INHIBITION; HEAD; RAPAMYCIN AB Sirolimus (rapamycin) is a mammalian target of rapamycin pathway blocker. The efficacy of sirolimus is currently studied for its antiproliferative properties in various malignancies and particularly in squamous cell carcinoma and other oral disorders. Topical application at the oral cavity can augment sirolimus availability at the site of action by increasing sirolimus levels in saliva and hence efficacy, along with improved safety (low levels in the blood to avoid side effects) and compliance. Our purpose was to evaluate the release profile and safety of a topical sirolimus sustained-release varnish drug delivery system. Sirolimus sustained-release varnish drug delivery system containing a total of 0.5 mg of the drug was applied to nine healthy male volunteers. Saliva and blood levels were determined utilizing mass spectrometry and chemiluminescent microparticle immunoassay, respectively. The prolonged release profile and safety were evaluated for the oral topical delivery system. After the application of the drug delivery system, a sustained-release profile was observed in the oral cavity. We have measured moderate sirolimus levels for up to 12 h. The safety was confirmed, and systemic sirolimus blood levels were negligible. After an application of sirolimus sustained-release varnish drug delivery system, prolonged drug levels can be achieved in the saliva. The oral topical sirolimus concentrations were potentially therapeutic along with minimal systemic exposure. These results broaden the potential clinical use of sustained-release oral topical rapalogs. C1 [Nudelman, Zakhar; Kirmayer, David; Friedman, Michael] Hebrew Univ Jerusalem, Inst Drug Res, Sch Pharm, Dept Pharmaceut,Fac Med, IL-91120 Jerusalem, Israel. [Findler, Mordechai; Pikovsky, Anna; Czerninski, Rakefet] Hebrew Univ Jerusalem, Dept Oral Med, Hadassah Sch Dent Med, IL-91120 Jerusalem, Israel. [Barasch, Dinorah; Nemirovski, Alina] Hebrew Univ Jerusalem, Inst Drug Res, Sch Pharm, Fac Med, IL-91120 Jerusalem, Israel. [Basheer, Maamoun] Hadassah Med Ctr, Lab Div, IL-91120 Jerusalem, Israel. [Gutkind, J. Silvio] Natl Inst Craniofacial & Dent Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. RP Czerninski, R (reprint author), Hebrew Univ Jerusalem, Dept Oral Med, Hadassah Sch Dent Med, POB 12272, IL-91120 Jerusalem, Israel. EM rakefetc@hadassah.org.il FU Israel Cancer Research Fund FX This study was supported by a Project Grant from the Israel Cancer Research Fund. NR 28 TC 1 Z9 1 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 EI 1432-0843 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD MAY PY 2015 VL 75 IS 5 BP 969 EP 974 DI 10.1007/s00280-015-2721-z PG 6 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA CH5DU UT WOS:000354055800011 PM 25757961 ER PT J AU Muzzio, M Hu, SC Holleran, JL Parise, RA Eiseman, JL Yellow-Duke, AE Covey, JM Glaze, ER Engelke, K Egorin, MJ McCormick, DL Beumer, JH AF Muzzio, Miguel Hu, Shu-Chieh Holleran, Julianne L. Parise, Robert A. Eiseman, Julie L. Yellow-Duke, Archibong E. Covey, Joseph M. Glaze, Elizabeth R. Engelke, Kory Egorin, Merrill J. McCormick, David L. Beumer, Jan H. TI Plasma pharmacokinetics of the indenoisoquinoline topoisomerase I inhibitor, NSC 743400, in rats and dogs SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE NSC 743400; Indenoisoquinolines; Topoisomerase I; Pharmacokinetics; Anticancer; Rat; Dog ID EXPRESSION AB NSC 743400 is a novel synthetic indenoisoquinoline analog under development as an anticancer agent. It is a potent topoisomerase I inhibitor with potential therapeutic advantages over FDA-approved camptothecin derivatives. In preparation for clinical development of NSC 743400, we determined the pharmacokinetics after administration to rats and dogs. NSC 743400 was administered intravenously at a dose of 12 or 24 mg/m(2) to rats (single bolus) or 10, 50, 100, 215, 430, or 646 mg/m(2) (intravenous infusion) or 860 or 1720 mg/m(2) (orally) to dogs. Intravenously administered NSC 743400 was eliminated from both species with an estimated t (1/2) of 2-5 h in rat and 6-14 h in dog. Elimination t (1/2) increased with dose in dog. Area under the plasma concentration-versus-time curve (AUC) was comparable in both species, at about 300-400 h ng/mL for the approximately 10 mg/m(2) dose groups. Overall, AUC values increased proportionally with dose for both species but had evidence of more than proportional exposure at the highest doses. Oral dosing resulted in variable drug absorption. The pharmacokinetic data were used to plan first-in-human clinical trials. C1 [Muzzio, Miguel; Hu, Shu-Chieh; McCormick, David L.] IIT Res Inst, Life Sci Grp, Chicago, IL 60616 USA. [Holleran, Julianne L.; Parise, Robert A.; Eiseman, Julie L.; Yellow-Duke, Archibong E.; Egorin, Merrill J.; Beumer, Jan H.] Univ Pittsburgh Canc Inst, Canc Therapeut Program, Pittsburgh, PA 15213 USA. [Parise, Robert A.; Beumer, Jan H.] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA. [Eiseman, Julie L.; Egorin, Merrill J.] Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15261 USA. [Covey, Joseph M.; Glaze, Elizabeth R.] NCI, Toxicol & Pharmacol Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Engelke, Kory] Bridge Global Pharmaceut Serv Inc, Toxicol Branch, Gaithersburg, MD 20879 USA. [Egorin, Merrill J.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15261 USA. [Beumer, Jan H.] Univ Pittsburgh Canc Inst, Melanoma Program, Pittsburgh, PA 15213 USA. RP Muzzio, M (reprint author), IIT Res Inst, Life Sci Grp, 10 West 35th St, Chicago, IL 60616 USA. EM MMuzzio@iitri.org; beumerj@gmail.com OI Beumer, Jan/0000-0002-8978-9401 FU NCI [N01-CM-42202, N01-CM-52202, HHSN261201100015C, N01-CM-42204]; [P30CA047904] FX This research was supported by NCI contracts N01-CM-42202 (IITRI), N01-CM-52202, HHSN261201100015C (University of Pittsburgh), and N01-CM-42204 (Bridge), and this project used the UPCI Cancer Pharmacokinetics and Pharmacodynamics Facility (CPPF) and was supported in part by award P30CA047904. NR 12 TC 2 Z9 2 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 EI 1432-0843 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD MAY PY 2015 VL 75 IS 5 BP 1015 EP 1023 DI 10.1007/s00280-015-2722-y PG 9 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA CH5DU UT WOS:000354055800016 PM 25776905 ER PT J AU Silverman, JL Gastrell, PT Karras, MN Solomon, M Crawley, JN AF Silverman, J. L. Gastrell, P. T. Karras, M. N. Solomon, M. Crawley, J. N. TI Cognitive Abilities on Transitive Inference Using a Novel Touchscreen Technology for Mice SO CEREBRAL CORTEX LA English DT Article DE autism; learning; mouse model; schizophrenia; translational ID BTBR MOUSE MODEL; NEUROSCIENCE TREATMENT RESEARCH; AUTISM SPECTRUM DISORDERS; PRADER-WILLI-SYNDROME; PREFRONTAL CORTEX; CONJUNCTIVE REPRESENTATIONS; ALZHEIMERS-DISEASE; IMPAIRED ATTENTION; PATTERN SEPARATION; IMPROVE COGNITION AB Cognitive abilities are impaired in neurodevelopmental disorders, including autism spectrum disorder (ASD) and schizophrenia. Preclinical models with strong endophenotypes relevant to cognitive dysfunctions offer a valuable resource for therapeutic development. However, improved assays to test higher order cognition are needed. We employed touchscreen technology to design a complex transitive inference (TI) assay that requires cognitive flexibility and relational learning. C57BL/6J (B6) mice with good cognitive skills and BTBR T +tf/J (BTBR), a model of ASD with cognitive deficits, were evaluated in simple and complex touchscreen assays. Both B6 and BTBR acquired visual discrimination and reversal. BTBR displayed deficits on components of TI, when 4 stimuli pairs were interspersed, which required flexible integrated knowledge. BTBR displayed impairment on the A > E inference, analogous to the A > E deficit in ASD. B6 and BTBR mice both reached criterion on the B > D comparison, unlike the B > D impairment in schizophrenia. These results demonstrate that mice are capable of complex discriminations and higher order tasks using methods and equipment paralleling those used in humans. Our discovery that a mouse model of ASD displays a TI deficit similar to humans with ASD supports the use of the touchscreen technology for complex cognitive tasks in mouse models of neurodevelopmental disorders. C1 [Silverman, J. L.; Solomon, M.; Crawley, J. N.] Univ Calif Davis, Sch Med, Dept Psychiat & Behav Sci, MIND Inst, Sacramento, CA 95817 USA. [Silverman, J. L.; Gastrell, P. T.; Karras, M. N.; Crawley, J. N.] NIMH, Lab Behav Neurosci, Intramural Res Program, Bethesda, MD 20892 USA. [Solomon, M.] Univ Calif Davis, Imaging Res Ctr, Sacramento, CA 95817 USA. RP Silverman, JL (reprint author), Univ Calif Davis, Sch Med, Dept Psychiat & Behav Sci, Sacramento, CA 95817 USA. EM jill.silverman@ucdmc.ucdavis.edu FU National Institute of Mental Health Intramural Research Program; MIND Institute, University of California Davis School of Medicine FX This work was supported by the National Institute of Mental Health Intramural Research Program and the MIND Institute, University of California Davis School of Medicine. NR 103 TC 8 Z9 8 U1 3 U2 18 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 EI 1460-2199 J9 CEREB CORTEX JI Cereb. Cortex PD MAY PY 2015 VL 25 IS 5 BP 1133 EP 1142 DI 10.1093/cercor/bht293 PG 10 WC Neurosciences SC Neurosciences & Neurology GA CH2EW UT WOS:000353839500001 PM 24293564 ER PT J AU Bornstein, MH Putnick, DL Gartstein, MA Hahn, CS Auestad, N O'Connor, DL AF Bornstein, Marc H. Putnick, Diane L. Gartstein, Maria A. Hahn, Chun-Shin Auestad, Nancy O'Connor, Deborah L. TI Infant Temperament: Stability by Age, Gender, Birth Order, Term Status, and Socioeconomic Status SO CHILD DEVELOPMENT LA English DT Article ID CROSS-CULTURAL DIFFERENCES; FOR-GESTATIONAL-AGE; BEHAVIOR QUESTIONNAIRE; EARLY-CHILDHOOD; FULL-TERM; MATERNAL CHARACTERISTICS; EMOTIONAL AVAILABILITY; INDIVIDUAL-DIFFERENCES; PARENTAL PERCEPTIONS; PRETERM INFANTS AB Two complementary studies focused on stability of infant temperament across the 1st year and considered infant age, gender, birth order, term status, and socioeconomic status (SES) as moderators. Study 1 consisted of 73 mothers of firstborn term girls and boys queried at 2, 5, and 13months of age. Study 2 consisted of 335 mothers of infants of different gender, birth order, term status, and SES queried at 6 and 12months. Consistent positive and negative affectivity factors emerged at all time points across both studies. Infant temperament proved stable and robust across gender, birth order, term status, and SES. Stability coefficients for temperament factors and scales were medium to large for shorter (<9months) interassessment intervals and small to medium for longer (>10months) intervals. C1 [Bornstein, Marc H.; Putnick, Diane L.; Hahn, Chun-Shin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. [Gartstein, Maria A.] Washington State Univ, Pullman, WA 99164 USA. [Auestad, Nancy] Dairy Res Inst, Bangalore, Karnataka, India. [O'Connor, Deborah L.] Univ Toronto, Toronto, ON M5S 1A1, Canada. [O'Connor, Deborah L.] Hosp Sick Children, Toronto, ON, Canada. RP Bornstein, MH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Child & Family Res, NIH, Suite 8030,6705 Rockledge Dr, Bethesda, MD 20892 USA. EM marc_h_bornstein@nih.gov OI Putnick, Diane/0000-0002-6323-749X FU Intramural NIH HHS [ZIA HD001119-23] NR 139 TC 5 Z9 5 U1 6 U2 25 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-3920 EI 1467-8624 J9 CHILD DEV JI Child Dev. PD MAY-JUN PY 2015 VL 86 IS 3 BP 844 EP 863 DI 10.1111/cdev.12367 PG 20 WC Psychology, Educational; Psychology, Developmental SC Psychology GA CH8KN UT WOS:000354285400012 PM 25865034 ER PT J AU Hontz, RD Guevara, C Halsey, ES Silvas, J Santiago, FW Widen, SG Wood, TG Casanova, W Vasilakis, N Watts, DM Kochel, TJ Ebihara, H Aguilar, PV AF Hontz, Robert D. Guevara, Carolina Halsey, Eric S. Silvas, Jesus Santiago, Felix W. Widen, Steven G. Wood, Thomas G. Casanova, Wilma Vasilakis, Nikos Watts, Douglas M. Kochel, Tadeusz J. Ebihara, Hideki Aguilar, Patricia V. TI Itaya virus, a Novel Orthobunyavirus Associated with Human Febrile Illness, Peru SO EMERGING INFECTIOUS DISEASES LA English DT Article ID GROUP-C ORTHOBUNYAVIRUS; VENEZUELAN EQUINE ENCEPHALITIS; SEQUENCES REQUIRE VALIDATION; FAMILY BUNYAVIRIDAE; AMAZON REGION; ARBOVIRUSES; FEVER; IQUITOS; MEMBERS; IDENTIFICATION AB Our genetic analyses of uncharacterized bunyaviruses isolated in Peru identified a possible reassortant virus containing small and large gene segment sequences closely related to the Caraparu virus and a medium gene segment sequence potentially derived from an unidentified group C orthobunyavirus. Neutralization tests confirmed serologic distinction among the newly identified virus and the prototype and Caraparu strains. This virus, named Itaya, was isolated in 1999 and 2006 from febrile patients in the cities of Iquitos and Yurimaguas in Peru. The geographic distance between the 2 cases suggests that the Itaya virus could be widely distributed throughout the Amazon basin in northeastern Peru. Identification of a new Orthobunya virus species that causes febrile disease in humans reinforces the need to expand viral disease surveillance in tropical regions of South America. C1 [Hontz, Robert D.] US Naval Med Res Unit 6, Vector Borne & Zoonot Dis Virol & Emerging Infect, Lima, Peru. [Guevara, Carolina; Halsey, Eric S.; Watts, Douglas M.; Kochel, Tadeusz J.] US Naval Med Res Unit 6, Lima, Peru. [Silvas, Jesus; Santiago, Felix W.; Widen, Steven G.; Wood, Thomas G.; Vasilakis, Nikos; Aguilar, Patricia V.] Univ Texas Med Branch, Galveston, TX 77555 USA. [Silvas, Jesus; Santiago, Felix W.; Vasilakis, Nikos; Aguilar, Patricia V.] Inst Human Infect & Immun, Galveston, TX USA. [Casanova, Wilma] Direcc Reg Salud Loreto, Iquitos, Peru. [Vasilakis, Nikos; Aguilar, Patricia V.] Ctr Biodef & Emerging Infect Dis, Galveston, TX USA. [Ebihara, Hideki] NIAID, NIH, Rocky Mt Labs, Hamilton, MT USA. RP Aguilar, PV (reprint author), Univ Texas Med Branch, Dept Pathol, 301 Univ Blvd, Galveston, TX 77555 USA. EM pvaguila@utmb.edu FU Peruvian Ministry of Health; US Department of Defense Global Emerging Infections Surveillance and Response System, a Division of the Armed Forces Health Surveillance Center Work Unit [847705.82000.25GB.B0016]; NIH [HHSN272201000040I/HHSN27200004/D04]; Institute for Human Infection and Immunity at UTMB; Department of Pathology; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We thank Robert Tesh for providing reagents. We also thank Roxana Caceda, Alfredo Huamarr, Roger Castillo, Vidal Felices, Cristhopher Cruz, and Juan Sulca for invaluable support. We thank the Peruvian Ministry of Health for supporting the study and the physicians at the study sites for their participation and help.; This research was supported by the US Department of Defense Global Emerging Infections Surveillance and Response System, a Division of the Armed Forces Health Surveillance Center Work Unit Number: 847705.82000.25GB.B0016; the NIH contract HHSN272201000040I/HHSN27200004/D04 to N.V. and P.V.A.; Institute for Human Infection and Immunity at UTMB; and start-up funds from the Department of Pathology to P.V.A. The work was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health to H.E. NR 39 TC 4 Z9 4 U1 1 U2 4 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD MAY PY 2015 VL 21 IS 5 BP 781 EP 788 DI 10.3201/eid2105.141368 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CG9BW UT WOS:000353610400006 PM 25898901 ER PT J AU Hassan, HK Bolcen, S Kubofcik, J Nutman, TB Eberhard, ML Middleton, K Wekesa, JW Ruedas, G Nelson, KJ Dubielzig, R De Lombaert, M Silverman, B Schorling, JJ Adler, PH Unnasch, TR Beeler, ES AF Hassan, Hassan K. Bolcen, Shanna Kubofcik, Joseph Nutman, Thomas B. Eberhard, Mark L. Middleton, Kelly Wekesa, Joseph Wakoli Ruedas, Gimena Nelson, Kimberly J. Dubielzig, Richard De Lombaert, Melissa Silverman, Bruce Schorling, Jamie J. Adler, Peter H. Unnasch, Thomas R. Beeler, Emily S. TI Isolation of Onchocerca lupi in Dogs and Black Flies, California, USA SO EMERGING INFECTIOUS DISEASES LA English DT Article ID CANINE OCULAR ONCHOCERCOSIS; OF-THE-LITERATURE; UNITED-STATES; ABERRANT INFECTION; DIPTERA; SIMULIIDAE; PARASITE; GREECE; HOST; IDENTIFICATION AB In southern California, ocular infections caused by Onchocerca lupi were diagnosed in 3 dogs (1 in 2006, 2 in 2012). The infectious agent was confirmed through morphologic analysis of fixed parasites in tissues and by PCR and sequencing of amplicons derived from 2 mitochondrially encoded genes and 1 nuclear-encoded gene. A nested PCR based on the sequence of the cytochrome oxidase subunit 1 gene of the parasite was developed and used to screen Simullum black flies collected from southern California for O. lupi DNA. Six (2.8%; 95% Cl 0.6%-5.0%) of 213 black flies contained O. lupi DNA. Partial mitochondril 16S rRNA gene sequences from the infected flies matched sequences derived from black fly larvae cytotaxonomically identified as Simulium tribulatum. These data implicate S. tribulatum flies as a putative vector for O. lupi in southern California. C1 [Hassan, Hassan K.] Univ S Florida, Dept Global Hlth, Tampa, FL USA. [Bolcen, Shanna; Unnasch, Thomas R.] Univ S Florida, Tampa, FL USA. [Kubofcik, Joseph; Nutman, Thomas B.] NIAID, Bethesda, MD 20892 USA. [Eberhard, Mark L.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Middleton, Kelly; Wekesa, Joseph Wakoli; Ruedas, Gimena; Nelson, Kimberly J.] San Gabriel Valley Mosquito & Vector Control Dist, West Covina, CA USA. [Dubielzig, Richard; De Lombaert, Melissa] Univ Wisconsin, Madison, WI USA. [Silverman, Bruce] Complete Anim Eye Care, Sherman Oaks, CA USA. [Schorling, Jamie J.] Eye Clin Anim, San Diego, CA USA. [Adler, Peter H.] Clemson Univ, Clemson, SC USA. [Beeler, Emily S.] Los Angeles Cty Dept Publ Hlth, Los Angeles, CA USA. RP Unnasch, TR (reprint author), Global Hlth Infect Dis Res Program, 3720 Spectrum Blvd,Ste 304, Tampa, FL 33612 USA. EM tunnasch@health.usf.edu FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This study was funded in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (J.K. and T.B.N.). NR 40 TC 5 Z9 5 U1 2 U2 9 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD MAY PY 2015 VL 21 IS 5 BP 789 EP 796 DI 10.3201/eid2105.142011 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA CG9BW UT WOS:000353610400007 PM 25897954 ER EF