FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Midthune, D Carroll, RJ Freedman, LS Kipnis, V AF Midthune, Douglas Carroll, Raymond J. Freedman, Laurence S. Kipnis, Victor TI Measurement error models with interactions SO BIOSTATISTICS LA English DT Article DE Interactions; Measurement error; Mixed models; Nonlinear mixed models; Nutritional epidemiology ID EXPLANATORY VARIABLES; ENERGY-EXPENDITURE; REGRESSION-MODELS; BIOMARKERS; CONSUMPTION; SURROGATE; DISEASE; DIET AB An important use of measurement error models is to correct regression models for bias due to covariate measurement error. Most measurement error models assume that the observed error-prone covariate (W) is a linear function of the unobserved true covariate (X) plus other covariates (Z) in the regression model. In this paper, we consider models for W that include interactions between X and Z. We derive the conditional distribution of X given W and Z and use it to extend the method of regression calibration to this class of measurement error models. We apply the model to dietary data and test whether self-reported dietary intake includes an interaction between true intake and body mass index. We also perform simulations to compare the model to simpler approximate calibration models. C1 [Midthune, Douglas; Kipnis, Victor] NCI, Canc Prevent Div, Biometry Res Grp, 9609 Med Ctr Dr,Room 5E122, Bethesda, MD 20892 USA. [Carroll, Raymond J.] Texas A&M Univ, Dept Stat, TAMU 3143, College Stn, TX 77843 USA. [Carroll, Raymond J.] Univ Technol Sydney, Sch Math Sci, Sydney, NSW 2007, Australia. [Freedman, Laurence S.] Sheba Med Ctr, Gertner Inst Epidemiol & Hlth Policy Res, IL-52161 Tel Hashomer, Israel. RP Midthune, D (reprint author), NCI, Canc Prevent Div, Biometry Res Grp, 9609 Med Ctr Dr,Room 5E122, Bethesda, MD 20892 USA. EM midthund@mail.nih.gov FU National Cancer Institute [U01-CA057030] FX R.J.C.'s research was supported by a grant from the National Cancer Institute (U01-CA057030). NR 23 TC 1 Z9 1 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1465-4644 EI 1468-4357 J9 BIOSTATISTICS JI Biostatistics PD APR PY 2016 VL 17 IS 2 BP 277 EP 290 DI 10.1093/biostatistics/kxv043 PG 14 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA DJ5GW UT WOS:000374235800006 PM 26530858 ER PT J AU Habes, M Erus, G Toledo, JB Zhang, TH Bryan, N Launer, LJ Rosseel, Y Janowitz, D Doshi, J Van der Auwera, S von Sarnowski, B Hegenscheid, K Hosten, N Homuth, G Volzke, H Schminke, U Hoffmann, W Grabe, HJ Davatzikos, C AF Habes, Mohamad Erus, Guray Toledo, Jon B. Zhang, Tianhao Bryan, Nick Launer, Lenore J. Rosseel, Yves Janowitz, Deborah Doshi, Jimit Van der Auwera, Sandra von Sarnowski, Bettina Hegenscheid, Katrin Hosten, Norbert Homuth, Georg Voelzke, Henry Schminke, Ulf Hoffmann, Wolfgang Grabe, Hans J. Davatzikos, Christos TI White matter hyperintensities and imaging patterns of brain ageing in the general population SO BRAIN LA English DT Article DE white matter hyperintensities; Alzheimer's disease; brain ageing; cardiovascular disease; mild cognitive impairment ID MILD COGNITIVE IMPAIRMENT; VOXEL-BASED MORPHOMETRY; VASCULAR RISK-FACTORS; SMALL VESSEL DISEASE; ALZHEIMERS-DISEASE; OLDER-ADULTS; CEREBROVASCULAR-DISEASE; FLUID INTELLIGENCE; SPATIAL-PATTERNS; ELDERLY-PEOPLE AB White matter hyperintensities are associated with increased risk of dementia and cognitive decline. The current study investigates the relationship between white matter hyperintensities burden and patterns of brain atrophy associated with brain ageing and Alzheimer's disease in a large populatison-based sample (n = 2367) encompassing a wide age range (20-90 years), from the Study of Health in Pomerania. We quantified white matter hyperintensities using automated segmentation and summarized atrophy patterns using machine learning methods resulting in two indices: the SPARE-BA index (capturing age-related brain atrophy), and the SPARE-AD index (previously developed to capture patterns of atrophy found in patients with Alzheimer's disease). A characteristic pattern of age-related accumulation of white matter hyperintensities in both periventricular and deep white matter areas was found. Individuals with high white matter hyperintensities burden showed significantly (P < 0.0001) lower SPARE-BA and higher SPARE-AD values compared to those with low white matter hyperintensities burden, indicating that the former had more patterns of atrophy in brain regions typically affected by ageing and Alzheimer's disease dementia. To investigate a possibly causal role of white matter hyperintensities, structural equation modelling was used to quantify the effect of Framingham cardiovascular disease risk score and white matter hyperintensities burden on SPARE-BA, revealing a statistically significant (P < 0.0001) causal relationship between them. Structural equation modelling showed that the age effect on SPARE-BA was mediated by white matter hyperintensities and cardiovascular risk score each explaining 10.4% and 21.6% of the variance, respectively. The direct age effect explained 70.2% of the SPARE-BA variance. Only white matter hyperintensities significantly mediated the age effect on SPARE-AD explaining 32.8% of the variance. The direct age effect explained 66.0% of the SPARE-AD variance. Multivariable regression showed significant relationship between white matter hyperintensities volume and hypertension (P = 0.001), diabetes mellitus (P = 0.023), smoking (P = 0.002) and education level (P = 0.003). The only significant association with cognitive tests was with the immediate recall of the California verbal and learning memory test. No significant association was present with the APOE genotype. These results support the hypothesis that white matter hyperintensities contribute to patterns of brain atrophy found in beyond-normal brain ageing in the general population. White matter hyperintensities also contribute to brain atrophy patterns in regions related to Alzheimer's disease dementia, in agreement with their known additive role to the likelihood of dementia. Preventive strategies reducing the odds to develop cardiovascular disease and white matter hyperintensities could decrease the incidence or delay the onset of dementia. C1 [Habes, Mohamad; Voelzke, Henry] Ernst Moritz Arndt Univ Greifswald, Inst Community Med, Greifswald, Germany. [Habes, Mohamad; Erus, Guray; Zhang, Tianhao; Bryan, Nick; Doshi, Jimit; Davatzikos, Christos] Univ Penn, Ctr Biomed Image Comp & Analyt, Philadelphia, PA 19104 USA. [Habes, Mohamad; Janowitz, Deborah; Van der Auwera, Sandra; Grabe, Hans J.] Ernst Moritz Arndt Univ Greifswald, Dept Psychiat, Greifswald, Germany. [Toledo, Jon B.] Univ Penn, Ctr Neurodegenerat Dis Res, Inst Aging, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Rosseel, Yves] Univ Ghent, Dept Data Anal, B-9000 Ghent, Belgium. [Van der Auwera, Sandra; Hoffmann, Wolfgang; Grabe, Hans J.] German Ctr Neurodegenerat Dis DZNE, Rostock, Germany. [von Sarnowski, Bettina; Schminke, Ulf] Ernst Moritz Arndt Univ Greifswald, Dept Neurol, Greifswald, Germany. [Hegenscheid, Katrin; Hosten, Norbert] Ernst Moritz Arndt Univ Greifswald, Dept Radiol, Greifswald, Germany. [Homuth, Georg] Ernst Moritz Arndt Univ Greifswald, Inst Genet & Funct Genom, Greifswald, Germany. RP Habes, M (reprint author), Univ Penn, Dept Radiol, 3700 Hamilton Walk, Philadelphia, PA 19104 USA. EM habesm@uphs.upenn.edu RI Habes, Mohamad/M-2865-2016; OI Habes, Mohamad/0000-0001-9447-5805; Toledo, Jon/0000-0003-4366-9268 FU Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012]; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg-West Pomerania; Siemens Healthcare, Erlangen, Germany; Federal State of Mecklenburg-West Pomerania; NIH [R01-AG14971]; German Federal Ministry of Education and Research (BMBF) [01ZX1314E]; 'Alfried Krupp von Bohlen und Halbach' foundation; [P01 AG032953]; [PO1 AG017586]; [P30 AG010124]; [P50 NS053488] FX 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 Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data in SHIP and MRI scans in SHIP and SHIP-TREND have been supported by a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. Genome-wide genotyping in SHIP-TREND-0 was supported by the Federal Ministry of Education and Research (grant no. 03ZIK012). This work was supported in part by NIH grant R01-AG14971. S.V.A. was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (Integrament; grant no. 01ZX1314E). J.B.T. is supported by P01 AG032953, PO1 AG017586, P30 AG010124 and P50 NS053488. M.H. was supported by 'Alfried Krupp von Bohlen und Halbach' foundation. No conflict of interest to be declared. NR 88 TC 3 Z9 3 U1 12 U2 19 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 EI 1460-2156 J9 BRAIN JI Brain PD APR PY 2016 VL 139 BP 1164 EP 1179 DI 10.1093/brain/aww008 PN 4 PG 16 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DJ5GN UT WOS:000374234900025 PM 26912649 ER PT J AU Vanegas-Arroyave, N Lauro, PM Huang, L Hallett, M Horovitz, SG Zaghloul, KA Lungu, C AF Vanegas-Arroyave, Nora Lauro, Peter M. Huang, Ling Hallett, Mark Horovitz, Silvina G. Zaghloul, Kareem A. Lungu, Codrin TI Tractography patterns of subthalamic nucleus deep brain stimulation SO BRAIN LA English DT Article DE deep brain stimulation; subthalamic nucleus; Parkinson's disease; tractography ID HIGH-FREQUENCY STIMULATION; PARKINSONS-DISEASE; BOLD ACTIVATION; MOTOR; CONNECTIONS; TISSUE; DBS; MRI; VISUALIZATION; INHIBITION AB Deep brain stimulation therapy is an effective symptomatic treatment for Parkinson's disease, yet the precise mechanisms responsible for its therapeutic effects remain unclear. Although the targets of deep brain stimulation are grey matter structures, axonal modulation is known to play an important role in deep brain stimulation's therapeutic mechanism. Several white matter structures in proximity to the subthalamic nucleus have been implicated in the clinical benefits of deep brain stimulation for Parkinson's disease. We assessed the connectivity patterns that characterize clinically beneficial electrodes in Parkinson's disease patients, after deep brain stimulation of the subthalamic nucleus. We evaluated 22 patients with Parkinson's disease (11 females, age 57 +/- 9.1 years, disease duration 13.3 +/- 6.3 years) who received bilateral deep brain stimulation of the subthalamic nucleus at the National Institutes of Health. During an initial electrode screening session, one month after deep brain stimulation implantation, the clinical benefits of each contact were determined. The electrode was localized by coregistering preoperative magnetic resonance imaging and postoperative computer tomography images and the volume of tissue activated was estimated from stimulation voltage and impedance. Brain connectivity for the volume of tissue activated of deep brain stimulation contacts was assessed using probabilistic tractography with diffusion-tensor data. Areas most frequently connected to clinically effective contacts included the thalamus, substantia nigra, brainstem and superior frontal gyrus. A series of discriminant analyses demonstrated that the strength of connectivity to the superior frontal gyrus and the thalamus were positively associated with clinical effectiveness. The connectivity patterns observed in our study suggest that the modulation of white matter tracts directed to the superior frontal gyrus and the thalamus is associated with favourable clinical outcomes and may contribute to the therapeutic effects of deep brain stimulation. Our method can be further developed to reliably identify effective deep brain stimulation contacts and aid in the programming process. C1 [Vanegas-Arroyave, Nora] Columbia Univ, Coll Phys & Surg, Dept Neurol, New York, NY USA. [Lauro, Peter M.; Huang, Ling; Lungu, Codrin] NINDS, Off Clin Director, NIH, Bldg 10,Room 7D37,10 Ctr Dr, Bethesda, MD 20892 USA. [Hallett, Mark; Horovitz, Silvina G.] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. [Zaghloul, Kareem A.] NINDS, Surg Neurol Branch, NIH, Bldg 10,Room 3D20,10 Ctr Dr, Bethesda, MD 20892 USA. RP Lungu, C (reprint author), NINDS, Off Clin Director, NIH, Bldg 10,Room 7D37,10 Ctr Dr, Bethesda, MD 20892 USA.; Zaghloul, KA (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 10,Room 3D20,10 Ctr Dr, Bethesda, MD 20892 USA. EM kareem.zaghloul@nih.gov; lunguci@ninds.nih.gov FU NIH/NINDS FX NIH/NINDS Intramural Program for all authors. NR 50 TC 5 Z9 5 U1 1 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 EI 1460-2156 J9 BRAIN JI Brain PD APR PY 2016 VL 139 BP 1200 EP 1210 DI 10.1093/brain/aww020 PN 4 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DJ5GN UT WOS:000374234900028 PM 26921616 ER PT J AU Hu, N Kadota, M Liu, HT Abnet, CC Su, H Wu, HL Freedman, ND Yang, HH Wang, CY Yan, CH Wang, LM Gere, S Hutchinson, A Song, GH Wang, Y Ding, T Qiao, YL Koshiol, J Dawsey, SM Giffen, C Goldstein, AM Taylor, PR Lee, MP AF Hu, Nan Kadota, Mitsutaka Liu, Huaitian Abnet, Christian C. Su, Hua Wu, Hailong Freedman, Neal D. Yang, Howard H. Wang, Chaoyu Yan, Chunhua Wang, Lemin Gere, Sheryl Hutchinson, Amy Song, Guohong Wang, Yuan Ding, Ti Qiao, You-Lin Koshiol, Jill Dawsey, Sanford M. Giffen, Carol Goldstein, Alisa M. Taylor, Philip R. Lee, Maxwell P. TI Genomic Landscape of Somatic Alterations in Esophageal Squamous Cell Carcinoma and Gastric Cancer SO CANCER RESEARCH LA English DT Article ID MUTATIONAL SIGNATURES; ADENOCARCINOMA; FUSION; GENES; EXOME; IDENTIFICATION; POPULATION; RISK AB Gastric cancer and esophageal cancer are the second and sixth leading causes of cancer-related death worldwide. Multiple genomic alterations underlying gastric cancer and esophageal squamous cell carcinoma (ESCC) have been identified, but the full spectrum of genomic structural variations and mutations have yet to be uncovered. Here, we report the results of whole-genome sequencing of 30 samples comprising tumor and blood from 15 patients, four of whom presented with ESCC, seven with gastric cardia adenocarcinoma (GCA), and four with gastric noncardia adenocarcinoma. Analyses revealed that an A>Cmutation was common in GCA, and in addition to the preferential nucleotide sequence of A located 5 prime to the mutation as noted in previous studies, we found enrichment of T in the 5 prime base. The A>C mutations in GCA suggested that oxidation of guanine may be a potential mechanism underlying cancer mutagenesis. Furthermore, we identified genes with mutations in gastric cancer and ESCC, including well-known cancer genes, TP53, JAK3, BRCA2, FGF2, FBXW7, MSH3, PTCH, NF1, ERBB2, and CHEK2, and potentially novel cancer-associated genes, KISS1R, AMH, MNX1, WNK2, and PRKRIR. Finally, we identified recurrent chromosome alterations in at least 30% of tumors in genes, including MACROD2, FHIT, and PARK2 that were often intragenic deletions. These structural alterations were validated using the The Cancer Genome Atlas dataset. Our studies provide new insights into understanding the genomic landscape, genome instability, and mutation profile underlying gastric cancer and ESCC development. C1 [Hu, Nan; Abnet, Christian C.; Su, Hua; Freedman, Neal D.; Wang, Chaoyu; Wang, Lemin; Hutchinson, Amy; Koshiol, Jill; Dawsey, Sanford M.; Goldstein, Alisa M.; Taylor, Philip R.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Kadota, Mitsutaka; Liu, Huaitian; Wu, Hailong; Yang, Howard H.; Yan, Chunhua; Gere, Sheryl; Song, Guohong; Lee, Maxwell P.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Hutchinson, Amy] Leidos, Canc Genom Res Lab, Gaithersburg, MD USA. [Wang, Yuan; Ding, Ti] Shanxi Canc Hosp, Taiyuan, Shanxi, Peoples R China. [Qiao, You-Lin] Chinese Acad Med Sci, Inst Canc, Beijing 100021, Peoples R China. [Giffen, Carol] Informat Management Serv Inc, Silver Spring, MD USA. RP Lee, MP (reprint author), NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA.; Taylor, PR (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Rm 6E444 MSC 90892, Rockville, MD USA. EM ptaylor@mail.nih.gov; leemax@mail.nih.gov RI Abnet, Christian/C-4111-2015; Qiao, You-Lin/B-4139-2012 OI Abnet, Christian/0000-0002-3008-7843; Qiao, You-Lin/0000-0001-6380-0871 FU Intramural NIH HHS [Z01 CP010154-08] NR 25 TC 6 Z9 6 U1 3 U2 5 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 APR 1 PY 2016 VL 76 IS 7 BP 1714 EP 1723 DI 10.1158/0008-5472.CAN-15-0338 PG 10 WC Oncology SC Oncology GA DJ4IW UT WOS:000374169600008 PM 26857264 ER PT J AU Hofmann, JN Birmann, BM Teras, LR Pfeiffer, RM Wang, Y Albanes, D Baris, D Colditz, GA De Roos, AJ Giles, GG Hosgood, HD Lan, Q Landgren, O Liao, LM Rothman, N Weinstein, SJ Pollak, MN Neuhouser, ML Purdue, MP AF Hofmann, Jonathan N. Birmann, Brenda M. Teras, Lauren R. Pfeiffer, Ruth M. Wang, Ye Albanes, Demetrius Baris, Dalsu Colditz, Graham A. De Roos, Anneclaire J. Giles, Graham G. Hosgood, H. Dean Lan, Qing Landgren, Ola Liao, Linda M. Rothman, Nathaniel Weinstein, Stephanie J. Pollak, Michael N. Neuhouser, Marian L. Purdue, Mark P. TI Low Levels of Circulating Adiponectin Are Associated with Multiple Myeloma Risk in Overweight and Obese Individuals SO CANCER RESEARCH LA English DT Article ID BODY-MASS INDEX; HEALTH; ACTIVATION; PROSTATE; DISEASE; DESIGN; COHORT; CELLS; WOMEN; TRIAL AB The association between obesity and multiple myeloma risk may be partly attributed to reduced circulating levels of adiponectin in obese individuals. To prospectively evaluate multiple myeloma risk in relation to adiponectin levels overall and stratified by body mass index and other characteristics, we conducted a pooled investigation of pre-diagnosed peripheral blood samples from 624 multiple myeloma cases and 1,246 individually matched controls from seven cohorts participating in the Multiple Myeloma Cohort Consortium. Analysis of circulating analyte levels measured by ELISA revealed that higher total adiponectin levels were associated with reduced multiple myeloma risk overall [highest quartile vs. lowest: OR, 0.64; 95% confidence interval (CI) 0.47-0.85; P-trend = 0.001]. This association was apparent among cases diagnosed six or more years after blood collection (OR, 0.60; 95% CI, 0.40-0.90; P-trend = 0.004) and was similar in magnitude for men and women (OR, 0.59 and 0.66, respectively). Interestingly, we observed strong associations among subjects who were overweight (OR, 0.41; 95% CI, 0.26-0.65) or obese (OR, 0.41; 95% CI, 0.17-0.98) but not among those with normal weight (OR, 1.20; 95% CI, 0.73-2.00; overweight/obese vs. normal weight, P-interaction = 0.04). Our findings provide the strongest epidemiologic evidence to date that adiponectin protects against multiple myeloma development, particularly among overweight and obese individuals, and offer a method for risk assessment in this susceptible population of heavier patients. C1 [Hofmann, Jonathan N.; Pfeiffer, Ruth M.; Albanes, Demetrius; Baris, Dalsu; Lan, Qing; Liao, Linda M.; Rothman, Nathaniel; Weinstein, Stephanie J.; Purdue, Mark P.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Birmann, Brenda M.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Birmann, Brenda M.] Harvard Univ, Sch Med, Boston, MA USA. [Teras, Lauren R.] Amer Canc Soc, Atlanta, GA 30329 USA. [Wang, Ye; Pollak, Michael N.] McGill Univ, Dept Oncol, Montreal, PQ, Canada. [Wang, Ye; Pollak, Michael N.] McGill Univ, Jewish Gen Hosp, Segal Canc Ctr, Montreal, PQ H3T 1E2, Canada. [Colditz, Graham A.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Colditz, Graham A.] Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. [Colditz, Graham A.] Washington Univ, Sch Med, Alvin J Siteman Canc Ctr, St Louis, MO USA. [Colditz, Graham A.] Barnes Jewish Hosp, St Louis, MO 63110 USA. [De Roos, Anneclaire J.] Drexel Univ, Sch Publ Hlth, Philadelphia, PA 19104 USA. [Giles, Graham G.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Hosgood, H. Dean] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Landgren, Ola] Mem Sloan Kettering Canc Ctr, Myeloma Serv, 1275 York Ave, New York, NY 10021 USA. [Neuhouser, Marian L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. RP Hofmann, JN (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 6E604,MSC 9771, Bethesda, MD 20892 USA. EM hofmannjn@mail.nih.gov OI Liao, Linda/0000-0002-1923-5294; Giles, Graham/0000-0003-4946-9099 FU Intramural NIH HHS [Z01 CP010136-12, ZIA CP010136-14]; NCI NIH HHS [K07 CA115687, UM1 CA167552, P01 CA087969, R01 CA149445, R01 CA049449, UM1 CA186107, R01 CA127435]; NHLBI NIH HHS [HHSN268201100046C, HHSN268201100001I, HHSN268201100002I, HHSN268201100004I]; NIA NIH HHS [HHSN271201100004C]; WHI NIH HHS [HHSN268201100003C, HHSN268201100001C, HHSN268201100004C, HHSN268201100002C] NR 33 TC 1 Z9 1 U1 4 U2 6 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 APR 1 PY 2016 VL 76 IS 7 BP 1935 EP 1941 DI 10.1158/0008-5472.CAN-15-2406 PG 7 WC Oncology SC Oncology GA DJ4IW UT WOS:000374169600028 PM 26921332 ER PT J AU Liang, X Zou, QH He, Y Yang, YH AF Liang, Xia Zou, Qihong He, Yong Yang, Yihong TI Topologically Reorganized Connectivity Architecture of Default-Mode, Executive-Control, and Salience Networks across Working Memory Task Loads SO CEREBRAL CORTEX LA English DT Article DE connectomics; default-mode network; executive-control network; module; salience network ID POSTERIOR CINGULATE CORTEX; RESTING-STATE NETWORKS; SCALE BRAIN NETWORKS; FUNCTIONAL ARCHITECTURE; PREFRONTAL CORTEX; COGNITIVE CONTROL; PERFORMANCE; FMRI; MANIPULATION; ORGANIZATION AB The human brain is topologically organized into a set of spatially distributed, functionally specific networks. Of these networks, the default-mode network (DMN), executive-control network (ECN), and salience network (SN) have received the most attention recently for their vital roles in cognitive functions. However, very little is known about whether and how the interactions within and between these 3 networks would be modulated by cognitive demands. Here, we employed graph-based modularity analysis to identify the DMN, ECN, and SN during an N-back working memory (WM) task and further investigated the modulation of intra- and inter-network interactions at different cognitive loads. As the task load elevated, functional connectivity decreased within the DMN while increased within the ECN, and the SN connected more with both the DMN and ECN. Within-network connectivity of the ventral and dorsal posterior cingulate cortex was differentially modulated by cognitive load. Further, the superior parietal regions in the ECN showed increased internetwork connections at higher WM loads, and these increases correlated positively with WM task performance. Together, these findings advance our understanding of dynamic integrations of specialized brain systems in response to cognitive demands and may serve as a baseline for assessing potential disruptions of these interactions in pathological conditions. C1 [Liang, Xia; Yang, Yihong] NIDA, Neuroimaging Res Branch, NIH, Baltimore, MD 21224 USA. [Liang, Xia; He, Yong] Beijing Normal Univ, State Key Lab Cognit Neurosci & Learning, Beijing 100875, Peoples R China. [Liang, Xia; He, Yong] Beijing Normal Univ, IDG McGovern Inst Brain Res, Beijing 100875, Peoples R China. [He, Yong] Beijing Normal Univ, Ctr Collaborat & Innovat Brain & Learning Sci, Beijing 100875, Peoples R China. [Zou, Qihong] Peking Univ, Ctr MRI Res, Beijing 100871, Peoples R China. [Zou, Qihong] Peking Univ, Beijing City Key Lab Med Phys & Engn, Beijing 100871, Peoples R China. RP Yang, YH (reprint author), NIDA, Neuroimaging Res Branch, NIH, Baltimore, MD 21224 USA.; He, Y (reprint author), Beijing Normal Univ, State Key Lab Cognit Neurosci & Learning, Beijing 100875, Peoples R China.; He, Y (reprint author), Beijing Normal Univ, IDG McGovern Inst Brain Res, Beijing 100875, Peoples R China. EM yong.he@bnu.edu.cn; yihongyang@intra.nida.nih.gov FU Intramural Research Program of the National Institute on Drug Abuse (NIDA), National Institutes of Health, USA; Natural Science Foundation of China [81030028, 31221003, 81201142]; National Science Fund for Distinguished Young Scholars Grant [81225012] FX This work was supported by the Intramural Research Program of the National Institute on Drug Abuse (NIDA), National Institutes of Health, USA; Natural Science Foundation of China Grants 81030028 and 31221003 (Y.H.); National Science Fund for Distinguished Young Scholars Grant 81225012 (Y.H.); and Natural Science Foundation of China Grant 81201142 (QH.Z). NR 55 TC 18 Z9 18 U1 9 U2 21 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 APR PY 2016 VL 26 IS 4 BP 1501 EP 1511 DI 10.1093/cercor/bhu316 PG 11 WC Neurosciences SC Neurosciences & Neurology GA DJ5KM UT WOS:000374246700014 PM 25596593 ER PT J AU Frankel, S Medvedeva, N Gutherz, S Kulick, C Kondratyev, A Forcelli, PA AF Frankel, Sari Medvedeva, Natalia Gutherz, Samuel Kulick, Catherine Kondratyev, Alexei Forcelli, Patrick A. TI Comparison of the long-term behavioral effects of neonatal exposure to retigabine or phenobarbital in rats SO EPILEPSY & BEHAVIOR LA English DT Article DE Anticonvulsant; Development; Neonatal; Epilepsy; Antiepileptic drug ID ANTIEPILEPTIC DRUG EXPOSURE; APOPTOTIC NEURODEGENERATION; DEVELOPING BRAIN; MOUSE-BRAIN; CELL-DEATH; IMMUNOHISTOCHEMICAL ANALYSIS; ANTICONVULSANT ACTION; POTASSIUM CHANNELS; PASSIVE-AVOIDANCE; IMMATURE BRAIN AB Anticonvulsant drugs, when given during vulnerable periods of brain development, can have long-lasting consequences on nervous system function. In rats, the second postnatal week approximately corresponds to the late third trimester of gestation/early infancy in humans. Exposure to phenobarbital during this period has been associated with deficits in learning and memory, anxiety-like behavior, and social behavior, among other domains. Phenobarbital is the most common anticonvulsant drug used in neonatology. Several other drugs, such as lamotrigine, phenytoin, and clonazepam, have also been reported to trigger behavioral changes. A new generation anticonvulsant drug, retigabine, has not previously been evaluated for long-term effects on behavior. Retigabine acts as an activator of KCNQ channels, a mechanism that is unique among anticonvulsants. Here, we examined the effects retigabine exposure from postnatal day (P)7 to P14 on behavior in adult rats. We compared these effects with those produced by phenobarbital (as a positive control) and saline (as a negative control). Motor behavior was assessed by using the open field and rotarod, anxiety-like behavior by the open field, elevated plus maze, and light-dark transition task, and learning/memory by the passive avoidance task; social interactions were assessed in same-treatment pairs, and nociceptive sensitivity was assessed via the tail-flick assay. Motor behavior was unaltered by exposure to either drug. We found that retigabine exposure and phenobarbital exposure both induced increased anxiety-like behavior in adult animals. Phenobarbital, but not retigabine, exposure impaired learning and memory. These drugs also differed in their effects on social behavior, with retigabine-exposed animals displaying greater social interaction than phenobarbital-exposed animals. These results indicate that neonatal retigabine induces a subset of behavioral alterations previously described for other anticonvulsant drugs and extend our knowledge of drug-induced behavioral teratogenesis to a new mechanism of anticonvulsant action. (C) 2016 Elsevier Inc. All rights reserved. C1 [Frankel, Sari; Medvedeva, Natalia; Gutherz, Samuel; Kulick, Catherine; Kondratyev, Alexei; Forcelli, Patrick A.] Georgetown Univ, Sch Med, Dept Physiol & Pharmacol, New Res Bldg,W209B, Washington, DC 20057 USA. [Kondratyev, Alexei] NIH, Ctr Sci Review, Bethesda, MD USA. RP Forcelli, PA (reprint author), Georgetown Univ, Sch Med, Dept Physiol & Pharmacol, New Res Bldg,W209B, Washington, DC 20057 USA. EM paf22@georgetown.edu FU GlaxoSmithKline; [HD046388] FX This work was supported by a research grant from GlaxoSmithKline to AK and PAF. PAF also received support from HD046388. We thank Colin Soper and Isabelle Orozco for assistance with treating and testing animals, respectively. NR 62 TC 1 Z9 1 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 1525-5050 EI 1525-5069 J9 EPILEPSY BEHAV JI Epilepsy Behav. PD APR PY 2016 VL 57 BP 34 EP 40 DI 10.1016/j.yebeh.2016.01.018 PN A PG 7 WC Behavioral Sciences; Clinical Neurology; Psychiatry SC Behavioral Sciences; Neurosciences & Neurology; Psychiatry GA DJ5NW UT WOS:000374256700007 PM 26921596 ER PT J AU Stote, KS Tracy, RP Taylor, PR Baer, DJ AF Stote, K. S. Tracy, R. P. Taylor, P. R. Baer, D. J. TI The effect of moderate alcohol consumption on biomarkers of inflammation and hemostatic factors in postmenopausal women SO EUROPEAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID C-REACTIVE PROTEIN; PLASMINOGEN-ACTIVATOR INHIBITOR-1; CARDIOVASCULAR RISK-FACTORS; CORONARY-HEART-DISEASE; RED WINE; MYOCARDIAL-INFARCTION; RANDOMIZED CROSSOVER; ADHESION MOLECULES; CONTROLLED DIET; FACTOR-VII AB BACKGROUND/OBJECTIVES: Inflammation and hemostasis contribute to the etiology of cardiovascular disease. We previously demonstrated that moderate alcohol consumption (1-2 drinks/day) may decrease risk for cardiovascular disease because of an improved lipid profile. In addition to these beneficial changes, the alcohol-mediated reduction in risk may be through its effect on inflammation and hemostasis. The objective of the study was to evaluate the effect of moderate alcohol consumption on biomarkers of inflammation and hemostasis in postmenopausal women. SUBJECTS/METHODS: As part of a controlled diet study, 53 postmenopausal women each consumed a weight-maintaining diet plus 0, 15 and 30 g/day of alcohol for 8 weeks, in a randomized crossover design. The controlled diet contained 15%, 53% and 32% of energy from protein, carbohydrate and fat, respectively. RESULTS: Soluble intercellular adhesion molecule-1 decreased by 5% (P<0.05) with consumption of both 15 and 30 g of alcohol. Fibrinogen concentrations decreased by 4% and 6% (P<0.05) after consumption of 15 and 30 g alcohol, respectively. Fibrin D-dimer decreased by 24% (P<0.05) after consumption of 30 g of alcohol. Plasminogen activator inhibitor-1 (PAI-1) concentrations were increased 27 and 54% (P<0.05) after consumption of 15 and 30 g of alcohol. Plasma high-sensitivity C-reactive protein, interleukin-6 and factor VII coagulant activity did not change with alcohol consumption. CONCLUSIONS: These data suggest that moderate alcohol consumption may have beneficial effects on inflammation and hemostasis in postmenopausal women, and this may be somewhat mitigated by an increase in PAI-1. C1 [Stote, K. S.; Baer, D. J.] ARS, Beltsville Human Nutr Res Ctr, USDA, Beltsville, MD USA. [Tracy, R. P.] Univ Vermont, Coll Med, Burlington, VT USA. [Taylor, P. R.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. SUNY Empire State Coll, Saratoga Springs, NY 12866 USA. RP Stote, KS (reprint author), SUNY Empire State Coll, 113 West Ave, Saratoga Springs, NY 12866 USA. EM Kim.Stote@esc.edu NR 41 TC 2 Z9 2 U1 3 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0954-3007 EI 1476-5640 J9 EUR J CLIN NUTR JI Eur. J. Clin. Nutr. PD APR PY 2016 VL 70 IS 4 BP 470 EP 474 DI 10.1038/ejcn.2015.182 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DJ3RO UT WOS:000374123500010 PM 26554758 ER PT J AU Gorczyca, AM Sjaarda, LA Mitchell, EM Perkins, NJ Schliep, KC Wactawski-Wende, J Mumford, SL AF Gorczyca, Anna M. Sjaarda, Lindsey A. Mitchell, Emily M. Perkins, Neil J. Schliep, Karen C. Wactawski-Wende, Jean Mumford, Sunni L. TI Changes in macronutrient, micronutrient, and food group intakes throughout the menstrual cycle in healthy, premenopausal women SO EUROPEAN JOURNAL OF NUTRITION LA English DT Article DE Menstrual cycle; Macronutrients; Micronutrients; Anovulatory ID NUTRIENT INTAKE; FREQUENCY QUESTIONNAIRE; PREMENSTRUAL-SYNDROME; DIETARY-INTAKE; ENERGY; OVULATION; PATTERNS; BIOCYCLE; HORMONES; PHASE AB It is thought that total energy intake in women is increased during the luteal versus follicular phase of the menstrual cycle; however, less is understood regarding changes in diet composition (i.e., macro- and micronutrient intakes) across the cycle. The aim of this study was to investigate changes in macronutrient, micronutrient, and food group intakes across phases of the menstrual cycle among healthy women, and to assess whether these patterns differ by ovulatory status. The BioCycle study (2005-2007) was a prospective cohort study of 259 healthy regularly menstruating women age 18-44 who were followed for up to two menstrual cycles. Dietary intake was measured using 24-h dietary recalls, and food cravings were assessed via questionnaire, up to four times per cycle, corresponding to menses, mid-follicular, expected ovulation, and luteal phases. Linear mixed models adjusting for total energy intake were used to evaluate changes across the cycle. Total protein (P = 0.03), animal protein (P = 0.05), and percent of caloric intake from protein (P = 0.02) were highest during the mid-luteal phase compared to the peri-ovulatory phase. There were also significant increases in appetite, craving for chocolate, craving for sweets in general, craving for salty flavor, and total craving score during the late luteal phase compared to the menstrual, follicular, and ovulatory phases (P < 0.001). Our findings suggest an increased intake of protein, and specifically animal protein, as well as an increase in reported food cravings, during the luteal phase of the menstrual cycle independent of ovulatory status. These results highlight a plausible link between macronutrient intake and menstrual cycle phase. C1 [Gorczyca, Anna M.; Sjaarda, Lindsey A.; Mitchell, Emily M.; Perkins, Neil J.; Schliep, Karen C.; Mumford, Sunni L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Epidemiol Branch, 6100 Executive Blvd 7B03, Rockville, MD 20852 USA. [Gorczyca, Anna M.] Indiana Univ, Dept Epidemiol & Biostat, Sch Publ Hlth, Bloomington, IN USA. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Epidemiol & Environm Hlth, Sch Publ Hlth & Hlth Profess, Buffalo, NY 14260 USA. RP Mumford, SL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Epidemiol Branch, 6100 Executive Blvd 7B03, Rockville, MD 20852 USA. EM mumfords@mail.nih.gov OI Perkins, Neil/0000-0002-6802-4733; Sjaarda, Lindsey/0000-0003-0539-8110 FU Intramural Research Program of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [HHSN275200403394C] FX This research was supported by the Intramural Research Program of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (Contract # HHSN275200403394C). JW-W designed and implemented the study; AMG and SLM developed the overall research plan and drafted the manuscript; AMG and EMM performed the statistical analysis; LAS, EMM, NJP, KCS, and SLM participated in data analysis and interpretation and critically reviewed the manuscript. All authors read the manuscript and approved the final manuscript. NR 27 TC 1 Z9 1 U1 4 U2 9 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1436-6207 EI 1436-6215 J9 EUR J NUTR JI Eur. J. Nutr. PD APR PY 2016 VL 55 IS 3 BP 1181 EP 1188 DI 10.1007/s00394-015-0931-0 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DJ3NS UT WOS:000374112900027 PM 26043860 ER PT J AU Revoredo, L Wang, SJ Bennett, EP Clausen, H Moremen, KW Jarvis, DL Ten Hagen, KG Tabak, LA Gerken, TA AF Revoredo, Leslie Wang, Shengjun Bennett, Eric Paul Clausen, Henrik Moremen, Kelley W. Jarvis, Donald L. Ten Hagen, Kelly G. Tabak, Lawrence A. Gerken, Thomas A. TI Mucin-type O-glycosylation is controlled by short- and long-range glycopeptide substrate recognition that varies among members of the polypeptide GalNAc transferase family SO GLYCOBIOLOGY LA English DT Article DE glycoprotein biosynthesis; glycosyltransferase; lectin; mucin ID ACETYL-D-GALACTOSAMINE; N-ACETYLGALACTOSAMINYLTRANSFERASES T1; UDP-GALNAC; LECTIN DOMAINS; DROSOPHILA-MELANOGASTER; LINKED GLYCOSYLATION; BINDING-SPECIFICITY; TUMORAL CALCINOSIS; THREONINE RESIDUES; SUGAR RECOGNITION AB A large family of UDP-GalNAc:polypeptide GalNAc transferases (ppGalNAc-Ts) initiates and defines sites of mucin-type Ser/Thr-O-GalNAc glycosylation. Family members have been classified into peptide- and glycopeptide-preferring subfamilies, although both families possess variable activities against glycopeptide substrates. All but one isoform contains a C-terminal carbohydrate-binding lectin domain whose roles in modulating glycopeptide specificity is just being understood. We have previously shown for several peptide-preferring isoforms that the presence of a remote Thr-O-GalNAc, 6-17 residues from a Ser/Thr acceptor site, may enhance overall catalytic activity in an N- or C-terminal direction. This enhancement varies with isoform and is attributed to Thr-O-GalNAc interactions at the lectin domain. We now report on the glycopeptide substrate utilization of a series of glycopeptide (human-ppGalNAc-T4, T7, T10, T12 and fly PGANT7) and peptide-preferring transferases (T2, T3 and T5) by exploiting a series of random glycopeptide substrates designed to probe the functions of their catalytic and lectin domains. Glycosylation was observed at the -3, -1 and +1 residues relative to a neighboring Thr-O-GalNAc, depending on isoform, which we attribute to specific Thr-O-GalNAc binding at the catalytic domain. Additionally, these glycopeptide-preferring isoforms show remote lectin domain-assisted Thr-O-GalNAc enhancements that vary from modest to none. We conclude that the glycopeptide specificity of the glycopeptide-preferring isoforms predominantly resides in their catalytic domain but may be further modulated by remote lectin domain interactions. These studies further demonstrate that both domains of the ppGalNAc-Ts have specialized and unique functions that work in concert to control and order mucin-type O-glycosylation. C1 [Revoredo, Leslie; Gerken, Thomas A.] Case Western Reserve Univ, Dept Chem, Cleveland, OH 44106 USA. [Gerken, Thomas A.] Case Western Reserve Univ, Dept Pediat & Biochem, Cleveland, OH 44106 USA. [Wang, Shengjun; Bennett, Eric Paul; Clausen, Henrik] Univ Copenhagen, Fac Hlth Sci, Dept Cellular & Mol Med, Copenhagen Ctr Glyc, DK-2200 Copenhagen N, Denmark. [Wang, Shengjun; Bennett, Eric Paul; Clausen, Henrik] Univ Copenhagen, Fac Hlth Sci, Dept Dent, Copenhagen Ctr Glyc, DK-2200 Copenhagen N, Denmark. [Moremen, Kelley W.] Univ Georgia, Complex Carbohydrate Res Ctr, 220 Riverbend Rd, Athens, GA 30602 USA. [Jarvis, Donald L.] Univ Wyoming, Dept Mol Biol, Laramie, WY 82071 USA. [Ten Hagen, Kelly G.] NIDCR, Dev Glycobiol Sect, US Dept HHS, NIH, Bethesda, MD 20892 USA. [Tabak, Lawrence A.] NIDCR, Sect Biol Chem, US Dept HHS, NIH, Bethesda, MD 20892 USA. RP Gerken, TA (reprint author), Case Western Reserve Univ, Dept Chem, Cleveland, OH 44106 USA.; Gerken, TA (reprint author), Case Western Reserve Univ, Dept Pediat & Biochem, Cleveland, OH 44106 USA. EM txg2@cwru.edu FU National Institutes of Health [R01-CA78834, U01-GM113534, P41-GM103390, P41-RR005351, P01-GM107012]; NIDCR intramural program grant; Danish National Research Foundation [DNRF107] FX This work was supported by grants from the National Institutes of Health: R01-CA78834 and U01-GM113534 (to T.A.G.), P41-GM103390 and P41-RR005351 (to K.W.M. and D.L.J.), P01-GM107012 (to G.J. Boons, Complex Carbohydrate Research Center, Athens, GA) and NIDCR intramural program grant (to L.A. T. and K.T.H.). Funding by the Danish National Research Foundation (DNRF107) is also acknowledged (to H.C.). NR 61 TC 3 Z9 3 U1 2 U2 12 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD APR PY 2016 VL 26 IS 4 BP 360 EP 376 DI 10.1093/glycob/cwv108 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DJ5CM UT WOS:000374224400005 PM 26610890 ER PT J AU Rinschen, MM Bharill, P Wu, XW Kohli, P Reinert, MJ Kretz, O Saez, I Schermer, B Hohne, M Bartram, MP Aravamudhan, S Brooks, BR Vilchez, D Huber, TB Muller, RU Kruger, M Benzing, T AF Rinschen, Markus M. Bharill, Puneet Wu, Xiongwu Kohli, Priyanka Reinert, Matthaeus J. Kretz, Oliver Saez, Isabel Schermer, Bernhard Hoehne, Martin Bartram, Malte P. Aravamudhan, Sriram Brooks, Bernard R. Vilchez, David Huber, Tobias B. Mueller, Roman-Ulrich Krueger, Marcus Benzing, Thomas TI The ubiquitin ligase Ubr4 controls stability of podocin/MEC-2 supercomplexes SO HUMAN MOLECULAR GENETICS LA English DT Article ID RESISTANT NEPHROTIC SYNDROME; KIDNEY FILTRATION BARRIER; CAENORHABDITIS-ELEGANS; C-ELEGANS; PROTEOMIC ANALYSIS; SLIT DIAPHRAGM; SWISS-MODEL; POSTTRANSLATIONAL MODIFICATIONS; GLOMERULAR PODOCYTE; MASS-SPECTROMETRY AB The PHB-domain protein podocin maintains the renal filtration barrier and its mutation is an important cause of hereditary nephrotic syndrome. Podocin and its Caenorhabditis elegans orthologue MEC-2 have emerged as key components of mechanosensitive membrane protein signalling complexes. Whereas podocin resides at a specialized cell junction at the podocyte slit diaphragm, MEC-2 is found in neurons required for touch sensitivity. Here, we show that the ubiquitin ligase Ubr4 is a key component of the podocin interactome purified both from cultured podocytes and native glomeruli. It colocalizes with podocin and regulates its stability. In C. elegans, this process is conserved. Here, Ubr4 is responsible for the degradation of mislocalized MEC-2 multimers. Ubiquitylomic analysis of mouse glomeruli revealed that podocin is ubiquitylated at two lysine residues. These sites were Ubr4-dependent and were conserved across species. Molecular dynamics simulations revealed that ubiquitylation of one site, K301, do not only target podocin/MEC-2 for proteasomal degradation, but may also affect stability and disassembly of the multimeric complex. We suggest that Ubr4 is a key regulator of podocyte foot process proteostasis. C1 [Rinschen, Markus M.; Bharill, Puneet; Kohli, Priyanka; Reinert, Matthaeus J.; Schermer, Bernhard; Hoehne, Martin; Bartram, Malte P.; Mueller, Roman-Ulrich; Benzing, Thomas] Univ Cologne, Dept Internal Med 2, D-50931 Cologne, Germany. [Rinschen, Markus M.; Schermer, Bernhard; Hoehne, Martin; Mueller, Roman-Ulrich; Krueger, Marcus; Benzing, Thomas] Univ Cologne, Ctr Mol Med Cologne, D-50931 Cologne, Germany. [Rinschen, Markus M.; Kohli, Priyanka; Saez, Isabel; Schermer, Bernhard; Hoehne, Martin; Vilchez, David; Mueller, Roman-Ulrich; Krueger, Marcus; Benzing, Thomas] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, D-50931 Cologne, Germany. [Rinschen, Markus M.; Bharill, Puneet; Schermer, Bernhard; Hoehne, Martin; Mueller, Roman-Ulrich; Benzing, Thomas] Univ Cologne, Syst Biol Ageing Cologne Sybacol, D-50931 Cologne, Germany. [Wu, Xiongwu; Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. [Kretz, Oliver; Huber, Tobias B.] Univ Hosp Freiburg, Div Renal, Freiburg, Germany. [Kretz, Oliver] Univ Freiburg, Neuroanat, Hugstetter Str 55, D-79106 Freiburg, Germany. [Aravamudhan, Sriram] Max Planck Inst Heart & Lung Res, Bad Nauheim, Germany. [Huber, Tobias B.] Univ Freiburg, BIOSS Ctr Biol Signalling Studies, Hugstetter Str 55, D-79106 Freiburg, Germany. RP Rinschen, MM (reprint author), Josef Stelzmann Str 26, D-50931 Cologne, Germany.; Benzing, T (reprint author), Kerpener Str 62, D-50937 Cologne, Germany. EM markus.rinschen@uk-koeln.de; thomas.benzing@uk-koeln.de RI Schermer, Bernhard/E-9972-2014; Vilchez, David/A-8446-2008 OI Schermer, Bernhard/0000-0002-5194-9000; Vilchez, David/0000-0002-0801-0743 FU DFG [BE2212, SFB 635]; DFG (UoC Postdoc Grant); Intramural Research Programs of National Heart, Lung, and Blood Institute [Z01 HL001027-30]; Alexander von Humboldt Foundation; NIH Office of Research Infrastructure Programs [P40 OD010440] FX T.B. was supported by the DFG (BE2212 and SFB 635). M.M.R. was supported by the DFG (UoC Postdoc Grant, Exzellenzinitiative) and by intramural grants (Stiftungsgelder). X.W. and B.R.B. were supported by the Intramural Research Programs of National Heart, Lung, and Blood Institute (Z01 HL001027-30). I.S. was supported by the Alexander von Humboldt Foundation. Following worm strains were used: Wild-type N2 and CB1515 received from CGC which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440) and strain TM3968 received from the NBRP and the Mitani Lab, Japan. NR 73 TC 2 Z9 3 U1 0 U2 4 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 APR 1 PY 2016 VL 25 IS 7 BP 1328 EP 1344 DI 10.1093/hmg/ddw016 PG 17 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA DJ5FA UT WOS:000374231000007 PM 26792178 ER PT J AU Liu, CQ Widen, SA Williamson, KA Ratnapriya, R Gerth-Kahlert, C Rainger, J Alur, RP Strachan, E Manjunath, SH Balakrishnan, A Floyd, JA Li, TS Waskiewicz, A Brooks, BP Lehmann, OJ FitzPatrick, DR Swaroop, A AF Liu, Chunqiao Widen, Sonya A. Williamson, Kathleen A. Ratnapriya, Rinki Gerth-Kahlert, Christina Rainger, Joe Alur, Ramakrishna P. Strachan, Erin Manjunath, Souparnika H. Balakrishnan, Archana Floyd, James A. Li, Tiansen Waskiewicz, Andrew Brooks, Brian P. Lehmann, Ordan J. FitzPatrick, David R. Swaroop, Anand CA UK10K Consortium TI A secreted WNT-ligand-binding domain of FZD5 generated by a frameshift mutation causes autosomal dominant coloboma SO HUMAN MOLECULAR GENETICS LA English DT Article ID FAMILIAL EXUDATIVE VITREORETINOPATHY; DEVELOPMENTAL ANOMALIES; DIAPHRAGMATIC-HERNIA; SKELETAL ANOMALIES; SIGNALING PATHWAYS; FRIZZLED RECEPTORS; OCULAR COLOBOMA; EYE DEVELOPMENT; NORRIE DISEASE; MICROPHTHALMIA AB Ocular coloboma is a common eye malformation resulting from incomplete fusion of the optic fissure during development. Coloboma is often associated with microphthalmia and/or contralateral anophthalmia. Coloboma shows extensive locus heterogeneity associated with causative mutations identified in genes encoding developmental transcription factors or components of signaling pathways. We report an ultra-rare, heterozygous frameshift mutation in FZD5 (p.Ala219Glufs*49) that was identified independently in two branches of a large family with autosomal dominant non-syndromic coloboma. FZD5 has a single-coding exon and consequently a transcript with this frameshift variant is not a canonical substrate for nonsense-mediated decay. FZD5 encodes a transmembrane receptor with a conserved extracellular cysteine rich domain for ligand binding. The frameshift mutation results in the production of a truncated protein, which retains the Wingless-type MMTV integration site family member-ligand-binding domain, but lacks the transmembrane domain. The truncated protein was secreted from cells, and behaved as a dominant-negative FZD5 receptor, antagonizing both canonical and non-canonical WNT signaling. Expression of the resultant mutant protein caused coloboma and microphthalmia in zebrafish, and disruption of the apical junction of the retinal neural epithelium in mouse, mimicking the phenotype of Fz5/Fz8 compound conditional knockout mutants. Our studies have revealed a conserved role of Wnt-Frizzled (FZD) signaling in ocular development and directly implicate WNT-FZD signaling both in normal closure of the human optic fissure and pathogenesis of coloboma. C1 [Liu, Chunqiao; Ratnapriya, Rinki; Manjunath, Souparnika H.; Balakrishnan, Archana; Li, Tiansen; Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, 6 Ctr Dr, Bethesda, MD 20892 USA. [Liu, Chunqiao] Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, State Key Lab Ophthalmol, Guangzhou 510060, Guangdong, Peoples R China. [Widen, Sonya A.; Waskiewicz, Andrew] Univ Alberta, Dept Biol Sci, Edmonton, AB T6G 2E9, Canada. [Williamson, Kathleen A.; Rainger, Joe; FitzPatrick, David R.] Univ Edinburgh, Inst Genet & Mol Med, MRC, Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland. [Gerth-Kahlert, Christina] Univ Zurich Hosp, Dept Ophthalmol, Frauenklin Str 24, CH-8091 Zurich, Switzerland. [Alur, Ramakrishna P.; Brooks, Brian P.] NEI, Unit Pediat Dev & Genet Eye Dis, 10 Ctr Dr, Bethesda, MD 20892 USA. [Strachan, Erin; Lehmann, Ordan J.] Univ Alberta, Dept Ophthalmol & Visual Sci, Edmonton, AB T6G 2H7, Canada. [Floyd, James A.; UK10K Consortium] Welcome Trust Sanger Inst, Cambridge CB10 1HH, England. [Lehmann, Ordan J.] Univ Alberta, Dept Med Genet, Edmonton, AB T6G 2H7, Canada. RP Waskiewicz, A (reprint author), Univ Alberta, Dept Biol Sci, Edmonton, AB T6G 2E9, Canada.; Lehmann, OJ (reprint author), Univ Alberta, Dept Ophthalmol & Visual Sci, Edmonton, AB T6G 2H7, Canada.; Swaroop, A (reprint author), NEI, Neurobiol Neurodegenerat & Repair Lab, 6 Ctr Dr, Bethesda, MD 20892 USA.; FitzPatrick, DR (reprint author), Univ Edinburgh, Western Gen Hosp, MRC, Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland. EM aw@ualberta.ca; olehmann@ualberta.ca; david.fitzpatrick@igmm.ed.ac.uk; swaroopa@nei.nih.gov OI Swaroop, Anand/0000-0002-1975-1141; FitzPatrick, David R./0000-0003-4861-969X; Rainger, Joe/0000-0003-1091-5100 FU National Eye Institute; UK Medical Research Council; Natural Sciences and Engineering Research Council of Canada; Alberta Innovates Technology Futures; Women and Children's Health Research Institute; Canadian Institutes of Health Research; WCHRI; 100 People Plan of Sun Yat-sen University; Welcome Trust [WT091310] FX These studies were supported by Intramural Research program of the National Eye Institute (A.S., T.L. and B.B.), a UK Medical Research Council block grant to the University of Edinburgh Medical Research Council Human Genetics Unit (D.R.F., K.A.W. and J.R.) and by grants from Natural Sciences and Engineering Research Council of Canada, Alberta Innovates Technology Futures and Women and Children's Health Research Institute (S.A.W. and A.J.W.), Canadian Institutes of Health Research and WCHRI (O.J.L.) and 100 People Plan of Sun Yat-sen University (C.L.). The Welcome Trust supported UK10K project (no. WT091310). NR 44 TC 2 Z9 2 U1 4 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 APR 1 PY 2016 VL 25 IS 7 BP 1382 EP 1391 DI 10.1093/hmg/ddw020 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA DJ5FA UT WOS:000374231000011 PM 26908622 ER PT J AU Sapra, KJ Louis, GMB Sundaram, R Joseph, KS Bates, LM Galea, S Ananth, CV AF Sapra, K. J. Louis, G. M. Buck Sundaram, R. Joseph, K. S. Bates, L. M. Galea, S. Ananth, C. V. TI Signs and symptoms associated with early pregnancy loss: findings from a population-based preconception cohort SO HUMAN REPRODUCTION LA English DT Article DE miscarriage; pregnancy loss; nausea; vomiting; bleeding; cramping; symptoms; signs; threatened abortion; prospective cohort studies ID HUMAN-REPRODUCTION; WOMEN; MISCARRIAGE; CONCEPTION; OVULATION; CYCLES; NAUSEA; RISK AB STUDY QUESTION: What is the relationship between signs and symptoms of early pregnancy and pregnancy loss < 20 weeks' gestation? SUMMARY ANSWER: Vaginal bleeding is associated with increased incidence of early pregnancy loss, with more severe bleeding and bleeding accompanied by lower abdominal cramping associated with greater incidence of loss; conversely, vomiting is associated with decreased incidence of early pregnancy loss, even in the setting of vaginal bleeding, while nausea alone is not. WHAT IS KNOWN ALREADY: Two previous cohort studies with preconception enrollment suggested that bleeding is associated with loss while nausea is inversely associated with loss though these studies were limited by small study size and reporting after loss ascertainment. No prior preconception cohort study has examined multiple signs and symptoms in relation to pregnancy loss. STUDY DESIGN, SIZE, DURATION: Population-based preconception cohort of 501 couples discontinuing contraception to try for pregnancy in 16 counties in Michigan and Texas, USA. Participants were followed daily until positive home pregnancy test or 12 months of trying without an hCG pregnancy; women who became pregnant were followed daily from 2 to 7 weeks post-conception. PARTICIPANTS, SETTING, METHODS: Three hundred and forty-seven women had a positive home pregnancy test denoting hCG pregnancy. Three hundred and forty-one women remained after excluding ineligible pregnancies. Women recorded daily from 2 to 7 weeks post-conception their signs and symptoms, including vaginal bleeding (none, spotting, light, moderate and heavy), lower abdominal cramping, nausea and vomiting. Pregnancy losses were ascertained by a subsequent negative home pregnancy test, clinical confirmation or onset of menses, depending on gestational age at loss; time-to-loss was measured in days post-conception. Cumulative incidence functions and 95% confidence intervals (CIs) were constructed for each sign or symptom, and hazard ratios (HRs) and 95% CIs for presence compared with absence of signs or symptoms were estimated using Cox proportional hazard models. MAIN RESULTS AND THE ROLE OF CHANCE: Women experienced lower abdominal cramping (85%), nausea (48%), vomiting (46%) and light/moderate/heavy vaginal bleeding (24%) during early pregnancy. Ninety-five (28%) women experienced a loss. Cumulative incidence of pregnancy loss varied by symptomatology: 19% for vomiting, 27% for lower abdominal cramping, 35% for nausea only, 52% for vaginal bleeding, 81% for vaginal bleeding with lower abdominal cramping. Incidence of pregnancy loss was increased among women with vaginal bleeding (HR: 3.62, 95% CI: 2.29-5.74) and among women with vaginal bleeding and lower abdominal cramping (HR: 5.03, 95% CI: 2.07-12.20). Incidence of pregnancy loss was decreased for women with vomiting (HR: 0.51, 95% CI: 0.30-0.86). In the setting of vaginal bleeding with lower abdominal cramping, vomiting reduced the incidence of pregnancy loss (HR: 0.24, 95% CI: 0.11-0.56). LIMITATIONS, REASONS FOR CAUTION: There were few losses beyond 14 weeks gestation; thus, the precision of our findings related to losses occurring after the first trimester is limited. WIDER IMPLICATIONS OF THE FINDINGS: By using sensitive home pregnancy tests, we are able to document and characterize the cumulative incidence of the earliest pregnancy losses, which constitute the majority of losses. The use of daily, prospective capture of signs and symptoms relative to ascertainment of pregnancy loss minimizes potential biases associated with reporting after rather than before a loss, which could potentially distort the relationship between signs and symptoms and pregnancy loss. The findings of our study suggest that it may be useful to develop prognostic models for pregnancy loss based on signs and symptoms. C1 [Sapra, K. J.; Louis, G. M. Buck; Sundaram, R.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, 6100 Execut Blvd,Room 7B05, Rockville, MD 20852 USA. [Sapra, K. J.; Bates, L. M.; Galea, S.; Ananth, C. V.] Columbia Univ, Joseph L Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Joseph, K. S.] Univ British Columbia, Childrens Womens Hosp British Columbia, Sch Populat & Publ Hlth, Dept Obstet & Gynaecol, Vancouver, BC V5Z 1M9, Canada. [Galea, S.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Ananth, C. V.] Columbia Univ Coll Phys & Surg, Dept Obstet & Gynecol, New York, NY 10032 USA. RP Sapra, KJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, 6100 Execut Blvd,Room 7B05, Rockville, MD 20852 USA. EM saprakj@mail.nih.gov OI Sundaram, Rajeshwari/0000-0002-6918-5002; Joseph, K.S./0000-0003-2317-5607; Buck Louis, Germaine/0000-0002-1774-4490 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [N01-HD-3-3355, N01-HD-3-3356, N01-HD-3-3358] FX This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (contract numbers N01-HD-3-3355; N01-HD-3-3356 and N01-HD-3-3358). NR 29 TC 3 Z9 3 U1 1 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 EI 1460-2350 J9 HUM REPROD JI Hum. Reprod. PD APR PY 2016 VL 31 IS 4 BP 887 EP 896 DI 10.1093/humrep/dew010 PG 10 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA DJ5DY UT WOS:000374228200021 PM 26936888 ER PT J AU Dybeck, EC Konig, G Brooks, BR Shirts, MR AF Dybeck, Eric C. Konig, Gerhard Brooks, Bernard R. Shirts, Michael R. TI Comparison of Methods To Reweight from Classical Molecular Simulations to QM/MM Potentials SO JOURNAL OF CHEMICAL THEORY AND COMPUTATION LA English DT Article ID FREE-ENERGY CALCULATIONS; CRYSTAL-STRUCTURE PREDICTION; HYDRATION FREE-ENERGIES; SOLVATION FREE-ENERGIES; QUANTUM-MECHANICAL CALCULATIONS; HISTOGRAM ANALYSIS METHOD; SMALL ORGANIC-MOLECULES; BLIND TEST; DYNAMICS SIMULATIONS; ENZYMATIC-REACTIONS AB We examine methods to reweight classical molecular mechanics solvation calculations to more expensive QM/MM energy functions. We first consider the solvation free energy difference between ethane and methanol in a QM/MM Hamiltonian from configurations generated in a cheaper MM potential. The solute molecules in the QM/MM Hamiltonian are treated with B3LYP/6-31G*, and the solvent water molecules are treated classically. The free energy difference in the QM/MM Hamiltonian is estimated using Boltzmann reweighting with both the non-Boltzmann Bennett method (NBB) and the multistate Bennett acceptance ratio (MBAR), and the variance of each method is directly compared for an identical data set. For this system, MBAR-derived methods are found to produce smaller overall uncertainties than NBB-based methods. Additionally, we show that to reduce the variance in the overall free energy difference estimate in this system for a fixed amount of QM/MM calculations, the energy re-evaluations in the Boltzmann reweighting step should be concentrated on the physical MM states with the highest overlap to the QM/MM states, rather than allocated equally over all sampled MM states. We also show that reallocating the QM/MM re-evaluations can be used to diagnose poor overlap between the sampled and target state. The solvation free energies for molecules in the SAMPL4 solvation data set are also calculated in the QM/MM Hamiltonian with NBB and MBAR, and the variances are marginally smaller for MBAR. Overall, NBB and MBAR produce similar variances for systems with poor sampling efficiency, and MBAR provides smaller variances than NBB in systems with high sampling efficiency. Both NBB and MBAR converge to identical solvation free energy estimates in the QM/MM Hamiltonian, and the RMSD to experimental values for molecules in the SAMPL4 solvation data set decreases by approximately 28% when switching from the MM Hamiltonian to the QM/MM Hamiltonian. C1 [Dybeck, Eric C.; Shirts, Michael R.] Univ Virginia, Dept Chem Engn, Charlottesville, VA 22904 USA. [Konig, Gerhard; Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, 5635 Fishers Lane,T-900 Suite, Rockville, MD 20852 USA. [Shirts, Michael R.] Univ Colorado, Dept Chem & Biol Engn, Boulder, CO 80309 USA. RP Shirts, MR (reprint author), Univ Virginia, Dept Chem Engn, Charlottesville, VA 22904 USA.; Shirts, MR (reprint author), Univ Colorado, Dept Chem & Biol Engn, Boulder, CO 80309 USA. EM michael.shirts@colorado.edu FU intramural research program of National Heart, Lung and Blood Institute of National Institutes of Health; NSF [NSF-CBET 1351635]; utilized the high-performance computational capabilities of the LoBoS and Biowulf Linux clusters at the National Institutes of Health FX We thank Stefan Boresch and Lee Woodcock for insightful discussions on the current status of reweighting methods. We also thank Ye Mei for carefully reading through this document and providing feedback, as well as generating the figure for the SAMPL4 molecule dataset. This work was partially supported by the intramural research program of the National Heart, Lung and Blood Institute of the National Institutes of Health and utilized the high-performance computational capabilities of the LoBoS and Biowulf Linux clusters at the National Institutes of Health (http://www.lobos.nih.gov and http://biowulf.nih.gov). This work was also supported financially by NSF through Grant NSF-CBET 1351635. NR 69 TC 6 Z9 6 U1 3 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9618 EI 1549-9626 J9 J CHEM THEORY COMPUT JI J. Chem. Theory Comput. PD APR PY 2016 VL 12 IS 4 BP 1466 EP 1480 DI 10.1021/acs.jctc.5b01188 PG 15 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA DJ4RV UT WOS:000374196400007 PM 26928941 ER PT J AU Balsamo, LM Sint, KJ Neglia, JP Brouwers, P Kadan-Lottick, NS AF Balsamo, Lyn M. Sint, Kyaw J. Neglia, Joseph P. Brouwers, Pim Kadan-Lottick, Nina S. TI The Association Between Motor Skills and Academic Achievement Among Pediatric Survivors of Acute Lymphoblastic Leukemia SO JOURNAL OF PEDIATRIC PSYCHOLOGY LA English DT Article DE academic achievement; childhood acute lymphoblastic leukemia; fine motor skills; visual-motor integration ID NONVERBAL LEARNING-DISABILITIES; CHEMOTHERAPY-ONLY TREATMENT; PRENATAL ALCOHOL EXPOSURE; LONG-TERM SURVIVORS; EXECUTIVE FUNCTION; NEUROPSYCHOLOGICAL PERFORMANCE; MATHEMATICS ACHIEVEMENT; EVOKED-POTENTIALS; CHILDHOOD-CANCER; CHILDREN AB Objective Assess the association between fine motor (FM) and visual-motor integration (VMI) skills and academic achievement in pediatric acute lymphoblastic leukemia (ALL) survivors. Method In this 28-site cross-sectional study of 256 children in first remission, a mean of 8.9 +/- 2.2 years after treatment for standard-risk precursor-B ALL, validated measures of FM, VMI, reading, math, and intelligence were administered at mean follow-up age of 12.8 +/- 2.5 years. Results VMI was significantly associated with written math calculation ability (p < .0069) after adjusting for intelligence (p < .0001). VMI was more strongly associated with math in those with lower intelligence (p = .0141). Word decoding was also significantly associated with VMI but with no effect modification by intelligence. FM skills were not associated with either reading or math achievement. Conclusion These findings suggest that VMI is associated with aspects of math and reading achievement in leukemia survivors. These skills may be amenable to intervention. C1 [Balsamo, Lyn M.; Kadan-Lottick, Nina S.] Yale Univ, Sch Med, Sect Pediat Hematol Oncol, POB 208064,333 Cedar St,LMP 2073, New Haven, CT 06520 USA. [Sint, Kyaw J.] Yale Univ, Sch Publ Hlth, New Haven, CT 06520 USA. [Neglia, Joseph P.] Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. [Brouwers, Pim] NIMH, NIH, Bethesda, MD 20892 USA. [Kadan-Lottick, Nina S.] Yale Comprehens Canc Ctr, New Haven, CT USA. RP Balsamo, LM (reprint author), Yale Univ, Sch Med, Sect Pediat Hematol Oncol, POB 208064,333 Cedar St,LMP 2073, New Haven, CT 06520 USA. EM lyn.balsamo@yale.edu FU American Cancer Society; CTSA from National Center for Research Resources, a component of the National Institutes of Health (NIH) [KL2 RR024138]; NIH Roadmap for Medical Research; Children's Oncology Group Chair's [U10 CA98543]; CCOP Grant [U10 CA95861]; [U10CA98413] FX This research was supported by research funding from the American Cancer Society (J.P.N.). K.-L. was supported in part by CTSA Grant Number KL2 RR024138 from the National Center for Research Resources, a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. K.-L. is a Hyundai Hope on Wheels Scholar. Additional support was obtained from Children's Oncology Group Chair's Grant U10 CA98543, Statistics and Data Center Grant U10CA98413, and CCOP Grant U10 CA95861. NR 75 TC 0 Z9 0 U1 2 U2 4 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 APR PY 2016 VL 41 IS 3 BP 319 EP 328 DI 10.1093/jpepsy/jsv103 PG 10 WC Psychology, Developmental SC Psychology GA DJ4QZ UT WOS:000374193700006 PM 26514641 ER PT J AU Berlin, I Singleton, EG Heishman, SJ AF Berlin, Ivan Singleton, Edward G. Heishman, Stephen J. TI A Comparison of the Fagerstrom Test for Cigarette Dependence and Cigarette Dependence Scale in a Treatment-Seeking Sample of Pregnant Smokers SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID NICOTINE DEPENDENCE; SMOKING-CESSATION; PARENTAL SMOKING; PREDICTIVE-VALIDITY; TOBACCO WITHDRAWAL; MATERNAL SMOKING; LIGHT SMOKERS; BIRTH COHORT; EXPOSURE; QUESTIONNAIRE AB Valid and reliable brief measures of cigarette dependence are essential for research purposes and effective clinical care. Two widely-used brief measures of cigarette dependence are the six-item Fagerstrom Test for Cigarette Dependence (FTCD) and five-item Cigarette Dependence Scale (CDS-5). Their respective metric characteristics among pregnant smokers have not yet been studied. This was a secondary analysis of data of pregnant smokers (N = 476) enrolled in a smoking cessation study. We assessed internal consistency, reliability, and examined correlations between the instruments and smoking-related behaviors for construct validity. We evaluated predictive validity by testing how well the measures predict abstinence 2 weeks after quit date. Cronbach's alpha coefficient for the CDS-5 was 0.62 and for the FTCD 0.55. Measures were strongly correlated with each other, although FTCD, but not CDS-5, was associated with saliva cotinine concentration. The FTCD, CDS-5, craving to smoke, and withdrawal symptoms failed to predict smoking status 2 weeks following the quit date. Suboptimal reliability estimates and failure to predict short-term smoking call into question the value of including either of the brief measures in studies that aim to explain the obstacles to smoking cessation during pregnancy. C1 [Berlin, Ivan] Univ Paris 06, Hop La Pitie Salpetriere, Fac Med, INSERM,U669, Paris, France. [Singleton, Edward G.] Co Headquarters, Interact Profess Serv, Catonsville, MD USA. [Heishman, Stephen J.] NIDA, Intramural Res Program, NIH, Baltimore, MD USA. RP Berlin, I (reprint author), Hop La Pitie Salpetriere, Dept Pharmacol, 47 Bd Hop, F-75013 Paris, France. EM ivan.berlin@aphp.fr FU French Ministry of Health [MA05 00150]; NIH Intramural Research Program, National Institute on Drug Abuse FX The main study was supported by the French Ministry of Health (grant number MA05 00150). Contribution of SJH was supported by the NIH Intramural Research Program, National Institute on Drug Abuse. Contribution of EGS was partly supported by the French Ministry of Health (grant number MA05 00150). NR 49 TC 1 Z9 1 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 EI 1469-994X J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD APR PY 2016 VL 18 IS 4 BP 477 EP 483 DI 10.1093/ntr/ntv108 PG 7 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA DJ5EE UT WOS:000374228800015 PM 25995159 ER PT J AU Austad, BC Hague, AB White, P Peluso, S Nair, SJ Depew, KM Grogan, MJ Charette, AB Yu, LC Lory, CD Grenier, L Lescarbeau, A Lane, BS Lombardy, R Behnke, ML Koney, N Porter, JR Campbell, MJ Shaffer, J Xiong, JM Helble, JC Foley, MA Adams, J Castro, AC Tremblay, MR AF Austad, Brian C. Hague, Andrew B. White, Priscilla Peluso, Stephane Nair, Somarajan J. Depew, Kristopher M. Grogan, Michael J. Charette, Andre B. Yu, Lin-Chen Lory, Caroline D. Grenier, Louis Lescarbeau, Andre Lane, Benjamin S. Lombardy, Richard Behnke, Mark L. Koney, Nii Porter, James R. Campbell, Matthew J. Shaffer, Jeanne Xiong, Jimin Helble, Joseph C. Foley, Michael A. Adams, Julian Castro, Alfredo C. Tremblay, Martin R. TI Development of a Multi Kilogram-Scale, Tandem Cyclopropanation Ring-Expansion Reaction en Route to Hedgehog Antagonist IPI-926 SO ORGANIC PROCESS RESEARCH & DEVELOPMENT LA English DT Article ID ASYMMETRIC CYCLOPROPANATION; DERIVATIVES; CYCLOPAMINE; REAGENT; POTENT; IODIDE AB The formation of the D-homocyclopamine ring system in IPI-926 is the key step in its semisynthesis and proceeds via a chemoselective cyclopropanation followed by a stereoselective acid-catalyzed carbocation rearrangement. In order to perform large-scale cyclopropanation reactions, we developed new iodomethylzinc bis(aryl)phosphate reagents that were found to be both effective and safe. These soluble reagents can be prepared under mild conditions and are stable during the course of the reaction. Importantly, they have favorable energetics relative to other cydopropanating agents such as EtZnCH2I. Herein, we describe the process optimization studies that led to successful large-scale production of the D-homocyclopamine core necessary for IPI-926. C1 [Austad, Brian C.; Hague, Andrew B.; White, Priscilla; Peluso, Stephane; Nair, Somarajan J.; Depew, Kristopher M.; Grogan, Michael J.; Yu, Lin-Chen; Lory, Caroline D.; Grenier, Louis; Lescarbeau, Andre; Lane, Benjamin S.; Behnke, Mark L.; Koney, Nii; Porter, James R.; Campbell, Matthew J.; Shaffer, Jeanne; Xiong, Jimin; Helble, Joseph C.; Foley, Michael A.; Adams, Julian; Castro, Alfredo C.; Tremblay, Martin R.] Infin Pharmaceut Inc, 784 Mem Dr, Cambridge, MA 02139 USA. [Charette, Andre B.] Univ Montreal, Fac Arts & Sci, Dept Chem, Stn Downtown, Roger Gaudry Bldg,D-644, Montreal, PQ H3C 3J7, Canada. [Lombardy, Richard] Johnson Matthey Pharma Serv, 25 Patton Rd, Devens, MA 01434 USA. [Austad, Brian C.] Karyopharm Therapeut, 85 Wells Ave,Second Floor, Newton, MA 02459 USA. [Grogan, Michael J.] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Lane, Benjamin S.] Agios, 88 Sidney St, Cambridge, MA 02139 USA. [Behnke, Mark L.] Natl Ctr Adv Translat Sci, 31 Ctr Dr,Suite 3B11, Bethesda, MD 20892 USA. [Koney, Nii] Mt Sinai St Lukes Hosp, 1111 Amsterdam Ave, New York, NY 10069 USA. [Foley, Michael A.] Triinst Therapeut Discovery Inst Inc, Well Cornell Coll, Belfer Res Bldg,413 E 69th St, New York, NY 10021 USA. RP Tremblay, MR (reprint author), Infin Pharmaceut Inc, 784 Mem Dr, Cambridge, MA 02139 USA. EM Martin.Tremblay@infi.com NR 31 TC 1 Z9 1 U1 2 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1083-6160 EI 1520-586X J9 ORG PROCESS RES DEV JI Org. Process Res. Dev. PD APR PY 2016 VL 20 IS 4 BP 786 EP 798 DI 10.1021/acs.oprd.6b00048 PG 13 WC Chemistry, Applied; Chemistry, Organic SC Chemistry GA DJ7ZM UT WOS:000374431900010 ER PT J AU Yeo, LM Romero, R AF Yeo, Lami Romero, Roberto TI Intelligent navigation to improve obstetrical sonography SO ULTRASOUND IN OBSTETRICS & GYNECOLOGY LA English DT Article DE 3D; 4D; fetus; manual navigation; spatiotemporal image correlation; STIC; three-dimensional; ultrasound; VIS-Assistance (R); Virtual Intelligent Sonographer Assistance ID SPATIOTEMPORAL IMAGE CORRELATION; FETAL ECHOCARDIOGRAPHIC PLANES; 11-14 WEEKS GESTATION; 3-DIMENSIONAL ULTRASOUND; 4-DIMENSIONAL ULTRASONOGRAPHY; OUTFLOW TRACTS; HEART; 2ND-TRIMESTER; REPRODUCIBILITY; EXPERIENCE AB 'Manual navigation' by the operator is the standard method used to obtain information from two-dimensional and volumetric sonography. Two-dimensional sonography is highly operator dependent and requires extensive training and expertise to assess fetal anatomy properly. Most of the sonographic examination time is devoted to acquisition of images, while 'retrieval' and display of diagnostic planes occurs rapidly (essentially instantaneously). In contrast, volumetric sonography has a rapid acquisition phase, but the retrieval and display of relevant diagnostic planes is often time-consuming, tedious and challenging. We propose the term 'intelligent navigation' to refer to a new method of interrogation of a volume dataset whereby identification and selection of key anatomical landmarks allow the system to: 1) generate a geometrical reconstruction of the organ of interest; and 2) automatically navigate, find, extract and display specific diagnostic planes. This is accomplished using operator-independent algorithms that are both predictable and adaptive. Virtual Intelligent Sonographer Assistance (VIS-Assistance(R)) is a tool that allows operator-independent sonographic navigation and exploration of the surrounding structures in previously identified diagnostic planes. The advantage of intelligent (over manual) navigation in volumetric sonography is the short time required for both acquisition and retrieval and display of diagnostic planes. Intelligent navigation technology automatically realigns the volume, and reorients and standardizes the anatomical position, so that the fetus and the diagnostic planes are consistently displayed in the same manner each time, regardless of the fetal position or the initial orientation. Automatic labeling of anatomical structures, subject orientation and each of the diagnostic planes is also possible. Intelligent navigation technology can operate on conventional computers, and is not dependent on specific ultrasound platforms or on the use of software to perform manual navigation of volume datasets. Diagnostic planes and VIS-Assistance videoclips can be transmitted by telemedicine so that expert consultants can evaluate the images to provide an opinion. The end result is a user-friendly, simple, fast and consistent method of obtaining sonographic images with decreased operator dependency. Intelligent navigation is one approach to improve obstetrical sonography. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. C1 [Yeo, Lami; Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Yeo, Lami; Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Yeo, Lami] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Yeo, Lami] Hutzel Womens Hosp, Detroit Med Ctr, Detroit, MI USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Romero, Roberto] Wayne State Univ, Dept Mol Obstet & Genet, Detroit, MI USA. RP Yeo, LM; Romero, R (reprint author), NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA.; Yeo, LM; Romero, R (reprint author), NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA.; Yeo, LM (reprint author), Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA.; Yeo, LM (reprint author), Hutzel Womens Hosp, Detroit Med Ctr, Detroit, MI USA.; Romero, R (reprint author), Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA.; Romero, R (reprint author), Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA.; Romero, R (reprint author), Wayne State Univ, Dept Mol Obstet & Genet, Detroit, MI USA. EM lyeo@med.wayne.edu; romeror@mail.nih.gov FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS; Wayne State University; Medge Platforms, Inc., New York, NY, USA; Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH); NICHD, NIH [HHSN275201300006C] FX This work was made possible by a partnership with two unique and outstanding computer scientists, Mr Gustavo Abella and Mr Ricardo Gayoso. The work of Dr Roberto Romero was supported by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS. Dr Roberto Romero contributed to this work as part of his official duties as an employee of the United States Federal Government. Dr Lami Yeo was funded by Wayne State University through a service contract in support of the Perinatology Research Branch. The contributions of Mr Abella and Mr Gayoso were funded by Medge Platforms, Inc., New York, NY, USA.; 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, National Institutes of Health, Department of Health and Human Services (NICHD/NIH); and, in part, with Federal funds from NICHD, NIH under Contract No. HHSN275201300006C. NR 26 TC 4 Z9 4 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0960-7692 EI 1469-0705 J9 ULTRASOUND OBST GYN JI Ultrasound Obstet. Gynecol. PD APR PY 2016 VL 47 IS 4 BP 403 EP 409 DI 10.1002/uog.12562 PG 7 WC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging GA DJ0SY UT WOS:000373915900001 PM 26525650 ER PT J AU Garcia, M Yeo, L Romero, R Haggerty, D Giardina, I Hassan, SS Chaiworapongsa, T Hernandez-Andrade, E AF Garcia, M. Yeo, L. Romero, R. Haggerty, D. Giardina, I. Hassan, S. S. Chaiworapongsa, T. Hernandez-Andrade, E. TI Prospective evaluation of the fetal heart using Fetal Intelligent Navigation Echocardiography (FINE) SO ULTRASOUND IN OBSTETRICS & GYNECOLOGY LA English DT Article DE 4D; cardiac; fetal heart; prenatal diagnosis; spatiotemporal image correlation; STIC; ultrasound; Virtual Intelligent Sonographer Assistance; VIS-Assistance (R) ID SPATIOTEMPORAL IMAGE CORRELATION; COMPUTER-AIDED ANALYSIS; TRACHEA VIEW 3VT; 4-DIMENSIONAL ULTRASOUND; PRENATAL-DIAGNOSIS; OUTFLOW TRACTS; INVERSION MODE; GREAT-ARTERIES; 4-CHAMBER VIEW; 3-DIMENSIONAL ULTRASOUND AB Objective To evaluate prospectively the performance of Fetal Intelligent Navigation Echocardiography (FINE) applied to spatiotemporal image correlation (STIC) volume datasets of the normal fetal heart. Methods In all women between 19 and 30 weeks' gestation with a normal fetal heart, an attempt was made to acquire STIC volume datasets of the apical four-chamber view if the following criteria were met: (1) fetal spine located between 5- and 7-o'clock positions; (2) minimal or absent shadowing (including a clearly visible transverse aortic arch); (3) absence of fetal breathing, hiccups, or movement; and (4) adequate image quality. Each STIC volume successfully acquired was evaluated by STICLoop(TM) to determine its appropriateness before applying the FINE method. Visualization rates of fetal echocardiography views using diagnostic planes and/or Virtual Intelligent Sonographer Assistance (VIS-Assistance(R)) were calculated. Results One or more STIC volumes (365 in total) were obtained successfully in 72.5% (150/207) of women undergoing ultrasound examination. Of the 365 volumes evaluated by STICLoop, 351 (96.2%) were considered to be appropriate. From the 351 STIC volumes, only one STIC volume per patient (n=150) was analyzed using the FINE method, and consequently nine fetal echocardiography views were generated in 76-100% of cases using diagnostic planes only, in 98-100% of cases using VIS-Assistance only, and in 98-100% of cases when using a combination of diagnostic planes and/or VIS-Assistance. Conclusions In women between 19 and 30 weeks' gestation with a normal fetal heart undergoing prospective sonographic examination, STIC volumes can be obtained successfully in 72.5% of cases. The FINE method can be applied to generate nine standard fetal echocardiography views in 98-100% of these cases using a combination of diagnostic planes and/or VIS-Assistance. This suggests that FINE could be implemented in fetal cardiac screening programs. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. C1 [Garcia, M.; Yeo, L.; Romero, R.; Haggerty, D.; Hassan, S. S.; Chaiworapongsa, T.; Hernandez-Andrade, E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Bethesda, MD USA. [Garcia, M.; Yeo, L.; Romero, R.; Haggerty, D.; Hassan, S. S.; Chaiworapongsa, T.; Hernandez-Andrade, E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Detroit, MI USA. [Garcia, M.; Yeo, L.; Haggerty, D.; Hassan, S. S.; Chaiworapongsa, T.; Hernandez-Andrade, E.] Hutzel Womens Hosp, Detroit Med Ctr, Detroit, MI USA. [Yeo, L.; Hassan, S. S.; Chaiworapongsa, T.; Hernandez-Andrade, E.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Romero, R.] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, R.] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Romero, R.] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Giardina, I.] Univ Perugia, Dept Obstet & Gynecol, I-06100 Perugia, Italy. RP Yeo, L; Romero, R (reprint author), NICHD, Perinatol Res Branch, NIH, DHHS,Hutzel Womens Hosp, 3990 John R,4 Brush, Detroit, MI 48201 USA. EM lyeo@med.wayne.edu; romeror@mail.nih.gov FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH); NICHD, NIH [HHSN275201300006C] FX 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, National Institutes of Health, Department of Health and Human Services (NICHD/NIH); and, in part, with Federal funds from NICHD, NIH under Contract No. HHSN275201300006C. NR 98 TC 6 Z9 7 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0960-7692 EI 1469-0705 J9 ULTRASOUND OBST GYN JI Ultrasound Obstet. Gynecol. PD APR PY 2016 VL 47 IS 4 BP 450 EP 459 DI 10.1002/uog.15676 PG 10 WC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging GA DJ0SY UT WOS:000373915900009 PM 26278116 ER PT J AU See, RB Awosika, OO Cambria, RP Conrad, MF Lancaster, RT Patel, VI Chitilian, HV Kumar, S Simon, MV AF See, Reiner B. Awosika, Oluwole O. Cambria, Richard P. Conrad, Mark F. Lancaster, Robert T. Patel, Virendra I. Chitilian, Hovig V. Kumar, Sandeep Simon, Mirela V. TI Extended Motor Evoked Potentials Monitoring Helps Prevent Delayed Paraplegia After Aortic Surgery SO ANNALS OF NEUROLOGY LA English DT Article ID THORACOABDOMINAL ANEURYSM REPAIR; COLLATERAL NETWORK CONCEPT; CEREBROSPINAL-FLUID DRAINAGE; SPINAL-CORD PERFUSION; NEUROLOGIC DEFICIT; RISK-FACTOR; MANAGEMENT; PROTECTION; PARALYSIS; OPERATION AB ObjectiveMotor evoked potentials (MEPs) monitoring can promptly detect spinal cord ischemia (SCI) from aortic clamping during open thoracoabdominal aneurysm repair (OTAAR) with distal aortic perfusion (DAP) and thus help decrease the risk of immediate postoperative SCI (IP-SCI). However, neither stable MEPs during aortic clamp interval (ACI) nor absence of IP-SCI eliminate the possibility of delayed postoperative SCI (DP-SCI). We hypothesized that extension of MEPs monitoring beyond ACI can also help decrease the risk of DP-SCI. MethodsWe identified 150 consecutive patients at our institution between April 2005 and October 2014 who underwent OTAAR with DAP and MEPs monitoring and had no IP-SCI. Using logistic regression analysis, we studied the independent effect of extended MEPs monitoring on the risk of developing DP-SCI. We used a propensity score analysis to adjust for potential confounders, such as poorly controlled hypertension, previous aneurysm surgery, splenectomy, acute aortic dissection, aneurysm type, older age, and history of diabetes and smoking. ResultsFrom the 150 patients, 129 (86%) remained neurologically intact whereas 21 (14%) developed DP-SCI. Nineteen of these twenty-one patients (90%) had no extended monitoring. Fifty-seven of fifty-nine (97%) patients who benefited from extended monitoring had no DP-SCI (p = 0.003). Extended MEPs monitoring was independently associated with decreased risk of DP-SCI (odds ratio = 0.14; 95% confidence interval: 0.03, 0.65; p = 0.01). InterpretationMEPs detect the lowest systemic blood pressure that ensures appropriate spinal cord perfusion in the postoperative period. Thus, they inform the hemodynamic management of patients post-OTAAR, particularly in the absence of a reliable neurological exam. Ann Neurol 2016;79:636-645 C1 [See, Reiner B.; Awosika, Oluwole O.; Simon, Mirela V.] Massachusetts Gen Hosp, Dept Neurol, WACC 739G,55 Fruit St, Boston, MA 02114 USA. [Awosika, Oluwole O.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Cambria, Richard P.; Conrad, Mark F.; Lancaster, Robert T.; Patel, Virendra I.] Massachusetts Gen Hosp, Dept Vasc Surg, Boston, MA 02114 USA. [Chitilian, Hovig V.] Massachusetts Gen Hosp, Dept Anesthesia, Boston, MA 02114 USA. [Kumar, Sandeep] Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02215 USA. RP Simon, MV (reprint author), Massachusetts Gen Hosp, Dept Neurol, WACC 739G,55 Fruit St, Boston, MA 02114 USA. EM mvsimon@mgh.harvard.edu NR 46 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0364-5134 EI 1531-8249 J9 ANN NEUROL JI Ann. Neurol. PD APR PY 2016 VL 79 IS 4 BP 636 EP 645 DI 10.1002/ana.24610 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DJ2AM UT WOS:000374006100012 PM 26841128 ER PT J AU Tinaz, S Lauro, P Hallett, M Horovitz, SG AF Tinaz, Sule Lauro, Peter Hallett, Mark Horovitz, Silvina G. TI Deficits in task-set maintenance and execution networks in Parkinson's disease SO BRAIN STRUCTURE & FUNCTION LA English DT Article DE Resting-state; Functional magnetic resonance imaging; Graph theory; Neural network; Anterior insula; Temporoparietal junction ID GRAPH-THEORETICAL ANALYSIS; RESTING-STATE FMRI; FUNCTIONAL CONNECTIVITY; BRAIN NETWORKS; NEURAL MECHANISMS; TEMPORAL GYRUS; PET; ACTIVATION; MOVEMENTS; STRIATUM AB Patients with Parkinson's disease have difficulties with self-initiating a task and maintaining a steady task performance. We hypothesized that these difficulties relate to reorganization in the sensorimotor execution, cingulo-opercular task-set maintenance, and frontoparietal adaptive control networks. We tested this hypothesis using graph theory-based network analysis of a composite network including a total of 86 nodes, derived from the three networks of interest. Resting-state functional magnetic resonance images were collected from 30 patients with Parkinson's disease (age 42-75 years, 11 females; Hoehn and Yahr score 2-3, average 2.4 +/- A 0.4) in their off-medication state and 30 matched control subjects (age 44-75 years, 10 females). For each node, we calculated strength as a general measure of connectivity, global efficiency and betweenness centrality as measures of functional integration, and clustering coefficient and local efficiency as measures of functional segregation. We found reduced node strength, clustering, and local efficiency in sensorimotor and posterior temporal nodes. There was also reduced node strength and betweenness centrality in the dorsal anterior insula and temporoparietal junction nodes of the cingulo-opercular network. These nodes are involved in integrating multimodal information, specifically related to self-awareness, sense of agency, and ultimately to intact perception of self-in-action. Moreover, we observed significant correlations between global disease severity and averaged graph metrics of the whole network. In addition to the well-known task-related frontostriatal mechanisms, we propose that the resting-state reorganization in the composite network can contribute to problems with self-initiation and task-set maintenance in Parkinson's disease. C1 [Tinaz, Sule; Hallett, Mark; Horovitz, Silvina G.] NINDS, Human Motor Control Sect, NIH, 10 Ctr Dr MSC 1428,Bldg 10,Room 7D42, Bethesda, MD 20892 USA. [Lauro, Peter] NINDS, Off Clin Director, NIH, Bethesda, MD 20892 USA. RP Tinaz, S (reprint author), NINDS, Human Motor Control Sect, NIH, 10 Ctr Dr MSC 1428,Bldg 10,Room 7D42, Bethesda, MD 20892 USA. EM tinaza@mail.nih.gov; peter.lauro@nih.gov; hallettm@ninds.nih.gov; silvina.horovitz@nih.gov FU National Institute of Neurological Disorders and Stroke Intramural Research Program FX This work was supported by the National Institute of Neurological Disorders and Stroke Intramural Research Program. The authors thank Kazumi Iseki and Cecile Gallea for their help with data collection, Pritha Ghosh and Sarah Kranick for their help with patient assessments, Patrick Malone for his help with pilot data analysis, Ziad Saad for his help with data preprocessing, and Devera Schoenberg, M.Sc., for editorial assistance. NR 74 TC 3 Z9 3 U1 4 U2 11 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1863-2653 EI 1863-2661 J9 BRAIN STRUCT FUNCT JI Brain Struct. Funct. PD APR PY 2016 VL 221 IS 3 BP 1413 EP 1425 DI 10.1007/s00429-014-0981-8 PG 13 WC Anatomy & Morphology; Neurosciences SC Anatomy & Morphology; Neurosciences & Neurology GA DI9DK UT WOS:000373801400014 PM 25567420 ER PT J AU Sandberg, C Pomeroy, J Thilen, U Gradmark, A Wadell, K Johansson, B AF Sandberg, Camilla Pomeroy, Jeremy Thilen, Ulf Gradmark, Anna Wadell, Karin Johansson, Bengt TI Habitual Physical Activity in Adults With Congenital Heart Disease Compared With Age- and Sex-Matched Controls SO CANADIAN JOURNAL OF CARDIOLOGY LA English DT Article ID ACTIVITY ENERGY-EXPENDITURE; CARDIOVASCULAR-DISEASE; SEDENTARY TIME; EXERCISE; ASSOCIATION; ADOLESCENTS; RISK; ACCELEROMETER; GUIDELINES; MORTALITY AB Background: Most adult patients with congenital heart disease (CHD) have reduced aerobic exercise capacity. Their habitual physical activity (PA) level is, however, less well studied. In this study, habitual PA level in a cohort of adults with CHD compared with healthy age-and sex-matched controls was investigated. Methods: Eighty adults with CHD, classed as either "complex" (n = 40) or "simple" (n = 40), and 42 healthy controls were studied with a combined uniaxial accelerometer and heart rate monitor worn during 4 consecutive days. We analyzed: (1) the time spent during moderate or vigorous PA; (2) accelerometer counts per day; and (3) to what extent the World Health Organization recommendations on PA were reached. Results: Patients with simple lesions had higher total accelerometer counts per day compared with patients with complex lesions and controls (simple lesions: median [interquartile range] 107.7 [76.3-139.1] vs complex lesions: 72.8 [49.2-101.0] and controls: 78.3 [58.7-106.9]; P <= 0.001 and P = 0.002). Furthermore, no differences in time spent during moderate or vigorous PA was found between patients and controls. In addition 46% of the patients with simple lesions, 55% of the patients with complex lesions, and 44% of the controls did not reach the World Health Organization-recommended level of daily PA, but no significant differences between groups were found. There were no differences in achieving recommended PA level between patients in New York Heart Association (NYHA) class I vs NYHA class II and III. Conclusions: Patients with CHD follow the same PA level pattern as the general population. Broad strategies to promote an active lifestyle are needed across the population and especially for patients with complex CHD and impaired NYHA class. C1 [Sandberg, Camilla; Gradmark, Anna; Johansson, Bengt] Umea Univ, Ctr Heart, SE-90185 Umea, Sweden. [Sandberg, Camilla; Gradmark, Anna; Johansson, Bengt] Umea Univ, Dept Publ Hlth & Clin Med, SE-90185 Umea, Sweden. [Sandberg, Camilla; Wadell, Karin] Umea Univ, Dept Community Med & Rehabil, Physiotherapy, SE-90185 Umea, Sweden. [Pomeroy, Jeremy] NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. [Thilen, Ulf] Lund Univ, Skane Univ Hosp, Dept Cardiol, Lund, Sweden. RP Sandberg, C (reprint author), Umea Univ, Ctr Heart, SE-90185 Umea, Sweden. EM camilla.sandberg@medicin.umu.se OI Sandberg, Camilla/0000-0002-4043-7130; Thilen, Ulf/0000-0001-8651-4878 NR 34 TC 1 Z9 1 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0828-282X EI 1916-7075 J9 CAN J CARDIOL JI Can. J. Cardiol. PD APR PY 2016 VL 32 IS 4 BP 547 EP 553 DI 10.1016/j.cjca.2015.08.021 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DI5XX UT WOS:000373574900020 PM 26777265 ER PT J AU Gupta, A Hussein, Z Hassan, R Wustner, J Maltzman, JD Wallin, BA AF Gupta, Anubha Hussein, Ziad Hassan, Raffit Wustner, Jason Maltzman, Julia D. Wallin, Bruce A. TI Population pharmacokinetics and exposure-response relationship of amatuximab, an anti-mesothelin monoclonal antibody, in patients with malignant pleural mesothelioma and its application in dose selection SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Monoclonal antibody; Amatuximab; Population pharmacokinetic/pharmacodynamic modeling; Malignant pleural mesothelioma ID PHASE-I; CANCER; ADENOCARCINOMAS; QUANTIFICATION; EXPRESSION; MORAB-009; PANCREAS; THERAPY; TUMORS; LIMIT AB To characterize amatuximab pharmacokinetics (PK) and the relationship of amatuximab exposure with response in patients with unresectable malignant pleural mesothelioma (MPM) receiving amatuximab with pemetrexed and cisplatin. A nonlinear mixed effects PK model was built using data from all of the amatuximab studies conducted to date. Patients received amatuximab alone or in combination with chemotherapy. The influence of demographic, laboratory and disease characteristics on PK parameters was assessed. Exposure-response analyses explored relationships between amatuximab exposure and overall survival (OS), progression-free survival (PFS) and safety. Alternative amatuximab dosing regimens were explored with simulations using population PK and parametric survival models. Amatuximab PK was best described by a two-compartment model with parallel linear and nonlinear elimination pathways. Body weight and an antidrug antibodies reaction with the titer > 64 affected volume of distribution and clearance, respectively. Exposure-response analyses demonstrated that the amatuximab exposure (C (min)) showed a significant effect on OS (log-rank test, P = 0.0202). For patients with amatuximab C (min) above the median (38.2 mu g/mL), the median OS was 583 days (90 % CI 418 -NE). For patients with C (min) a parts per thousand currency sign 38.2 mu g/mL, the median OS was 375 days (90 % CI 325-486). The amatuximab exposure showed similar significant effect on PFS. Exposure-response analysis for adverse events did not reveal any relationship. In patients with MPM, higher amatuximab exposure in combination with chemotherapy was shown to be associated with longer OS, supporting evaluation of more frequent dosing in future trials to achieve higher exposure and subsequently longer OS. C1 [Gupta, Anubha; Hussein, Ziad] Eisai Ltd, Clin Pharmacol, European Knowledge Ctr, Mosquito Way, Hatfield AL10 9SN, Herts, England. [Wustner, Jason; Maltzman, Julia D.; Wallin, Bruce A.] Morphotek Inc, Exton, PA USA. [Hassan, Raffit] NCI, Thorac & GI Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Hussein, Z (reprint author), Eisai Ltd, Clin Pharmacol, European Knowledge Ctr, Mosquito Way, Hatfield AL10 9SN, Herts, England. EM ziad_hussein@eisai.net FU Morphotek/Eisai FX The study was funded by Morphotek/Eisai. NR 22 TC 1 Z9 1 U1 2 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 APR PY 2016 VL 77 IS 4 BP 733 EP 743 DI 10.1007/s00280-016-2984-z PG 11 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA DJ3NF UT WOS:000374111500008 PM 26898299 ER PT J AU Pressman, A Jacobson, A Eguilos, R Gelfand, A Huynh, C Hamilton, L Avins, A Bakshi, N Merikangas, K AF Pressman, Alice Jacobson, Alice Eguilos, Roderick Gelfand, Amy Huynh, Cynthia Hamilton, Luisa Avins, Andrew Bakshi, Nandini Merikangas, Kathleen TI Prevalence of migraine in a diverse communityelectronic methods for migraine ascertainment in a large integrated health plan SO CEPHALALGIA LA English DT Article DE Migraine; headache; electronic health record (EHR); electronic medical record (EMR); pain; prevalence ID ETHNIC DISPARITIES; UNITED-STATES; AMERICAN MIGRAINE; HEADACHE; BURDEN; PAIN; EPIDEMIOLOGY; RACE/ETHNICITY; COMORBIDITY; SENSITIVITY AB Introduction The growing availability of electronic health data provides an opportunity to ascertain diagnosis-specific cases via systematic methods for sample recruitment for clinical research and health services evaluation. We developed and implemented a migraine probability algorithm (MPA) to identify migraine from electronic health records (EHR) in an integrated health plan. Methods We identified all migraine outpatient diagnoses and all migraine-specific prescriptions for a five-year period (April 2008-March 2013) from the Kaiser Permanente, Northern California (KPNC) EHR. We developed and evaluated the MPA in two independent samples, and derived prevalence estimates of medically-ascertained migraine in KPNC by age, sex, and race. Results The period prevalence of medically-ascertained migraine among KPNC adults during April 2008-March 2013 was 10.3% (women: 15.5%, men: 4.5%). Estimates peaked with age in women but remained flat for men. Prevalence among Asians was half that of whites. Conclusions We demonstrate the feasibility of an EHR-based algorithm to identify cases of diagnosed migraine and determine that prevalence patterns by our methods yield results comparable to aggregate estimates of treated migraine based on direct interviews in population-based samples. This inexpensive, easily applied EHR-based algorithm provides a new opportunity for monitoring changes in migraine prevalence and identifying potential participants for research studies. C1 [Pressman, Alice; Jacobson, Alice; Eguilos, Roderick] Sutter Hlth, Res Dev & Disseminat, 2121 North Calif Blvd,Suite 310, Walnut Creek, CA 94596 USA. [Pressman, Alice; Jacobson, Alice; Huynh, Cynthia; Hamilton, Luisa; Avins, Andrew] Kaiser Permanente, Div Res, Oakland, CA USA. [Gelfand, Amy] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Avins, Andrew] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Bakshi, Nandini] Kaiser Permanente, Dept Neurol, Walnut Creek, CA USA. [Merikangas, Kathleen] NIMH, Genet Epidemiol Res Branch, Intramural Res Program, Bethesda, MD USA. RP Pressman, A (reprint author), Sutter Hlth, Res Dev & Disseminat, 2121 North Calif Blvd,Suite 310, Walnut Creek, CA 94596 USA. EM pressmar@sutterhealth.org FU National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS) [5R01NS080863-03] FX This work was supported by the National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS) (grant number 5R01NS080863-03). NR 34 TC 2 Z9 2 U1 0 U2 2 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 APR PY 2016 VL 36 IS 4 BP 325 EP 334 DI 10.1177/0333102415590242 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DJ2DS UT WOS:000374014500004 PM 26069243 ER PT J AU Yao, JH Burns, JE Forsberg, D Seitel, A Rasoulian, A Abolmaesumi, P Hammernik, K Urschler, M Ibragimov, B Korez, R Vrtovec, T Castro-Mateos, I Pozo, JM Frangi, AF Summers, RM Li, S AF Yao, Jianhua Burns, Joseph E. Forsberg, Daniel Seitel, Alexander Rasoulian, Abtin Abolmaesumi, Purang Hammernik, Kerstin Urschler, Martin Ibragimov, Bulat Korez, Robert Vrtovec, Tomaz Castro-Mateos, Isaac Pozo, Jose M. Frangi, Alejandro F. Summers, Ronald M. Li, Shuo TI A multi-center milestone study of clinical vertebral CT segmentation SO COMPUTERIZED MEDICAL IMAGING AND GRAPHICS LA English DT Article ID LUMBAR SPINE; 3D CT; IMAGES; MODEL; 3-D AB A multiple center milestone study of clinical vertebra segmentation is presented in this paper. Vertebra segmentation is a fundamental step for spinal image analysis and intervention. The first half of the study was conducted in the spine segmentation challenge in 2014 International Conference on Medical Image Computing and Computer Assisted Intervention (MICCAI) Workshop on Computational Spine Imaging (CSI 2014). The objective was to evaluate the performance of several state-of-the-art vertebra segmentation algorithms on computed tomography (CT) scans using ten training and five testing dataset, all healthy cases; the second half of the study was conducted after the challenge, where additional 5 abnormal cases are used for testing to evaluate the performance under abnormal cases. Dice coefficients and absolute surface distances were used as evaluation metrics. Segmentation of each vertebra as a single geometric unit, as well as separate segmentation of vertebra substructures, was evaluated. Five teams participated in the comparative study. The top performers in the study achieved Dice coefficient of 0.93 in the upper thoracic, 0.95 in the lower thoracic and 0.96 in the lumbar spine for healthy cases, and 0.88 in the upper thoracic, 0.89 in the lower thoracic and 0.92 in the lumbar spine for osteoporotic and fractured cases. The strengths and weaknesses of each method as well as future suggestion for improvement are discussed. This is the first multi-center comparative study for vertebra segmentation methods, which will provide an up-to-date performance milestone for the fast growing spinal image analysis and intervention. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Yao, Jianhua; Summers, Ronald M.] NIH, Imaging Biomarkers & Comp Aided Detect Lab, Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Burns, Joseph E.] Univ Calif Irvine, Dept Radiol Sci, Irvine, CA 92688 USA. [Forsberg, Daniel] Sectra, Linkoping, Sweden. [Forsberg, Daniel] Linkoping Univ, Ctr Med Image Sci & Visualizat CMIV, Linkoping, Sweden. [Seitel, Alexander; Rasoulian, Abtin; Abolmaesumi, Purang] Univ British Columbia, Dept Elect & Comp Engn, Vancouver, BC V5Z 1M9, Canada. [Hammernik, Kerstin] Graz Univ Technol, BioTechMed, Inst Comp Graph & Vis, A-8010 Graz, Austria. [Urschler, Martin] Ludwig Boltzmann Inst Clin Forens Imaging, Graz, Austria. [Ibragimov, Bulat; Korez, Robert; Vrtovec, Tomaz] Univ Ljubljana, Fac Elect Engn, Ljubljana, Slovenia. [Castro-Mateos, Isaac; Pozo, Jose M.; Frangi, Alejandro F.] Univ Sheffield, Dept Mech Engn, Ctr Computat Imaging & Simulat Technol Biomed CIS, Sheffield, S Yorkshire, England. [Li, Shuo] GE Healthcare, London, ON, Canada. [Li, Shuo] Univ Western Ontario, London, ON, Canada. RP Li, S (reprint author), GE Healthcare, London, ON, Canada.; Li, S (reprint author), Univ Western Ontario, London, ON, Canada. EM slishuo@gmail.com RI Pozo, Jose M/F-5741-2016; Pozo, Jose M/M-7604-2016; Frangi, Alejandro/C-6500-2008; OI Pozo, Jose M/0000-0002-0759-3510; Pozo, Jose M/0000-0002-0759-3510; Frangi, Alejandro/0000-0002-2675-528X; Forsberg, Daniel/0000-0003-0908-9470 NR 38 TC 5 Z9 5 U1 1 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0895-6111 EI 1879-0771 J9 COMPUT MED IMAG GRAP JI Comput. Med. Imaging Graph. PD APR PY 2016 VL 49 BP 16 EP 28 DI 10.1016/j.compmedimag.2015.12.006 PG 13 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA DJ2YP UT WOS:000374071500002 PM 26878138 ER PT J AU DeWitt, I Rauschecker, JP AF DeWitt, Iain Rauschecker, Josef P. TI Convergent evidence for the causal involvement of anterior superior temporal gyrus in auditory single-word comprehension SO CORTEX LA English DT Editorial Material ID SENTENCE COMPREHENSION; VENTRAL STREAM; WERNICKES AREA; SPEECH; APHASIA; CORTEX C1 [DeWitt, Iain] NIDCD, Brain Imaging & Modeling Sect, NIH, Bldg 10,Rm 5D39,10 Ctr Dr,MSC 1402, Bethesda, MD 20892 USA. [Rauschecker, Josef P.] Georgetown Univ, Med Ctr, Dept Neurosci, 3970 Reservoir Rd NW,New Res Bldg WP19, Washington, DC 20007 USA. RP DeWitt, I (reprint author), NIDCD, Brain Imaging & Modeling Sect, NIH, Bldg 10,Rm 5D39,10 Ctr Dr,MSC 1402, Bethesda, MD 20892 USA.; Rauschecker, JP (reprint author), Georgetown Univ, Med Ctr, Dept Neurosci, 3970 Reservoir Rd NW,New Res Bldg WP19, Washington, DC 20007 USA. EM iain.dewitt@nih.gov; rauschej@georgetown.edu FU Intramural NIH HHS; NIDCD NIH HHS [R01DC03489]; NINDS NIH HHS [R01NS052494] NR 15 TC 0 Z9 0 U1 2 U2 4 PU ELSEVIER MASSON PI MILANO PA VIA PALEOCAPA 7, 20121 MILANO, ITALY SN 0010-9452 EI 1973-8102 J9 CORTEX JI Cortex PD APR PY 2016 VL 77 BP 164 EP 166 DI 10.1016/j.cortex.2015.08.016 PG 3 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA DJ3CE UT WOS:000374081600013 PM 26387007 ER PT J AU Perez-Chanona, E Trinchieri, G AF Perez-Chanona, Ernesto Trinchieri, Giorgio TI The role of microbiota in cancer therapy SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID UNTREATED MELANOMA; GUT MICROBIOTA; T-CELLS; TUMOR; CYCLOPHOSPHAMIDE; INFLAMMATION; MODULATION; IPILIMUMAB; NIVOLUMAB; EFFICACY AB The relationship between the host and the commensal microbiota regulates physiological functions including inflammation and immunity and it has been scrutinized in the context of cancer. While viruses and bacterial species have been implicated in oncogenesis, commensal microbes also have a beneficial role in the fight against cancer. Therapy efficacy, including adoptive T cell transfer, alkylating agents and immune checkpoint blockers, relies on immunity that receives its education from the gut microbiota. In cancer therapy with immunostimulating oligonucleotides and platinum salts, the microbiota also modulates the response by priming for the release of pro-inflammatory factors and reactive oxygen species, respectively. This new information offers promising clinical possibilities of modulating cancer therapy and its toxic side effects by targeting the microbiota. C1 [Perez-Chanona, Ernesto; Trinchieri, Giorgio] NCI, Canc & Inflammat Program, Bethesda, MD 20892 USA. [Perez-Chanona, Ernesto] Leidos Biomed Res Inc, Frederick, MD 21701 USA. RP Trinchieri, G (reprint author), NCI, Canc & Inflammat Program, Bethesda, MD 20892 USA. EM trinchig@mail.nih.gov FU Intramural NIH HHS [Z01 BC010793-01] NR 32 TC 9 Z9 10 U1 10 U2 29 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 EI 1879-0372 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD APR PY 2016 VL 39 BP 75 EP 81 DI 10.1016/j.coi.2016.01.003 PG 7 WC Immunology SC Immunology GA DJ0BI UT WOS:000373866000013 PM 26820225 ER PT J AU Yang, Q Bhandoola, A AF Yang, Qi Bhandoola, Avinash TI The development of adult innate lymphoid cells SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID NATURAL-KILLER-CELLS; TRANSCRIPTION FACTOR GATA3; ROR-GAMMA-T; MURINE BONE-MARROW; FACTOR BCL11B; AIRWAY HYPERREACTIVITY; FACTOR TOX; LINEAGE; TCF-1; DIFFERENTIATION AB Innate lymphoid cells (ILC) area specialized family of effector lymphocytes that transcriptionally and functionally mirror effector subsets of T cells, but differ from T cells in that they lack clonally distributed adaptive antigen receptors. Our understanding of this family of lymphocytes is still in its infancy. In this review, we summarize current understanding and discuss recent insights into the cellular and molecular events that occur during early ILC development in adult mice. We discuss how these events overlap and diverge with the early development of adaptive T cells, and how they may influence the molecular and functional properties of mature ILC. C1 [Yang, Qi; Bhandoola, Avinash] NCI, T Cell Biol & Dev Unit, Lab Genome Integr, Ctr Canc Res, Bethesda, MD 20892 USA. [Yang, Qi] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. RP Bhandoola, A (reprint author), NCI, T Cell Biol & Dev Unit, Lab Genome Integr, Ctr Canc Res, Bethesda, MD 20892 USA. EM avinash.bhandoola@nih.gov FU Intramural Research Program of the National Institutes of Health, the National Cancer Institute; Center for Cancer Research FX A.B. is supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute, and the Center for Cancer Research. NR 87 TC 5 Z9 5 U1 1 U2 11 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 EI 1879-0372 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD APR PY 2016 VL 39 BP 114 EP 120 DI 10.1016/j.coi.2016.01.006 PG 7 WC Immunology SC Immunology GA DJ0BI UT WOS:000373866000018 PM 26871595 ER PT J AU Raza, MH Domingues, CE Webster, R Sainz, E Paris, E Rahn, R Gutierrez, J Chow, HM Mundorff, J Kang, CS Riaz, N Basra, MAR Khan, S Riazuddin, S Moretti-Ferreira, D Braun, A Drayna, D AF Raza, M. Hashim Domingues, Carlos Ef Webster, Ronald Sainz, Eduardo Paris, Emily Rahn, Rachel Gutierrez, Joanne Chow, Ho Ming Mundorff, Jennifer Kang, Chang-soo Riaz, Naveeda Basra, Muhammad A. R. Khan, Shaheen Riazuddin, Sheikh Moretti-Ferreira, Danilo Braun, Allen Drayna, Dennis TI Mucolipidosis types II and III and non-syndromic stuttering are associated with different variants in the same genes SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article ID PHOSPHOTRANSFERASE ALPHA/BETA-SUBUNITS; MUTATIONS; TWIN AB Homozygous mutations in GNPTAB and GNPTG are classically associated with mucolipidosis II (ML II) alpha/beta and mucolipidosis III (ML III) alpha/beta/gamma, which are rare lysosomal storage disorders characterized by multiple pathologies. Recently, variants in GNPTAB, GNPTG, and the functionally related NAGPA gene have been associated with non-syndromic persistent stuttering. In a worldwide sample of 1013 unrelated individuals with non-syndromic persistent stuttering we found 164 individuals who carried a rare non-synonymous coding variant in one of these three genes. We compared the frequency of these variants with those in population-matched controls and genomic databases, and their location with those reported in mucolipidosis. Stuttering subjects displayed an excess of non-synonymous coding variants compared to controls and individuals in the 1000 Genomes and Exome Sequencing Project databases. We identified a total of 81 different variants in our stuttering cases. Virtually all of these were missense substitutions, only one of which has been previously reported in mucolipidosis, a disease frequently associated with complete loss-of-function mutations. We hypothesize that rare non-synonymous coding variants in GNPTAB, GNPTG, and NAGPA may account for as much as 16% of persistent stuttering cases, and that variants in GNPTAB and GNPTG are at different sites and may in general, cause less severe effects on protein function than those in ML II alpha/beta and ML III alpha/beta/gamma. C1 [Raza, M. Hashim; Domingues, Carlos Ef; Sainz, Eduardo; Paris, Emily; Rahn, Rachel; Gutierrez, Joanne; Chow, Ho Ming; Kang, Chang-soo; Braun, Allen; Drayna, Dennis] Natl Inst Deafness & Other Commun Disorders, Lab Commun Disorders, NIH, Porter Neurosci Res Ctr, 35A Convent Dr,Room 1F-127, Bethesda, MD 20892 USA. [Webster, Ronald; Mundorff, Jennifer] Hollins Commun Res Inst, Roanoke, VA USA. [Riaz, Naveeda] Int Islamic Univ, Dept Bioinformat & Biotechnol, Islamabad, Pakistan. [Basra, Muhammad A. R.; Khan, Shaheen; Riazuddin, Sheikh] Univ Hlth Sci, Allama Iqbal Med Coll, Dept Mol Biol, Lahore, Pakistan. [Moretti-Ferreira, Danilo] Sao Paulo State Univ, Dept Genet, Botucatu, SP, Brazil. [Paris, Emily] Stanford Univ, Dept Civil & Environm Engn, Stanford, CA 94305 USA. [Kang, Chang-soo] Sungshin Womens Univ, Dept Biol & Chem, Seoul, South Korea. [Basra, Muhammad A. R.] Univ Punjab, Inst Chem, Lahore, Pakistan. RP Drayna, D (reprint author), Natl Inst Deafness & Other Commun Disorders, Lab Commun Disorders, NIH, Porter Neurosci Res Ctr, 35A Convent Dr,Room 1F-127, Bethesda, MD 20892 USA. EM drayna@nidcd.nih.gov FU NIDCD intramural grant [Z1A-000046-14] FX This research was supported by the NIDCD intramural grant # Z1A-000046-14. We thank the Stuttering Foundation of America, the National Stuttering Association, the British Stammering Association, and the Speak Clear Association of Cameroon for assistance. We thank Linda Booth of HCRI for assistance in subject enrollment and sampling, and Drs Robert Morell and Thomas Friedman for helpful comments on the manuscript. We are particularly grateful to the subjects who participated in this study. NR 15 TC 5 Z9 5 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 EI 1476-5438 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD APR PY 2016 VL 24 IS 4 BP 529 EP 534 DI 10.1038/ejhg.2015.154 PG 6 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA DJ3RZ UT WOS:000374124800008 PM 26130485 ER PT J AU Boikos, SA Xekouki, P Fumagalli, E Faucz, FR Raygada, M Szarek, E Ball, E Kim, SY Miettinen, M Helman, LJ Carney, JA Pacak, K Stratakis, CA AF Boikos, Sosipatros A. Xekouki, Paraskevi Fumagalli, Elena Faucz, Fabio R. Raygada, Margarita Szarek, Eva Ball, Evan Kim, Su Young Miettinen, Markku Helman, Lee J. Carney, J. Aidan Pacak, Karel Stratakis, Constantine A. TI Carney triad can be (rarely) associated with germline succinate dehydrogenase defects SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GASTROINTESTINAL STROMAL TUMORS; PDGFRA MUTATIONS; SDH MUTATIONS; LACKING KIT; PARAGANGLIOMA; PHEOCHROMOCYTOMA; GENETICS; STRATAKIS AB Carney triad, the association of paragangliomas/pheochromocytomas, gastrointestinal stromal tumors and pulmonary chondromas, is a sporadic condition that is significantly more frequent in females; its genetic etiology remains unknown. Carney triad is distinct from the dyad of paragangliomas/pheochromocytomas and gastrointestinal stromal tumors, known as Carney-Stratakis syndrome, which is inherited in an autosomal-dominant manner and is almost always caused by succinate dehydrogenase subunit mutations. In the present study, we investigated the largest cohort of Carney triad patients that is available internationally: 63 unrelated patients. Six patients (9.5%) were found to have germline variants in the SDHA, SDHB or SDHC genes. All six patients, except one, had multifocal gastrointestinal stromal tumors, chondromas and/or paragangliomas. A patient with Carney triad and SDHC variant had a ganglioneuroma. One of the patients with Carney triad and SDHB mutation had a nephew with the same sequence defect, who developed a neuroblastoma. Other relatives, carriers of the identified SDHA, SDHB or SDHC mutations, have not developed any of the components of Carney triad or Carney-Stratakis syndrome. None of the other 57 Carney triad patients had any genomic defects of SDHA, SDHB or SDHC genes. We conclude that, in rare occasions, Carney triad can be allelic to Carney-Stratakis syndrome. Although for the vast majority of patients with Carney triad the causative defect(s) remain(s) unknown, testing for SDHA, SDHB or SDHC variations should be offered, as carriers may develop isolated paragangliomas/pheochromocytomas and occasionally other tumors. C1 [Boikos, Sosipatros A.; Xekouki, Paraskevi; Faucz, Fabio R.; Raygada, Margarita; Szarek, Eva; Ball, Evan; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet SEGEN, Program Dev Endocrinol & Genet PDEGEN, NIH, Bethesda, MD 20892 USA. [Fumagalli, Elena] Ist Nazl Tumori, Dept Canc Med, Adult Mesenchymal Tumour & Rare Canc Med Oncol Un, Via Venezian 1, I-20133 Milan, Italy. [Kim, Su Young; Helman, Lee J.] NCI, POB, NIH, Bethesda, MD 20892 USA. [Miettinen, Markku] NCI, Dept Diagnost Pathol, NIH, Bethesda, MD 20892 USA. [Carney, J. Aidan] Mayo Clin, Pathol Lab, Rochester, MN USA. [Pacak, Karel] NICHD, Program Reprod & Adult Endocrinol, Sect Neuroedocrinol SNE, NIH, Bethesda, MD USA. [Boikos, Sosipatros A.] Virginia Commonwealth Univ, Massey Canc Ctr, Div Hematol Oncol & Palliat Care, Sarcoma & Rare Tumors Program, Richmond, VA USA. RP Faucz, FR; Stratakis, CA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet SEGEN, Program Dev Endocrinol & Genet PDEGEN, NIH,NIH Clin Res Ctr, 1 0 Ctr Dr,Bldg 10,Room 1-3330,MSC1103, Bethesda, MD 20892 USA. EM fabio.faucz@nih.gov; stratakc@mail.nih.gov RI Fumagalli, Elena Rosa/E-2065-2017; OI Fumagalli, Elena Rosa/0000-0003-4814-7637; Miettinen, Markku/0000-0002-3282-8107 FU intramural research program of NICHD, NIH FX We thank the patients and their families for participating in our studies. This work was supported by the intramural research program of NICHD, NIH. NR 25 TC 5 Z9 5 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 EI 1476-5438 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD APR PY 2016 VL 24 IS 4 BP 569 EP 573 DI 10.1038/ejhg.2015.142 PG 5 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA DJ3RZ UT WOS:000374124800014 PM 26173966 ER PT J AU Park, JH Zhuang, J Li, J Hwang, PM AF Park, Ji-Hoon Zhuang, Jie Li, Jie Hwang, Paul M. TI p53 as guardian of the mitochondrial genome SO FEBS LETTERS LA English DT Review DE DNA repair; mitochondria; mtDNA; p53; reactive oxygen species; translocation ID BASE EXCISION-REPAIR; TUMOR-SUPPRESSOR P53; PARKIN-MEDIATED MITOPHAGY; COLORECTAL-CANCER CELLS; LI-FRAUMENI-SYNDROME; TRANSCRIPTION FACTOR; DNA-DAMAGE; HUMAN-DISEASE; MOUSE MODEL; PROTEIN AB Participating in the repair of nuclear DNA is one mechanism by which p53 suppresses tumorigenesis, but there is growing evidence that p53 also helps maintain the mitochondrial genome through its translocation into mitochondria and interactions with mtDNA repair proteins. Because of the susceptibility of mtDNA to oxidative damage and replication errors, it is vital to protect mtDNA genomic stability to preserve health and fitness. Here, we focus on reviewing the evidence for the involvement of p53 in maintaining the integrity of mtDNA through its activities in both the nucleus and the mitochondria. C1 [Park, Ji-Hoon; Zhuang, Jie; Li, Jie; Hwang, Paul M.] NHLBI, Ctr Mol Med, NIH, Bldg 10 CRC,Rm 5-5330, Bethesda, MD 20892 USA. RP Hwang, PM (reprint author), NHLBI, Ctr Mol Med, NIH, Bldg 10 CRC,Rm 5-5330, Bethesda, MD 20892 USA. EM hwangp@mail.nih.gov FU Korean Biomedical Scientist Fellowship Program (KBSFP); intramural program of National Heart, Lung and Blood Institute (NHLBI), NIH FX We thank William M. Kamp, Ju-Gyeong Kang, and Ping-yuan Wang for helpful discussions and critical review of the manuscript. J.H.P. is a recipient of the Korean Biomedical Scientist Fellowship Program (KBSFP) administered by the Korea Research Institute of Bioscience and Biotechnology (KRIBB). This work was supported by the intramural program of National Heart, Lung and Blood Institute (NHLBI), NIH. NR 98 TC 8 Z9 8 U1 5 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-5793 EI 1873-3468 J9 FEBS LETT JI FEBS Lett. PD APR PY 2016 VL 590 IS 7 BP 924 EP 934 DI 10.1002/1873-3468.12061 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA DJ0OW UT WOS:000373904800004 PM 26780878 ER PT J AU Vrljicak, P Tao, SJ Varshney, GK Quach, HNB Joshi, A LaFave, MC Burgess, SM Sampath, K AF Vrljicak, Pavle Tao, Shijie Varshney, Gaurav K. Quach, Helen Ngoc Bao Joshi, Adita LaFave, Matthew C. Burgess, Shawn M. Sampath, Karuna TI Genome-Wide Analysis of Transposon and Retroviral Insertions Reveals Preferential Integrations in Regions of DNA Flexibility SO G3-GENES GENOMES GENETICS LA English DT Article DE transposon; Ac; Ds; genome-wide analysis; integrations; gene targeting; genome engineering; functional genomics; Tol2; retrovirus; MMLV; mouse; ES cells; vertebrate genomes; zebrafish ID LEUKEMIA-VIRUS INTEGRATION; TRANSCRIPTION START SITES; LARGE GENE LISTS; SLEEPING-BEAUTY; ZEBRAFISH GENOME; MLV INTEGRATION; ELEMENTS; MUTAGENESIS; SELECTION; EVOLUTION AB DNA transposons and retroviruses are important transgenic tools for genome engineering. An important consideration affecting the choice of transgenic vector is their insertion site preferences. Previous large-scale analyses of Ds transposon integration sites in plants were done on the basis of reporter gene expression or germ-line transmission, making it difficult to discern vertebrate integration preferences. Here, we compare over 1300 Ds transposon integration sites in zebrafish with Tol2 transposon and retroviral integration sites. Genome-wide analysis shows that Ds integration sites in the presence or absence of marker selection are remarkably similar and distributed throughout the genome. No strict motif was found, but a preference for structural features in the target DNA associated with DNA flexibility (Twist, Tilt, Rise, Roll, Shift, and Slide) was observed. Remarkably, this feature is also found in transposon and retroviral integrations in maize and mouse cells. Our findings show that structural features influence the integration of heterologous DNA in genomes, and have implications for targeted genome engineering. C1 [Vrljicak, Pavle; Sampath, Karuna] Univ Warwick, Warwick Med Sch, Div Biomed Sci, Coventry CV4 7AJ, W Midlands, England. [Tao, Shijie; Quach, Helen Ngoc Bao; Joshi, Adita] Natl Univ Singapore, Temasek Life Sci Lab, Singapore 117604, Singapore. [Varshney, Gaurav K.; LaFave, Matthew C.; Burgess, Shawn M.] NHGRI, Bethesda, MD 20892 USA. RP Sampath, K (reprint author), Univ Warwick, Div Biomed Sci, Warwick Med Sch, Biomed Cell Biol, Gibbet Hill Rd, Coventry CV4 7AJ, W Midlands, England. EM K.Sampath@warwick.ac.uk OI LaFave, Matthew/0000-0001-9165-041X; Varshney, Gaurav K./0000-0002-0429-1904 FU Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health; Warwick Medical School FX We thank the Sampath laboratory for discussions and suggestions; H. Woodland and L. Sivashanmugam for suggestions to improve the manuscript. G.K.V., M.C.L., and S.M.B. were supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. K.S. and P.V. are supported by Warwick Medical School. NR 70 TC 1 Z9 1 U1 2 U2 6 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 APR 1 PY 2016 VL 6 IS 4 BP 805 EP 817 DI 10.1534/g3.115.026849 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA DJ2VI UT WOS:000374062800004 PM 26818075 ER PT J AU Camargo, MC Bowlby, R Chu, A Pedamallu, CS Thorsson, V Elmore, S Mungall, AJ Bass, AJ Gulley, ML Rabkin, CS AF Camargo, M. Constanza Bowlby, Reanne Chu, Andy Pedamallu, Chandra Sekhar Thorsson, Vesteinn Elmore, Sandra Mungall, Andrew J. Bass, Adam J. Gulley, Margaret L. Rabkin, Charles S. TI Validation and calibration of next-generation sequencing to identify Epstein-Barr virus-positive gastric cancer in The Cancer Genome Atlas SO GASTRIC CANCER LA English DT Article DE Stomach cancer; Molecular subtypes; EBV; TCGA ID NASOPHARYNGEAL CARCINOMA; MICRORNAS AB The Epstein-Barr virus (EBV)-positive subtype of gastric adenocarcinoma is conventionally identified by in situ hybridization (ISH) for viral nucleic acids, but next-generation sequencing represents a potential alternative. We therefore determined normalized EBV read counts by whole-genome, whole-exome, mRNA and miRNA sequencing for 295 fresh-frozen gastric tumor samples. Formalin-fixed, paraffin-embedded tissue sections were retrieved for ISH confirmation of 13 high-EBV and 11 low-EBV cases. In pairwise comparisons, individual samples were either concordantly high or concordantly low by all genomic methods for which data were available. Empiric cutoffs of sequencing counts identified 26 (9 %) tumors as EBV positive. EBV positivity or negativity by molecular testing was confirmed by EBER-ISH in all but one tumor evaluated by both approaches (kappa = 0.91). EBV-positive gastric tumors can be accurately identified by quantifying viral sequences in genomic data. Simultaneous analyses of human and viral DNA, mRNA and miRNA could streamline tumor profiling for clinical care and research. C1 [Camargo, M. Constanza; Rabkin, Charles S.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Bowlby, Reanne; Chu, Andy; Mungall, Andrew J.] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 4S6, Canada. [Pedamallu, Chandra Sekhar] MIT, Eli & Edythe L Broad Inst, Cambridge, MA 02142 USA. [Pedamallu, Chandra Sekhar] Harvard Univ, Cambridge, MA 02142 USA. [Thorsson, Vesteinn] Inst Syst Biol, Seattle, WA 98109 USA. [Elmore, Sandra; Gulley, Margaret L.] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. [Elmore, Sandra; Gulley, Margaret L.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Pedamallu, Chandra Sekhar; Bass, Adam J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. RP Rabkin, CS (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM rabkinc@mail.nih.gov RI Camargo, M. Constanza/R-9891-2016 FU Intramural Research Program; US National Institutes of Health [5U24CA143799, 5U24CA143835, 5U24CA143840, 5U24CA143843, 5U24CA143845, 5U24CA143848, 5U24CA143858, 5U24CA143866, 5U24CA143867, 5U24CA143882, 5U24CA143883, 5U24CA144025, U54HG003067, U54HG003079, U54HG003273, P30CA16672] FX This work was supported by the Intramural Research Program and the following grants from the US National Institutes of Health: 5U24CA143799, 5U24CA143835, 5U24CA143840, 5U24CA143843, 5U24CA143845, 5U24CA143848, 5U24CA143858, 5U24CA143866, 5U24CA143867, 5U24CA143882, 5U24CA143883, 5U24CA144025, U54HG003067, U54HG003079, U54HG003273 and P30CA16672. NR 17 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1436-3291 EI 1436-3305 J9 GASTRIC CANCER JI Gastric Cancer PD APR PY 2016 VL 19 IS 2 BP 676 EP 681 DI 10.1007/s10120-015-0508-x PG 6 WC Oncology; Gastroenterology & Hepatology SC Oncology; Gastroenterology & Hepatology GA DI8IW UT WOS:000373745700042 PM 26095338 ER PT J AU Kwak, JT Sankineni, S Xu, S Turkbey, B Choyke, PL Pinto, PA Merino, M Wood, BJ AF Kwak, Jin Tae Sankineni, Sandeep Xu, Sheng Turkbey, Baris Choyke, Peter L. Pinto, Peter A. Merino, Maria Wood, Bradford J. TI Correlation of magnetic resonance imaging with digital histopathology in prostate SO INTERNATIONAL JOURNAL OF COMPUTER ASSISTED RADIOLOGY AND SURGERY LA English DT Review DE Prostate; Histopathology; Image registration; Machine learning ID INTEROBSERVER REPRODUCIBILITY; CANCER; MR; CLASSIFICATION; CARCINOMA; SPECIMENS; DENSITY; ADC; T2 AB We propose a systematic approach to correlate MRI and digital histopathology in prostate. T2-weighted (T2W) MRI and diffusion-weighted imaging (DWI) are acquired, and a patient-specific mold (PSM) is designed from the MRI. Following prostatectomy, a whole mount tissue specimen is placed in the PSM and sectioned, ensuring that tissue blocks roughly correspond to MRI slices. Rigid body and thin plate spline deformable registration attempt to correct deformation during image acquisition and tissue preparation and achieve a more complete one-to-one correspondence between MRIs and tissue sections. Each tissue section is stained with hematoxylin and eosin and segmented by adopting a machine learning approach. Utilizing this tissue segmentation and image registration, the density of cellular and tissue components (lumen, nucleus, epithelium, and stroma) is estimated per MR voxel, generating density maps for the whole prostate. This study was approved by the local IRB, and informed consent was obtained from all patients. Registration of tissue specimens and MRIs was aided by the PSM and subsequent image registration. Tissue segmentation was performed using a machine learning approach, achieving 0.98 AUCs for lumen, nucleus, epithelium, and stroma. Examining the density map of tissue components, significant differences were observed between cancer, benign peripheral zone, and benign prostatic hyperplasia (p value 5e2). Similarly, the signal intensity of the corresponding areas in both T2W MRI and DWI was significantly different (p value 1e10). The proposed approach is able to correlate MRI and digital histopathology of the prostate and is promising as a potential tool to facilitate a more cellular and zonal tissue-based analysis of prostate MRI, based upon a correlative histopathology perspective. C1 [Kwak, Jin Tae; Xu, Sheng; Wood, Bradford J.] NIH, Ctr Intervent Oncol, Bethesda, MD 20892 USA. [Sankineni, Sandeep; 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. [Merino, Maria] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Kwak, JT; Wood, BJ (reprint author), NIH, Ctr Intervent Oncol, Bethesda, MD 20892 USA. EM jintae.kwak@nih.gov; bwood@cc.nih.gov NR 24 TC 1 Z9 1 U1 3 U2 6 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1861-6410 EI 1861-6429 J9 INT J COMPUT ASS RAD JI Int. J. Comput. Assist. Radiol. Surg. PD APR PY 2016 VL 11 IS 4 BP 657 EP 666 DI 10.1007/s11548-015-1287-x PG 10 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging; Surgery SC Engineering; Radiology, Nuclear Medicine & Medical Imaging; Surgery GA DJ3NT UT WOS:000374113100014 PM 26337442 ER PT J AU Coelho, SG Patri, AK Wokovich, AM McNeil, SE Howard, PC Miller, SA AF Coelho, Sergio G. Patri, Anil K. Wokovich, Anna M. McNeil, Scott E. Howard, Paul C. Miller, Sharon A. TI Repetitive Application of Sunscreen Containing Titanium Dioxide Nanoparticles on Human Skin SO JAMA DERMATOLOGY LA English DT Letter ID PERCUTANEOUS-ABSORPTION; STRATUM-CORNEUM; TIO2 C1 [Coelho, Sergio G.] NCI, Cell Biol Lab, NIH, Bldg 37,Room 2132, Bethesda, MD 20892 USA. [Patri, Anil K.; McNeil, Scott E.] Frederick Natl Lab Canc Res, Nanotechnol Characterizat Lab, Canc Res Technol Program, Leidos Biomed Res Inc, Frederick, MD USA. [Wokovich, Anna M.] US FDA, Div Pharmaceut Anal, Off Testing & Res, Off Pharmaceut Sci,Ctr Drug Evaluat & Res, St Louis, MO USA. [Howard, Paul C.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Miller, Sharon A.] US FDA, Div Radiol Hlth, Off In Vitro Diagnost & Radiol Hlth, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Coelho, SG (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37,Room 2132, Bethesda, MD 20892 USA. EM sergio.coelho@fda.hhs.gov RI Nanotechnology Characterization Lab, NCL/K-8454-2012 NR 6 TC 1 Z9 1 U1 4 U2 8 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6068 EI 2168-6084 J9 JAMA DERMATOL JI JAMA Dermatol. PD APR PY 2016 VL 152 IS 4 BP 470 EP 472 DI 10.1001/jamadermatol.2015.5944 PG 3 WC Dermatology SC Dermatology GA DJ0TF UT WOS:000373916600024 PM 26913928 ER PT J AU Traynor, BJ Abramzon, YA AF Traynor, Bryan J. Abramzon, Yevgeniya A. TI To Dement or Not to Dement, That Is the Question SO JAMA NEUROLOGY LA English DT Editorial Material ID AMYOTROPHIC-LATERAL-SCLEROSIS; APOLIPOPROTEIN-E; HEXANUCLEOTIDE REPEAT; C9ORF72; ALS; ASSOCIATION; EXPANSION; DISEASE; ONSET; FTD C1 [Traynor, Bryan J.; Abramzon, Yevgeniya A.] NIA, Neuromuscular Dis Res Sect, Neurogenet Lab, NIH, 35 Convent Dr,Room 1A-213, Bethesda, MD 20892 USA. [Traynor, Bryan J.] Johns Hopkins Univ, Dept Neurol, Brain Sci Inst, Baltimore, MD 21218 USA. [Abramzon, Yevgeniya A.] UCL, Inst Neurol, Sobell Dept Motor Neurosci & Movement Disorders, London, England. RP Traynor, BJ (reprint author), NIA, Neuromuscular Dis Res Sect, Neurogenet Lab, NIH, 35 Convent Dr,Room 1A-213, Bethesda, MD 20892 USA. EM traynorb@mail.nih.gov FU Intramural NIH HHS; NIA NIH HHS [Z01-AG000949-02] NR 14 TC 0 Z9 0 U1 2 U2 2 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 APR PY 2016 VL 73 IS 4 BP 383 EP 384 DI 10.1001/jamaneurol.2015.4984 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA DI8YV UT WOS:000373789400007 PM 26903123 ER PT J AU Maeda, Y Goto, K Honda, Y Kuroda, N Sentani, K Yasui, W Hayashi, T Teishima, J Matsubara, A Nakamura, Y Toyota, N Iida, M Awai, K AF Maeda, Yoko Goto, Keisuke Honda, Yukiko Kuroda, Naoto Sentani, Kazuhiro Yasui, Wataru Hayashi, Tetsutaro Teishima, Jun Matsubara, Akio Nakamura, Yuko Toyota, Naoyuki Iida, Makoto Awai, Kazuo TI A case of tubulocystic carcinoma of the kidney with aggressive features SO JAPANESE JOURNAL OF RADIOLOGY LA English DT Article DE Tubulocystic carcinoma; Kidney; Aggressive; CT; MRI ID RENAL-CELL CARCINOMA; CLASSIFICATION; PATHOLOGY; PAPILLARY; TUMORS AB Tubulocystic carcinoma of the kidney is rare and typically indolent. Our case involved an aggressive tubulocystic carcinoma as well as the radiological confirmation of its relation to papillary renal cell carcinoma. A 46-year-old male presented with renal multiloculated cysts with a solid part. On computed tomography and magnetic resonance imaging, the solid part showed the characteristics of papillary renal cell carcinoma. Contrast enhancement of the solid part was fluffy and sparse because of the coexistence of cysts. Perirenal fat invasion resulted in exophytic cysts, and renal-hilar cystic lymph node metastasis existed. The histopathological diagnosis was tubulocystic carcinoma associated with areas of papillary renal cell carcinoma and poorly differentiated carcinoma with metastasis. Our case suggests that the solid part enhancement of tubulocystic carcinoma tends to be fluffy and sparse, and exophytic cysts and cystic lymph nodes may show radiologically aggressive findings. C1 [Maeda, Yoko; Honda, Yukiko; Nakamura, Yuko; Iida, Makoto; Awai, Kazuo] Hiroshima Univ, Inst Biomed & Hlth, Dept Diagnost Radiol, Minami Ku, 1-2-3 Kasumi, Hiroshima 7340037, Japan. [Goto, Keisuke; Sentani, Kazuhiro; Yasui, Wataru] Hiroshima Univ, Inst Biomed & Hlth Sci, Dept Mol Pathol, Minami Ku, 1-2-3 Kasumi, Hiroshima 7340037, Japan. [Kuroda, Naoto] Kochi Red Cross Hosp, Dept Diagnost Pathol, 2-13-51 Shin Honmachi, Kochi 7808562, Japan. [Goto, Keisuke; Hayashi, Tetsutaro; Teishima, Jun; Matsubara, Akio] Hiroshima Univ, Inst Biomed & Hlth Sci, Dept Urol, Minami Ku, 1-2-3 Kasumi, Hiroshima 7340037, Japan. [Nakamura, Yuko] NCI, Mol Imaging Program, Ctr Canc Res, NIH, 9000 Kville Pike,Bldg 10,B3B47, Bethesda, MD 20892 USA. [Maeda, Yoko; Toyota, Naoyuki] Natl Hosp Org, Kure Med Ctr, Dept Diagnost Radiol, 3-1 Aoyama Cho, Kure, Hiroshima 7370023, Japan. RP Honda, Y (reprint author), Hiroshima Univ, Inst Biomed & Hlth, Dept Diagnost Radiol, Minami Ku, 1-2-3 Kasumi, Hiroshima 7340037, Japan. EM honday@hiroshima-u.ac.jp OI Honda, Yukiko/0000-0002-2291-0502 NR 14 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1867-1071 EI 1867-108X J9 JPN J RADIOL JI Jpn. J. Radiol. PD APR PY 2016 VL 34 IS 4 BP 307 EP 311 DI 10.1007/s11604-016-0525-7 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DJ3JE UT WOS:000374100200008 PM 26830902 ER PT J AU Wood, RA Kim, JS Lindblad, R Nadeau, K Henning, AK Dawson, P Plaut, M Sampson, HA AF Wood, Robert A. Kim, Jennifer S. Lindblad, Robert Nadeau, Kari Henning, Alice K. Dawson, Peter Plaut, Marshall Sampson, Hugh A. TI A randomized, double-blind, placebo-controlled study of omalizumab combined with oral immunotherapy for the treatment of cow's milk allergy SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Milk allergy; oral immunotherapy; omalizumab; desensitization; sustained unresponsiveness; double-blind; placebo-controlled trial; dose-related adverse reactions ID FC-EPSILON-RI; FOOD ALLERGY; TOLERANCE INDUCTION; NATURAL-HISTORY; PEANUT ALLERGY; FOLLOW-UP; IGE; CHILDREN; CELL; DESENSITIZATION AB Background: Although studies of oral immunotherapy (OIT) for food allergy have shown promise, treatment is frequently complicated by adverse reactions and, even when successful, has limited long-term efficacy because benefits usually diminish when treatment is discontinued. Objective: We sought to examine whether the addition of omalizumab to milk OIT reduces treatment-related reactions, improves outcomes, or both. Methods: This was a double-blind, placebo-controlled trial with subjects randomized to omalizumab or placebo. Open-label milk OIT was initiated after 4 months of omalizumab/placebo with escalation to maintenance over 22 to 40 weeks, followed by daily maintenance dosing through month 28. At month 28, omalizumab was discontinued, and subjects passing an oral food challenge (OFC) continued OIT for 8 weeks, after which OIT was discontinued with rechallenge at month 32 to assess sustained unresponsiveness (SU). Results: Fifty-seven subjects (7-32 years) were randomized, with no significant baseline differences in age, milk-specific IgE levels, skin test results, or OFC results. At month 28, 24 (88.9%) omalizumab-treated subjects and 20 (71.4%) placebo-treated subjects passed the 10-g "desensitization" OFC (P = .18). At month 32, SU was demonstrated in 48.1% in the omalizumab group and 35.7% in the placebo group (P = .42). Adverse reactions were markedly reduced during OIT escalation in omalizumab-treated subjects for percentages of doses per subject provoking symptoms (2.1% vs 16.1%, P = .0005), dose-related reactions requiring treatment (0.0% vs 3.8%, P = .0008), and doses required to achieve maintenance (198 vs 225, P = .008). Conclusions: In this first randomized, double-blind, placebo-controlled trial of omalizumab in combination with food OIT, we found significant improvements in measurements of safety but not in outcomes of efficacy (desensitization and SU). C1 [Wood, Robert A.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Kim, Jennifer S.] NorthShore Univ HealthSyst, Evanston, IL USA. [Lindblad, Robert; Henning, Alice K.; Dawson, Peter] EMMES Corp, Rockville, MD USA. [Nadeau, Kari] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Plaut, Marshall] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Sampson, Hugh A.] Icahn Sch Med Mt Sinai, 1425 Madison Ave,Box 1089, New York, NY 10029 USA. RP Sampson, HA (reprint author), Icahn Sch Med Mt Sinai, 1425 Madison Ave,Box 1089, New York, NY 10029 USA. EM hugh.sampson@mssm.edu FU National Institute of Allergy and Infectious Diseases [AI-44236]; National Center for Advancing Translational Sciences, National Institutes of Health [RR-026134, UL1 TR 001079]; Food Allergy Research and Education FX Omalizumab (Xolair) and omalizumab placebo for this trial were kindly provided by Genentech. The study was supported by grant AI-44236 from the National Institute of Allergy and Infectious Diseases and RR-026134 (Mount Sinai) and UL1 TR 001079 (Johns Hopkins) from the National Center for Advancing Translational Sciences, National Institutes of Health; and a supplemental grant from Food Allergy Research and Education. NR 35 TC 20 Z9 20 U1 6 U2 13 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 APR PY 2016 VL 137 IS 4 BP 1103 EP + DI 10.1016/j.jaci.2015.10.005 PG 19 WC Allergy; Immunology SC Allergy; Immunology GA DI2TG UT WOS:000373351200016 PM 26581915 ER PT J AU Jones, SM Burks, AW Keet, C Vickery, BP Scurlock, AM Wood, RA Liu, AH Sicherer, SH Henning, AK Lindblad, RW Dawson, P Berin, C Fleischer, DM Leung, DYM Plaut, M Sampson, HA AF Jones, Stacie M. Burks, A. Wesley Keet, Corinne Vickery, Brian P. Scurlock, Amy M. Wood, Robert A. Liu, Andrew H. Sicherer, Scott H. Henning, Alice K. Lindblad, Robert W. Dawson, Peter Berin, Cecilia Fleischer, David M. Leung, Donald Y. M. Plaut, Marshall Sampson, Hugh A. CA CoFAR TI Long-term treatment with egg oral immunotherapy enhances sustained unresponsiveness that persists after cessation of therapy SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Egg allergy; food allergy; oral immunotherapy; desensitization; sustained unresponsiveness; immune tolerance; IgE; follow-up ID COWS MILK ALLERGY; DOUBLE-BLIND; PEANUT ALLERGY; FOOD ALLERGY; NATURAL-HISTORY; FOLLOW-UP; CHILDREN; PREVALENCE; DESENSITIZATION AB Background: We previously reported the results of a randomized placebo-controlled study of egg oral immunotherapy (eOIT) in which 27.5% of subjects achieved sustained unresponsiveness (SU) after 2 years. Here we report the results of treatment through 4 years and long-term follow-up. Objective: We sought to evaluate the efficacy and safety of eOIT in participants treated up to 4 years. Methods: Children with egg allergy (5-18 years old) received eOIT (n = 40) for up to 4 years or placebo (n = 15) for 1 year or less. The key outcome was the percentage of subjects achieving SU by year 4. Safety and immunologic assessments were performed, and long-term follow-up questionnaires (LFQs) were administered after study conclusion (LFQ-1) and 1 year later (LFQ-2). Results: Of 40 eOIT-treated subjects, 20 (50.0%) of 40 demonstrated SU by year 4. For those subjects still dosing during years 3 and 4, mild symptoms were present in 12 (54.5%) of 22 subjects. At the time of the LFQ, more subjects receiving eOIT (LFQ-1, 23/34 [68%]; LFQ-2, 21/33 [64%]) were consuming unbaked and baked egg versus placebo (LFQ-1, 2/11 [18%], P = .006; LFQ-2, 3/12 [25%], P = .04). Of subjects achieving SU, 18 (90%) of 20 completed the LFQ, with 18 (100%) of 18 reporting consumption of all forms of egg. When compared with subjects not achieving SU, subjects achieving SU had higher IgG4 values (P = .001) and lower egg skin prick test scores (P = .0002) over time and a lower median baseline ratio of egg-specific IgE to total IgE (1.1% vs 2.7%, P = .04). Conclusions: SU after eOIT is enhanced with longer duration of therapy and increases the likelihood of tolerating unbaked egg in the diet. C1 [Jones, Stacie M.; Scurlock, Amy M.] Univ Arkansas Med Sci, Dept Pediat, 13 Childrens Way,Slot 512-13, Little Rock, AR 72202 USA. [Jones, Stacie M.; Scurlock, Amy M.] Arkansas Childrens Hosp, 800 Marshall St, Little Rock, AR 72202 USA. [Burks, A. Wesley; Vickery, Brian P.] Univ N Carolina, Dept Pediat, Chapel Hill, NC USA. [Keet, Corinne; Wood, Robert A.] Johns Hopkins Sch Med, Dept Pediat, Baltimore, MD USA. [Liu, Andrew H.; Fleischer, David M.; Leung, Donald Y. M.] Natl Jewish Hlth, Dept Pediat, Denver, CO USA. [Sicherer, Scott H.; Berin, Cecilia; Sampson, Hugh A.] Icahn Sch Med Mt Sinai, Dept Pediat, New York, NY 10029 USA. [Henning, Alice K.; Lindblad, Robert W.; Dawson, Peter] EMMES Corp, Rockville, MD USA. [Plaut, Marshall] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Jones, SM (reprint author), Univ Arkansas Med Sci, Dept Pediat, 13 Childrens Way,Slot 512-13, Little Rock, AR 72202 USA. EM JonesStacieM@uams.edu FU National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID) [U19AI066738, U01AI066560]; National Center for Research Resources (NCRR), a component of the NIH [UL1 TR000154, UL1 TR000067, UL1 TR000039, UL1 TR000083, UL1 TR000424] 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 grants UL1 TR000154 (National Jewish), UL1 TR000067 (Mount Sinai), UL1 TR000039 (Arkansas), UL1 TR000083 (North Carolina), and UL1 TR000424 (Johns Hopkins) from the National Center for Research Resources (NCRR), a component of the NIH. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the NCRR or NIH. NR 31 TC 5 Z9 5 U1 2 U2 6 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 APR PY 2016 VL 137 IS 4 BP 1117 EP + DI 10.1016/j.jaci.2015.12.1316 PG 21 WC Allergy; Immunology SC Allergy; Immunology GA DI2TG UT WOS:000373351200018 PM 26924470 ER PT J AU Gil-Krzewska, A Wood, SM Murakami, Y Nguyen, V Chiang, SCC Cullinane, AR Peruzzi, G Gahl, WA Coligan, JE Introne, WJ Bryceson, YT Krzewski, K AF Gil-Krzewska, Aleksandra Wood, Stephanie M. Murakami, Yousuke Victoria Nguyen Chiang, Samuel C. C. Cullinane, Andrew R. Peruzzi, Giovanna Gahl, William A. Coligan, John E. Introne, Wendy J. Bryceson, Yenan T. Krzewski, Konrad TI Chediak-Higashi syndrome: Lysosomal trafficking regulator domains regulate exocytosis of lytic granules but not cytokine secretion by natural killer cells SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Chediak-Higashi syndrome; lysosomal trafficking regulator; natural killer cell; cytotoxicity; cytotoxic lymphocyte; lysosomes; lytic granules; exocytosis; immune deficiency ID NK-CELL; DISEASE; FUSION; LYST; CYTOTOXICITY; GENE; BIOGENESIS; PHENOTYPE; HUMANS; DEFECT AB Background: Mutations in lysosomal trafficking regulator (LYST) cause Chediak-Higashi syndrome (CHS), a rare immunodeficiency with impaired cytotoxic lymphocyte function, mainly that of natural killer (NK) cells. Our understanding of NK cell function deficiency in patients with CHS and how LYST regulates lytic granule exocytosis is very limited. Objective: We sought to delineate cellular defects associated with LYST mutations responsible for the impaired NK cell function seen in patients with CHS. Methods: We analyzed NK cells from patients with CHS with missense mutations in the LYSTARM/HEAT(armadillo/huntingtin, elongation factor 3, protein phosphatase 2A, and the yeast kinase TOR1) or BEACH (beige and Chediak-Higashi) domains. Results: NK cells from patients with CHS displayed severely reduced cytotoxicity. Mutations in the ARM/HEAT domain led to a reduced number of perforin-containing granules, which were significantly increased in size but able to polarize to the immunologic synapse; however, they were unable to properly fuse with the plasma membrane. Mutations in the BEACH domain resulted in formation of normal or slightly enlarged granules that had markedly impaired polarization to the IS but could be exocytosed on reaching the immunologic synapse. Perforin-containing granules in NK cells from patients with CHS did not acquire certain lysosomal markers (lysosome-associated membrane protein 1/2) but were positive for markers of transport vesicles (cation-independent mannose 6-phosphate receptor), late endosomes (Ras-associated binding protein 27a), and, to some extent, early endosomes (early endosome antigen 1), indicating a lack of integrity in the endolysosomal compartments. NK cells from patients with CHS had normal cytokine compartments and cytokine secretion. Conclusion: LYST is involved in regulation of multiple aspects of NK cell lytic activity, ranging from governance of lytic granule size to control of their polarization and exocytosis, as well as regulation of endolysosomal compartment identity. LYST functions in the regulated exocytosis but not in the constitutive secretion pathway. C1 [Gil-Krzewska, Aleksandra; Murakami, Yousuke; Victoria Nguyen; Peruzzi, Giovanna; Coligan, John E.; Krzewski, Konrad] NIAID, Receptor Cell Biol Sect, Immunogenet Lab, NIH, Rockville, MD USA. [Wood, Stephanie M.; Chiang, Samuel C. C.; Bryceson, Yenan T.] Karolinska Univ Hosp Huddinge, Karolinska Inst, Dept Med, Ctr Infect Med, Stockholm, Sweden. [Cullinane, Andrew R.; Gahl, William A.; Introne, Wendy J.] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. RP Krzewski, K (reprint author), 12441 Parklawn Dr,Twinbrook 2,Rm 205, Rockville, MD 20852 USA. EM krzewskikj@niaid.nih.gov RI chiang, samuel/M-9267-2016; OI Peruzzi, Giovanna/0000-0002-6517-9107 FU National Institute of Allergy and Infectious Diseases; National Human Genome Research Institute; European Research Council under the European Union's Seventh Framework Programme (FP)/ERC [311335]; Swedish Research Council; Swedish Foundation for Strategic Research; Knut and Alice Wallenberg Foundation; Swedish Cancer Foundation; Swedish Children's Cancer Foundation; Karolinska Institute Research Foundation; Marie Curie FP7 International Incoming Fellowship FX Supported by the Intramural Programs of the National Institute of Allergy and Infectious Diseases (to A.G.-K., Y.M., V.N., K.K., and J.E.C.), and the Intramural Program of National Human Genome Research Institute (to A.R.C., W.A.G., and W.J.I.), the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement no. 311335, the Swedish Research Council, the Swedish Foundation for Strategic Research, the Knut and Alice Wallenberg Foundation, the Swedish Cancer Foundation, the Swedish Children's Cancer Foundation, and the Karolinska Institute Research Foundation (to Y.T.B.), and a Marie Curie FP7 International Incoming Fellowship (to S.M.W.). NR 59 TC 4 Z9 4 U1 1 U2 6 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 APR PY 2016 VL 137 IS 4 BP 1165 EP 1177 DI 10.1016/j.jaci.2015.08.039 PG 13 WC Allergy; Immunology SC Allergy; Immunology GA DI2TG UT WOS:000373351200024 PM 26478006 ER PT J AU Parker, A Gottesman, S AF Parker, Ashley Gottesman, Susan TI Small RNA Regulation of TolC, the Outer Membrane Component of Bacterial Multidrug Transporters SO JOURNAL OF BACTERIOLOGY LA English DT Article ID ENTERICA SEROVAR TYPHIMURIUM; GRAM-NEGATIVE BACTERIA; SMALL NONCODING RNAS; ESCHERICHIA-COLI; EFFLUX PUMPS; ANTIBIOTIC-RESISTANCE; POSITIVE REGULATION; 2-COMPONENT SYSTEM; BIOFILM FORMATION; GENE-EXPRESSION AB Bacteria use multidrug efflux pumps to export drugs and toxic compounds out of the cell. One of the most important efflux pumps in Escherichia coli is the AcrAB-TolC system. Small regulatory RNAs (sRNAs) are known to be major posttranscriptional regulators that can enhance or repress translation by binding to the 5' untranslated region (UTR) of mRNA targets with the help of a chaperone protein, Hfq. In this study, we investigated the expression of acrA, acrB, and tolC translational fusions using 27 Hfq-dependent sRNAs overexpressed from plasmids. No significant sRNA regulation of acrA or acrB was detected. SdsR (also known as RyeB), an abundant and well-conserved stationary-phase sRNA, was found to repress the expression of tolC, the gene encoding the outer membrane protein of many multidrug resistance efflux pumps. This repression was shown to be by direct base pairing occurring upstream from the ribosomal binding site. SdsR overexpression and its regulation of tolC were found to reduce resistance to novobiocin and crystal violet. Our results suggest that additional targets for SdsR exist that contribute to increased antibiotic sensitivity and reduced biofilm formation. In an effort to identify phenotypes associated with single-copy SdsR and its regulation of tolC, the effect of a deletion of sdsR or mutations in tolC that should block SdsR pairing were investigated using a Biolog phenotypic microarray. However, no significant phenotypes were identified. Therefore, SdsR appears to modulate rather than act as a major regulator of its targets. IMPORTANCE AcrAB-TolC is a major efflux pump present in E. coli and Gram-negative bacteria used to export toxic compounds; the pump confers resistance to many antibiotics of unrelated classes. In this study, we found that SdsR, a small RNA expressed in stationary phase, repressed the expression of tolC, resulting in increased sensitivity to some antibiotics. This extends the findings of previous studies showing that sRNAs contribute to the regulation of many outer membrane proteins; manipulating or enhancing their action might help in sensitizing bacteria to antibiotics. C1 [Parker, Ashley; Gottesman, Susan] NCI, Mol Biol Lab, Ctr Canc Res, Bldg 37, Bethesda, MD 20892 USA. [Parker, Ashley] Howard Univ, Coll Med, Dept Microbiol, Washington, DC USA. RP Gottesman, S (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, Bldg 37, Bethesda, MD 20892 USA. EM gottesms@helix.nih.gov FU HHS \ National Institutes of Health (NIH); Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; Howard University FX HHS vertical bar National Institutes of Health (NIH) provided funding to Ashley Parker and Susan Gottesman.; Funding was provided primarily by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. A.P. was supported in part by Howard University during her Ph.D. study. NR 72 TC 7 Z9 7 U1 8 U2 18 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 EI 1098-5530 J9 J BACTERIOL JI J. Bacteriol. PD APR PY 2016 VL 198 IS 7 BP 1101 EP 1113 DI 10.1128/JB.00971-15 PG 13 WC Microbiology SC Microbiology GA DJ3KL UT WOS:000374103800012 PM 26811318 ER PT J AU Weber, MM Noriea, NF Bauler, LD Lam, JL Sager, J Wesolowski, J Paumet, F Hackstadt, T AF Weber, Mary M. Noriea, Nicholas F. Bauler, Laura D. Lam, Jennifer L. Sager, Janet Wesolowski, Jordan Paumet, Fabienne Hackstadt, Ted TI A Functional Core of IncA Is Required for Chlamydia trachomatis Inclusion Fusion SO JOURNAL OF BACTERIOLOGY LA English DT Article ID MEMBRANE-PROTEINS; DEVELOPMENTAL CYCLE; ENDOCYTIC PATHWAY; EXPRESSION; TRANSFORMATION; LOCALIZATION; INFECTION; PSITTACI; SNARES; CELLS AB Chlamydia trachomatis is an obligate intracellular pathogen that is the etiological agent of a variety of human diseases, including blinding trachoma and sexually transmitted infections. Chlamydiae replicate within a membrane-bound compartment, termed an inclusion, which they extensively modify by the insertion of type III secreted proteins called Inc proteins. IncA is an inclusion membrane protein that encodes two coiled-coil domains that are homologous to eukaryotic SNARE (soluble N-ethylmaleimide-sensitive factor attachment receptor) motifs. Recent biochemical evidence suggests that a functional core, composed of SNARE-like domain 1 (SLD-1) and part of SNARE-like domain 2 (SLD-2), is required for the characteristic homotypic fusion of C. trachomatis inclusions in multiply infected cells. To verify the importance of IncA in homotypic fusion in Chlamydia, we generated an incA::bla mutant. Insertional inactivation of incA resulted in the formation of nonfusogenic inclusions, a phenotype that was completely rescued by complementation with full-length IncA. Rescue of homotypic inclusion fusion was dependent on the presence of the functional core consisting of SLD-1 and part of SLD-2. Collectively, these results confirm in vitro membrane fusion assays identifying functional domains of IncA and expand the genetic tools available for identification of chlamydia with a method for complementation of site-specific mutants. IMPORTANCE Chlamydia trachomatis replicates within a parasitophorous vacuole termed an inclusion. The chlamydial inclusions are nonfusogenic with vesicles in the endocytic pathway but, in multiply infected cells, fuse with each other to form a single large inclusion. This homotypic fusion is dependent upon the presence of a chlamydial inclusion membrane-localized protein, IncA. Specificity of membrane fusion in eukaryotic cells is regulated by SNARE (soluble N-ethylmaleimide sensitive factor attachment receptor) proteins on the cytosolic face of vesicles and target membranes. IncA contains two SNARE-like domains. Newly developed genetic tools for the complementation of targeted mutants in C. trachomatis are used to confirm the minimal requirement of SNARE-like motifs necessary to promote the homotypic fusion of inclusions. C1 [Weber, Mary M.; Noriea, Nicholas F.; Bauler, Laura D.; Lam, Jennifer L.; Sager, Janet; Hackstadt, Ted] NIAID, Host Parasite Interact Sect, Bacteriol Lab, Rocky Mt Labs,NIH, Hamilton, MT USA. [Wesolowski, Jordan; Paumet, Fabienne] Thomas Jefferson Univ, Dept Microbiol & Immunol, Philadelphia, PA 19107 USA. [Bauler, Laura D.] Western Michigan Univ, Div Epidemiol & Biostat, Homer Stryker MD Sch Med, Kalamazoo, MI 49008 USA. RP Hackstadt, T (reprint author), NIAID, Host Parasite Interact Sect, Bacteriol Lab, Rocky Mt Labs,NIH, Hamilton, MT USA. EM ted_hackstadt@nih.gov FU NIH [AI073486, AI116983]; NIAID/NIH [AI000567] FX NIH provided funding to Fabienne Paumet under grant numbers AI073486 and AI116983. NIAID/NIH provided funding to Ted Hackstadt under grant number AI000567. NR 41 TC 4 Z9 4 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 EI 1098-5530 J9 J BACTERIOL JI J. Bacteriol. PD APR PY 2016 VL 198 IS 8 BP 1347 EP 1355 DI 10.1128/JB.00933-15 PG 9 WC Microbiology SC Microbiology GA DJ3KQ UT WOS:000374104400018 PM 26883826 ER PT J AU Isakova, T Cai, X Lee, J Katz, R Cauley, JA Fried, LF Hoofnagle, AN Satterfield, S Harris, TB Shlipak, MG Sarnak, MJ Ix, JH AF Isakova, Tamara Cai, Xuan Lee, Jungwha Katz, Ronit Cauley, Jane A. Fried, Linda F. Hoofnagle, Andrew N. Satterfield, Suzanne Harris, Tamara B. Shlipak, Michael G. Sarnak, Mark J. Ix, Joachim H. CA Hlth ABC Study TI Associations of FGF23 With Change in Bone Mineral Density and Fracture Risk in Older Individuals SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE FIBROBLAST GROWTH FACTOR 23; BONE MINERAL DENSITY; FRACTURE; CHRONIC KIDNEY DISEASE ID FIBROBLAST GROWTH FACTOR-23; CHRONIC KIDNEY-DISEASE; VITAMIN-D METABOLISM; OSTEOPOROTIC FRACTURES; CARDIOVASCULAR HEALTH; DIETARY PHOSPHATE; HIP-FRACTURES; FGF-23; MEN; FIBROBLAST-GROWTH-FACTOR-23 AB Elevated levels of the phosphate-regulating hormone fibroblast growth factor 23 (FGF23) have been linked to greater risk of fractures in some studies, especially among individuals with chronic kidney disease (CKD). We evaluated FGF23 as a risk factor for bone loss and fractures in the Health, Aging, and Body Composition (Health ABC) study, which is a prospective biracial cohort of well-functioning adults aged 70 to 79 years recruited at two clinical centers in the United States. The sample for the bone mineral density (BMD) analyses consisted of 2234 participants who had at least two serial total hip areal BMD measures. The fracture analyses included 2786 participants, 567 of whom sustained a fracture during a median follow up of 4.95 years. Linear mixed-effects models were used for longitudinal measurements of total hip areal BMD and the proportional subdistribution hazard regression model subject to competing risks of death was used for risk of fracture. The median FGF23 was 46.7 (interquartile range [IQR] 36.7 to 60.2) pg/mL. The mean annualized percent change in total hip areal BMD did not vary significantly according to FGF23 quartile in all participants (p for trend=0.70), but the effect was modified by CKD status (adjusted p for interaction <0.001). Among participants with CKD, the unadjusted mean annualized percent change in total hip areal BMD was greater with higher levels of FGF23 (unadjusted p for trend=0.02), but the trend was attenuated with adjustment for estimated glomerular filtration rate and parathyroid hormone (adjusted p for trend=0.30). FGF23 was not significantly associated with fracture risk in crude (hazard ratio [HR] per doubling of FGF23, 0.97; 95% CI, 0.85 to 1.12) or adjusted models (HR per doubling of FGF23, 1.02; 95% CI, 0.86 to 1.22), and these findings were not modified by gender or CKD status. FGF23 levels are not associated with bone loss or fracture risk in older adults with low prevalence of CKD. (c) 2015 American Society for Bone and Mineral Research. C1 [Isakova, Tamara] Northwestern Univ Feinberg, Sch Med, Dept Med, Div Nephrol & Hypertens, Chicago, IL USA. [Isakova, Tamara; Cai, Xuan] Northwestern Univ Feinberg, Sch Med, Inst Publ Hlth & Med, Ctr Translat Metab & Hlth, Chicago, IL USA. [Lee, Jungwha] Northwestern Univ Feinberg, Sch Med, Dept Preventat Med, Div Biostat, Chicago, IL USA. [Katz, Ronit; Hoofnagle, Andrew N.] Univ Washington, Kidney Res Inst, Seattle, WA 98195 USA. [Cauley, Jane A.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Fried, Linda F.] Univ Pittsburgh, Sch Med, VA Pittsburgh Healthcare Syst, Renal Sect, Pittsburgh, PA USA. [Hoofnagle, Andrew N.] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [Satterfield, Suzanne] Univ Tennessee, Dept Prevent Med, Memphis, TN USA. [Harris, Tamara B.] NIA, Lab Epidemiol & Populat Sci, NIH, Rockville, MD USA. [Shlipak, Michael G.] Univ Calif San Francisco, Dept Epidemiol Biostat & Med, San Francisco, CA 94143 USA. [Shlipak, Michael G.] San Francisco VA Med Ctr, Dept Gen Internal Med, San Francisco, CA USA. [Sarnak, Mark J.] Tufts Med Ctr, Dept Med, Div Nephrol, Boston, MA USA. [Ix, Joachim H.] Univ Calif San Diego, Vet Affairs San Diego Healthcare Syst, Nephrol Sect, San Diego, CA 92103 USA. [Ix, Joachim H.] Univ Calif San Diego, Div Nephrol & Prevent Med, San Diego, CA 92103 USA. RP Isakova, T (reprint author), 633 N St Clair St, Chicago, IL 60611 USA. EM tamara.isakova@northwestern.edu RI Cauley, Jane/N-4836-2015 OI Cauley, Jane/0000-0003-0752-4408 FU Carl W. Gottschalk Research Scholar Grant from the American Society of Nephrology Foundation for Kidney Research; National Institutes on Aging [R01AG027002]; National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050]; NINR [R01-NR012459]; NIH, National Institute on Aging; [K23DK087858] FX TI was supported by K23DK087858 and by the Carl W. Gottschalk Research Scholar Grant from the American Society of Nephrology Foundation for Kidney Research. MGS, MS, and JHI and the FGF23 measurements were supported by a grant from the National Institutes on Aging (R01AG027002). The Health ABC Study was supported by the National Institute on Aging (NIA) Contracts N01-AG-6-2101; N01-AG-6-2103; N01-AG-6-2106; NIA grant R01-AG028050, and NINR grant R01-NR012459. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. NR 45 TC 2 Z9 2 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0884-0431 EI 1523-4681 J9 J BONE MINER RES JI J. Bone Miner. Res. PD APR PY 2016 VL 31 IS 4 BP 742 EP 748 DI 10.1002/jbmr.2750 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DJ2BH UT WOS:000374008200006 PM 26590361 ER PT J AU Roccella, EJ AF Roccella, Edward J. TI In Memoriam Patrick J. Mulrow, MD (1926-2015) SO JOURNAL OF CLINICAL HYPERTENSION LA English DT Biographical-Item C1 [Roccella, Edward J.] NHLBI, US Natl High Blood Pressure Educ Program, NIH, POB 594, Irvington, VA 22480 USA. RP Roccella, EJ (reprint author), NHLBI, US Natl High Blood Pressure Educ Program, NIH, POB 594, Irvington, VA 22480 USA. EM eroccella@cox.net NR 1 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1524-6175 EI 1751-7176 J9 J CLIN HYPERTENS JI J. Clin. Hypertens. PD APR PY 2016 VL 18 IS 4 BP 257 EP 258 DI 10.1111/jch.12802 PG 2 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DJ3ID UT WOS:000374097100001 PM 26988109 ER PT J AU Brown, WV Moriarty, PM Remaley, AT Tsimikas, S AF Brown, W. Virgil Moriarty, Patrick M. Remaley, Alan T. Tsimikas, Sotirios TI JCL Roundtable: Should we treat elevations in Lp(a)? SO JOURNAL OF CLINICAL LIPIDOLOGY LA English DT Editorial Material DE Lp(a); Lipoprotein; Vascular disease; LDL-Cholesterol; Pharmacotherapy AB The focus of this Roundtable discussion is the mysterious lipoprotein Lp(a). There is growing evidence that it confers significant risk of vascular disease at high plasma concentrations. The concentration in plasma is highly variable from person to person but relatively stable in any given individual. The issue of defining this as a target of treatment has many facets, which have stymied clinicians in their management of this risk factor. The pertinent questions are many such as: "How does one obtain the most meaningful measure as there are so many components?" "What agents are truly effective in lowering this lipoprotein particle?" "Does direct treatment with reduction affect risk?" "How does low-density lipoprotein-cholesterol relate to the risk?" "If low-density lipoprotein-cholesterol is reduced, is there residual risk related directly to Lp(a)?" and "Are there effective therapies under development?" For this Roundtable, I am fortunate to have three experts that have studied these questions in various settings and have agreed to answer my questions relevant to these clinical issues. These include Dr Moriarty from the University of Kansas, Dr Remaley from the National Institutes of Health, and Dr Tsimikas from the University of California San Diego. (C) 2016 National Lipid Association. All rights reserved. C1 [Brown, W. Virgil] Emory Univ, Sch Med, Emeritus Coll, Atlanta, GA USA. [Moriarty, Patrick M.] Univ Kansas, Med Ctr, Dept Med, Kansas City, KS 66103 USA. [Remaley, Alan T.] NHLBI, Lipoprot Metab Sect, NIH, Bldg 10, Bethesda, MD 20892 USA. [Tsimikas, Sotirios] UCSD Cardiol La Jolla, Perlman Ambulatory Ctr, Dept Med, Div Cardiovasc Dis, La Jolla, CA USA. RP Brown, WV (reprint author), Emory Univ, Emeritus Coll, 3208 Habersham Rd NW, Atlanta, GA 30305 USA. EM wbrow925@bellsouth.net NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1933-2874 EI 1876-4789 J9 J CLIN LIPIDOL JI J. Clin. Lipidol. PD APR PY 2016 VL 10 IS 2 BP 215 EP 224 DI 10.1016/j.jacl.2016.02.012 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DJ4UL UT WOS:000374203500002 PM 27055952 ER PT J AU Shamburek, RD Bakker-Arkema, R Auerbach, BJ Krause, BR Homan, R Amar, MJ Freeman, LA Remaley, AT AF Shamburek, Robert D. Bakker-Arkema, Rebecca Auerbach, Bruce J. Krause, Brian R. Homan, Reynold Amar, Marcelo J. Freeman, Lita A. Remaley, Alan T. TI Familial lecithin:cholesterol acyltransferase deficiency: First-in-human treatment with enzyme replacement SO JOURNAL OF CLINICAL LIPIDOLOGY LA English DT Article DE Cholesterol; HDL; Triglyceride; Renal disease; Lecithin cholesterol acyltransferase; Lecithin cholesterol acyltransferase deficiency; LCAT; Recombinant enzyme replacement; Lipoprotein-X ID LECITHIN-CHOLESTEROL ACYLTRANSFERASE; LCAT DEFICIENCY; IN-VIVO; PLASMA LECITHIN; TRANSPLANTATION; LIPOPROTEIN; PATIENT; DISEASE; LESIONS; HDL AB BACKGROUND: Humans with familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) have extremely low or undetectable high-density lipoprotein cholesterol (HDL-C) levels and by early adulthood develop many manifestations of the disorder, including corneal opacities, anemia, and renal disease. OBJECTIVE: To determine if infusions of recombinant human LCAT (rhLCAT) could reverse the anemia, halt progression of renal disease, and normalize HDL in FLD. METHODS: rhLCAT (ACP-501) was infused intravenously over 1 hour on 3 occasions in a dose optimization phase (0.3, 3.0, and 9.0 mg/kg), then 3.0 or 9.0 mg/kg every 1 to 2 weeks for 7 months in a maintenance phase. Plasma lipoproteins, lipids, LCAT levels, and several measures of renal function and other clinical labs were monitored. RESULTS: LCAT concentration peaked at the end of each infusion and decreased to near baseline over 7 days. Renal function generally stabilized or improved and the anemia improved. After infusion, HDL-C rapidly increased, peaking near normal in 8 to 12 hours; analysis of HDL particles by various methods all revealed rapid sequential disappearance of pre beta-HDL and small alpha-4 HDL and appearance of normal alpha-HDL. Low-density lipoprotein cholesterol increased more slowly than HDL-C. Of note, triglyceride routinely decreased after meals after infusion, in contrast to the usual postprandial increase in the absence of rhLCAT infusion. CONCLUSIONS: rhLCAT infusions were well tolerated in this first-in-human study in FLD; the anemia improved, as did most parameters related to renal function in spite of advanced disease. Plasma lipids transiently normalized, and there was rapid sequential conversion of small pre beta-HDL particles to mature spherical alpha-HDL particles. Published by Elsevier Inc. on behalf of National Lipid Association. C1 [Shamburek, Robert D.; Amar, Marcelo J.; Freeman, Lita A.; Remaley, Alan T.] NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Bakker-Arkema, Rebecca; Auerbach, Bruce J.; Krause, Brian R.; Homan, Reynold] AlphaCore Pharma, Ann Arbor, MI USA. [Bakker-Arkema, Rebecca] MedImmune LLC, Gaithersburg, MD USA. RP Shamburek, RD (reprint author), NIH, 10 Ctr Dr,MSC 1666,Bldg 10,Rm 8N-202, Bethesda, MD 20892 USA. EM bobs@mail.nih.gov FU Intramural Research Program of the Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute of the National Institutes of Health FX The Intramural Research Program of the Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute of the National Institutes of Health reviewed and supported the study. AlphaCore Pharma, LLC supplied the ACP-501. NR 21 TC 2 Z9 2 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1933-2874 EI 1876-4789 J9 J CLIN LIPIDOL JI J. Clin. Lipidol. PD APR PY 2016 VL 10 IS 2 BP 356 EP 367 DI 10.1016/j.jacl.2015.12.007 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DJ4UL UT WOS:000374203500017 PM 27055967 ER PT J AU Yun, JS Lim, TS Cha, SA Ahn, YB Song, KH Choi, JA Kwon, J Jee, D Cho, YK Park, YM Ko, SH AF Yun, Jae-Seung Lim, Tae-Seok Cha, Seon-Ah Ahn, Yu-Bae Song, Ki-Ho Choi, Jin A. Kwon, Jinwoo Jee, Donghyun Cho, Yang Kyung Park, Yong-Moon Ko, Seung-Hyun TI Lipoprotein(a) predicts the development of diabetic retinopathy in people with type 2 diabetes mellitus SO JOURNAL OF CLINICAL LIPIDOLOGY LA English DT Article DE Lipoprotein(a) [Lp(a)]; Diabetic retinopathy; Type 2 diabetes ID LOW-DENSITY-LIPOPROTEIN; RISK-FACTOR; CARDIOVASCULAR-DISEASE; PROGRESSION; ASSOCIATION; THERAPIES; SEVERITY; HEALTH AB BACKGROUND: Lipoprotein(a) [Lp(a)] has mainly been considered to be a predictor of the incidence of cardiovascular disease. In addition, previous studies have shown potential linkage between Lp(a) and diabetic microvascular complications. OBJECTIVES: We investigated the incidence and risk factors for the development of diabetic retinopathy (DR) in patients with type 2 diabetes. METHODS: A total of 787 patients with type 2 diabetes without DR were consecutively enrolled and followed up prospectively. Retinopathy evaluation was annually performed by ophthalmologists. The main outcome was new onset of DR. RESULTS: The median follow-up time was 11.1 years. Patients in the DR group had a longer duration of diabetes (P < .001), higher baseline HbA(1c) (P < .001), higher albuminuria level (P = .033), and higher level of Lp(a) (P = .005). After adjusting for sex, age, diabetes duration, presence of hypertension, renal function, LDL cholesterol, mean HbA(1c), and medications, the development of DR was significantly associated with the serum Lp(a) level (HR 1.57, 95% confidence interval [1.11-2.24]; P = .012, comparing the 4th vs 1st quartile of Lp(a)). The patient group with the highest quartile range of Lp(a) and mean HbA(1c) levels >= 7.0% had an HR of 5.09 (95% confidence interval [2.63-9.84]; P < .001) for developing DR compared with patients with lower levels of both factors. CONCLUSIONS: In this prospective cohort study, we demonstrated that the DR was independently associated with the serum Lp(a) level in patients with type 2 diabetes. (C) 2016 National Lipid Association. All rights reserved. C1 [Yun, Jae-Seung; Lim, Tae-Seok; Cha, Seon-Ah; Ahn, Yu-Bae; Ko, Seung-Hyun] Catholic Univ Korea, St Vincents Hosp, Coll Med, Div Endocrinol & Metab,Dept Internal Med, 222 Banpo Daero, Seoul 137701, South Korea. [Song, Ki-Ho] Catholic Univ Korea, Yeouido St Marys Hosp, Coll Med, Div Endocrinol & Metab,Dept Internal Med, Seoul 137701, South Korea. [Choi, Jin A.; Kwon, Jinwoo; Jee, Donghyun; Cho, Yang Kyung] Catholic Univ Korea, St Vincents Hosp, Coll Med, Dept Ophthalmol, Seoul 137701, South Korea. [Park, Yong-Moon] NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Ko, SH (reprint author), Catholic Univ Korea, St Vincents Hosp, Coll Med, Div Endocrinol & Metab,Dept Internal Med, 222 Banpo Daero, Seoul 137701, South Korea. EM kosh@catholic.ac.kr OI Kwon, Jin-woo/0000-0003-2093-4284; PARK, YONG-MOON/0000-0002-5879-6879 NR 40 TC 3 Z9 3 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1933-2874 EI 1876-4789 J9 J CLIN LIPIDOL JI J. Clin. Lipidol. PD APR PY 2016 VL 10 IS 2 BP 426 EP 433 DI 10.1016/j.jacl.2015.12.030 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DJ4UL UT WOS:000374203500024 PM 27055974 ER PT J AU Damluji, AA El-Maouche, D Alsulaimi, A Martin, P Shamburek, RD Goldberg, RB Baum, SJ de Marchena, EJ AF Damluji, Abdulla A. El-Maouche, Diala Alsulaimi, Ali Martin, Paul Shamburek, Robert D. Goldberg, Ronald B. Baum, Seth J. de Marchena, Eduardo J. TI Accelerated atherosclerosis and elevated lipoprotein (a) after liver transplantation SO JOURNAL OF CLINICAL LIPIDOLOGY LA English DT Editorial Material DE Lp(a); Lipids; Prevention; Cardiovascular disease; Therapy ID APOLIPOPROTEIN(A) ISOFORM; RISK-FACTOR; DISEASE AB Cumulative evidence suggests that lipoprotein(a) [Lp(a)] exerts an independent effect on the initiation and progression of atherosclerotic cardiovascular disease. The genetically mediated expression of apolipoprotein(a), which is the key structural and functional component of Lp(a), occurs in hepatocytes with subsequent extracellular Lp(a) assembly at the hepatic cell surface. Here, we describe a case of elevated Lp(a) concentrations identified after (and likely acquired by) orthotopic liver transplantation that contributed to accelerated atherosclerotic cardiovascular disease despite intensive therapeutic interventions. This case study represents an important example to include Lp(a) screening in routine lipid panel testing for all liver transplant donors and recipients; to reduce unanticipated and debilitating cardiovascular morbidity and mortality. (C) 2016 National Lipid Association. All rights reserved. C1 [Damluji, Abdulla A.; Alsulaimi, Ali; Baum, Seth J.; de Marchena, Eduardo J.] Univ Miami, Miller Sch Med, Div Cardiovasc, Miami, FL 33136 USA. [Damluji, Abdulla A.; Alsulaimi, Ali; Baum, Seth J.; de Marchena, Eduardo J.] Univ Miami, Miller Sch Med, Elaine & Sydney Sussman Cardiac Catheterizat Labs, Miami, FL 33136 USA. [El-Maouche, Diala; Goldberg, Ronald B.] Univ Miami, Miller Sch Med, Div Endocrinol Diabet & Metab, Miami, FL 33136 USA. [El-Maouche, Diala; Shamburek, Robert D.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Martin, Paul] Univ Miami, Miller Sch Med, Div Hepatol, Miami, FL 33136 USA. RP de Marchena, EJ (reprint author), Univ Miami, Miller Sch Med, Dept Med, Div Cardiovasc, 1400 NW 12th Ave,Suite 1179, Miami, FL 33136 USA. EM emarchen@med.miami.edu OI Damluji, Abdulla/0000-0002-8774-6416 NR 13 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 1933-2874 EI 1876-4789 J9 J CLIN LIPIDOL JI J. Clin. Lipidol. PD APR PY 2016 VL 10 IS 2 BP 434 EP 437 DI 10.1016/j.jacl.2015.12.022 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DJ4UL UT WOS:000374203500025 PM 27055975 ER PT J AU Mino, S Barrandeguy, M Parreno, V Parra, GI AF Mino, Samuel Barrandeguy, Maria Parreno, Viviana Parra, Gabriel I. TI Genetic linkage of capsid protein-encoding RNA segments in group A equine rotaviruses SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID MOLECULAR CHARACTERIZATION; INTERSPECIES TRANSMISSION; SEQUENCE-ANALYSIS; GENOME ANALYSES; STRAINS; GENOTYPES; HORSES; VP6; IDENTIFICATION; SURVEILLANCE AB Rotavirus virions are formed by three concentric protein layers that enclose the 11 dsRNA genome segments and the viral proteins VP1 and VP3. Interactions amongst the capsid proteins (VP2, VP6, VP7 and VP4) have been described to play a major role in viral fitness, whilst restricting the reassortment of the genomic segments during co-infection with different rotavirus strains. In this work we describe and characterize the linkage between VP6 and VP7 proteins based on structural and genomic analyses of group A rotavirus strains circulating in Argentinean horses. Strains with the VP7 genotype G3 showed a strong association with the VP6 genotype I6, whilst strains with G14 were associated with the I2 genotype. Most of the differences on the VP6 and VP7 proteins were observed in interactive regions between the two proteins, suggesting that VP6 : VP7 interactions may drive the co-evolution and co-segregation of their respective gene segments. C1 [Mino, Samuel; Barrandeguy, Maria; Parreno, Viviana] INTA Castelar, CICVyA, Inst Virol, Nicolas Repetto & Reseros S-N, RA-1816 Buenos Aires, DF, Argentina. [Barrandeguy, Maria] Univ Salvador, Escuela Vet, Champagnat 1599,Ruta Panamericana Km54-5,B1630AHU, Buenos Aires, DF, Argentina. [Parra, Gabriel I.] Univ Nacl Asuncion, Dept Mol Biol & Genet, Inst Invest Ciencias Salud, Asuncion, Paraguay. [Mino, Samuel] Chinese Acad Agr Sci, State Key Lab Vet Biotechnol, Harbin Vet Res Inst, Harbin, Peoples R China. [Parra, Gabriel I.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Mino, S (reprint author), INTA Castelar, CICVyA, Inst Virol, Nicolas Repetto & Reseros S-N, RA-1816 Buenos Aires, DF, Argentina.; Parra, GI (reprint author), Univ Nacl Asuncion, Dept Mol Biol & Genet, Inst Invest Ciencias Salud, Asuncion, Paraguay.; Mino, S (reprint author), Chinese Acad Agr Sci, State Key Lab Vet Biotechnol, Harbin Vet Res Inst, Harbin, Peoples R China.; Parra, GI (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM mino.samuel@inta.gob.ar; gabriel_parra@hotmail.com OI Parra, Gabriel/0000-0002-1102-4740 FU CVT INTA, Haras Agreement, Argentina FX This work was supported by CVT INTA, Haras Agreement, Argentina. V. P. is a member of the Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET). NR 45 TC 1 Z9 1 U1 0 U2 2 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 EI 1465-2099 J9 J GEN VIROL JI J. Gen. Virol. PD APR PY 2016 VL 97 BP 912 EP 921 DI 10.1099/jgv.0.000397 PN 4 PG 10 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA DJ3MF UT WOS:000374108900011 PM 26758293 ER PT J AU Davidson, WS Heink, A Sexmith, H Melchior, JT Gordon, SM Kuklenyik, Z Woollett, L Barr, JR Jones, JI Toth, CA Shah, AS AF Davidson, W. Sean Heink, Anna Sexmith, Hannah Melchior, John T. Gordon, Scott M. Kuklenyik, Zsuzsanna Woollett, Laura Barr, John R. Jones, Jeffrey I. Toth, Christopher A. Shah, Amy S. TI The effects of apolipoprotein B depletion on HDL subspecies composition and function SO JOURNAL OF LIPID RESEARCH LA English DT Article DE polyethylene glycol; dextran sulfate; heparin sodium; lipoproteins; high density lipoprotein; low density lipoprotein; proteomics; cholesterol efflux ID HIGH-DENSITY-LIPOPROTEINS; CHOLESTEROL EFFLUX CAPACITY; POLYETHYLENE-GLYCOL; DIFFERENT PATHWAYS; GEL-FILTRATION; PRECIPITATION; PARTICLES; ASSOCIATION; PLASMA; ATHEROSCLEROSIS AB HDL cholesterol (HDL-C) efflux function may be a more robust biomarker of coronary artery disease risk than HDL-C. To study HDL function, apoB-containing lipoproteins are precipitated from serum. Whether apoB precipitation affects HDL subspecies composition and function has not been thoroughly investigated. We studied the effects of four common apoB precipitation methods [polyethylene glycol (PEG), dextran sulfate/magnesium chloride (MgCl2), heparin sodium/manganese chloride (MnCl2), and LipoSep immunoprecipitation (IP)] on HDL subspecies composition, apolipoproteins, and function (cholesterol efflux and reduction of LDL oxidation). PEG dramatically shifted the size distribution of HDL and apolipoproteins (assessed by two independent methods), while leaving substantial amounts of reagent in the sample. PEG also changed the distribution of cholesterol efflux and LDL oxidation across size fractions, but not overall efflux across the HDL range. Dextran sulfate/MgCl2, heparin sodium/MnCl2, and LipoSep IP did not change the size distribution of HDL subspecies, but altered the quantity of a subset of apolipoproteins. Thus, each of the apoB precipitation methods affected HDL composition and/or size distribution. We conclude that careful evaluation is needed when selecting apoB depletion methods for existing and future bioassays of HDL function. C1 [Davidson, W. Sean; Melchior, John T.; Woollett, Laura] Univ Cincinnati, Dept Pathol & Lab Med, Ctr Lipid & Arteriosclerosis Sci, Cincinnati, OH 45237 USA. [Heink, Anna; Sexmith, Hannah; Shah, Amy S.] Cincinnati Childrens Hosp Res Fdn, Dept Pediat, Cincinnati, OH 45229 USA. [Gordon, Scott M.] NHLBI, Lipoprot Metab Sect, Bldg 10, Bethesda, MD 20892 USA. [Kuklenyik, Zsuzsanna; Barr, John R.; Jones, Jeffrey I.] Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Div Sci Lab, Atlanta, GA 30341 USA. [Toth, Christopher A.] Battelle Mem Inst, Analyt Serv, Atlanta, GA 30329 USA. RP Shah, AS (reprint author), Cincinnati Childrens Hosp Res Fdn, Dept Pediat, Cincinnati, OH 45229 USA. EM amy.shah@cchmc.org OI Toth, Christopher/0000-0001-9294-0144 FU National Heart, Lung, and Blood Institute [R01HL67093, R01HL104136, K23HL118132] FX This work was supported by National Heart, Lung, and Blood Institute Grants R01HL67093 (W.S.D.), R01HL104136 (W.S.D.), and K23HL118132 (A.S.S.). The authors declare no financial conflicts of interest relevant to this study. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 38 TC 3 Z9 3 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 EI 1539-7262 J9 J LIPID RES JI J. Lipid Res. PD APR PY 2016 VL 57 IS 4 BP 674 EP 686 DI 10.1194/jlr.M066613 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DJ0WH UT WOS:000373924600016 PM 26908829 ER PT J AU Bunn, PA Minna, JD Augustyn, A Gazdar, AF Ouadah, Y Krasnow, MA Berns, A Brambilla, E Rekhtman, N Massion, PP Niederst, M Peifer, M Yokota, J Govindan, R Poirier, JT Byers, LA Wynes, MW McFadden, DG MacPherson, D Hann, CL Farago, AF Dive, C Teicher, BA Peacock, CD Johnson, JE Cobb, MH Wendel, HG Spigel, D Sage, J Yang, P Pietanza, MC Krug, LM Heymach, J Ujhazy, P Zhou, CC Goto, K Dowlati, A Christensen, CL Park, K Einhorn, LH Edelman, MJ Giaccone, G Gerber, DE Salgia, R Owonikoko, T Malik, S Karachaliou, N Gandara, DR Slotman, BJ Blackhall, F Goss, G Thomas, R Rudin, CM Hirsch, FR AF Bunn, Paul A., Jr. Minna, John D. Augustyn, Alexander Gazdar, Adi F. Ouadah, Youcef Krasnow, Mark A. Berns, Anton Brambilla, Elisabeth Rekhtman, Natasha Massion, Pierre P. Niederst, Matthew Peifer, Martin Yokota, Jun Govindan, Ramaswamy Poirier, John T. Byers, Lauren A. Wynes, Murry W. McFadden, David G. MacPherson, David Hann, Christine L. Farago, Anna F. Dive, Caroline Teicher, Beverly A. Peacock, Craig D. Johnson, Jane E. Cobb, Melanie H. Wendel, Hans -Guido Spigel, David Sage, Julien Yang, Ping Pietanza, M. Catherine Krug, Lee M. Heymach, John Ujhazy, Peter Zhou, Caicun Goto, Koichi Dowlati, Afshin Christensen, Camilla Laulund Park, Keunchil Einhorn, Lawrence H. Edelman, Martin J. Giaccone, Giuseppe Gerber, David E. Salgia, Ravi Owonikoko, Taofeek Malik, Shakun Karachaliou, Niki Gandara, David R. Slotman, Ben J. Blackhall, Fiona Goss, Glenwood Thomas, Roman Rudin, Charles M. Hirsch, Fred R. TI Small Cell Lung Cancer: Can Recent Advances in Biology and Molecular Biology Be Translated into Improved Outcomes? SO JOURNAL OF THORACIC ONCOLOGY LA English DT Review DE Small cell lung cancer; Gene mutations; Therapy; Immunotherapy; Neuroendocrine ID PHASE-II-TRIAL; COMPREHENSIVE GENOMIC ANALYSIS; CIRCULATING TUMOR-CELLS; SOLID TUMORS; DOUBLE-BLIND; STEM-CELLS; NEUROENDOCRINE CARCINOMAS; THERAPEUTIC TARGET; AURORA KINASE; MOUSE MODEL C1 [Bunn, Paul A., Jr.; Hirsch, Fred R.] Univ Colorado, Ctr Canc, Aurora, CO 80045 USA. [Minna, John D.; Augustyn, Alexander; Gazdar, Adi F.; McFadden, David G.; Johnson, Jane E.; Cobb, Melanie H.; Gerber, David E.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Ouadah, Youcef; Krasnow, Mark A.; Sage, Julien] Stanford Univ, Stanford, CA 94305 USA. [Berns, Anton] Netherlands Canc Inst, Amsterdam, Netherlands. [Brambilla, Elisabeth] Grenoble Univ, Ctr Hosp, Grenoble, France. [Rekhtman, Natasha; Poirier, John T.; Wendel, Hans -Guido; Pietanza, M. Catherine; Krug, Lee M.; Rudin, Charles M.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Massion, Pierre P.] Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA. [Niederst, Matthew; Farago, Anna F.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Peifer, Martin; Thomas, Roman] Univ Cologne, D-50931 Cologne, Germany. [Yokota, Jun] Inst Predict & Personalized Med Canc, Barcelona, Spain. [Yokota, Jun] Natl Canc Ctr, Res Inst, Tokyo 104, Japan. [Govindan, Ramaswamy] Washington Univ, St Louis, MO USA. [Byers, Lauren A.; Heymach, John] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Wynes, Murry W.] Int Assoc Study Lung Canc, Aurora, CO USA. [MacPherson, David] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Hann, Christine L.] Johns Hopkins Sch Med, Baltimore, MD USA. [Dive, Caroline] Canc Res UK Manchester Inst, Manchester, Lancs, England. [Teicher, Beverly A.; Malik, Shakun] NCI, Bethesda, MD 20892 USA. [Peacock, Craig D.] Cleveland Clin, Cleveland, OH 44106 USA. [Spigel, David] Sara Cannon Res Inst, Nashville, TN USA. [Yang, Ping; Ujhazy, Peter] Mayo Clin, Ctr Canc, Rochester, MN USA. [Zhou, Caicun] Tongji Univ, Inst Canc, Sch Med, Shanghai 200092, Peoples R China. [Goto, Koichi] Natl Canc Ctr Hosp East, Chiba, Japan. [Dowlati, Afshin] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Dowlati, Afshin] Univ Hosp Case Med Ctr, Cleveland, OH USA. [Christensen, Camilla Laulund] Dana Farber Canc Inst, Boston, MA 02115 USA. [Park, Keunchil] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Seoul, South Korea. [Einhorn, Lawrence H.] Indiana Univ, Indianapolis, IN 46204 USA. [Edelman, Martin J.] Univ Maryland, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Giaccone, Giuseppe] Georgetown Univ, Washington, DC USA. [Salgia, Ravi] Univ Chicago, Chicago, IL 60637 USA. [Owonikoko, Taofeek] Emory Univ, Atlanta, GA 30322 USA. [Karachaliou, Niki] Quiron Dexeus Univ Hosp, Barcelona, Spain. [Gandara, David R.] Univ Calif Davis, Ctr Comprehens Canc, Davis, CA 95616 USA. [Slotman, Ben J.] Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands. [Blackhall, Fiona] Univ Manchester, Manchester, Lancs, England. [Goss, Glenwood] Univ Ottawa, Ottawa, ON, Canada. RP Hirsch, FR (reprint author), Univ Colorado, Ctr Canc, Aurora, CO 80045 USA. EM Fred.Hirsch@ucdenver.edu RI Giaccone, Giuseppe/E-8297-2017; OI Giaccone, Giuseppe/0000-0002-5023-7562; Dive, Caroline/0000-0002-1726-8850; Cobb, Melanie/0000-0003-0833-5473 FU NCI NIH HHS [F30 CA168264, K12 CA087723, P30 CA008748, P50 CA058187, P50 CA070907] NR 165 TC 14 Z9 14 U1 6 U2 16 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD APR PY 2016 VL 11 IS 4 BP 453 EP 474 DI 10.1016/j.jtho.2016.01.012 PG 22 WC Oncology; Respiratory System SC Oncology; Respiratory System GA DJ0AT UT WOS:000373864500002 PM 26829312 ER PT J AU Rawstron, AC Fazi, C Agathangelidis, A Villamor, N Letestu, R Nomdedeu, J Palacio, C Stehlikova, O Kreuzer, KA Liptrot, S O'Brien, D de Tute, RM Marinov, I Hauwel, M Spacek, M Dobber, J Kater, AP Gambell, P Soosapilla, A Lozanski, G Brachtl, G Lin, K Boysen, J Hanson, C Jorgensen, JL Stetler-Stevenson, M Yuan, C Broome, HE Rassenti, L Craig, F Delgado, J Moreno, C Bosch, F Egle, A Doubek, M Pospisilova, S Mulligan, S Westerman, D Sanders, CM Emerson, R Robins, HS Kirsch, I Shanafelt, T Pettitt, A Kipps, TJ Wierda, WG Cymbalista, F Hallek, M Hillmen, P Montserrat, E Ghia, P AF Rawstron, A. C. Fazi, C. Agathangelidis, A. Villamor, N. Letestu, R. Nomdedeu, J. Palacio, C. Stehlikova, O. Kreuzer, K-A Liptrot, S. O'Brien, D. de Tute, R. M. Marinov, I. Hauwel, M. Spacek, M. Dobber, J. Kater, A. P. Gambell, P. Soosapilla, A. Lozanski, G. Brachtl, G. Lin, K. Boysen, J. Hanson, C. Jorgensen, J. L. Stetler-Stevenson, M. Yuan, C. Broome, H. E. Rassenti, L. Craig, F. Delgado, J. Moreno, C. Bosch, F. Egle, A. Doubek, M. Pospisilova, S. Mulligan, S. Westerman, D. Sanders, C. M. Emerson, R. Robins, H. S. Kirsch, I. Shanafelt, T. Pettitt, A. Kipps, T. J. Wierda, W. G. Cymbalista, F. Hallek, M. Hillmen, P. Montserrat, E. Ghia, P. CA ERIC European Res Initiative CLL TI A complementary role of multiparameter flow cytometry and high-throughput sequencing for minimal residual disease detection in chronic lymphocytic leukemia: an European Research Initiative on CLL study SO LEUKEMIA LA English DT Article ID ASSAY; QUANTIFICATION; RITUXIMAB; SURVIVAL; THERAPY; ERADICATION; EXPRESSION; GUIDELINES; DIAGNOSIS; TRIAL AB In chronic lymphocytic leukemia (CLL) the level of minimal residual disease (MRD) after therapy is an independent predictor of outcome. Given the increasing number of new agents being explored for CLL therapy, using MRD as a surrogate could greatly reduce the time necessary to assess their efficacy. In this European Research Initiative on CLL (ERIC) project we have identified and validated a flow-cytometric approach to reliably quantitate CLL cells to the level of 0.0010% (10(-5)). The assay comprises a core panel of six markers (i.e. CD19, CD20, CD5, CD43, CD79b and CD81) with a component specification independent of instrument and reagents, which can be locally re-validated using normal peripheral blood. This method is directly comparable to previous ERIC-designed assays and also provides a backbone for investigation of new markers. A parallel analysis of high-throughput sequencing using the ClonoSEQ assay showed good concordance with flow cytometry results at the 0.010% (10(-4)) level, the MRD threshold defined in the 2008 International Workshop on CLL guidelines, but it also provides good linearity to a detection limit of 1 in a million (10(-6)). The combination of both technologies would permit a highly sensitive approach to MRD detection while providing a reproducible and broadly accessible method to quantify residual disease and optimize treatment in CLL. C1 [Rawstron, A. C.; de Tute, R. M.] St Jamess Inst Oncol, HMDS, Leeds, W Yorkshire, England. [Fazi, C.; Agathangelidis, A.; Ghia, P.] IRCCS San Raffaele Sci Inst, Milan, Italy. [Villamor, N.; Delgado, J.; Montserrat, E.] Hosp Clin Barcelona, IDIBAPS, Barcelona, Spain. [Letestu, R.; Cymbalista, F.] Hop Avicenne, AP HP, F-93009 Bobigny, France. [Nomdedeu, J.; Moreno, C.] Hosp Santa Creu & Sant Pau, Barcelona, Spain. [Palacio, C.; Bosch, F.] Hosp Univ Vall dHebron, Barcelona, Spain. [Stehlikova, O.; Doubek, M.; Pospisilova, S.] Univ Hosp Brno, Dept Internal Med Hematol & Oncol, Brno, Czech Republic. [Stehlikova, O.; Doubek, M.; Pospisilova, S.] Masaryk Univ, CEITEC, Brno, Czech Republic. [Kreuzer, K-A; Hallek, M.] Univ Hosp, Cologne, Germany. [Liptrot, S.; O'Brien, D.] St James Hosp, Dublin 8, Ireland. [Marinov, I.] Univ Hosp Prague, Inst Hematol & Blood Transfus, Prague, Czech Republic. [Hauwel, M.] Univ Hosp Geneva, Geneva, Switzerland. [Spacek, M.] Gen Univ Hosp, Prague, Czech Republic. [Dobber, J.; Kater, A. P.] Univ Amsterdam, Acad Med Ctr, Dept Hematol, NL-1105 AZ Amsterdam, Netherlands. [Gambell, P.; Westerman, D.] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Soosapilla, A.] Laverty Pathol, Hematol & Flow Cytometry, Sydney, NSW, Australia. [Lozanski, G.] Ohio State Univ, Med Ctr, Columbus, OH 43210 USA. [Brachtl, G.; Egle, A.] Paracelsus Med Univ, Dept Med 3, Salzburg, Austria. [Brachtl, G.] Paracelsus Med Univ, Spinal Cord & Tissue Regenerat Ctr, Expt & Clin Cell Therapy Inst, Salzburg, Austria. [Lin, K.; Pettitt, A.] Royal Liverpool & Broadgreen Univ Hosp NHS Trust, Liverpool, Merseyside, England. [Boysen, J.; Hanson, C.; Shanafelt, T.] Mayo Clin, Div Hematol, Rochester, MN USA. [Boysen, J.; Hanson, C.; Shanafelt, T.] Mayo Clin, Div Hematopathol, Rochester, MN USA. [Jorgensen, J. L.; Wierda, W. G.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Stetler-Stevenson, M.; Yuan, C.] NCI, NIH, Bethesda, MD 20892 USA. [Broome, H. E.; Rassenti, L.; Kipps, T. J.] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. [Craig, F.] Univ Pittsburgh, Pittsburgh, PA USA. [Mulligan, S.] Royal N Shore Hosp, Dept Haematol, Sydney, NSW, Australia. [Sanders, C. M.; Emerson, R.; Robins, H. S.; Kirsch, I.] Adapt Biotechnol, Seattle, WA USA. [Hillmen, P.] Univ Leeds, Leeds Inst Canc & Pathol, Leeds, W Yorkshire, England. [Ghia, P.] Univ Vita Salute San Raffaele, Milan, Italy. RP Rawstron, AC (reprint author), Leeds Teaching Hosp NHS Trust, St Jamess Inst Oncol, HMDS, Bexley Wing,Beckett St, Leeds LS9 7TF, W Yorkshire, England. EM andy.rawstron@hmds.org.uk RI Ghia, Paolo/K-7138-2016; OI Ghia, Paolo/0000-0003-3750-7342; Egle, Alexander/0000-0003-0648-4416; Delgado, Julio/0000-0002-5157-4376; Palacio-Garcia, Carles/0000-0002-9085-3327; Rawstron, Andy/0000-0003-0798-9790; Nomdedeu, Josep/0000-0003-3399-346X FU project CEITEC [MSMT CR CZ.1.05/1.1.00/02.0068]; project IGA MZ CR [NT13493-4/2012]; project PRVOUK [P27/LF1/1]; Celgene FX SP and MD: partially financed by project CEITEC (MSMT CR CZ.1.05/1.1.00/02.0068) and project IGA MZ CR NT13493-4/2012). MS: partially financed by project PRVOUK P27/LF1/1. ERIC Educational activities are partially supported by Celgene. BD Biosciences provided custom and commercial conjugates for testing and Frans Nauwelaers, Lucia Testolin, Jingyi Chen and Noel Warner from BD Biosciences provided advice and assistance with the project. Assessment of interoperator variation was performed by participants at three educational courses provided by the Swiss Flow Cytometry School in May 2014 (http://www.cytometryschool.ch), the Prague School of Flow Cytometry in May 2014 (see http://www.escca.eu/meetings) and the ICCS/ESCCA Bi-society Practical Clinical Cytometry Course (http://www.cytoed.org/web-clearwater/index.php). NR 28 TC 10 Z9 12 U1 6 U2 13 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD APR PY 2016 VL 30 IS 4 BP 929 EP 936 DI 10.1038/leu.2015.313 PG 8 WC Oncology; Hematology SC Oncology; Hematology GA DJ3RK UT WOS:000374123100020 PM 26639181 ER PT J AU Nikbakht, H Panditharatna, E Mikael, LG Li, R Gayden, T Osmond, M Ho, CY Kambhampati, M Hwang, EI Faury, D Siu, A Papillon-Cavanagh, S Bechet, D Ligon, KL Ellezam, B Ingram, WJ Stinson, C Moore, AS Warren, KE Karamchandani, J Packer, RJ Jabado, N Majewski, J Nazarian, J AF Nikbakht, Hamid Panditharatna, Eshini Mikael, Leonie G. Li, Rui Gayden, Tenzin Osmond, Matthew Ho, Cheng-Ying Kambhampati, Madhuri Hwang, Eugene I. Faury, Damien Siu, Alan Papillon-Cavanagh, Simon Bechet, Denise Ligon, Keith L. Ellezam, Benjamin Ingram, Wendy J. Stinson, Caedyn Moore, Andrew S. Warren, Katherine E. Karamchandani, Jason Packer, Roger J. Jabado, Nada Majewski, Jacek Nazarian, Javad TI Spatial and temporal homogeneity of driver mutations in diffuse intrinsic pontine glioma SO NATURE COMMUNICATIONS LA English DT Article ID ACTIVATING ACVR1 MUTATIONS; HIGH-GRADE ASTROCYTOMAS; EXOME-SEQUENCING DATA; INTRATUMOR HETEROGENEITY; PEDIATRIC GLIOBLASTOMA; HISTONE H3.3; TUMORS; SUBGROUPS; EVOLUTION; ANNOTATION AB Diffuse Intrinsic Pontine Gliomas (DIPGs) are deadly paediatric brain tumours where needle biopsies help guide diagnosis and targeted therapies. To address spatial heterogeneity, here we analyse 134 specimens from various neuroanatomical structures of whole autopsy brains from nine DIPG patients. Evolutionary reconstruction indicates histone 3 (H3) K27M-including H3.2K27M-mutations potentially arise first and are invariably associated with specific, high-fidelity obligate partners throughout the tumour and its spread, from diagnosis to end-stage disease, suggesting mutual need for tumorigenesis. These H3K27M ubiquitously-associated mutations involve alterations in TP53 cell-cycle (TP53/PPM1D) or specific growth factor pathways (ACVR1/PIK3R1). Later oncogenic alterations arise in sub-clones and often affect the PI3K pathway. Our findings are consistent with early tumour spread outside the brainstem including the cerebrum. The spatial and temporal homogeneity of main driver mutations in DIPG implies they will be captured by limited biopsies and emphasizes the need to develop therapies specifically targeting obligate oncohistone partnerships. C1 [Nikbakht, Hamid; Li, Rui; Gayden, Tenzin; Osmond, Matthew; Papillon-Cavanagh, Simon; Bechet, Denise; Jabado, Nada; Majewski, Jacek] McGill Univ, Dept Human Genet, Montreal, PQ H3A 1B1, Canada. [Nikbakht, Hamid; Li, Rui; Osmond, Matthew; Papillon-Cavanagh, Simon; Majewski, Jacek] McGill Univ, Montreal, PQ H3A 0G1, Canada. [Nikbakht, Hamid; Li, Rui; Osmond, Matthew; Papillon-Cavanagh, Simon; Majewski, Jacek] Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada. [Panditharatna, Eshini; Kambhampati, Madhuri; Nazarian, Javad] Childrens Natl Hlth Syst, Med Genet Res Ctr, Washington, DC 20010 USA. [Panditharatna, Eshini] George Washington Univ, Sch Med & Hlth Sci, Inst Biomed Sci, Washington, DC 20052 USA. [Mikael, Leonie G.; Faury, Damien; Jabado, Nada] McGill Univ, Dept Pediat, Montreal, PQ H4A 3J1, Canada. [Mikael, Leonie G.; Faury, Damien; Jabado, Nada] McGill Univ, Heath Ctr, Res Inst, Montreal, PQ H4A 3J1, Canada. [Ho, Cheng-Ying] Childrens Natl Hlth Syst, Div Pathol, Washington, DC 20010 USA. [Hwang, Eugene I.] Childrens Natl Hlth Syst, Ctr Canc & Blood Disorders, Washington, DC 20010 USA. [Siu, Alan] George Washington Univ, Sch Med & Hlth Sci, Dept Neurol Surg, Washington, DC 20052 USA. [Ligon, Keith L.] Dana Farber Canc Inst, Dept Med Oncol, Ctr Mol Oncol Pathol, Boston, MA 02115 USA. [Ellezam, Benjamin] Univ Montreal, Dept Pathol, CHU Ste Justine, Montreal, PQ H3T 1C5, Canada. [Ingram, Wendy J.; Moore, Andrew S.] Univ Queensland, Child Hlth Res Ctr, Brisbane, Qld 4101, Australia. [Stinson, Caedyn; Moore, Andrew S.] Univ Queensland, Diamantina Inst, Brisbane, Qld 4102, Australia. [Moore, Andrew S.] Childrens Hlth Queensland Hosp & Hlth Serv, Oncol Serv, Brisbane, Qld 4101, Australia. [Warren, Katherine E.] NCI, NIH, Bethesda, MD 20892 USA. [Karamchandani, Jason] McGill Univ, Dept Pathol, Montreal Neurol Hosp, Montreal, PQ H3A 2B4, Canada. [Packer, Roger J.] Childrens Natl Hlth Syst, Ctr Neurosci & Behav Med, Brain Tumour Inst, Washington, DC 20010 USA. [Nazarian, Javad] George Washington Univ, Sch Med & Hlth Sci, Dept Integrat Syst Biol, Washington, DC 20052 USA. RP Jabado, N; Majewski, J (reprint author), McGill Univ, Dept Human Genet, Montreal, PQ H3A 1B1, Canada.; Majewski, J (reprint author), McGill Univ, Montreal, PQ H3A 0G1, Canada.; Majewski, J (reprint author), Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada.; Nazarian, J (reprint author), Childrens Natl Hlth Syst, Med Genet Res Ctr, Washington, DC 20010 USA.; Jabado, N (reprint author), McGill Univ, Dept Pediat, Montreal, PQ H4A 3J1, Canada.; Jabado, N (reprint author), McGill Univ, Heath Ctr, Res Inst, Montreal, PQ H4A 3J1, Canada.; Nazarian, J (reprint author), George Washington Univ, Sch Med & Hlth Sci, Dept Integrat Syst Biol, Washington, DC 20052 USA. EM nada.jabado@mcgill.ca; Jacek.majewski@mcgill.ca; JNazarian@childrensnational.org RI Moore, Andrew/I-6275-2012; Ingram, Wendy/F-7317-2010 OI Moore, Andrew/0000-0001-8062-1779; Ingram, Wendy/0000-0002-7063-1081 FU Genome Canada; Genome Quebec; Institute for Cancer Research of the Canadian Institutes for Health Research (CIHR) McGill University; Montreal Children's Hospital Foundation; NIH National Center for Advancing Translational Sciences [UL1TR000075, KL2TR000076]; Smashing Walnuts Foundation (Middleburg, VA); Zickler Family Foundation (Chevy Chase, MD); Goldwin Foundation (St Lincoln, NE); Piedmont Community Foundation (Middleburg, VA); Musella Foundation (Hewlett, NY); Mathew Larson Foundation (Franklin Lake, NJ); Brain Tumour Foundation for Children Atlanta, GA); Chair de Recherche from le Fond de Recherche en Sante au Quebec; CIHR; T.D trust/Montreal Children's Hospital Foundation FX The authors would like to express their sincere gratitude toward all the patients' families, as well as the staff at the McGill University and Genome Quebec Innovation Centre for excellent technical expertise, library preparation and sequencing. This work was performed within the context of the I-CHANGE consortium (International Childhood Astrocytoma iNtegrated Genomics and Epigenomics consortium) and supported by funding from Genome Canada, Genome Quebec, The Institute for Cancer Research of the Canadian Institutes for Health Research (CIHR) McGill University and the Montreal Children's Hospital Foundation. It was also supported by UL1TR000075 and KL2TR000076 from the NIH National Center for Advancing Translational Sciences, The Smashing Walnuts Foundation (Middleburg, VA), The Zickler Family Foundation (Chevy Chase, MD), Goldwin Foundation (St Lincoln, NE), The Piedmont Community Foundation (Middleburg, VA), The Musella Foundation (Hewlett, NY), The Mathew Larson Foundation (Franklin Lake, NJ), and Brain Tumour Foundation for Children Atlanta, GA). N.J. is a member of the Penny Cole lab and the recipient of a Chair de Recherche from le Fond de Recherche en Sante au Quebec. J.M. holds a Canada Research Chair (tier 2). T.G. is supported by a studentship from the CIHR. D.B. is supported by a studentship from the T.D trust/Montreal Children's Hospital Foundation. E.P. is a predoctoral student in the Molecular Medicine Program of the Institute for Biomedical Sciences at the George Washington University. This work is from a dissertation to be presented to the above program in partial fulfillment of the requirements for the PhD degree. NR 39 TC 6 Z9 6 U1 3 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 APR PY 2016 VL 7 AR 11185 DI 10.1038/ncomms11185 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI9LD UT WOS:000373823300001 PM 27048880 ER PT J AU Yu, X He, Y Wang, MS Merkle, H Dodd, SJ Silva, AC Koretsky, AP AF Yu, Xin He, Yi Wang, Maosen Merkle, Hellmut Dodd, Stephen J. Silva, Afonso C. Koretsky, Alan P. TI Sensory and optogenetically driven single-vessel fMRI SO NATURE METHODS LA English DT Article ID CEREBRAL-BLOOD-FLOW; MAGNETIC-RESONANCE; HUMAN BRAIN; OPTICAL CONTROL; BOLD FMRI; MRI; STIMULATION; CORTEX; SIGNAL; RAT AB Magnetic resonance imaging (MRI) sensitivity approaches vessel specificity. We developed a single-vessel functional MRI (fMRI) method to image the contribution of vascular components to blood oxygenation level-dependent (BOLD) and cerebral blood volume (CBV) fMRI signal. We mapped individual vessels penetrating the rat somatosensory cortex with 100-ms temporal resolution by MRI with sensory or optogenetic stimulation. The BOLD signal originated primarily from venules, and the CBV signal from arterioles. The single-vessel fMRI method and its combination with optogenetics provide a platform for mapping the hemodynamic signal through the neurovascular network with specificity at the level of individual arterioles and venules. C1 [Yu, Xin; He, Yi; Wang, Maosen] Max Planck Inst Biol Cybernet, High Field Magnet Resonance Dept, Spemannstr 38, D-72076 Tubingen, Germany. [Merkle, Hellmut; Dodd, Stephen J.; Silva, Afonso C.; Koretsky, Alan P.] NINDS, Lab Funct & Mol Imaging, US NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Yu, X (reprint author), Max Planck Inst Biol Cybernet, High Field Magnet Resonance Dept, Spemannstr 38, D-72076 Tubingen, Germany.; Koretsky, AP (reprint author), NINDS, Lab Funct & Mol Imaging, US NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM xin.yu@tuebingen.mpg.de; korestkya@mail.nih.gov FU US National Institutes of Health; US National Institute of Neurological Disorders and Stroke; Max Planck Society FX This research was supported by the Intramural Research Program of the US National Institutes of Health, the US National Institute of Neurological Disorders and Stroke and internal funding from the Max Planck Society. We thank H. Schulz, S. Fischer, K. Sharer and N. Bouraoud for technical support and A. Bonci for help with the optogenetic setup. NR 27 TC 2 Z9 2 U1 4 U2 13 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 EI 1548-7105 J9 NAT METHODS JI Nat. Methods PD APR PY 2016 VL 13 IS 4 BP 337 EP 340 DI 10.1038/NMETH.3765 PG 4 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA DJ3DK UT WOS:000374084800021 PM 26855362 ER PT J AU Amable, L AF Amable, Lauren TI Cisplatin resistance and opportunities for precision medicine SO PHARMACOLOGICAL RESEARCH LA English DT Review DE Cisplatin resistance; Nucleotide excision repair; ERCC1; Copper transporters; ABC transporters; Glutathione ID CELL LUNG-CANCER; PLATINUM-BASED CHEMOTHERAPY; S-TRANSFERASE-PI; ADENOSINE-TRIPHOSPHATASE ATP7B; MESSENGER-RNA LEVELS; NUCLEOTIDE EXCISION-REPAIR; EPITHELIAL OVARIAN-CANCER; CASSETTE SUPERFAMILY TRANSPORTER; ERCC1 CODON-118 POLYMORPHISM; ORGANIC CATION TRANSPORTER-2 AB Cisplatin is one of the most commonly used chemotherapy drugs, treating a wide range of cancer types. Unfortunately, many cancers initially respond to platinum treatment but when the tumor returns, drug resistance frequently occurs. Resistance to cisplatin is attributed to three molecular mechanisms: increased DNA repair, altered cellular accumulation, and increased drug inactivation. The use of precision medicine to make informed decisions on a patient's cisplatin resistance status and predicting the tumor response would allow the clinician to tailor the chemotherapy program based on the biology of the disease. In this review, key biomarkers of each molecular mechanism will be discussed along with the current clinical research. Additionally, known polymorphisms for each biomarker will be discussed in relation to their influence on cisplatin resistance. Published by Elsevier Ltd. C1 [Amable, Lauren] Natl Inst Minor Hlth & Hlth Dispar, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Amable, L (reprint author), Natl Inst Minor Hlth & Hlth Dispar, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM lauren.amable@nih.gov FU Intramural Research Program of the NIH, National Institute on Minority Health and Health Disparities FX The research was supported by the Intramural Research Program of the NIH, National Institute on Minority Health and Health Disparities. This manuscript is dedicated to my former mentor, Dr. Eddie Reed. NR 153 TC 15 Z9 15 U1 10 U2 26 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-6618 J9 PHARMACOL RES JI Pharmacol. Res. PD APR PY 2016 VL 106 BP 27 EP 36 DI 10.1016/j.phrs.2016.01.001 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DJ3BW UT WOS:000374080800004 PM 26804248 ER PT J AU Song, DJ Chu, ZB Luo, M Tan, Z Li, PX Han, LY Bu, SZ Yang, JL Gonzalez, FJ Liu, AM AF Song, Danjun Chu, Zanbo Luo, Min Tan, Zhen Li, Pengxu Han, Liyuan Bu, Shizhong Yang, Julin Gonzalez, F. J. Liu, Aiming TI Gemfibrozil not fenofibrate decreases systemic glucose level via PPAR alpha SO PHARMAZIE LA English DT Article ID METABOLIC SYNDROME; DIABETES-MELLITUS; DYSLIPIDEMIA; THERAPY; PROFILE; RATS AB Background: Concurrence of high glucose or diabetes in patients with dyslipidemia is presenting major challenges for clinicians. Although sporadically reported, a rational basis for the use of fibrates for the treatment of dyslipidemia with concurrent metabolic syndrome has not been established. Methods: In this study, wild-type (WT) and Ppara-null (KO) mice were fed a serial gemfibrozil- and fenofibrate-containing diet under the same experimental conditions for 14 days. Glucose level in the blood, glycogen storage in the liver tissues, and the potential toxic responses were assayed. Genes involved in glucose metabolism were determined by quantitative polymerase chain reaction analysis. Results: Both the blood glucose level and the glycogen content in the liver were down-regulated by gemfibrozil but not by fenofibrate in WT mice, in a dose-dependent manner. This decrement did not occur in KO mice for either fibrate agent. Secondary regulation on the transcription of pyruvate kinase, and gluconolactonase were observed following gemfibrozil treatment, which was differential between WT mice and KO mice. Conclusions: Gemfibrozil, not fenofibrate, down-regulates systemic glucose level and glycogen storage in the liver dependent on PPAR alpha, suggesting its potential value for treatment of dyslipidemia with concurrent diabetes or high glucose levels. C1 [Song, Danjun; Chu, Zanbo; Luo, Min; Li, Pengxu; Han, Liyuan; Bu, Shizhong; Liu, Aiming] Ningbo Univ, Sch Med, 818 Fenghua Rd, Ningbo 315211, Zhejiang, Peoples R China. [Tan, Zhen] Hunan Normal Univ, Changsha, Hunan, Peoples R China. [Yang, Julin] Ningbo Coll Hlth Sci, Ningbo, Zhejiang, Peoples R China. [Gonzalez, F. J.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Liu, AM (reprint author), Ningbo Univ, Sch Med, 818 Fenghua Rd, Ningbo 315211, Zhejiang, Peoples R China. EM liuaiming@nbu.edu.cn FU National Natural Science Foundation of China [81273582, 81302848]; K.C. Wong Magna Fund in Ningbo University; National Cancer Institute Intramural Research Program FX This work was supported by National Natural Science Foundation of China [Grant 81273582 and 81302848], the K.C. Wong Magna Fund in Ningbo University and the National Cancer Institute Intramural Research Program. NR 26 TC 1 Z9 1 U1 2 U2 8 PU GOVI-VERLAG PHARMAZEUTISCHER VERLAG GMBH PI ESCHBORN PA PHARMAZEUTISCCARL MANNICH STR 26, D-65760 ESCHBORN, GERMANY SN 0031-7144 J9 PHARMAZIE JI Pharmazie PD APR PY 2016 VL 71 IS 4 BP 205 EP 212 DI 10.1691/ph.2016.5776 PG 8 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA DJ1MG UT WOS:000373966300009 PM 27209701 ER PT J AU Suls, J Green, PA Davidson, KW AF Suls, Jerry Green, Paige A. Davidson, Karina W. TI A Behavioral Framework to Address the Emerging Challenge of Multimorbidity SO PSYCHOSOMATIC MEDICINE LA English DT Review DE multimorbidity; comorbidity; behavioralmedicine; health psychology; biopsychosocial model; multiple chronic conditions ID MULTIPLE CHRONIC CONDITIONS; QUALITY-OF-LIFE; CARDIOVASCULAR-DISEASE; COLORECTAL-CANCER; OLDER PERSONS; RISK-FACTORS; HEALTH; COMORBIDITY; DEPRESSION; CARE AB Multimorbidity, the co-occurrence of multiple physical or psychological illnesses, is prevalent particularly among older adults. The number of Americans with multiple chronic diseases is projected to increase from 57 million in 2000 to 81 million in 2020. However, behavioral medicine and health psychology, while focusing on the co-occurrence of psychological/psychiatric disorders with primary medical morbidities, have historically tended to ignore the co-occurrence of primary medical comorbidities, such as diabetes and cancer, and their biopsychosocial implications. This approach may hinder our ecologically valid understanding of the etiology, prevention, and treatment for individual patients with multimorbidity. In this selective review, we propose a heuristic behavioral framework for the etiology of multimorbidity. More acknowledgment and systematic research on multiple, co-existing disorders in behavioral medicine are consistent with the biopsychosocial model's emphasis on treating the "whole person," which means not considering any single illness, its symptoms, risk factors, or mechanisms, in isolation. As systems analytics, big data, machine learning, and mixed-model trajectory analyses, among others, come online and become more widely available, we may be able to tackle multimorbidity more holistically, efficiently, and satisfactorily. C1 [Suls, Jerry] NCI, Off Associate Director, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Green, Paige A.] NCI, Behav & Psychol Sci Branch, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Davidson, Karina W.] Columbia Univ, Ctr Behav Cardiovasc Hlth, Dept Med, Coll Med, New York, NY USA. RP Suls, J (reprint author), NCI, Off Associate Director, Behav Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr,MSC 9761, Bethesda, MD 20892 USA. EM jerry.suls@nih.gov OI Green, Paige/0000-0001-7886-8924 FU National Heart, Lung, and Blood Institute [HL-101663, HL-84034, HL114924, HL-115941]; Patient-Centered Outcomes Research Institute [ME-1403-12304]; New York Presbyterian Hospital FX Authors Suls and Green received no support. Davidson's work was supported by Grants HL-101663, HL-84034, HL114924, and HL-115941 from the National Heart, Lung, and Blood Institute. Additional support was provided by contract ME-1403-12304 from Patient-Centered Outcomes Research Institute and the New York Presbyterian Hospital. Davidson is the co-owner of MJBK, a small business that provides mhealth technology solutions to consumers. She is also the co-owner of IOHealthWorks, a small consulting services company. She is a member of the United States Preventive Services Task Force. The authors have no conflicts of interest to report. NR 74 TC 2 Z9 2 U1 7 U2 15 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0033-3174 EI 1534-7796 J9 PSYCHOSOM MED JI Psychosom. Med. PD APR PY 2016 VL 78 IS 3 BP 281 EP 289 DI 10.1097/PSY.0000000000000294 PG 9 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA DJ1FY UT WOS:000373949900004 PM 26867072 ER PT J AU Kalarchian, MA King, WC Devlin, MJ Marcus, MD Garcia, L Chen, JY Yanovski, SZ Mitchell, JE AF Kalarchian, Melissa A. King, Wendy C. Devlin, Michael J. Marcus, Marsha D. Garcia, Luis Chen, Jia-Yuh Yanovski, Susan Z. Mitchell, James E. TI Psychiatric Disorders and Weight Change in a Prospective Study of Bariatric Surgery Patients: A 3-Year Follow-Up SO PSYCHOSOMATIC MEDICINE LA English DT Article DE psychiatric disorders; bariatric surgery; eating disorders; weight change ID LONGITUDINAL ASSESSMENT; GASTRIC BYPASS; EATING-DISORDERS; CANDIDATES; OUTCOMES; HEALTH; PREVALENCE; DEPRESSION; OBESITY; ABSORPTION AB Objectives: To document changes in Axis I psychiatric disorders after bariatric surgery and examine their relationship with postsurgery weight loss. Methods: As part of a three-site substudy of the Longitudinal Assessment of Bariatric Surgery Research Consortium, 199 patients completed the Structured Clinical Interview for DSM-IV before Roux-en-Y gastric bypass or laparoscopic adjustable gastric band. At 2 or 3 years after surgery, 165 (83%) patients completed a follow-up assessment (presurgery median body mass index = 44.8 kg/m(2), median age = 46 years, 92.7% white, 81.1% female). Linear-mixed modeling was used to test change in prevalence of psychiatric disorders over time, report remission and incidence, and examine associations between psychiatric disorders and weight loss. Results: Compared with status presurgery, the prevalence of any Axis I psychiatric disorder was significantly lower at 2 and 3 years after surgery (30.2% versus 16.8% [p =.003] and 18.4% [p =.012], respectively). Adjusting for site, age, sex, race, presurgery body mass index, and surgical procedure, presurgery mood, anxiety, eating or substance use disorders (lifetime or current) were not related to weight change, nor were postsurgery mood or anxiety disorders (p for all >.05). However, having a postsurgery eating disorder was independently associated with less weight loss at 2 or 3 years (beta = 6.7%, p = .035). Conclusions: Bariatric surgery was associated with decreases in psychiatric disorders through 3 years after surgery. Postsurgical eating disorders were associated with less weight loss after surgery, adding to the literature suggesting that disordered eating after surgery is related to suboptimal weight loss. C1 [Kalarchian, Melissa A.] Duquesne Univ, Sch Nursing, 600 Forbes Ave, Pittsburgh, PA 15282 USA. [King, Wendy C.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Chen, Jia-Yuh] Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15261 USA. [Devlin, Michael J.] Columbia Univ Coll Phys & Surg, New York State Psychiat Inst, 630 W 168th St, New York, NY 10032 USA. [Marcus, Marsha D.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Garcia, Luis] Sanford Hlth Syst, Grand Forks, ND USA. [Garcia, Luis] Univ N Dakota, Sch Med & Hlth Sci, Grand Forks, ND 58201 USA. [Yanovski, Susan Z.] NIDDK, Div Digest Dis & Nutr, Bethesda, MD 20892 USA. [Mitchell, James E.] Neuropsychiat Res Inst, Grand Forks, ND USA. [Mitchell, James E.] Univ N Dakota, Sch Med & Hlth Sci, Grand Forks, ND 58201 USA. RP Kalarchian, MA (reprint author), Duquesne Univ, Sch Nursing, 600 Forbes Ave, Pittsburgh, PA 15282 USA. EM kalarchianm@duq.edu OI King, Wendy/0000-0002-0740-0029 FU National Institute of Diabetes and Digestive and Kidney Diseases [DSS-U01DK066557, U01-DK66667, R01 DK084979]; Cornell University Medical Center CTSC [UL1-RR024996]; Neuropsychiatric Research Institute [U01-DK66471]; University of Pittsburgh Medical Center [U01-DK66585]; CTRC [UL1-RR0241531]; The Obesity Society/Nutrisystem; American Society for Metabolic and Bariatric Surgery FX This clinical study was a cooperative agreement funded by the National Institute of Diabetes and Digestive and Kidney Diseases (Grant DSS-U01DK066557; Columbia, U01-DK66667), in collaboration with Cornell University Medical Center CTSC (Grant UL1-RR024996], Neuropsychiatric Research Institute (Grant U01-DK66471), and University of Pittsburgh Medical Center (Grant U01-DK66585 [in collaboration with CTRC, Grant UL1-RR0241531]). In addition, this study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases (Grant R01 DK084979). Dr. Kalarchian reports receiving funding for research in bariatric surgery from The Obesity Society/Nutrisystem and the American Society for Metabolic and Bariatric Surgery. Dr. Devlin reports royalties from Wolters Kluwer Health. Dr. Marcus reports honoraria from the Scientific Advisory Board and Weight Watchers International. Dr. Mitchell reports royalties for books from American Psychiatric Press Inc, Guilford, and Routledge. Drs. King, Garcia, and Yanovski, and Ms. Chen report no conflicts of interest. NR 35 TC 6 Z9 7 U1 4 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0033-3174 EI 1534-7796 J9 PSYCHOSOM MED JI Psychosom. Med. PD APR PY 2016 VL 78 IS 3 BP 373 EP 381 DI 10.1097/PSY.0000000000000277 PG 9 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA DJ1FY UT WOS:000373949900014 PM 26569540 ER PT J AU Taber, JM Klein, WMP AF Taber, Jennifer M. Klein, William M. P. TI The Role of Conviction in Personal Disease Risk Perceptions: What Can We Learn From Research on Attitude Strength? SO SOCIAL AND PERSONALITY PSYCHOLOGY COMPASS LA English DT Article ID SOCIAL-COMPARISON INFORMATION; BREAST-CANCER RISK; PERCEIVED RISK; DONT KNOW; EDUCATIONAL INTERVENTIONS; BEHAVIORAL-RESPONSES; COLORECTAL-CANCER; PLANNED BEHAVIOR; DECISION-MAKING; METAANALYSIS AB Perceived risk for disease is included as a predictor of intentions and behavior in many health behavior theories. However, perceived risk is not always a strong predictor of intentions and behaviors. One reason may be suboptimal conceptualization and measurement of risk perceptions; in particular, research may not capture the conviction and certainty with which a risk perception is held. The rich and independent literature on attitudes might be leveraged to explore whether conviction is an important moderator of the effects of risk perceptions on intentions and behavior. Attitudes are more predictive of intentions when they are high in multiple aspects of attitude strength, including attitude certainty and being more accessible and stable over time. Working from the assumption that risk perceptions have a similar structure and function to attitudes, we consider whether factors known to strengthen the attitude-behavior correspondence might also strengthen the risk perception-behavior correspondence. Although by strict definition risk perceptions are not evaluations (a critical component of attitudes), the predictive validity of risk perceptions may be increased by attention to one's "conviction" or certainty of perceived risk. We also review recent strategies designed to improve risk perception measurement, including affective and experiential assessments of perceived risk and the importance of allowing people to indicate that they "don't know" their disease risk. The aim of this paper is to connect two disparate literatures - attitudes and persuasion in social psychology with risk perceptions in health psychology and decision science - in an attempt to stimulate more work on characteristics and proper measurement of risk perceptions. C1 [Taber, Jennifer M.; Klein, William M. P.] NCI, NIH, Bethesda, MD 20892 USA. RP Taber, JM (reprint author), Kent State Univ, Dept Psychol Sci, 309 Kent Hall Annex, Kent, OH 44242 USA. EM jtaber1@kent.edu FU Intramural NIH HHS [Z99 CA999999] NR 71 TC 0 Z9 0 U1 3 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1751-9004 J9 SOC PERSONAL PSYCHOL JI Soc. Personal. Psychol. Compass PD APR PY 2016 VL 10 IS 4 BP 202 EP 218 DI 10.1111/spc3.12244 PG 17 WC Psychology, Multidisciplinary SC Psychology GA DI8TJ UT WOS:000373774500003 PM 27127537 ER PT J AU Zhang, JW Landick, R AF Zhang, Jinwei Landick, Robert TI A Two-Way Street: Regulatory Interplay between RNA Polymerase and Nascent RNA Structure SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Review ID OPERON LEADER REGION; ELONGATION-FACTOR NUSA; ESCHERICHIA-COLI; TRIGGER LOOP; IN-VITRO; BACILLUS-SUBTILIS; TRANSCRIPTION ELONGATION; SECONDARY STRUCTURE; INVITRO TRANSCRIPTION; NUCLEOTIDE RESOLUTION AB The vectorial (5'-to-3' at varying velocity) synthesis of RNA by cellular RNA polymerases (RNAPs) creates a rugged kinetic landscape, demarcated by frequent, sometimes long-lived, pauses. In addition to myriad gene-regulatory roles, these pauses temporally and spatially program the co-transcriptional, hierarchical folding of biologically active RNAs. Conversely, these RNA structures, which form inside or near the RNA exit channel, interact with the polymerase and adjacent protein factors to influence RNA synthesis by modulating pausing, termination, antitermination, and slippage. Here, we review the evolutionary origin, mechanistic underpinnings, and regulatory consequences of this interplay between RNAP and nascent RNA structure. We categorize and rationalize the extensive linkage between the transcriptional machinery and its product, and provide a framework for future studies. C1 [Zhang, Jinwei] NIDDK, Mol Biol Lab, Bethesda, MD 20892 USA. [Landick, Robert] Univ Wisconsin, Dept Biochem, Madison, WI 53706 USA. [Landick, Robert] Univ Wisconsin, Dept Bacteriol, Madison, WI 53706 USA. RP Zhang, JW (reprint author), NIDDK, Mol Biol Lab, Bethesda, MD 20892 USA.; Landick, R (reprint author), Univ Wisconsin, Dept Biochem, Madison, WI 53706 USA.; Landick, R (reprint author), Univ Wisconsin, Dept Bacteriol, Madison, WI 53706 USA. EM jinwei.zhang@nih.gov; landick@biochem.wisc.edu FU NIH [GM38660]; NIDDK, NIH FX We thank David Brow, Andreas Mayer, and members of the Landick lab for many helpful suggestions on the manuscript. Research in the laboratory of R.L. is supported by a grant from the NIH (GM38660). Research in the laboratory of J.Z. is supported by the intramural research program of NIDDK, NIH. We apologize in advance to our colleagues that lack of space precluded us from citing all the relevant prior publications. NR 141 TC 6 Z9 6 U1 7 U2 13 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0968-0004 J9 TRENDS BIOCHEM SCI JI Trends Biochem.Sci. PD APR PY 2016 VL 41 IS 4 BP 293 EP 310 DI 10.1016/j.tibs.2015.12.009 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DJ2ZW UT WOS:000374075200003 PM 26822487 ER PT J AU Kirmse, B Yao, TJ Hofherr, S Kacanek, D Williams, PL Hobbs, CV Hazra, R Borkowsky, W Van Dyke, RB Summar, M AF Kirmse, Brian Yao, Tzy-Jyun Hofherr, Sean Kacanek, Deborah Williams, Paige L. Hobbs, Charlotte V. Hazra, Rohan Borkowsky, William Van Dyke, Russell B. Summar, Marshall CA PHACS TI Acylcarnitine Profiles in HIV-Exposed, Uninfected Neonates in the United States SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID FATTY-ACID OXIDATION; HUMAN-IMMUNODEFICIENCY-VIRUS; ANTIRETROVIRAL DRUG EXPOSURE; TANDEM MASS-SPECTROMETRY; PROTEASE INHIBITORS; IN-UTERO; INSULIN-RESISTANCE; METABOLIC PROFILES; GESTATIONAL-AGE; FUTURE HEALTH AB We sought to determine the prevalence of abnormal acylcarnitine profiles (ACP) in HIV-exposed uninfected (HEU) newborns and to explore the association of abnormal ACP with clinical laboratory outcomes and antiretroviral drug exposures. Clinically, ACP are used to assess for fatty acid oxidation (FAO) dysfunction and normal FAO is necessary for optimal fetal/neonatal growth and development. We analyzed serum ACP in 522 HEU neonates enrolled in the Surveillance Monitoring for ART Toxicities (SMARTT) study of the Pediatric HIV/AIDS Cohort Study (PHACS) and evaluated the associations of abnormal ACP with in utero exposure to combination antiretroviral therapy (cART) in logistic regression models, adjusting for maternal demographic, disease, and behavioral characteristics. We evaluated the associations of abnormal ACP with laboratory parameters and measures of neurodevelopment and growth. Of 522 neonates, 89 (17%) had abnormal ACP. In adjusted analyses, in utero exposure to a protease inhibitor (PI) was associated with higher odds of having an abnormal ACP [adjusted odds ratio (aOR)=2.35, 95% CI: 0.96, 5.76, p=0.06] with marginal significance while exposure to a nonnucleoside reverse transcriptase inhibitor (NNRTI) was associated with lower odds (aOR=0.23, 95% CI: 0.07, 0.80, p=0.02). Mean ALT levels were slightly higher in those with abnormal ACP, but no differences in lactate, glucose, or CPK were observed. ACP status was not associated with neurodevelopment at 1 year or growth at 2 and 3 years of age. Abnormal ACP in HEU neonates are associated with exposure to PI-containing as opposed to NNRTI-containing antiretroviral (ARV) regimens but are not associated with serious postnatal clinical problems. Further studies are needed to determine the long-term health implications of abnormal acylcarnitine metabolism at birth in HEU children. C1 [Kirmse, Brian; Hofherr, Sean; Summar, Marshall] Childrens Natl Hlth Syst, Div Genet & Metab, Washington, DC USA. [Yao, Tzy-Jyun; Kacanek, Deborah; Williams, Paige L.] Harvard TH Chan Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA USA. [Hobbs, Charlotte V.; Borkowsky, William] NYU, Langone Sch Med, Div Pediat Infect Dis & Immunol, New York, NY USA. [Hazra, Rohan] NICHD, NIH, Maternal & Pediat Infect Dis Branch, Bethesda, MD USA. [Van Dyke, Russell B.] Tulane Univ, Sch Med, New Orleans, LA 70118 USA. [Kirmse, Brian] Univ Mississippi, Med Ctr, Dept Pediat, Div Med Genet, Jackson, MS 39216 USA. RP Kirmse, B (reprint author), Childrens Natl Med Ctr Genet & Metab, 111 Michigan Ave NW Suite 4800, Washington, DC 20010 USA. EM bkirmse@cnmc.org FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute on Drug Abuse; National Institute of Allergy and Infectious Diseases; Office of AIDS Research; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; National Institute on Deafness and Other Communication Disorders; National Heart Lung and Blood Institute; National Institute of Dental and Craniofacial Research; National Institute on Alcohol Abuse and Alcoholism; Harvard University School of Public Health [HD052102]; Tulane University School of Medicine [HD052104]; NIH National Center for Advancing Translational Sciences [KL2TR000076] FX We thank the children and families for their participation in PHACS, and the individuals and institutions involved in the conduct of PHACS. The study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development with co-funding from the National Institute on Drug Abuse, the National Institute of Allergy and Infectious Diseases, the Office of AIDS Research, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Institute on Deafness and Other Communication Disorders, the National Heart Lung and Blood Institute, the National Institute of Dental and Craniofacial Research, and the National Institute on Alcohol Abuse and Alcoholism, through cooperative agreements with the Harvard University School of Public Health (HD052102) (Principal Investigator: George Seage; Project Director: Julie Alperen) and the Tulane University School of Medicine (HD052104) (Principal Investigator: Russell Van Dyke; Co-Principal Investigator: Kenneth Rich; Project Director: Patrick Davis). Data management services were provided by Frontier Science and Technology Research Foundation (PI: Suzanne Siminski) and regulatory services and logistical support were provided by Westat, Inc. (PI: Julie Davidson). B.K. was supported by KL2TR000076 from the NIH National Center for Advancing Translational Sciences. NR 50 TC 2 Z9 2 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD APR 1 PY 2016 VL 32 IS 4 BP 339 EP 348 DI 10.1089/aid.2015.0112 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DI5JE UT WOS:000373533900006 PM 26548585 ER PT J AU Spaulding, AB Yu, QL Civitello, L Mussi-Pinhata, MM Pinto, J Gomes, IM Alarcon, JO Siberry, GK Harris, R Hazra, R AF Spaulding, Alicen B. Yu, Qilu Civitello, Lucy Mussi-Pinhata, Marisa M. Pinto, Jorge Gomes, Ivete M. Alarcon, Jorge O. Siberry, George K. Harris, Robert Hazra, Rohan CA NISDI LILAC Study Team TI Neurologic Outcomes in HIV-Exposed/Uninfected Infants Exposed to Antiretroviral Drugs During Pregnancy in Latin America and the Caribbean SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID PERSISTENT MITOCHONDRIAL DYSFUNCTION; PERINATAL EXPOSURE; NUCLEOSIDE ANALOGS; UNINFECTED INFANTS; INFECTED WOMEN; CHILDREN; SCHIZOPHRENIA; TRANSMISSION; AGE; COMPROMISE AB To evaluate antiretroviral (ARV) drug exposure and other factors during pregnancy that may increase the risk of neurologic conditions (NCs) in HIV-exposed/uninfected (HEU) infants. A prospective cohort study was conducted at 24 clinical sites in Latin America and the Caribbean. Data on maternal demographics, health, HIV disease status, and ARV use during pregnancy were collected. Infant data included measurement of head circumference after birth and reported medical diagnoses at birth, 6-12 weeks, and 6 months. Only infants with maternal exposure to combination ARV therapy (cART) (3 drugs from 2 drug classes) during pregnancy were included. Microcephaly, defined as head circumference for age z-score less than -2, and NC were evaluated for their association with covariates, including individual ARVs, using bivariable and logistic regression analyses. From 2002 to 2009, 1,400 HEU infants met study inclusion criteria. At least one NC was reported in 134 (9.6%; 95% confidence interval [CI]: 8.1-11.2), microcephaly in 105 (7.5%; 95% CI: 6.2-9.0), and specific neurologic diagnoses in 33 (2.4%; 95% CI: 1.6-3.3) HEU infants. Microcephaly and NC were not significantly associated with any specific ARV analyzed (p>0.05). Covariates associated with increased odds of NC included male sex (odds ratio [OR]=1.9; 95% CI: 1.3-2.8), birth weight <2.5kg (OR=3.1; 95% CI: 2.1-4.8), 1-min Apgar score <7 (OR=2.5; 95% CI: 1.4-4.4), and infant infections (OR=2.5; 95% CI: 1.5-4.1). No ARV investigated was associated with adverse neurologic outcomes. Continued investigation of such associations may be warranted as new ARVs are used during pregnancy and cART exposure during the first trimester becomes increasingly common. C1 [Spaulding, Alicen B.] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Yu, Qilu; Harris, Robert] Westat Corp, Rockville, MD USA. [Civitello, Lucy] Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. [Mussi-Pinhata, Marisa M.] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pediat, Sao Paulo, Brazil. [Pinto, Jorge] Univ Fed Minas Gerais, Sch Med, Div Immunol, Belo Horizonte, MG, Brazil. [Gomes, Ivete M.] Hosp Geral Nova Iguacu, Rio De Janeiro, Brazil. [Alarcon, Jorge O.] Univ San Marcos, Inst Med Trop Daniel Alcides Carrion, Lima, Peru. [Siberry, George K.; Hazra, Rohan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Hazra, R (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, NIH, 6100 Execut Blvd,Room 4B11, Bethesda, MD 20892 USA. EM hazrar@mail.nih.gov OI Alarcon, Jorge/0000-0002-0800-2380 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [N01-HD-3-3345, HHSN267200800001C, HHSN275201300003C] FX The NICHD International Site Development Initiative Perinatal/LILAC Protocol principal investigators, coprincipal investigators, study coordinators, coordinating center representatives, and the NICHD staff include the following: Argentina: Buenos Aires: Marcelo H. Losso, Irene Foradori, Alejandro Hakim, Erica Stankievich, Silvina Ivalo (Hospital General de Agudos Jose 'Maria Ramos Mejia); Brazil: Belo Horizonte: Jorge A. Pinto, Victor H. Melo, Fabiana Kakehasi, Beatriz M. Andrade (Universidade Federal de Minas Gerais); Caxias do Sul: Rosa Dea Sperhacke, Nicole Golin, Silvia Mariani Costamilan (Universidade de Caxias do Sul/Servico Municipal de Infectologia); Nova Iguacu: Jose Pilotto, Luis Eduardo Fernandes, Gisely Falco (Hospital Geral Nova de Iguacu-HIV Family Care Clinic); Porto Alegre: Rosa Dea Sperhacke, Breno Riegel Santos, Rita de Cassia Alves Lira (Universidade de Caxias do Sul/Hospital Conceicao); Rosa Dea Sperhacke, Mario Ferreira Peixoto, Elizabete Teles (Universidade de Caxias do Sul/Hospital Femina); Regis Kreitchmann, Luis Carlos Ribeiro, Fabrizio Motta, Debora Fernandes Coelho (Irmandade da Santa Casa de Misericordia de Porto Alegre); Ribeirao Preto: Marisa M. Mussi-Pinhata, Geraldo Duarte, Adriana A. Tiraboschi Barbaro, Conrado Milani Coutinho, Fabiana Rezende Amaral, Anderson Sanches de Melo (Hospital das Clinicas da Faculdade de Medicina de Ribeirao Preto da Universidade de Sao Paulo); Rio de Janeiro: Ricardo Hugo S. Oliveira, Elizabeth S. Machado, Maria C. Chermont Sapia (Instituto de Puericultura e Pediatria Martagao Gesteira); Esau Custodio Joao, Leon Claude Sidi, Maria Leticia Santos Cruz, Maria Isabel Gouvea, Mariza Curto Saavedra, Clarisse Bressan, Fernanda Cavalcanti A. Jundi (Hospital dos Servidores do Estado); Sao Paulo: Regina Celia de Menezes Succi, Prescilla Chow (Escola Paulista de Medicina-Universidade Federal de Sao Paulo); Peru: Lima: Jorge O. Alarcon Villaverde (Instituto de Medicina Tropical "Daniel Alcides Carrion''- Seccion de Epidemiologia, UNMSM), Carlos Velasquez Vasquez (Instituto Nacional Materno Perinatal), Cesar Gutierrez Villafuerte (Instituto de Medicina Tropical "Daniel Alcides Carrion''- Seccion de Epidemiologia, UNMSM); Data Management and Statistical Center: Yolanda Bertucci, Rachel Cohen, Laura Freimanis Hance, Rene Gonin, D. Robert Harris, Roslyn Hennessey, James Korelitz, Margot Krauss, Sue Li, Karen Megazzini, Orlando Ortega, Sharon Sothern de Sanchez, Sonia K. Stoszek, Qilu Yu (Westat, Rockville, MD, USA); and NICHD: George K. Siberry, Rohan Hazra, Lynne M. Mofenson (Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA). This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) contracts N01-HD-3-3345 (2002-2007), HHSN267200800001C (2007-2012), and HHSN275201300003C (2012-2017). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 25 TC 1 Z9 1 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD APR 1 PY 2016 VL 32 IS 4 BP 349 EP 356 DI 10.1089/aid.2015.0254 PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DI5JE UT WOS:000373533900007 PM 26879281 ER PT J AU Hingson, R Zha, WX Simons-Morton, B White, A AF Hingson, Ralph Zha, Wenxing Simons-Morton, Bruce White, Aaron TI Alcohol-Induced Blackouts as Predictors of Other Drinking Related Harms Among Emerging Young Adults SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Blackouts; Emerging Adults; Predictors; Correlates; Incidence ID COLLEGE-STUDENTS; FRAGMENTARY BLACKOUTS; MEMORY BLACKOUTS; BINGE DRINKING; UNITED-STATES; PREVALENCE; SCHOOL; BRAIN; RISK; INTERVENTIONS AB BackgroundAlcohol-related blackouts are periods of amnesia that reflect the failure of the brain to record memories of what transpires while drinking. This paper examined the incidence, predictors, and behavioral correlates of blackouts among emerging adults and examined whether questions about blackouts could serve as better markers of risk for other alcohol related harms than questions about levels of consumption. MethodsIn 2012 to 2013, 1,463 (68%) of 2,140 respondents 1-year past high school reported having consumed alcohol. They were asked whether, in the past 6months because of drinking, they forgot where they were or what they did. The survey also explored demographics, substance use behaviors, and other alcohol-related problems in the past 6months. Chi-square and logistic regression analyses explored bivariate and multivariate predictors of blackouts and other alcohol-related problems. ResultsTwenty percent of respondents who ever drank alcohol reported a blackout in the past 6months. Blackouts were more prevalent among females and those who, in the past 30days, used multiple drugs, more frequently binged, were drunk, smoked, had lower body weight, and lived in college dorms. After controlling for drinking levels, having a blackout was the strongest independent predictor of most other alcohol problems examined, including in the past 6months because of drinking, missing class or work, getting behind in work or school, doing something respondents later regretted, arguing with friends, experiencing an overdose, and total number of alcohol problems reported. It was also an independent predictor of hangovers, damaging property, getting hurt, and trouble with police. ConclusionsBecause blackouts indicate drinking at levels that result in significant cognitive and behavioral impairment, questions about blackouts could serve as important, simple screeners for the risk of experiencing other alcohol related harms. Additional work on this subject is warranted. C1 [Hingson, Ralph; Zha, Wenxing] NIAAA, Div Epidemiol & Prevent Res, 5635 Fishers Lane,Room 2074, Bethesda, MD 20892 USA. [Simons-Morton, Bruce] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Rockville, MD USA. [White, Aaron] NIAAA, Rockville, MD 20852 USA. RP Hingson, R (reprint author), NIAAA, 5635 Fishers Lane,Room 2074, Bethesda, MD 20892 USA. EM rhingson@mail.nih.gov OI Simons-Morton, Bruce/0000-0003-1099-6617 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Heart, Lung and Blood Institute (NHLBI); National Institute on Alcohol Abuse and Alcoholism (NIAAA); Maternal and Child Health Bureau (MCHB) of the Health Resources and Services Administration (HRSA); National Institute on Drug Abuse (NIDA) [HHSN275201200001I] FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Heart, Lung and Blood Institute (NHLBI), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), and Maternal and Child Health Bureau (MCHB) of the Health Resources and Services Administration (HRSA), with supplemental support from the National Institute on Drug Abuse (NIDA). Contract # HHSN275201200001I. The authors have no conflicts of interest to report. NR 36 TC 4 Z9 4 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD APR PY 2016 VL 40 IS 4 BP 776 EP 784 DI 10.1111/acer.13010 PG 9 WC Substance Abuse SC Substance Abuse GA DI8GK UT WOS:000373739300015 PM 27012148 ER PT J AU Cashman, KD Dowling, KG Skrabakova, Z Gonzalez-Gross, M Valtuena, J De Henauw, S Moreno, L Damsgaard, CT Michaelsen, KF Molgaard, C Jorde, R Grimnes, G Moschonis, G Mavrogianni, C Manios, Y Thamm, M Mensink, GBM Rabenberg, M Busch, MA Cox, L Meadows, S Goldberg, G Prentice, A Dekker, JM Nijpels, G Pilz, S Swart, KM van Schoor, NM Lips, P Eiriksdottir, G Gudnason, V Cotch, MF Koskinen, S Lamberg-Allardt, C Durazo-Arvizu, RA Sempos, CT Kiely, M AF Cashman, Kevin D. Dowling, Kirsten G. Skrabakova, Zuzana Gonzalez-Gross, Marcela Valtuena, Jara De Henauw, Stefaan Moreno, Luis Damsgaard, Camilla T. Michaelsen, Kim F. Molgaard, Christian Jorde, Rolf Grimnes, Guri Moschonis, George Mavrogianni, Christina Manios, Yannis Thamm, Michael Mensink, Gert B. M. Rabenberg, Martina Busch, Markus A. Cox, Lorna Meadows, Sarah Goldberg, Gail Prentice, Ann Dekker, Jacqueline M. Nijpels, Giel Pilz, Stefan Swart, Karin M. van Schoor, Natasja M. Lips, Paul Eiriksdottir, Gudny Gudnason, Vilmundur Cotch, Mary Frances Koskinen, Seppo Lamberg-Allardt, Christel Durazo-Arvizu, Ramon A. Sempos, Christopher T. Kiely, Mairead TI Vitamin D deficiency in Europe: pandemic? SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE vitamin D deficiency; prevalence; 25(OH)D; standardized; Europe ID STANDARDIZATION PROGRAM PROTOCOLS; 25-HYDROXYVITAMIN D DATA; GERMAN HEALTH INTERVIEW; LIFE-STYLE; SERUM 25-HYDROXYVITAMIN-D; COHORT PROFILE; SCHOOL MEALS; D ASSAYS; DESIGN; ADOLESCENTS AB Background: Vitamin D deficiency has been described as being pandemic, but serum 25-hydroxyvitamin D [25(OH)D] distribution data for the European Union are of very variable quality. The NIH-led international Vitamin D Standardization Program (VDSP) has developed protocols for standardizing existing 25(OH)D values from national health/nutrition surveys. Objective: This study applied VDSP protocols to serum 25(OH)D data from representative childhood/teenage and adult/older adult European populations, representing a sizable geographical footprint, to better quantify the prevalence of vitamin D deficiency in Europe. Design: The VDSP protocols were applied in 14 population studies [reanalysis of subsets of serum 25(OH)D in 11 studies and complete analysis of all samples from 3 studies that had not previously measured it] by using certified liquid chromatography-tandem mass spectrometry on biobanked sera. These data were combined with standardized serum 25(OH)D data from 4 previously standardized studies (for a total n = 55,844). Prevalence estimates of vitamin D deficiency [using various serum 25(OH)D thresholds] were generated on the basis of standardized 25(OH)D data. Results: An overall pooled estimate, irrespective of age group, ethnic mix, and latitude of study populations, showed that 13.0% of the 55,844 European individuals had serum 25(OH)D concentrations <30 nmol/L on average in the year, with 17.7% and 8.3% in those sampled during the extended winter (October-March) and summer (April-November) periods, respectively. According to an alternate suggested definition of vitamin D deficiency (<50 nmol/L), the prevalence was 40.4%. Dark-skinned ethnic subgroups had much higher (3- to 71-fold) prevalence of serum 25(OH)D <30 nmol/L than did white populations. Conclusions: Vitamin D deficiency is evident throughout the European population at prevalence rates that are concerning and that require action from a public health perspective. What direction these strategies take will depend on European policy but should aim to ensure vitamin D intakes that are protective against vitamin D deficiency in the majority of the European population. C1 [Cashman, Kevin D.; Dowling, Kirsten G.; Skrabakova, Zuzana; Kiely, Mairead] Univ Coll Cork, Sch Food & Nutrit Sci, Cork Ctr Vitamin & Nutr Res, Cork, Ireland. [Cashman, Kevin D.] Univ Coll Cork, Dept Med, Cork, Ireland. [Kiely, Mairead] Univ Coll Cork, Irish Ctr Fetal & Neonatal Translat Res, Cork, Ireland. [Gonzalez-Gross, Marcela; Valtuena, Jara] Tech Univ Madrid, Dept Hlth & Human Performance, ImFINE Res Grp, Madrid, Spain. [Gonzalez-Gross, Marcela] Inst Salud Carlos III, CIBERobn, CIBER CB12/03/30038 Fisiopatol Obesidad Nutr, Madrid, Spain. [De Henauw, Stefaan] Univ Ghent, Dept Publ Hlth, B-9000 Ghent, Belgium. [Moreno, Luis] Univ Zaragoza, Fac Hlth Sci, Growth Exercise Nutr & Dev Res Grp, Zaragoza, Spain. [Damsgaard, Camilla T.; Michaelsen, Kim F.; Molgaard, Christian] Univ Copenhagen, Fac Sci, Dept Nutr Exercise & Sports, Frederiksberg, Denmark. [Jorde, Rolf; Grimnes, Guri] UiT Arct Univ Norway, Dept Clin Med, Tromso Endocrine Res Grp, Tromso, Norway. [Moschonis, George; Mavrogianni, Christina; Manios, Yannis] Harokopio Univ, Dept Nutr & Dietet, Athens, Greece. [Thamm, Michael; Mensink, Gert B. M.; Rabenberg, Martina; Busch, Markus A.] Robert Koch Inst, Dept Epidemiol & Hlth Monitoring, Berlin, Germany. [Cox, Lorna; Meadows, Sarah; Goldberg, Gail; Prentice, Ann] Elsie Widdowson Lab, Med Res Council Human Nutr Res Unit, Cambridge, England. [Dekker, Jacqueline M.; Swart, Karin M.; van Schoor, Natasja M.] Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res, Dept Epidemiol & Biostat, Amsterdam, Netherlands. [Nijpels, Giel] Vrije Univ Amsterdam, Med Ctr, Dept Gen Practice & Elderly Care Med, Amsterdam, Netherlands. [Lips, Paul] Vrije Univ Amsterdam, Med Ctr, Dept Internal Med Sect Endocrinol, Amsterdam, Netherlands. [Pilz, Stefan] Med Univ Graz, Dept Internal Med, Div Endocrinol & Metab, Graz, Austria. [Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Cotch, Mary Frances] NIH, Natl Eye Inst, Div Epidemiol & Clin Applicat, Bethesda, MD USA. [Sempos, Christopher T.] NIH, Off Dietary Supplements, Bethesda, MD USA. [Koskinen, Seppo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Dept Hlth Funct Capac & Welf, Helsinki, Finland. [Lamberg-Allardt, Christel] Univ Helsinki, Dept Food & Environm Sci, Helsinki, Finland. [Durazo-Arvizu, Ramon A.] Loyola Univ, Stritch Sch Med, Dept Publ Hlth Sci, Chicago, IL USA. RP Cashman, KD (reprint author), Univ Coll Cork, Sch Food & Nutrit Sci, Cork Ctr Vitamin & Nutr Res, Cork, Ireland.; Cashman, KD (reprint author), Univ Coll Cork, Dept Med, Cork, Ireland. EM k.cashman@ucc.ie RI Mensink, Gert/B-2447-2009 OI Mensink, Gert/0000-0001-6268-5998 FU European Commission [613977] FX Supported by funding from the European Commission under its Seventh Framework Programme (Food-based solutions for optimal vitamin D nutrition and health through the life cycle; grant 613977). The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the NIH, the US Department of Health and Human Services, or the US Department of Commerce. This is a free access article, distributed under terms (http://www.nutrition.org/publications/guidelines-and-policies/license/) that permit unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited. NR 58 TC 31 Z9 31 U1 11 U2 14 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 APR PY 2016 VL 103 IS 4 BP 1033 EP 1044 DI 10.3945/ajcn.115.120873 PG 12 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DI3VI UT WOS:000373426400012 PM 26864360 ER PT J AU Kim, JS Knickelbein, JE Jaworski, L Kaushal, P Vitale, S Nussenblatt, RB Sen, HN AF Kim, Jane S. Knickelbein, Jared E. Jaworski, Laurence Kaushal, Padmini Vitale, Susan Nussenblatt, Robert B. Sen, H. Nida TI Enhanced Depth Imaging Optical Coherence Tomography in Uveitis: An Intravisit and Interobserver Reproducibility Study SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID KOYANAGI-HARADA DISEASE; CHOROIDAL THICKNESS MEASUREMENTS; BIRDSHOT CHORIORETINOPATHY; CLINICAL MEASUREMENT; STANDARDIZATION AB PURPOSE: To determine the intravisit and interobserver reproducibility of subfoveal choroidal thickness (SFCT) measurements in patients with noninfectious uveitis. DESIGN: Reliability analysis. METHODS: Two consecutive enhanced depth imaging optical coherence tomography (EDI-OCT) scans were obtained at a single clinic visit for 97 uveitic eyes from patients >= 16 years of age with noninfectious anterior (n = 10), intermediate (n = 11), posterior (n = 26), and panuveitis (n = 13) at the National Eye Institute. SFCT was manually measured by 2 ophthalmologists using manufacturer's software. Intravisit and interobserver reproducibility of SFCT measurements were assessed by using the Bland-Altman method to determine the estimate of bias (mean difference in SFCT measurements), 95% limits of agreement, and coefficients of repeatability. The reproducibility of these measurements was also compared between groups by anatomic location and clinical activity. RESULTS: Of 97 eyes, 65 (67.0%) were clinically quiet, 18 (18.6%) were minimally active, and 14 (14.4%) were active at the time the scans were obtained. Manual SFCT measurements were reproducible within 32.4 +/- 3.8 mu m between sessions for the same observer and 51.4 +/- 8.5 mu m between observers for the same session. Coefficients of repeatability did not differ significantly by anatomic location or disease activity. CONCLUSIONS: Manual SFCT measurements obtained by EDI-OCT are reproducible in uveitis patients, with coefficients of repeatability that are nearly comparable to those published for normal eyes. This study provides guidance for using manual SFCT measurements in clinical practice, but further studies are still needed to determine their utility in clinical trials. Published by Elsevier Inc. C1 [Kim, Jane S.] Univ Calif San Diego, Sch Med, La Jolla, CA 92093 USA. [Kim, Jane S.; Knickelbein, Jared E.; Jaworski, Laurence; Kaushal, Padmini; Nussenblatt, Robert B.; Sen, H. Nida] NEI, Immunol Lab, NIH, 10 Ctr Dr,Bldg 10,Room 10N109, Bethesda, MD 20892 USA. [Vitale, Susan] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. RP Sen, HN (reprint author), NEI, Immunol Lab, NIH, 10 Ctr Dr,Bldg 10,Room 10N109, Bethesda, MD 20892 USA. EM senh@nei.nih.gov FU NIH; Pfizer Inc; Doris Duke Charitable Foundation; Newport Foundation; American Association for Dental Research; Howard Hughes Medical Institute; Colgate-Palmolive Company FX THIS RESEARCH WAS MADE POSSIBLE THROUGH THE NATIONAL EYE INSTITUTE INTRAMURAL RESEARCH Program (Bethesda, MD) and the National Institutes of Health (NIH) Medical Research Scholars Program (Bethesda, MD), a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer Inc, Doris Duke Charitable Foundation, Newport Foundation, American Association for Dental Research, Howard Hughes Medical Institute, Colgate-Palmolive Company, and other private donors. For a complete list, please visit the Foundation website at http://fnih.org/work/education-training-0/medical-research-scholars-prog ram. NR 28 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 EI 1879-1891 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD APR PY 2016 VL 164 BP 49 EP 56 DI 10.1016/j.ajo.2016.01.004 PG 8 WC Ophthalmology SC Ophthalmology GA DI7CS UT WOS:000373657300008 PM 26829594 ER PT J AU Bressler, SB Glassman, AR Almukhtar, T Bressler, NM Ferris, FL Googe, JM Gupta, SK Jampol, LM Melia, M Wells, JA AF Bressler, Susan B. Glassman, Adam R. Almukhtar, Talat Bressler, Neil M. Ferris, Frederick L. Googe, Joseph M., Jr. Gupta, Shailesh K. Jampol, Lee M. Melia, Michele Wells, John A., III CA Diabetic Retinopathy Clinical Res TI Five-Year Outcomes of Ranibizumab With Prompt or Deferred Laser Versus Laser or Triamcinolone Plus Deferred Ranibizumab for Diabetic Macular Edema SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article AB PURPOSE: To compare long-term vision and anatomic effects of ranibizumab with prompt or deferred laser vs laser or triamcinolone + laser with very deferred ranibizumab in diabetic macular edema (DME). DESIGN: Randomized clinical trial. METHODS: Eight hundred and twenty-eight study eyes (558 [67%] completed the 5-year visit), at 52 sites, with visual acuity 20/32 to 20/320 and DME involving the central macula were randomly assigned to intravitreous ranibizumab (0.5 mg) with either (1) prompt or (2) deferred laser; (3) sham injection + prompt laser; or (4) intravitreous triamcinolone (4 mg) + prompt laser. The latter 2 groups could initiate ranibizumab as early as 74 weeks from baseline, for persistent DME with vision impairment. The main outcome measures were visual acuity, optical coherence central subfield thickness, and number of injections through 5 years. RESULTS: At 5 years mean (+/- standard deviation) change in Early Treatment Diabetic Retinopathy Study visual acuity letter scores from baseline in the ranibizumab + deferred laser (N = 111), ranibizumab + prompt laser (N = 124), laser/very deferred ranibizumab (N = 198), and triamcinolone + laser/very deferred ranibizumab (N = 125) groups were 10 13, 8 13, 5 14, and 7 14, respectively. The difference (95% confidence interval) in mean change between ranibizumab + deferred laser and laser/very deferred ranibizumab and triamcinolone + laser/very deferred ranibizumab was 4.4 (1.2-7.6, P = .001) and 2.8 (-0.9 to 6.5, P = .067), respectively, at 5 years. CONCLUSIONS: Recognizing limitations of follow-up available at 5 years, eyes receiving initial ranibizumab therapy for center-involving DME likely have better long-term vision improvements than eyes managed with laser or triamcinolone + laser followed by very deferred ranibizumab for persistent thickening and vision impairment. (C) 2016 by Elsevier Inc. All rights reserved. C1 [Bressler, Susan B.; Bressler, Neil M.] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. [Glassman, Adam R.; Almukhtar, Talat; Melia, Michele] Jaeb Ctr Hlth Res Inc, 15310 Amberly Dr,Suite 350, Tampa, FL 33647 USA. [Ferris, Frederick L.] NEI, Bethesda, MD 20892 USA. [Googe, Joseph M., Jr.] Southeastern Retina Associates PC, Knoxville, TN USA. [Gupta, Shailesh K.] Univ Florida, Coll Med, Dept Ophthalmol, Jacksonville, FL USA. [Jampol, Lee M.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Wells, John A., III] Palmetto Retina Ctr, Columbia, SC USA. RP Glassman, AR (reprint author), Jaeb Ctr Hlth Res Inc, 15310 Amberly Dr,Suite 350, Tampa, FL 33647 USA. EM drcrstat2@jaeb.org FU NATIONAL EYE INSTITUTE; NAtional Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland [EY14231, EY23207, EY18817]; National Institutes of Health, Bethesda, MD; Genentech FX SUPPORTED THROUGH COOPERATIVE AGREEMENTS FROM THE NATIONAL EYE INSTITUTE AND THE NAtional Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (EY14231, EY23207, and EY18817). The funding organization (National Institutes of Health, Bethesda, MD) participated in oversight of the conduct of the study and review of the manuscript, but not directly in the design or conduct of the study; nor in the collection, management, analysis, or interpretation of the data; nor in the preparation of the manuscript. Genentech (South San Francisco, CA) provided the ranibizumab for the study. In addition, Genentech provided funds to DRCR.net to defray the study's clinical site costs. As described in the Diabetic Retinopathy Clinical Research Network (DRCR.net) Industry Collaboration Guidelines (available at www.drcr.net), the DRCR.net had complete control over the design of the protocol, ownership of the data, and all editorial content of presentations and publications related to the protocol. NR 5 TC 6 Z9 6 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 EI 1879-1891 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD APR PY 2016 VL 164 BP 57 EP 68 DI 10.1016/j.ajo.2015.12.025 PG 12 WC Ophthalmology SC Ophthalmology GA DI7CS UT WOS:000373657300009 PM 26802783 ER PT J AU Kempen, JH Gewaily, DY Newcomb, CW Liesegang, TL Kacmaz, RO Levy-Clarke, GA Nussenblatt, RB Rosenbaum, JT Sen, HN Suhler, EB Thorne, JE Foster, CS Jabs, DA Payal, A Fitzgerald, TD AF Kempen, John H. Gewaily, Dina Y. Newcomb, Craig W. Liesegang, Teresa L. Kacmaz, R. Oktay Levy-Clarke, Grace A. Nussenblatt, Robert B. Rosenbaum, James T. Sen, H. Nida Suhler, Eric B. Thorne, Jennifer E. Foster, C. Stephen Jabs, Douglas A. Payal, Abhishek Fitzgerald, Tonetta D. CA Systemic Immunosuppressive Therapy TI Remission of Intermediate Uveitis: Incidence and Predictive Factors SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID PARS-PLANA VITRECTOMY; OCULAR INFLAMMATORY DISEASES; CLINICAL-FEATURES; PLANITIS; THERAPY; PANUVEITIS; POSTERIOR; OUTCOMES; RISK; EYE AB PURPOSE: To evaluate the incidence of remission among patients with intermediate uveitis; to identify factors potentially predictive of remission. DESIGN: Retrospective cohort study. METHODS: Involved eyes of patients with primary noninfectious intermediate uveitis at 4 academic ocular inflammation subspecialty practices, followed sufficiently long to meet the remission outcome definition, were studied retrospectively by standardized chart review data. Remission of intermediate uveitis was defined as a lack of inflammatory activity at >= 2 visits spanning >= 90 days in the absence of any corticosteroid or immunosuppressant medications. Factors potentially predictive of intermediate uveitis remission were evaluated using survival analysis. RESULTS: Among 849 eyes (of 510 patients) with intermediate uveitis followed over 1934 eye-years, the incidence of intermediate uveitis remission was 8.6/100 eye-years (95% confidence interval [CI], 7.4-10.1). Factors predictive of disease remission included prior pars plana vitrectomy (PPV) (hazard ratio [HR] [vs no PPV] = 2.39; 95% CI, 1.42-4.00), diagnosis of intermediate uveitis within the last year (HR [vs diagnosis >5 years ago] = 3.82; 95% CI, 1.91-7.63), age >= 45 years (HR [vs age <45 years] = 1.79; 95% CI, 1.03-3.11), female sex (HR = 1.61; 95% CI, 1.04-2.49), and Hispanic race/ethnicity (HR [vs white race] = 2.81; 95% CI, 1.23-6.41). Presence/absence of a systemic inflammatory disease, laterality of uveitis, and smoking status, were not associated with differential incidence. CONCLUSIONS: Our results suggest that intermediate uveitis is a chronic disease with an overall low rate of remission. Recently diagnosed patients and older, female, and Hispanic patients were more likely to remit. With regard to management, pars plana vitrectomy was associated with increased probability of remission. (C) 2016 by Elsevier Inc. All rights reserved. C1 [Kempen, John H.; Gewaily, Dina Y.; Payal, Abhishek; Fitzgerald, Tonetta D.] Univ Penn, Perelman Sch Med, Dept Ophthalmol, Philadelphia, PA 19104 USA. [Kempen, John H.; Newcomb, Craig W.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Kempen, John H.; Newcomb, Craig W.] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Gewaily, Dina Y.] Deglin & Greene Retinal Ctr, Wynnewood, PA USA. [Liesegang, Teresa L.; Rosenbaum, James T.; Suhler, Eric B.] Oregon Hlth & Sci Univ, Dept Ophthalmol, Portland, OR 97201 USA. [Rosenbaum, James T.; Payal, Abhishek] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Kacmaz, R. Oktay; Foster, C. Stephen] Massachusetts Eye Res & Surg Inst, Waltham, MA USA. [Kacmaz, R. Oktay] Allergan Pharmaceut Inc, Dublin, Ireland. [Levy-Clarke, Grace A.; Nussenblatt, Robert B.; Sen, H. Nida] NEI, Immunol Lab, Bldg 10, Bethesda, MD 20892 USA. [Levy-Clarke, Grace A.] Tampa Bay Uveitis Ctr, Tampa, FL USA. [Rosenbaum, James T.] Devers Eye Inst, Portland, OR USA. [Suhler, Eric B.; Payal, Abhishek] Portland VA Med Ctr, Portland, OR USA. [Thorne, Jennifer E.] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21205 USA. [Thorne, Jennifer E.; Jabs, Douglas A.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Foster, C. Stephen] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Jabs, Douglas A.] Icahn Sch Med Mt Sinai, Dept Ophthalmol, New York, NY USA. [Jabs, Douglas A.] Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA. RP Kempen, JH (reprint author), Univ Penn, Dept Ophthalmol, Ctr Prevent Ophthalmol & Biostat, 3535 Market St,Suite 700, Philadelphia, PA 19104 USA. EM john.kempen@uphs.upenn.edu OI Payal, Abhishek/0000-0002-4484-8279 FU NATIONAL EYE INSTITUTE (BETHESDA, MD, USA) [EY014943]; Research to Prevent Blindness (New York, NY, USA); Paul and Evanina Mackall Foundation (New York, NY, USA); Lois Pope Life Foundation (New York, NY, USA); Veteran's Affairs Administration (Washington, DC, USA); National Eye Institute; Research to Prevent Blindness FX SUPPORTED PRIMARILY BY NATIONAL EYE INSTITUTE (BETHESDA, MD, USA) GRANT EY014943 (JOHN H. Kempen). Additional support was provided by Research to Prevent Blindness (New York, NY, USA), the Paul and Evanina Mackall Foundation (New York, NY, USA), and the Lois Pope Life Foundation (New York, NY, USA). During the course of the study, John H. Kempen was a Research to Prevent Blindness James S. Adams Special Scholar Award recipient, Jennifer E. Thorne was a Research to Prevent Blindness Harrington Special Scholar Award recipient, and Douglas A. Jabs and James T. Rosenbaum were Research to Prevent Blindness Senior Scientific Investigator Award recipients. Eric B. Suhler receives support from the Veteran's Affairs Administration (Washington, DC, USA). Grace A. Levy-Clarke was previously supported by and Robert B. Nussenblatt and H. Nida Sen continue to be supported by intramural funds of the National Eye Institute. The funding organizations had no role in the design or conduct of this research. NR 34 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 EI 1879-1891 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD APR PY 2016 VL 164 BP 110 EP 117 DI 10.1016/j.ajo.2015.12.034 PG 8 WC Ophthalmology SC Ophthalmology GA DI7CS UT WOS:000373657300014 PM 26772874 ER PT J AU Taber, JM Klein, WMP Ferrer, RA Kent, EE Harris, PR AF Taber, Jennifer M. Klein, William M. P. Ferrer, Rebecca A. Kent, Erin E. Harris, Peter R. TI Optimism and Spontaneous Self-affirmation are Associated with Lower Likelihood of Cognitive Impairment and Greater Positive Affect among Cancer Survivors SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Article DE Cancer survivors; Health Information National Trends Survey; Optimism; Self-affirmation; Cognitive impairment; Affect ID QUALITY-OF-LIFE; BREAST-CANCER; DISPOSITIONAL OPTIMISM; INFORMATION AVOIDANCE; PROSTATE-CANCER; CHEMOTHERAPY; POPULATION; PREDICT; STRESS; INTERVENTIONS AB Optimism and self-affirmation promote adaptive coping, goal achievement, and better health. The aim of this study is to examine the associations of optimism and spontaneous self-affirmation (SSA) with physical, mental, and cognitive health and information seeking among cancer survivors. Cancer survivors (n = 326) completed the Health Information National Trends Survey 2013, a national survey of US adults. Participants reported optimism, SSA, cognitive and physical impairment, affect, health status, and information seeking. Participants higher in optimism reported better health on nearly all indices examined, even when controlling for SSA. Participants higher in SSA reported lower likelihood of cognitive impairment, greater happiness and hopefulness, and greater likelihood of cancer information seeking. SSA remained significantly associated with greater hopefulness and cancer information seeking when controlling for optimism. Optimism and SSA may be associated with beneficial health-related outcomes among cancer survivors. Given the demonstrated malleability of self-affirmation, these findings represent important avenues for future research. C1 [Taber, Jennifer M.; Klein, William M. P.; Ferrer, Rebecca A.; Kent, Erin E.] NCI, NIH, 9609 Med Ctr Dr,Room 3E642, Bethesda, MD 20892 USA. [Harris, Peter R.] Univ Sussex, Sch Psychol, Brighton BN1 9RH, Falmer, England. RP Taber, JM (reprint author), NCI, NIH, 9609 Med Ctr Dr,Room 3E642, Bethesda, MD 20892 USA. EM jennifer.taber@nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 61 TC 1 Z9 1 U1 8 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD APR PY 2016 VL 50 IS 2 BP 198 EP 209 DI 10.1007/s12160-015-9745-9 PG 12 WC Psychology, Multidisciplinary SC Psychology GA DI6VS UT WOS:000373638900004 PM 26497697 ER PT J AU Driscoll, MA Davis, MC Aiken, LS Yeung, EW Sterling, EW Vanderhoof, V Calis, KA Popat, V Covington, SN Nelson, LM AF Driscoll, Mary A. Davis, Mary C. Aiken, Leona S. Yeung, Ellen W. Sterling, Evelina Weidman Vanderhoof, Vien Calis, Karim Anton Popat, Vaishali Covington, Sharon N. Nelson, Lawrence M. TI Psychosocial Vulnerability, Resilience Resources, and Coping with Infertility: A Longitudinal Model of Adjustment to Primary Ovarian Insufficiency SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Article DE Infertility; Coping; Adaptation; Risk; Resilience; POI; Premature menopause; Premature ovarian failure ID MENTAL-HEALTH; PSYCHOLOGICAL DISTRESS; DEFINITIVE INFERTILITY; NEGATIVE AFFECT; BREAST-CANCER; FIT INDEXES; SELF-ESTEEM; WOMEN; PERSONALITY; DEPRESSION AB The infertility associated with primary ovarian insufficiency (POI) presents significant emotional challenges requiring psychosocial adjustment. Few investigations have explored the longitudinal process of adaptation to POI. This longitudinal investigation tests a model of adjustment to POI that includes separate psychosocial vulnerability and resilience resource factors. Among 102 women with POI, personal attributes reflective of vulnerability and resilience were assessed at baseline. Coping strategies were assessed 4 months later and measures of distress and well-being 12 months later. As hypothesized, confirmatory factor analysis yielded separate, inversely correlated vulnerability and resilience resource factors at baseline, and distress and well-being factors at 12 months. Contrary to predictions, maladaptive and adaptive coping strategies were not bi-factorial. Moreover, a single stand-alone strategy, avoidance (i.e., refusing to acknowledge stress), mediated the association between baseline vulnerability and 12-month distress. For women with POI, interventional studies targeted to reduce avoidance are indicated. C1 [Driscoll, Mary A.] VA Connecticut Healthcare Syst, 950 Campbell Ave,Mail Code 11ACSL G, West Haven, CT 06516 USA. [Driscoll, Mary A.] Yale Univ, Sch Med, New Haven, CT USA. [Davis, Mary C.; Aiken, Leona S.; Yeung, Ellen W.] Arizona State Univ, Tempe, AZ USA. [Sterling, Evelina Weidman] Rachels Well Inc, Mclean, VA USA. [Vanderhoof, Vien; Calis, Karim Anton; Popat, Vaishali; Covington, Sharon N.; Nelson, Lawrence M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Driscoll, MA (reprint author), VA Connecticut Healthcare Syst, 950 Campbell Ave,Mail Code 11ACSL G, West Haven, CT 06516 USA.; Driscoll, MA (reprint author), Yale Univ, Sch Med, New Haven, CT USA. EM mary.driscoll3@va.gov FU Intramural NIH HHS NR 71 TC 0 Z9 0 U1 7 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD APR PY 2016 VL 50 IS 2 BP 272 EP 284 DI 10.1007/s12160-015-9750-z PG 13 WC Psychology, Multidisciplinary SC Psychology GA DI6VS UT WOS:000373638900009 PM 26637185 ER PT J AU Datta, M Via, LE Chen, W Baish, JW Xu, L Barry, CE Jain, RK AF Datta, Meenal Via, Laura E. Chen, Wei Baish, James W. Xu, Lei Barry, Clifton E., III Jain, Rakesh K. TI Mathematical Model of Oxygen Transport in Tuberculosis Granulomas SO ANNALS OF BIOMEDICAL ENGINEERING LA English DT Article DE Diffusion; Mycobacterium tuberculosis; Michaelis-Menten kinetics; Rabbit model; Pimonidazole ID MYCOBACTERIUM-BOVIS BCG; AVASCULAR TUMOR-GROWTH; IN-VITRO MODEL; NONREPLICATING PERSISTENCE; IMMUNE-RESPONSE; HYPOXIA MARKER; DRUG-DELIVERY; STRATEGIES; PIMONIDAZOLE; VASCULATURE AB Pulmonary granulomas-the hallmark of Mycobacterium tuberculosis (MTB) infection-are dense cellular lesions that often feature regions of hypoxia and necrosis, partially due to limited transport of oxygen. Low oxygen in granulomas can impair the host immune response, while MTB are able to adapt and persist in hypoxic environments. Here, we used a physiologically based mathematical model of oxygen diffusion and consumption to calculate oxygen profiles within the granuloma, assuming Michaelis-Menten kinetics. An approximate analytical solution-using a priori and newly estimated parameters from experimental data in a rabbit model of tuberculosis-was able to predict the size of hypoxic and necrotic regions in agreement with experimental results from the animal model. Such quantitative understanding of transport limitations can inform future tuberculosis therapeutic strategies that may include adjunct host-directed therapies that facilitate oxygen and drug delivery for more effective treatment. C1 [Datta, Meenal; Chen, Wei; Xu, Lei; Jain, Rakesh K.] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Labs, Cox 7,100 Blossom St, Boston, MA 02114 USA. [Datta, Meenal; Chen, Wei; Xu, Lei; Jain, Rakesh K.] Harvard Univ, Sch Med, Cox 7,100 Blossom St, Boston, MA 02114 USA. [Datta, Meenal] Tufts Univ, Dept Chem & Biol Engn, Medford, MA 02155 USA. [Via, Laura E.; Barry, Clifton E., III] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Via, Laura E.; Barry, Clifton E., III] Univ Cape Town, Fac Hlth Sci, Dept Clin Lab Sci, ZA-7701 Cape Town, South Africa. [Chen, Wei] Sun Yat Sen Univ, Affiliated Hosp 1, Dept Pancreatobiliary Surg, Guangzhou 510080, Guangdong, Peoples R China. [Baish, James W.] Bucknell Univ, Dept Biomed, Lewisburg, PA 17837 USA. [Baish, James W.] Bucknell Univ, Dept Mech Engn, Lewisburg, PA 17837 USA. RP Jain, RK (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Labs, Cox 7,100 Blossom St, Boston, MA 02114 USA.; Jain, RK (reprint author), Harvard Univ, Sch Med, Cox 7,100 Blossom St, Boston, MA 02114 USA. EM jain@steele.mgh.harvard.edu FU Bill and Melinda Gates Foundation; Imperial College; NIH, NIAID FX We thank Drs. Jerry Meldon and Stephen Matson for their insightful comments, and Drs. Vasileios Askoxylakis, Dai Fukumura, Giorgio Seano, Triantafyllos Stylianopoulos, and Joshua Tam for their assistance in manuscript editing. We would like to acknowledge Kathleen England, Daniel Schimel, and Danielle Weiner (Tuberculosis Research Section, Laboratory of Clinical Infectious Disease, National Institutes of Health/National Institute of Allergy and Infectious Diseases) for their technical assistance in the previously performed animal studies. Thanks to Carolyn Smith (Edwin L. Steele Laboratories, Massachusetts General Hospital/Harvard Medical School) for her support in the immunohistochemistry studies. This study was supported in part by Grants from the Bill and Melinda Gates Foundation (to R.K.J.), through the Grand Challenges in Global Health Program to Douglas Young, Imperial College (to C.E.B.), and from the Intramural Research Program of the NIH, NIAID (to C.E.B). NR 56 TC 3 Z9 3 U1 3 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0090-6964 EI 1573-9686 J9 ANN BIOMED ENG JI Ann. Biomed. Eng. PD APR PY 2016 VL 44 IS 4 BP 863 EP 872 DI 10.1007/s10439-015-1415-3 PG 10 WC Engineering, Biomedical SC Engineering GA DI8HJ UT WOS:000373741800003 PM 26253038 ER PT J AU Ozen, S Demirkaya, E Erer, B Livneh, A Ben-Chetrit, E Giancane, G Ozdogan, H Abu, I Gattorno, M Hawkins, PN Yuce, S Kallinich, T Bilginer, Y Kastner, D Carmona, L AF Ozen, Seza Demirkaya, Erkan Erer, Burak Livneh, Avi Ben-Chetrit, Eldad Giancane, Gabriella Ozdogan, Huri Abu, Illana Gattorno, Marco Hawkins, Philip N. Yuce, Sezin Kallinich, Tilmann Bilginer, Yelda Kastner, Daniel Carmona, Loreto TI EULAR recommendations for the management of familial Mediterranean fever SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Review ID PROTRACTED FEBRILE MYALGIA; SINGLE-CENTER EXPERIENCE; COLCHICINE TREATMENT; RISK-FACTORS; SUBCLINICAL INFLAMMATION; INTRAVENOUS COLCHICINE; RENAL-TRANSPLANTATION; THERAPEUTIC APPROACH; MUTATION ANALYSIS; DIAGNOSTIC-VALUE AB Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease, but many rheumatologists are not well acquainted with its management. The objective of this report is to produce evidence-based recommendations to guide rheumatologists and other health professionals in the treatment and follow-up of patients with FMF. A multidisciplinary panel, including rheumatologists, internists, paediatricians, a nurse, a methodologist and a patient representative, was assembled. Panellists came from the Eastern Mediterranean area, Europe and North America. A preliminary systematic literature search on the pharmacological treatment of FMF was performed following which the expert group convened to define aims, scope and users of the guidelines and established the need for additional reviews on controversial topics. In a second meeting, recommendations were discussed and refined in light of available evidence. Finally, agreement with the recommendations was obtained from a larger group of experts through a Delphi survey. The level of evidence (LoE) and grade of recommendation (GR) were then incorporated. The final document comprises 18 recommendations, each presented with its degree of agreement (0-10), LoE, GR and rationale. The degree of agreement was greater than 7/10 in all instances. The more controversial statements were those related to follow-up and dose change, for which supporting evidence is limited. A set of widely accepted recommendations for the treatment and monitoring of FMF is presented, supported by the best available evidence and expert opinion. It is believed that these recommendations will be useful in guiding physicians in the care of patients with FMF. C1 [Ozen, Seza] Hacettepe Univ, Dept Pediat Rheumatol, TR-06100 Ankara, Turkey. [Demirkaya, Erkan] Gulhane Mil Med Acad, FMF Arthrit Vasculitis & Orphan Dis Res Ctr FAVOR, Div Pediat Rheumatol, Ankara, Turkey. [Erer, Burak] Istanbul Univ, Istanbul Fac Med, Dept Internal Med, Div Rheumatol, Istanbul, Turkey. [Livneh, Avi] Chaim Sheba Med Ctr, Heller Inst Med Res & Med F, IL-52621 Tel Hashomer, Israel. [Livneh, Avi] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Ben-Chetrit, Eldad] Hadassah Hebrew Univ, Med Ctr, Rheumatol Unit, Jerusalem, Israel. [Giancane, Gabriella] Ist Giannina Gaslini, Pediat Reumatol 2, I-16148 Genoa, Italy. [Ozdogan, Huri] Cerrahpasa Med Fac, Rheumatol Unit, Istanbul, Turkey. [Abu, Illana] Sheba Med Ctr, Heller Inst Med Res & Med F, Tel Aviv, Turkey. [Gattorno, Marco] Ist Giannina Gaslini, UO Pediat 2, I-16148 Genoa, Italy. [Hawkins, Philip N.] Natl Amyloidosis Ctr UCL, London, England. [Hawkins, Philip N.] Royal Free Hosp, Pond St, London NW3 2QG, England. [Yuce, Sezin] Ankara Ataturk Chest Dis & Chest Surg Training &, Dept Radiat Oncol, Ankara, Turkey. [Kallinich, Tilmann] Charite, Dept Pediat Pneumol & Immunol, D-13353 Berlin, Germany. [Bilginer, Yelda] Hacettepe Univ, Fac Med, Pediat Rheumatol Unit, TR-06100 Ankara, Turkey. [Kastner, Daniel] NHGRI, NIH, Bethesda, MD 20892 USA. [Carmona, Loreto] Inst Salud Musculoesquelet, Madrid, Spain. RP Ozen, S (reprint author), Hacettepe Univ, Fac Med, Dept Pediat Rheumatol, TR-06100 Ankara, Turkey. EM sezaozen@hacettepe.edu.tr OI CARMONA, LORETO/0000-0002-4401-2551 FU EULAR [CLI071] FX EULAR (grant no. CLI071). NR 86 TC 10 Z9 10 U1 2 U2 6 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD APR PY 2016 VL 75 IS 4 BP 644 EP 651 DI 10.1136/annrheumdis-2015-208690 PG 8 WC Rheumatology SC Rheumatology GA DI3MW UT WOS:000373403800014 PM 26802180 ER PT J AU Huguet-Tapia, JC Lefebure, T Badger, JH Guan, DL Pettis, GS Stanhope, MJ Loria, R AF Huguet-Tapia, Jose C. Lefebure, Tristan Badger, Jonathan H. Guan, Dongli Pettis, Gregg S. Stanhope, Michael J. Loria, Rosemary TI Genome Content and Phylogenomics Reveal both Ancestral and Lateral Evolutionary Pathways in Plant-Pathogenic Streptomyces Species SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID SP-NOV; SEQUENCE; BIOSYNTHESIS; PROTEIN; GENES; TOOL; ACTINOBACTERIA; ACTINOMYCETOMA; IDENTIFICATION; PHYTOTOXIN AB Streptomyces spp. are highly differentiated actinomycetes with large, linear chromosomes that encode an arsenal of biologically active molecules and catabolic enzymes. Members of this genus are well equipped for life in nutrient-limited environments and are common soil saprophytes. Out of the hundreds of species in the genus Streptomyces, a small group has evolved the ability to infect plants. The recent availability of Streptomyces genome sequences, including four genomes of pathogenic species, provided an opportunity to characterize the gene content specific to these pathogens and to study phylogenetic relationships among them. Genome sequencing, comparative genomics, and phylogenetic analysis enabled us to discriminate pathogenic from saprophytic Streptomyces strains; moreover, we calculated that the pathogen-specific genome contains 4,662 orthologs. Phylogenetic reconstruction suggested that Streptomyces scabies and S. ipomoeae share an ancestor but that their biosynthetic clusters encoding the required virulence factor thaxtomin have diverged. In contrast, S. turgidiscabies and S. acidiscabies, two relatively unrelated pathogens, possess highly similar thaxtomin biosynthesis clusters, which suggests that the acquisition of these genes was through lateral gene transfer. C1 [Huguet-Tapia, Jose C.; Loria, Rosemary] Univ Florida, Dept Plant Pathol, Gainesville, FL 32611 USA. [Lefebure, Tristan; Stanhope, Michael J.] Cornell Univ, Dept Populat Med & Diagnost Sci, Ithaca, NY USA. [Badger, Jonathan H.] J Craig Venter Inst, La Jolla, CA USA. [Guan, Dongli; Pettis, Gregg S.] Louisiana State Univ, Dept Biol Sci, Baton Rouge, LA 70803 USA. [Pettis, Gregg S.] Louisiana State Univ, Ctr Agr, Dept Plant Pathol & Crop Physiol, Baton Rouge, LA 70803 USA. [Lefebure, Tristan] Univ Lyon, CNRS, Ecol Hydrosyst Nat & Anthropises UMR5023, Villeurbanne, France. [Badger, Jonathan H.] NCI, Jonathan H Badger Ctr Canc Res, Bethesda, MD 20892 USA. RP Loria, R (reprint author), Louisiana State Univ, Dept Biol Sci, Baton Rouge, LA 70803 USA. EM gpettis@lsu.edu; rloria@ufl.edu RI Lefebure, Tristan/A-6489-2009 OI Lefebure, Tristan/0000-0003-3923-8166 FU National Research Initiative of the U.S. Department of Agriculture (USDA) Cooperative State Research, Education, and Extension Service [2010-65110-20416]; USDA National Institute of Food and Agriculture (NIFA) [LAB94112] FX The National Research Initiative of the U.S. Department of Agriculture (USDA) Cooperative State Research, Education, and Extension Service provided funding to Gregg S. Pettis under grant number 2007-35600-17813 and to Rosemary Loria under grant number 2010-65110-20416. The USDA National Institute of Food and Agriculture (NIFA) provided funding to Gregg S. Pettis under Hatch project number LAB94112. NR 55 TC 2 Z9 2 U1 5 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 EI 1098-5336 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD APR PY 2016 VL 82 IS 7 BP 2146 EP 2155 DI 10.1128/AEM.03504-15 PG 10 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA DI2QV UT WOS:000373342400018 PM 26826232 ER PT J AU Krupovic, M Dutilh, BE Adriaenssens, EM Wittmann, J Vogensen, FK Sullivan, MB Rumnieks, J Prangishvili, D Lavigne, R Kropinski, AM Klumpp, J Gillis, A Enault, F Edwards, RA Duffy, S Clokie, MRC Barylski, J Ackermann, HW Kuhn, JH AF Krupovic, Mart Dutilh, Bas E. Adriaenssens, Evelien M. Wittmann, Johannes Vogensen, Finn K. Sullivan, Mathew B. Rumnieks, Janis Prangishvili, David Lavigne, Rob Kropinski, Andrew M. Klumpp, Jochen Gillis, Annika Enault, Francois Edwards, Rob A. Duffy, Siobain Clokie, Martha R. C. Barylski, Jakub Ackermann, Hans-Wolfgang Kuhn, Jens H. TI Taxonomy of prokaryotic viruses: update from the ICTV bacterial and archaeal viruses subcommittee SO ARCHIVES OF VIROLOGY LA English DT News Item ID COMPARATIVE GENOMICS; CLASSIFICATION; SUBFAMILY; BACTERIOPHAGES; PODOVIRIDAE; TOOLS C1 [Krupovic, Mart; Prangishvili, David] Inst Pasteur, Dept Microbiol, Unit Mol Biol Gene Extremophiles, 25 Rue Dr Roux, F-75015 Paris, France. [Dutilh, Bas E.] Univ Utrecht, Theoret Biol & Bioinformat, Utrecht, Netherlands. [Dutilh, Bas E.] Radboud Univ Nijmegen, Med Ctr, Ctr Mol & Biomol Informat, NL-6525 ED Nijmegen, Netherlands. [Dutilh, Bas E.] Univ Fed Rio de Janeiro, Inst Biol, Rio De Janeiro, Brazil. [Adriaenssens, Evelien M.] Univ Pretoria, Ctr Microbial Ecol & Genom, Dept Genet, Private Bag X20, ZA-0028 Pretoria, South Africa. [Wittmann, Johannes] DSMZ Deutsch Sammlung Mikroorganisme & Zellkultur, Leibniz Inst, Inhoffenstr 7B, D-38124 Braunschweig, Germany. [Vogensen, Finn K.] Univ Copenhagen, Dept Food Sci, Rolighedsvej 26, DK-1958 Frederiksberg C, Denmark. [Sullivan, Mathew B.] Ohio State Univ, Dept Microbiol, 496 W 12th Ave, Columbus, OH 43210 USA. [Sullivan, Mathew B.] Ohio State Univ, Dept Civil Environm & Geodet Engn, 470 Hitchcock Hall,2070 Neil Ave, Columbus, OH 43210 USA. [Rumnieks, Janis] Latvian Biomed Res & Study Ctr, Ratsupites 1, LV-1067 Riga, Latvia. [Lavigne, Rob] Katholieke Univ Leuven, Lab Gene Technol, Kasteelpk Arenberg 21-Box 2462, B-3001 Louvain, Belgium. [Klumpp, Jochen] ETH, Inst Food Nutr & Hlth, Schmelzbergstr 7, CH-8092 Zurich, Switzerland. [Gillis, Annika] Catholic Univ Louvain, Lab Food & Environm Microbiol, Croix Sud 2,L7-05-12, B-1348 Louvain La Neuve, Belgium. [Enault, Francois] Univ Clermont Ferrand, Clermont Univ, Lab Microorganismes Genome & Environm, Clermont Ferrand, France. [Enault, Francois] LMGE, CNRS, UMR 6023, Aubiere, France. [Edwards, Rob A.] San Diego State Univ, Dept Comp Sci, Bioinformat Lab, 5500 Campanile Dr, San Diego, CA 92182 USA. [Duffy, Siobain] Rutgers State Univ, Dept Ecol Evolut & Nat Resources, 14 Coll Farm Rd, New Brunswick, NJ 08901 USA. [Clokie, Martha R. C.] Univ Leicester, Dept Infect Immun & Inflammat, Univ Rd, Leicester LE1 9HN, Leics, England. [Barylski, Jakub] Adam Mickiewicz Univ, Inst Expt Biol, Dept Mol Virol, Umultowska 89, PL-61614 Poznan, Poland. [Ackermann, Hans-Wolfgang] Univ Laval, Inst Biol Integrat & Syst, Pavillon Charles Eugene Marchand,1030 Ave Med, Quebec City, PQ G1V 0A6, Canada. [Kuhn, Jens H.] NIAID, Integrated Res Facil Ft Detrick, NIH, Frederick, MD 21702 USA. [Kropinski, Andrew M.] Univ Guelph, Dept Food Sci, 50 Stone Rd E, Guelph, ON N1G 2W1, Canada. [Kropinski, Andrew M.] Univ Guelph, Dept Mol & Cellular Biol, 50 Stone Rd E, Guelph, ON N1G 2W1, Canada. [Kropinski, Andrew M.] Univ Guelph, Dept Pathobiol, 50 Stone Rd E, Guelph, ON N1G 2W1, Canada. RP Kropinski, AM (reprint author), Univ Guelph, Dept Food Sci, 50 Stone Rd E, Guelph, ON N1G 2W1, Canada.; Kropinski, AM (reprint author), Univ Guelph, Dept Mol & Cellular Biol, 50 Stone Rd E, Guelph, ON N1G 2W1, Canada.; Kropinski, AM (reprint author), Univ Guelph, Dept Pathobiol, 50 Stone Rd E, Guelph, ON N1G 2W1, Canada. EM Phage.Canada@gmail.com; kuhnjens@mail.nih.gov RI Dutilh, Bas/B-9719-2011; Krupovic, Mart/I-4209-2012; OI Dutilh, Bas/0000-0003-2329-7890; Krupovic, Mart/0000-0001-5486-0098; Kropinski, Andrew/0000-0002-6871-6799; Lavigne, Rob/0000-0001-7377-1314; Adriaenssens, Evelien/0000-0003-4826-5406 FU PHS HHS [HHSN272200700016I] NR 23 TC 4 Z9 4 U1 5 U2 13 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0304-8608 EI 1432-8798 J9 ARCH VIROL JI Arch. Virol. PD APR PY 2016 VL 161 IS 4 BP 1095 EP 1099 DI 10.1007/s00705-015-2728-0 PG 5 WC Virology SC Virology GA DI2AI UT WOS:000373297700040 PM 26733293 ER PT J AU Babaev, V Ding, L Zhang, YM May, JM Lin, PC Fazio, S Linton, MF AF Babaev, Vladimir Ding, Lei Zhang, Youmin May, James M. Lin, P. Charles Fazio, Sergio Linton, MacRae F. TI Macrophage IKK alpha Deficiency Suppresses Akt Phosphorylation, Reduces Cell Survival, and Decreases Early Atherosclerosis SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE apoptosis; atherosclerosis; cell survival; macrophages; phosphorylation ID NF-KAPPA-B; RICTOR-MTOR COMPLEX; MICE LACKING; MAMMALIAN TARGET; ACTIVATION; KINASE; APOPTOSIS; INTEGRITY; RAPAMYCIN; AKT/PKB AB Objective The IB kinase (IKK) is an enzyme complex that initiates the nuclear factor B transcription factor cascade, which is important in regulating multiple cellular responses. IKK is directly associated with 2 major prosurvival pathways, PI3K/Akt and nuclear factor B, but its role in cell survival is not clear. Macrophages play critical roles in the pathogenesis of atherosclerosis, yet the impact of IKK signaling on macrophage survival and atherogenesis remains unclear. Approach and Results Here, we demonstrate that genetic IKK deficiency, as well as pharmacological inhibition of IKK, in mouse macrophages significantly reduces Akt S-473 phosphorylation, which is accompanied by suppression of mTOR complex 2 signaling. Moreover, IKK null macrophages treated with lipotoxic palmitic acid exhibited early exhaustion of Akt signaling compared with wild-type cells. This was accompanied by a dramatic decrease in the resistance of IKK-/- monocytes and macrophages to different proapoptotic stimuli compared with wild-type cells. In vivo, IKK deficiency increased macrophage apoptosis in atherosclerotic lesions and decreased early atherosclerosis in both female and male low-density lipoprotein receptor (LDLR)(-/-) mice reconstituted with IKK-/- hematopoietic cells and fed with the Western diet for 8 weeks compared with control LDLR-/- mice transplanted with wild-type cells. Conclusions Hematopoietic IKK deficiency in mouse suppresses Akt signaling, compromising monocyte/macrophage survival and this decreases early atherosclerosis. C1 [Babaev, Vladimir; Ding, Lei; Zhang, Youmin; May, James M.; Linton, MacRae F.] Vanderbilt Univ, Med Ctr, Dept Med, Atherosclerosis Res Unit, Nashville, TN 37232 USA. [Linton, MacRae F.] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA. [Lin, P. Charles] NCI, Ctr Canc Res, Frederick, MD 21701 USA. [Fazio, Sergio] Oregon Hlth & Sci Univ, Dept Med, Ctr Prevent Cardiol, Portland, OR 97201 USA. RP Babaev, V; Linton, MF (reprint author), Vanderbilt Univ, Sch Med, 2220 Pierce Ave, Nashville, TN 37232 USA. EM vladimir.babaev@vanderbilt.edu; macrae.linton@vanderbilt.edu FU National Institutes of Health [HL105375, HL116263, DK50435, DK59637] FX This work was supported by National Institutes of Health grants HL105375, HL116263, DK50435, and DK59637 (Lipid, Lipoprotein, and Atherosclerosis Core of the Vanderbilt Mouse Metabolic Phenotype Centers). NR 48 TC 1 Z9 1 U1 4 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1079-5642 EI 1524-4636 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD APR PY 2016 VL 36 IS 4 BP 598 EP 607 DI 10.1161/ATVBAHA.115.306931 PG 10 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA DI4FB UT WOS:000373454700006 PM 26848161 ER PT J AU Castranova, D Davis, AE Lo, BD Miller, MF Paukstelis, PJ Swift, MR Pham, VN Torres-Vazquez, J Bell, K Shaw, KM Kamei, M Weinstein, BM AF Castranova, Daniel Davis, Andrew E. Lo, Brigid D. Miller, Mayumi F. Paukstelis, Paul J. Swift, Matthew R. Pham, Van N. Torres-Vazquez, Jesus Bell, Kameha Shaw, Kenna M. Kamei, Makoto Weinstein, Brant M. TI Aminoacyl-Transfer RNA Synthetase Deficiency Promotes Angiogenesis via the Unfolded Protein Response Pathway SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE endoplasmic reticulum; pathologic neovascularization; protein kinases; unfolded protein response; vascular endothelial growth factor A; zebrafish ID ENDOTHELIAL-GROWTH-FACTOR; VASCULAR DEVELOPMENT; FACTOR VEGF; ER STRESS; ZEBRAFISH DEVELOPMENT; TUMOR ANGIOGENESIS; A EXPRESSION; FRAGMENT; INDUCTION; HYPOXIA AB Objective Understanding the mechanisms regulating normal and pathological angiogenesis is of great scientific and clinical interest. In this report, we show that mutations in 2 different aminoacyl-transfer RNA synthetases, threonyl tRNA synthetase (tars(y58)) or isoleucyl tRNA synthetase (iars(y68)), lead to similar increased branching angiogenesis in developing zebrafish. Approach and Results The unfolded protein response pathway is activated by aminoacyl-transfer RNA synthetase deficiencies, and we show that unfolded protein response genes atf4, atf6, and xbp1, as well as the key proangiogenic ligand vascular endothelial growth factor (vegfaa), are all upregulated in tars(y58) and iars(y68) mutants. Finally, we show that the protein kinase RNA-like endoplasmic reticulum kinase-activating transcription factor 4 arm of the unfolded protein response pathway is necessary for both the elevated vegfaa levels and increased angiogenesis observed in tars(y58) mutants. Conclusions Our results suggest that endoplasmic reticulum stress acts as a proangiogenic signal via unfolded protein response pathway-dependent upregulation of vegfaa. C1 [Castranova, Daniel; Davis, Andrew E.; Lo, Brigid D.; Miller, Mayumi F.; Swift, Matthew R.; Pham, Van N.; Torres-Vazquez, Jesus; Bell, Kameha; Shaw, Kenna M.; Kamei, Makoto; Weinstein, Brant M.] NICHHD, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Paukstelis, Paul J.] Univ Maryland, Dept Chem & Biochem, Coll Comp Math & Nat Sci, College Pk, MD 20742 USA. [Swift, Matthew R.] Georgetown Univ, Med Ctr, Dept Oncol, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. [Torres-Vazquez, Jesus] NYU, Langone Med Ctr, Helen L & Martin S Kimmel Ctr Biol & Med, Skirball Inst Biomol Med, New York, NY USA. [Shaw, Kenna M.] Univ Texas Houston, MD Anderson Canc Ctr, Inst Personalized Canc Therapy, 1515 Holcombe Blvd, Houston, TX 77030 USA. [Kamei, Makoto] South Australian Hlth & Med Res Inst, N Terrace, Adelaide, SA, Australia. RP Weinstein, BM (reprint author), NICHD, Program Genom Differentiat, NIH, Bldg 6B,Room 413,6 Ctr Dr, Bethesda, MD 20892 USA. EM bw96w@nih.gov OI Kamei, Makoto/0000-0002-1438-0783 FU National Institute of Child Health and Human Development, NIH; Leducq Foundation; University of Maryland FX This research was supported by the intramural program of the National Institute of Child Health and Human Development, NIH (to B.M.W.), the Leducq Foundation (to B.M.W.), and by University of Maryland start up funds (to P.J.P.). The Funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article. NR 43 TC 2 Z9 2 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1079-5642 EI 1524-4636 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD APR PY 2016 VL 36 IS 4 BP 655 EP 662 DI 10.1161/ATVBAHA.115.307087 PG 8 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA DI4FB UT WOS:000373454700012 PM 26821951 ER PT J AU Pusic, I Rettig, MP DiPersio, JF Bauer, S McFarland, K Gale, RP Pavletic, SZ AF Pusic, I. Rettig, M. P. DiPersio, J. F. Bauer, S. McFarland, K. Gale, R. P. Pavletic, S. Z. TI Phase-1/-2 study of pomalidomide in chronic GvHD SO BONE MARROW TRANSPLANTATION LA English DT Letter ID VERSUS-HOST-DISEASE; CONSENSUS DEVELOPMENT PROJECT; WORKING GROUP-REPORT; CLINICAL-TRIALS; THALIDOMIDE; TRANSPLANTATION; CRITERIA; THERAPY C1 [Pusic, I.; Rettig, M. P.; DiPersio, J. F.; Bauer, S.; McFarland, K.] Washington Univ, Sch Med, Dept Med, Div Oncol, St Louis, MO 63110 USA. [Gale, R. P.] Univ London Imperial Coll Sci Technol & Med, Dept Med, Haematol Res Ctr, Div Expt Med, London, England. [Pavletic, S. Z.] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Pusic, I (reprint author), Washington Univ, Sch Med, Dept Med, Div Oncol, St Louis, MO 63110 USA. EM ipusic@dom.wustl.edu NR 15 TC 0 Z9 0 U1 0 U2 0 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 APR PY 2016 VL 51 IS 4 BP 612 EP 614 DI 10.1038/bmt.2015.298 PG 3 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA DI2WR UT WOS:000373360400028 PM 26657832 ER PT J AU Janes, K Symons-Liguori, AM Jacobson, KA Salvemini, D AF Janes, K. Symons-Liguori, A. M. Jacobson, K. A. Salvemini, D. TI Identification of A(3) adenosine receptor agonists as novel non-narcotic analgesics SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Review ID INDUCED NEUROPATHIC PAIN; CENTRAL-NERVOUS-SYSTEM; INDUCED PERIPHERAL NEUROPATHY; CULTURED MOUSE ASTROCYTES; SPINAL-CORD STIMULATION; RETINAL GANGLION-CELLS; RAT FORMALIN TEST; A(1) RECEPTOR; CONCISE GUIDE; MICE LACKING AB Chronic pain negatively impacts the quality of life in a variety of patient populations. The current therapeutic repertoire is inadequate in managing patient pain and warrants the development of new therapeutics. Adenosine and its four cognate receptors (A(1), A(2A), A(2B) and A(3)) have important roles in physiological and pathophysiological states, including chronic pain. Preclinical and clinical studies have revealed that while adenosine and agonists of the A(1) and A(2A) receptors have antinociceptive properties, their therapeutic utility is limited by adverse cardiovascular side effects. In contrast, our understanding of the A(3) receptor is only in its infancy, but exciting preclinical observations of A(3) receptor antinociception, which have been bolstered by clinical trials of A(3) receptor agonists in other disease states, suggest pain relief without cardiovascular side effects and with sufficient tolerability. Our goal herein is to briefly discuss adenosine and its receptors in the context of pathological pain and to consider the current data regarding A(3) receptor-mediated antinociception. We will highlight recent findings regarding the impact of the A(3) receptor on pain pathways and examine the current state of selective A(3) receptor agonists used for these studies. The adenosine-to-A(3) receptor pathway represents an important endogenous system that can be targeted to provide safe, effective pain relief from chronic pain. C1 [Janes, K.; Symons-Liguori, A. M.; Salvemini, D.] St Louis Univ, Sch Med, Dept Physiol & Pharmacol, 1402 South Grand Blvd, St Louis, MO 63104 USA. [Jacobson, K. A.] NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Salvemini, D (reprint author), St Louis Univ, Sch Med, Dept Physiol & Pharmacol, 1402 South Grand Blvd, St Louis, MO 63104 USA. EM salvemd@slu.edu RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Leukemia and Lymphoma Society Translational Research Program; National Cancer Institute [RO1CA16519]; Saint Louis Cancer Center; NIDDK Intramural Research Program FX We would like to thank Amanda Ford for her contributions to the experiments outlined in Figure 2. D. S. is funded by the Leukemia and Lymphoma Society Translational Research Program, the National Cancer Institute (RO1CA16519) and the Mayday Fund with additional support from the Saint Louis Cancer Center. K. A. J. acknowledges funding from the NIDDK Intramural Research Program. NR 170 TC 3 Z9 3 U1 2 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1188 EI 1476-5381 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD APR PY 2016 VL 173 IS 8 BP 1253 EP 1267 DI 10.1111/bph.13446 PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DI4QQ UT WOS:000373484800001 PM 26804983 ER PT J AU Praestegaard, C Kjaer, SK Nielsen, TSS Jensen, SM Webb, PM Nagle, CM Hogdall, E Risch, HA Rossing, MA Doherty, JA Wicklund, KG Goodman, MT Modugno, F Moysich, K Ness, RB Edwards, RP Goode, EL Winham, SJ Fridley, BL Cramer, DW Terry, KL Schildkraut, JM Berchuck, A Bandera, EV Paddock, L Kiemeney, LA Massuger, LF Wentzensen, N Pharoah, P Song, HL Whittemore, AS McGuire, V Sieh, W Rothstein, J Anton-Culver, H Ziogas, A Menon, U Gayther, SA Ramus, SJ Gentry-Maharaj, A Wu, AH Pearce, CL Pike, MC Lee, AW Chang-Claude, J Jensen, A AF Praestegaard, Camilla Kjaer, Susanne K. Nielsen, Thor S. S. Jensen, Signe M. Webb, Penelope M. Nagle, Christina M. Hogdall, Estrid Risch, Harvey A. Rossing, Mary Anne Doherty, Jennifer A. Wicklund, Kristine G. Goodman, Marc T. Modugno, Francesmary Moysich, Kirsten Ness, Roberta B. Edwards, Robert P. Goode, Ellen L. Winham, Stacey J. Fridley, Brooke L. Cramer, Daniel W. Terry, Kathryn L. Schildkraut, Joellen M. Berchuck, Andrew Bandera, Elisa V. Paddock, Lisa Kiemeney, Lambertus A. Massuger, Leon F. Wentzensen, Nicolas Pharoah, Paul Song, Honglin Whittemore, Alice S. McGuire, Valerie Sieh, Weiva Rothstein, Joseph Anton-Culver, Hoda Ziogas, Argyrios Menon, Usha Gayther, Simon A. Ramus, Susan J. Gentry-Maharaj, Aleksandra Wu, Anna H. Pearce, Celeste L. Pike, Malcolm C. Lee, Alice W. Chang-Claude, Jenny Jensen, Allan CA Australian Ovarian Canc Study Grp Ovarian Canc Assoc Consortium TI The association between socioeconomic status and tumour stage at diagnosis of ovarian cancer: A pooled analysis of 18 case-control studies SO CANCER EPIDEMIOLOGY LA English DT Article DE Epidemiology; Ovarian cancer; Pooled analysis; Socioeconomic status; Tumour stage ID ENDOMETRIAL CANCER; RISK; SURVIVAL; WOMEN; SMOKING; IMPACT; BREAST; EPIDEMIOLOGY; INEQUALITIES; INFLAMMATION AB Purpose: Socioeconomic status (SES) is a known predictor of survival for several cancers and it has been suggested that SES differences affecting tumour stage at diagnosis may be the most important explanatory factor for this. However, only a limited number of studies have investigated SES differences in tumour stage at diagnosis of ovarian cancer. In a pooled analysis, we investigated whether SES as represented by level of education is predictive for advanced tumour stage at diagnosis of ovarian cancer, overall and by histotype. The effect of cigarette smoking and body mass index (BMI) on the association was also evaluated. Methods: From 18 case-control studies, we obtained information on 10,601 women diagnosed with epithelial ovarian cancer. Study specific odds ratios (ORs) with corresponding 95% confidence intervals (CI) were obtained from logistic regression models and combined into a pooled odds ratio (pOR) using a random effects model. Results: Overall, women who completed <= high school had an increased risk of advanced tumour stage at diagnosis compared with women who completed >high school (pOR 1.15; 95% CI 1.03-1.28). The risk estimates for the different histotypes of ovarian cancer resembled that observed for ovarian cancers combined but did not reach statistical significance. Our results were unchanged when we included BMI and cigarette smoking. Conclusion: Lower level of education was associated with an increased risk of advanced tumour stage at diagnosis of ovarian cancer. The observed socioeconomic difference in stage at diagnosis of ovarian cancer calls for further studies on how to reduce this diagnostic delay. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Praestegaard, Camilla; Kjaer, Susanne K.; Nielsen, Thor S. S.; Hogdall, Estrid; Jensen, Allan] Danish Canc Soc Res Ctr, Lifestyle & Genes, Virus, Strandboulevarden 49, DK-2100 Copenhagen, Denmark. [Kjaer, Susanne K.] Univ Copenhagen Hosp, Rigshosp, Dept Gynecol, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. [Jensen, Signe M.] Danish Canc Soc Res Ctr, Stat Bioinformat & Registry, Strandboulevarden 49, DK-2100 Copenhagen, Denmark. [Webb, Penelope M.; Nagle, Christina M.] QIMR Berghofer Med Res Inst, Populat Hlth Dept, 300 Herston Rd, Brisbane, Qld 4006, Australia. [Webb, Penelope M.] Peter MacCallum Canc Ctr, East Melbourne, Vic, Australia. [Hogdall, Estrid] Copenhagen Univ Hosp, Herlev Hosp, Dept Pathol, Mol Unit, Herlev Ringvej 75, DK-2730 Herlev, Denmark. [Risch, Harvey A.] Yale Univ, Sch Publ Hlth, Dept Chron Dis Epidemiol, LEPH 413, 60 Coll St, New Haven, CT 06510 USA. [Rossing, Mary Anne; Wicklund, Kristine G.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, POB 19024, Seattle, WA 98109 USA. [Rossing, Mary Anne] Univ Washington, Dept Epidemiol, POB 19024, Seattle, WA 98109 USA. [Doherty, Jennifer A.] Dartmouth Coll, Geisel Sch Med, Sect Biostat & Epidemiol, Dept Community & Family Med, 1 Med Ctr Dr,7927 Rubin Bldg,Room 884, Hanover, NH 03756 USA. [Goodman, Marc T.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Canc Prevent & Control, 8700 Beverly Blvd,Room 1S37, Los Angeles, CA 90048 USA. [Goodman, Marc T.] Cedars Sinai Med Ctr, Dept Biomed Sci, Community & Populat Hlth Res Inst, 8700 Beverly Blvd,Room 1S37, Los Angeles, CA 90048 USA. [Modugno, Francesmary] Univ Pittsburgh, Magee Womens Hosp, Sch Med, Dept Obstet Gynecol & Reprod Sci,Div Gynecol Onco, 300 Halket St Room 2130, Pittsburgh, PA 15222 USA. [Modugno, Francesmary] Univ Pittsburgh, Magee Womens Hosp, Grad Sch Publ Hlth, Dept Epidemiol, 300 Halket St Room 2130, Pittsburgh, PA 15222 USA. [Modugno, Francesmary] Magee Womens Res Inst, Womens Canc Res Program, 300 Halket St Room 2130, Pittsburgh, PA 15222 USA. [Modugno, Francesmary] Univ Pittsburgh, Magee Womens Hosp, Inst Canc, 300 Halket St Room 2130, Pittsburgh, PA 15222 USA. [Moysich, Kirsten] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Elm & Carlton St, Buffalo, NY 14263 USA. [Ness, Roberta B.] Univ Texas Houston, Sch Publ Hlth, POB 20186, Houston, TX 77225 USA. [Edwards, Robert P.] Univ Pittsburgh, Sch Med, Magee Womens Hosp, Dept Obstet Gynecol & Reprod Sci, 300 Halket St Room 2130, Pittsburgh, PA 15222 USA. [Goode, Ellen L.] Mayo Clin, Dept Hlth Sci Res, Div Epidemiol, 200 First St SW,Charlton 6, Rochester, MN USA. [Winham, Stacey J.; Fridley, Brooke L.] Univ Kansas, Dept Biostat, 5028B Robinson Bldg,3901 Rainbow Blvd, Kansas City, KS 66160 USA. [Cramer, Daniel W.; Terry, Kathryn L.] Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, 221 Longwood Ave,RFB 368, Boston, MA 02115 USA. [Terry, Kathryn L.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, 221 Longwood Ave,RFB 368, Boston, MA 02115 USA. [Schildkraut, Joellen M.] Univ Virginia, Sch Med, Dept Publ Hlth Sci, Box 800717, Charlottesville, VA 22908 USA. [Berchuck, Andrew] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA. [Bandera, Elisa V.] Rutgers Canc Inst New Jersey, Canc Prevent & Control Program, 195 Little Albany St,Room 5568, New Brunswick, NJ 08903 USA. [Paddock, Lisa] New Jersey State Canc Registry, POB 369, Trenton, NJ 08625 USA. [Paddock, Lisa] Rutgers Sch Publ Hlth, Piscataway, NJ USA. [Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Dept Hlth Evidence, POB 9101, NL-6500 HB Nijmegen, Netherlands. [Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Dept Urol, POB 9101, NL-6500 HB Nijmegen, Netherlands. [Massuger, Leon F.] Radboud Univ Nijmegen, Med Ctr, Dept Obstet & Gynaecol, POB 9101, NL-6500 HB Nijmegen, Netherlands. [Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd, Rockville, MD 20852 USA. [Pharoah, Paul] Univ Cambridge, Dept Publ Hlth & Primary Care, Dept Oncol, Strangeways Res Lab, Wortscauseway, Cambridge CB1 8RN, England. [Song, Honglin] Univ Cambridge, Strangeways Res Lab, Dept Oncol, Wortscauseway, Cambridge CB1 8RN, England. [Whittemore, Alice S.; McGuire, Valerie; Sieh, Weiva; Rothstein, Joseph] Stanford Univ, Sch Med, Dept Hlth Res & Policy Epidemiol, 259 Campus Dr, Stanford, CA 94305 USA. [Anton-Culver, Hoda] Univ Calif Irvine, Ctr Canc Genet Res & Prevent, Sch Med, Dept Epidemiol, 224 Irvine Hall, Irvine, CA 92697 USA. [Ziogas, Argyrios] Univ Calif Irvine, Dept Epidemiol, 224 Irvine Hall, Irvine, CA 92697 USA. [Menon, Usha; Gayther, Simon A.; Gentry-Maharaj, Aleksandra] UCL, EGA Inst Womens Hlth, Womens Canc, Maple House 1st Floor,149 Tottenham Court Rd, London W1T 7DN, England. [Ramus, Susan J.; Wu, Anna H.; Pearce, Celeste L.; Pike, Malcolm C.; Lee, Alice W.] Univ So Calif, Norris Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Harlyne Norris Res Tower 1450 Biggy St,Off 2517G, Los Angeles, CA 90033 USA. [Pearce, Celeste L.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, 1415 Washington Hts,SPH Tower,Off 4642, Ann Arbor, MI 48109 USA. [Pike, Malcolm C.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, 307 East 63rd St, New York, NY 10065 USA. [Chang-Claude, Jenny] German Canc Res Ctr, Div Canc Epidemiol, Postfach 101949, D-69009 Heidelberg, Germany. RP Jensen, A (reprint author), Danish Canc Soc Res Ctr, Lifestyle & Genes, Virus, Strandboulevarden 49, DK-2100 Copenhagen, Denmark. EM allan@cancer.dk OI Webb, Penelope/0000-0003-0733-5930; Jensen, Signe Marie/0000-0002-7738-5231; Ramus, Susan/0000-0003-0005-7798; Winham, Stacey/0000-0002-8492-9102 FU European Commission [223175]; National Institutes of Health [P50 CA136393, R01 CA76016, R01 CA54419, P50 CA105009, P30 CA072720, P30 CA008748, K07 CA095666, R01 CA83918, K22 CA138563, U01 CA71966, R01 CA16056, K07 CA143047, U01 CA69417, R01 CA058860, R01 CA092044 a, PSA 042205, P30 CA14089, R01 CA61132, N01 PC67010]; Danish Cancer Society [94 222 52]; Mermaid 1; U.S. Army Medical Research and Materiel Command [DAMD17-01-1-0729]; National Health & Medical Research Council of Australia [199600, 400281]; Cancer Council of New South Wales; Cancer Council of Victoria; Cancer Council of Queensland; Cancer Council of South Australia; Cancer Council of Tasmania; Cancer Foundation of Western Australia; German Federal Ministry of Education and Research; Program of Clinical Biomedical Research [01GB9401]; German Cancer Research Center; US Army Medical Research and Material Command [DAMD17-02-1-0669, DAMD17-02-1-0666, W81XWH-10-1-02802]; Mayo Foundation; Minnesota Ovarian Cancer Alliance; Fred C. and Katherine B. Andersen Foundation; Cancer Institute of New Jersey; Radboud University Nijmegen Medical Centre; National Cancer Institute; Cancer Research UK [C490/A10119, C490/A10124]; Lon V Smith Foundation [LVS-39420]; Cancer Research UK; Eve Appeal; OAK Foundation; California Cancer Research Program [00-01389V-20170, N01 CN025403, R03 CA113148, R03 CA115195, 2II0200]; National Institute of Environmental Health Sciences [T32ES013678]; US National Cancer Institute [P01 CA17054, K07-CA80668, P50CA159981]; Center for Disease Control [5U58DP003931-02]; National Cancer Institute's Surveillance, Epidemiology, and End Results Program [HHSN 261201300021I NCI, N01PC-2013-00021]; Department of Health; The National Institutes of Health [R01 CA074850, R01 CA080742, R01 CA112523, R01 CA87538, R01 CA58598, N01 CN55424, N01 PC 67001, MO1-RR000056, R01 CA61107, R01 CA122443, P30 CA15083] FX This work was supported by the European Commission's Seventh Framework Programme grant agreement no. 223175 (HEALTH-F2-2009-223175). The work was also supported by the National Institutes of Health (R01 CA074850 and R01 CA080742 (CON), R01 CA112523 and R01 CA87538 (DOV), R01 CA58598, N01 CN55424 and N01 PC 67001 (HAW), MO1-RR000056 (HOP), R01 CA61107 (MAL), R01 CA122443, P30 CA15083 and P50 CA136393 (MAY), R01 CA76016 (NCO), R01 CA54419 and P50 CA105009 (NEC), P30 CA072720, P30 CA008748, K07 CA095666, R01 CA83918 and K22 CA138563 (NJO), U01 CA71966, R01 CA16056, K07 CA143047 and U01 CA69417 (STA), R01 CA058860, R01 CA092044 and PSA 042205 (UCI), P30 CA14089, R01 CA61132 and N01 PC67010 (USC)); Danish Cancer Society (94 222 52 (MAL)); Mermaid 1 (MAL); U.S. Army Medical Research and Materiel Command (DAMD17-01-1-0729) (AUS), National Health & Medical Research Council of Australia (199600 and 400281) (AUS); Cancer Councils of New South Wales, Victoria, Queensland, South Australia and Tasmania (AUS); Cancer Foundation of Western Australia (AUS); German Federal Ministry of Education and Research, Program of Clinical Biomedical Research (01GB9401 (GER)); German Cancer Research Center (GER); US Army Medical Research and Material Command (DAMD17-02-1-0669 (HOP), DAMD17-02-1-0666 (NCO) and W81XWH-10-1-02802 (NEC)); Mayo Foundation (MAY); Minnesota Ovarian Cancer Alliance (MAY); Fred C. and Katherine B. Andersen Foundation (MAY); The Cancer Institute of New Jersey (NJO); Radboud University Nijmegen Medical Centre (NTH); Intramural Research Program of the National Cancer Institute (POL); Cancer Research UK (C490/A10119 and C490/A10124 (SEA)); Lon V Smith Foundation (LVS-39420 (UCI)); Cancer Research UK (UKO, SEA); Eve Appeal (UKO); OAK Foundation (UKO); California Cancer Research Program (00-01389V-20170, N01 CN025403, R03 CA113148, R03 CA115195 (USC)); California Cancer Research Program (2II0200 (USC)); National Institute of Environmental Health Sciences T32ES013678 (USC) and US National Cancer Institute (P01 CA17054 (USC) and K07-CA80668 and P50CA159981 (HOP)). The New Jersey State Cancer Registry is funded by the Center for Disease Control (5U58DP003931-02) and The National Cancer Institute's Surveillance, Epidemiology, and End Results Program (HHSN 261201300021I NCI Control No. N01PC-2013-00021). A portion of this was done at UCLH/UCL within the 'Women's Health Theme' of the NIHR UCLH/UCL Comprehensive Biomedical Research Centre supported by the Department of Health (UKO). The German group thanks Ursula Eilber and Tanja Koehler for competent technical assistance (GER). The Australian group thanks all the clinical and scientific collaborators (http://www.aocstudy.org/) and the women for their contribution (AUS). The cooperation of the 32 Connecticut hospitals, including Stamford Hospital, in allowing patient access, is gratefully acknowledged (CON). Certain data in the CON study were obtained from the Connecticut Tumor Registry, Connecticut Department of Public Health. The CON study assumes full responsibility for analyses and interpretation of these data. The MALOVA study is grateful to Nick Martinussen for data management assistance (MAL). The NJO group thanks the New Jersey State Cancer Registry staff, M. King and L. Rodriguez. The SEARCH group thanks the SEARCH team, Craig Luccarini, Caroline Baynes and Don Conroy. The UKOPS group thanks I. Jacobs, M. Widschwendter, E. Wozniak, A. Ryan, J. Ford and N. Balogun for their contribution to the study (UKO). NR 52 TC 0 Z9 0 U1 2 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1877-7821 EI 1877-783X J9 CANCER EPIDEMIOL JI Cancer Epidemiol. PD APR PY 2016 VL 41 BP 71 EP 79 DI 10.1016/j.canep.2016.01.012 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DI7ZZ UT WOS:000373721800010 ER PT J AU Jensen, JD Holton, AE Krakow, M Weaver, J Donovan, E Tavtigian, S AF Jensen, Jakob D. Holton, Avery E. Krakow, Melinda Weaver, Jeremy Donovan, Erin Tavtigian, Sean TI Colorectal cancer prevention and intentions to use low-dose aspirin: A survey of 1000 US adults aged 40-65 SO CANCER EPIDEMIOLOGY LA English DT Article DE Low-dose aspirin; Colorectal cancer; Prevention; Health belief model ID RANDOMIZED-CONTROLLED-TRIALS; CARDIOVASCULAR-DISEASE; AFRICAN-AMERICANS; ALTERNATE-DAY; FOLLOW-UP; HEALTH; BEHAVIOR; VALIDITY; MODEL; RISK AB Objective: The Translating Research into Action (TRIA) study was initiated to gather dissemination information on emerging cancer control recommendations. Daily, low-dose aspirin has been identified as a promising means of preventing colorectal cancer, and stakeholders are already calling for research to facilitate dissemination. Thus, the current study sought to identify factors related to intention to use aspirin for colorectal cancer prevention. Methods: In April 2014, U.S. adults aged 40-65 (N = 1000) were recruited to participate in a survey grounded in the health belief model. Results: Older, Black males were more likely to intend to use low-dose aspirin to prevent colorectal cancer. Smokers, and those with a history of polyps, were also more receptive to initiating daily, low-dose aspirin use. Five psychosocial factors were related to intention including self-efficacy, response efficacy, perceived barriers, perceived susceptibility to colorectal cancer, and cancer information overload. Conclusion: Initial campaigns/interventions designed to increase daily, low-dose aspirin for colorectal cancer prevention may be more effective if they target receptive populations (older, Black males) using messages informed by the health belief model. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Jensen, Jakob D.; Holton, Avery E.; Weaver, Jeremy] Univ Utah, Dept Commun, 2423 LNCO,255 S Cent Campus Dr, Salt Lake City, UT 84112 USA. [Jensen, Jakob D.; Tavtigian, Sean] Huntsman Canc Inst, Salt Lake City, UT USA. [Krakow, Melinda] NCI, Bethesda, MD 20892 USA. [Donovan, Erin] Univ Texas Austin, Dept Commun Studies, Austin, TX 78712 USA. RP Jensen, JD (reprint author), Univ Utah, Dept Commun, 2423 LNCO,255 S Cent Campus Dr, Salt Lake City, UT 84112 USA. EM jakob.jensen@utah.edu FU Huntsman Cancer Institute FX Jakob D. Jensen is an Associate Professor in the Department of Communication and the Huntsman Cancer Institute at the University of Utah. Avery E. Holton is an Assistant Professor in the Department of Communication at the University of Utah. Melinda Krakow is a post-doctoral fellow at the National Cancer Institute. Jeremy Weaver is a doctoral candidate in the Department of Communication at the University of Utah. Erin Donovan is an Assistant Professor in the Department of Communication Studies at the University of Texas - Austin. Sean Tavtigian is a Professor in the Department of Oncological Sciences at the University of Utah. This research was funded by a pilot grant from the Huntsman Cancer Institute. The authors have no conflicts of interest to report. NR 39 TC 0 Z9 0 U1 3 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1877-7821 EI 1877-783X J9 CANCER EPIDEMIOL JI Cancer Epidemiol. PD APR PY 2016 VL 41 BP 99 EP 105 DI 10.1016/j.canep.2016.02.003 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DI7ZZ UT WOS:000373721800014 PM 26895085 ER PT J AU Martin, DN Lam, TK Brignole, K Ashing, KT Blot, WJ Burhansstipanov, L Chen, JT Dignan, M Gomez, SL Martinez, ME Matthews, A Palmer, JR Perez-Stable, EJ Schootman, M Vilchis, H Vu, A Srinivasan, S AF Martin, Damali N. Lam, Tram Kim Brignole, Katy Ashing, Kimlin T. Blot, William J. Burhansstipanov, Linda Chen, Jarvis T. Dignan, Mark Gomez, Scarlett Lin Martinez, Maria Elena Matthews, Alicia Palmer, Julie R. Perez-Stable, Eliseo J. Schootman, Mario Vilchis, Hugo Vu, Alexander Srinivasan, Shobha TI Recommendations for Cancer Epidemiologic Research in Understudied Populations and Implications for Future Needs SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID SOUTHERN COMMUNITY COHORT; ALASKA NATIVE WOMEN; ALL-CAUSE MORTALITY; PREVENTION RESEARCH; HEALTH DISPARITIES; AMERICAN-INDIANS; SEXUAL ORIENTATION; UNITED-STATES; PARTICIPATORY RESEARCH; AFGHAN REFUGEES AB Medically underserved populations in the United States continue to experience higher cancer burdens of incidence, mortality, and other cancer-related outcomes. It is imperative to understand how health inequities experienced by diverse population groups may contribute to our increasing unequal cancer burdens and disparate outcomes. The National Cancer Institute convened a diverse group of scientists to discuss research challenges and opportunities for cancer epidemiology in medically underserved and understudied populations. This report summarizes salient issues and discusses five recommendations from the group, including the next steps required to better examine and address cancer burden in the United States among our rapidly increasing diverse and understudied populations. (C) 2016 AACR. C1 [Martin, Damali N.; Lam, Tram Kim; Brignole, Katy; Srinivasan, Shobha] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Ashing, Kimlin T.] City Hope Canc Ctr, Ctr Community Alliance Res & Educ, Duarte, CA USA. [Blot, William J.] Vanderbilt Univ, Sch Med, Div Epidemiol, Nashville, TN 37212 USA. [Blot, William J.] Int Epidemiol Inst, Rockville, MD USA. [Burhansstipanov, Linda] Native Amer Canc Res Corp, Denver, CO USA. [Burhansstipanov, Linda] Native Amer Canc Initiat Inc, Boulder, CO USA. [Chen, Jarvis T.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Dignan, Mark] Univ Kentucky, Lucille P Markey Canc Ctr, Lexington, KY USA. [Gomez, Scarlett Lin] Canc Prevent Inst Calif, Fremont, CA USA. [Gomez, Scarlett Lin] Stanford Canc Inst, Stanford, CA USA. [Martinez, Maria Elena] Univ Calif San Diego, Dept Family Med & Publ Hlth, La Jolla, CA 92093 USA. [Matthews, Alicia] Univ Illinois, Sch Nursing, Chicago, IL USA. [Palmer, Julie R.] Boston Univ, Slone Epidemiol Ctr, Boston, MA 02215 USA. [Perez-Stable, Eliseo J.] Natl Inst Minor Hlth & Hlth Dispar, NIH, Bethesda, MD USA. [Schootman, Mario] St Louis Univ, Coll Publ Hlth & Social Justice, St Louis, MO 63103 USA. [Vilchis, Hugo] Burrell Coll Osteopath Med, Burrell Inst Hlth Policy & Res, Las Cruces, NM USA. [Vu, Alexander] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA. RP Martin, DN (reprint author), NCI, NIH, Shady Grove Bldg,Room 4E108,9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM martinda@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 77 TC 1 Z9 1 U1 2 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2016 VL 25 IS 4 BP 573 EP 580 DI 10.1158/1055-9965.EPI-15-1297 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DI4RB UT WOS:000373485900002 PM 27196089 ER PT J AU Croyle, RT Srinivasan, S AF Croyle, Robert T. Srinivasan, Shobha TI Informing Future Population Health Interventions SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Editorial Material C1 [Croyle, Robert T.; Srinivasan, Shobha] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. RP Croyle, RT (reprint author), NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 CA999999] NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2016 VL 25 IS 4 BP 583 EP 583 DI 10.1158/1055-9965.EPI-16-0141 PG 1 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DI4RB UT WOS:000373485900004 PM 27196091 ER PT J AU Trabert, B Brinton, LA Anderson, GL Pfeiffer, RM Falk, RT Strickler, HD Sliesoraitis, S Kuller, LH Gass, ML Fuhrman, BJ Xu, X Wentzensen, N AF Trabert, Britton Brinton, Louise A. Anderson, Garnet L. Pfeiffer, Ruth M. Falk, Roni T. Strickler, Howard D. Sliesoraitis, Sarunas Kuller, Lewis H. Gass, Margery L. Fuhrman, Barbara J. Xu, Xia Wentzensen, Nicolas TI Circulating Estrogens and Postmenopausal Ovarian Cancer Risk in the Women's Health Initiative Observational Study SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID MENOPAUSAL HORMONE-THERAPY; STEROID-HORMONES; METABOLITES; SERUM; EXPRESSION; RECEPTOR; GROWTH; BREAST AB Background: Hormonal and reproductive factors contribute to the development of ovarian cancer, but few studies have examined associations between circulating estrogens and estrogen metabolites and ovarian cancer risk. We evaluated whether serum estrogens and estrogen metabolite levels are associated with ovarian cancer risk among postmenopausal women in a nested case-control study in the Women's Health Initiative (WHI) Observational Study (OS). Methods: We selected all 169 eligible epithelial ovarian cancer cases and 412 matched controls from women enrolled in WHI-OS who were not using menopausal hormones at baseline. Baseline levels of 15 estrogens and estrogen metabolites were measured via liquid chromatography/tandem mass spectrometry. Associations with ovarian cancer risk overall and stratified by histologic subtype (serous/nonserous) were analyzed using logistic regression. The mean time from serum collection to cancer diagnosis was 6.9 years. Results: Overall, we observed modest ovarian cancer risk associations among women with higher levels of estrone [OR (95% confidence interval) quintile (Q) 5 vs. Q1:1.54 (0.82-2.90), P-trend = 0.05], as well as 2- and 4-methoxyestrone metabolites [2.03 (1.06-3.88), P-trend = 0.02; 1.86 (0.98-3.56), P-trend = 0.01, respectively]. Associations of estrogens and estrogen metabolites varied substantially by histologic subtype. Associations with serous tumors were universally null, while estrone [2.65 (1.09-6.45), P-trend = 0.01, P-heterogeneity = 0.04], unconjugated estradiol [2.72 (1.04-7.14), P-trend = 0.03, P-heterogeneity = 0.02] and many of the 2-, 4-, and 16-pathway metabolites were positively associated with nonserous tumors. Conclusions: Our study provides novel molecular data showing an association of the parent estrogens and several estrogen metabolites with nonserous ovarian cancers. Impact: These findings further support the heterogeneous etiology of ovarian cancer. (C) 2016 AACR. C1 [Trabert, Britton; Brinton, Louise A.; Pfeiffer, Ruth M.; Falk, Roni T.; Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Anderson, Garnet L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Canc Prevent Program, 1124 Columbia St, Seattle, WA 98104 USA. [Strickler, Howard D.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Sliesoraitis, Sarunas] Univ Texas San Antonio, Dept Hematol & Med Oncol, San Antonio, TX USA. [Kuller, Lewis H.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Gass, Margery L.] Cleveland Clin, Womens Hlth Inst, Cleveland, OH 44106 USA. [Fuhrman, Barbara J.] Univ Arkansas Med Sci, Fay W Boozman Coll Publ Hlth, Dept Epidemiol, Little Rock, AR 72205 USA. [Xu, Xia] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Canc Res Technol Program, Frederick, MD USA. RP Trabert, B (reprint author), NCI, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM britton.trabert@nih.gov RI Trabert, Britton/F-8051-2015 FU Intramural Research Program of the NCI; National Heart, Lung, and Blood Institute, NIH, U.S. Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C] FX This work was supported in part by the Intramural Research Program of the NCI (to B. Trabert, L.A. Brinton, R.M. Pfeiffer, R.T. Falk, N. Wentzensen). The WHI program is funded by the National Heart, Lung, and Blood Institute, NIH, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C (to G.L. Anderson, H.D. Strickler, L.H. Kuller, M.L. Gass). NR 24 TC 2 Z9 2 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2016 VL 25 IS 4 BP 648 EP 656 DI 10.1158/1055-9965.EPI-15-1272-T PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DI4RB UT WOS:000373485900012 PM 26908437 ER PT J AU Mondul, AM Weinstein, SJ Moy, KA Mannisto, S Albanes, D AF Mondul, Alison M. Weinstein, Stephanie J. Moy, Kristin A. Mannisto, Satu Albanes, Demetrius TI Circulating 25-Hydroxyvitamin D and Prostate Cancer Survival SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID VITAMIN-D PATHWAY; COHORT CONSORTIUM; GENETIC-VARIATION; PREVENTION TRIAL; RISK; BREAST; CELLS AB Background: Recent epidemiologic evidence suggests that higher circulating vitamin D does not protect against prostate cancer and, in fact, may increase the risk of developing this malignancy. However, few studies have examined the most clinically relevant outcome, prostate cancer mortality. Methods: We examined prediagnostic serum 25-hydroxyvitamin D (25(OH)D) and prostate cancer survival in a cohort of 1,000 cases in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. During 23 years of follow-up, 363 men died from their disease. Cox proportional hazards models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI) of death from prostate cancer by season-specific quintile of 25(OH)D. Multivariable models were adjusted for age, physical activity, cigarettes per day, and family history of prostate cancer. Results: Men with higher serum 25(OH)D were less likely to die from their prostate cancer (Q5 vs. Q1 HR, 0.72; 95% CI, 0.52-0.99; P-trend = 0.006). This finding was independent of stage or grade at diagnosis and appeared restricted to men who survived longer (survived < 3.3 years: Q5 vs. Q1 HR, 0.95; 95% CI, 0.61-1.50; P-trend, 0.53; survived >= 3.3 years: Q5 vs. Q1 HR, 0.53; 95% CI, 0.34-0.85; P-trend, 0.0002). Conclusions: In this population of men diagnosed with prostate cancer, higher serum 25(OH)D years prior to diagnosis was associated with longer prostate cancer survival. Impact: In light of inconsistent evidence regarding the role of vitamin D in the development of prostate cancer, the present findings regarding the most clinically relevant prostate cancer outcome, disease-specific mortality, could have important public health implications. (C) 2016 AACR. C1 [Mondul, Alison M.; Weinstein, Stephanie J.; Moy, Kristin A.; Albanes, Demetrius] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. [Mondul, Alison M.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Mannisto, Satu] Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland. RP Mondul, AM (reprint author), 1415 Washington Hts 4646, Ann Arbor, MI 48109 USA. EM amondul@umich.edu OI Mondul, Alison/0000-0002-8843-1416 FU Intramural Research Program of the NCI at the NIH (U.S. Public Health Service); U.S. Public Health Service [N01-CN-45165, N01-RC-45035, N01-RC-37004, HHSN261201000006C, HHSN261200800001E, HHSN261201500005C] FX The ATBC Study is supported by the Intramural Research Program of the NCI at the NIH (U.S. Public Health Service) and by U.S. Public Health Service Contract Numbers awarded to D. Albanes: N01-CN-45165, N01-RC-45035, N01-RC-37004, HHSN261201000006C, HHSN261200800001E, and HHSN261201500005C. NR 23 TC 4 Z9 4 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2016 VL 25 IS 4 BP 665 EP 669 DI 10.1158/1055-9965.EPI-15-0991 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DI4RB UT WOS:000373485900014 PM 26809275 ER PT J AU Siiskonen, SJ Zhang, MF Li, WQ Liang, LM Kraft, P Nijsten, T Han, JL Qureshi, AA AF Siiskonen, Satu J. Zhang, Mingfeng Li, Wen-Qing Liang, Liming Kraft, Peter Nijsten, Tamar Han, Jiali Qureshi, Abrar A. TI A Genome-Wide Association Study of Cutaneous Squamous Cell Carcinoma among European Descendants SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID NONMELANOMA SKIN-CANCER; GENETIC-VARIANTS; BREAST-CANCER; RISK; EXPRESSION; PIGMENTATION; LINES; BASAL; LOCI; ST3GAL-I AB Background: NoGWAS on the risk of cutaneous squamous cell carcinoma (SCC) has been published. We conducted a multistage genome-wide association study (GWAS) to identify novel genetic loci for SCC. Methods: The study included 745 SCC cases and 12,805 controls of European descent in the discovery stage and 531 SCC cases and 551 controls of European ancestry in the replication stage. We selected 64 independent loci that showed the most significant associations with SCC in the discovery stage (linkage disequilibrium r(2) < 0.4) for replication. Results: Rs8063761 in the DEF8 gene on chromosome 16 showed the strongest association with SCC (P = 1.7 +/- 10(-9) in the combined set; P = 1.0 +/- 10(-6) in the discovery set and P = 4.1 +/- 10(-4) in the replication set). The variant allele of rs8063761 (T allele) was associated with a decreased expression of DEF8 (P = 1.2 +/- 10(-6)). Besides, we validated four other SNPs associated with SCC in the replication set, including rs9689649 in PARK2 gene (P = 2.7 +/- 10(-6) in combined set; P = 3.2 +/- 10(-5) in the discovery; and P = 0.02 in the replication), rs754626 in the SRC gene (P = 1.1 +/- 10(-6) in combined set; P = 1.4 +/- 10(-5) in the discovery and P = 0.02 in the replication), rs9643297 in ST3GAL1 gene (P = 8.2 +/- 10(-6) in combined set; P = 3.3 +/- 10(-5) in the discovery; and P = 0.04 in the replication), and rs17247181 in ERBB2IP gene (P = 4.2 +/- 10(-6) in combined set; P = 3.1 +/- 10(-5) in the discovery; and P = 0.048 in the replication). Conclusion: Several genetic variants were associated with risk of SCC in a multistage GWAS of subjects of European ancestry. Impact: Further studies are warranted to validate our finding and elucidate the genetic function of these variants. (C) 2016 AACR. C1 [Siiskonen, Satu J.; Nijsten, Tamar] Erasmus MC, Dept Dermatol, Rotterdam, Netherlands. [Zhang, Mingfeng] Brigham & Womens Hosp, Dept Dermatol, 75 Francis St, Boston, MA 02115 USA. [Zhang, Mingfeng; Qureshi, Abrar A.] Harvard Univ, Sch Med, Boston, MA USA. [Li, Wen-Qing; Qureshi, Abrar A.] Brown Univ, Warren Alpert Med Sch, Dept Dermatol, Providence, RI 02912 USA. [Li, Wen-Qing; Qureshi, Abrar A.] Brown Univ, Sch Publ Hlth, Dept Epidemiol, Providence, RI 02912 USA. [Liang, Liming; Kraft, Peter; Han, Jiali] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Liang, Liming; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Han, Jiali] Indiana Univ, Dept Epidemiol, Richard M Fairbanks Sch Publ Hlth, Simon Canc Ctr, Indianapolis, IN 46204 USA. [Han, Jiali] Indiana Univ, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46204 USA. [Qureshi, Abrar A.] Rhode Isl Hosp, Dept Dermatol, Providence, RI USA. [Qureshi, Abrar A.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Zhang, Mingfeng] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Zhang, MF (reprint author), NIH, 8717 Grovemont Circle, Bethesda, MD 20892 USA. EM zhmingfeng@gmail.com FU Merck Research Laboratories FX Harvard GWAS: The authors thank Dr. Frank B. Hu and Dr. Eric B. Rimm for their work on the component GWAS sets, Constance Chen for programming support, and Pati Soule and Dr. Hardeep Ranu of the Dana Farber/Harvard Cancer Center High-Throughput Polymorphism Detection Core for sample handling and genotyping of the NHS and HPFS samples. The authors are grateful to Merck Research Laboratories for funding of the GWAS of coronary heart disease and are also indebted to the participants in all of these studies. The authors also thank the participants and staff of the NNHS, the HPFS for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. NR 37 TC 2 Z9 2 U1 2 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2016 VL 25 IS 4 BP 714 EP 720 DI 10.1158/1055-9965.EPI-15-1070 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DI4RB UT WOS:000373485900020 PM 26908436 ER PT J AU Bu, W Hayes, GM Liu, H Gemmell, L Schmeling, DO Radecki, P Aguilar, F Burbelo, PD Woo, J Balfour, HH Cohen, JI AF Bu, Wei Hayes, Gregory M. Liu, Hui Gemmell, Lorraine Schmeling, David O. Radecki, Pierce Aguilar, Fiona Burbelo, Peter D. Woo, Jennifer Balfour, Henry H., Jr. Cohen, Jeffrey I. TI Kinetics of Epstein-Barr Virus (EBV) Neutralizing and Virus-Specific Antibodies after Primary Infection with EBV SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID NUCLEAR ANTIGEN 1; T-CELL RESPONSES; MONONUCLEOSIS; VACCINE; GP350; IMMUNOGENICITY; IDENTIFICATION; EXPRESSION; SEVERITY; EVALUATE AB Prospective studies of antibodies to multiple Epstein-Barr virus (EBV) proteins and EBV neutralizing antibodies in the same individuals before, during, and after primary EBV infection have not been reported. We studied antibody responses to EBV in college students who acquired primary EBV infection during prospective surveillance and correlated the kinetics of antibody response with the severity of disease. Neutralizing antibodies and enzyme-linked immunosorbent assay (ELISA) antibodies to gp350, the major target of neutralizing antibody, reached peak levels at medians of 179 and 333 days after the onset of symptoms of infectious mononucleosis, respectively. No clear correlation was found between the severity of the symptoms of infectious mononucleosis and the peak levels of antibody to individual viral proteins or to neutralizing antibody. In summary, we found that titers of neutralizing antibody and antibodies to multiple EBV proteins increase over many months after primary infection with EBV. C1 [Bu, Wei; Radecki, Pierce; Aguilar, Fiona; Cohen, Jeffrey I.] NIAID, Med Virol Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Hayes, Gregory M.; Liu, Hui; Gemmell, Lorraine; Woo, Jennifer] Medimmune, Mountain View, CA USA. [Schmeling, David O.; Balfour, Henry H., Jr.] Univ Minnesota, Sch Med, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Burbelo, Peter D.] Natl Inst Dent & Craniofacial Res, Dent Clin Res, NIH, Bethesda, MD USA. [Balfour, Henry H., Jr.] Univ Minnesota, Sch Med, Dept Pathol, Minneapolis, MN 55455 USA. RP Cohen, JI (reprint author), NIAID, Med Virol Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jcohen@niaid.nih.gov FU University of Minnesota Foundation; University of Minnesota International Center for Antiviral Research and Epidemiology; Division of Intramural Research, National Institute of Dental and Craniofacial Research; Division of Intramural Research, National Institute of Allergy and Infectious Diseases (DIR, NIAID) FX University of Minnesota Foundation provided funding to David Schmeling and Henry Balfour Jr. University of Minnesota International Center for Antiviral Research and Epidemiology provided funding to David Schmeling and Henry Balfour Jr. Division of Intramural Research, National Institute of Dental and Craniofacial Research provided funding to Peter Burbelo. Division of Intramural Research, National Institute of Allergy and Infectious Diseases (DIR, NIAID) provided funding to Wei Bu and Jeffrey I Cohen. NR 29 TC 2 Z9 2 U1 6 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 EI 1556-679X J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD APR PY 2016 VL 23 IS 4 BP 363 EP 369 DI 10.1128/CVI.00674-15 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DI4SY UT WOS:000373490800013 PM 26888186 ER PT J AU Hinrichs, CS AF Hinrichs, Christian S. TI Molecular Pathways: Breaking the Epithelial Cancer Barrier for Chimeric Antigen Receptor and T-cell Receptor Gene Therapy SO CLINICAL CANCER RESEARCH LA English DT Article ID METASTATIC MELANOMA; ADOPTIVE IMMUNOTHERAPY; ESTABLISHED TUMORS; IN-VIVO; REGRESSION; BLOCKADE; INTERLEUKIN-12; CARCINOMA; RESPONSES; TOXICITY AB Adoptive transfer of T cells genetically engineered to express a tumor-targeting chimeric antigen receptor (CAR) or T-cell receptor (TCR) can mediate cancer regression in some patients. CARs are synthetic single-chain proteins that use antibody domains to target cell surface antigens. TCRs are natural heterodimeric proteins that can target intracellular antigens through recognition of peptides bound to human leukocyte antigens. CARs have shown promise in B-cell malignancies and TCRs in melanoma, but neither approach has achieved clear success in an epithelial cancer. Treatment of epithelial cancers may be particularly challenging because of a paucity of target antigens expressed by carcinomas and not by important healthy tissues. In addition, epithelial cancers may be protected by inhibitory ligands and soluble factors in the tumor microenvironment. One strategy to overcome these negative regulators is to modulate expression of T-cell genes to enhance intrinsic T-cell function. Programmable nucleases, which can suppress inhibitory genes, and inducible gene expression systems, which can enhance stimulatory genes, are entering clinical testing. Other work is delineating whether control of genes for immune checkpoint receptors (e.g., PDCD1, CTLA4) and cytokine and TCR signaling regulators (e.g., CBLB, CISH, IL12, IL15) can increase the antitumor activity of therapeutic T cells. (C) 2016 AACR. C1 [Hinrichs, Christian S.] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. RP Hinrichs, CS (reprint author), NCI, 10 Ctr Dr,Bldg 10,Room 4B04, Bethesda, MD 20892 USA. EM Hinrichs@nih.gov FU Intramural NIH HHS [ZIA BC011479-03] NR 47 TC 0 Z9 0 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD APR 1 PY 2016 VL 22 IS 7 BP 1559 EP 1564 DI 10.1158/1078-0432.CCR-15-1294 PG 6 WC Oncology SC Oncology GA DI2WT UT WOS:000373360600004 PM 27037253 ER PT J AU Schmitz, KH Gehlert, S Patterson, RE Colditz, GA Chavarro, JE Hu, FB Neuhouser, ML Sturgeon, KM Thornquist, M Tobias, D Nebeling, LC AF Schmitz, Kathryn H. Gehlert, Sarah Patterson, Ruth E. Colditz, Graham A. Chavarro, Jorge E. Hu, Frank B. Neuhouser, Marian L. Sturgeon, Kathleen M. Thornquist, Mark Tobias, Deirdre Nebeling, Linda C. TI TREC to WHERE? Transdisciplinary Research on Energetics and Cancer SO CLINICAL CANCER RESEARCH LA English DT Review ID INDUCED MAMMARY CARCINOGENESIS; BODY-MASS INDEX; BREAST-CANCER; TEAM SCIENCE; AFRICAN-AMERICAN; RISK-FACTORS; RACIAL DISPARITY; HORMONE-RECEPTOR; NURSES HEALTH; US ADULTS AB When information is exchanged across disciplinary boundaries, resources are shared, and discipline-specific approaches are altered to achieve a common scientific goal, we create a new intellectual space for transdisciplinary research. This approach, fostered heavily by multiple NCI-funded initiatives, has the potential to forge new understanding of major public health issues. By breaking down disciplinary barriers, we work toward making real, meaningful, and lasting forward motion in addressing key public health issues. One of the transdisciplinary initiatives of the NCI is TREC: Transdisciplinary Research on Energetics and Cancer. In this article, we review the goals and scope of TREC, as well as the ways in which the initiative promotes transdisciplinary science. A particular focus is on multiple examples of the most unique aspect of the initiative: the funding of developmental projects across multiple TREC centers, toward the goal of incubating high-risk science that has the potential to translate into major leaps forward in understanding energetics in cancer. As we enter an era of greater focus on investigator-initiated science, new approaches may be needed to ensure that the peer review process is not solely organized along disciplinary lines. Inclusion of expertise regarding transdisciplinarity, as well as representation from multiple scientific disciplines within a panel, may allow transdisciplinary research to receive an educated hearing. The body of researchers trained to work in a transdisciplinary research space is ideally suited to address these challenges. (C) 2016 AACR. C1 [Schmitz, Kathryn H.; Sturgeon, Kathleen M.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Gehlert, Sarah; Colditz, Graham A.] Washington Univ, Siteman Canc Ctr, St Louis, MO USA. [Patterson, Ruth E.] Univ Calif San Diego, Moores Canc Ctr, San Diego, CA 92103 USA. [Chavarro, Jorge E.; Hu, Frank B.; Tobias, Deirdre] Harvard Univ, Harvard TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Neuhouser, Marian L.; Thornquist, Mark] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Nebeling, Linda C.] NCI, Rockville, MD USA. RP Schmitz, KH (reprint author), Univ Penn, 8th Floor Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM Schmitz@mail.med.upenn.edu FU NCI Centers for TREC [U01 CA116850, U54 CA155626, U54 CA155435, U54 CA155850, U54 CA155496] FX This work was supported by the NCI Centers for TREC [U01 CA116850 (Coordination Center), U54 CA155626 (Harvard University), U54 CA155435 (University of California, San Diego), U54 CA155850 (University of Pennsylvania), and U54 CA155496 (Washington University)]. NR 41 TC 0 Z9 0 U1 1 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 APR 1 PY 2016 VL 22 IS 7 BP 1565 EP 1571 DI 10.1158/1078-0432.CCR-14-1214 PG 7 WC Oncology SC Oncology GA DI2WT UT WOS:000373360600005 PM 26792261 ER PT J AU Niemann, CU Herman, SEM Maric, I Gomez-Rodriguez, J Biancotto, A Chang, BY Martyr, S Stetler-Stevenson, M Yuan, CM Calvo, KR Braylan, RC Valdez, J Lee, YS Wong, DH Jones, J Sun, C Marti, GE Farooqui, MZH Wiestner, A AF Niemann, Carsten U. Herman, Sarah E. M. Maric, Irina Gomez-Rodriguez, Julio Biancotto, Angelique Chang, Betty Y. Martyr, Sabrina Stetler-Stevenson, Maryalice Yuan, Constance M. Calvo, Katherine R. Braylan, Raul C. Valdez, Janet Lee, Yuh Shan Wong, Deanna H. Jones, Jade Sun, Clare Marti, Gerald E. Farooqui, Mohammed Z. H. Wiestner, Adrian TI Disruption of in vivo Chronic Lymphocytic Leukemia Tumor-Microenvironment Interactions by Ibrutinib - Findings from an Investigator-Initiated Phase II Study SO CLINICAL CANCER RESEARCH LA English DT Article ID B-CELL RECEPTOR; T-CELLS; INHIBITOR; BTK; PCI-32765; SURVIVAL; PROLIFERATION; ACTIVATION; MIGRATION; ADHESION AB Purpose: Chronic lymphocytic leukemia (CLL) cells depend on microenvironmental interactions for proliferation and survival that are at least partially mediated through B-cell receptor (BCR) signaling. Ibrutinib, a Bruton tyrosine kinase inhibitor, disrupts BCR signaling and leads to the egress of tumor cells from the microenvironment. Although the on-target effects on CLL cells are well defined, the impact on the microenvironment is less well studied. We therefore sought to characterize the in vivo effects of ibrutinib on the tumor microenvironment. Experimental Design: Patients received single-agent ibrutinib on an investigator-initiated phase II trial. Serial blood and tissue samples were collected pretreatment and during treatment. Changes in cytokine levels, cellular subsets, and microenvironmental interactions were assessed. Results: Serum levels of key chemokines and inflammatory cytokines decreased significantly in patients on ibrutinib. Furthermore, ibrutinib treatment decreased circulating tumor cells and overall T-cell numbers. Most notably, a reduced frequency of the Th17 subset of CD4(+) T cells was observed concurrent with reduced expression of activation markers and PD-1 on T cells. Consistent with direct inhibition of T cells, ibrutinib inhibited Th17 differentiation of murine CD4(+) T cells in vitro. Finally, in the bone marrow microenvironment, we found that ibrutinib disaggregated the interactions of macrophages and CLL cells, inhibited secretion of CXCL13, and decreased the chemoattraction of CLL cells. Conclusions: In conjunction with inhibition of BCR signaling, these changes in the tumor microenvironment likely contribute to the antitumor activity of ibrutinib and may impact the efficacy of immunotherapeutic strategies in patients with CLL. (C) 2015 AACR. C1 [Niemann, Carsten U.; Herman, Sarah E. M.; Martyr, Sabrina; Valdez, Janet; Lee, Yuh Shan; Wong, Deanna H.; Jones, Jade; Sun, Clare; Marti, Gerald E.; Farooqui, Mohammed Z. H.; Wiestner, Adrian] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Niemann, Carsten U.] Copenhagen Univ Hosp, Dept Hematol, Rigshosp, Copenhagen, Denmark. [Maric, Irina; Calvo, Katherine R.; Braylan, Raul C.] NIH, Dept Lab Med, Clin Res Ctr, Bldg 10, Bethesda, MD 20892 USA. [Gomez-Rodriguez, Julio] NIH, Natl Human Genome Res Inst, Bldg 10, Bethesda, MD 20892 USA. [Biancotto, Angelique] NIH, Ctr Human Immunol Autoimmun & Inflammat, Bldg 10, Bethesda, MD 20892 USA. [Chang, Betty Y.] Pharmacyclics Inc, Sunnyvale, CA USA. [Stetler-Stevenson, Maryalice; Yuan, Constance M.] NCI, Lab Pathol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Jones, Jade] NIH, Med Res Scholars Program, Bldg 10, Bethesda, MD 20892 USA. RP Wiestner, A (reprint author), NHLBI, NIH, 10 Ctr Dr,Bldg 10,CRC 3-5140, Bethesda, MD 20892 USA. EM wiestnea@nhlbi.nih.gov FU Intramural Research Program of the National Heart, Lung, and Blood Institute (Bethesda, MD); Danish Cancer Society FX This research was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute (Bethesda, MD). C.U. Niemann was supported by the Danish Cancer Society. NR 50 TC 14 Z9 14 U1 4 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD APR 1 PY 2016 VL 22 IS 7 BP 1572 EP 1582 DI 10.1158/1078-0432.CCR-15-1965 PG 11 WC Oncology SC Oncology GA DI2WT UT WOS:000373360600006 PM 26660519 ER PT J AU Yang, YJ Jia, DW Kim, H Elmageed, ZYA Datta, A Davis, R Srivastav, S Moroz, K Crawford, BE Moparty, K Thomas, R Hudson, RS Ambs, S Abdel-Mageed, AB AF Yang, Yijun Jia, Dingwu Kim, Hogyoung Elmageed, Zakaria Y. Abd Datta, Amrita Davis, Rodney Srivastav, Sudesh Moroz, Krzysztof Crawford, Byron E. Moparty, Krishnarao Thomas, Raju Hudson, Robert S. Ambs, Stefan Abdel-Mageed, Asim B. TI Dysregulation of miR-212 Promotes Castration Resistance through hnRNPH1-Mediated Regulation of AR and AR-V7: Implications for Racial Disparity of Prostate Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEINS; ANDROGEN RECEPTOR TRANSACTIVATION; AFRICAN-AMERICAN; RESPONSE ELEMENT; ACCEPTOR SITES; HNRNP H1; EXPRESSION; MATRIX; PROTEINS; CELLS AB Purpose: The causes of disproportionate incidence and mortality of prostate cancer among African Americans (AA) remain elusive. The purpose of this study was to investigate the mechanistic role and assess clinical utility of the splicing factor heterogeneous nuclear ribonucleoprotein H1 (hnRNP H1) in prostate cancer progression among AA men. Experimental Design: We employed an unbiased functional genomics approach coupled with suppressive subtractive hybridization (SSH) and custom cDNA microarrays to identify differentially expressed genes in microdissected tumors procured from age-and tumor grade-matched AA and Caucasian American (CA) men. Validation analysis was performed in independent cohorts and tissue microarrays. The underlying mechanisms of hnRNPH1 regulation and its impact on androgen receptor (AR) expression and tumor progression were explored. Results: Aberrant coexpression of AR and hnRNPH1 and downregulation of miR-212 were detected in prostate tumors and correlate with disease progression in AA men compared with CA men. Ectopic expression of miR-212 mimics downregulated hnRNPH1 transcripts, which in turn reduced expression of AR and its splice variant AR-V7 (or AR3) in prostate cancer cells. hnRNPH1 physically interacts with AR and steroid receptor coactivator-3 (SRC-3) and primes activation of androgen-regulated genes in a ligand-dependent and independent manner. siRNA silencing of hnRNPH1 sensitized prostate cancer cells to bicalutamide and inhibited prostate tumorigenesis in vivo. Conclusions: Our findings define novel roles for hnRNPH1 as a putative oncogene, splicing factor, and an auxiliary AR coregulator. Targeted disruption of the hnRNPH1-AR axis may have therapeutic implications to improve clinical outcomes in patients with advanced prostate cancer, especially among AA men. (C) 2015 AACR. C1 [Yang, Yijun; Jia, Dingwu; Kim, Hogyoung; Elmageed, Zakaria Y. Abd; Datta, Amrita; Davis, Rodney; Moparty, Krishnarao; Thomas, Raju; Abdel-Mageed, Asim B.] Tulane Univ, Sch Med, Dept Urol, New Orleans, LA 70112 USA. [Moparty, Krishnarao] Southeast Louisiana Vet Hlth Care Syst, Div Urol, New Orleans, LA USA. [Moroz, Krzysztof; Crawford, Byron E.] Tulane Univ, Sch Med, Dept Pathol, New Orleans, LA 70112 USA. [Moroz, Krzysztof; Thomas, Raju; Abdel-Mageed, Asim B.] Tulane Univ, Sch Med, Tulane Canc Ctr, New Orleans, LA 70112 USA. [Hudson, Robert S.; Ambs, Stefan] NCI, Lab Human Carcinogenesis, NIH, Bethesda, MD 20892 USA. [Abdel-Mageed, Asim B.] Tulane Univ, Sch Med, Dept Pharmacol, New Orleans, LA 70112 USA. [Srivastav, Sudesh] Tulane Univ, Dept Biostat, Sch Publ Hlth & Trop Med, New Orleans, LA 70112 USA. RP Abdel-Mageed, AB (reprint author), Tulane Univ, Dept Urol, Hlth Sci Ctr, 1430 Tulane Ave,SL-42, New Orleans, LA 70112 USA. EM amageed@tulane.edu OI Datta, Amrita/0000-0003-2029-8134 FU American Cancer Society [RSGTCCE-116942]; Department of Defense [W81XWH-09-1-0200] FX The study was partially supported by grants from the American Cancer Society (RSGTCCE-116942; to A.B. Abdel-Mageed) and Department of Defense (W81XWH-09-1-0200; to A.B. Abdel-Mageed). NR 50 TC 5 Z9 5 U1 0 U2 1 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 APR 1 PY 2016 VL 22 IS 7 BP 1744 EP 1756 DI 10.1158/1078-0432.CCR-15-1606 PG 13 WC Oncology SC Oncology GA DI2WT UT WOS:000373360600022 PM 26553749 ER PT J AU Hyman, DM Eaton, A Ivy, SP Spriggs, DR Iasonos, A AF Hyman, David M. Eaton, Anne Ivy, S. Percy Spriggs, David R. Iasonos, Alexia TI Measuring Toxicity in Phase I Clinical Trials-Letter SO CLINICAL CANCER RESEARCH LA English DT Letter C1 [Hyman, David M.; Spriggs, David R.] Mem Sloan Kettering Canc Ctr, Dev Therapeut, Dept Med, New York, NY 10065 USA. [Hyman, David M.; Spriggs, David R.] Weill Cornell Med Coll, Dept Med, New York, NY USA. [Eaton, Anne; Iasonos, Alexia] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA. [Ivy, S. Percy] NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Hyman, DM (reprint author), Mem Sloan Kettering Canc Ctr, 300 E 66th St,Rm 1353, New York, NY 10065 USA. EM hymand@mskcc.org FU NCI NIH HHS [P30 CA008748] NR 4 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 APR 1 PY 2016 VL 22 IS 7 BP 1828 EP 1828 DI 10.1158/1078-0432.CCR-15-3043 PG 1 WC Oncology SC Oncology GA DI2WT UT WOS:000373360600032 PM 27037257 ER PT J AU Kim, Y Ge, YH Tao, C Zhu, JB Chapman, AB Torres, VE Yu, ASL Mrug, M Bennett, WM Flessner, MF Landsittel, DP Bae, KT AF Kim, Youngwoo Ge, Yinghui Tao, Cheng Zhu, Jianbing Chapman, Arlene B. Torres, Vicente E. Yu, Alan S. L. Mrug, Michal Bennett, William M. Flessner, Michael F. Landsittel, Doug P. Bae, Kyongtae T. CA Consortium Radiologic Imaging Stud TI Automated Segmentation of Kidneys from MR Images in Patients with Autosomal Dominant Polycystic Kidney Disease SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID RENAL CYSTS; VOLUME; ALGORITHMS; CONSORTIUM; PROGNOSIS; COHORT AB Background and objectives Our study developed a fully automated method for segmentation and volumetric measurements of kidneys from magnetic resonance images in patients with autosomal dominant polycystic kidney disease and assessed the performance of the automated method with the reference manual segmentation method. Design, setting, participants, & measurements Study patients were selected from the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease. At the enrollment of the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease Study in 2000, patients with autosomal dominant polycystic kidney disease were between 15 and 46 years of age with relatively preserved GFRs. Our fully automated segmentation method was on the basis of a spatial prior probability map of the location of kidneys in abdominal magnetic resonance images and regional mapping with total variation regularization and propagated shape constraints that were formulated into a level set framework. T2-weighted magnetic resonance image sets of 120 kidneys were selected from 60 patients with autosomal dominant polycystic kidney disease and divided into the training and test datasets. The performance of the automated method in reference to the manual method was assessed by means of two metrics: Dice similarity coefficient and intraclass correlation coefficient of segmented kidney volume. The training and test sets were swapped for crossvalidation and reanalyzed. Results Successful segmentation of kidneys was performed with the automated method in all test patients. The segmented kidney volumes ranged from 177.2 to 2634 ml (mean, 885.4 +/- 569.7 ml). The mean Dice similarity coefficient +/- SD between the automated and manual methods was 0.88 +/- 0.08. The mean correlation coefficient between the two segmentation methods for the segmented volume measurements was 0.97 (P<0.001 for each crossvalidation set). The results from the crossvalidation sets were highly comparable. Conclusions We have developed a fully automated method for segmentation of kidneys from abdominal magnetic resonance images in patients with autosomal dominant polycystic kidney disease with varying kidney volumes. The performance of the automated method was in good agreement with that of manual method. C1 [Kim, Youngwoo; Ge, Yinghui; Tao, Cheng; Zhu, Jianbing; Bae, Kyongtae T.] Univ Pittsburgh, Sch Med, Dept Radiol, 3362 Fifth Ave, Pittsburgh, PA 15213 USA. [Landsittel, Doug P.] Univ Pittsburgh, Sch Med, Dept Internal Med, Pittsburgh, PA 15213 USA. [Chapman, Arlene B.] Emory Univ, Sch Med, Dept Internal Med, Atlanta, GA 30322 USA. [Torres, Vicente E.] Mayo Coll Med, Dept Internal Med, Rochester, MN USA. [Yu, Alan S. L.] Univ Kansas, Med Ctr, Dept Internal Med, Kansas City, KS 66103 USA. [Mrug, Michal] Univ Alabama Birmingham, Div Nephrol, Birmingham, AL USA. [Bennett, William M.] Legacy Good Samaritan Hosp, Portland, OR USA. [Flessner, Michael F.] NIDDK, NIH, Bethesda, MD 20892 USA. RP Bae, KT (reprint author), Univ Pittsburgh, Sch Med, Dept Radiol, 3362 Fifth Ave, Pittsburgh, PA 15213 USA. EM baek@upmc.edu FU National Institute of Diabetes and Digestive and Kidney Diseases of National Institutes of Health [DK056943, DK056956, DK056957, DK056961]; National Center for Research Resources General Clinical Research Centers [RR000039, RR00585, RR23940, RR000032]; National Center for Research Resources Clinical and Translational Science Awards [RR025008, RR024150, RR033179, RR025777, UL1TR000165, RR024153, UL1TR000005] FX The CRISP Study is supported by National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health Cooperative Agreements DK056943, DK056956, DK056957, and DK056961; National Center for Research Resources General Clinical Research Centers Grants RR000039 (to Emory University), RR00585 (to Mayo College of Medicine), RR23940 (to Kansas University Medical Center), and RR000032 (to the University of Alabama at Birmingham); and National Center for Research Resources Clinical and Translational Science Awards RR025008 (to Emory University), RR024150 (to Mayo College of Medicine), RR033179 (to Kansas University Medical Center), RR025777 and UL1TR000165 (to the University of Alabama at Birmingham), and RR024153 and UL1TR000005 (to the University of Pittsburgh School of Medicine). NR 26 TC 1 Z9 1 U1 2 U2 5 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 APR PY 2016 VL 11 IS 4 BP 576 EP 584 DI 10.2215/CJN.08300815 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA DI5EV UT WOS:000373522600007 PM 26797708 ER PT J AU Gutierrez, OM Parsa, A Isakova, T Scialla, JJ Chen, J Flack, JM Nessel, LC Gupta, J Bellovich, KA Steigerwalt, S Sondheimer, JH Wright, JT Feldman, HI Kusek, JW Lash, JP Wolf, M AF Gutierrez, Orlando M. Parsa, Afshin Isakova, Tamara Scialla, Julia J. Chen, Jing Flack, John M. Nessel, Lisa C. Gupta, Jayanta Bellovich, Keith A. Steigerwalt, Susan Sondheimer, James H. Wright, Jackson T., Jr. Feldman, Harold I. Kusek, John W. Lash, James P. Wolf, Myles TI Genetic African Ancestry and Markers of Mineral Metabolism in CKD SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CHRONIC KIDNEY-DISEASE; SOCIOECONOMIC-STATUS; CALCIUM-ABSORPTION; RACIAL-DIFFERENCES; PHOSPHATE; AMERICANS; BLACKS; HEALTH; URINE; WOMEN AB Background and objectives Disorders of mineral metabolism are more common in African Americans with CKD than in European Americans with CKD. Previous studies have focused on the differences in mineral metabolism by self-reported race, making it difficult to delineate the importance of environmental compared with biologic factors. Design, setting, participants, & measurements In a cross-sectional analysis of 3013 participants of the Chronic Renal Insufficiency Cohort study with complete data, we compared markers of mineral metabolism (phosphorus, calcium, alkaline phosphatase, parathyroid hormone, fibroblast growth factor 23, and urine calcium and phosphorus excretion) in European Americans versus African Americans and separately, across quartiles of genetic African ancestry in African Americans (n=1490). Results Compared with European Americans, African Americans had higher blood concentrations of phosphorus, alkaline phosphatase, fibroblast growth factor 23, and parathyroid hormone, lower 24-hour urinary excretion of calcium and phosphorus, and lower urinary fractional excretion of calcium and phosphorus at baseline (P<0.001 for all). Among African Americans, a higher percentage of African ancestry was associated with lower 24-hour urinary excretion of phosphorus (P-trend<0.01) in unadjusted analyses. In linear regression models adjusted for socio-demographic characteristics, kidney function, serum phosphorus, and dietary phosphorus intake, higher percentage of African ancestry was significantly associated with lower 24-hour urinary phosphorus excretion (each 10% higher African ancestry was associated with 39.6 mg lower 24-hour urinary phosphorus, P<0.001) and fractional excretion of phosphorus (each 10% higher African ancestry was associated with an absolute 1.1% lower fractional excretion of phosphorus, P=0.01). Conclusions A higher percentage of African ancestry was independently associated with lower 24-hour urinary phosphorus excretion and lower fractional excretion of phosphorus among African Americans with CKD. These findings suggest that genetic variability might contribute to racial differences in urinary phosphorus excretion in CKD. C1 [Gutierrez, Orlando M.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Gutierrez, Orlando M.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL 35294 USA. [Parsa, Afshin] Univ Maryland, Sch Med, Div Nephrol, Dept Med, Baltimore, MD 21201 USA. [Isakova, Tamara; Wolf, Myles] Northwestern Univ, Dept Med, Inst Publ Hlth & Med, Chicago, IL 60611 USA. [Scialla, Julia J.] Duke Univ, Dept Med, Div Nephrol, Durham, NC USA. [Chen, Jing] Tulane Univ, Dept Med, New Orleans, LA 70118 USA. [Chen, Jing] Tulane Univ, Dept Epidemiol, New Orleans, LA 70118 USA. [Flack, John M.; Sondheimer, James H.] Wayne State Univ, Sch Med, Dept Med, Detroit, MI 48201 USA. [Nessel, Lisa C.; Feldman, Harold I.] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Gupta, Jayanta] Texas Tech Univ, Hlth Sci Ctr, Dept Biomed Sci, Paul L Foster Sch Med, El Paso, TX USA. [Bellovich, Keith A.] St Johns Hosp, Med Ctr, Div Nephrol, Detroit, MI USA. [Steigerwalt, Susan] Univ Michigan, Dept Med, Div Cardiol, Ann Arbor, MI 48109 USA. [Wright, Jackson T., Jr.] Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA. [Kusek, John W.] NIDDKD, NIH, Bethesda, MD USA. [Lash, James P.] Univ Illinois, Dept Med, Chicago, IL USA. RP Gutierrez, OM (reprint author), Univ Alabama Birmingham, 1720 2nd Ave S,ZRB 638, Birmingham, AL 35294 USA. EM ogutierr@uab.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, U01DK060902]; University of Pennsylvania Clinical and Translational Research Center Clinical and Translational Science Award [UL1 RR-024134]; Johns Hopkins University [UL1 RR-025005]; University of Maryland GCRC [M01 RR-16500]; Clinical and Translational Science Collaborative of Cleveland; National Center for Advancing Translational Sciences component of the National Institutes of Health (NIH) [UL1TR000439]; NISI roadmap for Medical Research; Michigan Institute for Clinical and Health Research [UL1RR024986]; University of Illinois at Chicago [CTSA UL1RR029879]; Tulane University Translational Research in Hypertension and Renal Biology [P30GM103337]; Kaiser NIH/NCRR UCSF-CTSI [UL1 RR-024131]; Strategically Focused Research Network Center on Health Disparities from American Heart Association; NIH [R01DK076116, R01DK081374, R01DK094796, K24DK093723, U01DK099930, R21DK100754]; [R01NS080850]; [R03DK095005] FX Funding for the CRIC study was obtained under a cooperative agreement from the National Institute of Diabetes and Digestive and Kidney Diseases (U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, and U01DK060902). In addition, this work was supported in part by the University of Pennsylvania Clinical and Translational Research Center Clinical and Translational Science Award UL1 RR-024134, Johns Hopkins University UL1 RR-025005, University of Maryland GCRC M01 RR-16500, Clinical and Translational Science Collaborative of Cleveland, UL1TR000439 from the National Center for Advancing Translational Sciences component of the National Institutes of Health (NIH) and NISI roadmap for Medical Research, Michigan Institute for Clinical and Health Research UL1RR024986, University of Illinois at Chicago CTSA UL1RR029879, Tulane University Translational Research in Hypertension and Renal Biology P30GM103337, and Kaiser NIH/NCRR UCSF-CTSI UL1 RR-024131.; O.M.G. was supported by grants R01NS080850, R03DK095005 and a Strategically Focused Research Network Center on Health Disparities from the American Heart Association; M.W. was supported by R01DK076116, R01DK081374, R01DK094796, K24DK093723, U01DK099930 and R21DK100754 from the NIH and a Strategically Focused Research Network Center on Health Disparities from the American Heart Association. NR 21 TC 1 Z9 1 U1 0 U2 0 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 APR PY 2016 VL 11 IS 4 BP 653 EP 662 DI 10.2215/CJN.08020715 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA DI5EV UT WOS:000373522600016 PM 26912553 ER PT J AU Narva, AS Norton, JM Boulware, LE AF Narva, Andrew S. Norton, Jenna M. Boulware, L. Ebony TI Educating Patients about CKD: The Path to Self-Management and Patient-Centered Care SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CHRONIC KIDNEY-DISEASE; GLOMERULAR-FILTRATION-RATE; RANDOMIZED CONTROLLED-TRIAL; SHARED DECISION-MAKING; STAGE RENAL-DISEASE; PREDIALYSIS PSYCHOEDUCATIONAL INTERVENTION; AFRICAN-AMERICAN PATIENTS; BLOOD-PRESSURE CONTROL; HEALTH LITERACY; APPROPRIATE INITIATION AB Patient education is associated with better patient outcomes and supported by international guidelines and organizations, but a range of barriers prevent widespread implementation of comprehensive education for people with progressive kidney disease, especially in the United States. Among United States patients, obstacles to education include the complex nature of kidney disease information, low baseline awareness, limited health literacy and numeracy, limited availability of CKD information, and lack of readiness to learn. For providers, lack of time and clinical confidence combine with competing education priorities and confusion about diagnosing CKD to limit educational efforts. At the system level, lack of provider incentives, limited availability of practical decision support tools, and lack of established interdisciplinary care models inhibit patient education. Despite these barriers, innovative education approaches for people with CKD exist, including self-management support, shared decision making, use of digital media, and engaging families and communities. Education efficiency may be increased by focusing on people with progressive disease, establishing interdisciplinary care management including community health workers, and providing education in group settings. New educational approaches are being developed through research and quality improvement efforts, but challenges to evaluating public awareness and patient education programs inhibit identification of successful strategies for broader implementation. However, growing interest in improving patient-centered outcomes may provide new approaches to effective education of people with CKD. C1 [Narva, Andrew S.; Norton, Jenna M.] NIDDKD, Div Kidney Urol & Hematol Dis, Natl Kidney Dis Educ Program, Bethesda, MD 20892 USA. [Boulware, L. Ebony] Duke Univ, Dept Med, Div Gen Internal Med, Durham, NC USA. RP Narva, AS (reprint author), NIDDKD, NIH, Natl Kidney Dis Educ Program, Bldg 31,Room 9A27,MSC 2560,31 Ctr Dr, Bethesda, MD 20892 USA. EM narvaa@niddk.nih.gov NR 113 TC 3 Z9 3 U1 6 U2 10 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 APR PY 2016 VL 11 IS 4 BP 694 EP 703 DI 10.2215/CJN.07680715 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA DI5EV UT WOS:000373522600020 PM 26536899 ER PT J AU Heldin, CH Lu, BS Evans, R Gutkind, JS AF Heldin, Carl-Henrik Lu, Benson Evans, Ron Gutkind, J. Silvio TI Signals and Receptors SO COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; GROWTH-FACTOR RECEPTOR; CADHERIN-MEDIATED ADHESION; ORPHAN NUCLEAR RECEPTORS; CELL CONTACT FORMATION; EGF RECEPTOR; NITRIC-OXIDE; TYROSINE KINASES; TRANSCRIPTION FACTOR; CYTOKINE RECEPTORS AB Communication between cells in a multicellular organism occurs by the production of ligands (proteins, peptides, fatty acids, steroids, gases, and other low-molecular-weight compounds) that are either secreted by cells or presented on their surface, and act on receptors on, or in, other target cells. Such signals control cell growth, migration, survival, and differentiation. Signaling receptors can be single-span plasma membrane receptors associated with tyrosine or serine/threonine kinase activities, proteins with seven transmembrane domains, or intracellular receptors. Ligand-activated receptors convey signals into the cell by activating signaling pathways that ultimately affect cytosolic machineries or nuclear transcriptional programs or by directly translocating to the nucleus to regulate transcription. C1 [Heldin, Carl-Henrik] Uppsala Univ, Ludwig Inst Canc Res, Sci Life Lab, SE-75124 Uppsala, Sweden. [Lu, Benson; Evans, Ron] Salk Inst Biol Studies, Gene Express Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA. [Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. RP Heldin, CH (reprint author), Uppsala Univ, Ludwig Inst Canc Res, Sci Life Lab, SE-75124 Uppsala, Sweden. EM c-h.heldin@licr.uu.se NR 190 TC 6 Z9 6 U1 2 U2 6 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1943-0264 J9 CSH PERSPECT BIOL JI Cold Spring Harbor Perspect. Biol. PD APR PY 2016 VL 8 IS 4 AR a005900 DI 10.1101/cshperspect.a005900 PG 27 WC Cell Biology SC Cell Biology GA DI4RL UT WOS:000373486900006 PM 27037414 ER PT J AU Buckley, AW Holmes, GL AF Buckley, Ashura W. Holmes, Gregory L. TI Epilepsy and Autism SO COLD SPRING HARBOR PERSPECTIVES IN MEDICINE LA English DT Article ID FRAGILE-X-SYNDROME; TUBEROUS SCLEROSIS COMPLEX; EARLY-LIFE SEIZURES; DE-LANGE-SYNDROME; PERVASIVE DEVELOPMENTAL DISORDER; EPILEPTIFORM EEG ABNORMALITIES; FUNCTIONAL BRAIN CONNECTIVITY; CHILDHOOD-ONSET EPILEPSY; PHELAN-MCDERMID SYNDROME; SMITH-MAGENIS-SYNDROME AB Epilepsy and autistic spectrum disorder frequently coexist in the same individual. Electroencephalogram (EEG) epileptiform activity is also present at a substantially higher rate in children with autism than normally developing children. As with epilepsy, there are a multitude of genetic and environmental factors that can result in autistic spectrum disorder. There is growing consensus from both animal and clinical studies that autism is a disorder of aberrant connectivity. As measured with functional magnetic resonance imaging (MRI) and EEG, the brain in autistic spectrum disorder may be under-or overconnected or have a mixture of over- and underconnectivity. In the case of comorbid epilepsy and autism, an imbalance of the excitatory/inhibitory (E/I) ratio in selected regions of the brain may drive overconnectivity. Understanding the mechanism by which altered connectivity in individuals with comorbid epilepsy and autistic spectrum disorder results in the behaviors specific to the autistic spectrum disorder remains a challenge. C1 [Buckley, Ashura W.] NIMH, Bethesda, MD 20892 USA. [Holmes, Gregory L.] Univ Vermont, Coll Med, Dept Neurol Sci, Burlington, VT 05405 USA. RP Buckley, AW (reprint author), NIMH, Bethesda, MD 20892 USA.; Holmes, GL (reprint author), Univ Vermont, Coll Med, Dept Neurol Sci, Burlington, VT 05405 USA. EM shu.buckley@nih.gov; gregory.holmes@uvm.edu FU National Institutes of Health (NIH) [NS074450, NS073083]; Emmory R. Shapses Research Fund; Michael J. Pietroniro Research Fund FX This work is supported by the National Institutes of Health (NIH) Grants NS074450, NS074450, and NS073083, and the Emmory R. Shapses Research Fund and Michael J. Pietroniro Research Fund (G.L.H.). NR 196 TC 1 Z9 1 U1 10 U2 16 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 2157-1422 J9 CSH PERSPECT MED JI Cold Spring Harb. Perspect. Med. PD APR PY 2016 VL 6 IS 4 AR a022749 DI 10.1101/cshperspect.a022749 PG 17 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DI6GK UT WOS:000373597000002 PM 26989064 ER PT J AU Sierra, F AF Sierra, Felipe TI The Emergence of Geroscience as an Interdisciplinary Approach to the Enhancement of Health Span and Life Span SO COLD SPRING HARBOR PERSPECTIVES IN MEDICINE LA English DT Article ID AGE-RELATED DISEASE; CAENORHABDITIS-ELEGANS; TELOMERE LENGTH; HUMAN LONGEVITY; EXTENDING LIFE; DIETARY RESTRICTION; COGNITIVE FUNCTION; OXIDATIVE STRESS; DNA-DAMAGE; MICE AB Research on the biology of aging has accelerated rapidly in the last two decades. It is now at the point where translation of the findings into useful approaches to improve the health of the elderly population seems possible. In trying to fill that gap, a new field termed geroscience will be articulated here that attempts to identify the biological underpinnings for the age-dependency of most chronic diseases. Herein, I will review the major conceptual issues leading to the formulation of geroscience as a field, as well as give examples of current areas of inquiry in which basic aging biology research could lead to therapeutic approaches to address age-related chronic diseases, not one at a time, but most of them in unison. C1 [Sierra, Felipe] NIA, Div Aging Biol, NIH, Bethesda, MD 20892 USA. RP Sierra, F (reprint author), NIA, Div Aging Biol, NIH, Bethesda, MD 20892 USA. EM sierraf@nia.nih.gov NR 103 TC 2 Z9 2 U1 3 U2 4 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 2157-1422 J9 CSH PERSPECT MED JI Cold Spring Harb. Perspect. Med. PD APR PY 2016 VL 6 IS 4 AR a025163 DI 10.1101/cshperspect.a025163 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DI6GK UT WOS:000373597000007 PM 26931460 ER PT J AU Milligan, KL Matsui, E Sharma, H AF Milligan, Ki Lee Matsui, Elizabeth Sharma, Hemant TI Asthma in Urban Children: Epidemiology, Environmental Risk Factors, and the Public Health Domain SO CURRENT ALLERGY AND ASTHMA REPORTS LA English DT Review DE Asthma; Asthma and urban children; Asthma in inner-city; Asthma and poverty; Asthma and environment ID INNER-CITY CHILDREN; INDOOR NITROGEN-DIOXIDE; RESPIRATORY SYNCYTIAL VIRUS; MOUSE ALLERGEN EXPOSURE; TOBACCO-SMOKE EXPOSURE; AMBIENT AIR-POLLUTION; HOUSE-DUST ENDOTOXIN; EARLY-LIFE EXPOSURE; NEW-YORK-CITY; CHILDHOOD ASTHMA AB Asthma is the most commonly reported chronic condition of childhood in developed countries, with 6.5 million children affected in the USA. A disparate burden of childhood asthma is seen among socioeconomically disadvantaged youth, often concentrated in urban areas with high poverty rates. Host factors that predispose a child to asthma include atopy, male gender, parental history of asthma, and also race, ethnicity, and genetic and epigenetic susceptibilities. Environmental factors, such as improved hygiene, ambient air pollution, and early life exposures to microbes and aeroallergens, also influence the development of asthma. With greater than 90% of time spent indoors, home exposures (such as cockroach, rodent, and indoor air pollution) are highly relevant for urban asthma. Morbidity reduction may require focused public health initiatives for environmental intervention in high priority risk groups and the addition of immune modulatory agents in children with poorly controlled disease. C1 [Milligan, Ki Lee] NIH, Bldg 10, Bethesda, MD 20892 USA. [Matsui, Elizabeth] Johns Hopkins Univ, Div Pediat Allergy & Immunol, Baltimore, MD USA. [Sharma, Hemant] George Washington Univ, Sch Med & Hlth Sci, Div Allergy & Immunol, Childrens Natl Hlth Syst, 111 Michigan Ave NW, Washington, DC 20010 USA. RP Sharma, H (reprint author), George Washington Univ, Sch Med & Hlth Sci, Div Allergy & Immunol, Childrens Natl Hlth Syst, 111 Michigan Ave NW, Washington, DC 20010 USA. EM hsharma@childrensnational.org FU Environmental Defense Fund; Church and Dwight; Inspirotec LLC; ThermoFisher, LLC FX Drs. Milligan and Sharma declare no conflicts of interest. Dr. Matsui reports personal fees from Environmental Defense Fund, from Church and Dwight; grants from Inspirotec LLC and from ThermoFisher, LLC; and non-financial support from Rabbit Air and from CleanBrands, LLC. NR 94 TC 2 Z9 3 U1 15 U2 32 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 APR PY 2016 VL 16 IS 4 AR 33 DI 10.1007/s11882-016-0609-6 PG 10 WC Allergy; Immunology SC Allergy; Immunology GA DI2UW UT WOS:000373355400009 PM 27026587 ER PT J AU Li, D Sinha, T Ajima, R Seo, HS Yamaguchi, TP Wang, JB AF Li, Ding Sinha, Tanvi Ajima, Riero Seo, Hwa-Seon Yamaguchi, Terry P. Wang, Jianbo TI Spatial regulation of cell cohesion by Wnt5a during second heart field progenitor deployment SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Wnt5a; Planar cell polarity; Second heart field; Outflow tract; Morphogenesis; Heart development; Cell adhesion ID N-CADHERIN; CONVERGENT EXTENSION; SIGNALING PATHWAY; OUTFLOW TRACT; CARDIAC DEVELOPMENT; PLANAR POLARITY; MORPHOGENESIS; GASTRULATION; EXPRESSION; REQUIRES AB Wnt5a, a non-canonical Wnt ligand critical for outflow tract (OFT) morphogenesis, is expressed specifically in second heart field (SHF) progenitors in the caudal splanchnic mesoderm (SpM) near the inflow tract (IFT). Using a conditional Wnt5a gain of function (GOP) allele and Islet1-Cre, we broadly over-expressed Wnt5a throughout the SHF lineage, including the entire SpM between the IFT and OFT. Wnt5a over-expression in Wnt5a null mutants can rescue the cell polarity and actin polymerization defects as well as severe SpM shortening, but fails to rescue OFT shortening. Moreover, Wnt5a over-expression in wild-type background is able to cause OFT shortening. We find that Wnt5a over-expression does not perturb SHF cell proliferation, apoptosis or differentiation, but affects the deployment of SHF cells by causing them to accumulate into a large bulge at the rostra! SpM and fail to enter the OFT. Our immunostaining analyses suggest an inverse correlation between cell cohesion and Wnt5a level in the wild-type SpM. Ectopic Wnt5a expression in the rostral SpM of Wn5a-GOF mutants diminishes the upregulation of adherens junction; whereas loss of Wnt5a in Wnt5a null mutants causes premature increase in adherens junction level in the caudal SpM. Over-expression of mouse Wnt5a in Xenopus animal cap cells also reduces C-cadherin distribution on the plasma membrane without affecting its overall protein level, suggesting that Wnt5a may play an evolutionarily conserved role in controlling the cell surface level of cadherin to modulate cell cohesion during tissue morphogenesis. Collectively, our data indicate that restricted expression of Wnt5a in the caudal SpM is essential for normal OFT morphogenesis, and uncover a novel function of spatially regulated cell cohesion by Wnt5a in driving the deployment of SHF cells from the SpM into the OFT. (C) 2016 Elsevier Inc. All rights reserved. C1 [Li, Ding; Sinha, Tanvi; Seo, Hwa-Seon; Wang, Jianbo] Univ Alabama Birmingham, Dept Cell Dev & Integrat Biol, Birmingham, AL 35294 USA. [Ajima, Riero] Natl Inst Genet, Mammalian Dev Lab, Yata 1111, Mishima, Shizuoka 4118540, Japan. [Yamaguchi, Terry P.] NCI, Canc & Dev Biol Lab, NIH, Frederick, MD 21702 USA. RP Wang, JB (reprint author), Univ Alabama Birmingham, Dept Cell Dev & Integrat Biol, Birmingham, AL 35294 USA. EM j18wang@uab.edu FU National Institute of Health [R01 HL109130]; American Heart Association [14GRNT20380467]; AHA pre-doctoral fellowship [12PRE12060081] FX We thank Dr. Masatoshi Takeichi for the N-cadherin probe for in situ hybridization. This work was supported by Grants from the National Institute of Health (R01 HL109130) and American Heart Association (14GRNT20380467) to J.W., and an AHA pre-doctoral fellowship (12PRE12060081) to T.S. NR 46 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 0012-1606 EI 1095-564X J9 DEV BIOL JI Dev. Biol. PD APR 1 PY 2016 VL 412 IS 1 BP 18 EP 31 DI 10.1016/j.ydbio.2016.02.017 PG 14 WC Developmental Biology SC Developmental Biology GA DI7EB UT WOS:000373660800002 PM 26916252 ER PT J AU Justice, AC McGinnis, KA Tate, JP Braithwaite, RS Bryant, KJ Cook, RL Edelman, EJ Fiellin, LE Freiberg, MS Gordon, AJ Kraemer, KL Marshall, BDL Williams, EC Fiellin, DA AF Justice, Amy C. McGinnis, Kathleen A. Tate, Janet P. Braithwaite, R. Scott Bryant, Kendall J. Cook, Robert L. Edelman, E. Jennifer Fiellin, Lynn E. Freiberg, Matthew S. Gordon, Adam J. Kraemer, Kevin L. Marshall, Brandon D. L. Williams, Emily C. Fiellin, David A. TI Risk of mortality and physiologic injury evident with lower alcohol exposure among HIV infected compared with uninfected men SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Alcohol; Mortality; Morbidity; VACS Index; AUDIT-C; Veteran; HIV ID VETERANS AGING COHORT; ALL-CAUSE MORTALITY; J-SHAPED CURVE; ANTIRETROVIRAL THERAPY; PRIMARY-CARE; AUDIT-C; MEDICATION ADHERENCE; ADMINISTRATIVE DATA; SCREENING SCORES; PROBLEM DRINKING AB Background: HIV infected (HIV+) individuals may be more susceptible to alcohol-related harm than uninfected individuals. Methods: We analyzed data on HIV+ and uninfected individuals in the Veterans Aging Cohort Study (VACS) with an Alcohol Use Disorders Identification Test-Consumption AUDIT-C score from 2008 to 2012. We used Cox proportional hazards models to examine the association between alcohol exposure and mortality through July, 2014; and linear regression models to assess the association between alcohol exposure and physiologic injury based on VACS Index Scores. Models were adjusted for age, race/ethnicity, smoking, and hepatitis C infection. Results: The sample included 18,145 HIV+ and 42,228 uninfected individuals. Among HIV+ individuals, 76% had undetectable HIV-1 RNA (<500 copies/ml). The threshold for an association of alcohol use with mortality and physiologic injury differed by HIV status. Among HIV+ individuals, AUDIT-C score >= 4 (hazard ratio [HR] 1.25, 95% CI 1.09-1.44) and >= 30 drinks per month (HR, 1.30, 95% CI 1.14-1.50) were associated with increased risk of mortality. Among uninfected individuals, AUDIT-C score >= 5 (HR, 1.19, 95% CI 1.07-1.32) and >= 70 drinks per month (HR 1.13, 95% CI 1.00-1.28) were associated with increased risk. Similarly, AUDIT-C threshold scores of 5-7 were associated with physiologic injury among HIV+ individuals (beta 0.47, 95% CI 0.22, 0.73) and a score of 8 or more was associated with injury in uninfected (beta 0.29, 95% CI 0.16, 0.42) individuals. Conclusions: Despite antiretroviral therapy, HIV+ individuals experienced increased mortality and physiologic injury at lower levels of alcohol use compared with uninfected individuals. Alcohol consumption limits should be lower among HIV+ individuals. Published by Elsevier Ireland Ltd. C1 [Justice, Amy C.; Tate, Janet P.; Edelman, E. Jennifer; Fiellin, David A.] West Haven VA Healthcare Syst, Vet Aging Cohort Study Coordinating Ctr, 950 Campbell Ave, West Haven, CT 06516 USA. [Justice, Amy C.; Tate, Janet P.; Edelman, E. Jennifer; Fiellin, Lynn E.; Fiellin, David A.] Yale Univ, Yale Sch Med, Dept Internal Med, 367 Cedar St, New Haven, CT 06510 USA. [Justice, Amy C.; Tate, Janet P.; Edelman, E. Jennifer; Fiellin, Lynn E.; Fiellin, David A.] Yale Univ, Yale Sch Med, CIRA, 367 Cedar St, New Haven, CT 06510 USA. [McGinnis, Kathleen A.; Gordon, Adam J.; Kraemer, Kevin L.] VA Pittsburgh Healthcare Syst, Univ Dr C, Pittsburgh, PA 15240 USA. [Braithwaite, R. Scott] NYU, Sch Med, Dept Populat Hlth, 227 East 30th St, New York, NY 10016 USA. [Bryant, Kendall J.] NIAAA, 5635 Fishers Lane,MSC 9304, Bethesda, MD 20892 USA. [Cook, Robert L.] Univ Florida, Dept Epidemiol, POB 100231, Gainesville, FL USA. [Freiberg, Matthew S.] Vanderbilt Univ, Sch Med, Div Cardiovasc Med, Nashville, TN 37212 USA. [Freiberg, Matthew S.] Vet Affairs Tennessee Valley Healthcare Syst, Geriatr Res Educ & Clin Ctr, 2525 West End Ave, Nashville, TN USA. [Gordon, Adam J.; Kraemer, Kevin L.] Univ Pittsburgh, Sch Med, Div Gen Internal Med, Suite 600,230 McKee Pl, Pittsburgh, PA 15213 USA. [Marshall, Brandon D. L.] Brown Univ, Sch Publ Hlth, Dept Epidemiol, 121 South Main St, Providence, RI 02912 USA. [Williams, Emily C.] Univ Washington, Sch Publ Hlth, 325 Ninth Ave,Box 359762, Seattle, WA 98195 USA. RP Justice, AC (reprint author), Yale Univ, Sch Med, VA Connecticut Healthcare Syst, 950 Campbell Ave,Bldg 35a Room 2-212 11 ACSLG, West Haven, CT 06516 USA. EM amy.Justice2@va.gov OI Fiellin, David/0000-0002-4006-010X; Justice, Amy/0000-0003-0139-5502 FU NHLBI NIH HHS [R01 HL090342, R01 HL095136, R01-HL090342, R01-HL095136, RC1 HL100347, RCI-HL100347]; NIA NIH HHS [R01 AG029154, R01-AG029154]; NIAAA NIH HHS [U10-AA13566, U10 AA013566, U13 AA022864, U24 AA022000, U24 AA022002, U24AA02002]; PHS HHS [U01-A1069918] NR 60 TC 13 Z9 13 U1 3 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD APR 1 PY 2016 VL 161 BP 95 EP 103 DI 10.1016/j.drugalcdep.2016.01.017 PG 9 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA DI3SP UT WOS:000373419100013 PM 26861883 ER PT J AU Murphy, SM Campbell, ANC Ghitza, UE Kyle, TL Bailey, GL Nunes, EV Polsky, D AF Murphy, Sean M. Campbell, Aimee N. C. Ghitza, Udi E. Kyle, Tiffany L. Bailey, Genie L. Nunes, Edward V. Polsky, Daniel TI Cost-effectiveness of an internet-delivered treatment for substance abuse: Data from a multisite randomized controlled trial SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Substance use disorders; Internet-based intervention; Cost effectiveness; Community reinforcement approach; Contingency management ID CONTINGENCY-MANAGEMENT; DEPENDENT OUTPATIENTS; BEHAVIORAL TREATMENT; ALCOHOL-CONSUMPTION; TREATMENT PROGRAMS; OPIOID DEPENDENCE; BUPRENORPHINE; COCAINE; INTERVENTION; INCENTIVES AB Background: Substance misuse and excessive alcohol consumption are major public health issues. Internet-based interventions for substance use disorders (SUDS) are a relatively new method for addressing barriers to access and supplementing existing care. This study examines cost-effectiveness in a multisite, randomized trial of an internet-based version of the community reinforcement approach (CRA) with contingency management (CM) known as the Therapeutic Education System (TES). Methods: Economic evaluation of the 12-week trial with follow-up at 24 and 36 weeks. 507 individuals who were seeking therapy for alcohol or other substance use disorders at 10 outpatient community-based treatment programs were recruited and randomized to either treatment as usual (TAU) or TES +TAU. Sub-analyses were completed on participants with a poorer prognosis (i.e., those not abstinent at study entry). Results: From the provider's perspective, TES +TAU as it was implemented in this study costs $278 (SE= 87) more than TAU alone after 12 weeks. The quality-adjusted life years gained by TES +TAU and TAU were similar; however, TES +TAU has at least a 95% chance of being considered cost-effective for providers and payers with willingness-to-pay thresholds as low as $20,000 per abstinent year. Findings for the subgroup not abstinent at study entry are slightly more favorable. Conclusions: With regard to the clinical outcome of abstinence, our cost-effectiveness findings of TES +TAU compare favorably to those found elsewhere in the CM literature. The analyses performed here serve as an initial economic framework for future studies integrating technology into SUD therapy. (c) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Murphy, Sean M.] Washington State Univ, Dept Hlth Policy & Adm, Spokane, WA USA. [Campbell, Aimee N. C.; Nunes, Edward V.] Columbia Univ, Dept Psychiat, New York State Psychiat Inst, New York, NY USA. [Ghitza, Udi E.] NIDA, Ctr Clin Trials Network, Bethesda, MD 20892 USA. [Kyle, Tiffany L.] Aspire Hlth Partners, Orlando, FL USA. [Bailey, Genie L.] Brown Univ, Dept Psychiat & Human Behav, Providence, RI 02912 USA. [Bailey, Genie L.] Stanley St Treatment & Resources, Fall River, MA USA. [Polsky, Daniel] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. RP Murphy, SM (reprint author), Dept Hlth Policy & Adm, POB 1495, Spokane, WA 99210 USA. EM sean.murphy@wsu.edu OI Murphy, Sean M./0000-0001-9104-0670; Kyle, Tiffany/0000-0002-8801-417X FU National Drug Abuse Treatment Clinical Trials Network, National Institute on Drug Abuse (NIDA) [U10 DA013035, U10 DA015831, U10 DA013034, U10 DA013720, U10 DA013732, U10 DA020024, U10 DA013714, U10 DA015815, K24 DA022412] FX Supported by grants from the National Drug Abuse Treatment Clinical Trials Network, National Institute on Drug Abuse (NIDA): U10 DA013035 (to Edward V. Nunes and John Rotrosen), U10 DA015831 (to Kathleen M. Carroll and Roger D. Weiss), U10 DA013034 (to Maxine Stitzer and Robert P. Schwartz), U10 DA013720 (to Josei Szapocznik and Lisa R. Metsch), U10 DA013732 (to Theresa Winhusen), U10 DA020024 (to Madhukar H. Trivedi), U10 DA013714 (to Dennis M. Donovan and John Roll), U10 DA015815 (to James L. Sorensen and Dennis McCarty), and K24 DA022412 (to Edward V. Nunes). NR 42 TC 0 Z9 0 U1 5 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD APR 1 PY 2016 VL 161 BP 119 EP 126 DI 10.1016/j.drugalcdep.2016.01.021 PG 8 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA DI3SP UT WOS:000373419100016 PM 26880594 ER PT J AU Trigo, JM Lagzdins, D Rehm, J Selby, P Gamaleddin, I Fischer, B Barnes, AJ Huestis, MA Le Foll, B AF Trigo, Jose M. Lagzdins, Dina Rehm, Juergen Selby, Peter Gamaleddin, Islam Fischer, Benedikt Barnes, Allan J. Huestis, Marilyn A. Le Foll, Bernard TI Effects of fixed or self-titrated dosages of Sativex on cannabis withdrawal and cravings SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Cannabis; Marijuana; Withdrawal; THC; Cannabidiol; Clinical trials.gov ID#NCT01748799 ID ADULTS SEEKING TREATMENT; SUBSTANCE USE DISORDERS; ORAL THC MAINTENANCE; MARIJUANA WITHDRAWAL; DOUBLE-BLIND; TOBACCO WITHDRAWAL; MASS-SPECTROMETRY; TREATMENT SEEKERS; OROMUCOSAL SPRAY; YOUNG-ADULTS AB Background: There is currently no pharmacological treatment approved for cannabis dependence. In this proof of concept study, we assessed the feasibility/effects of fixed and self-titrated dosages of Sativex (1:1, Delta(9)-tetrahydrocannabinol (THC)/cannabidiol (CBD)) on craving and withdrawal from cannabis among nine community-recruited cannabis-dependent subjects. Methods: Participants underwent an 8-week double-blind placebo-controlled trial (an ABACADAE design), with four smoke as usual conditions (SAU) (A) separated by four cannabis abstinence conditions (B-E), with administration of either self-titrated/fixed doses of placebo or Sativex (up to 108 mg THC/100 mg CBD). The order of medication administration during abstinence conditions was randomized and counterbalanced. Withdrawal symptoms and craving were assessed using the Cannabis Withdrawal Scale (CWS), Marijuana Withdrawal Checklist (MWC) and Marijuana Craving Questionnaire (MCQ). Medication use was assessed during the study by means of self-reports, vial weight control, toxicology and metabolite analysis. Cannabis use was assessed by means of self-reports. Results: High fixed doses of Sativex were well tolerated and significantly reduced cannabis withdrawal during abstinence, but not craving, as compared to placebo. Self-titrated doses were lower and showed limited efficacy as compared to high fixed doses. Participants reported a significantly lower "high" following Sativex or placebo as compared to SAU conditions. Cannabis/medication use along the study, as per self-reports, suggests compliance with the study conditions. Conclusions: The results found in this proof of concept study warrant further systematic exploration of Sativex as a treatment option for cannabis withdrawal and dependence. (c) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Trigo, Jose M.; Lagzdins, Dina; Gamaleddin, Islam; Le Foll, Bernard] CAMH, Campbell Family Mental Hlth Res Inst, Translat Addict Res Lab, Toronto, ON, Canada. [Rehm, Juergen; Fischer, Benedikt] CAMH, Social & Epidemiol Res Dept, Toronto, ON, Canada. [Rehm, Juergen] Univ Toronto, Dalla Lana Sch Publ Hlth, Addict Policy, Toronto, ON, Canada. [Rehm, Juergen] Univ Toronto, Fac Med, Inst Med Sci, Toronto, ON, Canada. [Rehm, Juergen; Selby, Peter; Fischer, Benedikt] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. [Rehm, Juergen] Tech Univ Dresden, Inst Clin Psychol & Psychotherapy, D-01062 Dresden, Germany. [Rehm, Juergen] Tech Univ Dresden, Ctr Clin Epidemiol & Longitudinal Studies CELOS, D-01062 Dresden, Germany. [Selby, Peter; Le Foll, Bernard] CAMH, Addict Div, Toronto, ON, Canada. [Selby, Peter] Univ Toronto, Dept Family & Community Med, Toronto, ON M5S 1A1, Canada. [Gamaleddin, Islam] Ain Shams Univ, Inst Environm Studies & Res, Dept Med Sci, Cairo, Egypt. [Gamaleddin, Islam] MOH, Directorate Poison Control Ctr, Riyadh, Saudi Arabia. [Fischer, Benedikt] Simon Fraser Univ, Fac Hlth Sci, Ctr Appl Res Mental Hlth & Addict, Vancouver, BC, Canada. [Barnes, Allan J.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab, NIH, Baltimore, MD USA. RP Le Foll, B (reprint author), Ctr Addict & Mental Hlth, 33 Russell St, Toronto, ON M5S 2S1, Canada. EM bernard.lefoll@camh.ca FU Canadian Institutes of Health Research (CIHR) FX This study was funded by Canadian Institutes of Health Research (CIHR). GW Pharma donated the active and placebo Sativex used in this study. NR 70 TC 1 Z9 1 U1 2 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD APR 1 PY 2016 VL 161 BP 298 EP 306 DI 10.1016/j.drugalcdep.2016.02.020 PG 9 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA DI3SP UT WOS:000373419100037 PM 26925704 ER PT J AU Luking, KR Pagliaccio, D Luby, JL Barch, DM AF Luking, Katherine R. Pagliaccio, David Luby, Joan L. Barch, Deanna M. TI Do Losses Loom Larger for Children Than Adults? SO EMOTION LA English DT Article DE development; gain approach; loss avoidance; behavioral inhibition system; behavioral activation system ID BEHAVIORAL ACTIVATION; INDIVIDUAL-DIFFERENCES; ADOLESCENT GIRLS; DECISION-MAKING; AGE-DIFFERENCES; RISK-TAKING; REWARD; DEPRESSION; SENSITIVITY; PUNISHMENT AB The large impact of loss of reward on behavior has been well documented in adult populations. However, whether responsiveness to loss relative to gain is similarly elevated in child versus adult populations remains unclear. It is also unclear whether relations between incentive behaviors and self-reported reward/punishment sensitivity are similar within different developmental stages. To investigate these questions, 7- to 10-year-old children (N = 70) and young adults (N = 70) completed the Behavioral Inhibition System/Behavioral Activation System (BIS/BAS) scale, along with 2 probabilistic incentive tasks assessing gain approach and loss avoidance behavior. BIS/BAS subscales were calculated per Pagliaccio et al. (2015), which established an age invariant model of the BIS/BAS. Bias toward responses more frequently followed by gain feedback and away from responses more frequently followed by loss feedback, approach, and avoidance behavior, respectively, were quantified via signal detection statistics. Gain approach behavior did not differ across age groups; however, children exhibited significantly elevated loss avoidance relative to adults. Children also showed greater reductions in accuracy and slower RTs specifically following loss feedback relative to adults. Interestingly, despite age group differences in loss avoidance behavior, relations between self-report measures and approach/avoidance behaviors were similar across age groups. Participants reporting elevated motivation (BAS Drive) showed both elevated gain approach and elevated loss avoidance, with both types of behavior predicting unique variance in BAS Drive. Results highlight the often-neglected developmental and motivational roles of responsiveness to loss of reward. C1 [Luking, Katherine R.] SUNY Stony Brook, Dept Psychol, Stony Brook, NY 11794 USA. [Pagliaccio, David] NIMH, Sect Dev & Affect Neurosci, Bethesda, MD 20892 USA. [Luby, Joan L.] Washington Univ, Dept Psychiat, St Louis, MO USA. [Barch, Deanna M.] Washington Univ, Dept Psychol, St Louis, MO 63130 USA. [Barch, Deanna M.] Washington Univ, Dept Psychiat, St Louis, MO 63130 USA. [Barch, Deanna M.] Washington Univ, Dept Radiol, St Louis, MO 63130 USA. [Barch, Deanna M.] Washington Univ, Dept Neurosci, St Louis, MO 63130 USA. RP Luking, KR (reprint author), SUNY Stony Brook, Dept Psychol, Stony Brook, NY 11794 USA. EM katherine.luking@gmail.com OI Pagliaccio, David/0000-0002-1214-1965 FU National Institute of Mental Health [F31 MH097335, MH090786, MH64769] FX This research was funded by National Institute of Mental Health Grants F31 MH097335, MH090786, MH64769. NR 40 TC 0 Z9 0 U1 4 U2 10 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1528-3542 EI 1931-1516 J9 EMOTION JI Emotion PD APR PY 2016 VL 16 IS 3 BP 338 EP 348 DI 10.1037/emo0000122 PG 11 WC Psychology, Experimental SC Psychology GA DI3LJ UT WOS:000373399800007 PM 26524484 ER PT J AU 't Mannetje, A De Roos, AJ Boffetta, P Vermeulen, R Benke, G Fritschi, L Brennan, P Foretova, L Maynadie, M Becker, N Nieters, A Staines, A Campagna, M Chiu, B Clavel, J de Sanjose, S Hartge, P Holly, EA Bracci, P Linet, MS Monnereau, A Orsi, L Purdue, MP Rothman, N Lan, Q Kane, E Costantini, AS Miligi, L Spinelli, JJ Zheng, TZ Cocco, P Kricker, A AF 't Mannetje, Andrea De Roos, Anneclaire J. Boffetta, Paolo Vermeulen, Roel Benke, Geza Fritschi, Lin Brennan, Paul Foretova, Lenka Maynadie, Marc Becker, Nikolaus Nieters, Alexandra Staines, Anthony Campagna, Marcello Chiu, Brian Clavel, Jacqueline de Sanjose, Silvia Hartge, Patricia Holly, Elizabeth A. Bracci, Paige Linet, Martha S. Monnereau, Alain Orsi, Laurent Purdue, Mark P. Rothman, Nathaniel Lan, Qing Kane, Eleanor Costantini, Adele Seniori Miligi, Lucia Spinelli, John J. Zheng, Tongzhang Cocco, Pierluigi Kricker, Anne TI Occupation and Risk of Non-Hodgkin Lymphoma and Its Subtypes: A Pooled Analysis from the InterLymph Consortium SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Review ID SOFT-TISSUE SARCOMA; FRANCISCO BAY AREA; UNITED-STATES; CANCER-MORTALITY; MALIGNANT-LYMPHOMAS; NEW-ZEALAND; LYMPHOPROLIFERATIVE DISEASES; MANUFACTURING WORKERS; HEMATOPOIETIC CANCER; DEATH-CERTIFICATE AB BACKGROUND: Various occupations have been associated with an elevated risk of non-Hodgkin lymphoma (NHL), but results have been inconsistent across studies. OBJECTIVES: We investigated occupational risk of NHL and of four common NHL subtypes with particular focus on occupations of a priori interest. METHODS: We conducted a pooled analysis of 10,046 cases and 12,025 controls from 10 NHL studies participating in the InterLymph Consortium. We harmonized the occupational coding using the 1968 International Standard Classification of Occupations (ISCO-1968) and grouped occupations previously associated with NHL into 25 a priori groups. Odds ratios (ORs) adjusted for center, age, and sex were determined for NHL overall and for the following four subtypes: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and peripheral T-cell lymphoma (PTCL). RESULTS: We confirmed previously reported positive associations between NHL and farming occupations [field crop/vegetable farm workers OR = 1.26; 95% confidence interval (CI): 1.05, 1.51; general farm workers OR = 1.19; 95% CI: 1.03, 1.37]; we also confirmed associations of NHL with specific occupations such as women's hairdressers (OR = 1.34; 95% CI: 1.02, 1.74), charworkers/cleaners (OR = 1.17; 95% CI: 1.01, 1.36), spray-painters (OR = 2.07; 95% CI: 1.30, 3.29), electrical wiremen (OR = 1.24; 95% CI: 1.00, 1.54), and carpenters (OR = 1.42; 95% CI: 1.04, 1.93). We observed subtype-specific associations for DLBCL and CLL/SLL in women's hairdressers and for DLBCL and PTCL in textile workers. CONCLUSIONS: Our pooled analysis of 10 international studies adds to evidence suggesting that farming, hairdressing, and textile industry-related exposures may contribute to NHL risk. Associations with women's hairdresser and textile occupations may be specific for certain NHL subtypes. C1 ['t Mannetje, Andrea] Massey Univ, Ctr Publ Hlth Res, Wellington Campus,Private Box 756, Wellington, New Zealand. [De Roos, Anneclaire J.] Drexel Univ, Sch Publ Hlth, Dept Environm & Occupat Hlth, Philadelphia, PA 19104 USA. [Boffetta, Paolo] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA. [Vermeulen, Roel] Univ Utrecht, Div Environm Epidemiol, Inst Risk Assessment Sci, Utrecht, Netherlands. [Benke, Geza] Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic 3004, Australia. [Fritschi, Lin] Curtin Univ, Sch Publ Hlth, Bentley, WA, Australia. [Brennan, Paul] Int Agcy Res Canc, 150 Cours Albert Thomas, F-69372 Lyon, France. [Foretova, Lenka] Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic. [Maynadie, Marc] Univ Burgundy, Biol Hematol Unit, Dijon, France. [Becker, Nikolaus] German Canc Res Ctr Heidelberg, Div Canc Epidemiol, Heidelberg, Germany. [Nieters, Alexandra] Univ Med Ctr Freiburg, Ctr Chron Immunodeficiency, Freiburg, Germany. [Staines, Anthony] Dublin City Univ, Sch Nursing & Human Sci, Dublin 9, Ireland. [Campagna, Marcello; Cocco, Pierluigi] Univ Cagliari, Dept Publ Hlth Clin & Mol Med, Cagliari, Italy. [Chiu, Brian] Univ Chicago, Dept Publ Hlth Sci, Chicago, IL 60637 USA. [Clavel, Jacqueline; Orsi, Laurent] INSERM, Epidemiol & Biostat Sorbonne Paris Cite Ctr CRESS, Villejuif, France. [Clavel, Jacqueline] French Natl Registry Childhood Hematol Malignanci, Villejuif, France. [de Sanjose, Silvia] Spain Inst Invest Biomed Bellvitge IDIBELL, Catalan Inst Oncol, Canc Epidemiol Res Programme, Barcelona, Spain. [de Sanjose, Silvia] CIBER Epidemiol & Salud Publ CIBERESP, Barcelona, Spain. [Hartge, Patricia] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Holly, Elizabeth A.; Bracci, Paige] Univ Calif San Francisco, Sch Med, Dept Epidemiol & Biostat, San Francisco, CA USA. [Linet, Martha S.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Monnereau, Alain] INSERM, CIC, Bordeaux, France. [Monnereau, Alain] Inst Bergonie, Registre Hemopathies Malignes Gironde, Bordeaux, France. [Purdue, Mark P.; Rothman, Nathaniel] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD USA. [Kane, Eleanor] Univ York, Epidemiol & Canc Stat Grp, Dept Hlth Sci, York YO10 5DD, N Yorkshire, England. [Costantini, Adele Seniori; Miligi, Lucia] ISPO Canc Res & Prevent Inst, Environmental & Occupat Epidemiol Unit, Florence, Italy. [Spinelli, John J.] British Columbia Canc Agcy, Canc Control Res, Vancouver, BC V5Z 4E6, Canada. [Zheng, Tongzhang] Yale Univ, Dept Environm Hlth Sci, Sch Publ Hlth, New Haven, CT USA. [Kricker, Anne] Univ Sydney, Sydney Sch Publ Hlth, Sydney, NSW 2006, Australia. RP 't Mannetje, A (reprint author), Massey Univ, Ctr Publ Hlth Res, Wellington Campus,Private Box 756, Wellington, New Zealand. EM a.mannetje@massey.ac.nz RI Clavel, Jacqueline/Q-2750-2016; Vermeulen, Roel/F-8037-2011 OI Clavel, Jacqueline/0000-0002-3616-7676; Vermeulen, Roel/0000-0003-4082-8163 FU Italian Ministry for Education, University and Research; Italian Association for Cancer Research (AIRC) [11855]; NIH [PAR-04-159] FX This pooled analysis was funded by an NIH R03 grant for cancer epidemiology (PAR-04-159). Support to P.C. was provided by the Italian Ministry for Education, University and Research (PRIN 2007 prot. 2007WEJLZB, PRIN 2009 prot. 20092ZELR2) and by the Italian Association for Cancer Research (AIRC, investigator grant 11855). NR 86 TC 2 Z9 2 U1 6 U2 15 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD APR PY 2016 VL 124 IS 4 BP 396 EP 405 DI 10.1289/ehp.1409294 PG 10 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DI9OU UT WOS:000373833100012 PM 26340796 ER PT J AU Dinse, GE Jusko, TA Whitt, IZ Co, CA Parks, CG Satoh, M Chan, EKL Rose, KM Walker, NJ Birnbaum, LS Zeldin, DC Weinberg, CR Miller, FW AF Dinse, Gregg E. Jusko, Todd A. Whitt, Irene Z. Co, Caroll A. Parks, Christine G. Satoh, Minoru Chan, Edward K. L. Rose, Kathryn M. Walker, Nigel J. Birnbaum, Linda S. Zeldin, Darryl C. Weinberg, Clarice R. Miller, Frederick W. TI Associations Between Selected Xenobiotics and Antinuclear Antibodies in the National Health and Nutrition Examination Survey, 1999-2004 SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; URINARY CONCENTRATIONS; AUTOIMMUNE-DISEASES; UNITED-STATES; PERFLUORINATED COMPOUNDS; HOST-RESISTANCE; PREGNANT-WOMEN; IMMUNE-SYSTEM; US POPULATION; GENERATION R AB BACKGROUND: Potential associations between background environmental chemical exposures and autoimmunity are understudied. OBJECTIVES: Our exploratory study investigated exposure to individual environmental chemicals and selected mixtures in relation to the presence of antinuclear antibodies (ANA), a widely used biomarker of autoimmunity, in a representative sample of the U.S. population. METHODS: This cross-sectional analysis used data on 4,340 participants from the National Health and Nutrition Examination Survey (1999-2004), of whom 14% were ANA positive, to explore associations between ANA and concentrations of dioxins, dibenzofurans, polychlorinated biphenyls, organochlorines, organophosphates, phenols, metals, and other environmental exposures and metabolites measured in participants' serum, whole blood, or urine. For dioxin-like compounds with toxic equivalency factors, we developed and applied a new statistical approach to study selected mixtures. Lognormal models and censored-data methods produced estimates of chemical associations with ANA in males, nulliparous females, and parous females; these estimates were adjusted for confounders and accommodated concentrations below detectable levels. RESULTS: Several associations between chemical concentration and ANA positivity were observed, but only the association in males exposed to triclosan remained statistically significant after correcting for multiple comparisons (mean concentration ratio = 2.8; 95% CI: 1.8, 4.5; p < 0.00001). CONCLUSIONS: These data suggest that background levels of most xenobiotic exposures typical in the U.S. population are not strongly associated with ANA. Future studies should ideally reduce exposure misclassification by including prospective measurement of the chemicals of concern and should track changes in ANA and other autoantibodies over time. C1 [Dinse, Gregg E.; Co, Caroll A.; Rose, Kathryn M.] Social & Sci Syst Inc, Biostat Ctr, Durham, NC USA. [Jusko, Todd A.] Univ Rochester, Sch Med & Dent, Dept Publ Hlth Sci, Rochester, NY USA. [Jusko, Todd A.] Univ Rochester, Sch Med & Dent, Dept Environm Med, Rochester, NY USA. [Whitt, Irene Z.] Duke Univ, Dept Internal Med, Div Rheumatol & Immunol, Durham, NC USA. [Parks, Christine G.] NIEHS, Epidemiol Branch, NIH, DHHS, POB 12233, Res Triangle Pk, NC 27709 USA. [Satoh, Minoru] Univ Occupat & Environm Hlth, Dept Clin Nursing, Kitakyushu, Fukuoka 807, Japan. [Chan, Edward K. L.] Univ Florida, Dept Oral Biol, Gainesville, FL 32610 USA. [Walker, Nigel J.] NIEHS, Div Natl Toxicol Program, NIH, DHHS, POB 12233, Res Triangle Pk, NC 27709 USA. [Birnbaum, Linda S.] NCI, Lab Toxicol & Toxicokinet, NIH, DHHS, Res Triangle Pk, NC USA. [Weinberg, Clarice R.] NIEHS, Div Intramural Res, NIH, DHHS, POB 12233, Res Triangle Pk, NC 27709 USA. [Weinberg, Clarice R.] NIEHS, Biostat & Computat Biol Branch, NIH, DHHS, POB 12233, Res Triangle Pk, NC 27709 USA. [Miller, Frederick W.] NIEHS, Environm Autoimmun Grp, NIH, DHHS, Bethesda, MD 20892 USA. RP Miller, FW (reprint author), NIEHS, Clin Res Branch, NIH, Clin Res Ctr, NIH 10,Room 4-2352,10 Ctr Dr,MSC 1301, Bethesda, MD 20892 USA. EM millerf@mail.nih.gov RI Walker, Nigel/D-6583-2012; OI Walker, Nigel/0000-0002-9111-6855; Miller, Frederick/0000-0003-2831-9593; Parks, Christine/0000-0002-5734-3456 FU Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS) [ZIA ES040006, ZIA ES101074]; NIH [K12 ES019852, P30 ES001247] FX This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS), under projects ZIA ES040006 and ZIA ES101074. T.A.J. received support from NIH grants K12 ES019852 and P30 ES001247. NR 77 TC 0 Z9 0 U1 4 U2 12 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD APR PY 2016 VL 124 IS 4 BP 426 EP 436 DI 10.1289/ehp.1409345 PG 11 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DI9OU UT WOS:000373833100016 PM 26252071 ER PT J AU Thayer, KA Taylor, KW Garantziotis, S Schurman, SH Kissling, GE Hunt, D Herbert, B Church, R Jankowich, R Churchwell, MI Scheri, RC Birnbaum, LS Bucher, JR AF Thayer, Kristina A. Taylor, Kyla W. Garantziotis, Stavros Schurman, Shepherd H. Kissling, Grace E. Hunt, Dawn Herbert, Brenda Church, Rebecca Jankowich, Rachael Churchwell, Mona I. Scheri, Richard C. Birnbaum, Linda S. Bucher, John R. TI Bisphenol A, Bisphenol S, and 4-Hydroxyphenyl 4-Isoprooxyphenylsulfone (BPSIP) in Urine and Blood of Cashiers SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID THERMAL PAPER RECEIPTS; SPRAGUE-DAWLEY RATS; UNITED-STATES; HUMAN EXPOSURE; SERUM; PRODUCTS; ANALOGS; PENETRATION; PROFILES; CHINA AB BACKGROUND: Bisphenol A (BPA) is a high-production-volume chemical associated with a wide range of health outcomes in animal and human studies. BPA is used as a developer in thermal paper products, including cash register receipt paper; however, little is known about exposure of cashiers to BPA and alternative compounds in receipt paper. OBJECTIVE: We determined whether handling receipt paper results in measurable absorption of BPA or the BPA alternatives bisphenol S (BPS) and 4-hydroxyphenyl 4-isoprooxyphenylsulfone (BPSIP). METHODS: Cashiers (n = 77) and non-cashiers (n = 25) were recruited from the Raleigh-Durham-Chapel Hill region of North Carolina during 2011-2013. Receipts were analyzed for the presence of BPA or alternatives considered for use in thermal paper. In cashiers, total urine and serum BPA, BPS, and BPSIP levels in post-shift samples (collected <= 2 hr after completing a shift) were compared with pre-shift samples. Levels of these compounds in urine from cashiers were compared to levels in urine from non-cashiers. RESULTS: Each receipt contained 1-2% by weight of the paper of BPA, BPS, or BPSIP. The post-shift geometric mean total urinary BPS concentration was significantly higher than the pre-shift mean in 33 cashiers who handled receipts containing BPS. The mean urine BPA concentrations in 31 cashiers who handled BPA receipts were as likely to decrease as to increase after a shift, but the mean post-shift concentrations were significantly higher than those in non-cashiers. BPSIP was detected more frequently in the urine of cashiers handling BPSIP receipts than in the urine of noncashiers. Only a few cashiers had detectable levels of total BPA or BPS in serum, whereas BPSIP tended to be detected more frequently. CONCLUSIONS: Thermal receipt paper is a potential source of occupational exposure to BPA, BPS, and BPSIP. C1 [Thayer, Kristina A.; Taylor, Kyla W.; Bucher, John R.] NIEHS, Div Natl Toxicol Program, NIH, DHHS, POB 12233, Res Triangle Pk, NC 27709 USA. [Garantziotis, Stavros; Schurman, Shepherd H.; Hunt, Dawn; Herbert, Brenda; Church, Rebecca; Jankowich, Rachael] NIEHS, Clin Res Unit, NIH, DHHS, POB 12233, Res Triangle Pk, NC 27709 USA. [Kissling, Grace E.] NIEHS, Biostat Branch, NIH, DHHS, POB 12233, Res Triangle Pk, NC 27709 USA. [Churchwell, Mona I.; Scheri, Richard C.] US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR USA. [Birnbaum, Linda S.] NCI, NIH, DHHS, Res Triangle Pk, NC USA. RP Thayer, KA (reprint author), NIEHS, POB 12233,MD K2-04, Res Triangle Pk, NC 27709 USA. EM thayer@niehs.nih.gov RI Garantziotis, Stavros/A-6903-2009; OI Garantziotis, Stavros/0000-0003-4007-375X; Schurman, Shepherd/0000-0002-9133-7906 FU intramural research programs of the NIEHS; National Cancer Institute (NCI), NIH FX This research was supported by the intramural research programs of the NIEHS and the National Cancer Institute (NCI), NIH. NR 37 TC 10 Z9 11 U1 18 U2 56 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD APR PY 2016 VL 124 IS 4 BP 437 EP 444 DI 10.1289/ehp.1409427 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DI9OU UT WOS:000373833100017 PM 26309242 ER PT J AU Thurston, GD Ahn, J Cromar, KR Shao, YZ Reynolds, HR Jerrett, M Lim, CC Shanley, R Park, Y Hayes, RB AF Thurston, George D. Ahn, Jiyoung Cromar, Kevin R. Shao, Yongzhao Reynolds, Harmony R. Jerrett, Michael Lim, Chris C. Shanley, Ryan Park, Yikyung Hayes, Richard B. TI Ambient Particulate Matter Air Pollution Exposure and Mortality in the NIH-AARP Diet and Health Cohort SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID LONG-TERM EXPOSURE; CARDIOVASCULAR MORTALITY; UNITED-STATES; 6 CITIES; ASSOCIATION; DISEASE; CANCER AB BACKGROUND: Outdoor fine particulate matter (<= 2.5 mu m; PM2.5) has been identified as a global health threat, but the number of large U.S. prospective cohort studies with individual participant data remains limited, especially at lower recent exposures. OBJECTIVES: We aimed to test the relationship between long-term exposure PM2.5 and death risk from all nonaccidental causes, cardiovascular (CVD), and respiratory diseases in 517,041 men and women enrolled in the National Institutes of Health-AARP cohort. METHODS: Individual participant data were linked with residence PM2.5 exposure estimates across the continental United States for a 2000-2009 follow-up period when matching census tract-level PM2.5 exposure data were available. Participants enrolled ranged from 50 to 71 years of age, residing in six U.S. states and two cities. Cox proportional hazard models yielded hazard ratio (HR) estimates per 10 mu g/m(3) of PM2.5 exposure. RESULTS: PM2.5 exposure was significantly associated with total mortality (HR = 1.03; 95% CI: 1.00, 1.05) and CVD mortality (HR = 1.10; 95% CI: 1.05, 1.15), but the association with respiratory mortality was not statistically significant (HR = 1.05; 95% CI: 0.98, 1.13). A significant association was found with respiratory mortality only among never smokers (HR = 1.27; 95% CI: 1.03, 1.56). Associations with 10-mu g/m(3) PM2.5 exposures in yearly participant residential annual mean, or in metropolitan area-wide mean, were consistent with baseline exposure model results. Associations with PM2.5 were similar when adjusted for ozone exposures. Analyses of California residents alone also yielded statistically significant PM2.5 mortality HRs for total and CVD mortality. CONCLUSIONS: Long-term exposure to PM2.5 air pollution was associated with an increased risk of total and CVD mortality, providing an independent test of the PM2.5-mortality relationship in a new large U.S. prospective cohort experiencing lower post-2000 PM2.5 exposure levels. C1 [Thurston, George D.; Cromar, Kevin R.; Lim, Chris C.] NYU, Sch Med, Dept Environm Med, New York, NY 10987 USA. [Ahn, Jiyoung; Shao, Yongzhao; Shanley, Ryan; Hayes, Richard B.] NYU, Sch Med, Dept Populat Hlth, New York, NY 10987 USA. [Reynolds, Harmony R.] NYU, Sch Med, Cardiovasc Clin Res Ctr, Dept Med, New York, NY 10987 USA. [Jerrett, Michael] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. [Park, Yikyung] Washington Univ, Sch Med, Dept Surg, Div Publ Hlth Sci, St Louis, MO 63110 USA. [Park, Yikyung] NCI, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Thurston, GD (reprint author), NYU, Sch Med, Nelson Inst Environm Med, Dept Environm Med, 57 Old Forge Rd, Tuxedo Pk, NY 10987 USA.; Thurston, GD (reprint author), NYU, Sch Med, Nelson Inst Environm Med, Dept Populat Hlth, 57 Old Forge Rd, Tuxedo Pk, NY 10987 USA. EM george.thurston@nyu.edu OI Reynolds, Harmony/0000-0003-0284-0655; jerrett, michael/0000-0002-4121-0587; Hayes, Richard/0000-0002-0918-661X; Park, Yikyung/0000-0002-6281-489X; Cromar, Kevin/0000-0002-7745-2780 FU National Institutes of Health [1R01ES019584-01A1, R21 ES021194]; NYU-NIEHS Center of Excellence [ES00260] FX This research was supported by investigator grants to the New York University School of Medicine from the National Institutes of Health (1R01ES019584-01A1 to G.D.T. and R.B.H., R21 ES021194 to G.D.T. and J.A.), as well as by the NYU-NIEHS Center of Excellence (grant ES00260). NR 27 TC 5 Z9 5 U1 5 U2 25 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD APR PY 2016 VL 124 IS 4 BP 484 EP 490 DI 10.1289/ehp.1509676 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DI9OU UT WOS:000373833100023 PM 26370657 ER PT J AU Birnbaum, LS Balbus, JM Tart, KT AF Birnbaum, Linda S. Balbus, John M. Tart, Kimberly Thigpen TI Marking a New Understanding of Climate and Health SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material C1 [Birnbaum, Linda S.; Balbus, John M.; Tart, Kimberly Thigpen] NIEHS, NIH, US Dept HHS, POB 12233, Res Triangle Pk, NC 27709 USA. RP Tart, KT (reprint author), NIEHS, NIH, US Dept HHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM thigpenk@niehs.nih.gov NR 3 TC 1 Z9 1 U1 1 U2 4 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD APR PY 2016 VL 124 IS 4 BP A59 EP A59 DI 10.1289/ehp.1611410 PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DI9OU UT WOS:000373833100001 PM 27035485 ER PT J AU Birnbaum, LS Burke, TA Jones, JJ AF Birnbaum, Linda S. Burke, Thomas A. Jones, James J. TI Informing 21st-Century Risk Assessments with 21st-Century Science SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article AB Understanding and preventing adverse impacts from chemicals in the environment is fundamental to protecting public health, and chemical risk assessments are used to inform public health decisions in the United States and around the world. Traditional chemical risk assessments focus on health effects of environmental contaminants on a chemical-by-chemical basis, largely based on data from animal models using exposures that are typically higher than those experienced by humans. Results from environmental epidemiology studies sometimes show effects that are not observed in animal studies at human exposure levels that are lower than those used in animal studies. In addition, new approaches such as Toxicology in the 21st Century ( Tox21) and exposure forecasting ( ExpoCast) are generating mechanistic data that provide broad coverage of chemical space, chemical mixtures, and potential associated health outcomes, along with improved exposure estimates. It is becoming clear that risk assessments in the future will need to use the full range of available mechanistic, animal, and human data to integrate multiple types of data and to consider nontraditional health outcomes and end points. This perspective was developed at the "Strengthening the Scientific Basis of Chemical Safety Assessments" workshop, which was cosponsored by the U.S. Environmental Protection Agency and the National Institute of Environmental Health Sciences, where gaps between the emerging science and traditional chemical risk assessments were explored, and approaches for bridging the gaps were considered. C1 [Birnbaum, Linda S.] NIEHS, Off Director, NIH, DHHS, POB 12233, Res Triangle Pk, NC 27709 USA. [Burke, Thomas A.] US EPA, Off Res & Dev, Washington, DC 20460 USA. [Jones, James J.] US EPA, Off Chem Safety & Pollut Prevent, Washington, DC 20460 USA. RP Birnbaum, LS (reprint author), NIEHS, Off Director, NIH, DHHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM birnbaumls@niehs.nih.gov NR 3 TC 0 Z9 0 U1 7 U2 18 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD APR PY 2016 VL 124 IS 4 BP A60 EP A63 DI 10.1289/ehp.1511135 PG 4 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DI9OU UT WOS:000373833100002 PM 27035154 ER PT J AU Calafat, AM Longnecker, MP Koch, HM Swan, SH Hauser, R Goldman, LR Lanphear, BP Rudel, RA Engel, SM Teitelbaum, SL Whyatt, RM Wolff, MS AF Calafat, Antonia M. Longnecker, Matthew P. Koch, Holger M. Swan, Shanna H. Hauser, Russ Goldman, Lynn R. Lanphear, Bruce P. Rudel, Ruthann A. Engel, Stephanie M. Teitelbaum, Susan L. Whyatt, Robin M. Wolff, Mary S. TI Response to "Comment on 'Optimal Exposure Biomarkers for Nonpersistent Chemicals in Environmental Epidemiology'" SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Letter ID BISPHENOL-A C1 [Calafat, Antonia M.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Longnecker, Matthew P.] NIEHS, NIH, US Dept HHS, POB 12233, Res Triangle Pk, NC 27709 USA. [Koch, Holger M.] Ruhr Univ Bochum, German Social Accid Insurance, Inst Prevent & Occupat Med, Univ Str 150, Bochum, Germany. [Swan, Shanna H.; Teitelbaum, Susan L.; Wolff, Mary S.] Icahn Sch Med Mt Sinai, One Gustave L Levy Pl,Box 1057, New York, NY 10029 USA. [Hauser, Russ] Harvard Univ, Harvard TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Goldman, Lynn R.] George Washington Univ, Milken Inst Sch Publ Hlth, Washington, DC USA. [Lanphear, Bruce P.] British Columbia Childrens Hosp, Vancouver, BC V6H 3V4, Canada. [Rudel, Ruthann A.] Silent Spring Inst, Boston, MA USA. [Engel, Stephanie M.] Univ N Carolina, Chapel Hill, NC USA. [Whyatt, Robin M.] Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. RP Wolff, MS (reprint author), Icahn Sch Med Mt Sinai, One Gustave L Levy Pl,Box 1057, New York, NY 10029 USA. EM mary.wolff@mssm.edu RI Koch, Holger/B-3277-2011; OI Koch, Holger/0000-0002-8328-2837; Longnecker, Matthew/0000-0001-6073-5322 NR 4 TC 1 Z9 1 U1 1 U2 8 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD APR PY 2016 VL 124 IS 4 BP A66 EP A67 DI 10.1289/ehp.1611282 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DI9OU UT WOS:000373833100006 PM 27035263 ER PT J AU Brown, L Gutherz, S Kulick, C Soper, C Kondratyev, A Forcelli, PA AF Brown, Lindsay Gutherz, Samuel Kulick, Catherine Soper, Colin Kondratyev, Alexei Forcelli, Patrick A. TI Profile of retigabine-induced neuronal apoptosis in the developing rat brain SO EPILEPSIA LA English DT Article DE Cell death; Neonatal; Gestational; Teratogen ID ANTIEPILEPTIC DRUG EXPOSURE; ANTICONVULSANT ACTION; CELL-DEATH; IMMUNOHISTOCHEMICAL ANALYSIS; POTASSIUM CHANNELS; POSTNATAL EXPOSURE; IMMATURE BRAIN; NEONATAL-RATS; MOUSE-BRAIN; NEURODEGENERATION AB Objective: Acute neonatal exposure to some, but not all, anticonvulsant drugs induces a profound increase in neuronal apoptosis in rats. Phenobarbital and phenytoin induce apoptosis at a therapeutically relevant dose range, lamotrigine and carbamazepine do so only at supratherapeutic doses or in polytherapy, and valproate does so even at subtherapeutic doses. Levetiracetam is devoid of pro-apoptotic effects. Retigabine, a new-generation drug, acts uniquely by enhancing the M-type potassium current. Because its safety profile in developing animals is unstudied, we sought to determine if retigabine would induce apoptosis. Methods: Postnatal day (P) 7 rat pups were treated with retigabine (5-30 mg/kg), vehicle (saline), or comparator drugs (phenobarbital, lamotrigine, levetiracetam, or carbamazepine). Cell death was assessed using amino-cupric-silver staining. A separate group of animals was treated repeatedly (three times over 24 h) with retigabine (15 mg/kg) or vehicle. To establish a pharmacokinetic profile for retigabine, we measured plasma and brain levels after drug treatment. Results: Consistent with prior studies from our group and others, we found phenobarbital-induced cell death throughout thalamus, nucleus accumbens, and several neocortical areas. By contrast, levetiracetam, lamotrigine, and carbamazepine were found to have no appreciable apoptotic effect on the aforementioned structures. Acute (single) exposure to retigabine, even at doses of 30 mg/kg, was also without effect on apoptosis. However, repeated (three times) exposure to retigabine triggered apoptosis in a subset of brain areas. The half-life of retigabine in plasma was 2.5 h, with appreciable concentrations reached in the brain within 1 h of administration. Significance: These data demonstrate that retigabine, like many other anticonvulsant drugs, is capable of triggering neuronal apoptosis in the developing rat brain. Unlike other drugs, repeated dosing of retigabine was necessary to induce this effect. This may be due to its shorter half-life as compared to other drugs, such as phenobarbital. C1 [Brown, Lindsay; Gutherz, Samuel; Kulick, Catherine; Soper, Colin; Kondratyev, Alexei; Forcelli, Patrick A.] Georgetown Univ, Sch Med, Dept Physiol & Pharmacol, New Res Bldg,W209B, Washington, DC USA. [Kondratyev, Alexei] NIH, Ctr Sci Review, Bldg 10, Bethesda, MD 20892 USA. RP Forcelli, PA (reprint author), Georgetown Univ, Sch Med, Dept Physiol & Pharmacol, New Res Bldg,W209B, Washington, DC USA. EM paf22@georgetown.edu FU GlaxoSmithKline; National Institutes of Health [HD046388, KL2TR001432]; [P30CA051008] FX We thank Dr. Robert Switzer and the staff at Neuroscience Associates for their excellent histologic services. This work was supported by a research grant from GlaxoSmithKline to AK and PAF. PAF also received support from National Institutes of Health grants HD046388 and KL2TR001432. We thank Dr. Amrita Cheema and Karen Luo of the Proteomics and Metabolomics Shared Resource at Georgetown (Core Support from P30CA051008) for assistance with mass spectroscopy. NR 42 TC 2 Z9 2 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0013-9580 EI 1528-1167 J9 EPILEPSIA JI Epilepsia PD APR PY 2016 VL 57 IS 4 BP 660 EP 670 DI 10.1111/epi.13335 PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA DI9DE UT WOS:000373800800018 PM 26865186 ER PT J AU Zarek, SM Mitchell, EM Sjaarda, LA Mumford, SL Silver, RM Stanford, JB Galai, N Schliep, KC Radin, RG Plowden, TC DeCherney, AH Schisterman, EF AF Zarek, Shvetha M. Mitchell, Emily M. Sjaarda, Lindsey A. Mumford, Sunni L. Silver, Robert M. Stanford, Joseph B. Galai, Noya Schliep, Karen C. Radin, Rose G. Plowden, Torie C. DeCherney, Alan H. Schisterman, Enrique F. TI Antimullerian hormone and pregnancy loss from the Effects of Aspirin in Gestation and Reproduction trial SO FERTILITY AND STERILITY LA English DT Article DE Antimullerian hormone; pregnancy loss; miscarriage; spontaneous abortion; aneuploidy ID ANTI-MULLERIAN HORMONE; POLYCYSTIC-OVARY-SYNDROME; OOCYTE QUALITY; RESERVE; IVF; AMH; QUANTIFICATION; ASSOCIATION; EXPRESSION; ANEUPLOIDY AB Objective: To evaluate if antimullerian hormone (AMH) is associated with pregnancy loss. Design: Prospective cohort study within a block-randomized, double-blind, placebo-controlled trial of low-dose aspirin. Setting: Not applicable. Patient(s): Women (n = 1,228) were of ages 18-40 years with a history of one to two pregnancy losses and were actively attempting pregnancy without fertility treatment. Intervention(s): Not applicable. Main Outcome Measure(s): Pregnancy loss. Result(s): Relative risks (and 95% confidence interval [CIs]) of human chorionic gonadotropin (hCG)-detected and clinical pregnancy loss were assessed with the use of log binomial models with robust variance and inverse probability weights adjusted for age, race, body mass index, income, trial treatment assignment, parity, number of previous losses, and time since most recent loss. AMH levels were defined as: low (<1.00 ng/mL; n = 124), normal (referent; 1.00-3.5 ng/mL; n = 595), and high (>3.5 ng/mL; n = 483). Of the 1,202 women with baseline AMH data, 19 (17.3%) with low AMH experienced a clinical loss, compared with 61 (11.4%) with normal AMH and 50 (11.8%) with high AMH levels. Low or high AMH levels, compared with normal AMH, were not associated with clinical loss. Results for hCG-detected pregnancy loss mirrored those of clinical loss. Conclusion(s): AMH values were not associated with hCG-detected or clinical pregnancy loss in unassisted conceptions in women with a history of one to two previous losses. Our data do not support routine AMH testing for prediction of pregnancy loss. (C) 2016 by American Society for Reproductive Medicine. C1 [Zarek, Shvetha M.; Mitchell, Emily M.; Sjaarda, Lindsey A.; Mumford, Sunni L.; Radin, Rose G.; Plowden, Torie C.; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Epidemiol Branch, Bethesda, MD USA. [Zarek, Shvetha M.; Plowden, Torie C.; DeCherney, Alan H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Bethesda, MD USA. [Silver, Robert M.; Stanford, Joseph B.] Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT USA. [Silver, Robert M.; Stanford, Joseph B.] Intermt Healthcare, Salt Lake City, UT USA. [Galai, Noya; Schliep, Karen C.] Univ Haifa, Dept Stat, IL-31999 Haifa, Israel. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Epidemiol Branch, 6100 Execut Blvd,7B03, Rockville, MD 20854 USA. EM schistee@mail.nih.gov OI Sjaarda, Lindsey/0000-0003-0539-8110; Schisterman, Enrique/0000-0003-3757-641X FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland [HHSN267200603423, HHSN267200603424, HHSN267200603426] FX 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, and HHSN267200603426). NR 37 TC 1 Z9 1 U1 5 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD APR PY 2016 VL 105 IS 4 BP 946 EP + DI 10.1016/j.fertnstert.2015.12.003 PG 9 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA DI3NZ UT WOS:000373406700021 PM 26707905 ER PT J AU Michels, KA Mumford, SL Sundaram, R Bell, EM Bello, SC Yeung, EH AF Michels, Kara A. Mumford, Sunni L. Sundaram, Rajeshwari Bell, Erin M. Bello, Scott C. Yeung, Edwina H. TI Differences in infant feeding practices by mode of conception in a United States cohort SO FERTILITY AND STERILITY LA English DT Article DE Breast feeding; assisted reproductive techniques; infant nutritional physiologic phenomena; infant food ID ASSISTED REPRODUCTIVE TECHNOLOGIES; IN-VITRO FERTILIZATION; NEW-YORK-STATE; BIRTH-DEFECTS; CHILDREN BORN; UPSTATE KIDS; METAANALYSIS; PREVALENCE; MOTHERS; QUALITY AB Objective: To identify associations between fertility treatment use (assisted reproductive technologies, ovulation induction, and artificial insemination) and subsequent infant feeding practices. Design: The Upstate KIDS population-based cohort enrolled mothers who delivered live births in New York (2008-2010), sampling on fertility treatment and plurality. Setting: Not applicable. Patient(s): Data regarding singletons and one randomly selected infant between twins were used. Intervention(s): Not applicable. Main Outcome Measure(s): Mothers reported breast feeding and formula feeding practices at 4, 8, and 12 months postpartum. Modified Poisson regression was used to compare risks for feeding practices by mode of conception. Marginal structural models were used to estimate the controlled direct effects of fertility treatment on feeding, independent of preterm birth. Result(s): Among 4,591 mothers, 1,361 (30%) conceived with the use of fertility treatments. Mothers who used fertility treatments were less likely to breast feed to 12 months after birth and were more likely to provide formula, solids, and juice by 4 months than mothers who did not conceive with treatments. Fertility treatment remained associated with breast feeding cessation and formula feeding in mediation analyses, suggesting that preterm birth does not fully explain these associations. Conclusion(s): Women who conceived with the use of fertility treatments were less likely to breast feed later in infancy and were more likely to provide formula, solids, and juice earlier in infancy. Our analyses accounted for confounding and preterm birth, but other contributing factors may include difficulties feeding twins or workplace breast feeding accommodations. (C) 2016 by American Society for Reproductive Medicine. C1 [Michels, Kara A.; Mumford, Sunni L.; Sundaram, Rajeshwari; Yeung, Edwina H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20852 USA. [Bell, Erin M.] SUNY Albany, Sch Publ Hlth, Dept Environm Hlth Sci, Rensselaer, NY USA. [Bell, Erin M.] SUNY Albany, Sch Publ Hlth, Dept Epidemiol & Biostat, Rensselaer, NY USA. [Bello, Scott C.] CapitalCare Pediat Troy, Troy, NY USA. RP Yeung, EH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Epidemiol Branch, 6100 Execut Blvd,7B03, Rockville, MD 20852 USA. EM yeungedw@mail.nih.gov OI Michels, Kara/0000-0003-2431-2079; Yeung, Edwina/0000-0002-3851-2613; Sundaram, Rajeshwari/0000-0002-6918-5002 FU National Institutes of Health; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development [HHSN275201200005C, HHSN267200700019C] FX K.A.M. has nothing to disclose. S.L.M. has nothing to disclose. R.S. has nothing to disclose. E.M.B. reports grants from the National Institutes of Health. S.C.B. has nothing to disclose. E.H.Y. has nothing to disclose.; Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts HHSN275201200005C and HHSN267200700019C). NR 33 TC 2 Z9 2 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD APR PY 2016 VL 105 IS 4 BP 1014 EP + DI 10.1016/j.fertnstert.2015.12.043 PG 10 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA DI3NZ UT WOS:000373406700030 PM 26773191 ER PT J AU Patel, A Malik, M Britten, J Cox, J Catherino, WH AF Patel, Amrita Malik, Minnie Britten, Joy Cox, Jeris Catherino, William H. TI Mifepristone inhibits extracellular matrix formation in uterine leiomyoma SO FERTILITY AND STERILITY LA English DT Article DE Collagen 1A1; dermatopontin; extracellular matrix; fibronectin; mifepristone; progesterone agonist; versican ID PROGESTERONE-RECEPTOR MODULATORS; GROWTH-FACTOR-I; CONTROLLED-TRIAL; ANTIPROGESTERONE RU486; DOUBLE-BLIND; FIBROIDS; EXPRESSION; MYOMETRIUM; MANAGEMENT; VERSICAN AB Objective: To characterize the efficacy of mifepristone treatment on extracellular matrix (ECM) production in leiomyomas. Design: Laboratory study. Setting: University research laboratory. Patient(s): None. Intervention(s): Treatment of human immortalized two-dimensional (2D) and three-dimensional (3D) leiomyoma and myometrial cells with mifepristone and the progestin promegestone (R5020). Main Outcome Measure(s): Expression of COL1A1, fibronectin, versican variant V0, and dermatopontin in treated leiomyoma cells by Western blot analysis and confirmatory immunohistochemistry staining of treated 3D cultures. Result(s): Treatment with progestin stimulated production of COL1A1, fibronectin, versican, and dermatopontin. Mifepristone treatment inhibited protein production of these genes, most notably with versican expression. Combination treatment with both the agonist and antagonist further inhibited protein expression of these genes. Immunohistochemistry performed on 3D cultures demonstrated generalized inhibition of ECM protein concentration. Conclusion(s): Our study demonstrated that the progesterone agonist R5020 directly stimulated extracellular matrix components COL1A1, fibronectin, versican, and dermatopontin production in human leiomyoma cells. Progesterone antagonist mifepristone decreased protein production of these genes to levels comparable with untreated leiomyoma cells. (C) 2016 by American Society for Reproductive Medicine. C1 [Patel, Amrita; Malik, Minnie; Britten, Joy; Cox, Jeris; Catherino, William H.] Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, Bldg A,Room 3078,4301 Jones Bridge Rd, Bethesda, MD 20814 USA. [Cox, Jeris; Catherino, William H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. RP Catherino, WH (reprint author), Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, Bldg A,Room 3078,4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM william.catherino@usuhs.edu FU Bayer Schering Pharma; American Society for Reproductive Medicine; Abbvie Pharmaceutical; American Board of Obstetrics and Gynecology; Kantar Health; Uniformed Services University of the Health Sciences [QP85GF13, R21, R085193713]; intramural research Program in Reproductive and Adult Endocrinology, National Institutes of Health FX A.P. has nothing to disclose. M.M. has nothing to disclose. J.B. has nothing to disclose. J.C. has nothing to disclose. W.H.C. has received grants from Bayer Schering Pharma and personal fees from the American Society for Reproductive Medicine, Abbvie Pharmaceutical, the American Board of Obstetrics and Gynecology, Kantar Health, and Grand Rounds Speaker, multiple sites; he also reports that his wife is an employee of Recombine (genetic testing, not related to leiomyomas or gonadal hormones).; Supported by an intramural grant from Uniformed Services University of the Health Sciences, QP85GF13 and R21, R085193713; and supported, in part, by the intramural research Program in Reproductive and Adult Endocrinology, National Institutes of Health. NR 48 TC 1 Z9 1 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD APR PY 2016 VL 105 IS 4 BP 1102 EP 1110 DI 10.1016/j.fertnstert.2015.12.021 PG 9 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA DI3NZ UT WOS:000373406700040 PM 26776909 ER PT J AU Vsevolozhskaya, OA Zaykin, DV Barondess, DA Tong, XR Jadhav, S Lu, Q AF Vsevolozhskaya, Olga A. Zaykin, Dmitri V. Barondess, David A. Tong, Xiaoren Jadhav, Sneha Lu, Qing TI Uncovering Local Trends in Genetic Effects of Multiple Phenotypes via Functional Linear Models SO GENETIC EPIDEMIOLOGY LA English DT Article DE multivariate analysis; pleiotropy; genome-wide association studies; sequencing studies; quantitative traits; qualitative traits; functional analysis ID KERNEL HILBERT-SPACES; QUANTITATIVE TRAITS; PENALIZED SPLINES; ASSOCIATION; REGRESSION; RESPONSES; SELECTION; VARIANTS; HDL AB Recent technological advances equipped researchers with capabilities that go beyond traditional genotyping of loci known to be polymorphic in a general population. Genetic sequences of study participants can now be assessed directly. This capability removed technology-driven bias toward scoring predominantly common polymorphisms and let researchers reveal a wealth of rare and sample-specific variants. Although the relative contributions of rare and common polymorphisms to trait variation are being debated, researchers are faced with the need for new statistical tools for simultaneous evaluation of all variants within a region. Several research groups demonstrated flexibility and good statistical power of the functional linear model approach. In this work we extend previous developments to allow inclusion of multiple traits and adjustment for additional covariates. Our functional approach is unique in that it provides a nuanced depiction of effects and interactions for the variables in the model by representing them as curves varying over a genetic region. We demonstrate flexibility and competitive power of our approach by contrasting its performance with commonly used statistical tools and illustrate its potential for discovery and characterization of genetic architecture of complex traits using sequencing data from the Dallas Heart Study. C1 [Vsevolozhskaya, Olga A.] Univ Kentucky, Dept Biostat, Lexington, KY 40536 USA. [Zaykin, Dmitri V.] NIEHS, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Barondess, David A.; Tong, Xiaoren; Lu, Qing] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Jadhav, Sneha] Michigan State Univ, Dept Stat, E Lansing, MI 48824 USA. RP Vsevolozhskaya, OA (reprint author), Univ Kentucky, Dept Biostat, Coll Publ Hlth, 725 Rose St, Lexington, KY 40536 USA. EM vsevolozhskaya@uky.edu FU Intramural NIH HHS; NCATS NIH HHS [UL1 TR001105]; NIDA NIH HHS [K01 DA033346, K01DA033346, T32 DA021129, R01 DA016558, R01DA016558, T32DA021129]; NIDCR NIH HHS [R03 DE022379] NR 60 TC 2 Z9 2 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD APR PY 2016 VL 40 IS 3 BP 210 EP 221 DI 10.1002/gepi.21955 PG 12 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA DI6HQ UT WOS:000373600200004 PM 27027515 ER PT J AU Wang, S Zhao, JH An, P Guo, XQ Jensen, RA Marten, J Huffman, JE Meidtner, K Boeing, H Campbell, A Rice, KM Scott, RA Yao, J Schulze, MB Wareham, NJ Borecki, IB Province, MA Rotter, JI Hayward, C Goodarzi, MO Meigs, JB Dupuis, J AF Wang, Shuai Zhao, Jing Hua An, Ping Guo, Xiuqing Jensen, Richard A. Marten, Jonathan Huffman, Jennifer E. Meidtner, Karina Boeing, Heiner Campbell, Archie Rice, Kenneth M. Scott, Robert A. Yao, Jie Schulze, Matthias B. Wareham, Nicholas J. Borecki, Ingrid B. Province, Michael A. Rotter, Jerome I. Hayward, Caroline Goodarzi, Mark O. Meigs, James B. Dupuis, Josee TI General Framework for Meta-Analysis of Haplotype Association Tests SO GENETIC EPIDEMIOLOGY LA English DT Article DE meta-analysis; haplotype association tests; family samples; linear mixed effects model ID GENOME-WIDE ASSOCIATION; FASTING GLUCOSE; EM ALGORITHM; TRAITS; LOCI; SUSCEPTIBILITY; REGRESSION; LASSO AB For complex traits, most associated single nucleotide variants (SNV) discovered to date have a small effect, and detection of association is only possible with large sample sizes. Because of patient confidentiality concerns, it is often not possible to pool genetic data from multiple cohorts, and meta-analysis has emerged as the method of choice to combine results from multiple studies. Many meta-analysis methods are available for single SNV analyses. As new approaches allow the capture of low frequency and rare genetic variation, it is of interest to jointly consider multiple variants to improve power. However, for the analysis of haplotypes formed by multiple SNVs, meta-analysis remains a challenge, because different haplotypes may be observed across studies. We propose a two-stage meta-analysis approach to combine haplotype analysis results. In the first stage, each cohort estimate haplotype effect sizes in a regression framework, accounting for relatedness among observations if appropriate. For the second stage, we use a multivariate generalized least square meta-analysis approach to combine haplotype effect estimates from multiple cohorts. Haplotype-specific association tests and a global test of independence between haplotypes and traits are obtained within our framework. We demonstrate through simulation studies that we control the type-I error rate, and our approach is more powerful than inverse variance weighted meta-analysis of single SNV analysis when haplotype effects are present. We replicate a published haplotype association between fasting glucose-associated locus (G6PC2) and fasting glucose in seven studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and we provide more precise haplotype effect estimates. C1 [Wang, Shuai; Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Zhao, Jing Hua] Univ Cambridge, MRC, Epidemiol Unit, Sch Clin Med,Inst Metab Sci, Box 285,Cambridge Biomed Campus, Cambridge, England. [An, Ping; Borecki, Ingrid B.; Province, Michael A.] Washington Univ, Sch Med, Dept Genet, Div Stat Gen, St Louis, MO 63110 USA. [Guo, Xiuqing; Yao, Jie; Rotter, Jerome I.] Univ Calif Los Angeles, Med Ctr, LABioMed Harbor, Dept Pediat,Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA. [Jensen, Richard A.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Jensen, Richard A.; Hayward, Caroline] Univ Washington, Dept Med, Seattle, WA USA. [Marten, Jonathan; Huffman, Jennifer E.] Univ Edinburgh, Human Genet Unit, MRC, MRC IGMM, Edinburgh EH8 9YL, Midlothian, Scotland. [Meidtner, Karina; Schulze, Matthias B.] German Inst Human Nutr Potsdam Rehbrucke, Dept Mol Epidemiol, Nuthetal, Germany. [Boeing, Heiner] German Inst Human Nutr Potsdam Rehbrucke, Dept Epidemiol, Nuthetal, Germany. [Campbell, Archie; Hayward, Caroline] Univ Edinburgh, Ctr Genom & Expt Med, Inst Genet & Mol Med, Generat Scotland,Western Gen Hosp, Edinburgh, Midlothian, Scotland. [Rice, Kenneth M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Schulze, Matthias B.] German Ctr Diabet Res DZD, Munich, Germany. [Goodarzi, Mark O.] Cedars Sinai Med Ctr, Div Endocrinol Diabet & Metab, Los Angeles, CA 90048 USA. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Meigs, James B.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Dupuis, Josee] NHLBI, Framingham Heart Study, Framingham, MA USA. RP Dupuis, J (reprint author), 3rd Floor,801 Massachusetts Ave, Boston, MA 02118 USA. EM dupuis@bu.edu OI Meidtner, Karina/0000-0001-5810-4062; Schulze, Matthias B./0000-0002-0830-5277 FU Chief Scientist Office [CZD/16/6, CZD/16/6/4]; Intramural NIH HHS; Medical Research Council [MC_PC_U127561128, MC_U106179471]; NCATS NIH HHS [UL1 TR000040, UL1 TR000124, UL1 TR001079, UL1-TR-000040, UL1-TR-001079, UL1TR000124]; NCRR NIH HHS [UL1-RR-025005, UL1 RR025005]; NHLBI NIH HHS [HHSN268200800007C, HHSN268201200036C, HL068986, HL080295, HL087652, HL103612, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, N01HC95159, N01HC95160, N01HC95161, N01HC95162, N01HC95163, N01HC95164, N01HC95165, N01HC95166, N01HC95167, N01HC95168, N01HC95169, N02HL64278, R01 HL068986, R01 HL071205, R01 HL071250, R01 HL071252, R01 HL071258, R01 HL071259, R01 HL080295, R01 HL087652, R01 HL087700, R01 HL088215, R01 HL103612, R01-HL-071051, R01-HL-071205, R01-HL-071250, R01-HL-071251, R01-HL-071252, R01-HL-071258, R01-HL-071259, R01-HL-087700, R01-HL-088215, U01 HL080295]; NIA NIH HHS [AG023629, R01 AG023629, R56 AG023629]; NIDDK NIH HHS [DK063491, K24 DK080140, P30 DK063491, R01 DK075681, R01 DK078616, R01 DK089256, R01-DK-075681, R01-DK-8925601, U01 DK078616]; PHS HHS [HHSN268200800007C, HHSN268201200036C]; Wellcome Trust NR 26 TC 0 Z9 0 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD APR PY 2016 VL 40 IS 3 BP 244 EP 252 DI 10.1002/gepi.21959 PG 9 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA DI6HQ UT WOS:000373600200007 PM 27027517 ER PT J AU Manoli, I Myles, JG Sloan, JL Shchelochkov, OA Venditti, CP AF Manoli, Irini Myles, Jennifer G. Sloan, Jennifer L. Shchelochkov, Oleg A. Venditti, Charles P. TI A critical reappraisal of dietary practices in methylmalonic acidemia raises concerns about the safety of medical foods. Part 1: isolated methylmalonic acidemias SO GENETICS IN MEDICINE LA English DT Article DE branched-chain amino acids; dietary guidelines; leucine; medical foods; methylmalonic acidemia ID SYRUP-URINE-DISEASE; CHAIN AMINO-ACIDS; INBORN-ERRORS; PROPIONIC ACIDEMIA; PLASMA AMINO; YOUNG MEN; LEUCINE; METABOLISM; MANAGEMENT; ACIDURIA AB Purpose: Medical foods for methylmalonic acidemias (MMAs) and propionic acidemias contain minimal valine, isoleucine, methionine, and threonine but have been formulated with increased leucine. We aimed to assess the effects of imbalanced branched-chain amino acid intake on metabolic and growth parameters in a cohort of patients with MMA ascertained via a natural history study. Methods: Cross-sectional anthropometric and body-composition measurements were correlated with diet content and disease-related biomarkers in 61 patients with isolated MMA (46 mut, 9 cblA, and 6 cblB). Results: Patients with MMA tolerated close to the recommended daily allowance (RDA) of complete protein (mut(0): 99.45 +/- 32.05% RDA). However, 85% received medical foods, in which the protein equivalent often exceeded complete protein intake (35%). Medical food consumption resulted in low plasma valine and isoleucine concentrations, prompting paradoxical supplementation with these propiogenic amino acids. Weight-and height-for-age z-scores correlated negatively with the leucine-to-valine intake ratio (r = -0.453; P = 0.014; R-2 = 0.209 and r = -0.341; P = 0.05; R-2 = 0.123, respectively). Conclusion: Increased leucine intake in patients with MMA resulted in iatrogenic amino acid deficiencies and was associated with adverse growth outcomes. Medical foods for propionate oxidation disorders need to be redesigned and studied prospectively to ensure efficacy and safety. C1 [Manoli, Irini; Sloan, Jennifer L.; Venditti, Charles P.] NHGRI, Organ Acid Res Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Myles, Jennifer G.] NIH, Dept Nutr, Bldg 10, Bethesda, MD 20892 USA. [Shchelochkov, Oleg A.] Univ Iowa Hosp & Clin, Div Genet, Stead Dept Pediat, Iowa City, IA 52242 USA. RP Venditti, CP (reprint author), NHGRI, Organ Acid Res Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. EM venditti@mail.nih.gov OI Manoli, Irini/0000-0003-1543-2941; Sloan, Jennifer/0000-0003-4520-0949 FU National Human Genome Research Institute, Bethesda, MD; National Institutes of Health clinical center; National Institutes of Health/National Institute of Child Health and Human Development [K12 HD027748] FX The authors thank all the patients and their families for their participation in our natural history protocol and donation of blood/tissues for our studies; referring physicians, nurses, and dietitians for their help with patient's evaluations; Isa Bernardini and Roxanne Fischer for processing patient samples; the nurses, research dietitians of the National Institutes of Health Clinical Research Center, and clinical fellows of the National Human Genome Research Institute genetics fellowship program for their help with patient care and dedication to clinical research. I.M, J.L.S., and C.P.V were supported by the Intramural Research Program of the National Human Genome Research Institute, Bethesda, MD. J.M. was supported by the National Institutes of Health clinical center. Oleg A. Shchelochkov was supported by National Institutes of Health/National Institute of Child Health and Human Development grant K12 HD027748. The authors also thank Cheryl Stimson, MS, RD (University of Iowa Hospitals and Clinic), for her help with patient care. NR 43 TC 4 Z9 5 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 EI 1530-0366 J9 GENET MED JI Genet. Med. PD APR PY 2016 VL 18 IS 4 BP 386 EP 395 DI 10.1038/gim.2015.102 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA DI2XK UT WOS:000373362300016 PM 26270765 ER PT J AU Manoli, I Myles, JG Sloan, JL Carrillo-Carrasco, N Morava, E Strauss, KA Morton, H Venditti, CP AF Manoli, Irini Myles, Jennifer G. Sloan, Jennifer L. Carrillo-Carrasco, Nuria Morava, Eva Strauss, Kevin A. Morton, Holmes Venditti, Charles P. TI A critical reappraisal of dietary practices in methylmalonic acidemia raises concerns about the safety of medical foods. Part 2: cobalamin C deficiency SO GENETICS IN MEDICINE LA English DT Article DE cobalamin C (cblC) deficiency; dietary guidelines; medical foods; methionine; methylmalonic acidemia ID COMBINED DEGENERATION; S-ADENOSYLMETHIONINE; INBORN-ERRORS; FATTY-ACIDS; ACIDURIA; HOMOCYSTINURIA; METABOLISM; CBLC; DISEASE; CYSTATHIONINEMIA AB Purpose: Cobalamin C (cblC) deficiency impairs the biosynthesis of 5'-deoxyadenosyl-adenosyl- and methyl-cobalamin, resulting in methylmalonic acidemia combined with hyperhomocysteinemia and hypomethioninemia. However, some patients with cblC deficiency are treated with medical foods, devoid of methionine and high in leucine content, that are formulated for patients with isolated propionate oxidative defects. We examined the effects of imbalanced branched-chain amino acid intake on growth outcomes in cblC-deficient patients. Methods: Dietary intake was correlated with biochemical, anthropometric, and body composition measurements and other disease parameters in a cohort of 28 patients with early-onset cblC deficiency. Results: Protein-restricted diets were followed by 21% of the patients, whereas 32% received medical foods. Patients on-protein-restricted diets had lower height-for-age z-score (P = 0.034), whereas patients consuming medical foods had lower head circumference Z-scores (P = 0.037), plasma methionine concentrations (P = 0.001), and predicted methionine influx through the blood-brain barrier Z-score (-1.29 vs. -0.0617; P = 0.007). The combination of age at diagnosis, a history of seizures, and the leucine-to-valine dietary intake ratio best predicted head circumference Z-score based on multiple regression modeling (R-2 = 0.945). Conclusions: Patients with cblC deficiency treated with medical foods designed for isolated methylmalonic acidemia are at risk for iatrogenic methionine deficiency that could adversely affect brain growth and development. C1 [Manoli, Irini; Sloan, Jennifer L.; Carrillo-Carrasco, Nuria; Venditti, Charles P.] NHGRI, Organ Acid Res Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. NIH, Dept Nutr, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Carrillo-Carrasco, Nuria] NIH, Therapeut Rare & Neglected Dis, Natl Ctr Advancing Translat Sci, Bldg 10, Bethesda, MD 20892 USA. [Morava, Eva] Tulane Univ, Sch Med, 1430 Tulane Ave, New Orleans, LA 70112 USA. [Strauss, Kevin A.; Morton, Holmes] Clin Special Children, Strasburg, PA USA. RP Venditti, CP (reprint author), NHGRI, Organ Acid Res Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. EM venditti@mail.nih.gov RI Carrillo-Carrasco, Nuria/B-9034-2009; OI Carrillo-Carrasco, Nuria/0000-0003-0374-0808; Manoli, Irini/0000-0003-1543-2941; Sloan, Jennifer/0000-0003-4520-0949 FU National Human Genome Research Institute, Bethesda, MD; National Institutes of Health Clinical Center FX The authors thank all the patients and their families for their participation in our natural history protocol and donation of blood/tissues for our studies; referring physicians, nurses and dietitians for their help with patient's evaluations; Isa Bernardini and Roxanne Fischer for processing patient samples; the nurses, research dietitians of the National Institutes of Health Clinical Research Center, and clinical fellows of the National Human Genome Research Institute genetics fellowship program for their help with patient care and dedication to clinical research. I.M, J.L.S., and C.P.V were supported by the Intramural Research Program of the National Human Genome Research Institute, Bethesda, MD. J.M. was supported by the National Institutes of Health Clinical Center. The authors dedicate this manuscript to the memory of Harvey S. Mudd, who inspired us to study the role of methionine, methylation, and transsulfuration cycles in human physiology and disease. His stimulating discussions contributed significantly to our understanding of dietary effects in the management of cblC-deficient patients. NR 47 TC 2 Z9 3 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 EI 1530-0366 J9 GENET MED JI Genet. Med. PD APR PY 2016 VL 18 IS 4 BP 396 EP 404 DI 10.1038/gim.2015.107 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA DI2XK UT WOS:000373362300017 PM 26270766 ER PT J AU Manoli, I Myles, JG Sloan, JL Shchelochkov, OA Venditti, CP AF Manoli, Irini Myles, Jennifer G. Sloan, Jennifer L. Shchelochkov, Oleg A. Venditti, Charles P. TI Role of medical food in MMA Response SO GENETICS IN MEDICINE LA English DT Letter ID PROPIONIC ACIDEMIA; SUPPLEMENTS; MANAGEMENT C1 [Manoli, Irini; Sloan, Jennifer L.; Shchelochkov, Oleg A.; Venditti, Charles P.] NHGRI, Organ Acid Res Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Myles, Jennifer G.] NIH, Dept Nutr, Bldg 10, Bethesda, MD 20892 USA. [Shchelochkov, Oleg A.] Univ Iowa Hosp & Clin, Div Genet, Stead Dept Pediat, Iowa City, IA 52242 USA. RP Venditti, CP (reprint author), NHGRI, Organ Acid Res Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. EM venditti@mail.nih.gov NR 7 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 1098-3600 EI 1530-0366 J9 GENET MED JI Genet. Med. PD APR PY 2016 VL 18 IS 4 BP 414 EP 415 DI 10.1038/gim.2016.12 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA DI2XK UT WOS:000373362300021 PM 26963280 ER PT J AU Biesecker, LG AF Biesecker, Leslie G. TI Overcalling secondary findings SO GENETICS IN MEDICINE LA English DT Letter C1 [Biesecker, Leslie G.] NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA. RP Biesecker, LG (reprint author), NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA. EM lesb@mail.nih.gov FU Intramural NIH HHS NR 3 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 1098-3600 EI 1530-0366 J9 GENET MED JI Genet. Med. PD APR PY 2016 VL 18 IS 4 BP 416 EP 416 DI 10.1038/gim.2016.19 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA DI2XK UT WOS:000373362300022 PM 26986879 ER PT J AU Mensah, GA AF Mensah, George A. TI Tackling Noncommunicable Diseases in Africa: Caveat Lector SO HEALTH EDUCATION & BEHAVIOR LA English DT Article DE Africa; chronic diseases; demographic changes; noncommunicable diseases; risk factors; urbanization ID RHEUMATIC HEART-DISEASE; SUB-SAHARAN AFRICA; SYSTEMATIC ANALYSIS; GLOBAL BURDEN; RISK-FACTORS; 188 COUNTRIES; TRANSITION; MORTALITY; OBESITY; URBANIZATION AB Noncommunicable disease (NCD), principally cardiovascular diseases, cancer, chronic lung disease, and diabetes, constitutes the major cause of death worldwide. Evidence of a continuing increase in the global burden of these diseases has generated recent urgent calls for global action to tackle and reduce related death and disability. Because the majority of NCD deaths occur in low- and middle-income countries, increased attention has been focused on this group of countries. However, in sub-Saharan Africa, where all countries are members of the low- and middle-income grouping, NCDs are not the leading causes of death or potential life years lost. Thus, strategies to tackle NCDs in sub-Saharan Africa are best conceived and executed in alignment with existing strategies for the prevention, treatment, and control of the actual leading causes of death in this region. This commentary addresses caveats to be considered as strategies are developed to tackle NCDs in sub-Saharan Africa as part of the global effort to prevent, treat, and control NCDs. C1 [Mensah, George A.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Mensah, GA (reprint author), NHLBI, Ctr Translat Res & Implementat Sci, NIH, One Rockledge Ctr,6705 Rockledge Dr,Suite 6070, Bethesda, MD 20892 USA. EM george.mensah@nih.gov NR 34 TC 2 Z9 2 U1 5 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1090-1981 EI 1552-6127 J9 HEALTH EDUC BEHAV JI Health Educ. Behav. PD APR PY 2016 VL 43 SU 1 BP 7S EP 13S DI 10.1177/1090198116633454 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DI7SH UT WOS:000373701800002 PM 27037151 ER PT J AU Keys, TR Kirkali, Z Badlani, G AF Keys, Tristan R. Kirkali, Ziya Badlani, Gopal TI Do we need new patient reported measures to evaluate lower urinary tract dysfunction? SO INDIAN JOURNAL OF UROLOGY LA English DT Editorial Material ID QUALITY-OF-LIFE; INCONTINENCE IMPACT QUESTIONNAIRE; UROGENITAL DISTRESS INVENTORY; SYMPTOMS; WOMEN; OUTCOMES C1 [Keys, Tristan R.; Badlani, Gopal] Wake Forest Univ, Bowman Gray Sch Med, Dept Urol, Winston Salem, NC 27103 USA. [Kirkali, Ziya] NIDDK, Bethesda, MD 20892 USA. RP Keys, TR (reprint author), Wake Forest Baptist Hlth, Dept Urol, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM tkeys@wakehealth.edu NR 13 TC 1 Z9 1 U1 0 U2 0 PU MEDKNOW PUBLICATIONS & MEDIA PVT LTD PI MUMBAI PA B-9, KANARA BUSINESS CENTRE, OFF LINK RD, GHAKTOPAR-E, MUMBAI, 400075, INDIA SN 0970-1591 EI 1998-3824 J9 INDIAN J UROL JI Indian J. Urol. PD APR-JUN PY 2016 VL 32 IS 2 BP 91 EP 92 DI 10.4103/0970-1591.179177 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA DI4OO UT WOS:000373479400002 PM 27127349 ER PT J AU Meeks, KAC Freitas-Da-Silva, D Adeyemo, A Beune, EJAJ Modesti, PA Stronks, K Zafarmand, MH Agyemang, C AF Meeks, Karlijn A. C. Freitas-Da-Silva, Deivisson Adeyemo, Adebowale Beune, Erik J. A. J. Modesti, Pietro A. Stronks, Karien Zafarmand, Mohammad H. Agyemang, Charles TI Disparities in type 2 diabetes prevalence among ethnic minority groups resident in Europe: a systematic review and meta-analysis SO INTERNAL AND EMERGENCY MEDICINE LA English DT Review DE Type 2 diabetes; Prevalence; Ethnic minority groups; IDF geographical regions; Meta-analysis ID CARDIOVASCULAR RISK-FACTORS; CORONARY-HEART-DISEASE; MULTIETHNIC POPULATION; SOCIOECONOMIC-STATUS; GLUCOSE-INTOLERANCE; ORIGIN POPULATIONS; ASIAN-AMERICANS; INNER-CITY; MELLITUS; IMMIGRANTS AB Many ethnic minorities in Europe have a higher type 2 diabetes (T2D) prevalence than their host European populations. The risk size differs between ethnic groups, but the extent of the differences in the various ethnic minority groups has not yet been systematically quantified. We conducted a meta-analysis of published data on T2D in various ethnic minority populations resident in Europe compared to their host European populations. We systematically searched MEDLINE (using PUBMED) and EMBASE for papers on T2D prevalence in ethnic minorities in Europe published between 1994 and 2014. The ethnic minority groups were classified into five population groups by geographical origin: South Asian (SA), Sub-Saharan African (SSA), Middle Eastern and North African (MENA), South and Central American (SCA), and Western Pacific (WP). Pooled odds ratios with corresponding 95 % confidence interval (CI) were calculated using Review Manager 5.3. Twenty articles were included in the analysis. Compared with the host populations, SA origin populations had the highest odds for T2D (3.7, 95 % CI 2.7-5.1), followed by MENA (2.7, 95 % CI 1.8-3.9), SSA (2.6, 95 % CI 2.0-3.5), WP (2.3, 95 % CI 1.2-4.1), and lastly SCA (1.3, 95 % CI 1.1-1.6). Odds ratios were in all ethnic minority populations higher for women than for men except for SCA. Among SA subgroups, compared with Europeans, Bangladeshi had the highest odds ratio of 6.2 (95 % CI 3.9-9.8), followed by Pakistani (5.4, 95 % CI 3.2-9.3) and Indians (4.1, 95 % CI 3.0-5.7). The risk of T2D among ethnic minority groups living in Europe compared to Europeans varies by geographical origin of the group: three to five times higher among SA, two to four times higher among MENA, and two to three times higher among SSA origin. Future research and policy initiatives on T2D among ethnic minority groups should take the interethnic differences into account. C1 [Meeks, Karlijn A. C.; Freitas-Da-Silva, Deivisson; Beune, Erik J. A. J.; Stronks, Karien; Zafarmand, Mohammad H.; Agyemang, Charles] Univ Amsterdam, Acad Med Ctr, Dept Publ Hlth, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [Adeyemo, Adebowale] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. [Modesti, Pietro A.] Univ Florence, Dept Clin & Expt Med, Florence, Italy. RP Meeks, KAC (reprint author), Univ Amsterdam, Acad Med Ctr, Dept Publ Hlth, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. EM k.a.meeks@amc.uva.nl OI Modesti, Pietro Amedeo/0000-0002-9511-2173 FU Science Without Borders, Brazil [SWG-122/2012] FX We acknowledge the support received from Science Without Borders (SWG-122/2012) Brazil, for the work of D. Freitas-Da-Silva. NR 45 TC 6 Z9 6 U1 6 U2 7 PU SPRINGER-VERLAG ITALIA SRL PI MILAN PA VIA DECEMBRIO, 28, MILAN, 20137, ITALY SN 1828-0447 EI 1970-9366 J9 INTERN EMERG MED JI Intern. Emerg. Med. PD APR PY 2016 VL 11 IS 3 BP 327 EP 340 DI 10.1007/s11739-015-1302-9 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA DI6UA UT WOS:000373634500006 PM 26370238 ER PT J AU Wingate, S AF Wingate, Sue TI Learning From Caregivers About the End of Life in Patients With a Left Ventricular Assist Device SO JAMA INTERNAL MEDICINE LA English DT Editorial Material ID DESTINATION; SUPPORT C1 [Wingate, Sue] NINR, NIH, 10 Ctr Dr,Room 2-1339, Bethesda, MD 20892 USA. RP Wingate, S (reprint author), NINR, NIH, 10 Ctr Dr,Room 2-1339, Bethesda, MD 20892 USA. EM suzanne.wingate@nih.gov NR 10 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 APR PY 2016 VL 176 IS 4 BP 540 EP 541 DI 10.1001/jamainternmed.2016.0275 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DI3EG UT WOS:000373380600027 PM 26999458 ER PT J AU Kim, C Prasad, V AF Kim, Chul Prasad, Vinay TI Balancing Accelerated Approval for Drugs With Accelerated Withdrawal Reply SO JAMA INTERNAL MEDICINE LA English DT Letter C1 [Kim, Chul] NCI, Med Oncol Serv, NIH, Bethesda, MD 20892 USA. [Prasad, Vinay] Oregon Hlth & Sci Univ, Div Hematol Oncol, Knight Canc Inst, Portland, OR 97239 USA. [Prasad, Vinay] Oregon Hlth & Sci Univ, Ctr Hlth Care Eth, Portland, OR 97239 USA. RP Prasad, V (reprint author), Oregon Hlth & Sci Univ, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM prasad@ohsu.edu NR 4 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 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD APR PY 2016 VL 176 IS 4 BP 567 EP 567 DI 10.1001/jamainternmed.2016.0374 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA DI3EG UT WOS:000373380600051 PM 27043117 ER PT J AU Kim, SYH De Vries, RG Peteet, JR AF Kim, Scott Y. H. De Vries, Raymond G. Peteet, John R. TI Euthanasia and Assisted Suicide of Patients With Psychiatric Disorders in the Netherlands 2011 to 2014 SO JAMA PSYCHIATRY LA English DT Article ID MEDICAL-PRACTICE; DEPRESSION; BELGIUM; CARE AB IMPORTANCE Euthanasia or assisted suicide (EAS) of psychiatric patients is increasing in some jurisdictions such as Belgium and the Netherlands. However, little is known about the practice, and it remains controversial. OBJECTIVES To describe the characteristics of patients receiving EAS for psychiatric conditions and how the practice is regulated in the Netherlands. DESIGN, SETTING, AND PARTICIPANTS This investigation reviewed psychiatric EAS case summaries made available online by the Dutch regional euthanasia review committees as of June 1, 2015. Two senior psychiatrists used directed content analysis to review and code the reports. In total, 66 cases from 2011 to 2014 were reviewed. MAIN OUTCOMES AND MEASURES Clinical and social characteristics of patients, physician review process of the patients' requests, and the euthanasia review committees' assessments of the physicians' actions. RESULTS Of the 66 cases reviewed, 70%(n = 46) were women. In total, 32%(n = 21) were 70 years or older, 44% (n = 29) were 50 to 70 years old, and 24% (n = 16) were 30 to 50 years old. Most had chronic, severe conditions, with histories of attempted suicides and psychiatric hospitalizations. Most had personality disorders and were described as socially isolated or lonely. Depressive disorders were the primary psychiatric issue in 55% (n = 36) of cases. Other conditions represented were psychotic, posttraumatic stress or anxiety, somatoform, neurocognitive, and eating disorders, as well as prolonged grief and autism. Comorbidities with functional impairments were common. Forty-one percent (n = 27) of physicians performing EAS were psychiatrists. Twenty-seven percent (n = 18) of patients received the procedure from physicians new to them, 14 of whom were physicians from the End-of-Life Clinic, a mobile euthanasia clinic. Consultation with other physicians was extensive, but 11% (n = 7) of cases had no independent psychiatric input, and 24%(n = 16) of cases involved disagreement among consultants. The euthanasia review committees found that one case failed to meet legal due care criteria. CONCLUSIONS AND RELEVANCE Persons receiving EAS for psychiatric disorders in the Netherlands are mostly women and of diverse ages, with complex and chronic psychiatric, medical, and psychosocial histories. The granting of their EAS requests appears to involve considerable physician judgment, usually involving multiple physicians who do not always agree (sometimes without independent psychiatric input), but the euthanasia review committees generally defer to the judgments of the physicians performing the EAS. C1 [Kim, Scott Y. H.] NIH, Dept Bioeth, 10 Ctr Dr,Room 1C118, Bethesda, MD 20892 USA. [De Vries, Raymond G.] Univ Michigan, Sch Med, Ctr Bioeth & Social Sci Med, Ann Arbor, MI USA. [De Vries, Raymond G.] Maastricht Univ, CAPHRI Sch Publ Hlth & Primary Care, NL-6200 MD Maastricht, Netherlands. [Peteet, John R.] Brigham & Womens Hosp, Dept Psychiat, 75 Francis St, Boston, MA 02115 USA. [Peteet, John R.] Harvard Univ, Sch Med, Boston, MA USA. RP Kim, SYH (reprint author), NIH, Dept Bioeth, 10 Ctr Dr,Room 1C118, Bethesda, MD 20892 USA. EM scott.kim@nih.gov NR 31 TC 14 Z9 14 U1 8 U2 16 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 APR PY 2016 VL 73 IS 4 BP 362 EP 368 DI 10.1001/jamapsychiatry.2015.2887 PG 7 WC Psychiatry SC Psychiatry GA DI4BI UT WOS:000373444700011 PM 26864709 ER PT J AU Blanco, C Hasin, DS Wall, MM Florez-Salamanca, L Hoertel, N Wang, S Kerridge, BT Olfson, M AF Blanco, Carlos Hasin, Deborah S. Wall, Melanie M. Florez-Salamanca, Ludwing Hoertel, Nicolas Wang, Shuai Kerridge, Bradley T. Olfson, Mark TI Cannabis Use and Risk of Psychiatric Disorders Prospective Evidence From a US National Longitudinal Study SO JAMA PSYCHIATRY LA English DT Article ID GENERAL-POPULATION SAMPLE; SOCIAL ANXIETY DISORDER; SUBSTANCE USE DISORDERS; ALCOHOL-USE-DISORDER; UNITED-STATES; MARIJUANA USE; MEDICAL MARIJUANA; PROPENSITY SCORE; DRUG-USE; YOUNG-PEOPLE AB IMPORTANCE With rising rates of marijuana use in the general population and an increasing number of states legalizing recreational marijuana use and authorizing medical marijuana programs, there are renewed clinical and policy concerns regarding the mental health effects of cannabis use. OBJECTIVE To examine prospective associations between cannabis use and risk of mental health and substance use disorders in the general adult population. DESIGN, SETTING, AND PARTICIPANTS A nationally representative sample of US adults aged 18 years or older was interviewed 3 years apart in the National Epidemiologic Survey on Alcohol and Related Conditions (wave 1, 2001-2002; wave 2, 2004-2005). The primary analyses were limited to 34 653 respondents who were interviewed in both waves. Data analysis was conducted from March 15 to November 30, 2015. MAIN OUTCOMES AND MEASURES We used multiple regression and propensity score matching to estimate the strength of independent associations between cannabis use at wave 1 and incident and prevalent psychiatric disorders at wave 2. Psychiatric disorders were measured with a structured interview (Alcohol Use Disorder and Associated Disabilities Interview Schedule-DSM-IV). In both analyses, the same set of wave 1 confounders was used, including sociodemographic characteristics, family history of substance use disorder, disturbed family environment, childhood parental loss, low self-esteem, social deviance, education, recent trauma, past and present psychiatric disorders, and respondent's history of divorce. RESULTS In the multiple regression analysis of 34 653 respondents (14 564 male [47.9% weighted]; mean [SD] age, 45.1 [17.3] years), cannabis use in wave 1 (2001-2002), which was reported by 1279 respondents, was significantly associated with substance use disorders in wave 2 (2004-2005) (any substance use disorder: odds ratio [OR], 6.2; 95% CI, 4.1-9.4; any alcohol use disorder: OR, 2.7; 95% CI, 1.9-3.8; any cannabis use disorder: OR, 9.5; 95% CI, 6.4-14.1; any other drug use disorder: OR, 2.6; 95% CI, 1.6-4.4; and nicotine dependence: OR, 1.7; 95% CI, 1.2-2.4), but not any mood disorder (OR, 1.1; 95% CI, 0.8-1.4) or anxiety disorder (OR, 0.9; 95% CI, 0.7-1.1). The same general pattern of results was observed in the multiple regression analyses of wave 2 prevalent psychiatric disorders and in the propensity score-matched analysis of incident and prevalent psychiatric disorders. CONCLUSIONS AND RELEVANCE Within the general population, cannabis use is associated with an increased risk for several substance use disorders. Physicians and policy makers should take these associations of cannabis use under careful consideration. C1 [Hasin, Deborah S.; Wall, Melanie M.; Hoertel, Nicolas; Wang, Shuai; Kerridge, Bradley T.; Olfson, Mark] Columbia Univ, Med Ctr, New York State Psychiat Inst, Dept Psychiat, 1051 Riverside Dr, New York, NY 10032 USA. [Blanco, Carlos] NIDA, Div Epidemiol Serv & Prevent Res, Bethesda, MD 20892 USA. [Florez-Salamanca, Ludwing; Hoertel, Nicolas] Corentin Celton Hosp, AP HP, Paris, France. [Florez-Salamanca, Ludwing; Hoertel, Nicolas] Paris Descartes Univ, Sorbonne Paris Cite, Pole Rech & Enseignement Super, Dept Psychiat, Paris, France. [Hoertel, Nicolas] Paris Descartes Univ, PRES Sorbonne Paris Cite, Psychiat & Neurosci Ctr, INSERM,Unite Mixte Rech 894, Paris, France. RP Olfson, M (reprint author), Columbia Univ, Med Ctr, New York State Psychiat Inst, Dept Psychiat, 1051 Riverside Dr, New York, NY 10032 USA. EM mo49@cumc.columbia.edu FU National Institute on Alcohol Abuse and Alcoholism; Intramural Program, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health; Agency for Healthcare Research and Quality [U18 HS021112]; New York State Psychiatric Institute FX The National Epidemiologic Survey on Alcohol and Related Conditions was sponsored by the National Institute on Alcohol Abuse and Alcoholism and funded, in part, by the Intramural Program, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health. This study was supported by grant U18 HS021112 from the Agency for Healthcare Research and Quality (Dr Olfson) and the New York State Psychiatric Institute (Drs Hasin, Olfson, and Wall). NR 49 TC 12 Z9 12 U1 11 U2 19 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 APR PY 2016 VL 73 IS 4 BP 388 EP 395 DI 10.1001/jamapsychiatry.2015.3229 PG 8 WC Psychiatry SC Psychiatry GA DI4BI UT WOS:000373444700014 PM 26886046 ER PT J AU Dau, J Weisman, M Ward, M Lee, M Rahbar, M Diekman, L Brown, M Gensler, L Reveille, J AF Dau, Jonathan Weisman, Michael Ward, Michael Lee, MinJae Rahbar, Mohammad Diekman, Laura Brown, Matthew Gensler, Lianne Reveille, John TI CLINICAL FACTORS IMPACTING OPIATE USAGE IN A LONGITUDINAL ANKYLOSING SPONDYLITIS COHORT SO JCR-JOURNAL OF CLINICAL RHEUMATOLOGY LA English DT Meeting Abstract C1 [Dau, Jonathan; Diekman, Laura; Reveille, John] Univ Texas Houston, Sch Med, Div Rheumatol, Houston, TX USA. [Weisman, Michael] Cedars Sinai Med Ctr, Div Rheumatol, Los Angeles, CA USA. [Ward, Michael] NIAMS, NIH, New York, NY USA. [Lee, MinJae; Rahbar, Mohammad] Univ Texas Hlth Sci Ctr Houston, Ctr Clin & Translat Sci, Houston, TX 77030 USA. [Brown, Matthew] Univ Queensland, Brisbane, Qld 4072, Australia. [Gensler, Lianne] Univ Calif San Francisco, Div Rheumatol, San Francisco, CA 94143 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1076-1608 EI 1536-7355 J9 JCR-J CLIN RHEUMATOL JI JCR-J. Clin. Rheumatol. PD APR PY 2016 VL 22 IS 3 MA 3287821 BP 143 EP 143 PG 1 WC Rheumatology SC Rheumatology GA DI1DO UT WOS:000373236400088 ER PT J AU Gibson, MC Lee, M Ward, M Gensler, L Brown, M Assassi, S Pence, C Diekman, L Rahbar, M Weisman, M Reveille, J AF Gibson, Mary Catherine Lee, MinJae Ward, Michael Gensler, Lianne Brown, Matthew Assassi, Shervin Pence, Colton Diekman, Laura Rahbar, Mohammad Weisman, Michael Reveille, John TI MEDICATION UTILIZATION OVER TIME AND FACTORS ASSOCIATED WITH ANTI-TNF USAGE IN ANKYLOSING SPONDYLITIS SO JCR-JOURNAL OF CLINICAL RHEUMATOLOGY LA English DT Meeting Abstract C1 [Gibson, Mary Catherine; Lee, MinJae; Assassi, Shervin; Pence, Colton; Diekman, Laura; Rahbar, Mohammad; Reveille, John] Univ Texas Houston, Houston, TX USA. [Ward, Michael] NIAMS, NIH, Bethesda, MD USA. [Gensler, Lianne] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Brown, Matthew] Univ Queensland, Diamantina Inst, Brisbane, Qld 4072, Australia. [Weisman, Michael] Cedars Sinai Med Ctr, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1076-1608 EI 1536-7355 J9 JCR-J CLIN RHEUMATOL JI JCR-J. Clin. Rheumatol. PD APR PY 2016 VL 22 IS 3 MA 3287828 BP 143 EP 144 PG 2 WC Rheumatology SC Rheumatology GA DI1DO UT WOS:000373236400089 ER PT J AU Voller, B Lines, E McCrossin, G Tinaz, S Lungu, C Grimes, G Starling, J Potti, G Buchwald, P Haubenberger, D Hallett, M AF Voller, Bernhard Lines, Emily McCrossin, Gayle Tinaz, Sule Lungu, Codrin Grimes, George Starling, Judith Potti, Gopal Buchwald, Peter Haubenberger, Dietrich Hallett, Mark TI Dose-escalation study of octanoic acid in patients with essential tremor SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID MOVEMENT-DISORDER; SCALE AB BACKGROUND. Recently, 1-octanol has been shown to have efficacy in treating patients with essential tremor (ET). The primary metabolite of 1-octanol is octanoic acid (OA), which is now thought to be the active substance that mediates tremor suppression. Our aim was to describe the maximum tolerated dose (MTD) of oral OA in patients with ET and assess the pharmacokinetics (PK) and pharmacodynamics (PD) profile of OA. METHODS. The MID was studied using an open-label, single-ascending 3 + 3 dose-escalation design. Predefined single doses ranged from 8 to 128 mg/kg, with grade 2 adverse events (AEs) defined as dose-limiting toxicity. Tremor was assessed using accelerometry, digital spiral analysis, and a standard clinical rating scale at baseline and up to 600 minutes after intake. Safety assessments and PK sampling were also performed. RESULTS. Dose-limiting toxicity was not reached. The most frequent AE was mild abdominal discomfort. Exposure (AUC) increased linearly with the dose. Secondary efficacy measures suggested a dose-dependent reduction of tremor. Accordingly, a single unified PK/PD model with an effect compartment and sigmoid maximum effect (E-max) response could be built that accounted well for the time profiles of plasma concentrations as well as effects on tremor severity across the 5 dose levels. CONCLUSION. Although our trial did not reach an MID, a dose-dependent effect was demonstrated in the PK/PD model as well as in secondary efficacy outcomes. Future studies are needed to explore the safety in higher dose ranges and to confirm dose-dependent efficacy in a placebo-controlled design. C1 [Voller, Bernhard; Lines, Emily; McCrossin, Gayle; Tinaz, Sule; Haubenberger, Dietrich; Hallett, Mark] NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Voller, Bernhard] Med Univ Vienna, Dept Neurol, Vienna, Austria. [Lungu, Codrin] NINDS, Off Clin Director, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Grimes, George; Starling, Judith; Potti, Gopal] NIH, Pharmaceut Dev Sect, Bldg 10, Bethesda, MD 20892 USA. [Buchwald, Peter] Univ Miami, Miller Sch Med, Dept Mol & Cellular Pharmacol, Miami, FL 33136 USA. [Haubenberger, Dietrich] NINDS, Clin Trials Unit, Off Clin Director, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, NIH, Bldg 10-7D37,10 Ctr Dr, Bethesda, MD 20892 USA. EM hallettm@ninds.nih.gov OI Buchwald, Peter/0000-0003-2732-8180 FU NINDS Intramural Program - TG Therapeutics Inc.; TG Therapeutics Inc. FX The study was supported by the NINDS Intramural Program with supplemental funding from TG Therapeutics Inc. B. Voller and E. Lines were both sponsored by TG Therapeutics Inc. B. Voller worked as a contractor and as a special volunteer at the NIH/NINDS in accordance with the Cooperative Research and Development Agreement (CRADA 02036). E. Lines worked through the Postbaccalaureate Intramural Research Training Award Program at NIH/NINDS. NR 20 TC 1 Z9 1 U1 5 U2 6 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 APR PY 2016 VL 126 IS 4 BP 1451 EP 1457 DI 10.1172/JCI83621 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DI5ES UT WOS:000373522300033 PM 26927672 ER PT J AU Faralli, H Wang, CC Nakka, K Benyoucef, A Sebastian, S Zhuang, LN Chu, A Palii, CG Liu, CY Camellato, B Brand, M Ge, K Dilworth, FJ AF Faralli, Herve Wang, Chaochen Nakka, Kiran Benyoucef, Aissa Sebastian, Soji Zhuang, Lenan Chu, Alphonse Palii, Carmen G. Liu, Chengyu Camellato, Brendan Brand, Marjorie Ge, Kai Dilworth, F. Jeffrey TI UTX demethylase activity is required for satellite cell-mediated muscle regeneration SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID EMBRYONIC STEM-CELLS; SKELETAL-MUSCLE; GENE-EXPRESSION; METHYLTRANSFERASE ACTIVITY; READ ALIGNMENT; SELF-RENEWAL; RNA-SEQ; POLYCOMB; CHROMATIN; MYOGENESIS AB The X chromosome-encoded histone demethylase UTX (also known as KDM6A) mediates removal of repressive trimethylation of histone H3 lysine 27 (H3K27me3) to establish transcriptionally permissive chromatin. Loss of UTX in female mice is embryonic lethal. Unexpectedly, male UTX-null mice escape embryonic lethality due to expression of UTY, a paralog that lacks H3K27 demethylase activity, suggesting an enzyme-independent role for UTX in development and thereby challenging the need for active H3K27 demethylation in vivo. However, the requirement for active H3K27 demethylation in stem cell-mediated tissue regeneration remains untested. Here, we employed an inducible mouse KO that specifically ablates Utx in satellite cells (SCs) and demonstrated that active H3K27 demethylation is necessary for muscle regeneration. Loss of UTX in SCs blocked myofiber regeneration in both male and female mice. Furthermore, we demonstrated that UTX mediates muscle regeneration through its H3K27 demethylase activity, as loss of demethylase activity either by chemical inhibition or knock-in of demethylase-dead UTX resulted in defective muscle repair. Mechanistically, dissection of the muscle regenerative process revealed that the demethylase activity of UTX is required for expression of the transcription factor myogenin, which in turn drives differentiation of muscle progenitors. Thus, we have identified a critical role for the enzymatic activity of UTX in activating muscle-specific gene expression during myofiber regeneration and have revealed a physiological role for active H3K27 demethylation in vivo. C1 [Faralli, Herve; Nakka, Kiran; Benyoucef, Aissa; Sebastian, Soji; Chu, Alphonse; Palii, Carmen G.; Camellato, Brendan; Brand, Marjorie; Dilworth, F. Jeffrey] Ottawa Hosp, Res Inst, Sprott Ctr Stem Cell Res, Ottawa, ON, Canada. [Faralli, Herve; Nakka, Kiran; Benyoucef, Aissa; Chu, Alphonse; Palii, Carmen G.; Brand, Marjorie; Dilworth, F. Jeffrey] Univ Ottawa, Ottawa Inst Syst Biol, Ottawa, ON, Canada. [Wang, Chaochen; Zhuang, Lenan; Ge, Kai] NIDDK, NIH, Bethesda, MD 20892 USA. [Liu, Chengyu] NHLBI, Transgen Core, Ctr Mol Med, NIH, Bldg 10, Bethesda, MD 20892 USA. [Camellato, Brendan; Brand, Marjorie; Dilworth, F. Jeffrey] Univ Ottawa, Dept Cellular & Mol Med, Ottawa, ON, Canada. RP Dilworth, FJ (reprint author), Ottawa Hosp, Res Inst, 501 Smyth Rd,Mailbox 511, Ottawa, ON K1H 8L6, Canada.; Ge, K (reprint author), NIDDK, 10 Ctr Dr,Bldg 10,Room 8N307, Bethesda, MD 20814 USA. EM kai.ge@nih.gov; jdilworth@ohri.ca OI Ge, Kai/0000-0002-7442-5138 FU Canadian Institutes of Health Research [MOP-136773, FDN-143330, MOP-89834]; NIH (Intramural Research Program of the NIDDK); Association Francaise contre les Myopathies; Canada Research Chair in the Epigenetic Regulation of Transcription FX We thank Odile Neyret (Molecular Biology Platform at the Institut de Recherche Clinique de Montreal) for library preparation and high-throughput sequencing, and we thank University of Ottawa Histological Core Facility for preparation of histological slides. This work was funded by the Canadian Institutes of Health Research (MOP-136773 and FDN-143330 to F.J. Dilworth and MOP-89834 to M. Brand) and the NIH (Intramural Research Program of the NIDDK to K. Ge). H. Faralli was funded by a fellowship from the Association Francaise contre les Myopathies. F.J. Dilworth was supported by a Canada Research Chair in the Epigenetic Regulation of Transcription. NR 55 TC 6 Z9 6 U1 2 U2 6 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 APR PY 2016 VL 126 IS 4 BP 1555 EP 1565 DI 10.1172/JCI83239 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DI5ES UT WOS:000373522300041 PM 26999603 ER PT J AU Wert, DM VanSwearingen, J Perera, S Studenski, S Brach, JS AF Wert, David M. VanSwearingen, Jessie Perera, Subashan Studenski, Stephanie Brach, Jennifer S. TI The Impact of a Portable Metabolic Measurement Device on Gait Characteristics of Older Adults With Mobility Limitations SO JOURNAL OF GERIATRIC PHYSICAL THERAPY LA English DT Article DE load carriage; elderly; gait analysis ID LOAD CARRIAGE; ENERGY-COST; WALKING; RELIABILITY; VARIABILITY; TRIAL; SPEED AB Background and Purpose: Increased carriage loads have been found to alter gait biomechanics in young healthy adults and military personnel; however, less is known regarding the influence of added carriage load on the gait characteristics of older adults-especially those with mobility limitations. The purpose of this study was to examine spatial and temporal gait characteristics during instrumented and noninstrumented overground walking in a sample of older adults with slow gait. Methods: Forty older adults with slow gait completed 2 bouts of walking (instrumented and noninstrumented) over a computerized walkway during 1 clinic visit. Mean spatial-temporal characteristics, gait variability, and gait speed over 8 passes were recorded. Paired t tests and intraclass correlation coefficients were used to quantify differences. Results and Discussion: Nine of the 10 gait variables did not differ statistically between instrumented and noninstrumented gait (P < .05). Intraclass correlation coefficients (ICCs) for mean gait characteristics were excellent (range ICC = 0.94-0.98; 95% confidence interval = 0.89-0.99), and for gait variability ranged from fair to excellent (range ICC = 0.56-0.79; 95% confidence interval = 0.28-0.89). Our study was able to demonstrate no significant impact of instrumentation on gait characteristics in a sample of older adults with slow gait. Conclusion: Our findings begin to fill in the gaps in the literature regarding the impact of added carriage loads on more vulnerable populations and lend support for the use of similar weighted metabolic devices as a component of gait assessment in older adults with confidence that the additional carriage-load will not significantly impact concurrent measures of gait. C1 [Wert, David M.; VanSwearingen, Jessie; Brach, Jennifer S.] Univ Pittsburgh, Dept Phys Therapy, 100 Technology Dr,Ste 210, Pittsburgh, PA 15219 USA. [Perera, Subashan] Univ Pittsburgh, Dept Med, Div Geriatr Med, Pittsburgh, PA USA. [Studenski, Stephanie] Harbor Hosp, NIA, Longitudinal Studies Sect, Baltimore, MD USA. RP Wert, DM (reprint author), Univ Pittsburgh, Dept Phys Therapy, 100 Technology Dr,Ste 210, Pittsburgh, PA 15219 USA. EM dmw29@pitt.edu FU Pittsburgh Claude D. Pepper Older Americans Independence Center [P30 AG024827]; National Institutes on Aging; American Federation of Aging Research Paul Beeson Career Development Award [K23 AG026766] FX This project was funded in part by the Pittsburgh Claude D. Pepper Older Americans Independence Center (Grant P30 AG024827), and J. S. Brach was supported by the National Institutes on Aging and American Federation of Aging Research Paul Beeson Career Development Award (K23 AG026766). NR 18 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1539-8412 EI 2152-0895 J9 J GERIATR PHYS THER JI J. Geriatr. Phys. Ther. PD APR-JUN PY 2016 VL 39 IS 2 BP 77 EP 82 DI 10.1519/JPT.0000000000000053 PG 6 WC Geriatrics & Gerontology; Rehabilitation SC Geriatrics & Gerontology; Rehabilitation GA DI5JS UT WOS:000373535300006 PM 25973568 ER PT J AU Jaigirdar, A Rosenberg, SA Parkhurst, M AF Jaigirdar, Adnan Rosenberg, Steven A. Parkhurst, Maria TI A High-avidity WT1-reactive T-Cell Receptor Mediates Recognition of Peptide and Processed Antigen but not Naturally Occurring WT1-positive Tumor Cells SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE immunotherapy; WT1; T-cell receptor ID GENE WT1; CANCER REGRESSION; LEUKEMIA-CELLS; LYMPHOCYTES; THERAPY; IMMUNOPROTEASOME; IDENTIFICATION; CHEMOTHERAPY; EXPRESSION; TARGETS AB Wilms tumor gene 1 (WT1) is an attractive target antigen for cancer immunotherapy because it is overexpressed in many hematologic malignancies and solid tumors but has limited, low-level expression in normal adult tissues. Multiple HLA class I and class II restricted epitopes have been identified in WT1, and multiple investigators are pursuing the treatment of cancer patients with WT1-based vaccines and adoptively transferred WT1-reactive T cells. Here we isolated an HLA-A*0201-restricted WT1-reactive T-cell receptor (TCR) by stimulating peripheral blood lymphocytes of healthy donors with the peptide WT1:126-134 in vitro. This TCR mediated peptide recognition down to a concentration of similar to 0.1 ng/mL when pulsed onto T2 cells as well as recognition of HLA-A*0201(+) target cells transfected with full-length WT1 cDNA. However, it did not mediate consistent recognition of many HLA-A*0201(+) tumor cell lines or freshly isolated leukemia cells that endogeneously expressed WT1. We dissected this pattern of recognition further and observed that WT1:126-134 was more efficiently processed by immunoproteasomes compared with standard proteasomes. However, pretreatment of WT1(+) tumor cell lines with interferon gamma did not appreciably enhance recognition by our TCR. In addition, we highly overexpressed WT1 in several leukemia cell lines by electroporation with full-length WT1 cDNA. Some of these lines were still not recognized by our TCR suggesting possible antigen processing defects in some leukemias. These results suggest WT1:126-134 may not be a suitable target for T-cell based tumor immunotherapies. C1 [Jaigirdar, Adnan; Rosenberg, Steven A.; Parkhurst, Maria] NCI, NIH, Surg Branch, Bldg CRC,Room 4-5744,9000 Rockville Pike, Bethesda, MD 20892 USA. RP Parkhurst, M (reprint author), NCI, NIH, Surg Branch, Bldg CRC,Room 4-5744,9000 Rockville Pike, Bethesda, MD 20892 USA. EM maria_parkhurst@nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 42 TC 1 Z9 1 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1524-9557 EI 1537-4513 J9 J IMMUNOTHER JI J. Immunother. PD APR PY 2016 VL 39 IS 3 BP 105 EP 116 DI 10.1097/CJI.0000000000000116 PG 12 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA DI9VS UT WOS:000373851400001 PM 26938944 ER PT J AU Biau, G Fischer, A Guedj, B Malley, JD AF Biau, Gerard Fischer, Aurelie Guedj, Benjamin Malley, James D. TI COBRA: A combined regression strategy SO JOURNAL OF MULTIVARIATE ANALYSIS LA English DT Article DE Combining estimators; Consistency; Nonlinearity; Nonparametric regression; Prediction AB A new method for combining several initial estimators of the regression function is introduced. Instead of building a linear or convex optimized combination over a collection of basic estimators r(1), ..., r(m), we use them as a collective indicator of the proximity between the training data and a test observation. This local distance approach is model-free and very fast. More specifically, the resulting nonparametric/nonlinear combined estimator is shown to perform asymptotically at least as well in the L-2 sense as the best combination of the basic estimators in the collective. A companion R package called COBRA (standing for COmBined Regression Alternative) is presented (downloadable on http://cran.r-project.org/web/packages/COBRA/index.html). Substantial numerical evidence is provided on both synthetic and real data sets to assess the excellent performance and velocity of our method in a large variety of prediction problems. (C) 2015 Elsevier Inc. All rights reserved. C1 [Biau, Gerard] Univ Paris 06, F-75252 Paris 05, France. [Biau, Gerard] Inst Univ France, Lyon, France. [Fischer, Aurelie] Univ Paris Diderot, Paris, France. [Guedj, Benjamin] Inria, Villers Les Nancy, France. [Malley, James D.] NIH, Bethesda, MD USA. RP Guedj, B (reprint author), Inria, Villers Les Nancy, France. EM benjamin.guedj@inria.fr NR 27 TC 2 Z9 2 U1 2 U2 3 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0047-259X J9 J MULTIVARIATE ANAL JI J. Multivar. Anal. PD APR PY 2016 VL 146 SI SI BP 18 EP 28 DI 10.1016/j.jmva.2015.04.007 PG 11 WC Statistics & Probability SC Mathematics GA DI6ZG UT WOS:000373648200003 ER PT J AU Poswar, FD da Fonseca, RMT de Albuquerque, LCP Zhou, Q Jardim, LB Monte, TL Aksentijevich, I Saute, JAM AF Poswar, Fabiano de Oliveira Tomkowski da Fonseca, Raymundo Mesko Pedroso de Albuquerque, Leonardo Cordenonzi Zhou, Qing Jardim, Laura Bannach Monte, Thais Lampert Aksentijevich, Ivona Morales Saute, Jonas Alex TI Adenosine deaminase 2 deficiency presenting as spastic paraplegia and systemic vasculitis SO JOURNAL OF NEUROLOGY LA English DT Letter ID VASCULOPATHY; MUTATIONS; STROKE; ADA2 C1 [Poswar, Fabiano de Oliveira; Jardim, Laura Bannach; Morales Saute, Jonas Alex] Hosp Clin Porto Alegre, Med Genet Serv, Rua Ramiro Barcelos 2350, BR-90035903 Porto Alegre, RS, Brazil. [Tomkowski da Fonseca, Raymundo Mesko; Pedroso de Albuquerque, Leonardo Cordenonzi; Monte, Thais Lampert] Hosp Clin Porto Alegre, Neurol Serv, Porto Alegre, RS, Brazil. [Jardim, Laura Bannach] Univ Fed Rio Grande do Sul, Dept Internal Med, Porto Alegre, RS, Brazil. [Zhou, Qing; Aksentijevich, Ivona] NHGRI, NIH, Bethesda, MD 20892 USA. [Monte, Thais Lampert; Morales Saute, Jonas Alex] Univ Fed Rio Grande do Sul, Med Sci, Porto Alegre, RS, Brazil. RP Saute, JAM (reprint author), Hosp Clin Porto Alegre, Med Genet Serv, Rua Ramiro Barcelos 2350, BR-90035903 Porto Alegre, RS, Brazil.; Saute, JAM (reprint author), Univ Fed Rio Grande do Sul, Med Sci, Porto Alegre, RS, Brazil. EM jsaute@hcpa.edu.br RI Yu, Xiaomin/I-6407-2016 NR 9 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0340-5354 EI 1432-1459 J9 J NEUROL JI J. Neurol. PD APR PY 2016 VL 263 IS 4 BP 818 EP 820 DI 10.1007/s00415-016-8070-y PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA DI8HR UT WOS:000373742600028 ER PT J AU Civelek, AC AF Civelek, A. Cahid TI New Insights: PET Imaging to Document Synergistic Therapy Effect of the "Old," Ancient Recipe and the "New," Modern Drug in Stroke SO JOURNAL OF NUCLEAR MEDICINE LA English DT Editorial Material ID MEDICINE; DISCOVERY C1 [Civelek, A. Cahid] NIH, Dept Radiol & Imaging Sci, Body Imaging MRI, Bldg 10, Bethesda, MD 20892 USA. [Civelek, A. Cahid] Johns Hopkins Med Inst, Div Nucl Med, Baltimore, MD 21205 USA. RP Civelek, AC (reprint author), Johns Hopkins Med Inst, Div Nucl Med, Baltimore, MD 21205 USA.; Civelek, AC (reprint author), Univ Louisville, Med Ctr, 530 S Jackson St,Suite C07, Louisville, KY 40202 USA. EM accivelek@gmail.com NR 8 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 APR 1 PY 2016 VL 57 IS 4 BP 499 EP 500 DI 10.2967/jnumed.115.166702 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DI6RN UT WOS:000373627800012 PM 26541779 ER PT J AU Niu, G Chen, XY AF Niu, Gang Chen, Xiaoyuan TI RGD PET: From Lesion Detection to Therapy Response Monitoring SO JOURNAL OF NUCLEAR MEDICINE LA English DT Editorial Material ID ALPHA(V)BETA(3) INTEGRIN EXPRESSION; POSITRON-EMISSION-TOMOGRAPHY; CANCER-PATIENTS; GA-68-PRGD2 PET/CT; ANGIOGENESIS; F-18-ALFATIDE; DISEASE C1 [Niu, Gang; Chen, Xiaoyuan] NIH, Lab Mol Imaging & Nanomed LOMIN, Inst Biomed Imaging & Bioengn NIBIB, Bethesda, MD 20892 USA. RP Chen, XY (reprint author), NIH, 35A Convent Dr,GD937, Bethesda, MD 20892 USA. EM shawn.chen@nih.gov FU Intramural NIH HHS [, Z99 EB999999, ZIA EB000073-07] NR 25 TC 1 Z9 1 U1 7 U2 15 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 APR 1 PY 2016 VL 57 IS 4 BP 501 EP 502 DI 10.2967/jnumed.115.168278 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DI6RN UT WOS:000373627800013 PM 26609181 ER PT J AU Jang, S Sun, JH Chen, P Lakshman, S Molokin, A Harnly, JM Vinyard, BT Urban, JF Davis, CD Solano-Aguilar, G AF Jang, Saebyeol Sun, Jianghao Chen, Pei Lakshman, Sukla Molokin, Aleksey Harnly, James M. Vinyard, Bryan T. Urban, Joseph F., Jr. Davis, Cindy D. Solano-Aguilar, Gloria TI Flavanol-Enriched Cocoa Powder Alters the Intestinal Microbiota, Tissue and Fluid Metabolite Profiles, and Intestinal Gene Expression in Pigs SO JOURNAL OF NUTRITION LA English DT Article DE cocoa flavanols; porcine model; gut microbiota; metabolites; Toll-like receptors ID TOLL-LIKE RECEPTORS; FECAL MICROBIOTA; IMMUNE-SYSTEM; CECUM MODEL; DISEASE; POLYPHENOLS; HEALTH; ACID; CELL; BIFIDOBACTERIA AB Background: Consumption of cocoa-derived polyphenols has been associated with several health benefits; however, their effects on the intestinal microbiome and related features of host intestinal health are not adequately understood. Objective: The objective of this study was to determine the effects of eating flavanol-enriched cocoa powder on the composition of the gut microbiota, tissue metabolite profiles, and intestinal immune status. Methods: Male pigs (5 mo old, 28 kg mean body weight) were supplemented with 0, 2.5, 10, or 20 g flavanol-enriched cocoa powder/d for 27 d. Metabolites in serum, urine, the proximal colon contents, liver, and adipose tissue; bacterial abundance in the intestinal contents and feces; and intestinal tissue gene expression of inflammatory markers and Toll-like receptors (TLRs) were then determined. Results: O-methyl-epicatechin-glucuronide conjugates dose-dependently increased (P < 0.01) in the urine (35- to 204-fold), serum (6- to 186-fold), and adipose tissue (34- to 1144-fold) of pigs fed cocoa powder. The concentration of 3-hydroxyphenylpropionic acid isomers in urine decreased as the dose of cocoa powder fed to pigs increased (75-85%, P < 0.05). Compared with the unsupplemented pigs, the abundance of Lactobacillus species was greater in the feces (7-fold, P = 0.005) and that of Bifidobacterium species was greater in the proximal colon contents (9-fold, P = 0.01) in pigs fed only 20 or 10 g cocoa powder/d, respectively. Moreover, consumption of cocoa powder reduced TLR9 gene expression in ileal Peyer's patches (67-80%, P < 0.05) and mesenteric lymph nodes (43-71%, P < 0.05) of pigs fed 2.5-20 g cocoa powder/d compared with pigs not supplemented with cocoa powder. Conclusion: This study demonstrates that consumption of cocoa powder by pigs can contribute to gut health by enhancing the abundance of Lactobacillus and Bifidobacterium species and modulating markers of localized intestinal immunity. C1 [Jang, Saebyeol; Lakshman, Sukla; Molokin, Aleksey; Urban, Joseph F., Jr.; Solano-Aguilar, Gloria] USDA, Beltsville Human Nutr Res Ctr, Diet Genom & Immunol Lab, Northeast Area, Beltsville, MD 20705 USA. [Sun, Jianghao; Chen, Pei; Harnly, James M.] USDA, Beltsville Human Nutr Res Ctr, Food Composit & Methods Dev Lab, Northeast Area, Beltsville, MD 20705 USA. [Vinyard, Bryan T.] USDA, Beltsville Human Nutr Res Ctr, Northeast Area, Biometr Consulting Serv, Beltsville, MD 20705 USA. [Davis, Cindy D.] NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA. RP Solano-Aguilar, G (reprint author), USDA, Beltsville Human Nutr Res Ctr, Diet Genom & Immunol Lab, Northeast Area, Beltsville, MD 20705 USA. EM Gloria.Solano-Aguilar@ars.usda.gov RI Sun, Jianghao/A-6134-2010 FU USDA project [8040-51530-056-00]; Office of Dietary Supplements at NIH [8040-51530-056-13] FX Supported by USDA project 8040-51530-056-00 and interagency agreement 8040-51530-056-13 with the Office of Dietary Supplements at the NIH. Barry-Callebaut supplied Acticoa. NR 50 TC 2 Z9 2 U1 8 U2 21 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 APR PY 2016 VL 146 IS 4 BP 673 EP 680 DI 10.3945/jn.115.222968 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DI3RA UT WOS:000373415000003 PM 26936136 ER PT J AU Bailey, RL Parker, EA Rhodes, DG Goldman, JD Clemens, JC Moshfegh, AJ Thuppal, SV Weaver, CM AF Bailey, Regan L. Parker, Elizabeth A. Rhodes, Donna G. Goldman, Joseph D. Clemens, John C. Moshfegh, Alanna J. Thuppal, Sowmyanarayanan V. Weaver, Connie M. TI Estimating Sodium and Potassium Intakes and Their Ratio in the American Diet: Data from the 2011-2012 NHANES SO JOURNAL OF NUTRITION LA English DT Article DE sodium; potassium; ratio; NHANES; Na:K; diet ID COMPLEX SURVEY DATA; INTAKE DISTRIBUTIONS; REPORT INSTRUMENTS; NUTRIENT INTAKE; BLOOD-PRESSURE; PUBLIC-HEALTH; RECALL DATA; VALIDATION; NUTRITION; VARIANCE AB Background: The dietary sodium-to-potassium ratio (Na:K) is shown to be more strongly associated with an increased risk of cardiovascular disease (CVD) and CVD-related mortality than either sodium or potassium intake alone. Objective: The aim was to estimate the Na: K in the diet of US adults. Methods: Among US adults from the 2011-2012 NHANES (>= 20 y; 2393 men and 2337 women), the National Cancer Institute method was used to estimate sodium and potassium intakes, Na: K, and the percentage of individuals with Na: K < 1.0 utilizing the complex, stratified, multistage probability cluster sampling design. Results: Overall, women had a significantly lower Na: K than men (mean +/- SE: 1.32 +/- 0.02 compared with 1.45 +/- 0.02). Non-Hispanic whites had a significantly lower Na: K than non-Hispanic blacks and non-Hispanic Asians (1.34 +/- 0.02 compared with 1.54 +/- 0.03 and 1.49 +/- 0.04, respectively). Only 12.2% +/- 1.5% of US adults had a Na: K < 1.0. The Na: K decreased linearly as age increased. Most adults (90% +/- 0.8%) had sodium intakes > 2300 mg/d, whereas < 3% had potassium intakes > 4700 mg/d. Grains and vegetables were among the highest contributors to sodium intakes for adults with Na: K < 1.0, compared with protein foods and grains for those with Na: K >= 1.0. Vegetables and milk and dairy products constituted the primary dietary sources of potassium for individuals with Na: K < 1.0, whereas mixed dishes and protein foods contributed the most potassium for individuals with ratios >= 1.0. Individuals with a Na: K < 1.0 were less likely to consume mixed dishes and condiments and were more likely to consume vegetables, milk and dairy products, and fruit than those with a Na: K >= 1.0. Conclusion: Only about one-tenth of US adults have a Na: K consistent with the WHO guidelines for reduced risk of mortality. Continued efforts to reduce sodium intake in tandem with novel strategies to increase potassium intake are warranted. C1 [Bailey, Regan L.] NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA. [Bailey, Regan L.; Thuppal, Sowmyanarayanan V.; Weaver, Connie M.] Purdue Univ, Dept Nutr Sci, W Lafayette, IN 47907 USA. [Parker, Elizabeth A.; Rhodes, Donna G.; Goldman, Joseph D.; Clemens, John C.; Moshfegh, Alanna J.] USDA ARS, Beltsville, MD USA. RP Bailey, RL (reprint author), NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA.; Bailey, RL (reprint author), Purdue Univ, Dept Nutr Sci, W Lafayette, IN 47907 USA. EM reganbailey@purdue.edu FU Agricultural Research Service, USDA [58-1950-7-707]; NIH Office of Dietary Supplements; Sodium Committee of the North American Branch of the International Life Sciences Institute FX Supported in part by resources from the Agricultural Research Service, USDA agreement 58-1950-7-707 and the NIH Office of Dietary Supplements. Data generation for this work was funded by the Sodium Committee of the North American Branch of the International Life Sciences Institute. NR 36 TC 2 Z9 2 U1 4 U2 6 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 APR PY 2016 VL 146 IS 4 BP 745 EP 750 DI 10.3945/jn.115.221184 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DI3RA UT WOS:000373415000012 ER PT J AU Taylor, CL Roseland, JM Coates, PM Pehrsson, PR AF Taylor, Christine L. Roseland, Janet M. Coates, Paul M. Pehrsson, Pamela R. TI The Emerging Issue of 25-Hydroxyvitamin D in Foods SO JOURNAL OF NUTRITION LA English DT Letter C1 [Taylor, Christine L.; Coates, Paul M.] NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA. [Roseland, Janet M.; Pehrsson, Pamela R.] ARS, USDA, Beltsville, MD USA. RP Taylor, CL (reprint author), NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA. EM taylorcl3@od.nih.gov NR 9 TC 0 Z9 0 U1 0 U2 1 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 APR PY 2016 VL 146 IS 4 BP 855 EP 856 DI 10.3945/jn.115.228510 PG 2 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DI3RA UT WOS:000373415000026 PM 27037407 ER PT J AU King, JC Brown, KH Gibson, RS Krebs, NF Lowe, NM Siekmann, JH Raiten, DJ AF King, Janet C. Brown, Kenneth H. Gibson, Rosalind S. Krebs, Nancy F. Lowe, Nicola M. Siekmann, Jonathan H. Raiten, Daniel J. TI Biomarkers of Nutrition for Development (BOND)-Zinc Review SO JOURNAL OF NUTRITION LA English DT Review DE zinc; zinc status; diet zinc; plasma zinc; zinc function ID PLASMA ZINC CONCENTRATION; PLACEBO-CONTROLLED TRIAL; TRACE-ELEMENT CONCENTRATIONS; RANDOMIZED CONTROLLED-TRIALS; DOSE-RESPONSE METAANALYSIS; PRIMARY-SCHOOL CHILDREN; LOW-INCOME COUNTRIES; X-RAY-FLUORESCENCE; BREAST-FED INFANTS; VITAMIN-A STATUS AB Zinc is required for multiple metabolic processes as a structural, regulatory, or catalytic ion. Cellular, tissue, and whole-body zinc homeostasis is tightly controlled to sustain metabolic functions over a wide range of zinc intakes, making it difficult to assess zinc insufficiency or excess. The BOND (Biomarkers of Nutrition for Development) Zinc Expert Panel recommends 3 measurements for estimating zinc status: dietary zinc intake, plasma zinc concentration (PZC), and height-for-age of growing infants and children. The amount of dietary zinc potentially available for absorption, which requires an estimate of dietary zinc and phytate, can be used to identify individuals and populations at risk of zinc deficiency. PZCs respond to severe dietary zinc restriction and to zinc supplementation; they also change with shifts in whole-body zinc balance and clinical signs of zinc deficiency. PZC cutoffs are available to identify individuals and populations at risk of zinc deficiency. However, there are limitations in using the PZC to assess zinc status. PZCs respond less to additional zinc provided in food than to a supplement administered between meals, there is considerable interindividual variability in PZCs with changes in dietary zinc, and PZCs are influenced by recent meal consumption, the time of day, inflammation, and certain drugs and hormones. Insufficient data are available on hair, urinary, nail, and blood cell zinc responses to changes in dietary zinc to recommend these biomarkers for assessing zinc status. Of the potential functional indicators of zinc, growth is the only one that is recommended. Because pharmacologic zinc doses are unlikely to enhance growth, a growth response to supplemental zinc is interpreted as indicating pre-existing zinc deficiency. Other functional indicators reviewed but not recommended for assessing zinc nutrition in clinical or field settings because of insufficient information are the activity or amounts of zinc-dependent enzymes and proteins and biomarkers of oxidative stress, inflammation, or DNA damage. C1 [King, Janet C.; Siekmann, Jonathan H.] Childrens Hosp Oakland, Res Inst, Oakland, CA 94609 USA. [King, Janet C.; Brown, Kenneth H.] Univ Calif Davis, Davis, CA 95616 USA. [Brown, Kenneth H.] Bill & Melinda Gates Fdn, Seattle, WA USA. [Gibson, Rosalind S.] Univ Otago, Dunedin, New Zealand. [Krebs, Nancy F.] Univ Colorado, Sch Med, Aurora, CO USA. [Lowe, Nicola M.] Univ Cent Lancashire, Preston PR1 2HE, Lancs, England. [Raiten, Daniel J.] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Raiten, DJ (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM raitend@mail.nih.gov FU Bill & Melinda Gates Foundation; PepsiCo; Division of Nutrition Research Coordination (DNRC, NIH); Office of Dietary Supplements (ODS, NIH); Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD, NIH); Division of Nutrition Research Coordination (DNRC, NIH), FX Published in a supplement to The Journal of Nutrition. The Biomarkers of Nutrition for Development (BOND) project was developed by the nutrition program staff of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) of the NIH within the US Department of Health and Human Services (DHHS). The initial 6 nutrients selected, iodine, vitamin A, iron, zinc, folate, and vitamin B-12, were chosen for their high public health importance. Expert panels on each nutrient were constituted and charged with developing comprehensive reviews for publication in the BOND series. The BOND program received its core funding from the Bill & Melinda Gates Foundation, PepsiCo, the Division of Nutrition Research Coordination (DNRC, NIH), the Office of Dietary Supplements (ODS, NIH), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD, NIH). The Supplement Coordinators for this supplement were Daniel J Raiten (NICHD, NIH) and Janet C King (Children's Hospital Oakland Research Institute and University of California, Davis). Supplement Coordinators disclosures: no conflicts of interest. Publication costs for this supplement were defrayed in part by the payment of page charges. This publication must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact. The opinions expressed in this publication are those of the authors and are not attributable to the sponsors or the publisher, Editor, or Editorial Board of The Journal of Nutrition.; The BOND project was funded in part by the Bill & Melinda Gates Foundation, PepsiCo, the Office of Dietary Supplements (ODS, NIH), the Division of Nutrition Research Coordination (DNRC, NIH), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD, NIH). The Zinc Review was written in response to an invitation from the NICHD of the NIH within the US Department of Health and Human Services (DHHS). NR 293 TC 8 Z9 8 U1 11 U2 16 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 EI 1541-6100 J9 J NUTR JI J. Nutr. PD APR PY 2016 VL 146 IS 4 BP 858S EP 885S DI 10.3945/jn.115.220079 PG 28 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DI3RA UT WOS:000373415000027 ER PT J AU Kumamoto, H Fukano, M Nakano, T Iwagami, K Takeyama, C Kohgo, S Imoto, S Amano, M Kuwata-Higashi, N Aoki, M Abe, H Mitsuya, H Fukuhara, K Haraguchi, K AF Kumamoto, Hiroki Fukano, Misato Nakano, Tomohiko Iwagami, Keito Takeyama, Chiaki Kohgo, Satoru Imoto, Shuhei Amano, Masayuki Kuwata-Higashi, Nobuyo Aoki, Manabu Abe, Hiroshi Mitsuya, Hiroaki Fukuhara, Kiyoshi Haraguchi, Kazuhiro TI Diastereoselective Synthesis of 6 ''-(Z)- and 6 ''-(E)-Fluoro Analogues of Anti-hepatitis B Virus Agent Entecavir and Its Evaluation of the Activity and Toxicity Profile of the Diastereomers SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID POTENTIAL INHIBITORS; REDUCING AGENT; INTERMEDIATE; STANNYLATION; HYDROLASE; OLEFINS; ACCESS; ROUTE AB A method for the diastereoselective synthesis of 6 ''-(Z)- and 6 ''-(E)-fluorinated analogues of the anti-HBV agent entecavir has been developed. Construction of the methylenecyclopentane skeleton of the target molecules has been accomplished by radical-mediated 5-exo-dig cyclization of the selenides 6 and 15 having the phenylsulfanylethynyl structure as a radical accepting moiety. In the radical reaction of the TBS-protected precursor 6, (Z)-anti-12 was formed as a major product. On the other hand, TIPS-protected 15 gave (E)-anti-12. The sulfur-extrusive stannylation of anti-12 furnished a mixture of geometric isomers of the respective vinylstannane, whereas benzoyl-protected 17 underwent the stannylation in the manner of retention of configuration. Following XeF2-mediated fluorination, introduction of the purine base and deoxygenation of the resulting carbocyclic guanosine gave the target (E)- and (Z)-3 after deprotection. Evaluation of the anti-HBV activity of 3 revealed that fluorine-substitution at the 6 ''-position of entecavir gave rise to a reduction in the cytotoxicity in HepG2 cells with retention of the antiviral activity. C1 [Kumamoto, Hiroki; Fukano, Misato; Nakano, Tomohiko; Iwagami, Keito; Takeyama, Chiaki; Fukuhara, Kiyoshi] Showa Univ, Sch Pharm, Shinagawa Ku, 1-5-8 Hatanodai, Tokyo 1428555, Japan. [Haraguchi, Kazuhiro] Nihon Pharmaceut Univ, 10281 Komuro, Ina, Saitama 3620806, Japan. [Kohgo, Satoru] Natl Ctr Global Hlth & Med, Ctr Clin Sci, Shinjuku Ku, 1-21-1 Toyama, Tokyo 1628655, Japan. [Imoto, Shuhei] Sojo Univ, Fac Pharmaceut Sci, 4-22-1 Ikeda, Kumamoto 8600082, Japan. [Amano, Masayuki; Kuwata-Higashi, Nobuyo] Kumamoto Univ, Dept Infect Dis & Hematol, Sch Med, Kumamoto 8608556, Japan. [Aoki, Manabu] Kumamoto Heath Sci Univ, Dept Med Technol, 325 Izumimachi, Kumamoto 8615598, Japan. [Abe, Hiroshi] Nagoya Univ, Grad Sch Sci, Dept Chem, Chikusa Ku, Furo Cho, Nagoya, Aichi 4648602, Japan. [Mitsuya, Hiroaki] NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. RP Kumamoto, H (reprint author), Showa Univ, Sch Pharm, Shinagawa Ku, 1-5-8 Hatanodai, Tokyo 1428555, Japan. EM kumamoto@pharm.showa-u.ac.jp RI Amano, Masayuki/N-7407-2016 OI Amano, Masayuki/0000-0003-0516-9502 FU Japan Society for the Promotion of Science (KAKENHI) [24590144]; Health and Labor Sciences Research Grant [Practical Research on Hepatitis (Research on the innovative development and the practical application of new drugs for hepatitis B)] FX Financial support from the Japan Society for the Promotion of Science (KAKENHI No. 24590144 to K.H.) and a Health and Labor Sciences Research Grant [Practical Research on Hepatitis (Research on the innovative development and the practical application of new drugs for hepatitis B)] is gratefully acknowledged. The authors are also grateful to Miss Y. Odanaka and Mrs.S. Matsubayashi (Center for Instrumental Analysis, Showa University) for technical assistance with NMR, MS, and elemental analyses. NR 29 TC 0 Z9 0 U1 4 U2 9 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 APR 1 PY 2016 VL 81 IS 7 BP 2827 EP 2836 DI 10.1021/acs.joc.6b00105 PG 10 WC Chemistry, Organic SC Chemistry GA DI5DX UT WOS:000373520200015 PM 27009432 ER PT J AU Brochard, S Mozingo, JD Alter, KE Sheehan, FT AF Brochard, Sylvain Mozingo, Joseph D. Alter, Katharine E. Sheehan, Frances T. TI Three dimensionality of gleno-humeral deformities in obstetrical brachial plexus palsy SO JOURNAL OF ORTHOPAEDIC RESEARCH LA English DT Article DE brachial plexus palsy; shoulder; glenoid version; humeral head migration; three dimensional imaging; validation; reliability ID BIRTH PALSY; GLENOHUMERAL DEFORMITY; SHOULDER; CHILDREN; SECONDARY; TOMOGRAPHY; INCLINATION; INJURIES; VERSION; MUSCLE AB The primary objective of this study was to test the hypothesis that gleno-humeral deformity in children and adolescent with obstetrical brachial plexus palsy is three-dimensional (3D). The study also compared the metrological properties of typical two-dimensional gleno-humeral measures to the newly developed 3D measures. Thirteen individuals (age=11.8 +/- 3.3 years) with obstetrical brachial plexus palsy participated in this IRB-approved study. 3D axial magnetic resonance images were acquired for both shoulders. Glenoid and humeral models were created in order to quantify 3D glenoid version, humeral head migration, and glenoid concavity. Two-dimensional (2D) measures were acquired as recommended in the literature. All measures were completed by two observers in this observer-blind study. Compared to the non-involved side, the glenoid was more retroverted (7.91 degrees, p=0.003) and inferiorly oriented (7.28 degrees, p=0.009). The humeral head was migrated more posteriorly (5.54mm, p=0.007), inferiorly (-3.96mm, p=0.013), and medially (-3.63mm,p=0.002). Eleven of the 13 glenoids were concave, based on the 3D glenoid models. The concurrent validity between three- and 2D measures were highly dependent of the parameter measured, the slice level used for the 2D analysis, and the presence/absence of pathology (0.633 degrees) was larger than that for the 3D measure of version (<1 degrees) on the involved side. This study clearly demonstrated that the gleno-humeral deformation in obstetrical brachial plexus palsy is 3D, emphasizing the need for 3D subject specific gleno-humeral shape analysis for follow-up and treatment plans in children with obstetrical brachial plexus palsy. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:675-682, 2016. C1 [Brochard, Sylvain; Mozingo, Joseph D.; Alter, Katharine E.; Sheehan, Frances T.] NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Bldg 10, Bethesda, MD 20892 USA. [Brochard, Sylvain] Univ Hosp, Dept Rehabil Med, Brest, France. [Brochard, Sylvain] INSERM, LaTIM, U1101, Brest, France. [Mozingo, Joseph D.] Mayo Clin, Dept Phys Med & Rehabil, Rochester, MN 55905 USA. [Alter, Katharine E.] Mt Washington Pediat Hosp, Baltimore, MD USA. RP Sheehan, FT (reprint author), NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Bldg 10, Bethesda, MD 20892 USA. EM gavellif@cc.nih.gov FU University Hospital of Brest; French Society of Physical Medicine and Rehabilitation (SOFMER); French Society of Research in Children with Disabilities (SFERHE); National Institutes of Health Clinical Center, Bethesda, MD, USA FX Grant sponsor: University Hospital of Brest; Grant sponsor: French Society of Physical Medicine and Rehabilitation (SOFMER); Grant sponsor: French Society of Research in Children with Disabilities (SFERHE); Grant sponsor: Intramural Research Program of the National Institutes of Health Clinical Center, Bethesda, MD, USA. NR 38 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0736-0266 EI 1554-527X J9 J ORTHOP RES JI J. Orthop. Res. PD APR PY 2016 VL 34 IS 4 BP 675 EP 682 DI 10.1002/jor.23049 PG 8 WC Orthopedics SC Orthopedics GA DI4ST UT WOS:000373490300016 PM 26363273 ER PT J AU Cantor, F Skala, J Heiss, J AF Cantor, F. Skala, J. Heiss, J. TI Pain characteristics before and after Chiari-1 surgery SO JOURNAL OF PAIN LA English DT Meeting Abstract C1 [Cantor, F.; Skala, J.; Heiss, J.] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD APR PY 2016 VL 17 IS 4 SU 1 MA 199 BP S25 EP S25 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DI5EZ UT WOS:000373523000101 PM 28162424 ER PT J AU Cantor, F Skala, J Wu, T AF Cantor, F. Skala, J. Wu, T. TI Interrelations between pain qualities, severity and disability SO JOURNAL OF PAIN LA English DT Meeting Abstract C1 [Cantor, F.; Skala, J.; Wu, T.] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD APR PY 2016 VL 17 IS 4 SU 1 MA 204 BP S26 EP S27 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DI5EZ UT WOS:000373523000106 PM 28162431 ER PT J AU Thompson, S Pitcher, M Tarum, F Niu, G Chen, X Kiesewetter, D Schweinhardt, P Bushnell, M AF Thompson, S. Pitcher, M. Tarum, F. Niu, G. Chen, X. Kiesewetter, D. Schweinhardt, P. Bushnell, M. TI Decreased opioid receptor availability in rat brain three months after peripheral nerve injury SO JOURNAL OF PAIN LA English DT Meeting Abstract C1 [Thompson, S.; Pitcher, M.; Tarum, F.; Niu, G.; Chen, X.; Kiesewetter, D.; Schweinhardt, P.; Bushnell, M.] NIH, Div Intramural Res, Natl Ctr Complementary & Integrat Hlth, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD APR PY 2016 VL 17 IS 4 SU 1 MA 335 BP S59 EP S59 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DI5EZ UT WOS:000373523000235 PM 28162573 ER PT J AU Luo, P Yu, HY Zhao, XJ Bao, YQ Hong, CS Zhang, P Tu, YF Yin, PY Gao, P Wei, L Zhuang, ZP Jia, WP Xu, GW AF Luo, Ping Yu, Haoyong Zhao, Xinjie Bao, Yuqian Hong, Christopher S. Zhang, Pin Tu, Yinfang Yin, Peiyuan Gao, Peng Wei, Li Zhuang, Zhengping Jia, Weiping Xu, Guowang TI Metabolomics Study of Roux-en-Y Gastric Bypass Surgery (RYGB) to Treat Type 2 Diabetes Patients Based on Ultraperformance Liquid Chromatography-Mass Spectrometry SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE metabolomics; metabolic profiling; Roux-en-Y gastric bypass; RYGB; diabetes ID STEAROYL-COA DESATURASE; CHAIN AMINO-ACIDS; INSULIN-RESISTANCE; BARIATRIC SURGERY; SKELETAL-MUSCLE; SERUM METABOLOMICS; BETA-OXIDATION; OBESE-PATIENTS; BILE-ACIDS; INFLAMMATION AB Roux-en-Y gastric bypass (RYGB) is one of the most effective treatments for long-term weight loss and diabetes remission; however, the mechanisms underlying these changes are not clearly understood. In this study, the serum metabolic profiles of 23 remission and 12 nonremission patients with type 2 diabetes mellitus (T2DM) were measured at baseline, 6- and 12-months after RYGB. A metabolomics analysis was performed based on ultra-performance liquid chromatography mass spectrometry. Clinical improvements in insulin sensitivity, energy metabolism, and inflammation were related to metabolic alterations of free fatty acids (FFAs), acylcarnitines, amino acids, bile acids, and lipids species. Differential metabolic profiles were observed between the two T2DM subgroups, and patients with severity fat accumulation and oxidation stress may be more suitable for RYGB. Baseline levels of tryptophan, bilirubin, and indoxyl sulfate measured prior to surgery as well as levels of FFA 16:0, FFA 18:3, FFA 17:2, and hippuric acid measured at 6 months after surgery best predicted the suitability and efficacy of RYGB for patients with T2DM. These metabolites represent potential biomarkers that may be clinically helpful in individualized treatment for T2DM patients by RYGB. C1 [Luo, Ping; Zhao, Xinjie; Yin, Peiyuan; Gao, Peng; Xu, Guowang] Chinese Acad Sci, Dalian Inst Chem Phys, Key Lab Separat Sci Analyt Chem, 457 Zhongshan Rd, Dalian 116023, Peoples R China. [Yu, Haoyong; Bao, Yuqian; Tu, Yinfang; Wei, Li; Jia, Weiping] Shanghai Jiao Tong Univ, Affiliated Peoples Hosp 6, Shanghai Key Lab Diabet Mellitus,Shanghai Diabet, Dept Endocrinol & Metab,Shanghai Clin Ctr Diabet, Yishan Rd 600, Shanghai 200233, Peoples R China. [Hong, Christopher S.; Zhuang, Zhengping] NINDS, NIH, Surg Neurol Branch, Bethesda, MD 20892 USA. [Zhang, Pin] Shanghai Jiao Tong Univ, Affiliated Peoples Hosp 6, Dept Gen Surg, Yishan Rd, Shanghai 200233, Peoples R China. RP Xu, GW (reprint author), Chinese Acad Sci, Dalian Inst Chem Phys, Key Lab Separat Sci Analyt Chem, 457 Zhongshan Rd, Dalian 116023, Peoples R China.; Jia, WP (reprint author), Shanghai Jiao Tong Univ, Affiliated Peoples Hosp 6, Shanghai Key Lab Diabet Mellitus,Shanghai Diabet, Dept Endocrinol & Metab,Shanghai Clin Ctr Diabet, Yishan Rd 600, Shanghai 200233, Peoples R China. EM wpjia@sjtu.edu.cn; xugw@dicp.ac.cn NR 58 TC 3 Z9 3 U1 11 U2 32 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 EI 1535-3907 J9 J PROTEOME RES JI J. Proteome Res. PD APR PY 2016 VL 15 IS 4 BP 1288 EP 1299 DI 10.1021/acs.jproteome.6b00022 PG 12 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA DI5DU UT WOS:000373519900018 PM 26889720 ER PT J AU Korada, SKC Zhao, D Gottesman, RF Guallar, E Lutsey, PL Alonso, A Sharrett, AR Post, WS Reis, JP Mosley, TH Michos, ED AF Korada, Sai Krishna C. Zhao, Di Gottesman, Rebecca F. Guallar, Eliseo Lutsey, Pamela L. Alonso, Alvaro Sharrett, A. Richey Post, Wendy S. Reis, Jared P. Mosley, Thomas H. Michos, Erin D. TI Parathyroid Hormone and Subclinical Cerebrovascular Disease: The Atherosclerosis Risk in Communities Brain Magnetic Resonance Imaging Study SO JOURNAL OF STROKE & CEREBROVASCULAR DISEASES LA English DT Article DE Parathyroid hormone; cerebrovascular disease; brain MRI; white matter hyperintensities; subclinical brain infarcts ID CARDIOVASCULAR HEALTH; VITAMIN-D; 25-HYDROXYVITAMIN D; OLDER-ADULTS; MORTALITY; EVENTS AB Background: Elevated parathyroid hormone (PTH) levels have been associated with cardiovascular disease risk factors and events. We hypothesized that elevated PTH levels would also be associated with subclinical cerebrovascular disease. We examined the relationship between elevated PTH level and white matter hyperintensities (WMHs) and subclinical infarcts measured on brain magnetic resonance imaging (MRI). Methods: PTH was measured at baseline (1993-1994) among participants free of prior clinical stroke who underwent a brain MRI at baseline (n = 1703) and a second brain MRI 10 years later (n = 948). PTH levels of 65 pg/mL or higher were considered elevated (n = 204). Participants who did not return for a follow-up MRI had, at baseline, higher PTH and a greater prevalence of cardiovascular risk factors (P < .05 for all); therefore, multiple imputation was used. The cross-sectional and prospective associations of PTH levels with WMH and MRI-defined infarcts (and their progression) were investigated using multivariable regression models. Results: At baseline, the participants had a mean age of 62 years and were 60% female and 49% black. Cross-sectionally, after adjusting for demographic and lifestyle factors, elevated PTH level was associated with higher WMH score (beta = .19, 95% confidence interval [CI] .04-.35) and increased odds of prevalent infarcts (odds ratio 1.56, 95% CI 1.02-2.36). Results were attenuated after adjustment for potential mediators of this association (i.e., hypertension). No prospective associations were found between PTH and incident infarcts or change in estimated WMH volume, although estimates were imprecise. Conclusions: Although associated cross-sectionally, we did not confirm any association between elevated PTH level and progression of cerebrovascular changes on brain MRIs obtained 10 years apart. The relationship of PTH with subclinical brain disease warrants further study. C1 [Korada, Sai Krishna C.] Northeast Ohio Med Univ, Rootstown, OH USA. [Zhao, Di; Gottesman, Rebecca F.; Guallar, Eliseo; Sharrett, A. Richey; Post, Wendy S.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Gottesman, Rebecca F.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Lutsey, Pamela L.; Alonso, Alvaro] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community, St Paul, MN 55108 USA. [Post, Wendy S.; Michos, Erin D.] Johns Hopkins Sch Med, Div Cardiol, Baltimore, MD USA. [Reis, Jared P.] NHLBI, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA. [Mosley, Thomas H.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. RP Michos, ED (reprint author), Johns Hopkins Univ, Sch Med, Div Cardiol, Ciccarone Ctr Prevent Heart Dis, Baltimore, MD 21287 USA. EM edonnell@jhmi.edu RI Alonso, Alvaro/A-4917-2010 OI Alonso, Alvaro/0000-0002-2225-8323 FU National Institutes of Health/National Institute of Neurological Disorders and Stroke [R01NS072243]; National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C]; [R01-HL70825] FX This work was supported by National Institutes of Health/National Institute of Neurological Disorders and Stroke grant R01NS072243. The Atherosclerosis Risk in Communities (ARIC) Brain Magnetic Resonance Imaging study was supported by grant R01-HL70825. 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). NR 25 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1052-3057 EI 1532-8511 J9 J STROKE CEREBROVASC JI J. Stroke Cerebrovasc. Dis. PD APR PY 2016 VL 25 IS 4 BP 883 EP 893 DI 10.1016/j.jstrokecerebrovasdis.2015.12.029 PG 11 WC Neurosciences; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA DI7ZJ UT WOS:000373720200028 PM 26825350 ER PT J AU Gupta, S Aitken, JF Bartels, U Brierley, J Dolendo, M Friedrich, P Fuentes-Alabi, S Garrido, CP Gatta, G Gospodarowicz, M Gross, T Howard, SC Molyneux, E Moreno, F Pole, JD Pritchard-Jones, K Ramirez, O Ries, LAG Rodriguez-Galindo, C Shin, HY Steliarova-Foucher, E Sung, LL Supriyadi, E Swaminathan, R Torode, J Vora, T Kutluk, T Frazier, AL AF Gupta, Sumit Aitken, Joanne F. Bartels, Ute Brierley, James Dolendo, Mae Friedrich, Paola Fuentes-Alabi, Soad Garrido, Claudia P. Gatta, Gemma Gospodarowicz, Mary Gross, Thomas Howard, Scott C. Molyneux, Elizabeth Moreno, Florencia Pole, Jason D. Pritchard-Jones, Kathy Ramirez, Oscar Ries, Lynn A. G. Rodriguez-Galindo, Carlos Shin, Hee Young Steliarova-Foucher, Eva Sung, Lillian Supriyadi, Eddy Swaminathan, Rajaraman Torode, Julie Vora, Tushar Kutluk, Tezer Frazier, A. Lindsay TI Paediatric cancer stage in population-based cancer registries: the Toronto consensus principles and guidelines SO LANCET ONCOLOGY LA English DT Review ID NON-HODGKIN-LYMPHOMA; CHILDHOOD-CANCER; CLASSIFICATION; CHILDREN; SYSTEM; SURVIVAL; LEUKEMIA; EUROPE; MEDULLOBLASTOMA; RECOMMENDATIONS AB Population-based cancer registries generate estimates of incidence and survival that are essential for cancer surveillance, research, and control strategies. Although data on cancer stage allow meaningful assessments of changes in cancer incidence and outcomes, stage is not recorded by most population-based cancer registries. The main method of staging adult cancers is the TNM classification. The criteria for staging paediatric cancers, however, vary by diagnosis, have evolved over time, and sometimes vary by cooperative trial group. Consistency in the collection of staging data has therefore been challenging for population-based cancer registries. We assembled key experts and stakeholders (oncologists, cancer registrars, epidemiologists) and used a modified Delphi approach to establish principles for paediatric cancer stage collection. In this Review, we make recommendations on which staging systems should be adopted by population-based cancer registries for the major childhood cancers, including adaptations for low-income countries. Wide adoption of these guidelines in registries will ease international comparative incidence and outcome studies. C1 [Gupta, Sumit; Bartels, Ute; Sung, Lillian] Hosp Sick Children, Div Hematol & Oncol, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. [Gupta, Sumit; Bartels, Ute; Sung, Lillian] Univ Toronto, Fac Med, Dept Paediat, Toronto, ON, Canada. [Aitken, Joanne F.] Fortitude Valley, Canc Council Queensland, Brisbane, Qld, Australia. [Brierley, James; Gospodarowicz, Mary] Princess Margaret Hosp, Dept Radiat Oncol, Toronto, ON M4X 1K9, Canada. [Dolendo, Mae] Southern Philippines Med Ctr, Bajada, Davao City, Philippines. [Friedrich, Paola; Rodriguez-Galindo, Carlos; Frazier, A. Lindsay] Dana Farber Boston Childrens Canc & Blood Disorde, Boston, MA USA. [Fuentes-Alabi, Soad] Hosp Nacl Ninos Benjamin Bloom, San Salvador, El Salvador. [Garrido, Claudia P.] Unidad Nacl Oncol Pediat, Guatemala City, Guatemala. [Gatta, Gemma] Fondazione IRCSS Inst Nazl Tumori, Evaluat Epidemiol Unit, Milan, Italy. [Gross, Thomas] Natl Canc Inst, Ctr Global Hlth, Bethesda, MD USA. [Howard, Scott C.] Univ Memphis, Memphis, TN 38152 USA. [Molyneux, Elizabeth] Coll Med, Blantyre, Malawi. [Moreno, Florencia] Natl Canc Inst, Argentinian Oncopediatr Registry ROHA, Buenos Aires, DF, Argentina. [Pole, Jason D.] Pediat Oncol Grp Ontario, Toronto, ON, Canada. [Pritchard-Jones, Kathy] UCL, Inst Child Hlth, Mortimer St, London, England. [Ramirez, Oscar] Univ Valle Oficina, Registro Poblac Canc Cali, Cali, Colombia. [Ries, Lynn A. G.] Natl Canc Inst, SEER Program, Bethesda, MD USA. [Shin, Hee Young] Seoul Natl Univ, Coll Med, Canc Res Inst, Dept Pediat, Seoul, South Korea. [Steliarova-Foucher, Eva] Int Agcy Res Canc, Sect Canc Surveillance, Lyon, France. [Supriyadi, Eddy] Gadjah Mada Univ, Sardjito Hosp, Dept Pediat, Div Pediat Hematol Oncol, Yogyakarta, Indonesia. [Swaminathan, Rajaraman] Epidemiol Biostat & Canc Registry Canc Inst, Chennai, Tamil Nadu, India. [Torode, Julie; Kutluk, Tezer] Union Int Canc Control, Geneva, Switzerland. [Vora, Tushar] Tata Mem Hosp Parel, Mumbai, Maharashtra, India. RP Gupta, S (reprint author), Hosp Sick Children, Div Hematol & Oncol, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. EM sumit.gupta@sickkids.ca FU Center for Global Health of the National Cancer Institute; Hospital for Sick Children FX The face-to-face meeting held for all panellists in Toronto, Canada on Oct 19, 2014, was supported by the Center for Global Health of the National Cancer Institute. In-kind funding and support was provided by the Hospital for Sick Children. Funding sources had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit for publication. We acknowledge the insights provided by Andrew Hallahan, Adele Green, Peter Baade, Danny Youlden, Patricia Valery, and Leisa Ward. We acknowledge the help of Rosanna Yankanah and Tiff any Jiminez, and the encouragement of James Whitlock. NR 49 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 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD APR PY 2016 VL 17 IS 4 BP E163 EP E172 PG 10 WC Oncology SC Oncology GA DI4VN UT WOS:000373497600027 PM 27300676 ER PT J AU Young, LH Periwal, V AF Young, LeAnne H. Periwal, Vipul TI Metabolic scaling predicts posthepatectomy liver regeneration after accounting for hepatocyte hypertrophy SO LIVER TRANSPLANTATION LA English DT Article ID PARTIAL-HEPATECTOMY; TRANSPLANTATION; DONORS; ADULT; MECHANISM; MODEL AB We adapted a mathematical model of posthepatectomy liver regeneration using data from a subset of patients in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study. The original model addressed changes in the number of quiescent, primed, and proliferating cells. Our adapted model takes into account hypertrophy of primed and replicating cells, and it is better able to predict liver volume. In addition, by building off the hypothesis that cell cycle parameters are approximately the same across all mammals, we found that changing only a single parameter characterizing metabolic load could model liver regeneration in 5 species of mammals. In conclusion, we improved a mathematical model of liver regeneration, predicted mammalian liver regeneration based on metabolism, and found correlations between model parameters and physiological measurements from liver donors. C1 [Young, LeAnne H.; Periwal, Vipul] NIDDKD, Lab Biol Modeling, NIH, Dept Hlth & Human Serv, Bldg 12A,Room 4007 MSC 5621,12 South Dr, Bethesda, MD 20892 USA. RP Periwal, V (reprint author), NIDDKD, Lab Biol Modeling, NIH, Dept Hlth & Human Serv, Bldg 12A,Room 4007 MSC 5621,12 South Dr, Bethesda, MD 20892 USA. EM vipulp@niddk.nih.gov FU National Institutes of Health, NIDDK FX Data from the A2ALL study was the basis of the analysis in this article. This research was supported by the Intramural Research Program of the National Institutes of Health, NIDDK. NR 26 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1527-6465 EI 1527-6473 J9 LIVER TRANSPLANT JI Liver Transplant. PD APR PY 2016 VL 22 IS 4 BP 476 EP 484 DI 10.1002/lt.24392 PG 9 WC Gastroenterology & Hepatology; Surgery; Transplantation SC Gastroenterology & Hepatology; Surgery; Transplantation GA DI5UU UT WOS:000373566800011 PM 26709233 ER PT J AU Yin, CL Chen, HI Li, LH Chien, YL Liao, HM Chou, MC Chou, WJ Tsai, WC Chiu, YN Wu, YY Lo, CZ Wu, JY Chen, YT Gau, SSF AF Yin, Chia-Lin Chen, Hsin-I Li, Ling-Hui Chien, Yi-Ling Liao, Hsiao-Mei Chou, Miao Chun Chou, Wen-Jiun Tsai, Wen-Che Chiu, Yen-Nan Wu, Yu-Yu Lo, Chen-Zen Wu, Jer-Yuarn Chen, Yuan-Tsong Gau, Susan Shur-Fen TI Genome-wide analysis of copy number variations identifies PARK2 as a candidate gene for autism spectrum disorder SO MOLECULAR AUTISM LA English DT Article DE PARK2; Autism spectrum disorder (ASD); Copy number variations (CNVs); Family study; Gene expression ID RECESSIVE JUVENILE PARKINSONISM; MUTATIONS; DISEASE; ASSOCIATION; PROTEIN; TAIWAN; REGION; DOMAIN; CNVS; CELL AB Background: Autism spectrum disorder (ASD) is an early-onset neurodevelopmental disorder with complex genetic underpinning in its etiology. Copy number variations (CNVs) as one of the genetic factors associated with ASD have been addressed in recent genome-wide association studies (GWAS). However, the significance of CNV has not been well investigated in non-Caucasian ASD population. Methods: To identify the pathogenic CNVs responsible for ASD in Han Chinese, we performed a segment-based GWAS of CNV in 335 ASD cases and 1093 healthy controls using Affymetrix single nucleotide polymorphism (SNP) array by focusing on case-specific CNVs. PARK2 was one of the important genes with several case-specific regions overlapped on it. The findings were validated in the initial screen sample set and replicated in another sample set by real-time quantitative PCR (qPCR). Results: A total of six CNVs at 6q26 that spanned different exons of PARK2 were identified. The PARK2 expression level was down-regulated at exon-dependent manner in cases with either deletion or duplication. The result revealed that the gene function might be disrupted by exonic deletion and duplication. We also observed that the ASD case with exonic duplication demonstrated a more severe interference of PARK2 expression and the clinical feature than the ones with deletion at the exons 2-4 of the PARK2 gene. Conclusions: Our finding provides evidence to support that CNVs affecting PARK2 function might contribute to genetic etiology of a proportion of cases with ASD. The intriguing results of this work warrant further study on characterizing the functional impact of various exonic CNVs on the PARK2 gene. C1 [Yin, Chia-Lin; Chen, Hsin-I; Chien, Yi-Ling; Liao, Hsiao-Mei; Tsai, Wen-Che; Chiu, Yen-Nan; Gau, Susan Shur-Fen] Natl Taiwan Univ Hosp & Coll Med, Dept Psychiat, 7 Chung Shan South Rd, Taipei 10002, Taiwan. [Yin, Chia-Lin] Natl Yang Ming Univ, Grad Inst Brain Sci, Taipei 11221, Taiwan. [Li, Ling-Hui; Lo, Chen-Zen; Wu, Jer-Yuarn; Chen, Yuan-Tsong] Acad Sinica, Inst Biomed Sci, Taipei 11529, Taiwan. [Liao, Hsiao-Mei] NIMH, Sect Mol Neurobiol, NIH, Bethesda, MD 20892 USA. [Chou, Miao Chun; Chou, Wen-Jiun] Chang Gung Univ, Coll Med, Chang Gung Mem Hosp, Dept Child Psychiat,Kaohsiung Med Ctr, Kaohsiung 83301, Taiwan. [Wu, Yu-Yu] Chang Gung Univ, Chang Gung Mem Hosp, Dept Child Psychiat, Coll Med, Taoyuan 33302, Taiwan. RP Gau, SSF (reprint author), Natl Taiwan Univ Hosp & Coll Med, Dept Psychiat, 7 Chung Shan South Rd, Taipei 10002, Taiwan. EM gaushufe@ntu.edu.tw OI CHIEN, YI-LING/0000-0002-3477-3015 FU National Science Council [NSC96-3112-B-002-033, NSC97-3112-B-002-009, NSC98-3112-B-002-004, NSC 99-3112-B-002-036]; Ministry of Science and Technology, Taiwan [MOST 103-2314-B-002-055-MY3]; National Taiwan University (AIM for Top University Excellent Research Project) [101R892103, 102R892103, 103R892103]; National Taiwan University Hospital [NTUH104-N2933] FX This work was supported by grants from the National Science Council (NSC96-3112-B-002-033, NSC97-3112-B-002-009, NSC98-3112-B-002-004, and NSC 99-3112-B-002-036), the Ministry of Science and Technology, Taiwan (MOST 103-2314-B-002-055-MY3), National Taiwan University (AIM for Top University Excellent Research Project: 101R892103, 102R892103, 103R892103), and National Taiwan University Hospital (NTUH104-N2933). NR 36 TC 3 Z9 3 U1 2 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2040-2392 J9 MOL AUTISM JI Mol. Autism PD APR 1 PY 2016 VL 7 AR 23 DI 10.1186/s13229-016-0087-7 PG 13 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA DI7JJ UT WOS:000373675200001 PM 27042285 ER PT J AU Gahl, WA Mulvihill, JJ Toro, C Markello, TC Wise, AL Ramoni, RB Adams, DR Tifft, CJ AF Gahl, William A. Mulvihill, John J. Toro, Camilo Markello, Thomas C. Wise, Anastasia L. Ramoni, Rachel B. Adams, David R. Tifft, Cynthia J. CA UDN TI The NIH Undiagnosed Diseases Program and Network: Applications to modern medicine SO MOLECULAR GENETICS AND METABOLISM LA English DT Article ID INSTITUTES-OF-HEALTH; AUTOSOMAL-DOMINANT LEUKODYSTROPHY; ONSET EPILEPTIC ENCEPHALOPATHY; MITOCHONDRIAL DISEASE; PRECISION MEDICINE; FUNCTION MUTATIONS; RARE DISEASES; GLYCOSYLATION; DEFICIENCY; DISORDER AB Introduction: The inability of some seriously and chronically ill individuals to receive a definitive diagnosis represents an unmet medical need. In 2008, the NIH Undiagnosed Diseases Program (UDP) was established to provide answers to patients with mysterious conditions that long eluded diagnosis and to advance medical knowledge. Patients admitted to the NIH UDP undergo a five-day hospitalization, facilitating highly collaborative clinical evaluations and a detailed, standardized documentation of the individual's phenotype. Bedside and bench investigations are tightly coupled. Genetic studies include commercially available testing, single nucleotide polymorphism microarray analysis, and family exomic sequencing studies. Selected gene variants are evaluated by collaborators using informatics, in vitro cell studies, and functional assays in model systems (fly, zebrafish, worm, or mouse). Insights from the UDP: In seven years, the UDP received 2954 complete applications and evaluated 863 individuals. Nine vignettes (two unpublished) illustrate the relevance of an undiagnosed diseases program to complex and common disorders, the coincidence of multiple rare single gene disorders in individual patients, newly recognized mechanisms of disease, and the application of precision medicine to patient care. Conclusions: The UDP provides examples of the benefits expected to accrue with the recent launch of a national Undiagnosed Diseases Network (UDN). The UDN should accelerate rare disease diagnosis and new disease discovery, enhance the likelihood of diagnosing known diseases in patients with uncommon phenotypes, improve management strategies, and advance medical research. Published by Elsevier Inc. C1 [Gahl, William A.; Mulvihill, John J.; Toro, Camilo; Markello, Thomas C.; Wise, Anastasia L.; Adams, David R.; Tifft, Cynthia J.] Off Director, Common Fund, NIH Undiagnosed Dis Network, Bethesda, MD 20892 USA. [Gahl, William A.; Mulvihill, John J.; Toro, Camilo; Markello, Thomas C.; Wise, Anastasia L.; Adams, David R.; Tifft, Cynthia J.] NHGRI, NIH, Bethesda, MD 20892 USA. [Mulvihill, John J.] Univ Oklahoma, Dept Pediat, Oklahoma City, OK USA. [Ramoni, Rachel B.] Harvard Univ, Sch Med, Dept Oral Hlth Policy & Epidemiol, Dept Biomed Informat,Dent Sch, Cambridge, MA 02138 USA. RP Mulvihill, JJ (reprint author), NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. EM John.Mulvihill@nih.gov FU Intramural NIH HHS NR 61 TC 7 Z9 7 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD APR PY 2016 VL 117 IS 4 BP 393 EP 400 DI 10.1016/j.ymgme.2016.01.007 PG 8 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA DJ0AW UT WOS:000373864800001 PM 26846157 ER PT J AU De Ravin, SS Reik, A Liu, PQ Li, LH Wu, XL Su, L Raley, C Theobald, N Choi, U Song, AH Chan, A Pearl, JR Paschon, DE Lee, J Newcombe, H Koontz, S Sweeney, C Shivak, DA Zarember, KA Peshwa, MV Gregory, PD Urnov, FD Malech, HL AF De Ravin, Suk See Reik, Andreas Liu, Pei-Qi Li, Linhong Wu, Xiaolin Su, Ling Raley, Castle Theobald, Narda Choi, Uimook Song, Alexander H. Chan, Andy Pearl, Jocelynn R. Paschon, David E. Lee, Janet Newcombe, Hannah Koontz, Sherry Sweeney, Colin Shivak, David A. Zarember, Kol A. Peshwa, Madhusudan V. Gregory, Philip D. Urnov, Fyodor D. Malech, Harry L. TI Targeted gene addition in human CD34(+) hematopoietic cells for correction of X-linked chronic granulomatous disease SO NATURE BIOTECHNOLOGY LA English DT Article ID SEVERE COMBINED IMMUNODEFICIENCY; ZINC-FINGER NUCLEASES; REGULATORY DNA; HUMAN GENOME; STEM-CELLS; THERAPY; EXPRESSION; VECTORS; OXIDASE AB Gene therapy with genetically modified human CD34(+) hematopoietic stem and progenitor cells (HSPCs) may be safer using targeted integration (TI) of transgenes into a genomic 'safe harbor' site rather than random viral integration. We demonstrate that temporally optimized delivery of zinc finger nuclease mRNA via electroporation and adeno-associated virus (AAV) 6 delivery of donor constructs in human HSPCs approaches clinically relevant levels of TI into the AAVS1 safe harbor locus. Up to 58% Venus(+) HSPCs with 6-16% human cell marking were observed following engraftment into mice. In HSPCs from patients with X-linked chronic granulomatous disease (X-CGD), caused by mutations in the gp91phox subunit of the NADPH oxidase, TI of a gp91phox transgene into AAVS1 resulted in similar to 15% gp91phox expression and increased NADPH oxidase activity in ex vivo-derived neutrophils. In mice transplanted with corrected HSPCs, 4-11% of human cells in the bone marrow expressed gp91phox. This method for TI into AAVS1 may be broadly applicable to correction of other monogenic diseases. C1 [De Ravin, Suk See; Theobald, Narda; Choi, Uimook; Lee, Janet; Newcombe, Hannah; Koontz, Sherry; Sweeney, Colin; Zarember, Kol A.; Malech, Harry L.] NIAID, Host Def Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Reik, Andreas; Liu, Pei-Qi; Song, Alexander H.; Chan, Andy; Pearl, Jocelynn R.; Paschon, David E.; Shivak, David A.; Gregory, Philip D.; Urnov, Fyodor D.] Sangamo BioSci Inc, Richmond, CA USA. [Li, Linhong] MaxCyte Inc, Gaithersburg, MD USA. [Wu, Xiaolin; Su, Ling; Raley, Castle; Peshwa, Madhusudan V.] Leidos Biomed Res Inc, Canc Res Technol Program, Frederick, MD USA. [Gregory, Philip D.] Blubird Bio, Cambridge, MA USA. RP Malech, HL (reprint author), NIAID, Host Def Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM hmalech@nih.gov FU intramural program of National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health [1 ZIA AI000644] FX These studies were supported in part by project 1 ZIA AI000644 of the intramural program of National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health. Human CD34+ HSPCs were obtained under NIAID IRB approved Protocol 94-I-0073 after written informed consent. Murine animal studies were performed under National Institutes of Allergy and Infectious Diseases (NIAID) Animal Care and Use Committee approved protocol Laboratory of Host Defenses (LHD) 3E. NR 24 TC 12 Z9 12 U1 4 U2 11 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 EI 1546-1696 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD APR PY 2016 VL 34 IS 4 BP 424 EP + DI 10.1038/nbt.3513 PG 8 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA DI6NL UT WOS:000373616100024 PM 26950749 ER PT J AU Fan, Q Verhoeven, VJM Wojciechowski, R Barathi, VA Hysi, PG Guggenheim, JA Hohn, R Vitart, V Khawaja, AP Yamashiro, K Hosseini, SM Lehtimaki, T Lu, Y Haller, T Xie, J Delcourt, C Pirastu, M Wedenoja, J Gharahkhani, P Venturini, C Miyake, M Hewitt, AW Guo, XB Mazur, J Huffman, JE Williams, KM Polasek, O Campbell, H Rudan, I Vatavuk, Z Wilson, JF Joshi, PK McMahon, G St Pourcain, B Evans, DM Simpson, CL Schwantes-An, TH Igo, RP Mirshahi, A Cougnard-Gregoire, A Bellenguez, C Blettner, M Raitakari, O Kaehoenen, M Seppala, I Zeller, T Meitinger, T Ried, JS Gieger, C Portas, L van Leeuwen, EM Amin, N Uitterlinden, AG Rivadeneira, F Hofman, A Vingerling, JR Wang, YX Wang, X Boh, ETH Ikram, MK Sabanayagam, C Gupta, P Tan, V Zhou, L Ho, CEH Lim, W Beuerman, RW Siantar, R Tai, ES Vithana, E Mihailov, E Khor, CC Hayward, C Luben, RN Foster, PJ Klein, BEK Klein, R Wong, HS Mitchell, P Metspalu, A Aung, T Young, TL He, MG Paerssinen, O van Duijn, CM Wang, JJ Williams, C Jonas, JB Teo, YY David, AMM Oexle, K Yoshimura, N Paterson, AD Pfeiffer, N Wong, TY Baird, PN Stambolian, D Bailey-Wilson, JE Cheng, CY Hammond, CJ Klaver, CCW Saw, SM Rahi, JS Korobelnik, JF Kemp, JP Timpson, NJ Smith, GD Craig, JE Burdon, KP Fogarty, RD Iyengar, SK Chew, E Janmahasatian, S Martin, NG MacGregor, S Xu, L Schache, M Nangia, V Panda-Jonas, S Wright, AF Fondran, JR Lass, JH Feng, S Zhao, JH Khaw, KT Wareham, NJ Rantanen, T Kaprio, J Pang, CP Chen, LJ Tam, PO Jhanji, V Young, AL Doering, A Raffel, LJ Cotch, MF Li, XH Yip, SP Yap, MKH Biino, G Vaccargiu, S Fossarello, M Fleck, B Yazar, S Tideman, JWL Tedja, M Deangelis, MM Morrison, M Farrer, L Zhou, XT Chen, W Mizuki, N Meguro, A Makela, KM AF Fan, Qiao Verhoeven, Virginie J. M. Wojciechowski, Robert Barathi, Veluchamy A. Hysi, Pirro G. Guggenheim, Jeremy A. Hoehn, Rene Vitart, Veronique Khawaja, Anthony P. Yamashiro, Kenji Hosseini, S. Mohsen Lehtimaki, Terho Lu, Yi Haller, Toomas Xie, Jing Delcourt, Cecile Pirastu, Mario Wedenoja, Juho Gharahkhani, Puya Venturini, Cristina Miyake, Masahiro Hewitt, Alex W. Guo, Xiaobo Mazur, Johanna Huffman, Jenifer E. Williams, Katie M. Polasek, Ozren Campbell, Harry Rudan, Igor Vatavuk, Zoran Wilson, James F. Joshi, Peter K. McMahon, George St Pourcain, Beate Evans, David M. Simpson, Claire L. Schwantes-An, Tae-Hwi Igo, Robert P. Mirshahi, Alireza Cougnard-Gregoire, Audrey Bellenguez, Celine Blettner, Maria Raitakari, Olli Kaehoenen, Mika Seppala, Ilkka Zeller, Tanja Meitinger, Thomas Ried, Janina S. Gieger, Christian Portas, Laura van Leeuwen, Elisabeth M. Amin, Najaf Uitterlinden, Andre G. Rivadeneira, Fernando Hofman, Albert Vingerling, Johannes R. Wang, Ya Xing Wang, Xu Boh, Eileen Tai-Hui Ikram, M. Kamran Sabanayagam, Charumathi Gupta, Preeti Tan, Vincent Zhou, Lei Ho, Candice E. H. Lim, Wan'e Beuerman, Roger W. Siantar, Rosalynn Tai, E-Shyong Vithana, Eranga Mihailov, Evelin Khor, Chiea-Chuen Hayward, Caroline Luben, Robert N. Foster, Paul J. Klein, Barbara E. K. Klein, Ronald Wong, Hoi-Suen Mitchell, Paul Metspalu, Andres Aung, Tin Young, Terri L. He, Mingguang Paerssinen, Olavi van Duijn, Cornelia M. Wang, Jie Jin Williams, Cathy Jonas, Jost B. Teo, Yik-Ying David, A. Mackey M. Oexle, Konrad Yoshimura, Nagahisa Paterson, Andrew D. Pfeiffer, Norbert Wong, Tien-Yin Baird, Paul N. Stambolian, Dwight Bailey-Wilson, Joan E. Cheng, Ching-Yu Hammond, Christopher J. Klaver, Caroline C. W. Saw, Seang-Mei Rahi, Jugnoo S. Korobelnik, Jean-Francois Kemp, John P. Timpson, Nicholas J. Smith, George Davey Craig, Jamie E. Burdon, Kathryn P. Fogarty, Rhys D. Iyengar, Sudha K. Chew, Emily Janmahasatian, Sarayut Martin, Nicholas G. MacGregor, Stuart Xu, Liang Schache, Maria Nangia, Vinay Panda-Jonas, Songhomitra Wright, Alan F. Fondran, Jeremy R. Lass, Jonathan H. Feng, Sheng Zhao, Jing Hua Khaw, Kay-Tee Wareham, Nick J. Rantanen, Taina Kaprio, Jaakko Pang, Chi Pui Chen, Li Jia Tam, Pancy O. Jhanji, Vishal Young, Alvin L. Doering, Angela Raffel, Leslie J. Cotch, Mary-Frances Li, Xiaohui Yip, Shea Ping Yap, Maurice K. H. Biino, Ginevra Vaccargiu, Simona Fossarello, Maurizio Fleck, Brian Yazar, Seyhan Tideman, Jan Willem L. Tedja, Milly Deangelis, Margaret M. Morrison, Margaux Farrer, Lindsay Zhou, Xiangtian Chen, Wei Mizuki, Nobuhisa Meguro, Akira Makela, Kari Matti CA Consortium Refractive Error Myopia TI Meta-analysis of gene-environment-wide association scans accounting for education level identifies additional loci for refractive error SO NATURE COMMUNICATIONS LA English DT Article ID RETINAL-PIGMENT EPITHELIUM; ACTIVATED PROTEIN-KINASE; RISK-FACTORS; OUTDOOR ACTIVITY; INCIDENT MYOPIA; TIME OUTDOORS; VARIANTS; EYE; POPULATION; RECEPTOR AB Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP x education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P < 8.5 x 10(-5)), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia. C1 [Fan, Qiao; Barathi, Veluchamy A.; Ikram, M. Kamran; Sabanayagam, Charumathi; Gupta, Preeti; Tan, Vincent; Zhou, Lei; Ho, Candice E. H.; Beuerman, Roger W.; Siantar, Rosalynn; Vithana, Eranga; Khor, Chiea-Chuen; Aung, Tin; Wong, Tien-Yin; Cheng, Ching-Yu; Klaver, Caroline C. W.; Saw, Seang-Mei] Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore 169856, Singapore. [Fan, Qiao; Barathi, Veluchamy A.; Ikram, M. Kamran; Sabanayagam, Charumathi; Beuerman, Roger W.; Tai, E-Shyong; Vithana, Eranga; Wong, Tien-Yin; Cheng, Ching-Yu; Saw, Seang-Mei] Duke NUS Med Sch, Singapore 169857, Singapore. [Verhoeven, Virginie J. M.; Vingerling, Johannes R.; Klaver, Caroline C. W.; Tideman, Jan Willem L.; Tedja, Milly] Erasmus MC, Dept Ophthalmol, NL-3000 CA Rotterdam, Netherlands. [Verhoeven, Virginie J. M.; van Leeuwen, Elisabeth M.; Amin, Najaf; Uitterlinden, Andre G.; Rivadeneira, Fernando; Hofman, Albert; van Duijn, Cornelia M.; Klaver, Caroline C. W.; Tideman, Jan Willem L.; Tedja, Milly] Erasmus MC, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands. [Wojciechowski, Robert; Simpson, Claire L.; Schwantes-An, Tae-Hwi; Bailey-Wilson, Joan E.] NHGRI, Computat & Stat Genom Branch, NIH, Baltimore, MD 21224 USA. [Wojciechowski, Robert] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Bethesda, MD 20205 USA. [Barathi, Veluchamy A.; Lim, Wan'e; Beuerman, Roger W.; Vithana, Eranga; Aung, Tin; Wong, Tien-Yin; Cheng, Ching-Yu; Saw, Seang-Mei] Natl Univ Singapore, Natl Univ Hlth Syst, Dept Ophthalmol, Singapore 119228, Singapore. [Hysi, Pirro G.; Venturini, Cristina; Williams, Katie M.; Hammond, Christopher J.] Kings Coll London, Sch Med, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England. [Guggenheim, Jeremy A.] Cardiff Univ, Sch Optometry & Vis Sci, Cardiff CF24 4HQ, S Glam, Wales. [Hoehn, Rene; Mirshahi, Alireza; Pfeiffer, Norbert] Univ Med Ctr Mainz, Dept Ophthalmol, D-55131 Mainz, Germany. [Hoehn, Rene] Univ Hosp Bern, Inselspital, Dept Ophthalmol, CH-3010 Bern, Switzerland. [Vitart, Veronique; Huffman, Jenifer E.; Hayward, Caroline; Wright, Alan F.] Univ Edinburgh, Inst Genet & Mol Med, Med Res Council Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland. [Khawaja, Anthony P.; Luben, Robert N.; Khaw, Kay-Tee] Univ Cambridge, Sch Clin Med, Inst Publ Hlth, Dept Publ Hlth & Primary Care, Cambridge CB2 0SR, England. [Yamashiro, Kenji; Miyake, Masahiro; Yoshimura, Nagahisa] Kyoto Univ, Grad Sch Med, Dept Ophthalmol & Visual Sci, Kyoto 6068507, Japan. [Hosseini, S. Mohsen; Wong, Hoi-Suen; Paterson, Andrew D.] Hosp Sick Children, Program Genet & Genome Biol, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. [Hosseini, S. Mohsen; Wong, Hoi-Suen; Paterson, Andrew D.] Hosp Sick Children, Inst Med Sci, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. [Lehtimaki, Terho; Seppala, Ilkka] Univ Tampere, Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland. [Lehtimaki, Terho; Seppala, Ilkka] Univ Tampere, Sch Med, Tampere 33520, Finland. [Lu, Yi; Gharahkhani, Puya; MacGregor, Stuart] QIMR Berghofer Med Res Inst, Stat Genet Lab, Brisbane, Qld 4029, Australia. [Haller, Toomas; Mihailov, Evelin; Metspalu, Andres] Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia. [Xie, Jing; Hewitt, Alex W.; Baird, Paul N.; Schache, Maria; Yazar, Seyhan] Univ Melbourne, Royal Victorian Eye & Ear Hosp, CERA, Melbourne, Vic 3002, Australia. [Delcourt, Cecile; Cougnard-Gregoire, Audrey] Univ Bordeaux, ISPED, F-33000 Bordeaux, France. [Delcourt, Cecile; Cougnard-Gregoire, Audrey] INSERM, U1219, Bordeaux Populat Hlth Res Ctr, F-33000 Bordeaux, France. [Pirastu, Mario; Portas, Laura; Vaccargiu, Simona; Fossarello, Maurizio] CNR, Inst Populat Genet, I-07100 Sassari, Italy. [Wedenoja, Juho] Univ Helsinki, Dept Publ Hlth, Helsinki 00014, Finland. [Wedenoja, Juho] Univ Helsinki, Dept Ophthalmol, Helsinki 00014, Finland. [Wedenoja, Juho] Helsinki Univ Hosp, Helsinki 00014, Finland. [Venturini, Cristina] UCL Inst Ophthalmol, London SE1 7EH, England. [Hewitt, Alex W.; David, A. Mackey M.] Univ Tasmania, Menzies Res Inst Tasmania, Hobart, Tas 7000, Australia. [Guo, Xiaobo] Sun Yat Sen Univ, Sch Math & Computat Sci, Dept Stat Sci, Guangzhou 510275, Guangdong, Peoples R China. [Mazur, Johanna; Blettner, Maria] Univ Med Ctr Mainz, Inst Med Biostat Epidemiol & Informat, D-55131 Mainz, Germany. [Williams, Katie M.; Hammond, Christopher J.] Kings Coll London, Dept Ophthalmol, London SE1 7EH, England. [Polasek, Ozren] Univ Split, Fac Med, Split 21000, Croatia. [Campbell, Harry; Rudan, Igor; Wilson, James F.; Joshi, Peter K.] Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Teviot Pl, Edinburgh EH8 9AG, Midlothian, Scotland. [Vatavuk, Zoran] Sisters Mercy Univ Hosp, Dept Ophthalmol, Zagreb 10000, Croatia. [McMahon, George; St Pourcain, Beate; Evans, David M.] Univ Bristol, MRC Integrat Epidemiol Unit IFU, Bristol BS8 2BN, Avon, England. [McMahon, George; St Pourcain, Beate; Evans, David M.; Williams, Cathy] Univ Bristol, Sch Social & Community Med, Bristol BS8 2BN, Avon, England. [St Pourcain, Beate] Max Planck Inst Psycholinguist, Wundtlaan 1, NL-6525 XD Nijmegen, Netherlands. [Evans, David M.] Univ Queensland, Diamantina Inst, Translat Res Inst, Brisbane, Qld 4102, Australia. [Simpson, Claire L.] Univ Tennessee, Ctr Hlth Sci, Dept Genet Genom & Informat, Memphis, TN 38163 USA. [Igo, Robert P.] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Mirshahi, Alireza] Dardenne Eye Hosp, Bonn Bad Godesberg, D-53177 Bonn, Germany. [Bellenguez, Celine] INSERM, U1167, F-59000 Lille, France. [Bellenguez, Celine] Univ Lille, U1167, F-59000 Lille, France. [Bellenguez, Celine] Univ Lille 2, F-59000 Lille, France. [Raitakari, Olli] Univ Turku, Res Ctr Appl & Prevent Med, FIN-20520 Turku, Finland. [Raitakari, Olli] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, FIN-20520 Turku, Finland. [Kaehoenen, Mika] Tampere Univ Hosp, Dept Clin Physiol, Tampere 33520, Finland. [Kaehoenen, Mika] Univ Tampere, Sch Med, Tampere 33520, Finland. [Zeller, Tanja] Univ Heart Ctr Hamburg, Clin Gen & Intervent Cardiol, D-20246 Hamburg, Germany. [Meitinger, Thomas] Helmholtz Zentrum Munchen, Inst Human Genet, D-85764 Neuherberg, Germany. [Meitinger, Thomas; Oexle, Konrad] Tech Univ Munich, Klinikum Rechts Isar, Inst Human Genet, D-81675 Munich, Germany. [Ried, Janina S.; Gieger, Christian] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Genet Epidemiol, D-85764 Neuherberg, Germany. [Uitterlinden, Andre G.; Rivadeneira, Fernando] Erasmus MC, Dept Internal Med, NL-3000 CA Rotterdam, Netherlands. [Uitterlinden, Andre G.; Rivadeneira, Fernando; Hofman, Albert] Netherlands Genom Initiat, Netherlands Consortium Hlth Ageing, NL-2518 AD The Hague, Netherlands. [Wang, Ya Xing; Jonas, Jost B.; Xu, Liang] Capital Med Univ, Beijing Tongren Hosp, Beijing Inst Ophthalmol, Beijing 100044, Peoples R China. [Wang, Xu; Boh, Eileen Tai-Hui; Tai, E-Shyong; Khor, Chiea-Chuen; Teo, Yik-Ying; Wong, Tien-Yin; Saw, Seang-Mei] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117549, Singapore. [Wang, Xu; Boh, Eileen Tai-Hui; Tai, E-Shyong; Khor, Chiea-Chuen; Teo, Yik-Ying; Wong, Tien-Yin; Saw, Seang-Mei] Natl Univ Hlth Syst, Singapore 117549, Singapore. [Siantar, Rosalynn] Tan Tock Seng Hosp, Natl Healthcare Grp Eye Inst, Singapore 308433, Singapore. [Tai, E-Shyong] Natl Univ Singapore, Dept Med, Singapore 119228, Singapore. [Khor, Chiea-Chuen; Teo, Yik-Ying] Genome Inst Singapore, Div Human Genet, Singapore 138672, Singapore. [Foster, Paul J.] UCL Inst Ophthalmol, Div Genet & Epidemiol, London EC1V 9EL, England. [Foster, Paul J.] Moorfields Eye Hosp NHS Fdn Trust, NIHR Biomed Res Ctr, London EC1V 2PD, England. [Foster, Paul J.] UCL Inst Ophthalmol, London EC1V 2PD, England. [Klein, Barbara E. K.; Klein, Ronald] Univ Wisconsin, Sch Med & Publ Hlth, Dept Ophthalmol & Visual Sci, Madison, WI 53726 USA. [Mitchell, Paul; Wang, Jie Jin] Univ Sydney, Westmead Inst Med Res, Ctr Vis Res, Dept Ophthalmol, Sydney, NSW 2145, Australia. [Young, Terri L.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Ophthalmol & Visual Sci, Madison, WI 53705 USA. [He, Mingguang] Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, State Key Lab Ophthalmol, Guangzhou 510060, Guangdong, Peoples R China. [Paerssinen, Olavi] Cent Hosp Cent Finland, Dept Ophthalmol, Jyvaskyla 40620, Finland. [Paerssinen, Olavi] Univ Jyvaskyla, Gerontol Res Ctr, Jyvaskyla 40014, Finland. [Paerssinen, Olavi] Univ Jyvaskyla, Dept Hlth Sci, Jyvaskyla 40014, Finland. [Jonas, Jost B.] Heidelberg Univ, Dept Ophthalmol, Med Fac Mannheim, Bergheimer Str 58, D-69115 Heidelberg, Germany. [Teo, Yik-Ying] Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore 117546, Singapore. [David, A. Mackey M.; Yazar, Seyhan] Univ Western Australia, Lions Eye Inst, Ctr Ophthalmol & Visual Sci, Perth, WA 6009, Australia. [Stambolian, Dwight] Univ Penn, Dept Ophthalmol, Philadelphia, PA 19104 USA. [Rahi, Jugnoo S.] UCL, Inst Child Hlth, Med Res Council Ctr Epidemiol Child Hlth, London WC1F 6BT, England. [Rahi, Jugnoo S.] Moorfields Eye Hosp, Inst Ophthalmol, City Rd, London EC1V 2PD, England. [Rahi, Jugnoo S.] UCL, Ulverscroft Vis Res Grp, Mortimer St, London WC1E 6BT, England. [Korobelnik, Jean-Francois] Univ Bordeaux, F-33400 Talence, France. [Korobelnik, Jean-Francois] INSERM, ISPED, Ctr INSERM Epidemiol Biostat U897, F-33076 Bordeaux, France. [Kemp, John P.; Timpson, Nicholas J.; Smith, George Davey] Univ Bristol, MRC Integrat Epidemiol Unit IEU, Bristol BS8 2BN, Avon, England. [Craig, Jamie E.; Burdon, Kathryn P.; Fogarty, Rhys D.] Flinders Univ S Australia, Dept Ophthalmol, Adelaide, SA 5001, Australia. [Iyengar, Sudha K.; Janmahasatian, Sarayut; Fondran, Jeremy R.; Lass, Jonathan H.] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Iyengar, Sudha K.; Lass, Jonathan H.] Case Western Reserve Univ, Dept Ophthalmol & Visual Sci, Cleveland, OH 44106 USA. [Iyengar, Sudha K.; Lass, Jonathan H.] Univ Hosp Eye Inst, Cleveland, OH 44106 USA. [Iyengar, Sudha K.] Case Western Reserve Univ, Dept Genet, Cleveland, OH 44106 USA. [Chew, Emily] NEI, NIH, Bethesda, MD 20892 USA. [Martin, Nicholas G.] QIMR Berghofer Med Res Inst, Genet Epidemiol Lab, Brisbane, Qld 4029, Australia. [Nangia, Vinay; Panda-Jonas, Songhomitra] Suraj Eye Inst, Nagpur 440001, Maharashtra, India. [Feng, Sheng] Duke Eye Ctr Human Genet, Dept Pediat Ophthalmol, Durham, NC 27710 USA. [Zhao, Jing Hua] Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 1TN, England. [Wareham, Nick J.] Addenbrookes Hosp, Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 0QQ, England. [Rantanen, Taina] Univ Jyvaskyla, Gerontol Res Ctr, Jyvaskyla 40014, Finland. [Kaprio, Jaakko] Univ Helsinki, Dept Publ Hlth, Helsinki 00014, Finland. [Kaprio, Jaakko] Univ Helsinki, Inst Mol Med, Helsinki 00014, Finland. [Kaprio, Jaakko] Natl Inst Hlth & Welf, Dept Mental Hlth & Alcohol Abuse Serv, Helsinki 00271, Finland. [Pang, Chi Pui; Tam, Pancy O.; Jhanji, Vishal; Young, Alvin L.] Chinese Univ Hong Kong, Hong Kong Eye Hosp, Dept Ophthalmol & Visual Sci, Kowloon, Hong Kong, Peoples R China. [Chen, Li Jia; Jhanji, Vishal; Young, Alvin L.] Chinese Univ Hong Kong, Prince Wales Hosp, Dept Ophthalmol & Visual Sci, Shatin, Hong Kong, Peoples R China. [Doering, Angela] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 1, D-85764 Neuherberg, Germany. [Doering, Angela] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, D-85764 Neuherberg, Germany. [Raffel, Leslie J.] Cedars Sinai Med Ctr, Med Genet Inst, Los Angeles, CA 90048 USA. [Cotch, Mary-Frances] NEI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. [Li, Xiaohui] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90502 USA. [Yip, Shea Ping; Yap, Maurice K. H.] Hong Kong Polytech Univ, Dept Hlth Technol & Informat, Hong Kong, Hong Kong, Peoples R China. [Biino, Ginevra] CNR, Inst Mol Genet, I-27100 Pavia, Italy. [Fleck, Brian] Princess Alexandra Eye Pavil, Edinburgh EH3 9HA, Midlothian, Scotland. [Deangelis, Margaret M.] Univ Utah, Moran Eye Ctr, Dept Ophthalmol & Visual Sci, Salt Lake City, UT 84132 USA. [Morrison, Margaux] Univ Utah, John Moran Eye Ctr, Dept Ophthalmol & Visual Sci, Salt Lake City, UT 84132 USA. [Farrer, Lindsay] Boston Univ, Sch Med, Dept Med Biomed Genet, Boston, MA 02118 USA. [Farrer, Lindsay] Boston Univ, Sch Med, Dept Ophthalmol, Boston, MA 02118 USA. [Farrer, Lindsay] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Farrer, Lindsay] Boston Univ, Sch Med, Dept Epidemiol & Biostat, Boston, MA 02118 USA. [Farrer, Lindsay] Boston Univ, Sch Publ Hlth, Dept Med Biomed Genet, Boston, MA 02118 USA. [Farrer, Lindsay] Boston Univ, Sch Publ Hlth, Dept Ophthalmol, Boston, MA 02118 USA. [Farrer, Lindsay] Boston Univ, Sch Publ Hlth, Dept Neurol, Boston, MA 02118 USA. [Farrer, Lindsay] Boston Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Boston, MA 02118 USA. [Zhou, Xiangtian; Chen, Wei] Wenzhou Med Univ, Sch Ophthalmol & Optometry, Wenzhou 325035, Peoples R China. [Mizuki, Nobuhisa; Meguro, Akira] Yokohama City Univ, Sch Med, Dept Ophthalmol, Yokohama, Kanagawa 2360027, Japan. [Makela, Kari Matti] Univ Tampere, Fimlab Labs, Dept Clin Chem, Tampere 33014, Finland. [Makela, Kari Matti] Univ Tampere, Sch Med, Tampere 33014, Finland. RP Saw, SM (reprint author), Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore 169856, Singapore.; Saw, SM (reprint author), Duke NUS Med Sch, Singapore 169857, Singapore.; Klaver, CCW (reprint author), Erasmus MC, Dept Ophthalmol, NL-3000 CA Rotterdam, Netherlands.; Klaver, CCW (reprint author), Erasmus MC, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands.; Saw, SM (reprint author), Natl Univ Singapore, Natl Univ Hlth Syst, Dept Ophthalmol, Singapore 119228, Singapore.; Saw, SM (reprint author), Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117549, Singapore.; Saw, SM (reprint author), Natl Univ Hlth Syst, Singapore 117549, Singapore. EM c.c.w.klaver@erasmusmc.nl; seang_mei_saw@nuhs.edu.sg RI Delcourt, Cecile/I-2627-2013; Chen, Li Jia/I-5078-2014; wang, YA XING/K-9671-2016; Fox, Laura /C-6249-2016; Wang, Jie Jin/P-1499-2014; Mitchell, Paul/P-1498-2014; Davey Smith, George/A-7407-2013; Polasek, Ozren/B-6002-2011; Paterson, Andrew/A-4088-2011; OI Timpson, Nicholas/0000-0002-7141-9189; Tai, E Shyong/0000-0003-2929-8966; Rantanen, Taina/0000-0002-1604-1945; Gharahkhani, Puya/0000-0002-4203-5952; Hohn, Rene /0000-0003-2870-1469; Wedenoja, Juho/0000-0002-6155-0378; Fossarello, Maurizio/0000-0003-1520-7760; Khawaja, Anthony/0000-0001-6802-8585; Hammond, Christopher/0000-0002-3227-2620; Kemp, John/0000-0002-9105-2249; Ikram, Mohammad Kamran/0000-0003-0173-9571; Evans, David/0000-0003-0663-4621; Kaprio, Jaakko/0000-0002-3716-2455; Williams, Katie M/0000-0003-4596-3938; Delcourt, Cecile/0000-0002-2099-0481; Chen, Li Jia/0000-0003-3500-5840; Gieger, Christian/0000-0001-6986-9554; wang, YA XING/0000-0003-2749-7793; Wang, Jie Jin/0000-0001-9491-4898; Davey Smith, George/0000-0002-1407-8314; Polasek, Ozren/0000-0002-5765-1862; Paterson, Andrew/0000-0002-9169-118X; Guggenheim, Jeremy/0000-0001-5164-340X; Hosseini, Mohsen/0000-0003-3626-9928; Wojciechowski, Robert/0000-0002-9593-4652 FU Department of Health [SRF/01/010]; Intramural NIH HHS [Z99 EY999999]; Medical Research Council [MC_UU_12013/4, G0401527, MC_PC_15018, MC_PC_U127561128, MC_UU_12013/1, MR/K006584/1, MR/K023721/1]; NEI NIH HHS [K08 EY022943, R01 EY014685, R01 EY024233]; Wellcome Trust [102215] NR 69 TC 3 Z9 3 U1 11 U2 24 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 APR PY 2016 VL 7 AR 11008 DI 10.1038/ncomms11008 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI9EL UT WOS:000373804800001 PM 27020472 ER PT J AU Gusev, A Shi, H Kichaev, G Pomerantz, M Li, F Long, HW Ingles, SA Kittles, RA Strom, SS Rybicki, BA Nemesure, B Isaacs, WB Zheng, W Pettaway, CA Yeboah, ED Tettey, Y Biritwum, RB Adjei, AA Tay, E Truelove, A Niwa, S Chokkalingam, AP John, EM Murphy, AB Signorello, LB Carpten, J Leske, MC Wu, SY Hennis, AJM Neslund-Dudas, C Hsing, AW Chu, L Goodman, PJ Klein, EA Witte, JS Casey, G Kaggwa, S Cook, MB Stram, DO Blot, WJ Eeles, RA Easton, D Kote-Jarai, Z Al Olama, AA Benlloch, S Muir, K Giles, GG Southey, MC Fitzgerald, LM Gronberg, H Wiklund, F Aly, M Henderson, BE Schleutker, J Wahlfors, T Tammela, TLJ Nordestgaard, BG Key, TJ Travis, RC Neal, DE Donovan, JL Hamdy, FC Pharoah, P Pashayan, N Khaw, KT Stanford, JL Thibodeau, SN McDonnell, SK Schaid, DJ Maier, C Vogel, W Luedeke, M Herkommer, K Kibel, AS Cybulski, C Wokolorczyk, D Kluzniak, W Cannon-Albright, L Teerlink, C Brenner, H Dieffenbach, AK Arndt, V Park, JY Sellers, TA Lin, HY Slavov, C Kaneva, R Mitev, V Batra, J Spurdle, A Clements, JA Teixeira, MR Pandha, H Michael, A Paulo, P Maia, S Kierzek, A Conti, DV Albanes, D Berg, C Berndt, SI Campa, D Crawford, ED Diver, WR Gapstur, SM Gaziano, JM Giovannucci, E Hoover, R Hunter, DJ Johansson, M Kraft, P Le Marchand, L Lindstrom, S Navarro, C Overvad, K Riboli, E Siddiq, A Stevens, VL Trichopoulos, D Vineis, P Yeager, M Trynka, G Raychaudhuri, S Schumacher, FR Price, AL Freedman, ML Haiman, CA Pasaniuc, B Cook, M Guy, M Govindasami, K Leongamornlert, D Sawyer, EJ Wilkinson, R Saunders, EJ Tymrakiewicz, M Dadaev, T Morgan, A Fisher, C Hazel, S Livni, N Lophatananon, A Pedersen, J Hopper, JL Adolfson, J Stattin, P Johansson, JE Cavalli-Bjoerkman, C Karlsson, A Broms, M Auvinen, A Kujala, P Maeaettaenen, L Murtola, T Taari, K Weischer, M Nielsen, SF Klarskov, P Roder, A Iversen, P Wallinder, H Gustafsson, S Cox, A Brown, P George, A Marsden, G Lane, A Davis, M Zheng, W Signorello, LB Blot, WJ Tillmans, L Riska, S Wang, L Rinckleb, A Lubiski, J Stegmaier, C Pow-Sang, J Park, H Radlein, S Rincon, M Haley, J Zachariah, B Kachakova, D Popov, E Mitkova, A Vlahova, A Dikov, T Christova, S Heathcote, P Wood, G Malone, G Saunders, P Eckert, A Yeadon, T Kerr, K Collins, A Turner, M Srinivasan, S Kedda, MA Alexander, K Omara, T Wu, HH Henrique, R Pinto, P Santos, J Barros-Silva, J AF Gusev, Alexander Shi, Huwenbo Kichaev, Gleb Pomerantz, Mark Li, Fugen Long, Henry W. Ingles, Sue A. Kittles, Rick A. Strom, Sara S. Rybicki, Benjamin A. Nemesure, Barbara Isaacs, William B. Zheng, Wei Pettaway, Curtis A. Yeboah, Edward D. Tettey, Yao Biritwum, Richard B. Adjei, Andrew A. Tay, Evelyn Truelove, Ann Niwa, Shelley Chokkalingam, Anand P. John, Esther M. Murphy, Adam B. Signorello, Lisa B. Carpten, John Leske, M. Cristina Wu, Suh-Yuh Hennis, Anslem J. M. Neslund-Dudas, Christine Hsing, Ann W. Chu, Lisa Goodman, Phyllis J. Klein, Eric A. Witte, John S. Casey, Graham Kaggwa, Sam Cook, Michael B. Stram, Daniel O. Blot, William J. Eeles, Rosalind A. Easton, Douglas Kote-Jarai, ZSofia Al Olama, Ali Amin Benlloch, Sara Muir, Kenneth Giles, Graham G. Southey, Melissa C. Fitzgerald, Liesel M. Gronberg, Henrik Wiklund, Fredrik Aly, Markus Henderson, Brian E. Schleutker, Johanna Wahlfors, Tiina Tammela, Teuvo L. J. Nordestgaard, Borge G. Key, Tim J. Travis, Ruth C. Neal, David E. Donovan, Jenny L. Hamdy, Freddie C. Pharoah, Paul Pashayan, Nora Khaw, Kay-Tee Stanford, Janet L. Thibodeau, Stephen N. McDonnell, Shannon K. Schaid, Daniel J. Maier, Christiane Vogel, Walther Luedeke, Manuel Herkommer, Kathleen Kibel, Adam S. Cybulski, Cezary Wokolorczyk, Dominika Kluzniak, Wojciech Cannon-Albright, Lisa Teerlink, Craig Brenner, Hermann Dieffenbach, Aida K. Arndt, Volker Park, Jong Y. Sellers, Thomas A. Lin, Hui-Yi Slavov, Chavdar Kaneva, Radka Mitev, Vanio Batra, Jyotsna Spurdle, Amanda Clements, Judith A. Teixeira, Manuel R. Pandha, Hardev Michael, Agnieszka Paulo, Paula Maia, Sofia Kierzek, Andrzej Conti, David V. Albanes, Demetrius Berg, Christine Berndt, Sonja I. Campa, Daniele Crawford, E. David Diver, W. Ryan Gapstur, Susan M. Gaziano, J. Michael Giovannucci, Edward Hoover, Robert Hunter, David J. Johansson, Mattias Kraft, Peter Le Marchand, Loic Lindstrom, Sara Navarro, Carmen Overvad, Kim Riboli, Elio Siddiq, Afshan Stevens, Victoria L. Trichopoulos, Dimitrios Vineis, Paolo Yeager, Meredith Trynka, Gosia Raychaudhuri, Soumya Schumacher, Frederick R. Price, Alkes L. Freedman, Matthew L. Haiman, Christopher A. Pasaniuc, Bogdan Cook, Margaret Guy, Michelle Govindasami, Koveela Leongamornlert, Daniel Sawyer, Emma J. Wilkinson, Rosemary Saunders, Edward J. Tymrakiewicz, Malgorzata Dadaev, Tokhir Morgan, Angela Fisher, Cyril Hazel, Steve Livni, Naomi Lophatananon, Artitaya Pedersen, John Hopper, John L. Adolfson, Jan Stattin, Paer Johansson, Jan-Erik Cavalli-Bjoerkman, Carin Karlsson, Ami Broms, Michael Auvinen, Anssi Kujala, Paula Maeaettaenen, Liisa Murtola, Teemu Taari, Kimmo Weischer, Maren Nielsen, Sune F. Klarskov, Peter Roder, Andreas Iversen, Peter Wallinder, Hans Gustafsson, Sven Cox, Angela Brown, Paul George, Anne Marsden, Gemma Lane, Athene Davis, Michael Zheng, Wei Signorello, Lisa B. Blot, William J. Tillmans, Lori Riska, Shaun Wang, Liang Rinckleb, Antje Lubiski, Jan Stegmaier, Christa Pow-Sang, Julio Park, Hyun Radlein, Selina Rincon, Maria Haley, James Zachariah, Babu Kachakova, Darina Popov, Elenko Mitkova, Atanaska Vlahova, Aleksandrina Dikov, Tihomir Christova, Svetlana Heathcote, Peter Wood, Glenn Malone, Greg Saunders, Pamela Eckert, Allison Yeadon, Trina Kerr, Kris Collins, Angus Turner, Megan Srinivasan, Srilakshmi Kedda, Mary-Anne Alexander, Kimberly Omara, Tracy Wu, Huihai Henrique, Rui Pinto, Pedro Santos, Joana Barros-Silva, Joao CA PRACTICAL Consortium TI Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation SO NATURE COMMUNICATIONS LA English DT Article ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; COMMON DISEASES; COMPLEX TRAITS; RISK; SNPS; ENHANCERS; ELEMENTS; PITFALLS; ENCODE AB Although genome-wide association studies have identified over 100 risk loci that explain similar to 33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa. C1 [Gusev, Alexander; Signorello, Lisa B.; Gaziano, J. 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[Schleutker, Johanna; Wahlfors, Tiina] Univ Tampere, BioMediTech, Tampere 33200, Finland. [Schleutker, Johanna; Wahlfors, Tiina] FimLab Labs, Tampere 33200, Finland. [Tammela, Teuvo L. J.] Univ Tampere, Dept Urol, Tampere Univ Hosp, Tampere 33200, Finland. [Tammela, Teuvo L. J.] Univ Tampere, Sch Med, Tampere 33200, Finland. [Nordestgaard, Borge G.; Weischer, Maren; Nielsen, Sune F.] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, DK-2730 Herlev, Denmark. [Nordestgaard, Borge G.; Nielsen, Sune F.] Univ Copenhagen, Fac Hlth & Med Sci, DK-1165 Copenhagen, Denmark. [Nordestgaard, Borge G.; Nielsen, Sune F.] Univ Copenhagen, Med Sci, DK-1165 Copenhagen, Denmark. [Key, Tim J.; Travis, Ruth C.] Univ Oxford, Canc Epidemiol, Nuffield Dept Populat Hlth, Oxford OX3 7LF, England. [Neal, David E.] Univ Cambridge, Dept Oncol, Addenbrookes Hosp, Cambridge CB2 0QQ, England. [Neal, David E.] Li Ka Shing Ctr, Canc Res UK Cambridge Res Inst, Cambridge, England. [Donovan, Jenny L.; Brown, Paul; George, Anne; Marsden, Gemma; Lane, Athene; Davis, Michael] Univ Bristol, Sch Social & Community Med, Canynge Hall,39Whatley Rd, Bristol BS8 2PS, Avon, England. [Hamdy, Freddie C.] Aarhus Univ, Epidemiol Sect, Dept Publ Hlth, Aarhus OX1 3PN, Denmark. [Hamdy, Freddie C.] Univ Oxford, John Radcliffe Hosp, Fac Med Sci, Oxford OX1 3PN, England. [Pharoah, Paul; Pashayan, Nora] Univ Cambridge, Dept Oncol, Strangeways Lab, Ctr Canc Genet Epidemiol, Worts Causeway, Cambridge CB1 8RN, England. [Pashayan, Nora] UCL, Dept Appl Hlth Res, 1-19 Torrington Pl, London WC1E 7HB, England. [Khaw, Kay-Tee] Univ Cambridge, Clin Gerontol Unit, Cambridge CB1 8RN, England. [Stanford, Janet L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Stanford, Janet L.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98109 USA. [Thibodeau, Stephen N.; McDonnell, Shannon K.; Schaid, Daniel J.; Tillmans, Lori; Riska, Shaun; Wang, Liang] Mayo Clin, Rochester, MN 55905 USA. [Maier, Christiane; Vogel, Walther] Univ Hosp Ulm, Inst Human Genet, D-89081 Ulm, Germany. [Luedeke, Manuel; Rinckleb, Antje] Univ Hosp Ulm, Dept Urol, D-89081 Ulm, Germany. [Herkommer, Kathleen] Tech Univ Munich, Klinikum Rechts Isar, Dept Urol, D-81675 Munich, Germany. [Kibel, Adam S.] Brigham & Womens Hosp, Dana Farber Canc Inst, Div Urol Surg, 75 Francis St, Boston, MA 02115 USA. [Cybulski, Cezary; Wokolorczyk, Dominika; Kluzniak, Wojciech; Lubiski, Jan] Pomeranian Med Univ, Dept Genet & Pathol, Int Hereditary Canc Ctr, Szczecin, Poland. [Cannon-Albright, Lisa; Teerlink, Craig] Univ Utah, Div Genet Epidemiol, Dept Med, Sch Med, Salt Lake City, UT 84132 USA. [Cannon-Albright, Lisa; Teerlink, Craig] George E Wahlen Dept Vet Affairs, Med Ctr, Salt Lake City, UT 84132 USA. [Brenner, Hermann; Dieffenbach, Aida K.; Arndt, Volker] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, D-69120 Heidelberg, Germany. [Brenner, Hermann; Dieffenbach, Aida K.] German Canc Consortium DKTK, D-69120 Heidelberg, Germany. [Park, Jong Y.; Sellers, Thomas A.; Pow-Sang, Julio; Park, Hyun; Radlein, Selina; Rincon, Maria; Haley, James; Zachariah, Babu] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, 12902 Magnolia Dr, Tampa, FL 33612 USA. [Lin, Hui-Yi] H Lee Moffitt Canc Ctr & Res Inst, Biostat Program, 12902 Magnolia Dr, Tampa, FL 33612 USA. [Slavov, Chavdar; Popov, Elenko] Med Univ, Dept Urol, Sofia 1431, Bulgaria. [Slavov, Chavdar; Popov, Elenko] Med Univ, Alexandrovska Univ Hosp, Sofia 1431, Bulgaria. [Kaneva, Radka; Mitev, Vanio; Kachakova, Darina; Mitkova, Atanaska] Med Univ, Mol Med Ctr, Dept Med Chem & Biochem, 2 Zdrave Str, Sofia 1431, Bulgaria. [Batra, Jyotsna; Clements, Judith A.; Vlahova, Aleksandrina; Heathcote, Peter; Wood, Glenn; Malone, Greg; Saunders, Pamela; Eckert, Allison; Yeadon, Trina; Kerr, Kris; Collins, Angus; Turner, Megan; Srinivasan, Srilakshmi; Kedda, Mary-Anne; Alexander, Kimberly; Omara, Tracy] Queensland Univ Technol, Australian Prostate Canc Res Ctr Qld, Inst Hlth & Biomed Innovat, Brisbane, Qld 4000, Australia. [Batra, Jyotsna; Clements, Judith A.; Heathcote, Peter; Wood, Glenn; Malone, Greg; Saunders, Pamela; Eckert, Allison; Yeadon, Trina; Kerr, Kris; Collins, Angus; Turner, Megan; Srinivasan, Srilakshmi; Kedda, Mary-Anne; Alexander, Kimberly; Omara, Tracy] Queensland Univ Technol, Sch Biomed Sci, Brisbane, Qld 4000, Australia. [Spurdle, Amanda] Queensland Inst Med Res, Mol Canc Epidemiol Lab, Brisbane, Qld 4000, Australia. [Teixeira, Manuel R.; Paulo, Paula; Maia, Sofia; Henrique, Rui; Pinto, Pedro; Santos, Joana; Barros-Silva, Joao] Portuguese Oncol Inst, Dept Genet, P-4200 Oporto, Portugal. [Teixeira, Manuel R.] Univ Porto, Biomed Sci Inst ICBAS, P-4200 Oporto, Portugal. [Pandha, Hardev; Michael, Agnieszka; Kierzek, Andrzej; Vlahova, Aleksandrina; Dikov, Tihomir; Christova, Svetlana] Univ Surrey, Guildford GU2 7XH, Surrey, England. [Conti, David V.; Schumacher, Frederick R.; Haiman, Christopher A.] Univ So Calif, Keck Sch Med, Norris Canc Ctr, Dept Prevent Med, Los Angeles, CA 90033 USA. [Albanes, Demetrius] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Berg, Christine; Overvad, Kim] Johns Hopkins Med, Dept Radiat Oncol & Mol Radiat Sci, Baltimore, MD 21287 USA. [Campa, Daniele] German Canc Res Ctr, Genom Epidemiol Grp, D-69121 Heidelberg, Germany. [Crawford, E. David] Univ Colorado, Urol Oncol, Denver Hlth Sci Ctr, Denver, CO 80230 USA. [Diver, W. Ryan; Gapstur, Susan M.; Stevens, Victoria L.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30303 USA. [Gaziano, J. Michael] Harvard Univ, Dept Med, Sch Med, Boston, MA 02115 USA. [Gaziano, J. Michael] Brigham & Womens Hosp, Div Aging, Boston, MA 02115 USA. [Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Johansson, Mattias] Int Agcy Res Canc, F-69008 Lyon, France. [Johansson, Mattias] Umea Univ, Dept Surg & Perioperat Sci Urol & Androl, S-90736 Umea, Sweden. [Kraft, Peter; Lindstrom, Sara] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Le Marchand, Loic] Univ Hawaii, Program Epidemiol, Ctr Canc, Honolulu, HI 96813 USA. [Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London SW7 2AZ, England. [Siddiq, Afshan] Univ London Imperial Coll Sci Technol & Med, Dept Genom Common Dis, London SW7 2AZ, England. [Trichopoulos, Dimitrios] Acad Athens, Bur Epidemiol Res, Athens 10679, Greece. [Trichopoulos, Dimitrios] Hellen Hlth Fdn, Athens 10679, Greece. [Vineis, Paolo] HuGeF Fdn, I-10126 Turin, Italy. [Vineis, Paolo] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London SW7 2AZ, England. [Trynka, Gosia; Raychaudhuri, Soumya] Brigham & Womens Hosp, Dept Med, Div Genet, 75 Francis St, Boston, MA 02115 USA. [Trynka, Gosia; Raychaudhuri, Soumya] Brigham & Womens Hosp, Dept Med, Div Rheumatol, 75 Francis St, Boston, MA 02115 USA. [Trynka, Gosia; Raychaudhuri, Soumya] Harvard Univ, Sch Med, Boston, MA USA. [Trynka, Gosia] Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge CB10 1SA, England. [Raychaudhuri, Soumya] Univ Manchester, Inst Inflammat & Repair, Manchester M13 9PT, Lancs, England. [Pasaniuc, Bogdan] Univ Calif Los Angeles, Dept Pathol, Los Angeles, CA 90024 USA. [Pasaniuc, Bogdan] Univ Calif Los Angeles, Dept Lab Med, Los Angeles, CA USA. [Pasaniuc, Bogdan] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA 90095 USA. [Pedersen, John] Tissupath Pty Ltd, Melbourne, Vic 3122, Australia. [Auvinen, Anssi] Univ Tampere, Sch Hlth Sci, Dept Epidemiol, Tampere 33014, Finland. [Kujala, Paula] Tampere Univ Hosp, Fimlab Labs, Tampere, Finland. [Maeaettaenen, Liisa] Finnish Canc Registry, FIN-00170 Helsinki, Finland. [Murtola, Teemu] Univ Tampere, Sch Med, FIN-33101 Tampere, Finland. [Murtola, Teemu] Tampere Univ Hosp, Dept Urol, Tampere, Finland. [Taari, Kimmo] Univ Helsinki, Cent Hosp, Dept Urol, SF-00100 Helsinki, Finland. [Taari, Kimmo] Univ Helsinki, SF-00100 Helsinki, Finland. [Klarskov, Peter] Copenhagen Univ Hosp, Herlev Hosp, Dept Urol, Ringvej 75, DK-230 Herlev, Denmark. [Roder, Andreas; Iversen, Peter] Copenhagen Univ Hosp, Dept Urol, Rigshosp, Copenhagen Prostate Canc Ctr, DK-2200 Copenhagen, Denmark. [Wallinder, Hans; Gustafsson, Sven] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London SW7 2AZ, England. [Cox, Angela] Univ Sheffield, CR UK YCR Sheffield Canc Res Ctr, Sheffield S10 2TN, S Yorkshire, England. [Zheng, Wei] Vanderbilt Univ, Med Ctr, Dept Med, Div Epidemiol, 2525 West End Ave, Nashville, TN 37232 USA. [Signorello, Lisa B.] NCI, NIH, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. [Signorello, Lisa B.] NCI, NIH, Rockville, MD 20850 USA. [Blot, William J.] Int Inst Epidemiol, 1555 Res Blvd,Suite 550, Rockville, MD 20850 USA. [Blot, William J.] Vanderbilt Univ, Sch Med, Div Epidemiol, Dept Med,Vanderbilt Epidemiol Ctr,Vanderbilt Ingr, Nashville, TN 37232 USA. [Stegmaier, Christa] Saarland Canc Registry, Saarbrucken, Germany. [Wu, Huihai] Univ Surrey, Guildford GU2 7XH, Surrey, England. RP Gusev, A (reprint author), Harvard TH Chan Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA.; Pasaniuc, B (reprint author), Univ Calif Los Angeles, Bioinformat Interdept Program, Los Angeles, CA 90095 USA. EM agusev@hsph.harvard.edu; pasaniuc@ucla.edu RI Cook, Michael/A-5641-2009; Batra, Jyotsna/B-4130-2011; Campa, Daniele/K-1617-2016; Zheng, Wei/O-3351-2013; Brenner, Hermann/B-4627-2017; OI Clements, Judith/0000-0001-6026-1964; Cook, Michael/0000-0002-0533-7302; Campa, Daniele/0000-0003-3220-9944; Zheng, Wei/0000-0003-1226-070X; Brenner, Hermann/0000-0002-6129-1572; Teerlink, Craig/0000-0002-1992-2326; albright, lisa/0000-0003-2602-3668; Taari, Kimmo/0000-0002-0077-4896 FU NIH fellowship [F32 GM106584]; NIH [R01 MH101244, R01 CA188392, U01 CA194393, R01 GM107427, R01 CA193910, CA63464, CA54281, CA098758, R01 CA092447]; Prostate Cancer Foundation Challenge Award; Wellcome Trust [076113]; European Commission's Seventh Framework Programme [223175 (HEALTH-F2-2009-223175)]; Cancer Research UK [C5047/A7357, C5047/A3354, C16913/A6135, C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A10123, C8197/A10865, C522/A8649, C490/A10124]; National Institute of Health (NIH) Cancer Post-Cancer GWAS initiative Grant [1 U19 CA 148537-01]; National Institutes of Health [CA128978]; Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]; Department of Defense [W81XWH-10-1-0341]; Linneus Centre [70867902]; Swedish Research Council [K2010-70X-20430-04-3]; Swedish Cancer Foundation [09-0677]; US National Cancer Institute, National Institutes of Health [RO1CA056678, RO1CA082664, RO1CA092579]; US National Cancer Institute [R01CA72818, R01CA128813]; National Health and Medical Research Council, Australia [126402, 209057, 251533, 396414, 450104, 504700, 504702, 504715, 623204, 940394, 614296]; Bulgarian National Science Fund, Ministry of Education and Science [DOO-119/2009, DUNK01/2-2009, DFNI-B01/28/2012]; NIHR Health Technology Assessment Programme [96/20/06, 96/20/99]; Medical Research Council of England [G0500966, 75466]; NCRI, UK; US Dept of Defense award [W81XWH-04-1-0280]; Australia Project Grant [614296, 390130, 1009458]; Prostate Cancer Foundation of Australia; Vanderbilt-Ingram Cancer Center [P30 CA68485]; UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge; Competitive Research Funding of the Tampere University Hospital [9N069, X51003]; National Cancer Institute [P30CA042014]; [G0500966/75466] FX This work was supported by NIH fellowship F32 GM106584 (AG), NIH grants R01 MH101244(A.G.), R01 CA188392 (B.P.), U01 CA194393(B.P.), R01 GM107427 (M.L.F.), R01 CA193910 (M.L.F./M.P.) and Prostate Cancer Foundation Challenge Award (M.L.F./M.P.). This study makes use of data generated by the Wellcome Trust Case Control Consortium and the Wellcome Trust Sanger Institute. A full list of the investigators who contributed to the generation of the Wellcome Trust Case Control Consortium data is available on www.wtccc.org.uk. Funding for the Wellcome Trust Case Control Consortium project was provided by the Wellcome Trust under award 076113. This study makes use of data generated by the UK10K Consortium. A full list of the investigators who contributed to the generation of the data is available online (http://www.UK10K.org). The PRACTICAL consortium was supported by the following grants: European Commission's Seventh Framework Programme grant agreement no 223175 (HEALTH-F2-2009-223175), Cancer Research UK Grants C5047/A7357, C1287/A10118, C5047/A3354, C5047/A10692, C16913/A6135 and The National Institute of Health (NIH) Cancer Post-Cancer GWAS initiative Grant: no. 1 U19 CA 148537-01 (the GAME-ON initiative); Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007 and 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 Defense (W81XWH-10-1-0341), A Linneus Centre (Contract ID 70867902), Swedish Research Council (grant no K2010-70X-20430-04-3), the Swedish Cancer Foundation (grant no 09-0677), grants RO1CA056678, RO1CA082664 and RO1CA092579 from the US National Cancer Institute, National Institutes of Health; US National Cancer Institute (R01CA72818); support from The National Health and Medical Research Council, Australia (126402, 209057, 251533, 396414, 450104, 504700, 504702, 504715, 623204, 940394 and 614296); NIH grants CA63464, CA54281 and CA098758; US National Cancer Institute (R01CA128813, PI: J.Y. Park); Bulgarian National Science Fund, Ministry of Education and Science (contract DOO-119/2009; DUNK01/2-2009; DFNI-B01/28/2012); Cancer Research UK grants [C8197/A10123] and [C8197/A10865]; grant code G0500966/75466; NIHR Health Technology Assessment Programme (projects 96/20/06 and 96/20/99); Cancer Research UK grant number C522/A8649, Medical Research Council of England grant number G0500966, ID 75466 and The NCRI, UK; The US Dept of Defense award W81XWH-04-1-0280; Australia Project Grant [390130, 1009458] and Enabling Grant [614296 to APCB]; the Prostate Cancer Foundation of Australia (Project Grant [PG7] and Research infrastructure grant [to APCB]); NIH grant R01 CA092447; Vanderbilt-Ingram Cancer Center (P30 CA68485); Cancer Research UK [C490/A10124] and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge; Competitive Research Funding of the Tampere University Hospital (9N069 and X51003); Award Number P30CA042014 from the National Cancer Institute. NR 39 TC 4 Z9 4 U1 0 U2 6 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 APR PY 2016 VL 7 AR 10979 DI 10.1038/ncomms10979 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI9EK UT WOS:000373804700001 PM 27052111 ER PT J AU Khan, SY Vasanth, S Kabir, F Gottsch, JD Khan, AO Chaerkady, R Lee, MCW Leitch, CC Ma, ZW Laux, J Villasmil, R Khan, SN Riazuddin, S Akram, J Cole, RN Talbot, CC Pourmand, N Zaghloul, NA Hejtmancik, JF Riazuddin, SA AF Khan, Shahid Y. Vasanth, Shivakumar Kabir, Firoz Gottsch, John D. Khan, Arif O. Chaerkady, Raghothama Lee, Mei-Chong W. Leitch, Carmen C. Ma, Zhiwei Laux, Julie Villasmil, Rafael Khan, Shaheen N. Riazuddin, Sheikh Akram, Javed Cole, Robert N. Talbot, C. Conover Pourmand, Nader Zaghloul, Norann A. Hejtmancik, J. Fielding Riazuddin, S. Amer TI FOXE3 contributes to Peters anomaly through transcriptional regulation of an autophagy-associated protein termed DNAJB1 SO NATURE COMMUNICATIONS LA English DT Article ID ANTERIOR SEGMENT MALFORMATIONS; RECESSIVE CONGENITAL CATARACTS; GENE; LENS; EXPRESSION; MUTATIONS; CELLS; PROLIFERATION; DYSGENESIS; DOMINANT AB FOXE3 is a lens-specific transcription factor that has been associated with anterior segment ocular dysgenesis. To determine the transcriptional target(s) of FOXE3 that are indispensable for the anterior segment development, we examined the transcriptome and the proteome of cells expressing truncated FOXE3 responsible for Peters anomaly identified through linkage-coupled next-generation whole-exome sequencing. We found that DNAJB1, an autophagy-associated protein, was the only candidate exhibiting differential expression in both screens. We confirmed the candidacy of DNAJB1 through chromatin immunoprecipitation and luciferase assays while knockdown of DNAJB1 in human lens epithelial cells resulted in a mitotic arrest. Subsequently, we targeted dnajb1a in zebrafish through injection of a splice-blocking morpholino. The dnajb1a morphants exhibited underdeveloped cataractous lenses with persistent apoptotic nuclei. In conclusion, here we report DNAJB1 is a transcriptional target of FOXE3 in a novel pathway that is crucial for the development of the anterior segment of the eye. C1 [Khan, Shahid Y.; Vasanth, Shivakumar; Kabir, Firoz; Gottsch, John D.; Riazuddin, S. Amer] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, 600 N Wolfe St, Baltimore, MD 21287 USA. [Khan, Arif O.] King Khalid Eye Specialist Hosp, Riyadh 11462, Saudi Arabia. [Chaerkady, Raghothama; Cole, Robert N.] Johns Hopkins Univ, Sch Med, Dept Biol Chem, 733 North Broadway, Baltimore, MD 21205 USA. [Lee, Mei-Chong W.; Pourmand, Nader] Univ Calif Santa Cruz, Dept Biomol Engn, Santa Cruz, CA 94305 USA. [Leitch, Carmen C.; Zaghloul, Norann A.] Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr, 660 West Redwood St, Baltimore, MD 21201 USA. [Ma, Zhiwei; Hejtmancik, J. Fielding] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. [Laux, Julie; Villasmil, Rafael] NEI, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Khan, Shaheen N.; Riazuddin, Sheikh] Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore 53700, Pakistan. [Riazuddin, Sheikh; Akram, Javed] Univ Hlth Sci, Allama Iqbal Med Coll, Lahore 54550, Pakistan. [Riazuddin, Sheikh; Akram, Javed] Shaheed Zulfiqar Ali Bhutto Med Univ, Natl Ctr Genet Dis, Islamabad 44000, Pakistan. [Talbot, C. Conover] Johns Hopkins Univ, Sch Med, Inst Basic Biomed Sci, 733 North Broadway, Baltimore, MD 21205 USA. RP Riazuddin, SA (reprint author), Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, 600 N Wolfe St, Baltimore, MD 21287 USA. EM riazuddin@jhmi.edu FU Kwok Research Fund; NIDDK/NIH [K01DK092402]; Knight Templar Eye Foundation Grant; King Khaled Eye Specialist Hospital-Johns Hopkins University collaboration grant; National Eye Institute Grant [R01EY022714] FX We are grateful to all family members for their participation in this study. This work was supported in part by the Kwok Research Fund (J.D.G.); NIDDK/NIH K01DK092402 (N.A.Z.); the Knight Templar Eye Foundation Grant (S.A.R.); the King Khaled Eye Specialist Hospital-Johns Hopkins University collaboration grant (S.A.R.); the National Eye Institute Grant R01EY022714 (S.A.R.). NR 40 TC 0 Z9 0 U1 3 U2 9 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 APR PY 2016 VL 7 AR 10953 DI 10.1038/ncomms10953 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI9EJ UT WOS:000373804600001 PM 27218149 ER PT J AU Mohiuddin, MM Singh, AK Corcoran, PC Thomas, ML Clark, T Lewis, BG Hoyt, RF Eckhaus, M Pierson, RN Belli, AJ Wolf, E Klymiuk, N Phelps, C Reimann, KA Ayares, D Horvath, KA AF Mohiuddin, Muhammad M. Singh, Avneesh K. Corcoran, Philip C. Thomas, Marvin L., III Clark, Tannia Lewis, Billeta G. Hoyt, Robert F. Eckhaus, Michael Pierson, Richard N., III Belli, Aaron J. Wolf, Eckhard Klymiuk, Nikolai Phelps, Carol Reimann, Keith A. Ayares, David Horvath, Keith A. TI Chimeric 2C10R4 anti-CD40 antibody therapy is critical for long-term survival of GTKO.hCD46.hTBM pig-to-primate cardiac xenograft SO NATURE COMMUNICATIONS LA English DT Article ID HETEROTOPIC HEART-TRANSPLANTATION; GENE-KNOCKOUT PIGS; COSTIMULATION BLOCKADE; HUMAN THROMBOMODULIN; TRANSGENIC PIGS; XENOTRANSPLANTATION; BABOONS; REJECTION; EXPERIENCE; PROSPECTS AB Preventing xenograft rejection is one of the greatest challenges of transplantation medicine. Here, we describe a reproducible, long-term survival of cardiac xenografts from alpha 1-3 galactosyltransferase gene knockout pigs, which express human complement regulatory protein CD46 and human thrombomodulin (GTKO.hCD46.hTBM), that were transplanted into baboons. Our immunomodulatory drug regimen includes induction with anti-thymocyte globulin and alpha CD20 antibody, followed by maintenance with mycophenolate mofetil and an intensively dosed alpha CD40 (2C10R4) antibody. Median (298 days) and longest (945 days) graft survival in five consecutive recipients using this regimen is significantly prolonged over our recently established survival benchmarks (180 and 500 days, respectively). Remarkably, the reduction of aCD40 antibody dose on day 100 or after 1 year resulted in recrudescence of anti-pig antibody and graft failure. In conclusion, genetic modifications (GTKO.hCD46.hTBM) combined with the treatment regimen tested here consistently prevent humoral rejection and systemic coagulation pathway dysregulation, sustaining long-term cardiac xenograft survival beyond 900 days. C1 [Mohiuddin, Muhammad M.; Singh, Avneesh K.; Corcoran, Philip C.; Horvath, Keith A.] NHLBI, Cardiothorac Surg Res Program, NIH, Bldg 10, Bethesda, MD 20892 USA. [Thomas, Marvin L., III; Lewis, Billeta G.; Eckhaus, Michael] NIH, Div Vet Resources, ORS, Bldg 10, Bethesda, MD 20892 USA. [Clark, Tannia] NICHD, NIH, Bethesda, MD 20892 USA. [Hoyt, Robert F.] Leidos Biomed Res Inc, Bethesda, MD 20892 USA. [Pierson, Richard N., III] Univ Maryland, Med Ctr, Baltimore, MD 20201 USA. [Belli, Aaron J.; Reimann, Keith A.] Univ Massachusetts, Sch Med, MassBiol, Boston, MA 02126 USA. [Wolf, Eckhard; Klymiuk, Nikolai] Univ Munich, D-81377 Munich, Germany. [Phelps, Carol; Ayares, David] Revivicor Inc, Blacksburg, VA 24060 USA. RP Mohiuddin, MM (reprint author), NHLBI, Cardiothorac Surg Res Program, NIH, Bldg 10, Bethesda, MD 20892 USA. EM mohiuddinm@mail.nih.gov RI Mohiuddin, Muhammad/M-4642-2013; OI Mohiuddin, Muhammad/0000-0003-4654-783X; Belli, Aaron/0000-0002-9598-115X; Wolf, Eckhard/0000-0002-0430-9510 FU Revivicor, Inc.; NIH [OD010976]; NIAID [HHSN272200130031C]; German Research Council [TR-CRC 127]; [HHSN268201300001C] FX We acknowledge Drs Cynthia Dunbar and Joshua Chan for careful review of our manuscript, Dr Justin Miller, NHLBI core facilities; Animal Surgery Resource, Flow Cytometry Core, Pathology Core, Division of Veterinary Resources, NIH, for their support in all experimental procedures and Ms Patricia Jackson for the administrative help. Work at NHLBI was funded through a contract HHSN268201300001C and gift funds from Revivicor, Inc. Antibody used in these studies was produced by the NIH Nonhuman Primate Reagent Resource funded by NIH grant OD010976 and NIAID contract HHSN272200130031C. Work at Ludwig Maximilian University was funded by German Research Council, TR-CRC 127. NR 32 TC 8 Z9 8 U1 3 U2 3 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 APR PY 2016 VL 7 AR 11138 DI 10.1038/ncomms11138 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI6OS UT WOS:000373619700001 PM 27045379 ER PT J AU Notarangelo, LD Kim, MS Walter, JE Lee, YN AF Notarangelo, Luigi D. Kim, Min-Sung Walter, Jolan E. Lee, Yu Nee TI Human RAG mutations: biochemistry and clinical implications SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID SEVERE COMBINED IMMUNODEFICIENCY; COMBINED IMMUNE-DEFICIENCY; RECOMBINATION-ACTIVATING GENE; HYPEREOSINOPHILIA OMENNS SYNDROME; COMMON VARIABLE IMMUNODEFICIENCY; IMMUNOGLOBULIN-SECRETING CELLS; REGULATORY T-CELLS; V(D)J RECOMBINATION; B-CELLS; GRANULOMATOUS-DISEASE AB The recombination-activating gene 1 (RAG1) and RAG2 proteins initiate the V(D)J recombination process, which ultimately enables the generation of T cells and B cells with a diversified repertoire of antigen-specific receptors. Mutations of the RAG genes in humans are associated with a broad spectrum of clinical phenotypes, ranging from severe combined immunodeficiency to autoimmunity. Recently, novel insights into the phenotypic diversity of this disease have been provided by resolving the crystal structure of the RAG complex, by developing novel assays to test recombination activity of the mutant RAG proteins and by characterizing the molecular and cellular basis of immune dysregulation in patients with RAG deficiency. C1 [Notarangelo, Luigi D.; Walter, Jolan E.; Lee, Yu Nee] Harvard Univ, Sch Med, Div Immunol, Boston Childrens Hosp, Boston, MA 02115 USA. [Kim, Min-Sung] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Walter, Jolan E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pediat Allergy & Immunol, Boston, MA 02114 USA. [Walter, Jolan E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis, Boston, MA 02114 USA. RP Notarangelo, LD (reprint author), Harvard Univ, Sch Med, Div Immunol, Boston Childrens Hosp, Boston, MA 02115 USA. EM luigi.notarangelo@childrens.harvard.edu FU NIAID NIH HHS [5K08AI103035, 5R01AI100887, K08 AI103035] NR 103 TC 9 Z9 9 U1 2 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 EI 1474-1741 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD APR PY 2016 VL 16 IS 4 BP 234 EP 246 DI 10.1038/nri.2016.28 PG 13 WC Immunology SC Immunology GA DH7MD UT WOS:000372977200009 PM 26996199 ER PT J AU Wacker, D Roth, BL AF Wacker, Daniel Roth, Bryan L. TI An alerting structure: human orexin receptor 1 SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Editorial Material ID ANTAGONISTS; DISCOVERY; INSOMNIA; NARCOLEPSY; HYPOCRETIN; NEURONS AB Structures of the human orexin receptor 1 (hOX(1)R) bound to a selective drug and the dual (hOX(1)R- and hOX(2)R-targeting) antagonist suvorexant reveal molecular mechanisms of selectivity in orexin-receptor subtypes. C1 [Wacker, Daniel; Roth, Bryan L.] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC USA. [Roth, Bryan L.] Univ N Carolina, Eshelman Sch Pharm, Div Chem Biol & Med Chem, Chapel Hill, NC USA. [Roth, Bryan L.] Univ N Carolina, Sch Med, NIMH PDSP, Chapel Hill, NC USA. RP Roth, BL (reprint author), Univ N Carolina, Dept Pharmacol, Chapel Hill, NC USA.; Roth, BL (reprint author), Univ N Carolina, Eshelman Sch Pharm, Div Chem Biol & Med Chem, Chapel Hill, NC USA.; Roth, BL (reprint author), Univ N Carolina, Sch Med, NIMH PDSP, Chapel Hill, NC USA. EM bryan_roth@med.unc.edu NR 18 TC 0 Z9 0 U1 3 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 EI 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD APR PY 2016 VL 23 IS 4 BP 265 EP 266 PG 2 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA DI7DC UT WOS:000373658300001 PM 27045444 ER PT J AU Wollscheid, HP Biancospino, M He, FH Magistrati, E Molteni, E Lupia, M Soffientini, P Rottner, K Cavallaro, U Pozzoli, U Mapelli, M Walters, KJ Polo, S AF Wollscheid, Hans-Peter Biancospino, Matteo He, Fahu Magistrati, Elisa Molteni, Erika Lupia, Michela Soffientini, Paolo Rottner, Klemens Cavallaro, Ugo Pozzoli, Uberto Mapelli, Marina Walters, Kylie J. Polo, Simona TI Diverse functions of myosin VI elucidated by an isoform-specific alpha-helix domain SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID BORDER CELL-MIGRATION; MEDIATED ENDOCYTOSIS; POTENTIAL ROLES; PROSTATE-CANCER; BINDING PARTNER; DROSOPHILA; ACTIN; CARGO; SPERMATOGENESIS; CYTOSKELETON AB Myosin VI functions in endocytosis and cell motility. Alternative splicing of myosin VI mRNA generates two distinct isoform types, myosin VIshort and myosin VIlong, which differ in the C-terminal region. Their physiological and pathological roles remain unknown. Here we identified an isoform-specific regulatory helix, named the alpha 2-linker, that defines specific conformations and hence determines the target selectivity of human myosin VI. The presence of the alpha 2-linker structurally defines a new clathrin-binding domain that is unique to myosin VIlong and masks the known RRL interaction motif. This finding is relevant to ovarian cancer, in which alternative myosin VI splicing is aberrantly regulated, and exon skipping dictates cell addiction to myosin VIshort in tumor-cell migration. The RRL interactor optineurin contributes to this process by selectively binding myosin VIshort. Thus, the alpha 2-linker acts like a molecular switch that assigns myosin VI to distinct endocytic (myosin VIlong) or migratory (myosin VIshort) functional roles. C1 [Wollscheid, Hans-Peter; Biancospino, Matteo; Magistrati, Elisa; Soffientini, Paolo; Polo, Simona] Fdn Ist FIRC Oncol Mol IFOM, Milan, Italy. [He, Fahu; Walters, Kylie J.] NCI, Ctr Canc Res, Frederick, MD 21701 USA. [Magistrati, Elisa; Pozzoli, Uberto] Sci Inst Eugenio Medea, Computat Biol, Bosisio Parini, Italy. [Lupia, Michela; Cavallaro, Ugo] European Inst Oncol, Program Mol Med, Milan, Italy. [Rottner, Klemens] Helmholtz Ctr Infect Res, Braunschweig, Germany. [Rottner, Klemens] Braunschweig Univ Technol, Braunschweig, Germany. [Mapelli, Marina] European Inst Oncol, Dept Expt Oncol, Milan, Italy. [Polo, Simona] Univ Milan, Dipartimento Oncol & Ematooncol DIPO, Milan, Italy. [Wollscheid, Hans-Peter] Inst Mol Biol, Mainz, Germany. RP Polo, S (reprint author), Fdn Ist FIRC Oncol Mol IFOM, Milan, Italy.; Polo, S (reprint author), Univ Milan, Dipartimento Oncol & Ematooncol DIPO, Milan, Italy. EM simona.polo@ifom.eu RI Cavallaro, Ugo/J-9745-2012; Polo, Simona/P-3509-2014; Molteni, Erika/P-4564-2016; OI Molteni, Erika/0000-0001-7773-8140; Pozzoli, Uberto/0000-0003-0670-7106 FU Association for International Cancer Research (AICR) [11-0051]; Italian Ministry of Education, Universities and Research [PAIN 20108MXN2J]; Intramural Research Program of the US National Cancer Institute; Associazione Italiana per la Ricerca sul Cancro (AIRC) - Marie Curie Actions; Fondazione Umberto Veronesi (FUV) FX We thank F. Buss for critically reading the manuscript and for helpful discussions and advice and M. Ladwein for performing initial wound healing experiments. We also thank E. Hirsch (University di Torino), S. Maddika (Centre for DNA Fingerprinting and Diagnostics), A. Israel (Institute Pasteur), F. Buss (Cambridge Institute for Medical Research), G. Serini (University di Torino) and F. Randow (Medical Research Council) for DNA constructs. This work was supported by the Association for International Cancer Research (AICR), grant 11-0051 (S.P.); from Italian Ministry of Education, Universities and Research, grant PAIN 20108MXN2J (S.P.) and the Intramural Research Program of the US National Cancer Institute (K.J.W.). H.-P.W. was supported by a fellowship from the Associazione Italiana per la Ricerca sul Cancro (AIRC) cofunded by Marie Curie Actions. M.B. was supported by a fellowship from the Fondazione Umberto Veronesi (FUV). NR 39 TC 1 Z9 1 U1 3 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 EI 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD APR PY 2016 VL 23 IS 4 BP 300 EP 308 DI 10.1038/nsmb.3187 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA DI7DC UT WOS:000373658300007 PM 26950368 ER PT J AU Liang, XP Shan, S Pan, L Zhao, JC Ranjan, A Wang, F Zhang, ZQ Huang, YZ Feng, HQ Wei, D Huang, L Liu, XH Zhong, Q Lou, JZ Li, GH Wu, C Zhou, Z AF Liang, Xiaoping Shan, Shan Pan, Lu Zhao, Jicheng Ranjan, Anand Wang, Feng Zhang, Zhuqiang Huang, Yingzi Feng, Hanqiao Wei, Debbie Huang, Li Liu, Xuehui Zhong, Qiang Lou, Jizhong Li, Guohong Wu, Carl Zhou, Zheng TI Structural basis of H2A.Z recognition by SRCAP chromatin-remodeling subunit YL1 SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID NUCLEOSOME CORE PARTICLE; HISTONE CHAPERONE; CRYSTAL-STRUCTURE; REMOVES H2A.Z; BAH DOMAIN; COMPLEX; SWR1; EXCHANGE; ANP32E; REPLACEMENT AB Histone variant H2A.Z, a universal mark of dynamic nucleosomes flanking gene promoters and enhancers, is incorporated into chromatin by SRCAP (SWR1), an ATP-dependent, multicomponent chromatin-remodeling complex. The YL1 (Swc2) subunit of SRCAP (SWR1) plays an essential role in H2A.Z recognition, but how it achieves this has been unclear. Here, we report the crystal structure of the H2A.Z-binding domain of Drosophila melanogaster YL1 (dYL1-Z) in complex with an H2A.Z-H2B dimer at 1.9-angstrom resolution. The dYL1-Z domain adopts a new whip-like structure that wraps over H2A.Z-H2B, and preferential recognition is largely conferred by three residues in loop 2, the hyperacidic patch and the extended alpha C helix of H2A.Z. Importantly, this domain is essential for deposition of budding yeast H2A.Z in vivo and SRCAP (SWR1)-catalyzed histone H2A.Z replacement in vitro. Our studies distinguish YL1-Z from known H2A.Z chaperones and suggest a hierarchical mechanism based on increasing binding affinity facilitating H2A.Z transfer from SRCAP (SWR1) to the nucleosome. C1 [Liang, Xiaoping; Shan, Shan; Pan, Lu; Zhao, Jicheng; Zhang, Zhuqiang; Huang, Yingzi; Huang, Li; Liu, Xuehui; Zhong, Qiang; Lou, Jizhong; Li, Guohong; Zhou, Zheng] Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing 100080, Peoples R China. [Liang, Xiaoping; Pan, Lu; Huang, Li; Zhou, Zheng] Univ Chinese Acad Sci, Beijing, Peoples R China. [Ranjan, Anand; Wu, Carl] Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA USA. [Wang, Feng; Feng, Hanqiao; Wei, Debbie; Wu, Carl] NCI, Lab Biochem & Mol Biol, Ctr Canc Res, Bethesda, MD 20892 USA. RP Zhou, Z (reprint author), Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing 100080, Peoples R China.; Zhou, Z (reprint author), Univ Chinese Acad Sci, Beijing, Peoples R China.; Wu, C (reprint author), Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA USA.; Wu, C (reprint author), NCI, Lab Biochem & Mol Biol, Ctr Canc Res, Bethesda, MD 20892 USA. EM wuc@janelia.hhmi.org; zhouzh@sun5.ibp.ac.cn OI Zhang, Zhuqiang/0000-0001-6513-2854 FU Chinese Ministry of Science and Technology [2015CB856200, 2013CB910203]; Natural Science Foundation of China [31521002, 31270833, 31123003]; Janelia Research Campus, Howard Hughes Medical Institute; Center for Cancer Research, US National Cancer Institute FX We thank Y. Bai, B. Zhu, C. Tang and Y. Huang for invaluable suggestions; Shanghai Synchrotron Radiation Facility beamline scientists for technical support with data collection; Y. Chen, H. Wang and J. Wang for advice on ITC analysis; and X. Yu for assistance with AUC analysis. The study was supported by grants from the Chinese Ministry of Science and Technology (2015CB856200 and 2013CB910203 to Z. Zhou) and grants from the Natural Science Foundation of China (31521002, 31270833 and 31123003 to Z. Zhou). C.W. and A.R. are supported by the Janelia Research Campus, Howard Hughes Medical Institute. F.W. and D.W. are supported by the Center for Cancer Research, US National Cancer Institute. Z. Zhou is supported as a CAS-Novo Nordisk Great Wall Professor. NR 27 TC 2 Z9 2 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 EI 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD APR PY 2016 VL 23 IS 4 BP 317 EP 323 DI 10.1038/nsmb.3190 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA DI7DC UT WOS:000373658300009 PM 26974124 ER PT J AU Ray, S Chintaluri, C Bhalla, US Wojcik, DK AF Ray, Subhasis Chintaluri, Chaitanya Bhalla, Upinder S. Wojcik, Daniel K. TI NSDF: Neuroscience Simulation Data Format SO NEUROINFORMATICS LA English DT Article DE Data sharing; Analysis tools; Visualization; Simulations; Data format ID NETWORK MODEL; NEURONS; TOOL; BIG AB Data interchange is emerging as an essential aspect of modern neuroscience. In the areas of computational neuroscience and systems biology there are multiple model definition formats, which have contributed strongly to the development of an ecosystem of simulation and analysis tools. Here we report the development of the Neuroscience Simulation Data Format (NSDF) which extends this ecosystem to the data generated in simulations. NSDF is designed to store simulator output across scales: from multiscale chemical and electrical signaling models, to detailed single-neuron and network models, to abstract neural nets. It is self-documenting, efficient, modular, and scalable, both in terms of novel data types and in terms of data volume. NSDF is simulator-independent, and can be used by a range of standalone analysis and visualization tools. It may also be used to store variety of experimental data. NSDF is based on the widely used HDF5 (Hierarchical Data Format 5) specification and is open, platform-independent, and portable. C1 [Ray, Subhasis; Bhalla, Upinder S.] Tata Inst Fundamental Res, Natl Ctr Biol Sci, Bangalore, Karnataka, India. [Chintaluri, Chaitanya; Wojcik, Daniel K.] Nencki Inst Expt Biol, Warsaw, Poland. [Ray, Subhasis] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Bhalla, US (reprint author), Tata Inst Fundamental Res, Natl Ctr Biol Sci, Bangalore, Karnataka, India.; Wojcik, DK (reprint author), Nencki Inst Expt Biol, Warsaw, Poland. EM bhalla@ncbs.res.in; d.wojcik@nencki.gov.pl RI Wojcik, Daniel/C-6334-2008; OI Wojcik, Daniel/0000-0003-0812-9872; Chintaluri, Hanuma Chaitanya/0000-0003-4252-1608 FU EC-FP7-PEOPLE [264872]; Polish Ministry for Science and Higher Education [2948/7.PR/2013/2]; National Centre for Biological Sciences; Tata institute of Fundamental Research, Bangalore, India FX This work is supported by EC-FP7-PEOPLE sponsored NAMASEN Marie-Curie ITN grant 264872, Polish Ministry for Science and Higher Education grant 2948/7.PR/2013/2, and by National Centre for Biological Sciences, Tata institute of Fundamental Research, Bangalore, India. The authors would like to thank the HDF Group/NASA for providing sample NASA HDF/HDF-EOS data files. Aviral Goel, Johannes Rieke and Matteo Cantarelli for their critical comments. NR 57 TC 2 Z9 2 U1 2 U2 8 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1539-2791 EI 1559-0089 J9 NEUROINFORMATICS JI Neuroinformatics PD APR PY 2016 VL 14 IS 2 BP 147 EP 167 DI 10.1007/s12021-015-9282-5 PG 21 WC Computer Science, Interdisciplinary Applications; Neurosciences SC Computer Science; Neurosciences & Neurology GA DI6WV UT WOS:000373641800003 PM 26585711 ER PT J AU Merrill, MJ Nai, D Ghosh, P Edwards, NA Hallett, M Ray-Chaudhury, A AF Merrill, M. J. Nai, D. Ghosh, P. Edwards, N. A. Hallett, M. Ray-Chaudhury, A. TI Neuropathology in a case of episodic ataxia type 4 SO NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY LA English DT Letter ID AUTOSOMAL-DOMINANT ATAXIA; VESTIBULOCEREBELLAR ATAXIA; SPINOCEREBELLAR; PATHOGENESIS C1 [Merrill, M. J.; Nai, D.; Edwards, N. A.; Ray-Chaudhury, A.] NINDS, NIH, Surg Neurol Branch, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Ghosh, P.; Hallett, M.] NINDS, NIH, Med Neurol Branch, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Ghosh, P.] George Washington Univ, Med Fac Associates, Dept Neurol, Washington, DC USA. RP Merrill, MJ (reprint author), NINDS, NIH, Surg Neurol Branch, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. FU Intramural NIH HHS; NICHD NIH HHS [N01-HD-9-0]; PHS HHS [HHSN275200900011C] NR 12 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0305-1846 EI 1365-2990 J9 NEUROPATH APPL NEURO JI Neuropathol. Appl. Neurobiol. PD APR PY 2016 VL 42 IS 3 BP 296 EP 300 DI 10.1111/nan.12262 PG 5 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA DI4TP UT WOS:000373492500008 PM 26264377 ER PT J AU Zhang, P Hire, D Espeland, MA Knowler, WC Thomas, S Tsai, AG Glick, HA AF Zhang, Ping Hire, Don Espeland, Mark A. Knowler, William C. Thomas, Sheikilya Tsai, Adam G. Glick, Henry A. CA Look AHEAD Res Grp TI Impact of intensive lifestyle intervention on preference-based quality of life in type 2 diabetes: Results from the Look AHEAD trial SO OBESITY LA English DT Article ID WEIGHT-LOSS INTERVENTION; HEALTH UTILITIES INDEX; IMPORTANT DIFFERENCE; OBESE ADULTS; MULTIATTRIBUTE; DISEASE; SYSTEM; SF-36; SF-6D; EQ-5D AB ObjectiveTo assess the effect of an intensive lifestyle intervention (ILI) compared with standard diabetes support and education (DSE) on preference-based health-related quality of life (HRQOL) in persons with overweight or obesity and type 2 diabetes. MethodsLook AHEAD was a multisite, randomized trial of 5,145 participants assigned to ILI or DSE. Four instruments were administered during the trial: Feeling Thermometer (FT), Health Utilities Index Mark 2 (HUI2), Health Utilities Index Mark 3 (HUI3), and Short Form 6D (SF-6D). Linear mixed effect models were used to estimate the mean difference in preference scores by treatment group for 9 years. ResultsThe ILI had higher mean FT (0.019, 95% CI, 0.015-0.024, P<0.001) and SF-6D (0.011, 95% CI, 0.006-0.014, P<0.001) scores than the DSE. No significant group differences were observed for the HUI2 (0.004, 95% CI, -0.003 to 0.010, P=0.23) and HUI3 (0.004, -0.004 to 0.012, P=0.36). In year 1, the ILI had higher mean preference scores for all instruments. Thereafter, the increases remained significant only for FT and SF-6D, and the effects also become smaller. ConclusionsILI aimed at reducing body weight among persons with overweight or obesity and type 2 diabetes improves preference-based HRQOL in the short term, but its long-term effect is unclear. C1 [Zhang, Ping] Ctr Dis Control & Prevent, Div Diabet Translat, Atlanta, GA USA. [Hire, Don; Espeland, Mark A.] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Knowler, William C.] NIDDKD, Phoenix, AZ USA. [Thomas, Sheikilya] Univ Alabama Birmingham, Div Prevent Med, Birmingham, AL USA. [Tsai, Adam G.] Univ Colorado, Sch Med, Div Internal Med, Aurora, CO USA. [Glick, Henry A.] Univ Penn, Div Gen Internal Med, Philadelphia, PA 19104 USA. RP Zhang, P (reprint author), Ctr Dis Control & Prevent, Div Diabet Translat, Atlanta, GA USA. EM pzhang@cdc.gov FU Department of Health and Human Services through National Institutes of Health (NIH) [DK57136, DK57149, DK56990, DK57177, DK57171, DK57151, DK57182, DK57131, DK57002, DK57078, DK57154, DK57178, DK57219, DK57008, DK57135, DK56992]; National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute; National Institute of Nursing Research; National Center on Minority Health and Health Disparities; Office of Research on Women's Health; Centers for Disease Control and Prevention; Department of Veterans Affairs; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; Johns Hopkins Medical Institutions Bayview General Clinical Research Center [M01RR02719]; Massachusetts General Hospital Mallinckrodt General Clinical Research Center; Massachusetts Institute of Technology General Clinical Research Center [M01RR01066]; University of Colorado Health Sciences Center General Clinical Research Center [M01RR00051]; Clinical Nutrition Research Unit [P30 DK48520]; University of Tennessee at Memphis General Clinical Research Center [M01RR0021140]; University of Pittsburgh General Clinical Research Center [M01RR000056]; Clinical Translational Research Center - Clinical & Translational Science Award [UL1 RR 024153]; NIH [DK 046204]; Frederic C. Bartter General Clinical Research Center [M01RR01346] FX This study is supported by the Department of Health and Human Services through the following cooperative agreements from the National Institutes of Health (NIH): DK57136, DK57149, DK56990, DK57177, DK57171, DK57151, DK57182, DK57131, DK57002, DK57078, DK57154, DK57178, DK57219, DK57008, DK57135, and DK56992. The following federal agencies have contributed support: National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute; National Institute of Nursing Research; National Center on Minority Health and Health Disparities; Office of Research on Women's Health; the Centers for Disease Control and Prevention; and the Department of Veterans Affairs. This research was supported in part by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. The Indian Health Service (I.H.S.) provided personnel, medical oversight, and use of facilities. The opinions expressed in this paper are those of the authors and do not necessarily reflect the views of the I.H.S. or other funding sources. Additional support was received from The Johns Hopkins Medical Institutions Bayview General Clinical Research Center (M01RR02719); the Massachusetts General Hospital Mallinckrodt General Clinical Research Center and the Massachusetts Institute of Technology General Clinical Research Center (M01RR01066); the University of Colorado Health Sciences Center General Clinical Research Center (M01RR00051) and Clinical Nutrition Research Unit (P30 DK48520); the University of Tennessee at Memphis General Clinical Research Center (M01RR0021140); the University of Pittsburgh General Clinical Research Center (M01RR000056) and the Clinical Translational Research Center funded by the Clinical & Translational Science Award (UL1 RR 024153) and NIH grant (DK 046204); and the Frederic C. Bartter General Clinical Research Center (M01RR01346). The following organizations have committed to make major contributions to Look AHEAD: FedEx Corporation; Health Management Resources; LifeScan, Inc., a Johnson & Johnson Company; OPTIFAST (R) of Nestle HealthCare Nutrition, Inc.; Hoffmann-La Roche Inc.; Abbott Nutrition; and Slim-Fast Brand of Unilever North America. NR 38 TC 0 Z9 0 U1 3 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD APR PY 2016 VL 24 IS 4 BP 856 EP 864 DI 10.1002/oby.21445 PG 9 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA DI6MM UT WOS:000373613200016 PM 27028282 ER PT J AU Mayuko, K Kaneko, H Sadatsuki, R Futami, I Hada, S Arita, H Shiozawa, J Hirasawa-Arikawa, E Yamada, Y Kaneko, K Ishijima, M AF Mayuko, K. Kaneko, H. Sadatsuki, R. Futami, I. Hada, S. Arita, H. Shiozawa, J. Hirasawa-Arikawa, E. Yamada, Y. Kaneko, K. Ishijima, M. TI PERLECAN REGULATES CHONDROGENIC DIFFERENTIATION FROM SYNOVIAL MESENCHYMAL CELLS VIA SMAD AND MAPK SIGNALING PATHWAYS SO OSTEOARTHRITIS AND CARTILAGE LA English DT Meeting Abstract CT World Congress of the Osteoarthritis-Research-Society-International (OARSI) on Osteoarthritis CY MAR 31-APR 03, 2016 CL Amsterdam, NETHERLANDS SP Osteoarthritis Res Soc Int C1 [Mayuko, K.; Sadatsuki, R.] Juntendo Univ, Grad Sch Med, JDept Orthoped & Motor Organ, Tokyo, Japan. [Kaneko, H.; Futami, I.; Hada, S.; Arita, H.; Shiozawa, J.; Kaneko, K.; Ishijima, M.] Juntendo Univ, Grad Sch Med, Dept Orthoped & Motor Organ, Tokyo, Japan. [Hirasawa-Arikawa, E.] Juntendo Univ, Grad Sch Med, Res Inst Dis Old Age, Tokyo, Japan. [Yamada, Y.] NIDCR, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1063-4584 EI 1522-9653 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD APR PY 2016 VL 24 SU S MA 296 BP S177 EP S177 PG 1 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA DI5KW UT WOS:000373538800326 ER PT J AU Rathbun, AM Yau, M Shardell, M Stuart, E Hochberg, M AF Rathbun, A. M. Yau, M. Shardell, M. Stuart, E. Hochberg, M. TI DEPRESSIVE SYMPTOMS AND STRUCTURAL DISEASE PROGRESSION IN KNEE OSTEOARTHRITIS: DATA FROM THE OSTEOARTHRITIS INITIATIVE SO OSTEOARTHRITIS AND CARTILAGE LA English DT Meeting Abstract CT World Congress of the Osteoarthritis-Research-Society-International (OARSI) on Osteoarthritis CY MAR 31-APR 03, 2016 CL Amsterdam, NETHERLANDS SP Osteoarthritis Res Soc Int C1 [Rathbun, A. M.; Hochberg, M.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Yau, M.] Harvard Univ, Sch Med, Inst Aging Res, Hebrew SeniorLife, Boston, MA USA. [Shardell, M.] NIA, Baltimore, MD 21224 USA. [Stuart, E.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1063-4584 EI 1522-9653 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD APR PY 2016 VL 24 SU S MA 363 BP S214 EP S215 PG 2 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA DI5KW UT WOS:000373538800393 ER PT J AU Rathbun, AM Stuart, E Shardell, M Yau, M Hochberg, M AF Rathbun, A. M. Stuart, E. Shardell, M. Yau, M. Hochberg, M. TI ESTIMATING THE IMPACT OF DEPRESSIVE SYMPTOMS ON OSTEOARTHRITIS PAIN USING MARGINAL STRUCTURAL MODELS: DATA FROM THE OSTEOARTHRITIS INITIATIVE SO OSTEOARTHRITIS AND CARTILAGE LA English DT Meeting Abstract CT World Congress of the Osteoarthritis-Research-Society-International (OARSI) on Osteoarthritis CY MAR 31-APR 03, 2016 CL Amsterdam, NETHERLANDS SP Osteoarthritis Res Soc Int C1 [Rathbun, A. M.; Hochberg, M.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Stuart, E.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Shardell, M.] NIA, Baltimore, MD 21224 USA. [Yau, M.] Harvard Univ, Sch Med, Inst Aging Res, Hebrew SeniorLife, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1063-4584 EI 1522-9653 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD APR PY 2016 VL 24 SU S MA 339 BP S199 EP S199 PG 1 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA DI5KW UT WOS:000373538800369 ER PT J AU van den Bosch, MH Blom, AB Maeda, A Kilts, TM van den Berg, WB Lafeber, FP van Lent, PL Young, MF van der Kraan, PM AF van den Bosch, M. H. Blom, A. B. Maeda, A. Kilts, T. M. van den Berg, W. B. Lafeber, F. P. van Lent, P. L. Young, M. F. van der Kraan, P. M. TI WISP1, A DOWNSTREAM MEDIATOR OF CANONICAL WNT SIGNALING, INDUCES PATHOLOGY IN EXPERIMENTAL OSTEOARTHRITIS AND PREDICTS DISEASE PROGRESSION IN EARLY OSTEOARTHRITIS PATIENTS. SO OSTEOARTHRITIS AND CARTILAGE LA English DT Meeting Abstract CT World Congress of the Osteoarthritis-Research-Society-International (OARSI) on Osteoarthritis CY MAR 31-APR 03, 2016 CL Amsterdam, NETHERLANDS SP Osteoarthritis Res Soc Int C1 [van den Bosch, M. H.; Blom, A. B.; van den Berg, W. B.; van Lent, P. L.; van der Kraan, P. M.] Radboud Univ Nijmegen, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Maeda, A.; Kilts, T. M.; Young, M. F.] NIDCR, NIH, Bethesda, MD USA. [Lafeber, F. P.] Univ Utrecht, Med Ctr, Utrecht, Netherlands. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1063-4584 EI 1522-9653 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD APR PY 2016 VL 24 SU S MA 75 BP S52 EP S53 PG 2 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA DI5KW UT WOS:000373538800105 ER PT J AU Becker, JB Koob, GF AF Becker, Jill B. Koob, George F. TI Sex Differences in Animal Models: Focus on Addiction SO PHARMACOLOGICAL REVIEWS LA English DT Review ID COCAINE-SEEKING BEHAVIOR; ACUTE ETHANOL WITHDRAWAL; MENSTRUAL-CYCLE PHASE; PITUITARY-ADRENAL AXIS; ANXIETY-LIKE BEHAVIOR; SPRAGUE-DAWLEY RATS; CORTICOTROPIN-RELEASING-FACTOR; VOLUNTARY ALCOHOL-CONSUMPTION; SELF-ADMINISTERED COCAINE; STRIATAL DOPAMINE RELEASE AB The purpose of this review is to discuss ways to think about and study sex differences in preclinical animal models. We use the framework of addiction, in which animal models have excellent face and construct validity, to illustrate the importance of considering sex differences. There are four types of sex differences: qualitative, quantitative, population, and mechanistic. A better understanding of the ways males and females can differ will help scientists design experiments to characterize better the presence or absence of sex differences in new phenomena that they are investigating. We have outlined major quantitative, population, and mechanistic sex differences in the addiction domain using a heuristic framework of the three established stages of the addiction cycle: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. Female rats, in general, acquire the self-administration of drugs and alcohol more rapidly, escalate their drug taking with extended access more rapidly, show more motivational withdrawal, and (where tested in animal models of "craving") show greater reinstatement. The one exception is that female rats show less motivational withdrawal to alcohol. The bases for these quantitative sex differences appear to be both organizational, in that estradiol-treated neonatal animals show the male phenotype, and activational, in that the female phenotype depends on the effects of gonadal hormones. In animals, differences within the estrous cycle can be observed but are relatively minor. Such hormonal effects seem to be most prevalent during the acquisition of drug taking and less influential once compulsive drug taking is established and are linked largely to progesterone and estradiol. This review emphasizes not only significant differences in the phenotypes of females and males in the domain of addiction but emphasizes the paucity of data to date in our understanding of those differences. C1 [Becker, Jill B.] Univ Michigan, Dept Psychiat, Mol & Behav Neurosci Inst, Dept Psychol, Ann Arbor, MI 48109 USA. [Koob, George F.] NIAAA, 5635 Fishers Lane,Room 2001,Suite 2000, Bethesda, MD 20852 USA. RP Koob, GF (reprint author), NIAAA, 5635 Fishers Lane,Room 2001,Suite 2000, Bethesda, MD 20852 USA. EM george.koob@nih.gov RI koob, george/P-8791-2016 FU National Institutes of Health, National Institute on Drug Abuse [5R21DA032747] FX This work was supported by the National Institutes of Health, National Institute on Drug Abuse [Grant 5R21DA032747]. NR 224 TC 30 Z9 31 U1 11 U2 32 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0031-6997 EI 1521-0081 J9 PHARMACOL REV JI Pharmacol. Rev. PD APR PY 2016 VL 68 IS 2 BP 242 EP 263 DI 10.1124/pr.115.011163 PG 22 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DI8WO UT WOS:000373783300001 PM 26772794 ER PT J AU DuMond, JF Ramkissoon, K Zhang, X Izumi, Y Wang, XJ Eguchi, K Gao, SG Mukoyama, M Burg, MB Ferraris, JD AF DuMond, Jenna F. Ramkissoon, Kevin Zhang, Xue Izumi, Yuichiro Wang, Xujing Eguchi, Koji Gao, Shouguo Mukoyama, Masashi Burg, Maurice B. Ferraris, Joan D. TI Peptide affinity analysis of proteins that bind to an unstructured NH2-terminal region of the osmoprotective transcription factor NFAT5 SO PHYSIOLOGICAL GENOMICS LA English DT Article DE intrinsic disorder; proteomics; osmolality ID INTRINSICALLY DISORDERED PROTEIN; DAMAGE-INDUCIBLE KINASE; LARGE GENE LISTS; HIGH-NACL; FACTOR TONEBP/OREBP; HYPERTONIC STRESS; NUCLEOCYTOPLASMIC TRAFFICKING; INTERACTION NETWORKS; MASS-SPECTROMETRY; OSMOTIC-STRESS AB NFAT5 is an osmoregulated transcription factor that particularly increases expression of genes involved in protection against hypertonicity. Transcription factors often contain unstructured regions that bind co-regulatory proteins that are crucial for their function. The NH2-terminal region of NFAT5 contains regions predicted to be intrinsically disordered. We used peptide aptamer-based affinity chromatography coupled with mass spectrometry to identify protein preys pulled down by one or more overlapping 20 amino acid peptide baits within a predicted NH2-terminal unstructured region of NFAT5. We identify a total of 467 unique protein preys that associate with at least one NH2-terminal peptide bait from NFAT5 in either cytoplasmic or nuclear extracts from HEK293 cells treated with elevated, normal, or reduced NaCl concentrations. Different sets of proteins are pulled down from nuclear vs. cytoplasmic extracts. We used GeneCards to ascertain known functions of the protein preys. The protein preys include many that were previously known, but also many novel ones. Consideration of the novel ones suggests many aspects of NFAT5 regulation, interaction and function that were not previously appreciated, for example, hypertonicity inhibits NFAT5 by sumoylating it and the NFAT5 protein preys include components of the CHTOP complex that desumoylate proteins, an action that should contribute to activation of NFAT5. C1 [DuMond, Jenna F.; Ramkissoon, Kevin; Zhang, Xue; Izumi, Yuichiro; Wang, Xujing; Gao, Shouguo; Burg, Maurice B.; Ferraris, Joan D.] NHLBI, Syst Biol Ctr, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA. [Izumi, Yuichiro; Eguchi, Koji; Mukoyama, Masashi] Kumamoto Univ, Grad Sch Med Sci, Dept Nephrol, Kumamoto, Japan. RP Burg, MB (reprint author), Bldg 10,Rm 6N307,9000 Rockville Pike, Bethesda, MD 20892 USA. EM Maurice_burg@nih.gov NR 58 TC 1 Z9 1 U1 3 U2 6 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1094-8341 EI 1531-2267 J9 PHYSIOL GENOMICS JI Physiol. Genomics PD APR 1 PY 2016 VL 48 IS 4 BP 290 EP 305 DI 10.1152/physiolgenomics.00110.2015 PG 16 WC Cell Biology; Genetics & Heredity; Physiology SC Cell Biology; Genetics & Heredity; Physiology GA DI4VJ UT WOS:000373497200005 PM 26757802 ER PT J AU Chen, CH Liao, HM Chen, HI Fang, JS Chen, YJ Lee, KF Gau, SSF AF Chen, Chia-Hsiang Liao, Hsiao-Mei Chen, Hsin-I Fang, Jye-Siung Chen, Yan-Jang Lee, Kuei-Fang Gau, Susan Shur-Fen TI Complex genomic variants contribute toward the genetic architecture of autism spectrum disorder SO PSYCHIATRIC GENETICS LA English DT Article C1 [Chen, Chia-Hsiang] Chang Gung Univ, Chang Gung Mem Hosp, Linkou Med Ctr, Dept Psychiat, Taoyuan, Taiwan. [Chen, Chia-Hsiang] Chang Gung Univ, Dept & Grad Inst Biomed, Taoyuan, Taiwan. [Liao, Hsiao-Mei; Chen, Hsin-I; Gau, Susan Shur-Fen] Natl Taiwan Univ Hosp, Dept Psychiat, 7 Chung Shan South Rd, Taipei 10002, Taiwan. [Liao, Hsiao-Mei; Chen, Hsin-I; Gau, Susan Shur-Fen] Coll Med, 7 Chung Shan South Rd, Taipei 10002, Taiwan. [Chen, Yan-Jang] Natl Yang Ming Univ, Dept Life Sci, Taipei 112, Taiwan. [Chen, Yan-Jang] Natl Yang Ming Univ, Inst Genome Sci, Taipei 112, Taiwan. [Gau, Susan Shur-Fen] Natl Taiwan Univ, Grad Inst Brain & Mind Sci, Taipei 10764, Taiwan. [Gau, Susan Shur-Fen] Natl Taiwan Univ, Grad Inst Clin Med, Taipei 10764, Taiwan. [Fang, Jye-Siung; Lee, Kuei-Fang] Tzu Chi Gen Hosp, Ctr Med Genet, Hualien, Taiwan. [Liao, Hsiao-Mei] NIMH, Mol Neurobiol Sect, NIH, Bethesda, MD 20892 USA. RP Gau, SSF (reprint author), Natl Taiwan Univ Hosp, Dept Psychiat, 7 Chung Shan South Rd, Taipei 10002, Taiwan.; Gau, SSF (reprint author), Coll Med, 7 Chung Shan South Rd, Taipei 10002, Taiwan. EM gaushufe@ntu.edu.tw FU National Science Council [NSC96-3112-B-002-033, NSC97-3112-B-002-009, NSC98-3112-B-002-004, NSC 99-3112-B-002-036]; National Taiwan University [10R81918-03, 101R892103, 102R892103]; National Health Research Institutes, Taiwan FX This work was supported by grants from the National Science Council (NSC96-3112-B-002-033, NSC97-3112-B-002-009, NSC98-3112-B-002-004, and NSC 99-3112-B-002-036 to S.S. Gau), the National Taiwan University (AIM for Top University Excellent Research Project: 10R81918-03, 101R892103, 102R892103 to S.S. Gau), and an intramural grant from the National Health Research Institutes (to C.H. Chen), Taiwan. NR 5 TC 1 Z9 1 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0955-8829 EI 1473-5873 J9 PSYCHIAT GENET JI Psychiatr. Genet. PD APR PY 2016 VL 26 IS 2 BP 95 EP 96 DI 10.1097/YPG.0000000000000120 PG 2 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA DI5GM UT WOS:000373526900008 PM 26901793 ER PT J AU Moskow, DM Addington, J Bearden, CE Cadenhead, KS Cornblatt, BA Heinssen, R Mathalon, DH McGlashan, TH Perkins, DO Seidman, LJ Tsuang, MT Cannon, TD Woods, SW Walker, EF AF Moskow, Danielle M. Addington, Jean Bearden, Carrie E. Cadenhead, Kristin S. Cornblatt, Barbara A. Heinssen, Robert Mathalon, Daniel H. McGlashan, Thomas H. Perkins, Diana O. Seidman, Larry J. Tsuang, Ming T. Cannon, Tyrone D. Woods, Scott W. Walker, Elaine F. TI The relations of age and pubertal development with cortisol and daily stress in youth at clinical risk for psychosis SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Schizophrenia; Psychosis; Puberty; Stress; Cortisol; Clinical high risk ID ULTRA-HIGH RISK; LIFE EVENTS; DEVELOPING SCHIZOPHRENIA; DEPRESSIVE SYMPTOMS; GENDER-DIFFERENCES; SALIVARY CORTISOL; ADOLESCENT BRAIN; HEALTHY CONTROLS; INITIAL FINDINGS; DISORDERS AB Background: Prodromal syndromes often begin in adolescence - a period of neurodevelopmental changes and heightened stress sensitivity. Research has shown elevated stress and cortisol in individuals at clinical high risk (CHR) for psychosis. This cross-sectional study examined relations of age and pubertal status with cortisol and self-reported stress in healthy controls (HCs) and CHR adolescents. It was hypothesized that the relations of age and pubertal stage with cortisol and stress would be more pronounced in CHR youth. Methods: Participants were 93 HCs and 348 CHR adolescents from the North American Prodrome Longitudinal Study (NAPLS). At baseline, measures of stress (Daily Stress Inventory-DSI), Tanner stage (TS), and salivary cortisol were obtained. Results: ANCOVA revealed increased DSI scores with age for both groups, and higher DSI scores in CHR adolescents than HCs, with a more pronounced difference for females. Contrary to prediction, with age controlled, HCs showed greater TS-related DSI increases. Analysis of cortisol showed no significant interactions, but a main effect of age and a trend toward higher cortisol in the CHR group. Correlations of cortisol with TS were higher in HC than CHR group. Conclusions: Stress measures increased with age in HC and CHR adolescents, and DSI scores also increased with TS in HCs. The results do not support a more pronounced age or TS increase in stress measures in CHR adolescents, but instead suggest that stress indices tend to be elevated earlier in adolescence in the CHR group. Potential determinants of findings and future directions are discussed. (C) 2016 Elsevier B.V. All rights reserved. C1 [Moskow, Danielle M.; Walker, Elaine F.] Emory Univ, 36 Eagle Row, Atlanta, GA 30322 USA. [Addington, Jean] Univ Calgary, 3280 Hosp Dr NW, Calgary, AB T2N 4Z6, Canada. [Bearden, Carrie E.] Univ Calif Los Angeles, 300 Med Plaza Suite 2265, Los Angeles, CA 90095 USA. [Cadenhead, Kristin S.] Univ Calif San Diego, 9500 Gilman Dr, La Jolla, CA 92093 USA. [Cornblatt, Barbara A.] Zucker Hillside Hosp, Glen Oaks, NY 11004 USA. [Heinssen, Robert] NIMH, 6001 Execut Blvd, Bethesda, MD 20893 USA. [Mathalon, Daniel H.] Univ Calif San Francisco, 4150 Clement St, San Francisco, CA 94121 USA. [McGlashan, Thomas H.; Woods, Scott W.] Yale Univ, 300 George St, New Haven, CT 06511 USA. [Perkins, Diana O.] Univ N Carolina, 101 Manning Dr, Chapel Hill, NC 27514 USA. [Seidman, Larry J.] Harvard Univ, 55 Friot St, Boston, MA 02114 USA. [Tsuang, Ming T.] Univ Calif San Diego, 9500 Gilman Dr, La Jolla, CA 92037 USA. [Cannon, Tyrone D.] Yale Univ, 1 Prospect St, New Haven, CT 06511 USA. [Moskow, Danielle M.] Columbia Univ, Med Ctr, New York State Psychiat Inst, 1051 Riverside Dr, New York, NY 10032 USA. RP Walker, EF (reprint author), Emory Univ, 36 Eagle Row, Atlanta, GA 30322 USA. EM dmoskow@nyspi.columbia.edu; jmadding@ucalgary.ca; cbearden@mednet.ucla.edu; kcadenhead@ucsd.edu; cornblat@lij.edu; rheinsse@mail.nih.gov; Daniel.Mathalon@ucsf.edu; thomas.mcglashan@yale.edu; diana_perkins@med.unc.edu; lseidman@caregroup.harvard.edu; mtsuang@ucsd.edu; ty-rone.cannon@yale.edu; scott.woods@yale.edu; psyefw@emory.edu OI Moskow, Danielle/0000-0002-3117-0091 FU National Institute of Mental Health (NIMH) at the National Institutes of Health [MH081902, MH081857, MH081988, MH081928, MH082004, MH082022, MH081984, MH066160]; NIMH [P50 MH066286, P50 MH080272]; Commonwealth of Massachusetts [SCDMH82101008006] FX Sources of grant and financial support: This research was supported by a collaborative U01 award from the National Institute of Mental Health (NIMH) at the National Institutes of Health (Grant Nos. MH081902 [TDC], MH081857 [BC], MH081988 [EW], MH081928 [LJS], MH082004 [DP], MH082022 [KC], MH081984 [JA], and MH066160 [SWW]) and NIMH Grant No. P50 MH066286 (CEB), NIMH Grant No. P50 MH080272, and the Commonwealth of Massachusetts (Grant No. SCDMH82101008006 [LJS]). NR 49 TC 2 Z9 2 U1 7 U2 15 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 EI 1573-2509 J9 SCHIZOPHR RES JI Schizophr. Res. PD APR PY 2016 VL 172 IS 1-3 BP 29 EP 34 DI 10.1016/j.schres.2016.02.002 PG 6 WC Psychiatry SC Psychiatry GA DI5GY UT WOS:000373528100005 PM 26905038 ER PT J AU Stone, WS Mesholam-Gately, RI Giuliano, AJ Woodberry, KA Addington, J Bearden, CE Cadenhead, KS Cannon, TD Cornblatt, BA Mathalon, DH McGlashan, TH Perkins, DO Tsuang, MT Walker, EF Woods, SW McCarley, RW Heinssen, R Green, MF Nuechterlein, K Seidman, LJ AF Stone, William S. Mesholam-Gately, Raquelle I. Giuliano, Anthony J. Woodberry, Kristen A. Addington, Jean Bearden, Carrie E. Cadenhead, Kristin S. Cannon, Tyrone D. Cornblatt, Barbara A. Mathalon, Daniel H. McGlashan, Thomas H. Perkins, Diana O. Tsuang, Ming T. Walker, Elaine F. Woods, Scott W. McCarley, Robert W. Heinssen, Robert Green, Michael F. Nuechterlein, Keith Seidman, Larry J. TI Healthy adolescent performance on the MATRICS Consensus Cognitive Battery (MCCB): Developmental data from two samples of volunteers SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Healthy controls; Adolescents; MATRICS Consensus Cognitive Battery; Psychosis; Clinical high risk; Schizophrenia; Cognition ID IQ-ADJUSTED NORMS; ONSET SCHIZOPHRENIA; NEUROCOGNITIVE BATTERY; SPECTRUM DISORDERS; CHILDHOOD-ONSET; ADULT-ONSET; FOLLOW-UP; PSYCHOSIS; MEMORY; STANDARDIZATION AB The MATRICS Consensus Cognitive Battery (MCCB) fills a significant need for a standardized battery of cognitive tests to use in clinical trials for schizophrenia in adults aged 20-59. A need remains, however, to develop norms for younger individuals, who also show elevated risks for schizophrenia. Toward this end, we assessed performance in healthy adolescents. Baseline MCCB, reading and IQ data were obtained from healthy controls (ages 12-19) participating in two concurrent NIMH-funded studies: North American Prodromal Longitudinal Study phase 2 (NAPLS-2; n = 126) and Boston Center for Intervention Development and Applied Research (CIDAR; n = 13). All MCCB tests were administered except the Managing Emotions subtest from the Mayer-Salovey-Caruso Emotional Intelligence Test. Data were collected from 8 sites across North America. MCCB scores were presented in four 2-year age cohorts as T-scores for each test and cognitive domain, and analyzed for effects of age and sex. Due to IQ differences between age-grouped subsamples, IQ served as a covariate in analyses. Overall and sex-based raw scores for individual MCCB tests are presented for each age-based cohort. Adolescents generally showed improvement with age in most MCCB cognitive domains, with the clearest linear trends in Attention/Vigilance and Working Memory. These control data show that healthy adolescence is a dynamic period for cognitive development that is marked by substantial improvement in MCCB performance through the 12-19 age range. They also provide healthy comparison raw scores to facilitate clinical evaluations of adolescents, including those at risk for developing psychiatric disorders such as schizophrenia-related conditions. (C) 2016 Elsevier B.V. All rights reserved. C1 [Stone, William S.; Mesholam-Gately, Raquelle I.; Woodberry, Kristen A.; Seidman, Larry J.] Massachusetts Mental Hlth Ctr, 75 Fenwood Rd, Boston, MA 02115 USA. [Stone, William S.; Mesholam-Gately, Raquelle I.; Woodberry, Kristen A.; Seidman, Larry J.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA USA. [Giuliano, Anthony J.] Worcester Recovery Ctr & Hosp, Dept Psychol, Worcester, MA USA. [Addington, Jean] Univ Calgary, Hotchkiss Brain Inst, Dept Psychiat, Calgary, AB T2N 1N4, Canada. [Bearden, Carrie E.] Univ Calif Los Angeles, Dept Psychiat & Biobehavioral Sci & Psychol, Los Angeles, CA USA. [Cadenhead, Kristin S.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Cannon, Tyrone D.] Yale Univ, Dept Psychol, New Haven, CT USA. [Cannon, Tyrone D.] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. [Cornblatt, Barbara A.] Zucker Hillside Hosp, Dept Psychiat, Long Isl City, NY USA. [Mathalon, Daniel H.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [McGlashan, Thomas H.; Woods, Scott W.] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. [Perkins, Diana O.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Tsuang, Ming T.] Univ Calif San Diego, Dept Psychiat, Ctr Behav Gen, Inst Genom Med, La Jolla, CA 92093 USA. [Walker, Elaine F.] Emory Univ, Dept Psychiat & Psychol, Atlanta, GA 30322 USA. [McCarley, Robert W.] Harvard Univ, Sch Med, Brockton VA Med Ctr, Dept Psychiat, Brockton, MA 02401 USA. [Heinssen, Robert] NIMH, Div Adult Translat Res & Treatment Dev, Bethesda, MD 20892 USA. [Green, Michael F.] Univ Calif Los Angeles, Geffen Sch Med, Dept Psychiat & Biobehavioral Sci, Los Angeles, CA USA. [Green, Michael F.] VA Greater Angeles Healthcare Syst, Los Angeles, CA USA. [Nuechterlein, Keith] Univ Calif Los Angeles, David Geffen Sch Med, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90095 USA. [Seidman, Larry J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA USA. RP Stone, WS (reprint author), Massachusetts Mental Hlth Ctr, 75 Fenwood Rd, Boston, MA 02115 USA. EM wstone@bidmc.Harvard.edu FU National Institute of Mental Health [U01MH0818902, U01MH081984, P50MH066286, U01MH082022, U01MH081857, U01MH082004, U01MH081928, U01MH081988, U01MH066160, P50MH080272]; Commonwealth Research Center of the Massachusetts Department of Mental Health [SCDMH82101008006]; Harvard Catalyst; Harvard Clinical and Translational Science Center Harvard Catalyst Clinical Research Center at Beth Israel Deaconess Medical Center; Harvard University Clinical and Translational Science Center Research Unit (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health) [1UL1 TR001102-01] FX National Institute of Mental Health grants (U01MH0818902 to T.D.C., U01MH081984 to J.M.A., P50MH066286 to C.E.B., U01MH082022 to K.S.C., U01MH081857 to B.A.C., U01MH082004 to D.O.P., U01MH081928 to L.J.S., U01MH081988 to E.F.W., U01MH066160 to S.W.W., P50MH080272 to R.W.M.) and the Commonwealth Research Center of the Massachusetts Department of Mental Health (SCDMH82101008006 to L.J.S.). This work was also conducted with support from Harvard Catalyst, The Harvard Clinical and Translational Science Center Harvard Catalyst Clinical Research Center at Beth Israel Deaconess Medical Center, A Harvard University Clinical and Translational Science Center Research Unit (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award 1UL1 TR001102-01 financial contributions from Harvard University and its affiliated academic health care centers). The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centers, or the National Institutes of Health. NR 60 TC 1 Z9 1 U1 4 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 EI 1573-2509 J9 SCHIZOPHR RES JI Schizophr. Res. PD APR PY 2016 VL 172 IS 1-3 BP 106 EP 113 DI 10.1016/j.schres.2016.02.003 PG 8 WC Psychiatry SC Psychiatry GA DI5GY UT WOS:000373528100017 PM 26896388 ER PT J AU Lee, MR Wehring, HJ McMahon, RP Liu, F Linthicum, J Verbalis, JG Buchanan, RW Strauss, GP Rubin, LH Kelly, DL AF Lee, Mary R. Wehring, Heidi J. McMahon, Robert P. Liu, Fang Linthicum, Jared Verbalis, Joseph G. Buchanan, Robert W. Strauss, Gregory P. Rubin, Leah H. Kelly, Deanna L. TI Relationship of plasma oxytocin levels to baseline symptoms and symptom changes during three weeks of daily oxytocin administration in people with schizophrenia SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Oxytocin; Schizophrenia; Negative symptoms; Oxytocin levels; Positive symptoms; Intranasal ID RANDOMIZED CONTROLLED-TRIAL; CEREBROSPINAL-FLUID; NEGATIVE SYMPTOMS; INTRANASAL OXYTOCIN; DOUBLE-BLIND; OLFACTORY IDENTIFICATION; SOCIAL COGNITION; VASOPRESSIN; PERCEPTION; INDIVIDUALS AB Several clinical studies have found an inverse relationship between clinical symptoms and peripheral oxytocin (OT) levels in people with schizophrenia. As oxytocin is a putative treatment for schizophrenia, the effect of repeated dosing of OT on OT levels, clinical symptoms and the relationship between the two is of interest. In a, randomized, double blind, parallel group 3 week study (N=28) with daily administration of intranasal OT (20 IU twice daily) or placebo (PBO), we examined the effect of OT administration on the correlation between the change in peripheral OT levels and change in clinical symptoms in patients with schizophrenia. At baseline, there were no significant treatment group differences in OT levels. There were no significant associations between baseline OT levels and any symptom measures. After 3 weeks of OT/PBO dosing, there was no significant difference in the magnitude of change in OT levels between the two treatment groups. Correlations between changes in peripheral OT levels and changes in the BPRS total and negative symptom scores were not different between treatment groups. Larger studies are needed to examine the effect of exogenous OT on peripheral OT levels and the relationship between the latter and clinical symptoms. Clinical Trials. gov=NCT00884897. Published by Elsevier B.V. C1 [Lee, Mary R.] NIAAA, NIH, Sect Clin Psychoneuroendocrinol & Neuropsychophar, Bethesda, MD 20892 USA. [Wehring, Heidi J.; McMahon, Robert P.; Liu, Fang; Linthicum, Jared; Buchanan, Robert W.; Kelly, Deanna L.] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Bethesda, MD USA. [Verbalis, Joseph G.] Georgetown Univ, Med Ctr, Georgetown Howard Univ Ctr Clin & Translat Sci, Washington, DC 20057 USA. [Strauss, Gregory P.] SUNY Binghamton, Dept Psychol, Binghamton, NY USA. [Rubin, Leah H.] Univ Illinois, Womens Mental Hlth Res Program, Chicago, IL USA. RP Lee, MR (reprint author), NIAAA, 10 Ctr Dr, Bethesda, MD 20892 USA. EM leemary@mail.nih.gov FU National Institute on Drug Abuse (NIDA) [N01-DA-5-9909]; National Institute on Mental Health (NIMH) [P50 MH082999] FX This study was funded by a National Institute on Drug Abuse (NIDA) contract (N01-DA-5-9909; Kelly PI) and a National Institute on Mental Health (NIMH) grant (P50 MH082999; Carpenter PI). NR 28 TC 2 Z9 2 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 EI 1573-2509 J9 SCHIZOPHR RES JI Schizophr. Res. PD APR PY 2016 VL 172 IS 1-3 BP 165 EP 168 DI 10.1016/j.schres.2016.02.014 PG 4 WC Psychiatry SC Psychiatry GA DI5GY UT WOS:000373528100026 PM 26879587 ER PT J AU Alfraih, F Aljurf, M Fitzhugh, CD Kassim, AA AF Alfraih, Feras Aljurf, Mahmoud Fitzhugh, Courtney D. Kassim, Adetola A. TI Alternative donor allogeneic hematopoietic cell transplantation for hemoglobinopathies SO SEMINARS IN HEMATOLOGY LA English DT Article DE Alternative donor; Allogeneic hematopoietic stem cell transplantation; Hemoglobinopathies; Sickle cell disease; Thalassemia ID BONE-MARROW-TRANSPLANTATION; CORD BLOOD TRANSPLANTATION; SINGLE-CENTER EXPERIENCE; DOSE POSTTRANSPLANTATION CYCLOPHOSPHAMIDE; BETA-THALASSEMIA MAJOR; QUALITY-OF-LIFE; PERIPHERAL-BLOOD; CONDITIONING REGIMEN; STEM-CELLS; DISEASE AB Allogeneic hematopoietic stem cell transplantation (HSCT) offers a curative therapy for patients with hemoglobinopathies, mainly severe sickle cell disease (SCD) and thalassemia (TM). However, the applicability of HSCT has been limited mainly by donor availability, with a less than 25%-30% of eligible patients having human leukocyte antigen (HLA)-matched sibling donors. Previous outcomes using alternate donor options have been markedly inferior due to increased regimen-related toxicity, transplant-related mortality, graft failure, and graft-versus-host disease (GVHD). Advances in transplant technology, including high-resolution HLA typing, improved GVHD prophylactic approaches with tolerance induction, and better supportive care over the last decade, are addressing these historical challenges, resulting in increasing donor options. Herein, we review alternate donor HSCT approaches for severe SCD and TM using unrelated donors, umbilical cord blood units, or related haploidentical donors. Though this is an emerging field, early results are promising and in selected patients, this may be the preferred option to mitigate against the age-related morbidity and early mortality associated with these disorders. (c) 2016 Elsevier Inc. All rights reserved. C1 [Alfraih, Feras] King Faisal Hosp & Res Ctr, Adult Hematol & Hematopoiet Stem Cell Transplanta, Riyadh, Saudi Arabia. [Aljurf, Mahmoud] NHLBI, Mol & Clin Hematol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Fitzhugh, Courtney D.; Kassim, Adetola A.] Vanderbilt Univ, Med Ctr, Dept Med, Div Hematol & Oncol, Nashville, TN USA. [Fitzhugh, Courtney D.; Kassim, Adetola A.] Vanderbilt Univ, Med Ctr, Vanderbilt Meharry Ctr Excellence Sickle Cell Dis, Nashville, TN USA. RP Alfraih, F (reprint author), King Faisal Hosp & Res Ctr, Hematol & Allogene Blood & Marrow Transplant Prog, Altakassusi Rd,POB 3354, Riyadh 11211, Saudi Arabia. EM Falfraih@kfshrc.edu.sa NR 70 TC 1 Z9 2 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 0037-1963 EI 1532-8686 J9 SEMIN HEMATOL JI Semin. Hematol. PD APR PY 2016 VL 53 IS 2 BP 120 EP 128 DI 10.1053/j.seminhematol.2016.01.001 PG 9 WC Hematology SC Hematology GA DI5QU UT WOS:000373554500012 PM 27000737 ER PT J AU Newman, KA AF Newman, Kam A. TI Commentary on "Perceptions of Older Adults, Hematologists, and Medical Oncologists in Cancer Care" SO SOUTHERN MEDICAL JOURNAL LA English DT Editorial Material ID SHARED DECISION-MAKING C1 [Newman, Kam A.] NIAMSD, NIH, 10 Ctr Dr,Room 6 N216, Bethesda, MD 20892 USA. RP Newman, KA (reprint author), NIAMSD, NIH, 10 Ctr Dr,Room 6 N216, Bethesda, MD 20892 USA. EM Kam.Newman@NIH.gov NR 5 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0038-4348 EI 1541-8243 J9 SOUTH MED J JI South.Med.J. PD APR PY 2016 VL 109 IS 4 BP 265 EP 266 DI 10.14423/SMJ.0000000000000448 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DI1UT UT WOS:000373282400015 PM 27043812 ER PT J AU Tofler, GH Massarob, J O'Donnell, CJ Wilson, PWF Vasan, RS Sutherland, PA Meigs, JB Levy, D D'Agostino, RB AF Tofler, G. H. Massarob, J. O'Donnell, C. J. Wilson, P. W. F. Vasan, R. S. Sutherland, P. A. Meigs, J. B. Levy, D. D'Agostino, R. B., Sr. TI Plasminogen activator inhibitor and the risk of cardiovascular disease: The Framingham Heart Study SO THROMBOSIS RESEARCH LA English DT Article DE Plasminogen activator inhibitor 1; Tissue plasminogen activator; Myocardial infarction; Cardiovascular diseases ID LEFT-VENTRICULAR HYPERTROPHY; LINKED-IMMUNOSORBENT-ASSAY; CORONARY-ARTERY-DISEASE; MYOCARDIAL-INFARCTION; FIBRINOLYTIC FACTORS; PLASMA; EVENTS; PAI-1; PREDICTION; WOMEN AB Introduction: Although plasminogen activator inhibitor (PAI-1) plays a key regulatory role in fibrinolysis, it has not been clearly shown to independently predict cardiovascular disease (CVD) among individuals without prior CVD. We investigated, in the Framingham Heart Study offspring cohort, whether PAI-1 predicted CVD risk among individuals without prior CVD. Methods: Plasma PAI-1 antigen and tissue plasminogen activator (TPA) antigen were measured in 3203 subjects without prior CVD between 1991 and 1995; average follow-up of 10 years. PAI-1 was remeasured 4 years after baseline, to determine the effect of serial change on risk. Results: PAI-1 levels (mean +/- SD) were 29.1 ng/ml (19.2) versus 22.1 (16.5) for those and without incident CVD; p < 0.001, and TPA levels were 12.0 ng/ml (5.7) versus 9.0 (4.7); p < 0.001. PAI-1 and TPA antigen levels had a strong unadjusted linear relation with incident CVD (p < 0.001). After adjustment for conventional risk factors, the hazard ratios (HRs) for higher quartiles of PAI-1, compared with the lowest, were 1.9, 1.9, 2.6 (linear trend p=0.006), and 1.6, 1.6, 2.9 (p < 0.001) for TPA antigen. The adjusted HRs for increasing quartiles of serial change in PAI-1 at 4 years, compared with the lowest, were 0.9, 0.8, 1.3 (p=0.050). C statistic assessment showed that adding PAI-1 or TPA to conventional risk factors resulted in small increases in discrimination and modest reclassification of risk, which was statistically significant for TPA (net reclassification 6.8%, p = 0.037) but not PAI-1 (4.8%, p = 0.113). Conclusion: PAI-1 and TPA antigen levels are predictive of CVD events after accounting for established risk factors. A serial increase in PAI-1 is associated with a further increase in risk. These findings support the importance of fibrinolytic potential in CVD. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Tofler, G. H.] Univ Sydney, Royal N Shore Hosp, Sydney, NSW 2006, Australia. [Massarob, J.; D'Agostino, R. B., Sr.] Boston Univ, Boston, MA 02215 USA. [O'Donnell, C. J.; Vasan, R. S.; Sutherland, P. A.; Levy, D.] NHLBI, Framingham Heart Study, NIH, Bethesda, MD USA. [O'Donnell, C. J.; Sutherland, P. A.; Levy, D.] NHLBI, Populat Sci Branch, NIH, Bethesda, MD USA. [O'Donnell, C. J.; Meigs, J. B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Wilson, P. W. F.] Emory Univ, Atlanta, GA 30322 USA. RP Tofler, GH (reprint author), Royal N Shore Hosp, Dept Cardiol, St Leonards, NSW 2065, Australia. EM Geoffrey.Tofler@health.nsw.gov.au OI Ramachandran, Vasan/0000-0001-7357-5970 FU AHA [92011960]; National Institutes of Health [RO1-HL-48157]; National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195]; Ducker Bequest and Heart Research Australia FX This work was supported by an AHA Grant-in-Aid (92011960), the National Institutes of Health (RO1-HL-48157), the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195), and the Ducker Bequest and Heart Research Australia. NR 35 TC 5 Z9 5 U1 2 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0049-3848 J9 THROMB RES JI Thromb. Res. PD APR PY 2016 VL 140 BP 30 EP 35 DI 10.1016/j.thromres.2016.02.002 PG 6 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA DI8DX UT WOS:000373732600005 PM 26896607 ER PT J AU Guthrie, PJ Thomas, JV Peker, D Turkbey, B Rais-Bahrami, S AF Guthrie, Patrick J. Thomas, John V. Peker, Deniz Turkbey, Baris Rais-Bahrami, Soroush TI Perivesical unicentric Castleman disease initially suspected to be metastatic prostate cancer SO UROLOGY ANNALS LA English DT Article DE Castleman disease; ferumoxytol; fusion biopsy; multiparametric magnetic resonance imaging; prostate adenocarcinoma ID SPECTRUM; BIOPSY AB Unicentric Castleman disease (UCD) is a relatively rare lymphoproliferative disease, which commonly presents as a mediastinal mass and less frequently involves abdomen, pelvis, and retroperitoneum. We report a case of a 64-year-old man with newly diagnosed low-volume, Gleason 3 + 3 = 6 prostate adenocarcinoma, who in considering active surveillance versus treatment was found to have a left perivesical and iliac chain lymphadenopathy concerning for potential metastatic involvement. He underwent magnetic resonance imaging with ferumoxytol to assist in the diagnostic evaluation to better characterize his lymphadenopathy. Subsequently, he underwent robotic-assisted laparoscopic bilateral pelvic lymph node dissection and resection of left perivesical mass exhibiting hyaline vascular variant of UCD. C1 [Guthrie, Patrick J.; Rais-Bahrami, Soroush] Univ Alabama Birmingham, Dept Urol, Fac Off Tower 1107,510 20th St South, Birmingham, AL 35294 USA. [Thomas, John V.; Rais-Bahrami, Soroush] Univ Alabama Birmingham, Dept Radiol, Birmingham, AL 35294 USA. [Peker, Deniz] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. [Turkbey, Baris] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. RP Rais-Bahrami, S (reprint author), Univ Alabama Birmingham, Dept Urol, Fac Off Tower 1107,510 20th St South, Birmingham, AL 35294 USA. EM sraisbahrami@uabmc.edu OI Rais-Bahrami, Soroush/0000-0001-9466-9925 NR 15 TC 0 Z9 0 U1 0 U2 0 PU MEDKNOW PUBLICATIONS & MEDIA PVT LTD PI MUMBAI PA B-9, KANARA BUSINESS CENTRE, OFF LINK RD, GHAKTOPAR-E, MUMBAI, 400075, INDIA SN 0974-7796 EI 0974-7834 J9 UROL ANNALS JI Urol. Annals PD APR-JUN PY 2016 VL 8 IS 2 BP 245 EP 248 DI 10.4103/0974-7796.177196 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA DI4PA UT WOS:000373480600027 PM 27141204 ER PT J AU Boyington, JEA Antman, MD Patel, KC Lauer, MS AF Boyington, Josephine E. A. Antman, Melissa D. Patel, Katherine C. Lauer, Michael S. TI Toward Independence: Resubmission Rate of Unfunded National Heart, Lung, and Blood Institute R01 Research Grant Applications Among Early Stage Investigators SO ACADEMIC MEDICINE LA English DT Article AB Purpose The current, budget-driven low rate of National Institutes of Health (NIH) funding for biomedical research has raised concerns about new investigators' ability to become independent scientists and their willingness to persist in efforts to secure funding. The authors sought to determine resubmission rates for unfunded National Heart, Lung, and Blood Institute (NHLBI) early stage investigator (ESI) independent research grant (R01) applications and to identify resubmission predictors. Method The authors used a retrospective cohort study design and retrieved applications submitted in fiscal years 2010-2012 from NIH electronic research administrative sources. They defined ESI applicants as those who have received no prior R01 (or equivalent) funding and are within 10 years of completion of their terminal research degree or medical residency training. ESI applications at the NHLBI were eligible for special funding consideration if they scored above, but within 10 points of, the payline. The primary outcome was application resubmission after failing to secure funding with the first R01 submission. Results Over half of the unfunded applications were resubmitted. Some of these were discussed and percentiled. Among percentiled applications, the only significant predictor of resubmission was the percentile score. Over half (59%) of the ESI R01 grants funded by NHLBI in fiscal years 2010-2012 had percentile scores above but within 10 points of the NHLBI payline, and benefited from the special funding considerations. Conclusions The only independent predictor of resubmission of NHLBI ESI R01 grant applications was percentile score; applicant demographics and institutional factors were not predictive of resubmission. C1 [Boyington, Josephine E. A.] NHLBI, Clin Applicat & Prevent Branch, Div Cardiovasc Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. [Antman, Melissa D.] NHLBI, Off Extramural Policy & Training, Div Extramural Res Act, NIH, Bldg 10, Bethesda, MD 20892 USA. [Patel, Katherine C.] NIH, Div Stat Anal & Reporting, Off Planning Anal & Commun, Off Extramural Res,Off Director, Bldg 10, Bethesda, MD 20892 USA. [Lauer, Michael S.] NHLBI, Div Cardiovasc Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Boyington, JEA (reprint author), 6701 Rockledge Dr,Suite 10224,Rockledge 2, Bethesda, MD 20892 USA. EM boyingtonje@mail.nih.gov FU National Institutes of Health FX The authors are employees of the National Institutes of Health, and this work was conducted as part of their work activities. No extra funding was received. NR 26 TC 2 Z9 2 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-2446 EI 1938-808X J9 ACAD MED JI Acad. Med. PD APR PY 2016 VL 91 IS 4 BP 556 EP 562 PG 7 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA DH6XW UT WOS:000372936400031 PM 26650674 ER PT J AU Hser, YI Evans, E Huang, D Weiss, R Saxon, A Carroll, KM Woody, G Liu, D Wakim, P Matthews, AG Hatch-Maillette, M Jelstrom, E Wiest, K McLaughlin, P Ling, W AF Hser, Yih-Ing Evans, Elizabeth Huang, David Weiss, Robert Saxon, Andrew Carroll, Kathleen M. Woody, George Liu, David Wakim, Paul Matthews, Abigail G. Hatch-Maillette, Mary Jelstrom, Eve Wiest, Katharina McLaughlin, Paul Ling, Walter TI Long-term outcomes after randomization to buprenorphine/naloxone versus methadone in a multi-site trial SO ADDICTION LA English DT Article DE Buprenorphine; methadone; opioid dependence; longitudinal; outcomes; opioid use; mortality ID MAINTENANCE THERAPY; OPIOID DEPENDENCE; RETENTION; ADDICTION; METHAMPHETAMINE; PERSPECTIVES; MEDICATION; HEALTH; ENTRY; USERS AB AimsTo compare long-term outcomes among participants randomized to buprenorphine or methadone. Design, Setting and ParticipantsFollow-up was conducted in 2011-14 of 1080 opioid-dependent participants entering seven opioid treatment programs in the United States between 2006 and 2009 and randomized (within each program) to receive open-label buprenorphine/naloxone or methadone for up to 24weeks; 795 participants completed in-person interviews (similar to 74% follow-up interview rate) covering on average 4.5years. MeasurementsOutcomes were indicated by mortality and opioid use. Covariates included demographics, site, cocaine use and treatment experiences. FindingsMortality was not different between the two randomized conditions, with 23 (3.6%) of 630 participants randomized to buprenorphine having died versus 26 (5.8%) of 450 participants randomized to methadone. Opioid use at follow-up was higher among participants randomized to buprenorphine relative to methadone [42.8 versus 31.7% positive opioid urine specimens, P<0.01, effect size (h)=0.23 (0.09, 0.38); 5.8days versus 4.4days of past 30-day heroin use, P<0.05, effect size (d)=0.14 (0.00, 0.28)]. Opioid use during the follow-up period by randomization condition was also significant (F-(7,F-39600)=3.16; P<0.001) due mainly to less treatment participation among participants randomized to buprenorphine than methadone. Less opioid use was associated with both buprenorphine and methadone treatment (relative to no treatment); no difference was found between the two treatments. Individuals who are white or used cocaine at baseline responded better to methadone than to buprenorphine. ConclusionsThere are few differences in long-term outcomes between buprenorphine and methadone treatment for opioid dependence, and treatment with each medication is associated with a strong reduction in opioid use. C1 [Hser, Yih-Ing; Evans, Elizabeth; Huang, David; Weiss, Robert; Ling, Walter] Univ Calif Los Angeles, Los Angeles, CA USA. [Saxon, Andrew] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Carroll, Kathleen M.] Yale Univ, Sch Med, New Haven, CT USA. [Woody, George] Univ Penn, Philadelphia, PA 19104 USA. [Liu, David; Wakim, Paul] NIDA, Bethesda, MD 20892 USA. [Matthews, Abigail G.; Jelstrom, Eve] Emmes Corp, Rockville, MD USA. [Hatch-Maillette, Mary] Univ Washington, Seattle, WA 98195 USA. [Wiest, Katharina] CODA Inc, Portland, OR USA. [McLaughlin, Paul] Hartford Dispensary, Hartford, CT USA. RP Hser, YI (reprint author), Univ Calif Los Angeles, Integrated Subst Abuse Programs, 11075 Santa Monica Blvd,Suite 200, Los Angeles, CA USA. EM yhser@ucla.edu FU National Institute on Drug Abuse (NIDA) through the Clinical Trials Network (CTN) [U10 DA01714, U10 DA 015815, U10 DA13038, U10 DA13043, U10 DA13045]; NIDA [P30DA016383] FX The corresponding author, Yih-Ing Hser, has 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. Sincere appreciation to our participating networks: the Pacific Northwest Node and Evergreen Treatment Services; the Western States Node and CODA Inc. and Bi-Valley Medical Clinic; the New England Node and Connecticut Counseling Centers and Yale and Hartford Dispensary; the Delaware Valley Node and NET Steps; the Pacific Region Node and Matrix Institute; and the EMMES Corporation (CCC); the CCTN and NIDA. The main study funding was provided by the National Institute on Drug Abuse (NIDA) through the Clinical Trials Network (CTN) through a series of grants provided to each participating node: the Pacific Northwest Node (U10 DA01714); the Western States Node (U10 DA 015815); the New England Node (U10 DA13038); the Delaware Valley Node (U10 DA13043); and he Pacific Region Node (U10 DA13045). Funding was also provided by NIDA through grant number P30DA016383. NR 29 TC 2 Z9 2 U1 5 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0965-2140 EI 1360-0443 J9 ADDICTION JI Addiction PD APR PY 2016 VL 111 IS 4 BP 695 EP 705 DI 10.1111/add.13238 PG 11 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA DH6NM UT WOS:000372907400022 PM 26599131 ER PT J AU Rodriguez, SA Grochova, D McKenna, T Borate, B Trivedi, NS Erdos, MR Eriksson, M AF Rodriguez, Sofia A. Grochova, Diana McKenna, Tomas Borate, Bhavesh Trivedi, Niraj S. Erdos, Michael R. Eriksson, Maria TI Global genome splicing analysis reveals an increased number of alternatively spliced genes with aging SO AGING CELL LA English DT Article DE aging; alternative splicing; HGPS; NF-B; progeria; spliceosome; transcriptome ID HUTCHINSON-GILFORD-PROGERIA; MALE C57BL/6J MICE; MICROARRAY ANALYSIS; HUMAN BRAIN; EXPRESSION; LAMIN; AGE; MISREGULATION; CELLS; ARCHITECTURE AB Alternative splicing (AS) is a key regulatory mechanism for the development of different tissues; however, not much is known about changes to alternative splicing during aging. Splicing events may become more frequent and widespread genome-wide as tissues age and the splicing machinery stringency decreases. Using skin, skeletal muscle, bone, thymus, and white adipose tissue from wild-type C57BL6/J male mice (4 and 18months old), we examined the effect of age on splicing by AS analysis of the differential exon usage of the genome. The results identified a considerable number of AS genes in skeletal muscle, thymus, bone, and white adipose tissue between the different age groups (ranging from 27 to 246 AS genes corresponding to 0.3-3.2% of the total number of genes analyzed). For skin, skeletal muscle, and bone, we included a later age group (28months old) that showed that the number of alternatively spliced genes increased with age in all three tissues (P<0.01). Analysis of alternatively spliced genes across all tissues by gene ontology and pathway analysis identified 158 genes involved in RNA processing. Additional analysis of AS in a mouse model for the premature aging disease Hutchinson-Gilford progeria syndrome was performed. The results show that expression of the mutant protein, progerin, is associated with an impaired developmental splicing. As progerin accumulates, the number of genes with AS increases compared to in wild-type skin. Our results indicate the existence of a mechanism for increased AS during aging in several tissues, emphasizing that AS has a more important role in the aging process than previously known. C1 [Rodriguez, Sofia A.; Grochova, Diana; McKenna, Tomas; Eriksson, Maria] Karolinska Inst, Ctr Innovat Med, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden. [Borate, Bhavesh; Trivedi, Niraj S.; Erdos, Michael R.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Eriksson, M (reprint author), Karolinska Inst, Ctr Innovat Med, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden. EM maria.eriksson.2@ki.se FU Swedish Research Council; Intramural Research Program of the National Human Genome Research Program, National Institutes of Health FX This study was supported by grants from the Swedish Research Council. This work was also supported in part by the Intramural Research Program of the National Human Genome Research Program, National Institutes of Health. NR 43 TC 5 Z9 5 U1 3 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1474-9718 EI 1474-9726 J9 AGING CELL JI Aging Cell PD APR PY 2016 VL 15 IS 2 BP 267 EP 278 DI 10.1111/acel.12433 PG 12 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA DH6DF UT WOS:000372880500008 PM 26685868 ER PT J AU Magidson, JF Li, X Mimiaga, MJ Moore, AT Srithanaviboonchai, K Friedman, RK Limbada, M Hughes, JP Cummings, V Gaydos, CA Elharrar, V Celentano, D Mayer, KH Safren, SA AF Magidson, Jessica F. Li, Xin Mimiaga, Matthew J. Moore, Ayana T. Srithanaviboonchai, Kriengkrai Friedman, Ruth Khalili Limbada, Mohammad Hughes, James P. Cummings, Vanessa Gaydos, Charlotte A. Elharrar, Vanessa Celentano, David Mayer, Kenneth H. Safren, Steven A. TI Antiretroviral Medication Adherence and Amplified HIV Transmission Risk Among Sexually Active HIV-Infected Individuals in Three Diverse International Settings SO AIDS AND BEHAVIOR LA English DT Article DE Adherence; Treatment as prevention; HIV transmission; Amplified risk; Alcohol use; MSM; Biomedical prevention ID CARE; PREVALENCE; BEHAVIORS; THERAPY; SCALE; MEN AB Successful biomedical prevention/treatment-as-prevention (TasP) requires identifying individuals at greatest risk for transmitting HIV, including those with antiretroviral therapy (ART) nonadherence and/or 'amplified HIV transmission risk,' defined as condomless sex with HIV-uninfected/unknown-status partners when infectious (i.e., with detectable viremia or STI diagnosis according to Swiss criteria for infectiousness). This study recruited sexually-active, HIV-infected patients in Brazil, Thailand, and Zambia to examine correlates of ART nonadherence and 'amplified HIV transmission risk'. Lower alcohol use (OR = .71, p < .01) and higher health-related quality of life (OR = 1.10, p < .01) were associated with greater odds of ART adherence over and above region. Of those with viral load data available (in Brazil and Thailand only), 40 % met Swiss criteria for infectiousness, and 29 % had 'amplified HIV transmission risk.' MSM had almost three-fold (OR = 2.89, p < .001) increased odds of 'amplified HIV transmission risk' (vs. heterosexual men) over and above region. TasP efforts should consider psychosocial and contextual needs, particularly among MSM with detectable viremia. C1 [Magidson, Jessica F.; Mimiaga, Matthew J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, One Bowdoin Sq,7th Floor, Boston, MA 02114 USA. [Li, Xin; Hughes, James P.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Mimiaga, Matthew J.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Mimiaga, Matthew J.; Mayer, Kenneth H.; Safren, Steven A.] Fenway Hlth, Fenway Inst, Boston, MA USA. [Moore, Ayana T.] FHI360, Durham, NC USA. [Srithanaviboonchai, Kriengkrai] Chiang Mai Univ, Res Inst Hlth Sci, Chiang Mai 50000, Thailand. [Srithanaviboonchai, Kriengkrai] Chiang Mai Univ, Fac Med, Chiang Mai 50000, Thailand. [Friedman, Ruth Khalili] Inst Pesquisa Clin Evandro Chagas, Rio De Janeiro, Brazil. [Limbada, Mohammad] Ctr Infect Dis Res Zambia, Lusaka, Zambia. [Hughes, James P.] Univ Washington, Seattle, WA 98195 USA. [Cummings, Vanessa; Gaydos, Charlotte A.] Johns Hopkins Sch Med, Div Infect Dis, Dept Pathol & Med, Baltimore, MD USA. [Elharrar, Vanessa] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Celentano, David] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Mayer, Kenneth H.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Safren, Steven A.] Univ Miami, Dept Psychol, Coral Gables, FL 33124 USA. RP Magidson, JF (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, One Bowdoin Sq,7th Floor, Boston, MA 02114 USA. EM jmagidson@mgh.harvard.edu OI Srithanaviboonchai, Kriengkrai/0000-0002-1683-4259 FU NIH [T32MH093310, K24MH094214]; Harvard University Center for AIDS Research (HU CFAR) NIH [P30AI060354]; Division of AIDS (DAIDS), National Institute of Allergy and Infectious Disease (NIAID), National Institute on Drug Abuse (NIDA); National Institute of Mental Health (NIMH) [UM1AI068619] FX HPTN 063 was funded by the Division of AIDS (DAIDS), National Institute of Allergy and Infectious Disease (NIAID), National Institute on Drug Abuse (NIDA), and the National Institute of Mental Health (NIMH) under Cooperative Agreement # UM1AI068619. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or The HIV Prevention Trials Network. The authors would also like to acknowledge the staff at the HPTN 063 study sites for their contributions to the study. Additionally, Dr. Magidson's work on this manuscript was supported by NIH Grant T32MH093310, and Dr. Safren was supported by NIH Grant K24MH094214. Dr. Mayer and Dr. Safren were also supported by the Harvard University Center for AIDS Research (HU CFAR) NIH P30AI060354. This manuscript was supported by consultation from other members of the HU CFAR Social and Behavioral Sciences Core. NR 20 TC 2 Z9 2 U1 1 U2 3 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 APR PY 2016 VL 20 IS 4 BP 699 EP 709 DI 10.1007/s10461-015-1142-7 PG 11 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA DH7HF UT WOS:000372962700001 PM 26246068 ER PT J AU Wolf, MJ Lee, EK Nicolson, SC Pearson, GD Witte, MK Huckaby, J Gaies, M Shekerdemian, LS Mahle, WT AF Wolf, Michael J. Lee, Eva K. Nicolson, Susan C. Pearson, Gail D. Witte, Madolin K. Huckaby, Jeryl Gaies, Michael Shekerdemian, Lara S. Mahle, William T. CA Pediatric Heart Network TI Rationale and methodology of a collaborative learning project in congenital cardiac care SO AMERICAN HEART JOURNAL LA English DT Article ID VENTRICLE RECONSTRUCTION TRIAL; HEART-DISEASE; JOINT COUNCIL; NORWOOD PROCEDURE; SURGERY; CLASSIFICATION; PALLIATION; CHILDREN; INFANTS AB Background Collaborative learning is a technique through which individuals or teams learn together by capitalizing on one another's knowledge, skills, resources, experience, and ideas. Clinicians providing congenital cardiac care may benefit from collaborative learning given the complexity of the patient population and team approach to patient care. Rationale and development Industrial system engineers first performed broad-based time-motion and process analyses of congenital cardiac care programs at 5 Pediatric Heart Network core centers. Rotating multidisciplinary team site visits to each center were completed to facilitate deep learning and information exchange. Through monthly conference calls and an in-person meeting, we determined that duration of mechanical ventilation following infant cardiac surgery was one key variation that could impact a number of clinical outcomes. This was underscored by one participating center's practice of early extubation in the majority of its patients. A consensus clinical practice guideline using collaborative learning was developed and implemented by multidisciplinary teams from the same 5 centers. The 1-year prospective initiative was completed in May 2015, and data analysis is under way. Conclusion Collaborative learning that uses multidisciplinary team site visits and information sharing allows for rapid structured fact-finding and dissemination of expertise among institutions. System modeling and machine learning approaches objectively identify and prioritize focused areas for guideline development. The collaborative learning framework can potentially be applied to other components of congenital cardiac care and provide a complement to randomized clinical trials as a method to rapidly inform and improve the care of children with congenital heart disease. C1 [Wolf, Michael J.; Mahle, William T.] Emory Univ, Sch Med, Childrens Healthcare Atlanta, Atlanta, GA USA. [Lee, Eva K.] Georgia Inst Technol, Sch Ind & Syst Engn, Atlanta, GA 30332 USA. [Nicolson, Susan C.] Univ Penn, Perelman Sch Med, Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Pearson, Gail D.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Witte, Madolin K.] Univ Utah, Sch Med, Primary Childrens Hosp, Salt Lake City, UT USA. [Huckaby, Jeryl] Childrens Healthcare Atlanta, Atlanta, GA USA. [Gaies, Michael] Univ Michigan, Sch Med, CS Mott Childrens Hosp, Ann Arbor, MI USA. [Shekerdemian, Lara S.] Texas Childrens Hosp, Baylor Coll Med, Houston, TX 77030 USA. RP Wolf, MJ (reprint author), Emory Univ, Sch Med, Sibley Heart Ctr, 2835 Brandywine Rd, Atlanta, GA 30341 USA. EM wolfm@kidsheart.com FU National Heart, Lung, and Blood Institute [HL068269, HL068270, HL068279, HL068281, HL068285, HL068292, HL068290, HL068288, HL085057, HL109781, HL109737]; National Science Foundation [IIP-0832390, IIP-1361532] FX The study was supported by U01 grants from the National Heart, Lung, and Blood Institute (HL068269, HL068270, HL068279, HL068281, HL068285, HL068292, HL068290, HL068288, HL085057, HL109781, HL109737) and the National Science Foundation (IIP-0832390, IIP-1361532). The contents of this work are solely the responsibility of the authors and do not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Science Foundation. NR 26 TC 2 Z9 2 U1 1 U2 3 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 APR PY 2016 VL 174 BP 129 EP 137 DI 10.1016/j.ahj.2016.01.013 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DH1IV UT WOS:000372538500019 PM 26995379 ER PT J AU Pau, AK Lane, HC Masur, H AF Pau, Alice K. Lane, H. Clifford Masur, Henry TI The pharmacist: An indispensable partner in HIV care SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT Editorial Material C1 [Pau, Alice K.; Lane, H. Clifford] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Masur, Henry] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD USA. RP Pau, AK (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM apau@niaid.nih.gov NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEALTH-SYSTEM PHARMACISTS PI BETHESDA PA 7272 WISCONSIN AVE, BETHESDA, MD 20814 USA SN 1079-2082 EI 1535-2900 J9 AM J HEALTH-SYST PH JI Am. J. Health-Syst. Pharm. PD APR 1 PY 2016 VL 73 IS 7 BP 431 EP 431 DI 10.2146/ajhp160077 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DH9CI UT WOS:000373093600004 PM 27001981 ER PT J AU Bachy, E Estell, JA Van de Neste, E Bouabdallah, R Bargay, J Delmer, A Gelas-Dore, B da Silva, MG Fitoussi, O Belada, D Maisonneuve, H Intragumtornchai, T Lamy, T Dartigues, P Seymour, JF Salles, G AF Bachy, Emmanuel Estell, Jane A. Van de Neste, Eric Bouabdallah, Reda Bargay, Joan Delmer, Alain Gelas-Dore, Benedicte da Silva, Maria Gomes Fitoussi, Olivier Belada, David Maisonneuve, Herve Intragumtornchai, Tanin Lamy, Thierry Dartigues, Peggy Seymour, John Francis Salles, Gilles TI Statin use is safe and does not impact prognosis in patient with de novo follicular lymphoma treated with immunochemotherapy: An exploratory analysis of the PRIMA cohort study SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID B-CELL LYMPHOMA; NON-HODGKIN-LYMPHOMA; TERM-FOLLOW-UP; MONOCLONAL-ANTIBODY; INDOLENT LYMPHOMA; PLUS RITUXIMAB; FREE SURVIVAL; THERAPY; CHOP; CHEMOTHERAPY AB An adverse prognostic impact of statin use in lymphoma was first suspected from in vitro data showing an impairment of anti-CD20 antibody binding. However, further clinical studies suggested an improved outcome associated with their use in hematological malignancies. In particular, a survival benefit was reported for patients with follicular lymphoma on statins. Our objective was to assess the outcome of follicular lymphoma patients treated in the PRIMA study with immunochemotherapy according to the use of statins. Among the 1,217 patients enrolled in the PRIMA study, 1,135 were included in the present study. Concomitant treatments at registration were available for all patients. Among those 1,135 patients, 119 were on statins (10.5%) at diagnosis. Adverse events frequencies, event-free survival (EFS), time to next lymphoma treatment (TTNLT), time to next chemotherapy (TTNCT), and overall survival (OS) were evaluated according to the use of statins. The rates of overall and specific cardiovascular adverse events between the two groups of patients were comparable both during induction and maintenance. Outcome in terms of response rates or EFS, TTNLT, TTNCT, and OS were similar regardless of the use of statins (P=0.57, P=0.85, P=0.30, and P=0.43, respectively) in univariate analysis and after further adjustments for potential confounding factors in multivariate analysis. In conclusion, statin use does not impact the prognosis of patients with follicular lymphoma treated with immunochemotherapy. Am. J. Hematol. 91:410-415, 2016. (c) 2016 Wiley Periodicals, Inc. C1 [Bachy, Emmanuel; Salles, Gilles] Hop Lyon Sud, Dept Hematol, Pierre Benite, France. [Bachy, Emmanuel; Salles, Gilles] Univ Lyon 1, Pierre Benite, France. [Estell, Jane A.] Concord Hosp, Dept Hematol, Concord, NSW, Australia. [Van de Neste, Eric] Clin Univ St Luc, Dept Hematol, B-1200 Brussels, Belgium. [Bouabdallah, Reda] Inst J Paoli I Calmettes, Dept Hematol, F-13009 Marseille, France. [Bargay, Joan] Hosp Son Llatzer, Dept Hematol, Palma De Mallorca, Spain. [Delmer, Alain] CHU Reims, Dept Hematol, Reims, France. [Gelas-Dore, Benedicte] Lysarc, Dept Biostat, Lyon, France. [da Silva, Maria Gomes] Portuguese Inst Oncol, Dept Hematol, Lisbon, Portugal. Polyclin Bordeaux Nord Aquitaine, Dept Hematol, Bordeaux, France. [Belada, David] Univ Hosp Hradec Kralove, Dept Hematol, Prague, Czech Republic. [Maisonneuve, Herve] Ctr Hosp La Roche Sur Yon, Lyon, France. [Intragumtornchai, Tanin] Chulalongkorn Univ, Dept Hematol, Bangkok, Thailand. [Lamy, Thierry] Ctr Hosp Pontchaillou, Dept Hematol, Rennes, France. [Dartigues, Peggy] Inst Gustave Roussy, Dept Hematol, Villejuif, France. [Seymour, John Francis] Peter MacCallum Canc Ctr, Dept Hematol, Melbourne, Vic, Australia. [Seymour, John Francis] Univ Melbourne, Melbourne, Vic, Australia. RP Bachy, E (reprint author), NCI, Ctr Canc Res, NIH, Bldg 10,Room 5A02, Bethesda, MD 20892 USA. EM emmanuel.bachy@nih.gov OI Gomes da Silva, Maria/0000-0002-6993-2450 NR 30 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD APR PY 2016 VL 91 IS 4 BP 410 EP 415 DI 10.1002/ajh.24305 PG 6 WC Hematology SC Hematology GA DH8CN UT WOS:000373021200017 PM 26799234 ER PT J AU Young, NM Sherathiya, K Gutierrez, L Nguyen, E Bekmezian, S Huang, JC Hallgrimsson, B Lee, JS Marcucio, RS AF Young, Nathan M. Sherathiya, Krunal Gutierrez, Luis Nguyen, Emerald Bekmezian, Sona Huang, John C. Hallgrimsson, Benedikt Lee, Janice S. Marcucio, Ralph S. TI Facial surface morphology predicts variation in internal skeletal shape SO AMERICAN JOURNAL OF ORTHODONTICS AND DENTOFACIAL ORTHOPEDICS LA English DT Article ID CRANIOFACIAL GROWTH; INTEGRATION; MEDICINE; PATTERN AB Introduction: The regular collection of 3-dimensional (3D) imaging data is critical to the development and implementation of accurate predictive models of facial skeletal growth. However, repeated exposure to x-ray-based modalities such as cone-beam computed tomography has unknown risks that outweigh many potential benefits, especially in pediatric patients. One solution is to make inferences about the facial skeleton from external 3D surface morphology captured using safe nonionizing imaging modalities alone. However, the degree to which external 3D facial shape is an accurate proxy of skeletal morphology has not been previously quantified. As a first step in validating this approach, we tested the hypothesis that population-level variation in the 3D shape of the face and skeleton significantly covaries. Methods: We retrospectively analyzed 3D surface and skeletal morphology from a previously collected cross-sectional cone-beam computed tomography database of nonsurgical orthodontics patients and used geometric morphometrics and multivariate statistics to test the hypothesis that shape variation in external face and internal skeleton covaries. Results: External facial morphology is highly predictive of variation in internal skeletal shape ([R-v] = 0.56, P < 0.0001; partial least squares [PLS] 1-13 = 98.7% covariance, P < 0.001) and asymmetry (Rv = 0.34, P < 0.0001; PLS 1-5 = 90.2% covariance, P < 0.001), whereas age-related (r(2) = 0.84, P < 0.001) and size-related (r(2) = 0.67, P < 0.001) shape variation was also highly correlated. Conclusions: Surface morphology is a reliable source of proxy data for the characterization of skeletal shape variation and thus is particularly valuable in research designs where reducing potential long-term risks associated with radiologic imaging methods is warranted. We propose that longitudinal surface morphology from early childhood through late adolescence can be a valuable source of data that will facilitate the development of personalized craniodental and treatment plans and reduce exposure levels to as low as reasonably achievable. C1 [Young, Nathan M.; Marcucio, Ralph S.] Univ Calif San Francisco, Sch Med, Dept Orthopaed Surg, San Francisco, CA USA. [Sherathiya, Krunal; Nguyen, Emerald; Bekmezian, Sona; Huang, John C.] Univ Calif San Francisco, Sch Dent, Dept Orofacial Sci, San Francisco, CA USA. [Gutierrez, Luis] Univ Colorado, Sch Dent, Dept Orthodont, Denver, CO 80262 USA. [Hallgrimsson, Benedikt] Univ Calgary, Dept Cell Biol & Anat, Calgary, AB, Canada. [Lee, Janice S.] Natl Inst Dent & Craniofacial Res, Bethesda, MD USA. RP Young, NM (reprint author), Univ Calif San Francisco, San Francisco Gen Hosp, Program Craniofacial Biol, Dept Orthopaed Surg, Bldg 9,Room 346,2550 23rd Ave, San Francisco, CA 94110 USA. EM nathan.young@ucsf.edu FU National Institute of Dental and Craniofacial Research [F32DE018596, R01DE021708, R01DE019638]; UCSF Academic Senate [UL1TR000004]; National Institutes of Health; Clinical and Translational Science Institute Strategic Opportunities Support Grant [UL1TR000004] FX Supported by the National Institute of Dental and Craniofacial Research (F32DE018596 (N.M.Y.), R01DE021708 (R.S.M., B.H.) and R01DE019638 (R.S.M., B.H.), the UCSF Academic Senate (Grant UL1TR000004) (J.C.H., J.S.L.), and a National Institutes of Health and Clinical and Translational Science Institute Strategic Opportunities Support Grant (UL1TR000004) (N.M.Y.). NR 32 TC 1 Z9 1 U1 4 U2 7 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0889-5406 EI 1097-6752 J9 AM J ORTHOD DENTOFAC JI Am. J. Orthod. Dentofac. Orthop. PD APR PY 2016 VL 149 IS 4 BP 501 EP 508 DI 10.1016/j.ajodo.2015.09.028 PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DH4LS UT WOS:000372758100013 PM 27021454 ER PT J AU Benyo, Z Ruisanchez, E Leszl-Ishiguro, M Sandor, P Pacher, P AF Benyo, Zoltan Ruisanchez, Eva Leszl-Ishiguro, Miriam Sandor, Peter Pacher, Pal TI Endocannabinoids in cerebrovascular regulation SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Review DE cerebral circulation; endocannabinoids; cannabinoid receptors; TRPV1 channel; neurovascular unit ID CEREBRAL-BLOOD-FLOW; CB1 CANNABINOID RECEPTORS; TRAUMATIC BRAIN-INJURY; NITRIC-OXIDE SYNTHASE; MESSENGER-RNA EXPRESSION; VASCULAR SMOOTH-MUSCLE; RAT MICROGLIAL CELLS; ACID AMIDE HYDROLASE; ANEURYSMAL SUBARACHNOID HEMORRHAGE; MICROVASCULAR ENDOTHELIAL-CELLS AB The cerebral blood flow is tightly regulated by myogenic, endothelial, metabolic, and neural mechanisms under physiological conditions, and a large body of recent evidence indicates that inflammatory pathways have a major influence on the cerebral blood perfusion in certain central nervous system disorders, like hemorrhagic and ischemic stroke, traumatic brain injury, and vascular dementia. All major cell types involved in cerebrovascular control pathways (i.e., smooth muscle, endothelium, neurons, astrocytes, pericytes, microglia, and leukocytes) are capable of synthesizing endocannabinoids and/or express some or several of their target proteins [i.e., the cannabinoid 1 and 2 (CB1 and CB2) receptors and the transient receptor potential vanilloid type 1 ion channel]. Therefore, the endocannabinoid system may importantly modulate the regulation of cerebral circulation under physiological and pathophysiological conditions in a very complex manner. Experimental data accumulated since the late 1990s indicate that the direct effect of cannabinoids on cerebral vessels is vasodilation mediated, at least in part, by CB1 receptors. Cannabinoid-induced cerebrovascular relaxation involves both a direct inhibition of smooth muscle contractility and a release of vasodilator mediator(s) from the endothelium. However, under stress conditions (e.g., in conscious restrained animals or during hypoxia and hypercapnia), cannabinoid receptor activation was shown to induce a reduction of the cerebral blood flow, probably via inhibition of the electrical and/or metabolic activity of neurons. Finally, in certain cerebrovascular pathologies (e.g., subarachnoid hemorrhage, as well as traumatic and ischemic brain injury), activation of CB2 (and probably yet unidentified non-CB1/non-CB2) receptors appear to improve the blood perfusion of the brain via attenuating vascular inflammation. C1 [Benyo, Zoltan; Ruisanchez, Eva; Leszl-Ishiguro, Miriam; Sandor, Peter] Semmelweis Univ, Inst Expt Clin Res, Tuzolto U 37-47, H-1094 Budapest, Hungary. [Pacher, Pal] NIAAA, Lab Cardiovasc Physiol & Tissue Injury, NIH, Bethesda, MD USA. RP Benyo, Z (reprint author), Semmelweis Univ, Inst Expt Clin Res, Tuzolto U 37-47, H-1094 Budapest, Hungary. EM benyo.zoltan@med.semmelweis-univ.hu FU Hungarian Scientific Research Fund [OTKA K-62375, K-101775, K-112964]; Intramural Research Program of the National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism FX The authors' own work presented in the review has been supported by the Hungarian Scientific Research Fund (OTKA K-62375, K-101775, and K-112964) and by the Intramural Research Program of the National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism. NR 261 TC 6 Z9 6 U1 6 U2 9 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 EI 1522-1539 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD APR 1 PY 2016 VL 310 IS 7 BP H785 EP H801 DI 10.1152/ajpheart.00571.2015 PG 17 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA DI1RC UT WOS:000373272200001 PM 26825517 ER PT J AU Lateef, DM Xiao, CY Brychta, RJ Diedrich, A Schnermann, J Reitman, ML AF Lateef, Dalya M. Xiao, Cuiying Brychta, Robert J. Diedrich, Andre Schnermann, Jurgen Reitman, Marc L. TI Bombesin-like receptor 3 regulates blood pressure and heart rate via a central sympathetic mechanism SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE bombesin-like receptor 3; blood pressure; heart rate; sympathetic nervous system; energy metabolism ID NERVOUS-SYSTEM; MELANOCORTIN-4 RECEPTOR; SUBTYPE-3 AGONIST; CONSCIOUS RABBITS; BODY-TEMPERATURE; MICE; OBESITY; PHARMACOLOGY; HYPERTENSION; MK-5046 AB Bombesin-like receptor 3 (BRS-3) is an orphan G protein-coupled receptor that regulates energy expenditure, food intake, and body weight. We examined the effects of BRS-3 deletion and activation on blood pressure and heart rate. In free-living, telemetered Brs3 null mice the resting heart rate was 10% lower than wild-type controls, while the resting mean arterial pressure was unchanged. During physical activity, the heart rate and blood pressure increased more in Brs3 null mice, reaching a similar heart rate and higher mean arterial pressure than control mice. When sympathetic input was blocked with propranolol, the heart rate of Brs3 null mice was unchanged, while the heart rate in control mice was reduced to the level of the null mice. The intrinsic heart rate, measured after both sympathetic and parasympathetic blockade, was similar in Brs3 null and control mice. Intravenous infusion of the BRS-3 agonist MK-5046 increased mean arterial pressure and heart rate in wild-type but not in Brs3 null mice, and this increase was blocked by pretreatment with clonidine, a sympatholytic, centrally acting alpha(2)-adrenergic agonist. In anesthetized mice, hypothalamic infusion of MK-5046 also increased both mean arterial pressure and heart rate. Taken together, these data demonstrate that BRS-3 contributes to resting cardiac sympathetic tone, but is not required for activity-induced increases in heart rate and blood pressure. The data suggest that BRS-3 activation increases heart rate and blood pressure via a central sympathetic mechanism. C1 [Lateef, Dalya M.; Xiao, Cuiying; Brychta, Robert J.; Reitman, Marc L.] NIDDKD, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD USA. [Diedrich, Andre] Vanderbilt Univ, Sch Med, Auton Dysfunct Ctr, Nashville, TN 37212 USA. [Schnermann, Jurgen] NIDDKD, Kidney Dis Branch, NIH, Bethesda, MD USA. RP Reitman, ML (reprint author), NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bldg 10 CRC,Rm 5-5940,10 Ctr Dr, Bethesda, MD 20892 USA. EM marc.reitman@nih.gov FU NIDDK Intramural Research Program [DK-075057, DK-075063]; NHLBI Grant [5-P01-HL-56693] FX This research was supported by NIDDK Intramural Research Program Grants DK-075057 and DK-075063, and by NHLBI Grant 5-P01-HL-56693 (A. Diedrich). NR 55 TC 0 Z9 0 U1 2 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 EI 1522-1539 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD APR 1 PY 2016 VL 310 IS 7 BP H891 EP H898 DI 10.1152/ajpheart.00963.2015 PG 8 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA DI1RC UT WOS:000373272200010 PM 26801314 ER PT J AU Reiss, TF Moss, J Watkins, TR Malhotra, A AF Reiss, Theodore F. Moss, Joel Watkins, Timothy R. Malhotra, Atul TI BEAR Cage: Mentoring through Engagement SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Editorial Material ID INNOVATION C1 [Reiss, Theodore F.] Celgene Corp, Clin Res & Dev, Summit, NJ USA. [Moss, Joel] NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Watkins, Timothy R.] Gilead Sci Inc, Clin Res, Seattle, WA USA. [Malhotra, Atul] Univ Calif San Diego, Thorac Soc, San Diego, CA 92103 USA. RP Reiss, TF (reprint author), Celgene Corp, Clin Res & Dev, Summit, NJ USA. FU Intramural NIH HHS NR 7 TC 2 Z9 2 U1 2 U2 5 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 APR 1 PY 2016 VL 193 IS 7 BP 714 EP 716 DI 10.1164/rccm.201602-0297ED PG 4 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DI1OH UT WOS:000373264900009 PM 26910761 ER PT J AU Dickert, NW Brown, J Cairns, CB Eaves-Leanos, A Goldkind, SF Kim, SYH Nichol, G O'Conor, KJ Scott, JD Sinert, R Wendler, D Wright, DW Silbergleit, R AF Dickert, Neal W. Brown, Jeremy Cairns, Charles B. Eaves-Leanos, Aaliyah Goldkind, Sara F. Kim, Scott Y. H. Nichol, Graham O'Conor, Katie J. Scott, Jane D. Sinert, Richard Wendler, David Wright, David W. Silbergleit, Robert TI Confronting Ethical and Regulatory Challenges of Emergency Care Research With Conscious Patients SO ANNALS OF EMERGENCY MEDICINE LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; INFORMED-CONSENT; COMMUNITY CONSULTATION; PATIENTS PERCEPTIONS; CLINICAL-RESEARCH; CARDIAC-ARREST; TRIAL; ENROLLMENT; EXCEPTION; SURVIVAL AB Barriers to informed consent are ubiquitous in the conduct of emergency care research across a wide range of conditions and clinical contexts. They are largely unavoidable; can be related to time constraints, physical symptoms, emotional stress, and cognitive impairment; and affect patients and surrogates. US regulations permit an exception from informed consent for certain clinical trials in emergency settings, but these regulations have generally been used to facilitate trials in which patients are unconscious and no surrogate is available. Most emergency care research, however, involves conscious patients, and surrogates are often available. Unfortunately, there is neither clear regulatory guidance nor established ethical standards in regard to consent in these settings. In this report the result of a workshop convened by the National Institutes of Health Office of Emergency Care Research and Department of Bioethics to address ethical challenges in emergency care research we clarify potential gaps in ethical understanding and federal regulations about research in emergency care in which limited involvement of patients or surrogates in enrollment decisions is possible. We propose a spectrum of approaches directed toward realistic ethical goals and a research and policy agenda for addressing these issues to facilitate clinical research necessary to improve emergency care. C1 [Dickert, Neal W.] Emory Univ, Sch Med, Dept Med, Atlanta, GA USA. [Wright, David W.] Emory Univ, Sch Med, Dept Emergency Med, Atlanta, GA USA. [Dickert, Neal W.] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. [Brown, Jeremy] Natl Inst Gen Med Sci, Off Emergency Care Res, Bethesda, MD USA. [Cairns, Charles B.] Univ Arizona, Coll Med, Tucson, AZ USA. [Eaves-Leanos, Aaliyah] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Goldkind, Sara F.] US FDA, Off Commissioner, Silver Spring, MD USA. [Goldkind, Sara F.] St Louis Univ, Res & Clin Bioeth Consultant, St Louis, MO 63103 USA. [Eaves-Leanos, Aaliyah] St Louis Univ, Albert Gnaegi Ctr Hlth Care Eth, St Louis, MO 63103 USA. [Kim, Scott Y. H.; Wendler, David] NIH, Dept Bioeth, Bldg 10, Bethesda, MD 20892 USA. [Nichol, Graham] Univ Washington, Harborview Ctr Prehospital Emergency Care, Seattle, WA 98195 USA. [O'Conor, Katie J.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Scott, Jane D.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Sinert, Richard] Suny Downstate Med Ctr, Dept Emergency Med, New York, NY USA. [Silbergleit, Robert] Univ Michigan, Sch Med, Dept Emergency Med, Ann Arbor, MI USA. RP Dickert, NW (reprint author), Emory Univ, Sch Med, Dept Med, Atlanta, GA USA.; Dickert, NW (reprint author), Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. EM njr@emory.edu FU National Institutes of Health Office (NIH) of Emergency Care Research and Department of Bioethics FX By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist and provided the following details: This workshop was supported by the National Institutes of Health Office (NIH) of Emergency Care Research and Department of Bioethics. Drs. Brown, Goldkind, Kim, Scott, and Wendler and Ms. Eaves-Leanos were federal employees during this workshop (NIH and Food and Drug Administration [FDA]). NR 40 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD APR PY 2016 VL 67 IS 4 BP 538 EP 545 DI 10.1016/j.annemergmed.2015.10.026 PG 8 WC Emergency Medicine SC Emergency Medicine GA DI1FK UT WOS:000373241800022 PM 26707358 ER PT J AU Ridley, A Hatano, H Wong-Baeza, I Shaw, J Matthews, KK Al-Mossawi, H Ladell, K Price, DA Bowness, P Kollnberger, S AF Ridley, Anna Hatano, Hiroko Wong-Baeza, Isabel Shaw, Jacqueline Matthews, Katherine K. Al-Mossawi, Hussein Ladell, Kristin Price, David A. Bowness, Paul Kollnberger, Simon TI Activation-Induced Killer Cell Immunoglobulin-like Receptor 3DL2 Binding to HLA-B27 Licenses Pathogenic T Cell Differentiation in Spondyloarthritis SO ARTHRITIS & RHEUMATOLOGY LA English DT Article ID HLA CLASS-I; PRONE HLA-B27-TRANSGENIC RATS; ANKYLOSING-SPONDYLITIS; DENDRITIC CELLS; TH17 CELLS; TNF-ALPHA; EXPRESSION; KIR3DL2; SPONDYLARTHRITIS; HOMODIMERS AB Objective. In the spondyloarthritides (SpA), increased numbers of CD4+ T cells express killer cell immunoglobulin-like receptor 3DL2 (KIR-3DL2). The aim of this study was to determine the factors that induce KIR-3DL2 expression, and to characterize the relationship between HLA-B27 and the phenotype and function of KIR-3DL2-expressing CD4+ T cells in SpA. Methods In total, 34 B27+ patients with SpA, 28 age- and sex-matched healthy controls (20 B27- and 8 B27+), and 9 patients with rheumatoid arthritis were studied. KIR-3DL2 expression and other phenotypic characteristics of peripheral blood and synovial fluid CD4+ T cells were studied by flow cytometry, quantitative polymerase chain reaction, and Western blotting. T cell receptor clonality was determined by template-switch anchored reverse transcription-polymerase chain reaction and sequencing analysis. Cytokines were measured by enzyme-linked immunosorbent assay. Results. Cellular activation induced KIR-3DL2 expression on both naive and effector CD4+ T cells. KIR-3DL2 binding to B27+ cells promoted expression of KIR-3DL2, the Th17-specific transcription factor retinoic acid receptor-related orphan nuclear receptor t, and the antiapoptotic factor B cell lymphoma 2. KIR-3DL2+CD4+ T cells in patients with ankylosing spondylitis were oligoclonal and enriched for markers of T cell activation and for the gut homing receptor CCR9. In the presence of B27+ antigen-presenting cells, KIR-3DL2+CD4+ T cells produced less interleukin-2 (IL-2) but more IL-17. This effect was blocked by HC10, an antibody that inhibits the binding of KIR-3DL2 to B27 heavy chains. Conclusion. KIR-3DL2 binding to HLA-B27 licenses Th17 cell differentiation in SpA. These findings raise the therapeutic potential of targeting HLA-B27-KIR-3DL2 interactions for the treatment of B27+ patients with SpA. C1 [Ridley, Anna; Hatano, Hiroko; Wong-Baeza, Isabel; Shaw, Jacqueline; Al-Mossawi, Hussein; Bowness, Paul; Kollnberger, Simon] Univ Oxford, Botnar Res Ctr, Nuffield Dept Orthopaed Rheumatol & Musculoskelet, Oxford, England. [Wong-Baeza, Isabel] Natl Polytech Inst, Natl Sch Biol Sci, Mexico City, DF, Mexico. [Matthews, Katherine K.] QIMR, Berghofer Med Res Inst, Brisbane, Qld, Australia. [Ladell, Kristin; Price, David A.; Kollnberger, Simon] Cardiff Univ, Sch Med, Cardiff CF14 4XN, S Glam, Wales. [Price, David A.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Kollnberger, S (reprint author), Cardiff Univ, Sch Med, Inst Infect & Immun, Henry Wellcome Bldg, Cardiff CF14 4XN, S Glam, Wales. EM KollnbergerS@cardiff.ac.uk RI Price, David/C-7876-2013; Wong-Baeza, Isabel/A-3947-2013; OI Price, David/0000-0001-9416-2737; Wong-Baeza, Isabel/0000-0002-2516-0081; Al-Mossawi, Hussein/0000-0002-2312-3754; bowness, paul/0000-0003-4597-0484 FU Oxford NIHR Biomedical Research Centre; Oxford NIHR Biomedical Research Unit; Japan Society for the Promotion of Science; Mexican National Council of Science and Technology; Arthritis Research UK; Wellcome Trust FX Drs. Ridley, Bowness, and Kollnberger's work was supported by the Oxford NIHR Biomedical Research Centre; Dr. Bowness' work was also supported by the Oxford NIHR Biomedical Research Unit. Dr. Hatano's work was supported by the Japan Society for the Promotion of Science. Dr. Wong-Baeza's work was supported by the Mexican National Council of Science and Technology. Mrs. Shaw and Dr. Kollnberger's work was supported by Arthritis Research UK. Drs. Al-Mossawi, Ladell, and Price's work was supported by the Wellcome Trust. Dr. Price is a Wellcome Trust Senior Investigator. NR 38 TC 5 Z9 5 U1 3 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD APR PY 2016 VL 68 IS 4 BP 901 EP 914 DI 10.1002/art.39515 PG 14 WC Rheumatology SC Rheumatology GA DH9QH UT WOS:000373130300015 PM 26841353 ER PT J AU Maniscalco, B Peters, MAK Lau, H AF Maniscalco, Brian Peters, Megan A. K. Lau, Hakwan TI Heuristic use of perceptual evidence leads to dissociation between performance and metacognitive sensitivity SO ATTENTION PERCEPTION & PSYCHOPHYSICS LA English DT Article DE Visual awareness; Signal detection theory; Bayesian modeling ID PROBABILISTIC POPULATION CODES; DECISION-MAKING; VISUAL-PERCEPTION; SIGNAL-DETECTION; CONFIDENCE; CORTEX; OVERCONFIDENCE; COMPUTATION; BLINDSIGHT; ACCURACY AB Zylberberg et al. [Zylberberg, Barttfeld, & Sigman (Frontiers in Integrative Neuroscience, 6; 79, 2012), Frontiers in Integrative Neuroscience 6:79] found that confidence decisions, but not perceptual decisions, are insensitive to evidence against a selected perceptual choice. We present a signal detection theoretic model to formalize this insight, which gave rise to a counter-intuitive empirical prediction: that depending on the observer's perceptual choice, increasing task performance can be associated with decreasing metacognitive sensitivity (i.e., the trial-by-trial correspondence between confidence and accuracy). The model also provides an explanation as to why metacognitive sensitivity tends to be less than optimal in actual subjects. These predictions were confirmed robustly in a psychophysics experiment. In a second experiment we found that, in at least some subjects, the effects were replicated even under performance feedback designed to encourage optimal behavior. However, some subjects did show improvement under feedback, suggesting the tendency to ignore evidence against a selected perceptual choice may be a heuristic adopted by the perceptual decision-making system, rather than reflecting inherent biological limitations. We present a Bayesian modeling framework that explains why this heuristic strategy may be advantageous in real-world contexts. C1 [Maniscalco, Brian] NIH, 10 Ctr Dr,Bldg 10,Room 1D51A,MSC 1065, Bethesda, MD 20892 USA. [Maniscalco, Brian] Columbia Univ, Dept Psychol, 1190 Amsterdam Ave,MC 5501, New York, NY 10027 USA. [Peters, Megan A. K.; Lau, Hakwan] Univ Calif Los Angeles, Dept Psychol, 1285 Franz Hall,Box 951563, Los Angeles, CA 90095 USA. [Lau, Hakwan] Univ Calif Los Angeles, Brain Res Inst, 695 Charles E Young Dr South, Los Angeles, CA 90095 USA. RP Maniscalco, B (reprint author), NIH, 10 Ctr Dr,Bldg 10,Room 1D51A,MSC 1065, Bethesda, MD 20892 USA.; Maniscalco, B (reprint author), Columbia Univ, Dept Psychol, 1190 Amsterdam Ave,MC 5501, New York, NY 10027 USA. EM bmaniscalco@gmail.com FU Templeton Foundation [6-40689]; National Institutes of Health [NIH R01 NS088628-01] FX This work is partially supported by a grant from the Templeton Foundation (6-40689) and the National Institutes of Health (NIH R01 NS088628-01). NR 39 TC 4 Z9 4 U1 1 U2 8 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 APR PY 2016 VL 78 IS 3 BP 923 EP 937 DI 10.3758/s13414-016-1059-x PG 15 WC Psychology; Psychology, Experimental SC Psychology GA DI1BH UT WOS:000373230500018 PM 26791233 ER PT J AU Williams, KM Cheng, GS Pusic, I Jagasia, M Burns, L Ho, VT Pidala, J Palmer, J Johnston, L Mayer, S Chien, JW Jacobsohn, DA Pavletic, SZ Martin, PJ Storer, BE Inamoto, Y Chai, XY Flowers, MED Lee, SJ AF Williams, Kirsten M. Cheng, Guang-Shing Pusic, Iskra Jagasia, Madan Burns, Linda Ho, Vincent T. Pidala, Joseph Palmer, Jeanne Johnston, Laura Mayer, Sebastian Chien, Jason W. Jacobsohn, David A. Pavletic, Steven Z. Martin, Paul J. Storer, Barry E. Inamoto, Yoshihiro Chai, Xiaoyu Flowers, Mary E. D. Lee, Stephanie J. TI Fluticasone, Azithromycin, and Montelukast Treatment for New-Onset Bronchiolitis Obliterans Syndrome after Hematopoietic Cell Transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Bronchiolitis obliterans syndrome; Fluticasone; Azithromycin; Montelukast; Hematopoietic cell transplantation; Lung chronic graft-versus-host disease; Leukotrienes ID VERSUS-HOST-DISEASE; BONE-MARROW-TRANSPLANTATION; CONSENSUS DEVELOPMENT PROJECT; AIR-FLOW OBSTRUCTION; WORKING GROUP-REPORT; MEASURING THERAPEUTIC RESPONSE; RECEPTOR ENBREL ETANERCEPT; PLACEBO-CONTROLLED TRIAL; LONG-TERM SURVIVORS; LUNG TRANSPLANTATION AB Bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic cell transplantation (HCT) is associated with high mortality. We hypothesized that inhaled fluticasone, azithromycin, and montelukast (FAM) with a brief steroid pulse could avert progression of new-onset BOS. We tested this in a phase II, single-arm, open-label, multicenter study (NCT01307462). Thirty-six patients were enrolled within 6 months of BOS diagnosis. The primary endpoint was treatment failure, defined as 10% or greater forced expiratory volume in 1 second decline at 3 months. At 3 months, 6% (2 of 36, 95% confidence interval, 1% to 19%) had treatment failure (versus 40% in historical controls, P < .001). FAM was well tolerated. Steroid dose was reduced by 50% or more at 3 months in 48% of patients who could be evaluated (n = 27). Patient-reported outcomes at 3 months were statistically significantly improved for Short-Form 36 social functioning score and mental component score, Functional Assessment of Cancer Therapies emotional well-being, and Lee symptom scores in lung, skin, mouth, and the overall summary score compared to enrollment (n = 24). At 6 months, 36% had treatment failure (95% confidence interval, 21% to 54%, n = 13 of 36, with 6 documented failures, 7 missing pulmonary function tests). Overall survival was 97% (95% confidence interval, 84% to 100%) at 6 months. These data suggest that FAM was well tolerated and that treatment with FAM and steroid pulse may halt pulmonary decline in new-onset BUS in the majority of patients and permit reductions in systemic steroid exposure, which collectively may improve quality of life. However, additional treatments are needed for progressive BUS despite FAM. (C) 2016 American Society for Blood and Marrow Transplantation. C1 [Williams, Kirsten M.; Jacobsohn, David A.] Childrens Natl Hlth Syst, Childrens Res Inst, Div Blood & Marrow Transplantat, Washington, DC USA. [Williams, Kirsten M.; Pavletic, Steven Z.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Cheng, Guang-Shing; Martin, Paul J.; Storer, Barry E.; Chai, Xiaoyu; Flowers, Mary E. D.; Lee, Stephanie J.] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. [Pusic, Iskra] Washington Univ, Div Med & Oncol, St Louis, MO USA. [Jagasia, Madan] Vandebilt Univ, Div Hematol Oncol, Nashville, TN USA. [Burns, Linda] Univ Minnesota, Div Hematol Oncol & Transplantat, Minneapolis, MN USA. [Ho, Vincent T.] Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. [Pidala, Joseph] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Blood & Marrow Transplantat, Tampa, FL 33682 USA. [Palmer, Jeanne] Mayo Clin, Div Hematol Oncol, Scottsdale, AZ USA. [Johnston, Laura] Stanford Univ, Div Blood & Marrow Transplantat, Stanford, CA 94305 USA. [Mayer, Sebastian] Weill Cornell Med Coll, Dept Med, New York, NY USA. [Chien, Jason W.] Gilead Sci Inc, Seattle, WA USA. [Inamoto, Yoshihiro] Natl Canc Ctr, Div Hematopoiet Stem Cell Transplantat, 1-1 Tsukiji 5 chome, Tokyo, Japan. RP Williams, KM (reprint author), George Washington Univ, Med Ctr, Childrens Natl Med Ctr, Div Blood & Marrow Transplantat,Ctr Canc & Blood, 111 Michigan Ave NW, Washington, DC 20010 USA. EM kmwillia@cnmc.org FU NCATS; National Cancer Institute; GlaxoSmithKline [113611] FX The Chronic GVHD Consortium (U54 CA163438) is part of the NCATS Rare Diseases Clinical Research Network (RDCRN). RDCRN is an initiative of the Office of Rare Disease Research NCATS, funded through a collaboration between NCATS and the National Cancer Institute. GlaxoSmithKline provided fluticasone propionate under grant number 113611, and Merck provided montelukast. NR 50 TC 9 Z9 9 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD APR PY 2016 VL 22 IS 4 BP 710 EP 716 DI 10.1016/j.bbmt.2015.10.009 PG 7 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DH9CH UT WOS:000373093500017 PM 26475726 ER PT J AU Merkel, EC Mitchell, SA Lee, SJ AF Merkel, Emily C. Mitchell, Sandra A. Lee, Stephanie J. TI Content Validity of the Lee Chronic Graft-versus-Host Disease Symptom Scale as Assessed by Cognitive Interviews SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Allogeneic hematopoietic cell transplantation; Chronic graft-versus-host disease; Patient-reported outcome; Symptoms; FDA qualification; Cognitive interview ID CONSENSUS DEVELOPMENT PROJECT; WORKING GROUP-REPORT; MEASURING THERAPEUTIC RESPONSE; TASK-FORCE REPORT; CLINICAL-TRIALS; PRO INSTRUMENTS; CRITERIA AB The Lee Chronic Graft-versus-Host Disease (cGVHD) Symptom Scale has been recommended for use by the 2005 and 2014 National Institutes of Health (NIH) Consensus Conferences to capture cGVHD symptoms. Although the cGVHD Symptom Scale was previously validated, this study aims to reexamine the instrument's content validity by exploring the clarity, comprehensibility, relevance, and ease of use in a contemporary cGVHD sample, toward Food and Drug Administration (FDA) qualification of this patient-reported outcomes (PRO) instrument as a drug development tool. Attaining FDA qualification means that an instrument has been judged to be a reliable and valid measure of clinical benefit. Twenty adult patients with a median age of 58 year (range, 31 to 79 years) participated. The median duration of cGVHD was 33 months (range, 0 to 134.4 months), and current NIH severity score was mild in 1 patient, moderate in 10 patients, and severe in 9 patients, with a median of 5.5 treatments (range, 0 to 14) ever used for cGVHD. The median summary score was 23 (range, 8 to 51), and the median time to complete the scale was 2 minutes, 7 seconds (range, 1 minute, 8 seconds to 4 minutes). Symptoms of cGVHD were well captured on the Lee cGVHD Symptom Scale, although 4 additional symptoms/signs were mentioned by 15% of the participants. Participants mostly reported that item wording was clear and provided accurate definitions of specific terminologies; however, 7 participants (35%) reported finding 1 or more items in the skin domain unclear, reporting, for example, that rashes and itchy skin seemed synonymous. Two of 19 participants (10.5%) described how their answers would have changed had they been asked about their symptoms within the past month instead of within the past week, owing to recently resolved symptoms. All participants were able to accurately explain the concept of "bother" in their own words and distinguish it from symptom severity or other related symptom attributes. In summary, participants found the Lee GVHD Symptom Scale to be a comprehensive and understandable way to report their cGVHD symptom experience. Future work will focus on options for the recall period, the phrasing of skin items, and whether some very rare symptoms (eg, feeding tube, use of oxygen) should continue to be a part of the scale. (C) 2016 American Society for Blood and Marrow Transplantation. C1 [Merkel, Emily C.] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [Mitchell, Sandra A.] NCI, Div Canc Control & Populat Sci, Healthcare Delivery Res Program, Outcomes Res Branch, Bethesda, MD 20892 USA. [Lee, Stephanie J.] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1100 Fairview Ave N,D5-290, Seattle, WA 98109 USA. RP Lee, SJ (reprint author), Fred Hutchinson Canc Res Ctr, Div Clin Res, 1100 Fairview Ave N,D5-290, Seattle, WA 98109 USA. EM sjlee@fredhutch.org OI Lee, Stephanie/0000-0003-2600-6390 FU American Cancer Society [CA118953, CA163438]; NCATS; National Cancer Institute FX Funding for this study was provided by the American Cancer Society (ECM) and CA118953 and CA163438 (SJL). The Chronic GVHD Consortium U54 CA163438 is part of the NCATS Rare Diseases Clinical Research Network (RDCRN). RDCRN is an initiative of the Office of Rare Diseases Research (ORDR), NCATS, funded through a collaboration between NCATS and the National Cancer Institute. NR 20 TC 1 Z9 1 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD APR PY 2016 VL 22 IS 4 BP 752 EP 758 DI 10.1016/j.bbmt.2015.12.026 PG 7 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DH9CH UT WOS:000373093500022 PM 26751003 ER PT J AU Matzke, LAM Fombonne, B Watson, PH Moore, HM AF Matzke, Lise Anne Marie Fombonne, Benjamin Watson, Peter Hamilton Moore, Helen Marie TI Fundamental Considerations for Biobank Legacy Planning SO BIOPRESERVATION AND BIOBANKING LA English DT Review ID FRAMEWORK AB Biobanking in its various forms is an activity involving the collection of biospecimens and associated data and their storage for differing lengths of time before use. In some cases, biospecimens are immediately used, but in others, they are stored typically for the term of a specified project or in perpetuity until the materials are used up or declared to be of little scientific value. Legacy planning involves preparing for the phase that follows either biobank closure or a significant change at an operational level. In the case of a classical finite collection, this may be brought about by the completion of the initial scientific goals of a project, a loss of funding, or loss of or change in leadership. Ultimately, this may require making a decision about when and where to transfer materials or whether to destroy them. Because biobanking in its entirety is a complex endeavour, legacy planning touches on biobank operations as well as ethical, legal, financial, and governance parameters. Given the expense and time that goes into setting up and maintaining biobanks, coupled with the ethical imperative to appropriately utilize precious resources donated to research, legacy planning is an activity that every biobanking entity should think about. This article describes some of the fundamental considerations for preparing and executing a legacy plan, and we envisage that this article will facilitate dialogue to help inform best practices and policy development in the future. C1 [Matzke, Lise Anne Marie; Watson, Peter Hamilton] Univ British Columbia, Dept Pathol & Lab Med, OBER, Vancouver, BC V5Z 1M9, Canada. [Fombonne, Benjamin; Moore, Helen Marie] NCI, Biorepositories & Biospecimen Res Branch, Bethesda, MD 20892 USA. [Watson, Peter Hamilton] Vancouver Isl Ctr, BC Canc Agcy, TTR, Victoria, BC, Canada. RP Matzke, LAM (reprint author), Univ British Columbia, Vancouver Gen Hosp, Dept Pathol & Lab Med, OBER, JPPN Rm 3202,West 10th Ave, Vancouver, BC V5Z 4E3, Canada. EM lmatzke@pathology.ubc.ca NR 13 TC 1 Z9 1 U1 0 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1947-5535 EI 1947-5543 J9 BIOPRESERV BIOBANK JI Biopreserv. Biobank. PD APR 1 PY 2016 VL 14 IS 2 BP 99 EP 106 DI 10.1089/bio.2015.0073 PG 8 WC Cell Biology; Chemistry, Applied; Medical Laboratory Technology SC Cell Biology; Chemistry; Medical Laboratory Technology GA DI0UQ UT WOS:000373213200003 PM 26890981 ER PT J AU Parrish, RS Garafalo, AV Ndifor, V Goetz, KE Reeves, MJ Yim, A Cooper, RC Iano-Fletcher, J Wang, XJ Tumminia, SJ AF Parrish, Rebecca S. Garafalo, Alexandra V. Ndifor, Vida Goetz, Kerry E. Reeves, Melissa J. Yim, Annette Cooper, Remy C. Iano-Fletcher, Jemma Wang, Xinjing Tumminia, Santa J. TI Sample Confirmation Testing: A Short Tandem Repeat-Based Quality Assurance and Quality Control Procedure for the eyeGENE Biorepository SO BIOPRESERVATION AND BIOBANKING LA English DT Article ID AUTHENTICATION AB Quality assurance and quality control (QA/QC) procedures are vital to good biorepository management. The National Eye Institute (NEI) core CLIA-certified laboratory of the eyeGENE((R)) Network receives blood from individuals with inherited eye conditions and isolates DNA for clinical genetic diagnostic testing and research. Clinical genetic test results are returned to the affected individuals, making it imperative that sample integrity is preserved throughout laboratory processing. A clinically validated, short tandem repeat (STR)-based approach, termed Sample Confirmation Testing (SCT), was developed to ensure that no significant laboratory errors occurred during processing. SCT uses modified protocols from commercial kits to create and compare STR profiles for each participant's original blood and derived DNA. This QA/QC procedure has been performed on 47% of the more than 6000 participants in the eyeGENE Biorepository and has identified significant laboratory errors in 0.4% of samples tested. SCT improves the quality of the data returned to affected individuals and the data distributed to researchers using eyeGENE samples by ensuring the integrity of the samples and aiding in curation of the biorepository. This approach serves as a model for other repositories to improve sample quality and management procedures. C1 [Parrish, Rebecca S.; Garafalo, Alexandra V.; Ndifor, Vida; Goetz, Kerry E.; Reeves, Melissa J.; Yim, Annette; Cooper, Remy C.; Iano-Fletcher, Jemma; Wang, Xinjing] NEI, NIH, Ophthalm Genet & Visual Funct Branch, Bethesda, MD 20892 USA. [Tumminia, Santa J.] NEI, NIH, Bldg 31,Rm 6A03 31 Ctr Dr MSC 2510, Bethesda, MD 20892 USA. RP Tumminia, SJ (reprint author), NEI, NIH, Bldg 31,Rm 6A03 31 Ctr Dr MSC 2510, Bethesda, MD 20892 USA. EM tumminias@nei.nih.gov FU Department of Health and Human Services/National Institutes of Health/National Eye Institute Intramural Research Program under National Ophthalmic Disease Genotyping and Phenotyping Network [HHS-N-260-2007-00001-C] FX Supported by the Department of Health and Human Services/National Institutes of Health/National Eye Institute Intramural Research Program under National Ophthalmic Disease Genotyping and Phenotyping Network (ClinicalTrials.gov Identifier NCT00378742), which has been funded, in part, under Contract No. HHS-N-260-2007-00001-C. NR 15 TC 2 Z9 2 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1947-5535 EI 1947-5543 J9 BIOPRESERV BIOBANK JI Biopreserv. Biobank. PD APR 1 PY 2016 VL 14 IS 2 BP 149 EP 155 DI 10.1089/bio.2015.0098 PG 7 WC Cell Biology; Chemistry, Applied; Medical Laboratory Technology SC Cell Biology; Chemistry; Medical Laboratory Technology GA DI0UQ UT WOS:000373213200009 PM 26891080 ER PT J AU Combs, CA Schuit, E Caritis, SN Lim, AC Garite, TJ Maurel, K Rouse, D Thom, E Tita, AT Mol, BWJ AF Combs, C. A. Schuit, E. Caritis, S. N. Lim, A. C. Garite, T. J. Maurel, K. Rouse, D. Thom, E. Tita, A. T. Mol, B. W. J. CA Global Obstet Network GONet Collab TI 17-Hydroxyprogesterone caproate in triplet pregnancy: an individual patient data meta-analysis SO BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY LA English DT Review DE 17-Hydroxyprogesterone caproate; multiple gestation; preterm birth prevention; progestogens; triplet pregnancy ID ORDER MULTIPLE GESTATION; PRETERM BIRTH; 17-ALPHA-HYDROXYPROGESTERONE CAPROATE; DOUBLE-BLIND; RANDOMIZED-TRIALS; NEONATAL OUTCOMES; INFANT-MORTALITY; TWIN PREGNANCIES; PREVENTION; PROGESTERONE AB BackgroundPreterm birth complicates almost all triplet pregnancies and no preventive strategy has proven effective. ObjectiveTo determine, using individual patient data (IPD) meta-analysis, whether the outcome of triplet pregnancy is affected by prophylactic administration of 17-hydroxyprogesterone caproate (17OHPc). Search strategyWe searched literature databases, trial registries and references in published articles. Selection criteriaRandomised controlled trials (RCTs) of progestogens versus control that included women with triplet pregnancies. Data collection and analysisInvestigators from identified RCTs collaborated on the protocol and contributed their IPD. The primary outcome was a composite measure of adverse perinatal outcome. The secondary outcome was the rate of birth before 32weeks of gestation. Other pre-specified outcomes included randomisation-to-delivery interval and rates of birth at <24, <28 and <34weeks of gestation. Main resultsThree RCTs of 17OHPc versus placebo included 232 mothers with triplet pregnancies and their 696 offspring. Risk-of-bias scores and between-study heterogeneity were low. Baseline characteristics were comparable between 17OHPc and placebo groups. The rate of the composite adverse perinatal outcome was similar among those treated with 17OHPc and those treated with placebo (34 and 35%, respectively; risk ratio [RR] 0.98, 95% confidence interval [95% CI] 0.79-1.2). The rate of birth at <32weeks was also similar in the two groups (35 and 38%, respectively; RR 0.92, 95% CI 0.55-1.56). There were no significant between-group differences in perinatal mortality rate, randomisation-to-delivery interval, or other specified outcomes. ConclusionProphylactic 17OHPc given to mothers with triplet pregnancies had no significant impact on perinatal outcome or pregnancy duration. C1 [Combs, C. A.; Garite, T. J.; Maurel, K.] Mednax Natl Med Grp, Obstetrix Collaborat Res Network, Ctr Res Educ & Qual, Sunrise, FL USA. [Schuit, E.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Schuit, E.] Stanford Univ, Stanford Prevent Res Ctr, Stanford, CA 94305 USA. [Caritis, S. N.] Univ Pittsburgh, Dept Obstet & Gynecol, Pittsburgh, PA USA. [Lim, A. C.; Mol, B. W. J.] Acad Med Ctr Amsterdam, Dept Obstet & Gynaecol, Amsterdam, Netherlands. [Garite, T. J.] Univ Calif Irvine, Dept Obstet & Gynecol, Irvine, CA 92717 USA. [Rouse, D.; Thom, E.; Tita, A. T.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network MFMU, Bethesda, MD USA. [Rouse, D.] Brown Univ, Women & Infants Hosp, Alpert Med Sch, Dept Obstet & Gynecol, Providence, RI 02912 USA. [Rouse, D.] Brown Univ, Dept Epidemiol, Sch Publ Hlth, Providence, RI 02912 USA. [Thom, E.] George Washington Univ, Biostat Ctr, Washington, DC USA. [Tita, A. T.] Univ Alabama Birmingham, Dept Obstet & Gynecol, Birmingham, AL USA. [Tita, A. T.] Univ Alabama Birmingham, Ctr Womens Reprod Hlth, Birmingham, AL USA. [Mol, B. W. J.] Univ Adelaide, Robinson Res Inst, Sch Paediat & Reprod Hlth, Adelaide, SA, Australia. [Mol, B. W. J.] South Australian Hlth & Med Res Inst, Adelaide, SA, Australia. RP Combs, CA (reprint author), Obstetrix Med Grp, 900 East Hamilton Ave,Suite 220, Campbell, CA 95008 USA. EM andrewcombs@me.com FU NICHD NIH HHS [U10 HD036801] NR 62 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1470-0328 EI 1471-0528 J9 BJOG-INT J OBSTET GY JI BJOG PD APR PY 2016 VL 123 IS 5 BP 682 EP 690 DI 10.1111/1471-0528.13779 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DI2ZX UT WOS:000373369000007 PM 26663620 ER PT J AU Rangel, MC Bertolette, D Castro, NP Klauzinska, M Cuttitta, F Salomon, DS AF Rangel, Maria Cristina Bertolette, Daniel Castro, Nadia P. Klauzinska, Malgorzata Cuttitta, Frank Salomon, David S. TI Developmental signaling pathways regulating mammary stem cells and contributing to the etiology of triple-negative breast cancer SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Review DE Cripto-1; Notch/CSL; Wnt/beta-catenin; fMaSC/aMaSC; TIC/CSC; TNBC ID EPITHELIAL-MESENCHYMAL TRANSITION; GLAND DEVELOPMENT; GENE-EXPRESSION; IN-VIVO; STEM/PROGENITOR CELLS; THERAPEUTIC TARGET; LUMINAL PROGENITOR; EMBRYONIC GENE; POOR-PROGNOSIS; BETA-CATENIN AB Cancer has been considered as temporal and spatial aberrations of normal development in tissues. Similarities between mammary embryonic development and cell transformation suggest that the underlying processes required for mammary gland development are also those perturbed during various stages of mammary tumorigenesis and breast cancer (BC) development. The master regulators of embryonic development Cripto-1, Notch/CSL, and Wnt/beta-catenin play key roles in modulating mammary gland morphogenesis and cell fate specification in the embryo through fetal mammary stem cells (fMaSC) and in the adult organism particularly within the adult mammary stem cells (aMaSC), which determine mammary progenitor cell lineages that generate the basal/myoepithelial and luminal compartments of the adult mammary gland. Together with recognized transcription factors and embryonic stem cell markers, these embryonic regulatory molecules can be inappropriately augmented during tumorigenesis to support the tumor-initiating cell (TIC)/cancer stem cell (CSC) compartment, and the effects of their deregulation may contribute for the etiology of BC, in particular the most aggressive subtype of BC, triple-negative breast cancer (TNBC). This in depth review will present evidence of the involvement of Cripto-1, Notch/CSL, and Wnt/beta-catenin in the normal mammary gland morphogenesis and tumorigenesis, from fMaSC/aMaSC regulation to TIC generation and maintenance in TNBC. Specific therapies for treating TNBC by targeting these embryonic pathways in TICs will be further discussed, providing new opportunities to destroy not only the bulk tumor, but also TICs that initiate and promote the metastatic spread and recurrence of this aggressive subtype of BC. C1 [Rangel, Maria Cristina; Bertolette, Daniel; Castro, Nadia P.; Klauzinska, Malgorzata; Cuttitta, Frank; Salomon, David S.] NCI, Tumor Growth Factor Sect, Mouse Canc Genet Program, Ctr Canc Res, Bldg 560,Room 32-40B,1050 Boyles St, Frederick, MD 21702 USA. RP Salomon, DS (reprint author), NCI, Tumor Growth Factor Sect, Mouse Canc Genet Program, Ctr Canc Res, Bldg 560,Room 32-40B,1050 Boyles St, Frederick, MD 21702 USA. EM salomond@mail.nih.gov NR 123 TC 2 Z9 2 U1 10 U2 23 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 EI 1573-7217 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD APR PY 2016 VL 156 IS 2 BP 211 EP 226 DI 10.1007/s10549-016-3746-7 PG 16 WC Oncology SC Oncology GA DI0DI UT WOS:000373164800001 PM 26968398 ER PT J AU Gruden, G Barutta, F Kunos, G Pacher, P AF Gruden, G. Barutta, F. Kunos, G. Pacher, P. TI Role of the endocannabinoid system in diabetes and diabetic complications SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Review ID CB1 CANNABINOID RECEPTORS; INDUCED INSULIN-RESISTANCE; CELL-DEATH; ADIPOSE-TISSUE; CONCISE GUIDE; OXIDATIVE STRESS; METABOLIC SYNDROME; LIPID-METABOLISM; PROXIMAL TUBULE; OBESITY AB Increasing evidence suggests that an overactive endocannabinoid system (ECS) may contribute to the development of diabetes by promoting energy intake and storage, impairing both glucose and lipid metabolism, by exerting pro-apoptotic effects in pancreatic beta cells and by facilitating inflammation in pancreatic islets. Furthermore, hyperglycaemia associated with diabetes has also been implicated in triggering perturbations of the ECS amplifying the pathological processes mentioned above, eventually culminating in a vicious circle. Compelling evidence from preclinical studies indicates that the ECS also influences diabetes-induced oxidative stress, inflammation, fibrosis and subsequent tissue injury in target organs for diabetic complications. In this review, we provide an update on the contribution of the ECS to the pathogenesis of diabetes and diabetic microvascular (retinopathy, nephropathy and neuropathy) and cardiovascular complications. The therapeutic potential of targeting the ECS is also discussed. Linked ArticlesThis article is part of a themed section on Endocannabinoids. To view the other articles in this section visit C1 [Gruden, G.; Barutta, F.] Univ Turin, Dept Med Sci, Lab Diabet Nephropathy, Turin, Italy. [Kunos, G.; Pacher, P.] NIAAA, Lab Physiol Studies, NIH, 5625 Fishers Lane,MSC 9413, Bethesda, MD 20892 USA. RP Pacher, P (reprint author), NIAAA, Lab Physiol Studies, NIH, 5625 Fishers Lane,MSC 9413, Bethesda, MD 20892 USA. EM pacher@mail.nih.gov FU European Federation for the Study of Diabetes; Societa Italiana di Diabetologia, Piedmont Region; NIAAA FX Research in the authors' laboratory was supported by European Federation for the Study of Diabetes, Societa Italiana di Diabetologia, Piedmont Region and Intramural Research Program of NIAAA. We apologize to all the investigators whose important works have not been cited due to space restrictions. P. P. dedicates this review to a friend/collaborator Itai Bab. NR 71 TC 1 Z9 1 U1 4 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1188 EI 1476-5381 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD APR PY 2016 VL 173 IS 7 SI SI BP 1116 EP 1127 DI 10.1111/bph.13226 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DH6NC UT WOS:000372906400002 PM 26076890 ER PT J AU Smith, AW Seibel, NL Lewis, DR Albritton, KH Blair, DF Blanke, CD Bleyer, WA Freyer, DR Geiger, AM Hayes-Lattin, B Tricoli, JV Wagner, LI Zebrack, BJ AF Smith, Ashley Wilder Seibel, Nita L. Lewis, Denise R. Albritton, Karen H. Blair, Donald F. Blanke, Charles D. Bleyer, W. Archie Freyer, David R. Geiger, Ann M. Hayes-Lattin, Brandon Tricoli, James V. Wagner, Lynne I. Zebrack, Bradley J. TI Next steps for adolescent and young adult oncology workshop: An update on progress and recommendations for the future SO CANCER LA English DT Review DE adolescent; biology; cancer; cancer care; epidemiology; quality of life; young adult ID QUALITY-OF-LIFE; ACUTE LYMPHOBLASTIC-LEUKEMIA; CLINICAL-TRIAL ENROLLMENT; GENERIC CORE SCALES; STAGE BREAST-CANCER; UNITED-STATES; MOLECULAR CHARACTERIZATION; POSTTRAUMATIC STRESS; TRANSCRIPTION FACTOR; COLORECTAL-CANCER AB Each year, 70,000 adolescents and young adults (AYAs) between ages 15 and 39 years in the United States are diagnosed with cancer. In 2006, a National Cancer Institute (NCI) Progress Review Group (PRG) examined the state of science associated with cancer among AYAs. To assess the impact of the PRG and examine the current state of AYA oncology research, the NCI, with support from the LIVESTRONG Foundation, sponsored a workshop entitled Next Steps in Adolescent and Young Adult Oncology on September 16 and 17, 2013, in Bethesda, Maryland. This report summarizes the findings from the workshop, opportunities to leverage existing data, and suggestions for future research priorities. Multidisciplinary teams that include basic scientists, epidemiologists, trialists, biostatisticians, clinicians, behavioral scientists, and health services researchers will be essential for future advances for AYAs with cancer. Cancer 2016;122:988-999. (c) 2016 American Cancer Society This report provides an overview of the National Cancer Institute and LIVESTRONG Foundation workshop on adolescent and young adult cancer research. Current science, including epidemiology, basic biology, clinical trials, health services, and health-related quality-of-life research, is reviewed with recommendations for future research priorities. C1 [Smith, Ashley Wilder; Lewis, Denise R.; Geiger, Ann M.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Seibel, Nita L.; Tricoli, James V.] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Albritton, Karen H.] Cook Childrens Med Ctr, Houston, TX USA. [Albritton, Karen H.] Univ N Texas, Hlth Sci Ctr, Houston, TX USA. [Blair, Donald F.] NCI, Div Canc Biol, Bethesda, MD 20892 USA. [Blanke, Charles D.; Hayes-Lattin, Brandon] Oregon Hlth & Sci Univ, Div Hematol & Med Oncol, Portland, OR 97201 USA. [Bleyer, W. Archie] Oregon Hlth & Sci Univ, Radiat Med Dept, Portland, OR 97201 USA. [Freyer, David R.] Univ So Calif, Keck Sch Med, Childrens Hosp Los Angeles, Los Angeles, CA 90033 USA. [Wagner, Lynne I.] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. [Zebrack, Bradley J.] Univ Michigan, Sch Social Work, Ann Arbor, MI 48109 USA. RP Smith, AW (reprint author), 9609 Med Ctr Dr,3E454,MSC 9762, Bethesda, MD 20892 USA. EM smithas@mail.nih.gov FU NCI NIH HHS [UG1 CA189974] NR 93 TC 8 Z9 8 U1 4 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD APR 1 PY 2016 VL 122 IS 7 BP 988 EP 999 DI 10.1002/cncr.29870 PG 12 WC Oncology SC Oncology GA DI3AK UT WOS:000373370400004 PM 26849003 ER PT J AU Barr, RD Ries, LAG Lewis, DR Harlan, LC Keegan, THM Pollock, BH Bleyer, WA AF Barr, Ronald D. Ries, Lynn A. G. Lewis, Denise R. Harlan, Linda C. Keegan, Theresa H. M. Pollock, Bradley H. Bleyer, W. Archie CA US Natl Canc Inst Sci Adolescent TI Incidence and incidence trends of the most frequent cancers in adolescent and young adult Americans, including "nonmalignant/noninvasive" tumors SO CANCER LA English DT Article DE adolescent; cancer incidence; United States; young adult ID UNITED-STATES; VACCINATION; PREVALENCE; ONCOLOGY AB BACKGROUNDIncidence rates and trends of cancers in adolescents and young adults (AYAs) ages 15 to 39 years were reexamined a decade after the US National Cancer Institute AYA Oncology Progress Review Group was established. METHODSData from the Surveillance, Epidemiology, and End Results program through 2011 were used to ascertain incidence trends since the year 2000 of the 40 most frequent cancers in AYAs, including tumors with nonmalignant/noninvasive behavior. RESULTSSeven cancers in AYAs exhibited an overall increase in incidence; in 4, the annual percent change (APC) exceeded 3 (kidney, thyroid, uterus [corpus], and prostate cancer); whereas, in 3, the APC was between 0.7 and 1.4 (acute lymphoblastic leukemia and cancers of the colorectum and testis). Eight cancers exhibited statistically significant decreases in incidence among AYAs: Kaposi sarcoma (KS), fibromatous neoplasms, melanoma, and cancers of the anorectum, bladder, uterine cervix, esophagus, and lung, each with an APC less than -1. AYAs had a higher proportion of noninvasive tumors than either older or younger patients. CONCLUSIONSAn examination of cancer incidence patterns in AYAs observed over the recent decade reveal a complex pattern. Thyroid cancer by itself accounts for most of the overall increase and is likely caused by overdiagnosis. Reductions in cervix and lung cancer, melanoma, and KS can be attributed to successful national prevention programs. A higher proportion of noninvasive tumors in AYAs than in children and older adults indicates a need to revise the current system of classifying tumors in this population. Cancer 2016;122:1000-1008. (c) 2016 American Cancer Society In American adolescents and young adults (AYAs), 7 cancers have increased and 8 have decreased in incidence since 2000, with thyroid cancer accounting for most of the increase, likely because of overdiagnosis, whereas incidence reductions may reflect the impact of successful programs of prevention. A higher proportion of noninvasive tumors in AYAs than in children and older adults prompts a need to revise the current system of classifying tumors in this population. C1 [Barr, Ronald D.] McMaster Univ, Dept Pediat, 1280 Main St W, Hamilton, ON L8S 4J9, Canada. [Barr, Ronald D.] McMaster Univ, Dept Pathol, 1280 Main St W, Hamilton, ON L8S 4J9, Canada. [Barr, Ronald D.] McMaster Univ, Dept Med, 1280 Main St W, Hamilton, ON L8S 4J9, Canada. [Ries, Lynn A. G.; Lewis, Denise R.] NCI, Surveillance Res Program, NIH, Bethesda, MD 20892 USA. [Harlan, Linda C.] NCI, Appl Res Program, NIH, Bethesda, MD USA. [Keegan, Theresa H. M.] Univ Calif Davis, Sch Med, Dept Internal Med, Div Hematol & Oncol, Sacramento, CA 95817 USA. [Pollock, Bradley H.] Univ Calif Davis, Dept Publ Hlth Sci, Sacramento, CA 95817 USA. [Bleyer, W. Archie] Oregon Hlth & Sci Univ, Dept Radiat Med, Portland, OR 97201 USA. [Bleyer, W. Archie] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. RP Barr, RD (reprint author), McMaster Univ, Dept Pediat, 1280 Main St W, Hamilton, ON L8S 4J9, Canada. EM rbarr@mcmaster.ca FU National Cancer Institute FX Lynn A. G. Ries and Bradley H. Pollock report funding from the National Cancer Institute during the conduct of the study NR 24 TC 3 Z9 3 U1 5 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD APR 1 PY 2016 VL 122 IS 7 BP 1000 EP 1008 DI 10.1002/cncr.29867 PG 9 WC Oncology SC Oncology GA DI3AK UT WOS:000373370400005 PM 26848808 ER PT J AU Keegan, THM Ries, LAG Barr, RD Geiger, AM Dahlke, DV Pollock, BH Bleyer, WA AF Keegan, Theresa H. M. Ries, Lynn A. G. Barr, Ronald D. Geiger, Ann M. Dahlke, Deborah Vollmer Pollock, Bradley H. Bleyer, W. Archie CA Natl Canc Inst Next Steps Adolesce Young Adult Oncol Epidemiol Workin TI Comparison of cancer survival trends in the United States of adolescents and young adults with those in children and older adults SO CANCER LA English DT Article DE adolescent; adult; cancer; children; survival; trends; United States; young adult ID EARLY 21ST-CENTURY; INSURANCE; LEUKEMIA; OUTCOMES AB BACKGROUNDWith prior reports indicating a lack of progress in survival improvement in older adolescents and young adults (AYAs) aged 15 to 39 years with cancer compared with both younger and older patients with cancer, the current analysis provides an update of survival trends of cancers among AYAs, children, and older adults. METHODSData from the National Cancer Institute Surveillance, Epidemiology, and End Results database for 13 regions were used to ascertain survival trends of the 34 most frequent cancers diagnosed in AYAs compared with children and older adults. RESULTSAs of 2002 through 2006, the 5-year relative survival rate for all invasive cancers in AYAs was 82.5% (standard error, 0.2%). In AYAs, 14 cancers demonstrated evidence of a statistically significant improvement in their 5-year relative survival since 1992. Survival improved less in AYAs than in children for acute myeloid leukemia and medulloblastoma. Fourteen cancers had survival improvements that were found to be less in AYAs compared with older adults, including hepatic carcinoma, acute myeloid leukemia, high-grade astrocytoma, acute lymphocytic leukemia, pancreatic carcinoma, low-grade astrocytoma, gastric carcinoma, renal carcinoma, cancer of the oral cavity and pharynx, Hodgkin lymphoma, ovarian cancer, fibromatous sarcoma, other soft tissue sarcoma, and thyroid carcinoma. CONCLUSIONSImprovements in the survival of several cancer types that occur frequently in AYAs are encouraging. However, survival does not appear to be improving to the same extent in AYAs as in children or older adults for several cancers. Further investment in exploring the distinct biology of tumors in this age group, and of their hosts, must be a priority in AYA oncology. Cancer 2016;122:1009-1016. (c) 2016 American Cancer Society In the United States, survival improved for 14 types of cancers among adolescents and young adults since 1992. However, survival is not improving to the same extent in adolescents and young adults as in children or older adults for a number of cancers. C1 [Keegan, Theresa H. M.] Univ Calif Davis, Sch Med, Div Hematol & Oncol, Dept Internal Med, Sacramento, CA 95817 USA. [Ries, Lynn A. G.] NCI, Surveillance Res Program, NIH, Bethesda, MD 20892 USA. [Barr, Ronald D.] McMaster Univ, Dept Pediat, Hamilton, ON, Canada. [Barr, Ronald D.] McMaster Univ, Dept Pathol, Hamilton, ON, Canada. [Barr, Ronald D.] McMaster Univ, Dept Med, Hamilton, ON, Canada. [Geiger, Ann M.] NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Dahlke, Deborah Vollmer] Texas A&M Hlth Sci Ctr, Sch Publ Hlth, College Stn, TX USA. [Pollock, Bradley H.] Univ Calif Davis, Dept Publ Hlth Sci, Davis, CA 95616 USA. [Bleyer, W. Archie] St Charles Reg Canc Ctr, Bend, OR USA. [Bleyer, W. Archie] Oregon Hlth & Sci Univ, Dept Radiat Med, Portland, OR 97201 USA. RP Keegan, THM (reprint author), Univ Calif Davis, Ctr Comprehens Canc, Div Hematol & Oncol, 4501 X St,Suite,3016, Sacramento, CA 95817 USA. EM tkeegan@ucdavis.edu FU National Cancer Institute [HHSN261201300308P, HHSN261201200422P] FX Lynn A.G. Ries was funded under contracts HHSN261201300308P and HHSN261201200422P from the National Cancer Institute. W. Archie Bleyer has acted as a paid consultant for Sigma Tau Pharmaceuticals for work performed outside of the current study. NR 21 TC 10 Z9 10 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD APR 1 PY 2016 VL 122 IS 7 BP 1009 EP 1016 DI 10.1002/cncr.29869 PG 8 WC Oncology SC Oncology GA DI3AK UT WOS:000373370400006 PM 26848927 ER PT J AU Tricoli, JV Blair, DG Anders, CK Bleyer, WA Boardman, LA Khan, J Kummar, S Hayes-Lattin, B Hunger, SP Merchant, M Seibel, NL Thurin, M Willman, CL AF Tricoli, James V. Blair, Donald G. Anders, Carey K. Bleyer, W. Archie Boardman, Lisa A. Khan, Javed Kummar, Shivaani Hayes-Lattin, Brandon Hunger, Stephen P. Merchant, Melinda Seibel, Nita L. Thurin, Magdalena Willman, Cheryl L. TI Biologic and clinical characteristics of adolescent and young adult cancers: Acute lymphoblastic leukemia, colorectal cancer, breast cancer, melanoma, and sarcoma SO CANCER LA English DT Review DE acute lymphoblastic leukemia (ALL); breast; colorectal; melanoma; sarcoma ID MINIMAL RESIDUAL DISEASE; CHILDRENS ONCOLOGY GROUP; GENOME-WIDE ASSOCIATION; GENE-EXPRESSION; MOLECULAR CHARACTERIZATION; FAMILY-HISTORY; EWINGS-SARCOMA; B-PROGENITOR; HUMAN-COLON; SPITZ NEVI AB Adolescent and young adult (AYA) patients with cancer have not attained the same improvements in overall survival as either younger children or older adults. One possible reason for this disparity may be that the AYA cancers exhibit unique biologic characteristics, resulting in differences in clinical and treatment resistance behaviors. This report from the biologic component of the jointly sponsored National Cancer Institute and LiveStrong Foundation workshop entitled Next Steps in Adolescent and Young Adult Oncology summarizes the current status of biologic and translational research progress for 5 AYA cancers; colorectal cancer breast cancer, acute lymphoblastic leukemia, melanoma, and sarcoma. Conclusions from this meeting included the need for basic biologic, genomic, and model development for AYA cancers as well as translational research studies to elucidate any fundamental differences between pediatric, AYA, and adult cancers. The biologic questions for future research are whether there are mutational or signaling pathway differences (for example, between adult and AYA colorectal cancer) that can be clinically exploited to develop novel therapies for treating AYA cancers and to develop companion diagnostics. Cancer 2016;122:1017-1028. (c) 2016 American Cancer Society There is a need for basic biologic, genomic, and model development for cancers in adolescents and young adults (AYAs) as well as translational research studies to elucidate any fundamental differences between pediatric, AYA, and adult cancers. If these differences can be elucidated, then the information can be used to start the development of novel therapies for treating AYA cancers and companion diagnostics to accompany these treatments. C1 [Tricoli, James V.; Kummar, Shivaani; Seibel, Nita L.; Thurin, Magdalena] NCI, Div Canc Treatment & Diag, Rockville, MD USA. [Blair, Donald G.] NCI, Div Canc Biol, Rockville, MD USA. [Anders, Carey K.] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Bleyer, W. Archie; Hayes-Lattin, Brandon] Oregon Hlth & Sci Univ, Div Hematol & Med Oncol, Portland, OR 97201 USA. [Boardman, Lisa A.] Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN USA. [Khan, Javed; Merchant, Melinda] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Hunger, Stephen P.] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Willman, Cheryl L.] Univ New Mexico, Ctr Canc, Albuquerque, NM 87131 USA. RP Tricoli, JV (reprint author), NCI, Canc Diag Program, 9609 Med Ctr Dr, Rockville, MD 20892 USA.; Tricoli, JV (reprint author), NCI, Div Canc Treatment & Diag, Canc Diag Program, Diagnost Biomarkers & Technol Branch, 9609 Med Ctr Dr, Rockville, MD 20892 USA. EM tricolij@mail.nih.gov FU National Cancer Institute (NCI) American Recovery & Reinvestment Act (ARRA) Challenge Grant [CA145707]; NCI [K23157728] FX The research in this publication was supported by a National Cancer Institute (NCI) American Recovery & Reinvestment Act of 2009 (ARRA) Challenge Grant CA145707 (Cheryl L. Willman) and by NCI grant K23157728 (Carey K. Anders). NR 104 TC 5 Z9 5 U1 7 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD APR 1 PY 2016 VL 122 IS 7 BP 1017 EP 1028 DI 10.1002/cncr.29871 PG 12 WC Oncology SC Oncology GA DI3AK UT WOS:000373370400007 PM 26849082 ER PT J AU Warner, EL Kent, EE Trevino, KM Parsons, HM Zebrack, BJ Kirchhoff, AC AF Warner, Echo L. Kent, Erin E. Trevino, Kelly M. Parsons, Helen M. Zebrack, Bradley J. Kirchhoff, Anne C. TI Social well-being among adolescents and young adults with cancer: A systematic review SO CANCER LA English DT Review DE adolescent and young adult; cancer; education; employment; social support ID QUALITY-OF-LIFE; SURVIVORS; HEALTH; CARE; CONCEPTIONS; SUPPORT; IMPACT; PERSPECTIVES; POPULATION; TRANSITION AB BACKGROUNDA cancer diagnosis during adolescence or young adulthood may negatively influence social well-being. The existing literature concerning the social well-being of adolescents and young adults (AYAs) with cancer was reviewed to identify gaps in current research and highlight priority areas for future research. METHODSA systematic review of the scientific literature published in English from 2000 through 2014 was performed. Eligible studies included patients and survivors diagnosed between the ages of 15 to 39 years that reported on social well-being domains in the City of Hope Cancer Survivor Quality of Life Model. Each article was reviewed for relevance using a standardized template. A total of 253 potential articles were identified. After exclusions, a final sample of 26 articles identified domains of social well-being that are believed to be understudied among AYAs with cancer: 1) educational attainment, employment, and financial burden; 2) social relationships; and 3) supportive care. Articles were read in their entirety, single coded, and summarized according to domain. RESULTSAYAs with cancer report difficulties related to employment, educational attainment, and financial stability. They also report problems with the maintenance and development of peer and family relationships, intimate and marital relationships, and peer support. Supportive services are desired among AYAs. Few studies have reported results in reference to comparison samples or by cancer subtypes. CONCLUSIONSFuture research studies on AYAs with cancer should prioritize the inclusion of underserved AYA populations, more heterogeneous cancer samples, and comparison groups to inform the development of supportive services. Priority areas for potential intervention include education and employment reintegration, and social support networks. Cancer 2016;122:1029-1037. (c) 2016 American Cancer Society A cancer diagnosis during adolescence and young adulthood can lead to considerable problems with regard to social well-being. The current study systematically reviews the literature concerning the social well-being of adolescents and young adults with cancer and finds consistent difficulties related to employment/educational attainment, financial stability, social relationships, and supportive care. C1 [Warner, Echo L.; Kirchhoff, Anne C.] Huntsman Canc Inst, Canc Control & Populat Sci, 2000 Circle Hope,Rm 4145, Salt Lake City, UT 84112 USA. [Kent, Erin E.] NCI, Outcomes Res Branch, NIH, Bethesda, MD 20892 USA. [Trevino, Kelly M.] Weill Cornell Med, Dept Med, New York, NY USA. [Parsons, Helen M.] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. [Zebrack, Bradley J.] Univ Michigan, Sch Social Work, Ann Arbor, MI 48109 USA. [Kirchhoff, Anne C.] Univ Utah, Dept Pediat, Salt Lake City, UT USA. RP Kirchhoff, AC (reprint author), Huntsman Canc Inst, Canc Control & Populat Sci, 2000 Circle Hope,Rm 4145, Salt Lake City, UT 84112 USA. EM anne.kirchhoff@hci.utah.edu FU National Cancer Institute [K07CA175063] FX Helen M. Parsons was supported by National Cancer Institute grant K07CA175063 for work performed as part of the current study. NR 52 TC 9 Z9 9 U1 6 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD APR 1 PY 2016 VL 122 IS 7 BP 1029 EP 1037 DI 10.1002/cncr.29866 PG 9 WC Oncology SC Oncology GA DI3AK UT WOS:000373370400008 PM 26848713 ER PT J AU Milgroom, A Ralston, E AF Milgroom, Andrew Ralston, Evelyn TI Clearing skeletal muscle with CLARITY for light microscopy imaging SO CELL BIOLOGY INTERNATIONAL LA English DT Article DE CLARITY; deep tissue imaging; optical clearing; second harmonic generation imaging; skeletal muscle ID SINGLE-CELL RESOLUTION; RECONSTRUCTION; FLUORESCENCE; TISSUE; BRAIN; ORGANS AB Viewing subcellular details over large tissue volumes is becoming an essential condition of the success of large-scale projects aimed at visualizing cell connections in whole organs or tissues. However, tissue opacity remains an obstacle to deep tissue imaging. This situation has brought renewed interest for techniques of tissue clearing; new protocols, such as CLARITY (Clear Lipid-exchanged Acrylamide-hybridized Rigid Imaging/Immunostaining/In situ hybridization-compatible Tissue-hYdrogel), have recently been developed. So far, most of the tests of these techniques have been applied to brain or other soft tissues. Here we show that CLARITY clears mouse hindlimb skeletal muscles and maintains the basic structural features of muscle and its fibers. However, tagging with fluorescent markers was not successful. C1 [Milgroom, Andrew; Ralston, Evelyn] NIAMSD, Light Imaging Sect, Off Sci & Technol, NIH, Bethesda, MD 20892 USA. [Milgroom, Andrew] Trinity Partners, 230 3rd Ave, Waltham, MA 02451 USA. RP Ralston, E (reprint author), NIAMSD, Light Imaging Sect, Off Sci & Technol, NIH, Bethesda, MD 20892 USA. EM evelyn.ralston@nih.gov FU National Institutes of Arthritis and Musculoskeletal and Skin Diseases FX We thank Gary Melvin for help with the CLARITY chambers, members of the lab for useful suggestions, and Kristien J. Zaal for critical reading of the manuscript. This project was supported by the Intramural Program of the National Institutes of Arthritis and Musculoskeletal and Skin Diseases. NR 21 TC 0 Z9 0 U1 8 U2 18 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-6995 EI 1095-8355 J9 CELL BIOL INT JI Cell Biol. Int. PD APR PY 2016 VL 40 IS 4 BP 478 EP 483 DI 10.1002/cbin.10578 PG 6 WC Cell Biology SC Cell Biology GA DH6WH UT WOS:000372932300013 PM 26732743 ER PT J AU Haam, JH Kim, YS Koo, HS Haam, J Seo, NK Kim, HY Park, KC Park, KS Kim, MJ AF Haam, Ji-Hee Kim, Young-Sang Koo, Hyung Suk Haam, Juhee Seo, Nam Kyoung Kim, Hyung Yuk Park, Kyung-Chae Park, Kye-Seon Kim, Moon Jong TI Intermuscular adipose tissue is associated with monocyte chemoattractant protein-1, independent of visceral adipose tissue SO CLINICAL BIOCHEMISTRY LA English DT Article DE Obesity; MCP-1; Adiponectin; Leptin; Intermuscular adipose tissue ID BODY-FAT DISTRIBUTION; INSULIN SENSITIVITY; CARDIOVASCULAR-DISEASE; LEPTIN; OBESITY; INFLAMMATION; ADIPONECTIN; RESISTANCE; GLUCOSE; WOMEN AB Objectives: Emerging evidence suggests that intermuscular adipose tissue is a risk factor for insulin resistance, but the underlying mechanism still remains unclear. We investigated whether the levels of leptin, adiponectin, and monocyte chemoattractant protein-1 are associated with intermuscular adipose tissue in obese subjects. Design and methods: A cross-sectional study was performed on 77 obese Korean women. Areas of visceral adipose tissue, subcutaneous adipose tissue, and intermuscular adipose tissue were measured by computed tomography scan, and serum concentrations of adipokines were measured by enzyme-linked immunosorbent assays. Correlation between the levels of adipokines and the fat areas was assessed using Pearson correlation and covariate-adjusted multivariable regression. Results: Leptin was positively correlated with subcutaneous adipose tissue (r = 0.452, P < 0.001), fasting insulin (r = 0.403, P < 0.001), and homeostasis model assessment of insulin resistance (r = 0.360, P = 0.001), whereas monocyte chemoattractant protein-1 was positively correlated with intermuscular adipose tissue (r = 0.483, P < 0.001). After adjustment for age, height, and other body composition metrics, leptin was still related to subcutaneous adipose tissue (beta = 0.390, P = 0.001). Monocyte chemoattractant protein-1 was associated with intermuscular adipose tissue (beta = 0.433, P = 0.001) after adjustment for visceral adipose tissue. Conclusions: Intermuscular adipose tissue was correlated with monocyte chemoattractant protein-1, suggesting its role in the development of insulin resistance. (C) 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. C1 [Haam, Ji-Hee; Kim, Young-Sang; Seo, Nam Kyoung; Kim, Hyung Yuk; Park, Kyung-Chae; Park, Kye-Seon; Kim, Moon Jong] CHA Univ, CHA Bundang Med Ctr, Dept Family Med, 59 Yatap Ro, Songnam, Gyeonggi Do, South Korea. [Koo, Hyung Suk] Dongguk Univ, Bundang Oriental Hosp, Dept Family Med, 268 Buljeong Ro, Songnam, Gyeonggi Do, South Korea. [Haam, Juhee] Natl Inst Environm Hlth Sci, Neurobiol Lab, NIH, 111 TW Alexander Dr, Durham, NC 27709 USA. RP Kim, MJ (reprint author), CHA Univ, CHA Bundang Med Ctr, Dept Family Med, 59 Yatap Ro, Songnam, Gyeonggi Do, South Korea. EM mjkimfm@cha.ac.kr FU National Institutes of Health (NIH); Daesang Corporation (Seoul, Korea); Ministry of Science, ICT and Future Planning [NRF 2013M3A9C4078153]; Ministry of Education, Science and Technology [BK21PLUS 22A20130012143] FX We are grateful to the participants in this study. This work was supported by the National Institutes of Health (NIH) intramural research program. This study was supported by Daesang Corporation (Seoul, Korea), the Ministry of Science, ICT and Future Planning (NRF 2013M3A9C4078153), and the Ministry of Education, Science and Technology (BK21PLUS 22A20130012143). The funding sources had no involvement in the design, collection, analysis, and interpretation of the data; the writing of this report; or the decision to submit this manuscript for publication. NR 44 TC 1 Z9 1 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0009-9120 EI 1873-2933 J9 CLIN BIOCHEM JI Clin. Biochem. PD APR PY 2016 VL 49 IS 6 BP 439 EP 443 DI 10.1016/j.clinbiochem.2015.12.003 PG 5 WC Medical Laboratory Technology SC Medical Laboratory Technology GA DI0TI UT WOS:000373209700004 PM 26705742 ER PT J AU Thorsteinsdottir, I Aspelund, T Gudmundsson, E Eiriksdottir, G Harris, TB Launer, LJ Gudnason, V Venge, P AF Thorsteinsdottir, Ingunn Aspelund, Thor Gudmundsson, Elias Eiriksdottir, Gudny Harris, Tamara B. Launer, Lenore J. Gudnason, Vilmundur Venge, Per TI High-Sensitivity Cardiac Troponin I Is a Strong Predictor of Cardiovascular Events and Mortality in the AGES-Reykjavik Community-Based Cohort of Older Individuals SO CLINICAL CHEMISTRY LA English DT Article ID CORONARY-HEART-DISEASE; ELDERLY POPULATION; MYOCARDIAL-INFARCTION; ATHEROSCLEROSIS RISK; GENERAL-POPULATION; ASSAY; ASSOCIATION; BIOMARKERS; FAILURE; IMPACT AB BACKGROUND: The objective of this study was to investigate the predictive power of a high-sensitivity cardiac troponin I (hs-cTnI) assay for cardiovascular events and mortality in a large population of older community dwellers. METHODS: Blood was collected from 5764 individuals (age 66-98 years) during the period of 2002-2006 and the outcome as to all-cause death and incidence of cardiovascular disease (CVD) and coronary heart disease (CHD) followed up to 10 years. hs-cTnI (Abbott) was measured in serum to assess the association of this marker with CVD, CHD and death, and finally, to compare the results with conventional risk factors by multivariable statistical analysis. RESULTS: The median (interquartile range) concentrations of hs-cTnI were 8.4 ng/L (5.6-14.2 ng/L) and 5.3 ng/L (3.8-8.1 ng/L) in men (2416) and women (3275), respectively, and the concentrations increased linearly with age. Outcomes as to all-cause death and incidence of CVD and CHD were significantly associated with increasing concentrations of hs-cTnI beginning well below the 99th percentile concentrations. The associations with outcome remained after adjustments for conventional risk factors and were similar in men and women. CONCLUSIONS: Our findings suggest that hs-cTnI reflects the status of the myocardium even in seemingly healthy individuals and that the measurements of hs-cTnI may be useful for primary prediction of heart disease; this should form the basis for future prospective clinical trials for determining whether measuring hs-cTnI can be used in the prevention of CVD/CHD. (C) 2016 American Association for Clinical Chemistry C1 [Thorsteinsdottir, Ingunn; Aspelund, Thor; Gudmundsson, Elias; Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc, Res Inst, Kopavogur, Iceland. [Thorsteinsdottir, Ingunn] Landspitali Univ Hosp, Dept Clin Biochem, Reykjavik, Iceland. [Aspelund, Thor; Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Harris, Tamara B.; Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. [Venge, Per] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. RP Venge, P (reprint author), Univ Uppsala Hosp, Dept Med Sci, SE-75185 Uppsala, Sweden. EM per.venge@medsci.uu.se FU National Institutes of Health, USA [N01-AG-12100]; National Institute on Aging Intramural Research Program, the National Eye Institute USA [Z01-EY000401]; National Institutes of Health; Hjartavernd (the Icelandic Heart Association); Althingi (Icelandic Parliament); Abbott Diagnostics FX The National Institutes of Health, USA (contract N01-AG-12100), the National Institute on Aging Intramural Research Program, the National Eye Institute USA (Z01-EY000401), National Institutes of Health, Hjartavernd (the Icelandic Heart Association), and Althingi (Icelandic Parliament); the assay of hs-cTnI was supported by a grant from Abbott Diagnostics; P. Venge, Abbott Diagnostics. NR 24 TC 2 Z9 2 U1 1 U2 4 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 EI 1530-8561 J9 CLIN CHEM JI Clin. Chem. PD APR PY 2016 VL 62 IS 4 BP 623 EP 630 DI 10.1373/clinchem.2015.250811 PG 8 WC Medical Laboratory Technology SC Medical Laboratory Technology GA DH9DR UT WOS:000373097100013 PM 26936931 ER PT J AU Beck, TF Mullikin, JC Biesecker, LG AF Beck, Tyler F. Mullikin, James C. Biesecker, Leslie G. CA NISC Comparative Sequencing Progra TI Systematic Evaluation of Sanger Validation of Next-Generation Sequencing Variants SO CLINICAL CHEMISTRY LA English DT Article ID EXOME; MUTATIONS; GENES AB BACKGROUND: Next-generation sequencing (NGS) data are used for both clinical care and clinical research. DNA sequence variants identified using NGS are often returned to patients/participants as part of clinical or research protocols. The current standard of care is to validate NGS variants using Sanger sequencing, which is costly and time-consuming. METHODS: We performed a large-scale, systematic evaluation of Sanger-based validation of NGS variants using data from the ClinSeq (R) project. We first used NGS data from 19 genes in 5 participants, comparing them to high throughput Sanger sequencing results on the same samples, and found no discrepancies among 234 NGS variants. We then compared NGS variants in 5 genes from 684 participants against data from Sanger sequencing. RESULTS: Of over 5800 NGS-derived variants, 19 were not validated by Sanger data. Using newly designed sequencing primers, Sanger sequencing confirmed 17 of the NGS variants, and the remaining 2 variants had low quality scores from exome sequencing. Overall, we measured a validation rate of 99.965% for NGS variants using Sanger sequencing, which was higher than many existing medical tests that do not necessitate orthogonal validation. CONCLUSIONS: A single round of Sanger sequencing is more likely to incorrectly refute a true-positive variant from NGS than to correctly identify a false-positive variant from NGS. Validation of NGS-derived variants using Sanger sequencing has limited utility, and best practice standards should not include routine orthogonal Sanger validation of NGS variants. (C) 2016 American Association for Clinical Chemistry C1 [Beck, Tyler F.; Biesecker, Leslie G.] NHGRI, NIH, 49 Convent Dr,4A56, Bethesda, MD 20830 USA. [NISC Comparative Sequencing Progra] NIH, Intramural Sequencing Ctr, Rockville, MD USA. RP Biesecker, LG (reprint author), NHGRI, NIH, 49 Convent Dr,4A56, Bethesda, MD 20830 USA. EM lesb@mail.nih.gov FU Intramural Research Program of the National Human Genome Research Institute FX The Intramural Research Program of the National Human Genome Research Institute. NR 29 TC 4 Z9 4 U1 0 U2 4 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 EI 1530-8561 J9 CLIN CHEM JI Clin. Chem. PD APR PY 2016 VL 62 IS 4 BP 647 EP 654 DI 10.1373/clinchem.2015.249623 PG 8 WC Medical Laboratory Technology SC Medical Laboratory Technology GA DH9DR UT WOS:000373097100016 PM 26847218 ER PT J AU Han, B Crosby, AE Ortega, LAG Parks, SE Compton, WM Gfroerer, J AF Han, Beth Crosby, Alex E. Ortega, LaVonne A. G. Parks, Sharyn E. Compton, Wilson M. Gfroerer, Joseph TI Suicidal ideation, suicide attempt, and occupations among employed adults aged 18-64 years in the United States SO COMPREHENSIVE PSYCHIATRY LA English DT Article ID MORTALITY; PATTERNS; POLICE; CANADA AB Objective: Approximately 70% of all US suicides are among working-age adults. This study was to determine whether and how 12-month suicidal ideation and suicide attempt were associated with specific occupations among currently employed adults aged 18-64 in the U.S. Methods: Data were from 184,300 currently employed adults who participated in the 2008-2013 National Surveys on Drug Use and Health (NSDUH). NSDUH provides nationally representative data on suicidal ideation and suicide attempt. Descriptive analyses and multivariable logistic regressions were conducted. Results: Among currently employed adults aged 18-64 in the U.S., 3.5% had suicidal ideation in the past 12 months (3.1% had suicidal ideation only, and 0.4% had suicidal ideation and attempted suicide). Compared with adults in farming, fishing, and forestry occupations (model adjusted prevalence (MAP) = 1.6%), adults in the following occupations were 3.0-3.6 times more likely to have suicidal ideation in the past year (model adjusted relative risks (MARRs) = 3.0-3.6): lawyers, judges, and legal support workers (MAP = 4.8%), social scientists and related workers (MAP = 5.4%), and media and communication workers (MAP = 5.8%). Conclusions: Among employed adults aged 18-64 in the U.S., the 12-month prevalence of suicidal ideation varies by occupations. Adults in occupations that are at elevated risk for suicidal ideation may warrant focused suicide prevention. Published by Elsevier Inc. C1 [Han, Beth; Gfroerer, Joseph] Subst Abuse & Mental Hlth Serv Adm, Paris, France. [Crosby, Alex E.; Parks, Sharyn E.] Ctr Dis Control & Prevent, Natl Ctr Injury Prevent & Control, Div Violence Prevent, Atlanta, GA USA. [Ortega, LaVonne A. G.] Ctr Dis Control & Prevent, Ctr Surveillance Epidemiol & Lab Serv, Div Sci Educ & Profess Dev, Atlanta, GA USA. [Compton, Wilson M.] NIDA, NIH, Bethesda, MD USA. RP Han, B (reprint author), 5600 Fishers Lane 15E13B, Rockville, MD 20857 USA. EM Beth.Han@SAMHSA.HHS.GOV FU Intramural CDC HHS [CC999999] NR 37 TC 0 Z9 0 U1 3 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0010-440X EI 1532-8384 J9 COMPR PSYCHIAT JI Compr. Psychiat. PD APR PY 2016 VL 66 BP 176 EP 186 DI 10.1016/j.comppsych.2016.02.001 PG 11 WC Psychiatry SC Psychiatry GA DH4ML UT WOS:000372760000023 PM 26995251 ER PT J AU Sogoba, N Rosenke, K Adjemian, J Diawara, SI Maiga, O Keita, M Konate, D Keita, AS Sissoko, I Boisen, M Nelson, D Oottamasathien, D Millett, M Garry, RF Branco, LM Traore, SF Doumbia, S Feldmann, H Safronetz, D AF Sogoba, Nafomon Rosenke, Kyle Adjemian, Jennifer Diawara, Sory Ibrahim Maiga, Ousmane Keita, Moussa Konate, Drissa Keita, Abdoul Salam Sissoko, Ibrahim Boisen, Matt Nelson, Diana Oottamasathien, Darin Millett, Molly Garry, Robert F. Branco, Luis M. Traore, Sekou F. Doumbia, Seydou Feldmann, Heinz Safronetz, David TI Lassa Virus Seroprevalence in Sibirilia Commune, Bougouni District, Southern Mali SO EMERGING INFECTIOUS DISEASES LA English DT Article ID SIERRA-LEONE; WEST-AFRICA; MASTOMYS-NATALENSIS; CLINICAL-FEATURES; RISK-FACTORS; FEVER; DISEASE; REGION; EPIDEMIOLOGY; LIBERIA AB Lassa virus (LASV) is endemic to several nations in West Africa. In Mali, LASV was unknown until an exported case of Lassa fever was reported in 2009. Since that time, rodent surveys have found evidence of LASV-infected Mastomys natalensis rats in several communities in southern Mali, near the border with Cote d'Ivoire. Despite increased awareness, to date only a single case of Lassa fever has been confirmed in Mali. We conducted a survey to determine the prevalence of LASV exposure among persons in 3 villages in southern Mali where the presence of infected rodents has been documented. LASV IgG seroprevalence ranged from 14.5% to 44% per village. No sex bias was noted; however, seropositivity rates increased with participant age. These findings confirm human LASV exposure in Mali and suggest that LASV infection/Lassa fever is a potential public health concern in southern Mali. C1 [Sogoba, Nafomon; Diawara, Sory Ibrahim; Maiga, Ousmane; Keita, Moussa; Konate, Drissa; Keita, Abdoul Salam; Sissoko, Ibrahim; Traore, Sekou F.; Doumbia, Seydou] Univ Sci Tech & Technol Bamako, Bamako, Mali. [Rosenke, Kyle; Feldmann, Heinz; Safronetz, David] NIH, Hamilton, MT USA. [Adjemian, Jennifer] NIH, Bldg 10, Bethesda, MD 20892 USA. [Boisen, Matt; Nelson, Diana; Oottamasathien, Darin; Millett, Molly] Corgenix Med Corp Inc, Broomfield, CO USA. [Garry, Robert F.] Tulane Sch Med, New Orleans, LA USA. [Branco, Luis M.] Zalgen Labs LLC, Germantown, MD USA. [Safronetz, David] Publ Hlth Agcy Canada, Winnipeg, MB, Canada. RP Safronetz, D (reprint author), Publ Hlth Agcy Canada, Natl Microbiol Lab, Zoonot Dis & Special Pathogens, 1015 Arlington St, Winnipeg, MB R3E 3R2, Canada. EM david.safronetz@phac-aspc.gc.ca OI Branco, Luis/0000-0001-8161-0182 FU International Centers for Excellence in Research program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the International Centers for Excellence in Research program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 35 TC 1 Z9 1 U1 4 U2 8 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 APR PY 2016 VL 22 IS 4 BP 657 EP 663 DI 10.3201/eid2204.151814 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DH3LM UT WOS:000372688500010 PM 26981786 ER PT J AU Commodaro, AG Chiasson, M Sundar, N Rizzo, LV Belfort, R Grigg, ME AF Commodaro, Alessandra G. Chiasson, Melissa Sundar, Natarajan Rizzo, Luiz Vicente Belfort, Rubens, Jr. Grigg, Michael E. TI Elevated Toxoplasma gondii Infection Rates for Retinas from Eye Banks, Southern Brazil SO EMERGING INFECTIOUS DISEASES LA English DT Article ID OCULAR TOXOPLASMOSIS; STRAINS AB We found significantly higher incidence of Toxoplasma gondii DNA in eye bank specimens from Joinville in southern Brazil (13/15, 87%) than in Sao Paulo (3/42, 7%; p = 2.1 x 10E-8). PCR DNA sequence analysis was more sensitive at locus NTS2 than at locus 131; a high frequency of mixed co-infections was detected. C1 [Commodaro, Alessandra G.; Chiasson, Melissa; Sundar, Natarajan; Grigg, Michael E.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Commodaro, Alessandra G.; Belfort, Rubens, Jr.] Univ Fed Sao Paulo, Sao Paulo, Brazil. [Rizzo, Luiz Vicente] Hosp Albert Einstein, Sao Paulo, Brazil. RP Grigg, ME (reprint author), NIAID, Parasit Dis Lab, 4 Ctr Dr,Rm B1-06, Bethesda, MD 20892 USA. EM griggm@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico [237252/2012]; FundaCao de Amparo a Perquisa do Estado de Sao Paulo; Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior FX This work was supported in part by the National Institute of Allergy and Infectious Diseases, National Institutes of Health (to M.E.G.), Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (grant no. 237252/2012), FundaCao de Amparo a Perquisa do Estado de Sao Paulo, and Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior. R.B.J. and L.V.R. are researchers at Conselho Nacional de Desenvolvimento Cientifico e Tecnologico Brazil. M.E.G. is a scholar at the Canadian Institute for Advanced Research Integrated Microbial Biodiversity Program. NR 15 TC 1 Z9 1 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 APR PY 2016 VL 22 IS 4 BP 691 EP 693 DI 10.3201/eid2204.141819 PG 3 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DH3LM UT WOS:000372688500015 PM 26982526 ER PT J AU Zhang, YM Boerwinkel, DF Qin, XM He, S Xue, LY Weusten, BLAM Dawsey, SM Fleischer, DE Dou, LZ Liu, Y Lu, N Bergman, JJGHM Wang, GQ AF Zhang, Yue-Ming Boerwinkel, David F. Qin, Xiumin He, Shun Xue, Liyan Weusten, Bas L. A. M. Dawsey, Sanford M. Fleischer, David E. Dou, Li-Zhou Liu, Yong Lu, Ning Bergman, Jacques J. G. H. M. Wang, Gui-Qi TI A randomized trial comparing multiband mucosectomy and cap-assisted endoscopic resection for endoscopic piecemeal resection of early squamous neoplasia of the esophagus SO ENDOSCOPY LA English DT Article ID CELL CARCINOMA; BARRETTS-ESOPHAGUS; MUCOSAL RESECTION; LOCAL RECURRENCE; LYMPH-NODE; CANCER; FEASIBILITY; METASTASIS AB Background and aim: Piecemeal endoscopic resection for esophageal high grade intraepithelial neoplasia (HGIN) or early squamous cell carcinoma (ESCC) is usually performed by cap-assisted endoscopic resection. This requires submucosal lifting and multiple snares. Multiband mucosectomy (MBM) uses a modified variceal band ligator without submucosal lifting. In high-risk areas where ESCC is common and endoscopic expertise is limited, MBM may be a better technique. We aimed to compare MBM to the cap-assisted technique for piecemeal endoscopic resection of esophageal ESCCs. Methods: Patients with mucosal HGIN/ESCC (2-6 cm, maximum two-thirds of esophageal circumference) were included. Lesions, delineated by 1.25% Lugol staining, were randomized to MBM or cap-assisted piecemeal resection. Endpoints were procedure time and costs, complete endoscopic resection, adverse events, and absence of HGIN/ESCC at 3-month and 12-month follow-up. Results: Endoscopic resection was performed in 84 patients (59 men, mean age 60) using MBM (n= 42) or the endoscopic resection cap (n= 42). There were no differences in baseline characteristics. Endoscopic complete resection was achieved in all lesions. Procedure time was significantly shorter with MBM (11 vs. 22 minutes, P< 0.0001). One perforation, seen after using the endoscopic resection cap, was treated conservatively. Total costs of disposables were lower for MBM ((sic)200 vs. (sic)251, P=0.04). At 3-month and 12-month follow-ups none of the patients had HGIN/ESCC at the resection site. Conclusion: Piecemeal endoscopic resection of esophageal ESCC with MBM is faster and cheaper than with the endoscopic resection cap. Both techniques are highly effective and safe. MBM may have significant advantages over the endoscopic resection cap technique, especially in countries where ESCC is extremely common but limited endoscopic expertise and resources exist. (Netherlands trial register: NTR 3246.) C1 [Boerwinkel, David F.; Weusten, Bas L. A. M.; Bergman, Jacques J. G. H. M.] Univ Amsterdam, Acad Med Ctr, Dept Gastroenterol & Hepatol, C2-220, NL-1105 AZ Amsterdam, Netherlands. [Zhang, Yue-Ming; Qin, Xiumin; He, Shun; Dou, Li-Zhou; Liu, Yong; Wang, Gui-Qi] Chinese Acad Med Sci, Canc Inst & Hosp, Dept Endoscopy, Beijing 100730, Peoples R China. [Xue, Liyan; Lu, Ning] Chinese Acad Med Sci, Canc Inst & Hosp, Dept Pathol, Beijing 100730, Peoples R China. [Weusten, Bas L. A. M.] St Antonius Hosp, Dept Gastroenterol & Hepatol, Nieuwegein, Netherlands. [Dawsey, Sanford M.] NCI, Dept Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Fleischer, David E.] Mayo Clin, Dept Gastroenterol & Hepatol, Scottsdale, AZ USA. RP Bergman, JJGHM (reprint author), Univ Amsterdam, Acad Med Ctr, Dept Gastroenterol & Hepatol, C2-220, NL-1105 AZ Amsterdam, Netherlands.; Wang, GQ (reprint author), Dept Endoscopy, 17 Panjiayuan, Beijing 100021, Peoples R China. EM J.J.Bergman@AMC.UVA.NL; wangguiq@126.com FU Cook Medical FX J. Bergman has received research support for this study and consultancy and speakers fee by Cook Medical. NR 18 TC 0 Z9 0 U1 0 U2 0 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0013-726X EI 1438-8812 J9 ENDOSCOPY JI Endoscopy PD APR PY 2016 VL 48 IS 4 BP 330 EP 338 DI 10.1055/s-0034-1393358 PG 9 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA DH9VB UT WOS:000373143000004 PM 26545174 ER PT J AU Mooring, EQ Bansal, S AF Mooring, E. Q. Bansal, S. TI Increasing herd immunity with influenza revaccination SO EPIDEMIOLOGY AND INFECTION LA English DT Article DE Disease control; epidemiology; influenza (seasonal); mathematical modelling; vaccines ID VACCINE EFFECTIVENESS; HEALTHY-CHILDREN; EFFICACY; VIRUS; IMMUNIZATION; DISEASE; IMPACT; ADULTS; PROTECTION; MORTALITY AB Seasonal influenza is a significant public health concern globally. While influenza vaccines are the single most effective intervention to reduce influenza morbidity and mortality, there is considerable debate surrounding the merits and consequences of repeated seasonal vaccination. Here, we describe a two-season influenza epidemic contact network model and use it to demonstrate that increasing the level of continuity in vaccination across seasons reduces the burden on public health. We show that revaccination reduces the influenza attack rate not only because it reduces the overall number of susceptible individuals, but also because it better protects highly connected individuals, who would otherwise make a disproportionately large contribution to influenza transmission. We also demonstrate that our results hold on an empirical contact network, in the presence of assortativity in vaccination status, and are robust for a range of vaccine coverage and efficacy levels. Our work contributes a population-level perspective to debates about the merits of repeated influenza vaccination and advocates for public health policy to incorporate individual vaccine histories. C1 [Mooring, E. Q.; Bansal, S.] Georgetown Univ, Dept Biol, Washington, DC 20057 USA. [Bansal, S.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. RP Bansal, S (reprint author), Georgetown Univ, Dept Biol, Washington, DC 20057 USA. EM shweta@sbansal.com OI Bansal, Shweta/0000-0002-1740-5421 FU Howard Hughes Medical Institute Precollege and Undergraduate Science Education Program; RAPIDD Program of the Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX The authors thank Lauren Ancel Meyers for the Vancouver contact network dataset and Sarah Kramer for helpful discussions on vaccine efficacy. This work was supported by the Howard Hughes Medical Institute Precollege and Undergraduate Science Education Program; and the RAPIDD Program of the Science & Technology Directorate, Department of Homeland Security and the Fogarty International Center, National Institutes of Health. NR 52 TC 1 Z9 1 U1 3 U2 8 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0950-2688 EI 1469-4409 J9 EPIDEMIOL INFECT JI Epidemiol. Infect. PD APR PY 2016 VL 144 IS 6 BP 1267 EP 1277 DI 10.1017/S0950268815002253 PG 11 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA DH9JW UT WOS:000373113400016 PM 26482721 ER PT J AU Bichsel, KJ Hammiller, B Trempus, CS Li, YH Hansen, LA AF Bichsel, Kyle J. Hammiller, Brianna Trempus, Carol S. Li, Yanhua Hansen, Laura A. TI The epidermal growth factor receptor decreases Stathmin 1 and triggers catagen entry in the mouse SO EXPERIMENTAL DERMATOLOGY LA English DT Article DE catagen; epidermal growth factor receptor; hair follicle cycling; Rcc2; Stathmin 1 ID HAIR FOLLICLE DEVELOPMENT; TUMOR-SUPPRESSOR; DOWN-REGULATION; CANCER-CELLS; STEM-CELLS; CYCLE; PROTEIN; MICE; SKIN; MICROTUBULES AB The epidermal growth factor receptor (EGFR) is necessary for normal involution of hair follicles after the growth phase of anagen, although the mechanisms through which it acts are not well understood. In this report, we used transcriptional profiling of microdissected hair follicles from mice with skin-targeted deletion of Egfr to investigate how EGFR activation triggers catagen. Immunofluorescence for phospho-EGFR in mouse skin revealed increased activation of EGFR in follicular keratinocytes at catagen onset. Consistent with other models of EGFR deficiency, mice with skin-targeted deletion of Egfr (Krt14-Cre(+)/Egfr(fl/fl)) exhibited a delayed and asynchronous catagen entry. Transcriptional profiling at the time of normal catagen onset at post-natal day (P) 17 revealed increased expression of the mitotic regulator Rcc2 in hair follicles lacking EGFR. Rcc2 protein was strongly immunopositive in the nuclei of control follicular keratinocytes at P16 then rapidly decreased until it was undetectable between P18 and 21. In contrast, Rcc2 expression continued in Egfr mutant follicles throughout this period. Proliferation, measured by bromodeoxyuridine incorporation, was also significantly increased in Egfr mutant follicular keratinocytes compared to controls at P18-21. Similarly, Rcc2-regulated mitotic regulator Stathmin 1 was strikingly reduced in control but not Egfr mutant follicles between P17 and P19. Deletion of Stmn1, in turn, accelerated catagen entry associated with premature cessation of proliferation in the hair follicles. These data reveal EGFR suppression of mitotic regulators including Rcc2 and Stathmin 1 as a mechanism for catagen induction in mouse skin. C1 [Bichsel, Kyle J.; Hammiller, Brianna; Li, Yanhua; Hansen, Laura A.] Creighton Univ, Sch Med, Dept Biomed Sci, 2500 Calif Plaza, Omaha, NE 68178 USA. [Trempus, Carol S.] NIEHS, Immun Inflammat & Dis Lab, POB 12233, Res Triangle Pk, NC 27709 USA. [Li, Yanhua] Yangzhou Univ, Coll Med, Yangzhou 225009, Jiangsu, Peoples R China. RP Hansen, LA (reprint author), Creighton Univ, Sch Med, Dept Biomed Sci, 2500 Calif Plaza, Omaha, NE 68178 USA. EM LHansen@creighton.edu FU NIEHS NIH HHS [1R01 ES015585] NR 48 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0906-6705 EI 1600-0625 J9 EXP DERMATOL JI Exp. Dermatol. PD APR PY 2016 VL 25 IS 4 BP 275 EP 281 DI 10.1111/exd.12921 PG 7 WC Dermatology SC Dermatology GA DI3HJ UT WOS:000373389400007 PM 26661905 ER PT J AU Jang, H Banerjee, A Chavan, TS Lu, SY Zhang, J Gaponenko, V Nussinov, R AF Jang, Hyunbum Banerjee, Avik Chavan, Tanmay S. Lu, Shaoyong Zhang, Jian Gaponenko, Vadim Nussinov, Ruth TI The higher level of complexity of K-Ras4B activation at the membrane SO FASEB JOURNAL LA English DT Article DE KRAS; GDP/GTP exchange; farnesyl insertion; signaling; phospholipids ID AMYLOID ION CHANNELS; ATOMIC-FORCE MICROSCOPY; MOLECULAR-DYNAMICS SIMULATIONS; EFFECTOR-BINDING SITE; SMALL GTPASE K-RAS4B; ALL-D-ENANTIOMER; H-RAS PROTEIN; HYPERVARIABLE REGION; LIPID-BILAYERS; ALZHEIMERS-DISEASE AB Is nucleotide exchange sufficient to activate K-Ras4B? To signal, oncogenic rat sarcoma (Ras) anchors in the membrane and recruits effectors by exposing its effector lobe. With the use of NMR and molecular dynamics (MD) simulations, we observed that in solution, farnesylated guanosine 5'-diphosphate (GDP)-bound K-Ras4B is predominantly autoinhibited by its hypervariable region (HVR), whereas the GTP-bound state favors an activated, HVR-released state. On the anionic membrane, the catalytic domain adopts multiple orientations, including parallel (similar to 180 degrees) and perpendicular (similar to 90 degrees) alignments of the allosteric helices, with respect to the membrane surface direction. In the autoinhibited state, the HVR is sandwiched between the effector lobe and the membrane; in the active state, with membrane-anchored farnesyl and unrestrained HVR, the catalytic domain fluctuates reinlessly, exposing its effector-binding site. Dimerization and clustering can reduce the fluctuations. This achieves preorganized, productive conformations. Notably, we also observe HVR-autoinhibited K-Ras4B-GTP states, with GDP-bound-like orientations of the helices. Thus, we propose that the GDP/GTP exchange may not be sufficient for activation; instead, our results suggest that the GDP/GTP exchange, HVR sequestration, farnesyl insertion, and orientation/localization of the catalytic domain at the membrane conjointly determine the active or inactive state of K-Ras4B. Importantly, K-Ras4B-GTP can exist in active and inactive states; on its own, GTP binding may not compel K-Ras4B activation. C1 [Jang, Hyunbum; Lu, Shaoyong; Nussinov, Ruth] Natl Canc Inst Frederick, Basic Sci Program, Leidos Biomed Res, Frederick Natl Lab Canc Res,Canc & Inflammat Prog, Frederick, MD USA. [Banerjee, Avik] Univ Illinois, Dept Chem, Chicago, IL USA. [Chavan, Tanmay S.; Gaponenko, Vadim] Univ Illinois, Dept Med Chem, Chicago, IL USA. [Gaponenko, Vadim] Univ Illinois, Dept Biochem & Mol Genet, 900 S Ashland Ave, Chicago, IL 60607 USA. [Lu, Shaoyong; Zhang, Jian] Shanghai Jiao Tong Univ, Dept Pathophysiol, Key Lab Cell Differentiat & Apoptosis, Chinese Minist Educ,Sch Med, Shanghai 200030, Peoples R China. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Mol Genet & Biochem, IL-69978 Tel Aviv, Israel. [Chavan, Tanmay S.] Stanford Univ, Stanford, CA 94305 USA. RP Gaponenko, V (reprint author), Univ Illinois, Dept Biochem & Mol Genet, 900 S Ashland Ave, Chicago, IL 60607 USA.; Nussinov, R (reprint author), Natl Canc Inst Frederick, Frederick Natl Lab Canc Res, Leidos Biomed Res, 1050 Boyles St, Frederick, MD 21702 USA. EM vadimg@uic.edu; nussinor@helix.nih.gov FU American Cancer Society [RGS-09-057-01-GMC]; U.S. National Institutes of Health [NIH] [R01 CA135341, R01 CA188427, R21 HL118588]; NIH Frederick National Laboratory for Cancer Research [HHSN261200800001E]; NIH Intramural Research Program, Frederick National Lab, Center for Cancer Research FX The authors gratefully acknowledge the generous support from the American Cancer Society (Grant RGS-09-057-01-GMC) and the U.S. National Institutes of Health [NIH; Grants R01 CA135341, R01 CA188427 (National Cancer Institute), and R21 HL118588 (National Heart, Lung, and Blood Institute); to V.G.]. This project has been funded, in whole or in part, with federal funds from the NIH Frederick National Laboratory for Cancer Research, under Contract HHSN261200800001E. This research was supported, in part, by the NIH Intramural Research Program, Frederick National Lab, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the U.S. Department of Health and Human Services nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. All simulations had been performed with the use of the high-performance computational facilities of the Biowulf PC/Linux cluster at the NIH (https://hpc.nih.gov/). H.J. and A.B. are co-first authors. NR 60 TC 8 Z9 8 U1 2 U2 6 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD APR PY 2016 VL 30 IS 4 BP 1643 EP 1655 DI 10.1096/fj.15-279091 PG 13 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA DH2PR UT WOS:000372629100025 PM 26718888 ER PT J AU Crabb, DW Bataller, R Chalasani, NP Kamath, PS Lucey, M Mathurin, P McClain, C McCullough, A Mitchell, MC Morgan, TR Nagy, L Radaeva, S Sanyal, A Shah, V Szabo, G AF Crabb, David W. Bataller, Ramon Chalasani, Naga P. Kamath, Patrick S. Lucey, Michael Mathurin, Philippe McClain, Craig McCullough, Arthur Mitchell, Mack C. Morgan, Timothy R. Nagy, Laura Radaeva, Svetlana Sanyal, Arun Shah, Vijay Szabo, Gyongyi CA NIAAA Alcoholic Hepatitis TI Standard Definitions and Common Data Elements for Clinical Trials in Patients With Alcoholic Hepatitis: Recommendation From the NIAAA Alcoholic Hepatitis Consortia SO GASTROENTEROLOGY LA English DT Editorial Material ID LIVER-DISEASE; CIRRHOSIS; PROGNOSIS; DIAGNOSIS; FAILURE; INJURY; RISK C1 [Crabb, David W.; Chalasani, Naga P.] Indiana Univ Sch Med, Dept Med, Div Gastroenterol & Hepatol, Indianapolis, IN 46202 USA. [Bataller, Ramon] Univ N Carolina, Dept Med, Div Gastroenterol & Hepatol, Chapel Hill, NC USA. [Kamath, Patrick S.; Shah, Vijay] Mayo Clin, Gastroenterol Res Unit, Dept Gastroenterol & Hepatol, Rochester, MN USA. [Lucey, Michael] Univ Wisconsin, Dept Med, Div Gastroenterol & Hepatol, Madison, WI USA. [Mathurin, Philippe] Univ Lille 2, CHRU Lille, Serv Malad Appareil Digestif, F-59800 Lille, France. [Mathurin, Philippe] Univ Lille 2, CHRU Lille, INSERM, U995, F-59800 Lille, France. [McClain, Craig] Univ Louisville, Sch Med, Dept Med, Div Gastroenterol Hepatol & Nutr, Louisville, KY 40292 USA. [McCullough, Arthur] Cleveland Clin, Dept Gastroenterol, Cleveland, OH 44106 USA. [McCullough, Arthur] Cleveland Clin, Dept Hepatol, Cleveland, OH 44106 USA. [McCullough, Arthur] Cleveland Clin, Dept Transplant Surg, Cleveland, OH 44106 USA. [Mitchell, Mack C.] UT Southwestern Med Ctr, Dept Internal Med, Div Digest & Liver Dis, Dallas, TX USA. [Morgan, Timothy R.] VA Long Beach Healthcare Syst, Long Beach, CA USA. [Nagy, Laura] Cleveland Clin Fdn, Lerner Res Inst, Dept Pathobiol, 9500 Euclid Ave, Cleveland, OH 44195 USA. [Radaeva, Svetlana] NIAAA, Lab Liver Dis, NIH, Bethesda, MD USA. [Sanyal, Arun] Virginia Commonwealth Univ, Sch Med, Dept Internal Med, Div Gastroenterol Hepatol & Nutr, Richmond, VA USA. [Szabo, Gyongyi] Univ Massachusetts, Sch Med, Dept Med, Div Gastroenterol, Worcester, MA USA. RP Crabb, DW (reprint author), Indiana Univ Sch Med, Dept Med F2 600, 720 Eskenazi Ave, Indianapolis, IN 46202 USA. EM dcrabb@iu.edu FU NIAAA NIH HHS [U01 AA 021840, U01 AA021908, U01 AA 021886, U01 AA021840, U01 AA 021893, U01 AA021890, U01 AA021893, P50 AA024337, U01 AA021883, U01 AA021886]; NIGMS NIH HHS [P20 GM113226] NR 20 TC 6 Z9 6 U1 0 U2 7 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD APR PY 2016 VL 150 IS 4 BP 785 EP 790 DI 10.1053/j.gastro.2016.02.042 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DH4BH UT WOS:000372730000007 PM 26921783 ER PT J AU Robles, AI Traverso, G Zhang, M Roberts, NJ Khan, MA Joseph, C Lauwers, GY Selaru, FM Popoli, M Pittman, ME Ke, XQ Hruban, RH Meltzer, SJ Kinzler, KW Vogelstein, B Harris, CC Papadopoulos, N AF Robles, Ana I. Traverso, Giovanni Zhang, Ming Roberts, Nicholas J. Khan, Mohammed A. Joseph, Christine Lauwers, Gregory Y. Selaru, Florin M. Popoli, Maria Pittman, Meredith E. Ke, Xiquan Hruban, Ralph H. Meltzer, Stephen J. Kinzler, Kenneth W. Vogelstein, Bert Harris, Curtis C. Papadopoulos, Nickolas TI Whole-Exome Sequencing Analyses of Inflammatory Bowel Disease-Associated Colorectal Cancers SO GASTROENTEROLOGY LA English DT Article DE Exome; Sequencing; Ulcerative Colitis; Crohn's Disease ID C-KI-RAS; COLITIS-ASSOCIATED NEOPLASMS; SPORADIC COLON-CARCINOMA; ULCERATIVE-COLITIS; MICROSATELLITE INSTABILITY; GENE-MUTATIONS; GASTRIC-CANCER; NITRIC-OXIDE; ESOPHAGEAL ADENOCARCINOMA; ABERRANT METHYLATION AB BACKGROUND & AIMS: A long duration of inflammatory bowel disease (IBD) increases the risk for colorectal cancer. Mutation analysis of limited numbers of genes has indicated that colorectal tumors that develop in patients with IBD differ from those of patients without IBD. We performed whole-exome sequencing analyses to characterize the genetic landscape of these tumors. METHODS: We collected colorectal tumor and non-neoplastic tissues from 31 patients with IBD and colorectal cancer (15 with ulcerative colitis, 14 with Crohn's disease, and 2 with indeterminate colitis) and performed whole-exome sequencing analyses of the micro-dissected tumor and matched nontumor tissues. We identified somatic alterations by comparing matched specimens. The prevalence of mutations in sporadic colorectal tumors was obtained from previously published exome-sequencing studies. RESULTS: Two specimens had somatic mutations in the DNA proofreading or mismatch repair genes POLE, MLH1, and MSH6 and the tumor cells had a hypermutable phenotype. The remaining tumors had, on average, 71 alterations per sample. TP53 was the most commonly mutated gene, with prevalence similar to that of sporadic colorectal tumors (63% of cases). However, tumors from the patients with IBD had a different mutation spectrum. APC and KRAS were mutated at significantly lower rates in tumors from patients with IBD than in sporadic colorectal tumors (13% and 20% of cases, respectively). Several genes were mutated more frequently or uniquely in tumors from patients with IBD, including SOX9 and EP300 (which encode proteins in the WNT pathway), NRG1 (which encodes an ERBB ligand), and IL16 (which encodes a cytokine). Our study also revealed recurrent mutations in components of the Rho and Rac GTPase network, indicating a role for noncanonical WNT signaling in development of colorectal tumors in patients with IBD. CONCLUSIONS: Colorectal tumors that develop in patients with IBD have distinct genetic features from sporadic colorectal tumors. These findings could be used to develop disease-specific markers for diagnosis and treatment of patients with IBD and colorectal cancer. C1 [Robles, Ana I.; Khan, Mohammed A.; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 3068A,MSC 4258, Bethesda, MD 20892 USA. [Traverso, Giovanni] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gastroenterol, Boston, MA USA. [Traverso, Giovanni] MIT, Dept Chem Engn, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Zhang, Ming; Roberts, Nicholas J.; Joseph, Christine; Popoli, Maria; Kinzler, Kenneth W.; Vogelstein, Bert; Papadopoulos, Nickolas] Ludwig Ctr Johns Hopkins, Baltimore, MD 21287 USA. [Roberts, Nicholas J.; Pittman, Meredith E.; Hruban, Ralph H.] Johns Hopkins Univ, Sch Med, Dept Pathol, Sol Goldman Pancreat Canc Res Ctr, Baltimore, MD 21205 USA. [Lauwers, Gregory Y.] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Selaru, Florin M.; Ke, Xiquan; Meltzer, Stephen J.] Johns Hopkins Univ, Sch Med, Div Gastroenterol, Baltimore, MD USA. [Vogelstein, Bert] Howard Hughes Med Inst, Chevy Chase, MD USA. [Kinzler, Kenneth W.; Vogelstein, Bert; Papadopoulos, Nickolas] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 3068A,MSC 4258, Bethesda, MD 20892 USA.; Vogelstein, B; Papadopoulos, N (reprint author), Ludwig Ctr Johns Hopkins, Dept Oncol, 1650 Orleans St,CRB1 Room 585, Baltimore, MD 21287 USA. EM bertvog@gmail.com; harrisc@mail.nih.gov; npapado1@jhmi.edu FU Intramural NIH HHS; NCI NIH HHS [R01 CA133012, CA057345, CA133012, CA152753, CA190040, CA43460, CA62924, P50 CA062924, R01 CA057345, R01 CA190040, R37 CA043460, R37 CA057345, U01 CA152753]; NIDDK NIH HHS [P30 DK089502, T32 DK007191, T32-DK007191-38-S1] NR 98 TC 14 Z9 14 U1 6 U2 12 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD APR PY 2016 VL 150 IS 4 BP 931 EP 943 DI 10.1053/j.gastro.2015.12.036 PG 13 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DH4BH UT WOS:000372730000032 PM 26764183 ER PT J AU Persson, EC Shiels, MS Dawsey, SM Bhatia, K Anderson, LA Engels, EA AF Persson, E. Christina Shiels, Meredith S. Dawsey, Sanford M. Bhatia, Kishor Anderson, Lesley A. Engels, Eric A. TI Increased Risk of Stomach and Esophageal Malignancies in People With AIDS (Retraction of vol 143, pg 943, 2012) SO GASTROENTEROLOGY LA English DT Correction C1 [Persson, E. Christina; Shiels, Meredith S.; Dawsey, Sanford M.; Bhatia, Kishor; Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Anderson, Lesley A.] Queens Univ Belfast, Canc Epidemiol & Hlth Serv Res Grp, Ctr Publ Hlth, Inst Clin & Populat Sci, Belfast, Antrim, North Ireland. RP Engels, EA (reprint author), NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. EM engelse@exchange.nih.gov NR 1 TC 0 Z9 0 U1 2 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 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD APR PY 2016 VL 150 IS 4 BP 1048 EP 1048 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DH4BH UT WOS:000372730000044 ER PT J AU Makrogiannis, S Fishbein, KW Moore, AZ Spencer, RG Ferrucci, L AF Makrogiannis, S. Fishbein, K. W. Moore, A. Z. Spencer, R. G. Ferrucci, L. TI Image-Based Tissue Distribution Modeling for Skeletal Muscle Quality Characterization SO IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING LA English DT Article DE Magnetic resonance imaging (MRI); probabilistic modeling; tissue identification and characterization ID INTERMUSCULAR ADIPOSE-TISSUE; WATER/FAT SEPARATION; MR-IMAGES; FAT; HEALTH; QUANTIFICATION; STRENGTH; THIGH AB The identification and characterization of regional body tissues is essential to understand changes that occur with aging and age-related metabolic diseases such as diabetes and obesity and how these diseases affect trajectories of health and functional status. Imaging technologies are frequently used to derive volumetric, area, and density measurements of different tissues. Despite the significance and direct applicability of automated tissue quantification and characterization techniques, these topics have remained relatively underexplored in the medical image analysis literature. We present a method for identification and characterization of muscle and adipose tissue in the midthigh region using MRI. We propose an image-based muscle quality prediction technique that estimates tissue-specific probability density models and their eigen-structures in the joint domain of water-and fat-suppressed voxel signal intensities along with volumetric and intensity-based tissue characteristics computed during the quantification stage. We evaluated the predictive capability of our approach against reference biomechanical muscle quality (MQ) measurements using statistical tests and classification performance experiments. The reference standard for MQ is defined as the ratio of muscle strength to muscle mass. The results show promise for the development of noninvasive image-based MQ descriptors. C1 [Makrogiannis, S.] Delaware State Univ, Dept Math Sci, Dover, DE 19901 USA. [Fishbein, K. W.; Moore, A. Z.; Spencer, R. G.; Ferrucci, L.] NIA, NIH, Bethesda, MD 20892 USA. RP Makrogiannis, S (reprint author), Delaware State Univ, Dept Math Sci, Dover, DE 19901 USA. EM smakrogiannis@desu.edu OI Fishbein, Kenneth/0000-0002-6353-4603 FU National Institute of General Medical Sciences of the National Institutes of Health (NIH) [SC3GM113754]; National Institute on Aging, NIH; Center for Research and Education in Optical Sciences and Applications (CREOSA) of Delaware State University - NSF [CREST-8763] FX This work was supported by in part by the National Institute of General Medical Sciences of the National Institutes of Health (NIH) under Grant SC3GM113754, in part by the Intramural Research Program of National Institute on Aging, NIH, and in part by the Center for Research and Education in Optical Sciences and Applications (CREOSA) of Delaware State University funded by NSF CREST-8763. NR 23 TC 0 Z9 0 U1 1 U2 4 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0018-9294 EI 1558-2531 J9 IEEE T BIO-MED ENG JI IEEE Trans. Biomed. Eng. PD APR PY 2016 VL 63 IS 4 BP 805 EP 813 DI 10.1109/TBME.2015.2474305 PG 9 WC Engineering, Biomedical SC Engineering GA DH7OO UT WOS:000372983800013 PM 26336111 ER PT J AU Suzuki, J Maruyama, S Tamauchi, H Kuwahara, M Horiuchi, M Mizuki, M Ochi, M Sawasaki, T Zhu, JF Yasukawa, M Yamashita, M AF Suzuki, Junpei Maruyama, Saho Tamauchi, Hidekazu Kuwahara, Makoto Horiuchi, Mika Mizuki, Masumi Ochi, Mizuki Sawasaki, Tatsuya Zhu, Jinfang Yasukawa, Masaki Yamashita, Masakatsu TI Gfi1, a transcriptional repressor, inhibits the induction of the T helper type 1 programme in activated CD4 T cells SO IMMUNOLOGY LA English DT Article DE epigenetics; histone H3K4 methylation; T helper type 1 differentiation; T helper type 1 immune response ID ROR-GAMMA-T; TGF-BETA; T(H)17 DIFFERENTIATION; PROTEIN; GATA3; COMMITMENT; MECHANISMS; EXPRESSION; PATHWAY; PLAYS AB A transcriptional repressor Gfi1 promotes T helper type 2 (Th2) cell development and inhibits Th17 and inducible regulatory T-cell differentiation. However, the role of Gfi1 in regulating Th1 cell differentiation and the Th1-type immune response remains to be investigated. We herein demonstrate that Gfi1 inhibits the induction of the Th1 programme in activated CD4 T cells. The activated Gfi1-deficient CD4 T cells spontaneously develop into Th1 cells in an interleukin-12-and interferon-gamma-independent manner. The increase of Th1-type immune responses was confirmed in vivo in Gfi1-deficient mice using a murine model of nickel allergy and delayed-type hypersensitivity (DTH). The expression levels of Th1-related transcription factors were found to increase in Gfi1-deficient activated CD4 T cells. Tbx21, Eomes and Runx2 were identified as possible direct targets of Gfi1. Gfi1 binds to the Tbx21, Eomes and Runx2 gene loci and reduces the histone H3K4 methylation levels in part by modulating Lsd1 recruitment. Together, these findings demonstrate a novel regulatory role of Gfi1 in the regulation of the Th1-type immune response. C1 [Suzuki, Junpei; Yasukawa, Masaki] Ehime Univ, Grad Sch Med, Dept Haematol Clin Immunol & Infect Dis, Toon, Ehime 7910295, Japan. [Suzuki, Junpei; Kuwahara, Makoto; Yamashita, Masakatsu] Ehime Univ Hosp, Translat Res Ctr, Dept Translat Immunol, Toon, Ehime, Japan. [Maruyama, Saho; Kuwahara, Makoto; Horiuchi, Mika; Mizuki, Masumi; Ochi, Mizuki; Yamashita, Masakatsu] Ehime Univ, Grad Sch Med, Dept Immunol, Toon, Ehime 7910295, Japan. [Tamauchi, Hidekazu] Ehime Prefectural Univ Hlth Sci, Dept Med Technol, Div Fundamental Med Technol, Tobe, Ehime, Japan. [Kuwahara, Makoto; Yamashita, Masakatsu] Ehime Univ, Proteosci Ctr, Dept Proteoinovat, Div Immune Regulat, Matsuyama, Ehime, Japan. [Ochi, Mizuki; Sawasaki, Tatsuya] Ehime Univ, Proteosci Ctr, Dept Proteores, Div Cell Free Sci, Matsuyama, Ehime, Japan. [Zhu, Jinfang] NIAID, Mol & Cellular Immunoregulat Unit, Immunol Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Yamashita, M (reprint author), Ehime Univ, Grad Sch Med, Dept Immunol, Toon, Ehime 7910295, Japan. EM yamamasa@m.ehime-u.ac.jp RI Zhu, Jinfang/B-7574-2012 FU JSPS KAKENHI [23390075, 25118718, 25860376, 15K19133, 26462852]; Naito Foundation Natural Science Scholarship; Uehara Memorial Foundation; Daiichi Sankyo Foundation of Life Science; Intramural Research Program of NIH, NIAID FX We thank T. Kiyoi, T. Watanabe, K. Sato, M. Takazawa and A. Tamai for their valuable technical assistance. We also thank Dr Jun Komotori for providing nickel-titanium alloys. This work was supported by JSPS KAKENHI (Grant Numbers, 23390075, 25118718, 25860376, 15K19133, 26462852), the Naito Foundation Natural Science Scholarship, the Uehara Memorial Foundation and the Daiichi Sankyo Foundation of Life Science. JZ is supported by the Intramural Research Program of NIH, NIAID. NR 34 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0019-2805 EI 1365-2567 J9 IMMUNOLOGY JI Immunology PD APR PY 2016 VL 147 IS 4 BP 476 EP 487 DI 10.1111/imm.12580 PG 12 WC Immunology SC Immunology GA DH6UF UT WOS:000372926900010 PM 26749286 ER PT J AU Khalid, W Rozi, S Ali, TS Azam, I Mullen, MT Illyas, S Qamar-un-Nisa, Soomro, N Kamal, AK AF Khalid, Wardah Rozi, Shafquat Ali, Tazeen S. Azam, Iqbal Mullen, Michael T. Illyas, Saleem Qamar-un-Nisa Soomro, Nabila Kamal, Ayeesha K. TI Quality of life of stroke survivors and their primary caregivers in Pakistan SO INTERNATIONAL JOURNAL OF STROKE LA English DT Letter ID HEALTH C1 [Khalid, Wardah] Aga Khan Univ Hosp, Fogarty Int Ctr, Natl Inst Hlth, Int Cerebrovasc Translat Clin Res Training Progra, Karachi, Pakistan. [Rozi, Shafquat; Azam, Iqbal] Aga Khan Univ Hosp, Dept Community Hlth Sci, Karachi, Pakistan. [Ali, Tazeen S.] Aga Khan Univ Hosp Karachi, Dept Community Hlth Sci, Sch Nursing & Midwifery SONAM, Karachi, Pakistan. [Mullen, Michael T.] Univ Penn, Dept Neurol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Illyas, Saleem] DOW Univ Hlth Sci, Profess Dev Ctr, Dept Neurol, Karachi, Pakistan. [Qamar-un-Nisa] DOW Univ Hlth Sci, Dept Neurol, Karachi, Pakistan. [Qamar-un-Nisa] Aga Khan Univ Hosp, Dept Med, Neurol Sect, Karachi, Pakistan. [Soomro, Nabila] DOW Univ Hlth Sci, Inst Phys Med & Rehabil, Karachi, Pakistan. [Kamal, Ayeesha K.] Aga Khan Univ Hosp, Int Cerebrovasc Translat Clin Res Training Progra, Fogarty Int Ctr, Natl Inst Hlth,Dept Med, Karachi, Pakistan. RP Kamal, AK (reprint author), Aga Khan Univ, Stadium Rd,Fac Off Bldg, Karachi 74800, Pakistan. EM ayeesha.kamal@aku.edu FU FIC NIH HHS [5D43TW008660-04] NR 6 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 1747-4930 EI 1747-4949 J9 INT J STROKE JI Int. J. Stroke PD APR PY 2016 VL 11 IS 3 BP NP34 EP NP35 DI 10.1177/1747493015626153 PG 2 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DH5FL UT WOS:000372811200002 PM 26763926 ER PT J AU Craven, M Kasper, SH Canfield, MJ Diaz-Morales, RR Hrabie, JA Cady, NC Strickland, AD AF Craven, M. Kasper, S. H. Canfield, M. J. Diaz-Morales, R. R. Hrabie, J. A. Cady, N. C. Strickland, A. D. TI Nitric oxide-releasing polyacrylonitrile disperses biofilms formed by wound-relevant pathogenic bacteria SO JOURNAL OF APPLIED MICROBIOLOGY LA English DT Article DE biofilm; biofilm dispersal; chronic wounds; nitric oxide; polymer ID PSEUDOMONAS-AERUGINOSA; ANTIBIOTIC-RESISTANCE; SILICA NANOPARTICLES; INFECTIONS; EFFICACY; GROWTH; CELLS AB AimsTo test the antimicrobial and antibiofilm properties of a nitric oxide (NO)-releasing polymer against wound-relevant bacterial pathogens. Methods and ResultsUsing a variety of 96-well plate assay systems that include standard well plates and the minimum biofilm eradication concentration biofilm assay well plate, a NO-releasing polymer based on (poly)acrylonitrile (PAN/NO) was studied for antimicrobial and antibiofilm activity against the common wound pathogens Pseudomonas aeruginosa (PAO1), Staphylococcus aureus (Mu50) and Enterococcus faecalis (V583). The polymer was capable of dispersing single-species biofilms of Ps.aeruginosa as well as a more clinically relevant multispecies biofilm that incorporates Ps.aeruginosa along with Staph.aureus and Ent.faecalis. PAN/NO also synergistically enhanced the susceptibility of the multispecies biofilms to the common broad-spectrum antibiotic, ciprofloxacin. Multiple invitro biocompatibility assays show that PAN/NO has limited potential for mammalian cytotoxicity. ConclusionThis study demonstrates the feasibility of utilizing the NO-releasing polymer, PAN/NO, to manage biofilms formed by wound-relevant pathogens, and provides proof-of-concept for use of this NO-releasing polymer platform across multiple disciplines where bacterial biofilms pose significant problems. Significance and Impact of StudyIn the clinical sector, bacterial biofilms represent a substantial treatment challenge for health care professionals and are widely recognized as a key factor in prolonging patient morbidity. This study highlights the potential role for the ubiquitous signalling molecule nitric oxide (NO) as an antibiofilm therapy. C1 [Craven, M.; Canfield, M. J.; Diaz-Morales, R. R.; Strickland, A. D.] iFyber LLC, Ithaca, NY USA. [Kasper, S. H.; Cady, N. C.] SUNY Albany, Polytech Inst, Coll Nanoscale Sci & Engn, Albany, NY 12222 USA. [Hrabie, J. A.] NCI, Frederick Natl Lab Canc Res, Frederick, MD 21701 USA. RP Strickland, AD (reprint author), iFyber LLC, VP Res & Dev, 950 Danby Rd,Suite 300, Ithaca, NY 14850 USA. EM astrick@ifyber.com NR 41 TC 1 Z9 1 U1 2 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1364-5072 EI 1365-2672 J9 J APPL MICROBIOL JI J. Appl. Microbiol. PD APR PY 2016 VL 120 IS 4 BP 1085 EP 1099 DI 10.1111/jam.13059 PG 15 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA DH9IW UT WOS:000373110800024 PM 26784529 ER PT J AU Dong, M Fisher, C Anez, G Rios, M Nakhasi, HL Hobson, JP Beanan, M Hockman, D Grigorenko, E Duncan, R AF Dong, M. Fisher, C. Anez, G. Rios, M. Nakhasi, H. L. Hobson, J. P. Beanan, M. Hockman, D. Grigorenko, E. Duncan, R. TI Standardized methods to generate mock (spiked) clinical specimens by spiking blood or plasma with cultured pathogens SO JOURNAL OF APPLIED MICROBIOLOGY LA English DT Article DE blood-borne; mock specimens; molecular quantification; pathogen spiking; standardized methods ID MODIFIER PROTEIN UFM1; LEISHMANIA-DONOVANI; EXPRESSION; PARASITE; DELETION; GROWTH AB AimsTo demonstrate standardized methods for spiking pathogens into human matrices for evaluation and comparison among diagnostic platforms. Methods and ResultsThis study presents detailed methods for spiking bacteria or protozoan parasites into whole blood and virus into plasma. Proper methods must start with a documented, reproducible pathogen source followed by steps that include standardized culture, preparation of cryopreserved aliquots, quantification of the aliquots by molecular methods, production of sufficient numbers of individual specimens and testing of the platform with multiple mock specimens. Results are presented following the described procedures that showed acceptable reproducibility comparing in-house real-time PCR assays to a commercially available multiplex molecular assay. ConclusionsA step by step procedure has been described that can be followed by assay developers who are targeting low prevalence pathogens. Significance and Impact of the StudyThe development of diagnostic platforms for detection of low prevalence pathogens such as biothreat or emerging agents is challenged by the lack of clinical specimens for performance evaluation. This deficit can be overcome using mock clinical specimens made by spiking cultured pathogens into human matrices. To facilitate evaluation and comparison among platforms, standardized methods must be followed in the preparation and application of spiked specimens. C1 [Dong, M.; Fisher, C.; Anez, G.; Rios, M.; Nakhasi, H. L.; Duncan, R.] US FDA, CBER, Div Emerging & Transfus Transmitted Dis, Lab Emerging Pathogens, Silver Spring, MD 20993 USA. [Hobson, J. P.] US FDA, CDRH, Div Microbiol Devices, Off In Vitro Diagnost & Radiol Hlth OIR, Silver Spring, MD 20993 USA. [Beanan, M.] NIAID, DMID, Off Biodef Res Resources & Translat Res, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Hockman, D.; Grigorenko, E.] Diatherix Lab, Huntsville, AL USA. [Anez, G.] Sanofi Pasteur, Swiftwater, PA USA. RP Duncan, R (reprint author), US FDA, Bldg 52-72,Room 4312,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM Robert.duncan@fda.hhs.gov RI Hockman, Donna/D-7237-2017; Duncan, Robert/I-8168-2015; OI Hockman, Donna/0000-0002-1790-0895; Duncan, Robert/0000-0001-8409-2501; Anez, German/0000-0001-5361-3001 FU NIAID [AAI13005-001] FX We wish to acknowledge that this work was supported by NIAID through an Interagency Agreement AAI13005-001 awarded to CBER/FDA. Members of the NIAID/Office of Biodefense, Research Resources, and Translational Research, Division of Microbiology and Infectious Diseases aided in the editing of the text. Yukiko Kozaki LEP/DETTD/CBER graciously assisted with statistical analysis. Healthy human blood and plasma was obtained thanks to the NIH Clinical Center, Department of Transfusion Medicine. NR 18 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1364-5072 EI 1365-2672 J9 J APPL MICROBIOL JI J. Appl. Microbiol. PD APR PY 2016 VL 120 IS 4 BP 1119 EP 1129 DI 10.1111/jam.13082 PG 11 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA DH9IW UT WOS:000373110800027 PM 26835651 ER PT J AU Ferrer, RA Stanley, JT Graff, K Klein, WMP Goodman, N Nelson, WL Salazar, S AF Ferrer, Rebecca A. Stanley, Jennifer Tehan Graff, Kaitlin Klein, William M. P. Goodman, Nina Nelson, Wendy L. Salazar, Silvia TI The Effect of Emotion on Visual Attention to Information and Decision Making in the Context of Informed Consent Process for Clinical Trials SO JOURNAL OF BEHAVIORAL DECISION MAKING LA English DT Article DE emotion; visual attention; information processing; informed consent ID BREAST-CANCER DIAGNOSIS; EYE-MOVEMENTS; SEX-DIFFERENCES; DISCRETE EMOTIONS; PERCEIVED RISKS; NEGATIVE AFFECT; PHASE-I; JUDGMENT; ANGER; COGNITION AB The aim of this study was to examine the influence of emotion on visual information processing and decision making in the context of informed consent. Researchers are ethically obligated to ensure informed consent in clinical trials; however, many volunteers have unrealistic expectations about the value of an experimental therapy. Moreover, suboptimal participation rates for clinical trials may be partially attributable to perceptions that ethical obligations to volunteers are not met. This study examines whether discrete negative emotions (fear, anger, and sadness) differentially influence information processing, visual attention, and decisions in the context of clinical trial informed consent. Community participants completed a standard emotion induction (or control) and then read an actual consent form from a clinical trial while eye movements were tracked. Fear and anger produced the most prominently different patterns of systematic processing and visual attention, such that fear induced longer fixations to information presented, whereas anger induced shorter fixations. Moreover, among women only, fear increased decisions to participate, compared with anger and neutral emotion. Examinations of associations between eye-tracking variables and self-reported outcomes indicated that for angry participants only, less systematic processing was associated with greater decisions to participate. Negative emotions of any kind decreased accurate perceptions of trial benefit. These patterns suggest a complex interplay among emotion, processing style, and decision making. Future research is necessary to further probe these effects among potential clinical trial volunteers. Published 2016. This article is a U.S Government work and is in the public domain in the USA. C1 [Ferrer, Rebecca A.; Graff, Kaitlin; Klein, William M. P.; Goodman, Nina; Nelson, Wendy L.; Salazar, Silvia] NCI, Rockville, MD 20892 USA. [Stanley, Jennifer Tehan] Univ Akron, Akron, OH 44325 USA. RP Ferrer, RA (reprint author), NCI, Basic Biobehav & Psychol Sci Branch, Rockville, MD 20892 USA. EM ferrerra@mail.nih.gov NR 73 TC 0 Z9 0 U1 3 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-3257 EI 1099-0771 J9 J BEHAV DECIS MAKING JI J. Behav. Decis. Mak. PD APR-JUL PY 2016 VL 29 IS 2-3 BP 245 EP 253 DI 10.1002/bdm.1871 PG 9 WC Psychology, Applied SC Psychology GA DI2EY UT WOS:000373309700012 ER PT J AU Pearson, RM Bornstein, MH Cordero, M Scerif, G Mahedy, L Evans, J Abioye, A Stein, A AF Pearson, Rebecca M. Bornstein, Marc H. Cordero, Miguel Scerif, Gaia Mahedy, Liam Evans, Jonathan Abioye, Abu Stein, Alan TI Maternal perinatal mental health and offspring academic achievement at age 16: the mediating role of childhood executive function SO JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY LA English DT Article DE ALSPAC; postnatal depression; prenatal anxiety; executive function; academic achievement; math ID LONGITUDINAL ASSOCIATIONS; DEPRESSIVE SYMPTOMS; WORKING-MEMORY; DISORDERS; MOTHERS; INTERVENTIONS; PERFORMANCE; PREGNANCY; INFANTS; PERIOD AB BackgroundElucidating risk pathways for under-achieving at school can inform strategies to reduce the number of adolescents leaving school without passing grades in core subjects. Maternal depression can compromise the quality of parental care and is associated with multiple negative child outcomes. However, only a few small studies have investigated the association between perinatal maternal depression and poor academic achievement in adolescence. The pathways to explain the risks are also unclear. MethodProspective observational data from 5,801 parents and adolescents taking part in a large UK population cohort (Avon-Longitudinal-Study-of-Parents-and-Children) were used to test associations between maternal and paternal depression and anxiety in the perinatal period, executive function (EF) at age 8, and academic achievement at the end of compulsory school at age 16. ResultsAdolescents of postnatally depressed mothers were 1.5 times (1.19, 1.94, p=.001) as likely as adolescents of nondepressed mothers to fail to achieve a pass' grade in math; antenatal anxiety was also an independent predictor of poor math. Disruption in different components of EF explained small but significant proportions of these associations: attentional control explained 16% (4%, 27%, p<.001) of the association with postnatal depression, and working memory explained 17% (13%, 30%, p=.003) of the association with antenatal anxiety. A similar pattern was seen for language grades, but associations were confounded by maternal education. There was no evidence that paternal factors were independently associated with impaired child EF or adolescent exams. ConclusionMaternal postnatal depression and antenatal anxiety are risk factors for adolescents underachieving in math. Preventing, identifying, and treating maternal mental health in the perinatal period could, therefore, potentially increase adolescents' academic achievement. Different aspects of EF partially mediated these associations. Further work is needed, but if these pathways are causal, improving EF could reduce underachievement in math. C1 [Pearson, Rebecca M.; Cordero, Miguel; Evans, Jonathan] Univ Bristol, Sch Social & Community Med, Oakfield House Oakfield Grove Bristol, Bristol BS8 2BN, Avon, England. [Pearson, Rebecca M.; Abioye, Abu; Stein, Alan] Univ Oxford, Dept Psychiat, Sect Child & Adolescent Psychiat, Oxford, England. [Bornstein, Marc H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Child & Family Res, Bethesda, MD USA. [Scerif, Gaia] Univ Oxford, Dept Expt Psychol, S Parks Rd, Oxford OX1 3UD, England. [Mahedy, Liam] Cardiff Univ, Inst Psychol Med & Clin Neurosci, Cardiff CF10 3AX, S Glam, Wales. [Stein, Alan] Univ Witwatersrand, Sch Publ Hlth, Johannesburg, South Africa. RP Pearson, RM (reprint author), Univ Bristol, Sch Social & Community Med, Oakfield House Oakfield Grove Bristol, Bristol BS8 2BN, Avon, England. EM rebecca.pearson@bristol.ac.uk OI Evans, Jonathan/0000-0003-3171-640X; Mahedy, Liam/0000-0001-5417-6595 FU National Institute of Health; Welcome Trust; Medical Research Council FX Funding for this work was supported by the National Institute of Health, the Welcome Trust and the Medical Research Council. The authors are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. NR 43 TC 3 Z9 3 U1 10 U2 22 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9630 EI 1469-7610 J9 J CHILD PSYCHOL PSYC JI J. Child Psychol. Psychiatry PD APR PY 2016 VL 57 IS 4 BP 491 EP 501 DI 10.1111/jcpp.12483 PG 11 WC Psychology, Developmental; Psychiatry; Psychology SC Psychology; Psychiatry GA DH9JU UT WOS:000373113200007 PM 26616637 ER PT J AU Michalska, KJ Zeffiro, TA Decety, J AF Michalska, Kalina J. Zeffiro, Thomas A. Decety, Jean TI Brain response to viewing others being harmed in children with conduct disorder symptoms SO JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY LA English DT Article DE Conduct disorder; callousness; affective arousal; emotional empathy; insula; anterior cingulate cortex ID CALLOUS-UNEMOTIONAL TRAITS; ANTISOCIAL-BEHAVIOR; NEURAL RESPONSES; PSYCHOPATHIC TENDENCIES; OPPOSITIONAL DEFIANT; PROACTIVE AGGRESSION; AMYGDALA RESPONSE; COMMUNITY SAMPLE; EARLY-ONSET; EMPATHY AB BackgroundDeficient empathic processing is thought to foster conduct disorder (CD). It is important to determine the extent to which neural response associated with perceiving harm to others predicts CD symptoms and callous disregard for others. MethodsA total of 107 9- to 11-year-old children (52 female) were recruited from pediatric and mental health clinics, representing a wide range of CD symptoms. Children were scanned with functional magnetic resonance imaging while viewing brief video clips of persons being harmed intentionally or accidentally. ResultsPerceiving harm evoked increased hemodynamic response in the anterior insula (aINS), anterior cingulate cortex (ACC), amygdala, periaqueductal gray (PAG), caudate, and inferior parietal lobe (IPL) across all participants. Intentionally caused, relative to unintentional harm was associated with greater activity in the aINS, amygdala, and temporal pole. There was an inverse association of number of CD symptoms with right posterior insula in both the Harm>No Harm and the Intentional>Unintentional Harm contrasts. Furthermore, an inverse association between callousness and posterior insula activation was found in the Harm>No Harm contrast, with the opposite pattern for reactive aggression scores. An interaction revealed a stronger association in girls between CD symptoms and the right posterior superior temporal sulcus (pSTS) in the Intentional Harm versus Unintentional Harm contrast. ConclusionsChildren with greater CD and callousness exhibit dampened hemodynamic response to viewing others being harmed in the insula, a region which plays a key role in empathy and emotional awareness. Sex differences in the neural correlates of CD were observed. C1 [Michalska, Kalina J.; Decety, Jean] Univ Chicago, Dept Psychol, 5848 S Univ Ave, Chicago, IL 60637 USA. [Michalska, Kalina J.] NIMH, Bethesda, MD 20892 USA. [Michalska, Kalina J.] Univ Maryland, Dept Human Dev, College Pk, MD 20742 USA. [Zeffiro, Thomas A.] Massachusetts Gen Hosp, Neural Syst Grp, Charlestown, MA USA. [Decety, Jean] Univ Chicago Med, Dept Psychiat & Behav Neurosci, Chicago, IL USA. RP Decety, J (reprint author), Univ Chicago, Child Neurosuite, 5848 S Univ Ave, Chicago, IL 60637 USA. EM decety@uchicago.edu FU NIMH [R01-MH084934] FX This study was supported by NIMH grant R01-MH084934 to J.D. The authors are grateful to Jason M. Cowell for helpful suggestions and to Carrie Swetlik and Talia Reiter for their help with data collection and entry. The authors have declared that they have no competing or potential conflicts of interests. NR 49 TC 6 Z9 6 U1 18 U2 20 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9630 EI 1469-7610 J9 J CHILD PSYCHOL PSYC JI J. Child Psychol. Psychiatry PD APR PY 2016 VL 57 IS 4 BP 510 EP 519 DI 10.1111/jcpp.12474 PG 10 WC Psychology, Developmental; Psychiatry; Psychology SC Psychology; Psychiatry GA DH9JU UT WOS:000373113200009 PM 26472591 ER PT J AU Haley, NJ Siepker, C Hoon-Hanks, LL Mitchell, G Walter, WD Manca, M Monello, RJ Powers, JG Wild, MA Hoover, EA Caughey, B Richt, JA AF Haley, Nicholas J. Siepker, Chris Hoon-Hanks, Laura L. Mitchell, Gordon Walter, W. David Manca, Matteo Monello, Ryan J. Powers, Jenny G. Wild, Margaret A. Hoover, Edward A. Caughey, Byron Richt, Juergen A. TI Seeded Amplification of Chronic Wasting Disease Prions in Nasal Brushings and Recto-anal Mucosa-Associated Lymphoid Tissues from Elk by Real-Time Quaking-Induced Conversion SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID ROCKY-MOUNTAIN ELK; CERVUS-ELAPHUS-NELSONI; WHITE-TAILED DEER; CREUTZFELDT-JAKOB-DISEASE; BOVINE SPONGIFORM ENCEPHALOPATHY; MULE DEER; ODOCOILEUS-HEMIONUS; RECTAL MUCOSA; OLFACTORY EPITHELIUM; CYCLIC AMPLIFICATION AB Chronic wasting disease (CWD), a transmissible spongiform encephalopathy of cervids, was first documented nearly 50 years ago in Colorado and Wyoming and has since been detected across North America and the Republic of Korea. The expansion of this disease makes the development of sensitive diagnostic assays and antemortem sampling techniques crucial for the mitigation of its spread; this is especially true in cases of relocation/reintroduction or prevalence studies of large or protected herds, where depopulation may be contraindicated. This study evaluated the sensitivity of the real-time quaking-induced conversion (RT-QuIC) assay of recto-anal mucosa-associated lymphoid tissue (RAMALT) biopsy specimens and nasal brushings collected antemortem. These findings were compared to results of immunohistochemistry (IHC) analysis of ante-and postmortem samples. RAMALT samples were collected from populations of farmed and free-ranging Rocky Mountain elk (Cervus elaphus nelsoni; n = 323), and nasal brush samples were collected from a subpopulation of these animals (n = 205). We hypothesized that the sensitivity of RT-QuIC would be comparable to that of IHC analysis of RAMALT and would correspond to that of IHC analysis of postmortem tissues. We found RAMALT sensitivity (77.3%) to be highly correlative between RT-QuIC and IHC analysis. Sensitivity was lower when testing nasal brushings (34%), though both RAMALT and nasal brush test sensitivities were dependent on both the PRNP genotype and disease progression determined by the obex score. These data suggest that RT-QuIC, like IHC analysis, is a relatively sensitive assay for detection of CWD prions in RAMALT biopsy specimens and, with further investigation, has potential for large-scale and rapid automated testing of antemortem samples for CWD. C1 [Haley, Nicholas J.; Siepker, Chris; Richt, Juergen A.] Kansas State Univ, Coll Vet Med, Dept Diagnost Med & Pathobiol, Manhattan, KS 66506 USA. [Hoon-Hanks, Laura L.; Hoover, Edward A.] Colorado State Univ, Coll Vet Med & Biomed Sci, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80523 USA. [Mitchell, Gordon] Canadian Food Inspect Agcy, Natl & OIE Reference Lab Scrapie & CWD, Ottawa Lab Fallowfield, Ottawa, ON, Canada. [Walter, W. David] Penn State Univ, US Geol Survey, Penn Cooperat Fish & Wildlife Res Unit, University Pk, PA 16802 USA. [Manca, Matteo; Caughey, Byron] NIAID, TSE Prion Biochem Sect, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT USA. [Monello, Ryan J.; Powers, Jenny G.; Wild, Margaret A.] Natl Pk Serv, Biol Resources Div, Ft Collins, CO USA. [Haley, Nicholas J.] Midwestern Univ, Dept Microbiol & Immunol, Glendale, AZ USA. RP Haley, NJ (reprint author), Kansas State Univ, Coll Vet Med, Dept Diagnost Med & Pathobiol, Manhattan, KS 66506 USA.; Haley, NJ (reprint author), Midwestern Univ, Dept Microbiol & Immunol, Glendale, AZ USA. EM nicholas.j.haley@gmail.com FU Elk Research Council; Merial; Intramural Research Program of NIAID; HHS \ NIH \ National Center for Research Resources (NCRR) [NIH NCRR K01OD010994] FX Elk Research Council provided funding to Nicholas J. Haley. Merial provided funding to Chris Siepker. Intramural Research Program of the NIAID provided funding to Matteo Manca. HHS vertical bar NIH vertical bar National Center for Research Resources (NCRR) provided funding to Nicholas J. Haley under grant number NIH NCRR K01OD010994. NR 67 TC 5 Z9 5 U1 3 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD APR PY 2016 VL 54 IS 4 BP 1117 EP 1126 DI 10.1128/JCM.02700-15 PG 10 WC Microbiology SC Microbiology GA DI2OX UT WOS:000373337100037 PM 26888899 ER PT J AU Hughes, HY Conlan, SP Lau, AF Dekker, JP Michelin, AV Youn, JH Henderson, DK Frank, KM Segre, JA Palmore, TN AF Hughes, Heather Y. Conlan, Sean P. Lau, Anna F. Dekker, John P. Michelin, Angela V. Youn, Jung-Ho Henderson, David K. Frank, Karen M. Segre, Julia A. Palmore, Tara N. TI Detection and Whole-Genome Sequencing of Carbapenemase-Producing Aeromonas hydrophila Isolates from Routine Perirectal Surveillance Culture SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID METALLO-BETA-LACTAMASE; PSEUDOMONAS-AERUGINOSA; ANTIBIOTIC-RESISTANCE; KPC; IDENTIFICATION; ENVIRONMENT; PATIENT; FRANCE; STRAIN; TEM-24 AB Perirectal surveillance cultures and a stool culture grew Aeromonas species from three patients over a 6-week period and were without epidemiological links. Detection of the bla(KPC-2) gene in one isolate prompted inclusion of non-Enterobacteriaceae in our surveillance culture workup. Whole-genome sequencing confirmed that the isolates were unrelated and provided data for Aeromonas reference genomes. C1 [Hughes, Heather Y.; Palmore, Tara N.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Conlan, Sean P.; Segre, Julia A.] NHGRI, NIH, Bethesda, MD 20892 USA. [Lau, Anna F.; Dekker, John P.; Michelin, Angela V.; Youn, Jung-Ho; Henderson, David K.; Frank, Karen M.; Palmore, Tara N.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Palmore, TN (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.; Palmore, TN (reprint author), NIH, Ctr Clin, Bethesda, MD 20892 USA. EM tpalmore@mail.nih.gov FU NIH Clinical Center; intramural research programs of the National Human Genome Research Institute; National Institute of Allergy and Infectious Diseases FX This research was supported by the NIH Clinical Center and the intramural research programs of the National Human Genome Research Institute and the National Institute of Allergy and Infectious Diseases. NR 23 TC 0 Z9 0 U1 1 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD APR PY 2016 VL 54 IS 4 BP 1167 EP 1170 DI 10.1128/JCM.03229-15 PG 4 WC Microbiology SC Microbiology GA DI2OX UT WOS:000373337100049 PM 26888898 ER PT J AU Peer, CJ Goey, AKL Sissung, TM Erlich, S Lee, MJ Tomita, Y Trepel, JB Piekarz, R Balasubramaniam, S Bates, SE Figg, WD AF Peer, Cody J. Goey, Andrew K. L. Sissung, Tristan M. Erlich, Sheryl Lee, Min-Jung Tomita, Yusuke Trepel, Jane B. Piekarz, Richard Balasubramaniam, Sanjeeve Bates, Susan E. Figg, William D. TI UGT1A1 genotype-dependent dose adjustment of belinostat in patients with advanced cancers using population pharmacokinetic modeling and simulation SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE clinical pharmacology; oncology; population; pharmacokinetics; pharmacometrics; pharmacogenetics ID DEACETYLASE INHIBITOR BELINOSTAT; THYMIC EPITHELIAL TUMORS; SOLID TUMORS; UGT1A1-ASTERISK-28 POLYMORPHISM; QUANTIFICATION LIMIT; ACTIVE METABOLITE; GILBERTS-SYNDROME; GENETIC-BASIS; HANDLING DATA; PHASE I/II AB Belinostat is a second-generation zinc-binding histone deacetylase inhibitor that is approved for peripheral T-cell lymphoma and is currently being studied in small cell lung cancer and other advanced carcinomas as a 48-hour continuous intravenous infusion. Belinostat is predominantly metabolized by UGT1A1, which is polymorphic. Preliminary analyses revealed a difference in belinostat clearance based on UGT1A1 genotype. A 2-compartment population pharmacokinetic (PK) model was developed and validated that incorporated the UGT1A1 genotype, albumin, and creatinine clearance on the clearance parameter; body weight was a significant covariate on volume. Simulated doses of 600 and 400mg/m(2)/24h given to patients considered extensive or impaired metabolizers, respectively, provided equivalent AUCs. This model and subsequent simulations supported additional PK/toxicity and pharmacogenomics/toxicity analyses to suggest a UGT1A1 genotype-based dose adjustment to normalize belinostat exposure and allow for more tolerable therapy. In addition, global protein lysine acetylation was modeled with PK and demonstrated a reversible belinostat exposure/response relationship, consistent with previous reports. C1 [Peer, Cody J.; Goey, Andrew K. L.; Sissung, Tristan M.; Erlich, Sheryl; Figg, William D.] NCI, Clin Pharmacol Program, NIH, Bethesda, MD 20892 USA. [Lee, Min-Jung; Tomita, Yusuke; Trepel, Jane B.; Balasubramaniam, Sanjeeve; Bates, Susan E.] NCI, Dev Therapeut Branch, NIH, Bethesda, MD 20892 USA. [Piekarz, Richard] NCI, Canc Therapy Evaluat Program, NIH, Bethesda, MD 20892 USA. [Figg, William D.] NCI, Genitourinary Malignancies Branch, NIH, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Clin Pharmacol Program, CCR, NIH, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. EM wf13e@nih.gov RI Figg Sr, William/M-2411-2016; OI Balasubramaniam, Sanjeeve/0000-0002-0643-2117 FU National Cancer Institute, National Institutes of Health; NIH, National Cancer Institute, Center for Cancer Research FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health. This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 32 TC 1 Z9 1 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0091-2700 EI 1552-4604 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD APR PY 2016 VL 56 IS 4 BP 450 EP 460 DI 10.1002/jcph.627 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DH5PY UT WOS:000372845400010 PM 26637161 ER PT J AU Goey, AKL Sissung, TM Peer, CJ Trepel, JB Lee, MJ Tomita, Y Ehrlich, S Bryla, C Balasubramaniam, S Piekarz, R Steinberg, SM Bates, SE Figg, WD AF Goey, Andrew K. L. Sissung, Tristan M. Peer, Cody J. Trepel, Jane B. Lee, Min-Jung Tomita, Yusuke Ehrlich, Sheryl Bryla, Christine Balasubramaniam, Sanjeeve Piekarz, Richard Steinberg, Seth M. Bates, Susan E. Figg, William D. TI Effects of UGT1A1 genotype on the pharmacokinetics, pharmacodynamics, and toxicities of belinostat administered by 48-hour continuous infusion in patients with cancer SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE belinostat; UGT1A1; pharmacogenomics; pharmacokinetics; pharmacodynamics ID IRINOTECAN-INDUCED NEUTROPENIA; UGT1A1-ASTERISK-28 GENOTYPE; GENETIC-VARIANTS; HAPLOTYPES; BILIRUBIN; JAPANESE; TUMORS; RISK AB The histone deacetylase inhibitor belinostat is eliminated through glucuronidation by UGT1A1. Polymorphisms that reduce UGT1A1 function could result in increased belinostat exposure and toxicities. We wanted to determine which single-nucleotide polymorphisms alter belinostat exposure and toxicity. In a phase 1 trial (belinostat over 48 hours in combination with cisplatin and etoposide), belinostat (400, 500, 600, or 800mg/m(2)/24h, 48-hour continuous infusion) was administered to patients with cancer in combination with cisplatin and etoposide (n=25). Patients were genotyped for UGT1A1 variants associated with reduced function: UGT1A1*6, UGT1A1*28, and UGT1A1*60. End points were associations between UGT1A1 genotype and belinostat pharmacokinetics (PK), toxicities, and global protein lysine acetylation (AcK). Belinostat AUC was increased (P=.003), and t(1/2) increased (P=.0009) in UGT1A1*28 and UGT1A1*60 carriers who received more than 400mg/m(2)/24h. The incidence of grades 3-4 thrombocytopenia (P=.0081) was associated with UGT1A1 polymorphisms. The US Food and Drug Administration-approved package insert recommends dose adjustment of belinostat for UGT1A1*28. However, our data suggest dose adjustment is also necessary for UGT1A1*60. UGT1A1 polymorphisms were associated with increased systemic belinostat exposure, increased AcK, and increased incidence of toxicities, particularly at doses > 400mg/m(2)/24h. C1 [Goey, Andrew K. L.; Peer, Cody J.; Figg, William D.] NCI, Clin Pharmacol Program, NIH, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. [Sissung, Tristan M.; Ehrlich, Sheryl] NCI, Mol Pharmacol Program, NIH, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. [Trepel, Jane B.; Lee, Min-Jung; Tomita, Yusuke] NCI, Dev Therapeut Branch, NIH, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. [Bryla, Christine; Balasubramaniam, Sanjeeve; Bates, Susan E.] NCI, Med Oncol Serv, NIH, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. [Piekarz, Richard] NCI, Canc Therapy Evaluat Program, NIH, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, NIH, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Clin Pharmacol Program, CCR, NIH, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. EM figgw@helix.nih.gov RI Figg Sr, William/M-2411-2016; OI Balasubramaniam, Sanjeeve/0000-0002-0643-2117 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 15 TC 4 Z9 4 U1 4 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0091-2700 EI 1552-4604 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD APR PY 2016 VL 56 IS 4 BP 461 EP 473 DI 10.1002/jcph.625 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DH5PY UT WOS:000372845400011 PM 26313268 ER PT J AU Merchant, AT Georgantopoulos, P Howe, CJ Virani, SS Morales, DA Haddock, KS AF Merchant, A. T. Georgantopoulos, P. Howe, C. J. Virani, S. S. Morales, D. A. Haddock, K. S. TI Effect of Long-Term Periodontal Care on Hemoglobin A1c in Type 2 Diabetes SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE periodontal treatment; periodontal maintenance; glycemic control; marginal structural model; hemoglobin A; glycosylated ID A(1C) LEVELS; GLYCEMIC CONTROL; METAANALYSIS; THERAPY; TRIALS; COMPLICATIONS; ASSOCIATION; ADJUSTMENT; MELLITUS; OUTCOMES AB This was a prospective cohort study evaluating 126,805 individuals with diabetes and periodontal disease receiving care at all Veterans Administration medical centers and clinics in the United States from 2005 through 2012. The exposures were periodontal treatment at baseline (PT0) and at follow-up (PT2). The outcomes were change in HbA1c following initial treatment (HbA1c(1)) and follow-up treatment (HbA1c(2)), and diabetes control was defined as HbA1c at <7% and <9% following initial and follow-up treatment, respectively. Marginal structural models were used to account for potential confounding and selection bias. The objective was to evaluate the impact of long-term treatment of periodontal disease on glycemic control among individuals with type 2 diabetes. Participants were 64 y old on average, 97% were men, and 71% were white. At baseline, the average diabetes duration was 4 y, 12% of participants were receiving insulin, and 60% had HbA1c <7%. After an average 1.7 y of follow-up, the mean HbA1c increased from 7.03% to 7.21%. About 29.4% of participants attended their periodontal maintenance visit following baseline. Periodontal treatment at baseline and follow-up reduced HbA1c by -0.02% and -0.074%, respectively. Treatment at follow-up increased the likelihood of individuals achieving diabetes control by 5% and 3% at the HbA1c <7% and HbA1c <9% thresholds, respectively, and was observed even among never smokers. HbA1c reduction after periodontal treatment at follow-up was greater (HbA1c(2) = -0.25%) among individuals with higher baseline HbA1c. Long-term periodontal care provided in a clinical setting improved long-term glycemic control among individuals with type 2 diabetes and periodontal disease. C1 [Merchant, A. T.; Georgantopoulos, P.] Univ S Carolina, Arnold Sch Publ Hlth, Dept Epidemiol & Biostat, 915 Greene St, Columbia, SC 29208 USA. [Merchant, A. T.; Georgantopoulos, P.; Morales, D. A.; Haddock, K. S.] WJB Dorn VA Med Ctr, Columbia, SC USA. [Georgantopoulos, P.] Univ S Carolina, South Carolina Coll Pharm, South Carolina Ctr Econ Excellence Medicat Safety, Southern Network Adverse React SONAR Project, Columbia, SC 29208 USA. [Howe, C. J.] Brown Univ, Sch Publ Hlth, Dept Epidemiol, Ctr Populat Hlth & Clin Epidemiol, Providence, RI 02912 USA. [Virani, S. S.] Michael E DeBakey VA Med Ctr, Houston, TX USA. [Virani, S. S.] Baylor Coll Med, Houston, TX 77030 USA. [Morales, D. A.] Natl Inst Dent & Craniofacial Res, Bethesda, MD USA. RP Merchant, AT (reprint author), Univ S Carolina, Arnold Sch Publ Hlth, Dept Epidemiol & Biostat, 915 Greene St, Columbia, SC 29208 USA. EM merchant@mailbox.sc.edu OI Virani, Salim/0000-0001-9541-6954 FU National Institutes of Health (NIH) [DE022785] FX The study was funded by the National Institutes of Health (NIH), grant DE022785 (Merchant), "Marginal Structural Models to Get Periodontal Treatment Effects on A1C in Diabetes." The NIH had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; the preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication. We are grateful to Dr. Terry O'Toole, DDS, Director, Dental Informatics and Analytics, VHA Office of Dentistry, Washington, DC, for giving us access to the dental registry data (no compensation); Mr. Yifan Tang, MSPH, University of South Carolina, for help with data manipulation (compensation); and Mr. Samuel Brunson (Junior, BS Biology), University of South Carolina (no compensation), for help with literature search and data presentation. This material is the result of work supported with resources and the use of facilities at the William Jennings Bryan Dorn VA Medical Center in Columbia, South Carolina. These data were presented in abstract form at the International Association for Dental Research, Boston, MA, March 11-14, 2015. The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article. NR 39 TC 2 Z9 2 U1 1 U2 8 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 EI 1544-0591 J9 J DENT RES JI J. Dent. Res. PD APR PY 2016 VL 95 IS 4 BP 408 EP 415 DI 10.1177/0022034515622197 PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DH8YE UT WOS:000373082000007 PM 26701348 ER PT J AU Sinha, A Patel, YA Cruise, M Matsukuma, K Zaheer, A Afghani, E Yadav, D Makary, MA Hirose, K Andersen, DK Singh, VK AF Sinha, Amitasha Patel, Yuval A. Cruise, Michael Matsukuma, Karen Zaheer, Atif Afghani, Elham Yadav, Dhiraj Makary, Martin A. Hirose, Kenzo Andersen, Dana K. Singh, Vikesh K. TI Predictors of Post-Operative Pain Relief in Patients with Chronic Pancreatitis Undergoing the Frey or Whipple Procedure SO JOURNAL OF GASTROINTESTINAL SURGERY LA English DT Article DE Chronic pancreatitis; Post-operative pain relief; Alcohol; Smoking ID PYLORUS-PRESERVING-PANCREATICODUODENECTOMY; LONG-TERM OUTCOMES; SURGICAL-TREATMENT; LONGITUDINAL PANCREATICOJEJUNOSTOMY; RANDOMIZED-TRIAL; RESECTION; DUCT; DRAINAGE; SURGERY; PANCREATECTOMY AB Post-operative pain relief in chronic pancreatitis (CP) is variable. Our objective was to determine clinical imaging or histopathologic predictor(s) of post-operative pain relief in CP patients undergoing the Whipple or Frey procedure. All patients who underwent a Whipple (n = 30) or Frey procedure (n = 30) for painful CP between January 2003 and September 2013 were evaluated. A toxic etiology was defined as a history of alcohol use and/or smoking. The pre-operative abdominal CT was evaluated for calcification(s) and main pancreatic duct (MPD) dilation (a parts per thousand yen5 mm). The post-operative histopathology was evaluated for severe fibrosis. Clinical imaging and histopathologic features were evaluated as predictors of post-operative pain relief using univariable and multivariable regression analysis. A total of 60 patients (age 51.6 years, 53 % males) were included in our study, of whom 42 (70 %) reported post-operative pain relief over a mean follow-up of 1.1 years. There were 37 (62 %) patients with toxic etiology, 36 (60 %) each with calcification(s) and MPD dilation. A toxic etiology, calcifications, and severe fibrosis were associated with post-operative pain relief on univariable analysis (all p < 0.01). However, only a toxic etiology was an independent predictor of post-operative pain relief (OR 5.7, 95 % CI 1.3, 24.5, p = 0.02). Only a toxic etiology, and not imaging or histopathologic findings, independently predicts post-operative pain relief in CP patients undergoing the Whipple or Frey procedure. C1 [Sinha, Amitasha; Patel, Yuval A.; Afghani, Elham; Singh, Vikesh K.] Johns Hopkins Med Inst, Div Gastroenterol, Baltimore, MD 21205 USA. [Cruise, Michael; Matsukuma, Karen] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. [Zaheer, Atif] Johns Hopkins Med Inst, Dept Radiol & Radiol Sci, 600 N Wolfe St, Baltimore, MD 21205 USA. [Yadav, Dhiraj] Univ Pittsburgh, Sch Med, Div Gastroenterol, Pittsburgh, PA USA. [Makary, Martin A.; Hirose, Kenzo] Johns Hopkins Med Inst, Dept Surg, Baltimore, MD 21205 USA. [Andersen, Dana K.] NIDDKD, NIH, Bethesda, MD USA. [Zaheer, Atif; Makary, Martin A.; Hirose, Kenzo; Singh, Vikesh K.] Johns Hopkins Med Inst, Pancreatitis Ctr, Baltimore, MD 21205 USA. RP Singh, VK (reprint author), Johns Hopkins Med Inst, Div Gastroenterol, Baltimore, MD 21205 USA.; Singh, VK (reprint author), Johns Hopkins Med Inst, Pancreatitis Ctr, Baltimore, MD 21205 USA. EM amitashasinha@gmail.com; yuval.patel@duke.edu; mwcruise@gmail.com; kmatsuku@gmail.com; azaheer1@jhmi.edu; ellie.afghani@gmail.com; yadavd@upmc.edu; mmakary1@jhmi.edu; khirose1@jhmi.edu; andersendk@mail.nih.gov; vsingh1@jhmi.edu FU Pancreatitis Research Fund at the Johns Hopkins Medical Institutions FX This study was supported by the Pancreatitis Research Fund at the Johns Hopkins Medical Institutions (VKS). NR 36 TC 1 Z9 1 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1091-255X EI 1873-4626 J9 J GASTROINTEST SURG JI J. Gastrointest. Surg. PD APR PY 2016 VL 20 IS 4 BP 734 EP 740 DI 10.1007/s11605-016-3081-7 PG 7 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA DI0BB UT WOS:000373158700010 PM 26813017 ER PT J AU Tosteson, ANA Beaber, EF Tiro, J Kim, J McCarthy, AM Quinn, VP Doria-Rose, VP Wheeler, CM Barlow, WE Bronson, M Garcia, M Corley, DA Haas, JS Halm, EA Kamineni, A Rutter, CM Tosteson, TD Trentham-Dietz, A Weaver, DL AF Tosteson, Anna N. A. Beaber, Elisabeth F. Tiro, Jasmin Kim, Jane McCarthy, Anne Marie Quinn, Virginia P. Doria-Rose, V. Paul Wheeler, Cosette M. Barlow, William E. Bronson, Mackenzie Garcia, Michael Corley, Douglas A. Haas, Jennifer S. Halm, Ethan A. Kamineni, Aruna Rutter, Carolyn M. Tosteson, Tor D. Trentham-Dietz, Amy Weaver, Donald L. CA PROSPR Consortium TI Variation in Screening Abnormality Rates and Follow-Up of Breast, Cervical and Colorectal Cancer Screening within the PROSPR Consortium SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE breast cancer screening; colorectal cancer screening; cervical cancer screening; practice variation ID FORCE RECOMMENDATION STATEMENT; EARLY-DETECTION PROGRAM; PERSONALIZED REGIMENS; CONCEPTUAL-MODEL; NATIONAL BREAST; UNITED-STATES; PRIMARY-CARE; TIMELINESS; WOMEN; MAMMOGRAPHY AB Primary care providers and health systems have prominent roles in guiding effective cancer screening. To characterize variation in screening abnormality rates and timely initial follow-up for common cancer screening tests. Population-based cohort undergoing screening in 2011, 2012, or 2013 at seven research centers comprising the National Cancer Institute-sponsored Population-based Research Optimizing Screening through Personalized Regimens (PROSPR) consortium. Adults undergoing mammography with or without digital breast tomosynthesis (n = 97,683 ages 40-75 years), fecal occult blood or fecal immunochemical tests (n = 759,553 ages 50-75 years), or Papanicolaou with or without human papillomavirus tests (n = 167,330 ages 21-65 years). Breast, colorectal, or cervical cancer screening. Abnormality rates per 1000 screens; percentage with timely initial follow-up (within 90 days, except 9-month window for BI-RADS 3). Primary care clinic-level variation in percentage with screening abnormality and percentage with timely initial follow-up. There were 10,248/97,683 (104.9 per 1000) abnormal breast cancer screens, 35,847/759,553 (47.2 per 1000) FOBT/FIT-positive colorectal cancer screens, and 13,266/167,330 (79.3 per 1000) abnormal cervical cancer screens. The percentage with timely follow-up was 93.2 to 96.7 % for breast centers, 46.8 to 68.7 % for colorectal centers, and 46.6 % for the cervical cancer screening center (low-grade squamous intraepithelial lesions or higher). The primary care clinic variation (25th to 75th percentile) was smaller for the percentage with an abnormal screen (breast, 8.5-10.3 %; colorectal, 3.0-4.8 %; cervical, 6.3-9.9 %) than for the percentage with follow-up within 90 days (breast, 90.2-95.8 %; colorectal, 43.4-52.0 %; cervical, 29.6-61.4 %). Variation in both the rate of screening abnormalities and their initial follow-up was evident across organ sites and primary care clinics. This highlights an opportunity for improving the delivery of cancer screening through focused study of patient, provider, clinic, and health system characteristics associated with timely follow-up of screening abnormalities. C1 [Tosteson, Anna N. A.; Bronson, Mackenzie; Tosteson, Tor D.] Geisel Sch Med Dartmouth, Lebanon, NH USA. [Tosteson, Anna N. A.; Tosteson, Tor D.] Norris Cotton Canc Ctr, Lebanon, NH USA. [Beaber, Elisabeth F.; Garcia, Michael] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Tiro, Jasmin] Univ Texas Southwestern, Dallas, TX USA. [Kim, Jane] Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [McCarthy, Anne Marie] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Quinn, Virginia P.] Kaiser Permanente So Calif, Pasadena, CA 91101 USA. [Doria-Rose, V. Paul] NCI, Bethesda, MD 20892 USA. [Wheeler, Cosette M.] Univ New Mexico, Albuquerque, NM 87131 USA. [Barlow, William E.] Canc Res & Biostat, Seattle, WA USA. [Corley, Douglas A.] Kaiser Permanente No Calif, Oakland, CA USA. [Haas, Jennifer S.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Halm, Ethan A.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Kamineni, Aruna] Grp Hlth, Seattle, WA USA. [Rutter, Carolyn M.] RAND Corp, Santa Monica, CA USA. [Trentham-Dietz, Amy] Univ Wisconsin, Madison, WI USA. [Weaver, Donald L.] Univ Vermont, Burlington, VT USA. RP Tosteson, ANA (reprint author), Geisel Sch Med Dartmouth, Lebanon, NH USA. EM Anna.Tosteson@Dartmouth.edu OI Doria-Rose, Vincent/0000-0002-8802-5143 FU National Cancer Institute (NCI) [U01CA163304, U54CA163303, U54CA163307, U54CA163313, U54CA163308, U54CA163308-04S1, U54CA163261, U54CA163261-04S1, U54CA163262, U54CA163262-04S1, U54CA164336] FX This work was supported by the National Cancer Institute (NCI)-funded Population-based Research Optimizing Screening through Personalized Regimens (PROSPR) consortium (grant numbers U01CA163304 to M.T., W.B.; U54CA163303 to D.L.W., B.S.; U54CA163307 to A.N.A.T., T.O., J.H.; U54CA163313 to K.A., M.S.; U54CA163308 to C.S.S., E.H.; U54CA163308-04S1 to C.S.S., J.A.T.; U54CA163261 to C.R.; U54CA163261-04S1 to J.C., A.K.; U54CA163262 to A.G.Z., D.C., C.D., T.L.; U54CA163262-04S1 to D.C., M.S.; and U54CA164336 to C.W.). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the Department of Veterans Affairs or the United States government. NR 41 TC 5 Z9 5 U1 3 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD APR PY 2016 VL 31 IS 4 BP 372 EP 379 DI 10.1007/s11606-015-3552-7 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA DI0BR UT WOS:000373160300005 PM 26658934 ER PT J AU Powell-Wiley, TM AF Powell-Wiley, Tiffany M. TI Capsule Commentary on Rana et al., Diabetes and Prior Coronary Heart Disease Are Not Necessarily Risk Equivalent for Future Coronary Heart Disease Events SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material ID SCIENTIFIC STATEMENT; ASSOCIATION; MELLITUS C1 [Powell-Wiley, Tiffany M.] NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Powell-Wiley, TM (reprint author), NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. EM Tiffany.powell@nih.gov NR 5 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD APR PY 2016 VL 31 IS 4 BP 413 EP 413 DI 10.1007/s11606-016-3605-6 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA DI0BR UT WOS:000373160300012 PM 26873149 ER PT J AU Xie, YD Pope, BA Hunter, AJ AF Xie, Yingda Pope, Bailey A. Hunter, Alan J. TI Cotton Fever: Does the Patient Know Best? SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE cotton fever; drug abuse; case report; intravenous drug abuse ID INJECTION-DRUG USERS; INFECTIVE ENDOCARDITIS; COHORT; RISK AB Fever and leukocytosis have many possible etiologies in injection drug users. We present a case of a 22-year-old woman with fever and leukocytosis that were presumed secondary to cotton fever, a rarely recognized complication of injection drug use, after an extensive workup. Cotton fever is a benign, self-limited febrile syndrome characterized by fevers, leukocytosis, myalgias, nausea and vomiting, occurring in injection drug users who filter their drug suspensions through cotton balls. While this syndrome is commonly recognized amongst the injection drug user population, there is a paucity of data in the medical literature. We review the case presentation and available literature related to cotton fever. C1 [Xie, Yingda] NIH, Bldg 10, Bethesda, MD 20892 USA. [Pope, Bailey A.; Hunter, Alan J.] Oregon Hlth & Sci Univ, Dept Med, 3181 SW Sam Jackson Pk Rd,BTE 119, Portland, OR 97239 USA. RP Pope, BA (reprint author), Oregon Hlth & Sci Univ, Dept Med, 3181 SW Sam Jackson Pk Rd,BTE 119, Portland, OR 97239 USA. EM popeb@ohsu.edu NR 18 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD APR PY 2016 VL 31 IS 4 BP 442 EP 444 DI 10.1007/s11606-015-3424-1 PG 3 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA DI0BR UT WOS:000373160300020 PM 26105678 ER PT J AU Murphy, J Mark, H Anderson, J Farley, J Allen, J AF Murphy, Jeanne Mark, Hayley Anderson, Jean Farley, Jason Allen, Jerilyn TI A Randomized Trial of Human Papillomavirus Self-Sampling as an Intervention to Promote Cervical Cancer Screening Among Women With HIV SO JOURNAL OF LOWER GENITAL TRACT DISEASE LA English DT Article DE cancer of cervix; human papillomavirus; cancer screening tests; HIV ID AFRICAN-AMERICAN WOMEN; HEALTH BELIEF MODEL; SMEAR TEST; RISK; BARRIERS; INFECTION; PEOPLE; BREAST; SCALE; CARE AB Objective Women living with HIV experience higher risk of cervical cancer, but screening rates in the United States are lower than recommended. The purpose of this study was to examine whether an intervention using self-sampling of cervicovaginal cells for human papillomavirus (HPV) with results counseling would increase cervical cytology ("Pap") testing among women with HIV. Materials and Methods This was a randomized controlled trial to test the effectiveness of an intervention of self-sampling for HPV and results counseling. Participants were 94 women older than 18 years, with HIV infection, attending an HIV clinic for a primary care visit, whose last cervical cancer screening was 18 months or more before baseline. Women were assigned to the intervention or information-only group. The primary outcome was completion of cervical cytology testing within 6 months of baseline. The secondary outcome was the women's perceived threat of developing cervical cancer. Results A total of 94 women were enrolled and analyzed in the study. The cytology completion rate overall was 35% by 6 months from baseline. There were no differences in comparing HPV-positive with HPV-negative women nor comparing them with the information-only group. In the intervention group, a positive HPV test increased perceived threat of cervical cancer. Conclusions The intervention did not improve cytology test attendance, although education about HPV and cervical cancer risk as part of study procedures was associated with testing for 35% of this group of women whose previous cytology occurred an average of 3.6 years before the baseline appointment. Self-sampling for HPV testing was feasible. C1 [Murphy, Jeanne; Mark, Hayley; Farley, Jason; Allen, Jerilyn] Johns Hopkins Univ, Sch Nursing, Dept Gynecol & Obstet, Baltimore, MD USA. [Anderson, Jean] Johns Hopkins Sch Med, Baltimore, MD USA. RP Murphy, J (reprint author), NCI, Canc Prevent Fellowship Program, 9609 Med Ctr Dr,Room 2W-136, Bethesda, MD 20850 USA. EM jeanne.murphy@nih.gov FU National Institute of Nursing Research, National Institutes of Health National Research Service Award [F31-NR013633]; Council for the Advancement of Nursing Science/Southern Nursing Research Society Dissertation Grant Award FX This study was funded by the National Institute of Nursing Research, National Institutes of Health National Research Service Award F31-NR013633, 2012-2014, and the Council for the Advancement of Nursing Science/Southern Nursing Research Society 2013 Dissertation Grant Award ($5000, to J.M.). NR 34 TC 3 Z9 3 U1 6 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1089-2591 EI 1526-0976 J9 J LOW GENIT TRACT DI JI J. Low. Genit. Tract. Dis. PD APR PY 2016 VL 20 IS 2 BP 139 EP 144 DI 10.1097/LGT.0000000000000195 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DH5RQ UT WOS:000372849900005 PM 27015260 ER PT J AU Cremer, ML Maza, M Alfaro, KM Kim, JJ Ditzian, LR Villalta, S Alonzo, TA Felix, JC Castle, PE Gage, JC AF Cremer, Miriam L. Maza, Mauricio Alfaro, Karla M. Kim, Jane J. Ditzian, Lauren R. Villalta, Sofia Alonzo, Todd A. Felix, Juan C. Castle, Philip E. Gage, Julia C. TI Introducing a High-Risk HPV DNA Test Into a Public Sector Screening Program in El Salvador SO JOURNAL OF LOWER GENITAL TRACT DISEASE LA English DT Article DE Latin America; human papillomavirus; cervical cancer; careHPV; screening program ID LOW-RESOURCE SETTINGS; COST-EFFECTIVENESS; RURAL CHINA; CRYOTHERAPY; LESIONS AB Objective In a primary human papillomavirus (HPV) screening program, we compared the 6-month follow-up among colposcopy and noncolposcopy-based management strategies for screen-positive women. Materials and Methods Women aged 30 to 49 years were screened with HPV DNA tests using both self-collection and provider collection of samples. Women testing positive received either (1) colposcopy management (CM) consisting of colposcopy and management per local guidelines or (2) screen-and-treat (ST) management using visual inspection with acetic acid to determine cryotherapy eligibility, with eligible women undergoing immediate cryotherapy. One thousand women were recruited in each cohort. Of these, 368 (18.4%) of 2000 women were recruited using a more intensive outreach strategy. Demographics, HPV positivity, and treatment compliance were compared across recruitment and management strategies. Results More women in the ST cohort received treatment within 6 months compared with those in the CM cohort (117/119 [98.3%] vs 64/93 [68.8%]; p < .001). Women recruited through more intensive outreach were more likely to be HPV positive, lived in urban areas, were more educated, and had higher numbers of lifetime sexual partners and fewer children. Conclusions Women in the CM arm were less likely to complete care than women in the ST arm. Targeted outreach to underscreened women successfully identified women with higher prevalence of HPV and possibly higher disease burden. C1 [Cremer, Miriam L.; Maza, Mauricio; Alfaro, Karla M.; Ditzian, Lauren R.] Basic Hlth Int, San Salvador, El Salvador. [Cremer, Miriam L.] Cleveland Clin, Obstet Gynecol & Womens Hlth Inst, 9500 Euclid Ave, Cleveland, OH 44195 USA. [Kim, Jane J.] Harvard Univ, Sch Publ Hlth, Ctr Hlth Decis Sci, 665 Huntington Ave, Boston, MA 02115 USA. [Villalta, Sofia] Minist Hlth El Salvador, San Salvador, El Salvador. [Alonzo, Todd A.] Univ So Calif, Childrens Oncol Grp, Dept Prevent Med, Arcadia, CA USA. [Felix, Juan C.] Univ So Calif, Dept Pathol, Los Angeles, CA 90089 USA. [Castle, Philip E.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Gage, Julia C.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Cremer, ML (reprint author), Cleveland Clin, Obstet Gynecol & Womens Hlth Inst, 9500 Euclid Ave, Cleveland, OH 44195 USA. EM bhisubmissions@gmail.com FU Einhorn Family Charitable Trust FX The study was supported by Einhorn Family Charitable Trust. NR 16 TC 2 Z9 2 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1089-2591 EI 1526-0976 J9 J LOW GENIT TRACT DI JI J. Low. Genit. Tract. Dis. PD APR PY 2016 VL 20 IS 2 BP 145 EP 150 DI 10.1097/LGT.0000000000000188 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DH5RQ UT WOS:000372849900006 PM 26890683 ER PT J AU Liu, AH Gold, MA Schiffman, M Smith, KM Zuna, RE Dunn, ST Gage, JC Walker, JL Wentzensen, N AF Liu, Angela H. Gold, Michael A. Schiffman, Mark Smith, Katie M. Zuna, Rosemary E. Dunn, S. Terence Gage, Julia C. Walker, Joan L. Wentzensen, Nicolas TI Comparison of Colposcopic Impression Based on Live Colposcopy and Evaluation of Static Digital Images SO JOURNAL OF LOWER GENITAL TRACT DISEASE LA English DT Article DE static digital image of the cervix; colposcopy; cervical intraepithelial neoplasias; diagnostic accuracies; colposcopic impressions ID CERVICAL INTRAEPITHELIAL NEOPLASIA; EARLY END-POINTS; CONSENSUS GUIDELINES; CANCER; WOMEN; CYTOLOGY; MANAGEMENT; DETERMINANTS; PROGRESSION; ACCURACY AB Objective The aim of the study was to evaluate the agreement and compare diagnostic accuracy of colposcopic impressions from live colposcopy versus evaluation of static digital images. Materials and Methods Live impressions and corresponding static images obtained during colposcopy of 690 women were independently compared. Diagnostic accuracy was calculated for colposcopic impressions from both methods, varying hypothetical thresholds for colposcopically directed cervical biopsies (acetowhitening or worse, low grade or worse, high grade or worse). Stratified analyses investigated the impact of referral cytology, human papillomavirus 16 infection, and age on colposcopic impression. Results Overall agreement between live and static colposcopic visualization was 43.0% (kappa = 0.20; 95% CI = 0.14-0.26) over normal, acetowhitening, low-grade, and high-grade impressions. Classification of acetowhitening or worse impressions showed the highest agreement (92.2%; kappa = 0.39; 95% CI = 0.21-0.57); both methods achieved more than 95% sensitivity for CIN 2+. Agreement between live and static colposcopic visualization was 69.3% for rating low-grade or worse impressions (kappa = 0.23; 95% CI = 0.14-0.33) and 71% when rating high-grade impressions (kappa = 0.33; 95% CI = 0.24-0.42). Live colposcopic impressions were more likely to be rated low grade or worse (p < .01; odds ratio = 3.5; 95% CI = 2.4-5.0), yielding higher sensitivity for CIN 2+ at this threshold than static image assessment (95.4% vs 79.8%, p < .01). Overall, colposcopic impressions were more likely rated high grade on live assessment among women referred with high-grade cytology (odds ratio = 3.3; 95% CI = 1.8-6.4), significantly improving the sensitivity for CIN 2+ (66.3% vs 48.5%, p < .01). Conclusions Colposcopic impressions of acetowhitening or worse are highly sensitive for identifying cervical precancers and reproducible on static image-based pattern recognition. C1 [Liu, Angela H.; Schiffman, Mark; Gage, Julia C.; Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 7E-216, Oklahoma City, OK USA. [Gold, Michael A.] Tulsa Canc Inst, Oklahoma City, OK USA. [Gold, Michael A.] Univ Oklahoma, Sch Community Med, Oklahoma City, OK USA. [Smith, Katie M.; Zuna, Rosemary E.; Dunn, S. Terence; Walker, Joan L.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. RP Liu, AH (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 7E-216, Oklahoma City, OK USA. EM angela.liu@nih.gov OI Liu, Angela/0000-0002-2567-0671 FU National Cancer Institute FX The study was supported by the Intramural Research Program of the National Cancer Institute. The funding source has no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the article. NR 25 TC 1 Z9 1 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1089-2591 EI 1526-0976 J9 J LOW GENIT TRACT DI JI J. Low. Genit. Tract. Dis. PD APR PY 2016 VL 20 IS 2 BP 154 EP 161 DI 10.1097/LGT.0000000000000194 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DH5RQ UT WOS:000372849900008 PM 27015261 ER PT J AU Huntoon, K Wu, TX Elder, B Butman, JA Chew, EY Linehan, WM Oldfield, EH Lonser, RR AF Huntoon, Kristin Wu, Tianxia Elder, Bradley Butman, John A. Chew, Emily Y. Linehan, W. Marston Oldfield, Edward H. Lonser, Russell R. TI Biological and clinical impact of hemangioblastoma-associated peritumoral cysts in von Hippel-Lindau disease SO JOURNAL OF NEUROSURGERY LA English DT Article DE cyst; central nervous system; hemangioblastoma; natural history; treatment; von Hippel-Lindau disease; oncology ID CENTRAL-NERVOUS-SYSTEM; NATURAL-HISTORY; TUMOR; MANIFESTATIONS; PATHOGENESIS; MANAGEMENT; RESECTION; FEATURES; ARTICLE; LESIONS AB OBJECTIVE Peritumoral cysts are frequently associated with CNS hemangioblastomas and often underlie neurological morbidity and mortality. To determine their natural history and clinical impact, the authors prospectively analyzed hemangioblastoma-associated peritumoral cysts in patients with von Hippel-Lindau (VHL) disease. METHODS Patients with VHL disease who had 2 or more years of follow-up and who were enrolled in a prospective study at the National Institutes of Health were included. Serial prospectively acquired laboratory, genetic, imaging, and clinical data were analyzed. RESULTS One hundred thirty-two patients (of 225 in the VHL study with at least 2 years of follow-up) had peritumoral cysts that were followed for more than 2 years (total of 292 CNS peritumoral cysts). The mean age at study entrance was 37.4 +/- 13.1 years ([mean +/- SD], median 37.9, range 12.3-65.1 years). The mean follow-up was 7.0 +/- 1.7 years (median 7.3, range 2.1-9.0 years). Over the study period, 121 of the 292 peritumoral cysts (41.4%) became symptomatic. Development of new cysts was associated with a larger number cysts at study enrollment (p = 0.002) and younger age (p < 0.0001). Cyst growth rate was associated with anatomical location (cerebellum cysts grew faster than spine and brainstem cysts; p = 0.0002 and p = 0.0008), younger age (< 35 years of age; p = 0.0006), and development of new neurological symptoms (p < 0.0001). Cyst size at symptom production depended on anatomical location (p < 0.0001; largest to smallest were found, successively, in the cerebellum, spinal cord, and brainstem). The most common location for peritumoral cysts was the cerebellum (184 cysts [63%]; p < 0.0001). CONCLUSIONS Peritumoral cysts frequently underlie symptom formation that requires surgical intervention in patients with VHL disease. Development of new cysts was associated with a larger number of cysts at study enrollment and younger age. Total peritumoral cyst burden was associated with germline partial deletion of the VHL gene. C1 [Huntoon, Kristin; Elder, Bradley; Lonser, Russell R.] Ohio State Univ, Dept Neurol Surg, Wexner Med Ctr, 410 W 10th Ave,Doan Hall N1047, Columbus, OH 43210 USA. [Huntoon, Kristin; Oldfield, Edward H.; Lonser, Russell R.] NINDS, Surg Neurol Branch, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Wu, Tianxia] NINDS, Off Clin Director, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Butman, John A.] NIH, Neuroradiol Sect, Diagnost Radiol, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Chew, Emily Y.] NEI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. [Linehan, W. Marston] NIH, Urol Oncol Branch, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. [Oldfield, Edward H.] Univ Virginia, Hlth Sci Ctr, Dept Neurol Surg, Charlottesville, VA 22908 USA. RP Lonser, RR (reprint author), Ohio State Univ, Dept Neurol Surg, Wexner Med Ctr, 410 W 10th Ave,Doan Hall N1047, Columbus, OH 43210 USA. EM russell.lonser@osumc.edu FU NCI NIH HHS [Z01 BC011028-01, Z01 BC011038-01, Z01 BC011089-01] NR 28 TC 1 Z9 1 U1 0 U2 3 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 EI 1933-0693 J9 J NEUROSURG JI J. Neurosurg. PD APR PY 2016 VL 124 IS 4 BP 971 EP 976 DI 10.3171/2015.4.JNS1533 PG 6 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA DH3EA UT WOS:000372669100011 PM 26517769 ER PT J AU Shaikh, N Hoberman, A Keren, R Ivanova, A Gotman, N Chesney, RW Carpenter, MA Moxey-Mims, M Wald, ER AF Shaikh, Nader Hoberman, Alejandro Keren, Ron Ivanova, Anastasia Gotman, Nathan Chesney, Russell W. Carpenter, Myra A. Moxey-Mims, Marva Wald, Ellen R. TI Predictors of Antimicrobial Resistance among Pathogens Causing Urinary Tract Infection in Children SO JOURNAL OF PEDIATRICS LA English DT Article ID RISK-FACTORS; PATTERNS; AGE; SUSCEPTIBILITY; LESIONS AB Objective To determine which children with urinary tract infection are likely to have pathogens resistant to narrow-spectrum antimicrobials. Study design Children, 2-71 months of age (n = 769) enrolled in the Randomized Intervention for Children with Vesicoureteral Reflux or Careful Urinary Tract Infection Evaluation studies were included. We used logistic regression models to test the associations between demographic and clinical characteristics and resistance to narrow-spectrum antimicrobials. Results Of the included patients, 91% were female and 76% had vesicoureteral reflux. The risk of resistance to narrow-spectrum antibiotics in uncircumcised males was approximately 3 times that of females (OR 3.1; 95% CI 1.4-6.7); in children with bladder bowel dysfunction, the risk was 2 times that of children with normal function (OR 2.2; 95% CI 1.2-4.1). Children who had received 1 course of antibiotics during the past 6 months also had higher odds of harboring resistant organisms (OR 1.6; 95% CI 1.1-2.3). Hispanic children had higher odds of harboring pathogens resistant to some narrow-spectrum antimicrobials. Conclusions Uncircumcised males, Hispanic children, children with bladder bowel dysfunction, and children who received 1 course of antibiotics in the past 6 months were more likely to have a urinary tract infection caused by pathogens resistant to 1 or more narrow-spectrum antimicrobials. C1 [Shaikh, Nader; Hoberman, Alejandro] Univ Pittsburgh, Childrens Hosp Pittsburgh, Sch Med, Div Gen Acad Pediat, Pittsburgh, PA 15213 USA. [Keren, Ron] Childrens Hosp Philadelphia, Div Gen Pediat, Ctr Pediat Clin Effectiveness, Philadelphia, PA 19104 USA. [Ivanova, Anastasia; Gotman, Nathan; Carpenter, Myra A.] Univ N Carolina, Dept Biostat, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA. [Chesney, Russell W.] Univ Tennessee, Ctr Hlth Sci, Dept Pediat, Memphis, TN 38163 USA. [Moxey-Mims, Marva] NIDDK, NIH, Bethesda, MD 20892 USA. [Wald, Ellen R.] Univ Wisconsin, Dept Pediat, Sch Med & Publ Hlth, Madison, WI USA. RP Shaikh, N (reprint author), Univ Pittsburgh, Childrens Hosp Pittsburgh, Sch Med, Div Gen Acad Pediat, Pittsburgh, PA 15213 USA. OI Shaikh, Nader/0000-0002-1602-343X FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services [U01 DK074059, U01 DK074053, U01 DK074082, U01 DK074064, U01 DK074062, U01 DK074063] FX Supported by National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services (U01 DK074059, U01 DK074053, U01 DK074082, U01 DK074064, U01 DK074062, U01 DK074063). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding bodies. The authors declare no conflicts of interest. NR 16 TC 4 Z9 4 U1 2 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD APR PY 2016 VL 171 BP 116 EP 121 DI 10.1016/j.jpeds.2015.12.044 PG 6 WC Pediatrics SC Pediatrics GA DH4KC UT WOS:000372753600026 PM 26794472 ER PT J AU Li, CM Hoffman, HJ Ward, BK Cohen, HS Rine, RM AF Li, Chuan-Ming Hoffman, Howard J. Ward, Bryan K. Cohen, Helen S. Rine, Rose Marie TI Epidemiology of Dizziness and Balance Problems in Children in the United States: A Population-Based Study SO JOURNAL OF PEDIATRICS LA English DT Article ID MIDDLE-EAR EFFUSION; PAROXYSMAL VERTIGO; PREVALENCE; DISORDERS; DIAGNOSIS; MIGRAINE AB Objective To study national prevalence of dizziness and balance problems in US children and explore associated risk factors and patterns of healthcare utilization. Study design A multistage, nationally representative, probability sample of children (n=10 954; aged 3-17 years) was examined based on the 2012 National Health Interview Survey Child Balance Supplement. Parents were asked if during the past year their child was bothered by symptoms of dizziness and balance problems: vertigo (motion sensation), light-headedness/fainting, clumsiness/poor coordination, poor balance/unsteadiness when standing-up or walking, frequent falls, or other dizziness and balance problems. Logistic regression was used to examine associations with sociodemographic information, birth weight, developmental delays, and significant health conditions. Results Prevalence of dizziness and balance problems was 5.3% (3.3 million US children); females, 5.7%, males, 5.0%. Non-Hispanic white (6.1%) had increased prevalence compared with Hispanic (4.6%) and non-Hispanic black (4.3%) children, P=.01. Prevalence increased with age, from 4.1% for children aged 3-5 years to 7.5% for children aged 15-17 years, P<.001. Even though the majority had symptoms rated as "no problem" or "a small problem," 18.6% (600 000 US children) had symptoms rated as " moderate," " big," or " very big" problems. Overall, 36.0% of children with dizziness and balance problems were seen by healthcare professionals during the past year and 29.9% received treatment. Among children with dizziness and balance problems rated as moderate/big/very big problems, 71.6% had seen healthcare professionals and 62.4% received treatment for dizziness and balance problems. Conclusions The risk factors identified provide useful epidemiologic information about dizziness and balance problems in children and will be used in tracking the Healthy People 2020 goal to increase utilization of healthcare services for these children. C1 [Li, Chuan-Ming; Hoffman, Howard J.] Natl Inst Deafness & Other Commun Disorders NIDCD, Epidemiol & Stat Program, Div Sci Programs, NIH, 6001 Execut Blvd,Suite 8300, Bethesda, MD 20892 USA. [Ward, Bryan K.] Johns Hopkins Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21205 USA. [Cohen, Helen S.] Baylor Coll Med, Bobby R Alford Dept Otolaryngol Head & Neck Surg, Houston, TX 77030 USA. [Rine, Rose Marie] Specialty Therapy Source LLC, Jacksonville, FL USA. [Rine, Rose Marie] Marshall Univ, Sch Phys Therapy, Huntington, WV USA. RP Hoffman, HJ (reprint author), Natl Inst Deafness & Other Commun Disorders, Epidemiol & Stat Program, NIH, 6001 Execut Blvd,Suite 8300, Bethesda, MD 20892 USA. EM hoffmanh@nidcd.nih.gov FU NIDCD/NIH; National Center for Health Statistics (NCHS)/Centers for Disease Control and Prevention (CDC) [Y1-DC-7001] FX The National Health Interview Survey (NHIS) Child Balance Supplement was co-funded by the NIDCD/NIH and National Center for Health Statistics (NCHS)/Centers for Disease Control and Prevention (CDC) via Interagency Agreement Y1-DC-7001. NCHS staff contributed to the overall design and conduct of the NHIS, but they were not involved in the analysis or interpretation of results in this manuscript. The findings and conclusions in this report are solely those of the authors and do not necessarily represent official views of the authors' respective Federal agency or university affiliations. NR 28 TC 2 Z9 2 U1 3 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD APR PY 2016 VL 171 BP 240 EP + DI 10.1016/j.jpeds.2015.12.002 PG 11 WC Pediatrics SC Pediatrics GA DH4KC UT WOS:000372753600049 PM 26826885 ER PT J AU Conway, KP Swendsen, J Husky, MM He, JP Merikangas, KR AF Conway, Kevin P. Swendsen, Joel Husky, Mathilde M. He, Jian-Ping Merikangas, Kathleen R. TI Association of Lifetime Mental Disorders and Subsequent Alcohol and Illicit Drug Use: Results From the National Comorbidity Survey-Adolescent Supplement SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE adolescence; alcohol use; comorbidity; drug use; epidemiology ID SUBSTANCE USE DISORDERS; 10-YEAR FOLLOW-UP; AGE-OF-ONSET; SURVEY REPLICATION; NCS-A; EPIDEMIOLOGIC SURVEY; SELF-MEDICATION; ANXIETY DISORDERS; UNITED-STATES; HEALTH SURVEY AB Objective: To estimate the association of prior lifetime mental disorders with transitions across stages of substance use in a cross-sectional, nationally representative sample of US adolescents. Method: The sample includes 10,123 adolescents aged 13 to 18 years who participated in the National Comorbidity Survey Adolescent Supplement (NCS-A), and who were directly interviewed with the Composite International Diagnostic Interview (CIDI) Version 3.0 that generates criteria for DSM-IV disorders. Results: Adolescents with prior lifetime mental disorders had high rates of both alcohol (10.3%) and illicit drug (14.9%) abuse, with or without dependence. Alcohol and drug abuse were highest among adolescents with prior anxiety disorders (17.3% and 20%, respectively) and behavior disorders (15.6% and 24%, respectively). Any prior disorder significantly increased the risk of transition from nonuse to first use, and from use to problematic use of either alcohol or illicit drugs. Multivariate models attenuated the magnitude of the risk of transition associated with each disorder, although prior weekly smoking and illicit drug use demonstrated significant risks of transitions across the 3 stages of alcohol or drug use, as did behavior disorders. Conclusion: The findings provide the first evidence from a nationally representative sample that prior mental disorders represent risk factors for the transition from nonuse to use, and the progression to drug-and alcohol-related problems. Treatment of primary mental disorders is likely to be an important target for the prevention of secondary substance use disorders in youth. C1 [Conway, Kevin P.] NIDA, Div Epidemiol Serv & Prevent Res, Rockville, MD USA. [Swendsen, Joel] Ecole Prat Hautes Etud, Paris, France. [Swendsen, Joel] CNRS, Paris, France. [Swendsen, Joel] Univ Bordeaux, Bordeaux, France. [Husky, Mathilde M.] Univ Paris 05, Paris, France. [He, Jian-Ping; Merikangas, Kathleen R.] NIMH, Genet Epidemiol Res Branch, Intramural Res Program, 35 Convent Dr,MSC 3720, Bethesda, MD 20892 USA. RP Merikangas, KR (reprint author), NIMH, Genet Epidemiol Res Branch, Intramural Res Program, 35 Convent Dr,MSC 3720, Bethesda, MD 20892 USA. EM merikank@mail.nih.gov OI Conway, Kevin/0000-0002-7638-339X FU Intramural Research Program of the National Institute of Mental Health [Z01MH002808-08]; National Institute of Mental Health [U01-MH60220] FX This work was supported by the Intramural Research Program of the National Institute of Mental Health (Z01MH002808-08). The National Comorbidity Survey Adolescent Supplement (NCS-A) and the larger program of related NCS surveys are supported by the National Institute of Mental Health (U01-MH60220). The views and opinions expressed in this article are those of the authors and should not be construed to represent the views of any of the sponsoring organizations, agencies, or US government. NR 49 TC 4 Z9 4 U1 11 U2 21 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD APR PY 2016 VL 55 IS 4 BP 280 EP 288 DI 10.1016/j.jaac.2016.01.006 PG 9 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA DI2HD UT WOS:000373315400006 PM 27015718 ER PT J AU Adler, M Ramm, S Hafner, M Muhlich, JL Gottwald, EM Weber, E Jaklic, A Ajay, AK Svoboda, D Auerbach, S Kelly, EJ Himmelfarb, J Vaidya, VS AF Adler, Melanie Ramm, Susanne Hafner, Marc Muhlich, Jeremy L. Gottwald, Esther Maria Weber, Elijah Jaklic, Alenka Ajay, Amrendra Kumar Svoboda, Daniel Auerbach, Scott Kelly, Edward J. Himmelfarb, Jonathan Vaidya, Vishal S. TI A Quantitative Approach to Screen for Nephrotoxic Compounds In Vitro SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID URINARY HEME OXYGENASE-1; PROXIMAL TUBULAR CELLS; ACUTE KIDNEY INJURY; PROBE LEVEL DATA; PRIMARY CULTURES; BIOMARKERS; TOXICITY; EXPRESSION; TRANSPORT; IDENTIFICATION AB Nephrotoxicity due to drugs and environmental chemicals accounts for significant patient mortality and morbidity, but there is no high throughput in vitro method for predictive nephrotoxicity assessment. We show that primary human proximal tubular epithelial cells (HPTECs) possess characteristics of differentiated epithelial cells rendering them desirable to use in such in vitro systems. To identify a reliable biomarker of nephrotoxicity, we conducted multiplexed gene expression profiling of HPTECs after exposure to six different concentrations of nine human nephrotoxicants. Only overexpression of the gene encoding heme oxygenase-1 (HO-1) significantly correlated with increasing dose for six of the compounds, and significant HO-1 protein deregulation was confirmed with each of the nine nephrotoxicants. Translatability of HO-1 increase across species and platforms was demonstrated by computationally mining two large rat toxicogenomic databases for kidney tubular toxicity and by observing a significant increase in HO-1 after toxicity using an ex vivo three-dimensional microphysiologic system (kidney on-a-chip). The predictive potential of HO-1 was tested using an additional panel of 39 mechanistically distinct nephrotoxic compounds. Although HO-1 performed better (area under the curve receiver-operator characteristic curve [AUC-ROC]=0.89) than traditional endpoints of cell viability (AUC-ROC for ATP=0.78; AUC-ROC for cell count=0.88), the combination of HO-1 and cell count further improved the predictive ability (AUC-ROC=0.92). We also developed and optimized a homogenous time-resolved fluorescence assay to allow high throughput quantitative screening of nephrotoxic compounds using HO-1 as a sensitive biomarker. This cell-based approach may facilitate rapid assessment of potential nephrotoxic therapeutics and environmental chemicals. C1 [Adler, Melanie; Ramm, Susanne; Hafner, Marc; Muhlich, Jeremy L.; Vaidya, Vishal S.] Harvard Univ, Sch Med, Lab Syst Pharmacol, Harvard Program Therapeut Sci, Boston, MA USA. [Adler, Melanie; Gottwald, Esther Maria; Ajay, Amrendra Kumar; Vaidya, Vishal S.] Brigham & Womens Hosp, Dept Med, Div Renal, Boston, MA 02115 USA. [Weber, Elijah; Jaklic, Alenka; Kelly, Edward J.] Univ Washington, Dept Pharmaceut, Seattle, WA 98195 USA. [Svoboda, Daniel] Social & Sci Syst, Durham, NC USA. [Auerbach, Scott] NIEHS, Natl Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. [Himmelfarb, Jonathan] Univ Washington, Dept Med, Kidney Res Inst, Seattle, WA USA. [Vaidya, Vishal S.] Harvard Univ, Dept Environm Hlth, TH Chan Sch Publ Hlth, Boston, MA USA. RP Vaidya, VS (reprint author), Harvard Inst Med, Rm 562,77 Ave Louis Pasteur, Boston, MA 02115 USA. EM vvaidya@bwh.harvard.edu OI Hafner, Marc/0000-0003-1337-7598; Ramm, Susanne/0000-0003-1108-5620 FU Colgate Palmolive Postdoctoral Fellowship Award through the Society of Toxicology; Swiss National Science Foundation [P300P3_147876]; Innovation in Regulatory Science Award from Burroughs Wellcome Fund; Regulatory Science Ignition Award from Harvard Program in Therapeutic Sciences at Harvard Medical School; Harvard-NIEHS Center for Environmental Health [P30ES000002]; National Institutes of Health (NIH) [UH3-TR000504]; NIH LINCS [U54-HG006097] FX M. Adler was supported by a Colgate Palmolive Postdoctoral Fellowship Award through the Society of Toxicology and M. Hafner was supported by the Swiss National Science Foundation (P300P3_147876).; This work in the Vaidya laboratory was supported by an Innovation in Regulatory Science Award from Burroughs Wellcome Fund, Regulatory Science Ignition Award from Harvard Program in Therapeutic Sciences at Harvard Medical School, a pilot project grant from the Harvard-NIEHS Center for Environmental Health (P30ES000002), National Institutes of Health (NIH) grant UH3-TR000504 and resources made available through the NIH LINCS grant U54-HG006097.; The authors appreciate the support of ICCB-Longwood facility at Harvard Medical School in training M. Adler and S. Ramm for compound library preparation and high throughput HO-1 cell staining.; The authors also appreciate the support of Harvard Catalyst, The Harvard Clinical and Translational Science Centre for statistical advice. NR 43 TC 6 Z9 6 U1 1 U2 11 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD APR PY 2016 VL 27 IS 4 BP 1015 EP 1028 DI 10.1681/ASN.2015010060 PG 14 WC Urology & Nephrology SC Urology & Nephrology GA DH8GW UT WOS:000373032500010 PM 26260164 ER PT J AU He, J Mills, KT Appel, LJ Yang, W Chen, J Lee, BT Rosas, SE Porter, A Makos, G Weir, MR Hamm, LL Kusektt, JW AF He, Jiang Mills, Katherine T. Appel, Lawrence J. Yang, Wei Chen, Jing Lee, Belinda T. Rosas, Sylvia E. Porter, Anna Makos, Gail Weir, Matthew R. Hamm, L. Lee Kusektt, John W. CA Chronic Renal Insufficiency Cohort TI Urinary Sodium and Potassium Excretion and CKD Progression SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CHRONIC RENAL-INSUFFICIENCY; CHRONIC KIDNEY-DISEASE; MODEST SALT REDUCTION; BLOOD-PRESSURE; DIETARY-SODIUM; CARDIOVASCULAR EVENTS; RISK-FACTORS; OUTCOMES; COHORT; METAANALYSIS AB CKD is a major risk factor for ESRD, cardiovascular disease, and premature death. Whether dietary sodium and potassium intake affect CKD progression remains unclear. We prospectively studied the association of urinary sodium and potassium excretion with CKD progression and all-cause mortality among 3939 patients with CKD in the Chronic Renal Insufficiency Cohort Study. Urinary sodium and potassium excretion were measured using three 24-hour urine specimens, and CKD progression was defined as incident ESRD or halving of eGFR. During follow-up, 939 CKD progression events and 540 deaths occurred. Compared with the lowest quartile of urinary sodium excretion (<116.8 mmol/24 h), hazard ratios (95% confidence intervals) for the highest quartile of urinary sodium excretion (>= 194.6 mmol/24 h) were 1.54 (1.23 to 1.92) for CKD progression, 1.45 (1.08 to 1.95) for all-cause mortality, and 1.43 (1.18 to 1.73) for the composite outcome of CKD progression and all-cause mortality after adjusting for multiple covariates, including baseline eGFR. Additionally, compared with the lowest quartile of urinary potassium excretion (<39.4 mmol/24 h), hazard ratios for the highest quartile of urinary potassium excretion (>= 67.1 mmol/24 h) were 1.59 (1.25 to 2.03) for CKD progression, 0.98 (0.71 to 1.35) for all-cause mortality, and 1.42 (1.15 to 1.74) for the composite outcome. These data indicate that high urinary sodium and potassium excretion are associated with increased risk of CKD progression. Clinical trials are warranted to test the effect of sodium and potassium reduction on CKD progression. C1 [He, Jiang; Mills, Katherine T.; Chen, Jing; Hamm, L. Lee] Tulane Univ, Dept Epidemiol, New Orleans, LA 70112 USA. [He, Jiang; Chen, Jing; Lee, Belinda T.; Hamm, L. Lee] Tulane Univ, Dept Med, New Orleans, LA 70112 USA. [Appel, Lawrence J.] Johns Hopkins Sch Med, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Yang, Wei; Rosas, Sylvia E.] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Porter, Anna] Univ Illinois, Coll Med, Dept Med, Chicago, IL USA. [Makos, Gail] St John Hosp & Med Ctr, Div Nephrol, Detroit, MI USA. [Weir, Matthew R.] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Kusektt, John W.] NIDDK, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD 20892 USA. RP He, J (reprint author), Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, 1440 Canal St,,Suite 2000, New Orleans, LA 70112 USA. EM jhe@tulane.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [R01-DK074615, U01-DK060990, U01-DK060984, U01-DK061022, U01-DK061021, U01-DK061028, U01-DK060980, U01-DK060963, U01-DK060902]; University of Pennsylvania Clinical and Translational Science Award National Institutes of Health (NIH)/National Center for Advancing Translational Sciences [UL1-TR000003]; Johns Hopkins University [UL1-TR000424]; University of Maryland [GCRC M01-RR16500]; Clinical and Translational Science Collaborative of Cleveland [UL1-TR000439]; Michigan Institute for Clinical and Health Research [UL1-TR000433]; University of Illinois at Chicago Grant CTSA [UL1-RR029879]; Tulane University Translational Research in Hypertension and Renal Biology [P30-GM103337]; Kaiser NIH/National Center for Research Resources Grant UCSF-CTSI [UL1-RR024131] FX This study was funded by National Institute of Diabetes and Digestive and Kidney Diseases Research Grant R01-DK074615. Funding for the Chronic Renal Insufficiency Cohort (CRIC) Study was obtained under a cooperative agreement with National Institute of Diabetes and Digestive and Kidney Diseases Grants U01-DK060990, U01-DK060984, U01-DK061022, U01-DK061021, U01-DK061028, U01-DK060980, U01-DK060963, and U01-DK060902. In addition, this work was supported, in part, by University of Pennsylvania Clinical and Translational Science Award National Institutes of Health (NIH)/National Center for Advancing Translational Sciences Grant UL1-TR000003, Johns Hopkins University Grant UL1-TR000424, University of Maryland Grant GCRC M01-RR16500, Clinical and Translational Science Collaborative of Cleveland Grant UL1-TR000439, Michigan Institute for Clinical and Health Research Grant UL1-TR000433, University of Illinois at Chicago Grant CTSA UL1-RR029879, Tulane University Translational Research in Hypertension and Renal Biology Grant P30-GM103337, and Kaiser NIH/National Center for Research Resources Grant UCSF-CTSI UL1-RR024131. NR 37 TC 13 Z9 13 U1 8 U2 12 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD APR PY 2016 VL 27 IS 4 BP 1202 EP 1212 DI 10.1681/ASN.2015010022 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA DH8GW UT WOS:000373032500025 PM 26382905 ER PT J AU Griffith, JW Stephens-Shields, AJ Hou, XL Naliboff, BD Pontari, M Edwards, TC Williams, DA Clemens, JQ Afari, N Tu, F Lloyd, RB Patrick, DL Mullins, C Kusek, JW Sutcliffe, S Hong, BA Lai, HH Krieger, JN Bradley, CS Kim, J Landis, JR AF Griffith, James W. Stephens-Shields, Alisa J. Hou, Xiaoling Naliboff, Bruce D. Pontari, Michel Edwards, Todd C. Williams, David A. Clemens, J. Quentin Afari, Niloofar Tu, Frank Lloyd, R. Brett Patrick, Donald L. Mullins, Chris Kusek, John W. Sutcliffe, Siobhan Hong, Barry A. Lai, H. Henry Krieger, John N. Bradley, Catherine S. Kim, Jayoung Landis, J. Richard TI Pain and Urinary Symptoms Should Not be Combined into a Single Score: Psychometric Findings from the MAPP Research Network SO JOURNAL OF UROLOGY LA English DT Article DE urinary bladder; prostatitis; cystitis, interstitial; chronic pain; factor analysis, statistical ID QUALITY-OF-LIFE; INTERSTITIAL CYSTITIS; PSYCHOLOGICAL-FACTORS; HOSPITAL ANXIETY; DEPRESSION SCALE; BLADDER; PREVALENCE; NUMBER; INDEX; MEN AB Purpose: The purpose of this study was to create symptom indexes, that is scores derived from questionnaires to accurately and efficiently measure symptoms of interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome, collectively referred to as urological chronic pelvic pain syndromes. We created these indexes empirically by investigating the structure of symptoms using exploratory factor analysis. Materials and Methods: As part of the MAPP (Multi-Disciplinary Approach to the Study of Chronic Pelvic Pain) Research Network 424 participants completed questionnaires, including GUPI (Genitourinary Pain Index), ICSI (Interstitial Cystitis Symptom Index) and ICPI (Interstitial Cystitis Problem Index). Individual items from questionnaires about bladder and pain symptoms were evaluated by principal component and exploratory factor analyses to identify indexes with fewer questions to comprehensively quantify symptom severity. Additional analyses included correlating symptom indexes with symptoms of depression, which is a known comorbidity of patients with pelvic pain. Results and Conclusions: Exploratory factor analyses suggested that the 2 factors pain severity and urinary severity provided the best psychometric description of items in GUPI, ICSI and ICPI. These factors were used to create 2 symptom indexes for pain and urinary symptoms. Pain, but not urinary symptoms, was associated with symptoms of depression on multiple regression analysis, suggesting that these symptoms may impact patients with urological chronic pelvic pain syndromes differently (B +/- SE for pain severity = 0.24 +/- 0.04, 95% CI 0.16-0.32, beta = 0.32, p < 0.001). Our results suggest that pain and urinary symptoms should be assessed separately rather than combined into 1 total score. Total scores that combine the separate factors of pain and urinary symptoms into 1 score may be limited for clinical and research purposes. C1 [Griffith, James W.; Lloyd, R. Brett] Northwestern Univ, Chicago, IL 60611 USA. [Tu, Frank] NorthShore Univ HealthSyst, Chicago, IL USA. [Tu, Frank] Univ Chicago, Chicago, IL 60637 USA. [Stephens-Shields, Alisa J.; Hou, Xiaoling; Landis, J. Richard] Univ Penn, Philadelphia, PA 19104 USA. [Pontari, Michel] Temple Univ, Philadelphia, PA 19122 USA. [Naliboff, Bruce D.] Univ Calif Los Angeles, Los Angeles, CA USA. [Kim, Jayoung] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Afari, Niloofar] Univ Calif San Diego, San Diego, CA 92103 USA. [Afari, Niloofar] Vet Affairs Ctr Excellence Stress & Mental Hlth, San Diego, CA USA. [Edwards, Todd C.; Krieger, John N.] Univ Washington, Seattle, WA 98195 USA. [Williams, David A.; Clemens, J. Quentin] Univ Michigan, Ann Arbor, MI 48109 USA. [Mullins, Chris; Kusek, John W.] NIDDK, NIH, Bethesda, MD 20892 USA. [Sutcliffe, Siobhan; Hong, Barry A.; Lai, H. Henry] Washington Univ, St Louis, MO USA. [Bradley, Catherine S.] Univ Iowa, Iowa City, IA USA. RP Griffith, JW (reprint author), Northwestern Univ, Med Social Sci, 633 North St Clair, Chicago, IL 60611 USA. EM j-griffith@northwestern.edu RI Griffith, James/O-2551-2016 OI Griffith, James/0000-0002-4840-8692 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH) [DK082370, DK082342, DK082315, DK082344, DK082325, DK082345, DK082333, DK082316, DK103260, DK103277, DK103271] FX Funding for the MAPP Research Network was obtained under a cooperative agreement from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Grants DK082370, DK082342, DK082315, DK082344, DK082325, DK082345, DK082333, DK082316, DK103260, DK103277 and DK103271. NR 30 TC 1 Z9 1 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD APR PY 2016 VL 195 IS 4 BP 949 EP 954 DI 10.1016/j.juro.2015.11.012 PN 1 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA DI3LW UT WOS:000373401200044 PM 26585679 ER PT J AU Kauffman, EC Lee, MJ Alarcon, SV Lee, S Hoang, AN Diaz, AW Chelluri, R Vourganti, S Trepel, JB Pinto, PA AF Kauffman, Eric C. Lee, Min-Jung Alarcon, Sylvia V. Lee, Sunmin Hoang, Anthony N. Diaz, Annerleim Walton Chelluri, Raju Vourganti, Srinivas Trepel, Jane B. Pinto, Peter A. TI Lack of Impact of Robotic Assisted Laparoscopic Radical Prostatectomy on Intraoperative Levels of Prostate Cancer Circulating Tumor Cells SO JOURNAL OF UROLOGY LA English DT Article DE prostatic neoplasms; neoplastic cells; circulating; prostatectomy; robotics; laparoscopy ID TOUCH ISOLATION TECHNIQUE; EFFLUENT VENOUS-BLOOD; LUNG-CANCER; SURGICAL MANIPULATION; COLORECTAL-CANCER; HEMATOGENOUS DISSEMINATION; HEPATOCELLULAR-CARCINOMA; MOLECULAR-DETECTION; PANCREATIC-CANCER; SURGERY AB Purpose: While the significance of circulating tumor cells in clinically localized cancer remains controversial, it has been reported that surgical tumor manipulation can increase circulating tumor cells, including during open prostatectomy. To our knowledge it is unknown whether this cell shedding also occurs during minimally invasive prostatectomy, which minimizes tumor palpation and uses earlier vascular control. We tested the impact of robotic assisted laparoscopic radical prostatectomy on intraoperative circulating tumor cell levels. Materials and Methods: Circulating tumor cell counts were compared in peripheral blood specimens from 25 patients treated with robotic assisted laparoscopic radical prostatectomy preoperatively vs intraoperatively after prostate excision, in addition to 11 healthy blood donors. Circulating tumor cell detection was performed using EpCAM immunomagnetic enrichment and multiparametric flow cytometry quantification of viable EpCAM positive/prostate specific membrane antigen positive/CD45 negative cells. Intraoperative cell counts and increases were tested in univariable analyses for associations with perioperative variables, histopathology and postoperative progression. Results: Circulating tumor cells were detected in 0% of healthy controls compared to 48% and 52% of prostatectomy cases preoperatively and intraoperatively, respectively (range 1 to 8 cells). There was no difference in the incidence or mean number of circulating tumor cells preoperatively vs intraoperatively. Of the patients 60% had no intraoperative change from preoperative levels. Intraoperative cell increases vs decreases were equally infrequent (each 20%) with no intraoperative increase greater than 1 circulating tumor cell. Intraoperative circulating tumor cell detection was not significantly associated with prostatectomy operative characteristics, histopathology or early postoperative progression at a median 21-month followup. Conclusions: Robotic assisted laparoscopic radical prostatectomy does not cause significant intraoperative increases in circulating tumor cells in contrast to historical reports of open prostatectomy. These findings may aid urologists in counseling candidates for robotic assisted laparoscopic radical prostatectomy regarding the possibility of intraoperative tumor cell shedding. C1 [Kauffman, Eric C.; Hoang, Anthony N.; Diaz, Annerleim Walton; Chelluri, Raju; Vourganti, Srinivas; Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Lee, Min-Jung; Alarcon, Sylvia V.; Lee, Sunmin; Trepel, Jane B.] NCI, Dev Therapeut Branch, NIH, Bethesda, MD 20892 USA. [Kauffman, Eric C.] Roswell Pk Canc Inst, Dept Urol, Elm & Carlton Sts, Buffalo, NY 14263 USA. [Kauffman, Eric C.] Roswell Pk Canc Inst, Dept Canc Genet, Buffalo, NY 14263 USA. [Vourganti, Srinivas] SUNY Upstate Med Univ, Dept Urol, Syracuse, NY 13210 USA. RP Kauffman, EC (reprint author), Roswell Pk Canc Inst, Dept Urol, Elm & Carlton Sts, Buffalo, NY 14263 USA.; Kauffman, EC (reprint author), Roswell Pk Canc Inst, Dept Canc Genet, Buffalo, NY 14263 USA. EM Eric.Kauffman@RoswellPark.org NR 30 TC 3 Z9 3 U1 5 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD APR PY 2016 VL 195 IS 4 BP 1136 EP 1142 DI 10.1016/j.juro.2015.11.013 PN 1 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA DI3LW UT WOS:000373401200111 PM 26581128 ER PT J AU Souza, ACP Bocharov, AV Baranova, IN Vishnyakova, TG Huang, YNG Wilkins, KJ Hu, XZ Street, JM Alvarez-Prats, A Mullick, AE Patterson, AP Remaley, AT Eggerman, TL Yuen, PST Star, RA AF Souza, Ana Carolina P. Bocharov, Alexander V. Baranova, Irina N. Vishnyakova, Tatyana G. Huang, Yuning G. Wilkins, Kenneth J. Hu, Xuzhen Street, Jonathan M. Alvarez-Prats, Alejandro Mullick, Adam E. Patterson, Amy P. Remaley, Alan T. Eggerman, Thomas L. Yuen, Peter S. T. Star, Robert A. TI Antagonism of scavenger receptor CD36 by 5A peptide prevents chronic kidney disease progression in mice independent of blood pressure regulation SO KIDNEY INTERNATIONAL LA English DT Article DE albuminuria; glomerulosclerosis; inflammasome; inflammation; interstitial fibrosis; remnant kidney model; telemetry ID NLRP3 INFLAMMASOME ACTIVATION; FIBROBLAST GROWTH FACTOR-23; CHRONIC-RENAL-FAILURE; CARDIOVASCULAR-DISEASE; GENE-EXPRESSION; OXIDIZED PHOSPHOLIPIDS; CHOLESTEROL EFFLUX; METABOLIC SYNDROME; A-I/II; ATHEROSCLEROSIS AB Scavenger receptor CD36 participates in lipid metabolism and inflammatory pathways important for cardiovascular disease and chronic kidney disease (CKD). Few pharmacological agents are available to slow the progression of CKD. However, apolipoprotein A-I-mimetic peptide 5A antagonizes CD36 in vitro. To test the efficacy of 5A, and to test the role of CD36 during CKD, we compared wild-type to CD36 knockout mice and wild-type mice treated with 5A, in a progressive CKD model that resembles human disease. Knockout and 5A-treated wildtype mice were protected from CKD progression without changes in blood pressure and had reductions in cardiovascular risk surrogate markers that are associated with CKD. Treatment with 5A did not further protect CD36 knockout mice from CKD progression, implicating CD36 as its main site of action. In a separate model of kidney fibrosis, 5A-treated wild-type mice had less macrophage infiltration and interstitial fibrosis. Peptide 5A exerted anti-inflammatory effects in the kidney and decreased renal expression of inflammasome genes. Thus, CD36 is a new therapeutic target for CKD and its associated cardiovascular risk factors. Peptide 5A may be a promising new agent to slow CKD progression. C1 [Souza, Ana Carolina P.; Huang, Yuning G.; Hu, Xuzhen; Street, Jonathan M.; Alvarez-Prats, Alejandro; Yuen, Peter S. T.; Star, Robert A.] Natl Inst Diabet & Digest & Kidney Dis NIDDK, Renal Diagnost & Therapeut Unit, NIH, Bethesda, MD USA. [Bocharov, Alexander V.; Baranova, Irina N.; Vishnyakova, Tatyana G.; Patterson, Amy P.; Eggerman, Thomas L.] NIH, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Wilkins, Kenneth J.] NIDDK, Biostat Program, NIH, Bethesda, MD 20892 USA. [Mullick, Adam E.] ISIS Pharmaceut, 2280 Faraday Ave, Carlsbad, CA 92008 USA. [Patterson, Amy P.] NIH, Off Director, Bldg 10, Bethesda, MD 20892 USA. [Remaley, Alan T.] NHLBI, Lipoprotein Metab Sect, NIH, Bldg 10, Bethesda, MD 20892 USA. [Eggerman, Thomas L.] NIDDK, Div Diabet Endocrinol & Metab Dis, NIH, Bethesda, MD 20892 USA. RP Star, RA (reprint author), NIDDK, Div Kidney Urol & Hematol Dis, NIH, 6707 Democracy Blvd,Room 625, Bethesda, MD 20892 USA. EM starr@niddk.nih.gov RI Yuen, Peter/B-1954-2008 OI Yuen, Peter/0000-0001-9557-3909 FU Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute; Clinical Center FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute; and Clinical Center. NR 50 TC 4 Z9 5 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 EI 1523-1755 J9 KIDNEY INT JI Kidney Int. PD APR PY 2016 VL 89 IS 4 BP 809 EP 822 DI 10.1016/j.kint.2015.12.043 PG 14 WC Urology & Nephrology SC Urology & Nephrology GA DH1CD UT WOS:000372521100013 PM 26994575 ER PT J AU Schmeltzer, PA Kosinski, AS Kleiner, DE Hoofnagle, JH Stolz, A Fontana, RJ Russo, MW AF Schmeltzer, Paul A. Kosinski, Andrzej S. Kleiner, David E. Hoofnagle, Jay H. Stolz, Andrew Fontana, Robert J. Russo, Mark W. CA Drug-Induced Liver Injury Network TI Liver injury from nonsteroidal anti-inflammatory drugs in the United States SO LIVER INTERNATIONAL LA English DT Article DE diclofenac; hepatotoxicity; medication; nonsteroidal ID ARTHRITIS PATIENTS; HEPATOTOXICITY; POPULATION; TOXICITY; OUTCOMES AB Background & Aims: Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used and have been associated with hepatotoxicity. Studies of liver injury from NSAIDs have been retrospective and prospective data are lacking. The aim was to report the features and outcomes of the subjects with severe drug-induced liver injury from NSAIDS. Methods: The U.S. Drug Induced Liver Injury Network is a prospective registry of idiosyncratic drug hepatotoxicity. All patients are evaluated in a standard fashion and followed up for at least 6 months. Results: Of 1221 Drug Induced Liver Injury Network cases that were adjudicated, 30 cases were attributed to eight different NSAIDs. The mean age was 52 years old, 24 (80%) were women, and 21 (70%) were Caucasian. The mean latency was 67 days. Common signs and symptoms at presentation were nausea (73%), jaundice (67%) and dark urine (67%). Mean peak serum aspartate aminotransferase, alanine aminotransferase, total bilirubin and alkaline phosphatase were 898 U/L, 1060 U/L, 12.2 mg/dl and 326 U/L. The most common pattern of injury was hepatocellular (70%) and autoantibodies were detected in 33% of cases. Diclofenac, was the most frequently implicated NSAID (16/30 cases), and characterized by hepatocellular injury. Seventeen cases resulted in hospitalization or prolongation of hospitalization and one patient died from complications of Stevens-Johnson syndrome because of diclofenac. Conclusions: Hepatocellular injury is the most common pattern seen with NSAID hepatotoxicity, and diclofenac is the most frequently implicated agent. Given the number of NSAID alternatives, diclofenac should be reserved for patients who fail other NSAIDs and a high level of suspicion for hepatotoxicity should be maintained. C1 [Schmeltzer, Paul A.; Russo, Mark W.] Carolinas Med Ctr, Div Hepatol, Charlotte, NC 28204 USA. [Kosinski, Andrzej S.] Duke Univ, Duke Clin Res Inst, Durham, NC USA. [Kleiner, David E.; Hoofnagle, Jay H.] NIDDK, NIH, Bethesda, MD 20892 USA. [Stolz, Andrew] Univ So Calif, Div Gastrointestinal & Liver Dis, Los Angeles, CA USA. [Fontana, Robert J.] Univ Michigan, Sch Med, Dept Med, Ann Arbor, MI 48104 USA. RP Russo, MW (reprint author), Carolinas Med Ctr, Transplant Ctr, 6th Floor Morehead Med Plaza,1025 Morehead Med Dr, Charlotte, NC 28204 USA. EM mark.russo@carolinashealthcare.org FU NIDDK, NIH FX Study supported by NIDDK, NIH. See DILIN website https://dilin.dcri.duke.edu/publications-1 for a complete listing of funding sources, sites, investigators, co-investigators, coordinators, and staff. NR 20 TC 1 Z9 2 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1478-3223 EI 1478-3231 J9 LIVER INT JI Liver Int. PD APR PY 2016 VL 36 IS 4 BP 603 EP 609 DI 10.1111/liv.13032 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DH9NH UT WOS:000373122300019 PM 26601797 ER PT J AU Sabatino, SA Thompson, TD Guy, GP de Moor, JS Tangka, FK AF Sabatino, Susan A. Thompson, Trevor D. Guy, Gery P., Jr. de Moor, Janet S. Tangka, Florence K. TI Mammography Use Among Medicare Beneficiaries After Elimination of Cost Sharing SO MEDICAL CARE LA English DT Article DE cost sharing; early detection of cancer; Medicare; mammography ID TASK-FORCE RECOMMENDATIONS; PREVENTIVE SERVICES; COLORECTAL CANCERS; UNITED-STATES; BREAST-CANCER; HEALTH PLANS; CARE; COVERAGE; WOMEN; INTERVENTIONS AB Background: We examined mammography use before and after Medicare eliminated cost sharing for screening mammography in January 2011. Methods: Using National Health Interview Survey data, we examined changes in mammography use between 2010 and 2013 among Medicare beneficiaries aged 65-74 years. Logistic regression and predictive margins were used to examine changes in use after adjusting for covariates. Results: In 2013, 74.7% of women reported a mammogram within 2 years, a 3.5 percentage point increase (95% confidence interval, -0.3, 7.2) compared with 2010. Increases occurred among women aged 65-69 years, unmarried women, and women with usual sources of care and 2-5 physician visits in the prior year. After adjustment, mammography use increased in 2013 versus 2010 (74.8% vs. 71.3%, P=0.039). Interactions between year and income, insurance, race, or ethnicity were not significant. Conclusions: There was a modest increase in mammography use from 2010 to 2013 among Medicare beneficiaries aged 65-74 years, possibly consistent with an effect of eliminating Medicare cost sharing during this time. Findings suggest that eliminating cost sharing might increase use of recommended screening services. C1 [Sabatino, Susan A.; Thompson, Trevor D.; Guy, Gery P., Jr.; Tangka, Florence K.] Ctr Dis Control & Prevent, Div Canc Prevent & Control, 4770 Buford Highway F-76, Atlanta, GA 30341 USA. [de Moor, Janet S.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Sabatino, SA (reprint author), Ctr Dis Control & Prevent, Div Canc Prevent & Control, 4770 Buford Highway F-76, Atlanta, GA 30341 USA. EM ssabatino@cdc.gov FU US government FX The National Health Interview Survey and manuscript preparation were funded by the US government. NR 34 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD APR PY 2016 VL 54 IS 4 BP 394 EP 399 DI 10.1097/MLR.0000000000000495 PG 6 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA DH6XK UT WOS:000372935200009 PM 26759983 ER PT J AU Swaminathan, V Fischer, RS Waterman, CM AF Swaminathan, Vinay Fischer, R. S. Waterman, Clare M. TI The FAK-Arp2/3 interaction promotes leading edge advance and haptosensing by coupling nascent adhesions to lamellipodia actin SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID CELL-MIGRATION; FOCAL ADHESIONS; ARP2/3 COMPLEX; PAXILLIN PHOSPHORYLATION; KINASE; FAK; DYNAMICS; MOTILITY; FLOW; RECRUITMENT AB Cell migration is initiated in response to biochemical or physical cues in the environment that promote actin-mediated lamellipodial protrusion followed by the formation of nascent integrin adhesions (NAs) within the protrusion to drive leading edge advance. Although FAK is known to be required for cell migration through effects on focal adhesions, its role in NA formation and lamellipodial dynamics is unclear. Live-cell microscopy of FAK(-/-) cells with expression of phosphorylation deficient or a FERM-domain mutant deficient in Arp2/3 binding revealed a requirement for FAK in promoting the dense formation, transient stabilization, and timely turnover of NA within lamellipodia to couple actin-driven protrusion to adhesion and advance of the leading edge. Phosphorylation on Y397 of FAK promotes dense NA formation but is dispensable for transient NA stabilization and leading edge advance. In contrast, transient NA stabilization and advance of the cell edge requires FAK-Arp2/3 interaction, which promotes Arp2/3 localization to NA and reduces FAK activity. Haptosensing of extracellular matrix (ECM) concentration during migration requires the interaction between FAK and Arp2/3, whereas FAK phosphorylation modulates mechanosensing of ECM stiffness during spreading. Taken together, our results show that mechanistically separable functions of FAK in NA are required for cells to distinguish distinct properties of their environment during migration. C1 [Swaminathan, Vinay; Fischer, R. S.; Waterman, Clare M.] NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Waterman, CM (reprint author), NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM watermancm@nhlbi.nih.gov FU Division of Intramural Research, National Heart, Lung and Blood Institute, National Institutes of Health FX We thank Dave Schlaepfer for the kind gift of FAK-/- and FAK+/+ fibroblasts, members of the Waterman Lab for helpful discussion, Bill Shin for maintenance of the microscopes, and Schwanna Thacker for administrative assistance. This work was supported by the Division of Intramural Research, National Heart, Lung and Blood Institute, National Institutes of Health. NR 48 TC 7 Z9 7 U1 1 U2 5 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD APR 1 PY 2016 VL 27 IS 7 BP 1085 EP 1100 DI 10.1091/mbc.E15-08-0590 PG 16 WC Cell Biology SC Cell Biology GA DH7JZ UT WOS:000372971100004 PM 26842895 ER PT J AU Dunning, AM Michailidou, K Kuchenbaecker, KB Thompson, D French, JD Beesley, J Healey, CS Kar, S Pooley, KA Lopez-Knowles, E Dicks, E Barrowdale, D Sinnott-Armstrong, NA Sallari, RC Hillman, KM Kaufmann, S Sivakumaran, H Marjaneh, MM Lee, JS Hills, M Jarosz, M Drury, S Canisius, S Bolla, MK Dennis, J Wang, Q Hopper, JL Southey, MC Broeks, A Schmidt, MK Lophatananon, A Muir, K Beckmann, MW Fasching, PA dos-Santos-Silva, I Peto, J Sawyer, EJ Tomlinson, I Burwinkel, B Marme, F Guenel, P Truong, T Bojesen, SE Flyger, H Gonzalez-Neira, A Perez, JIA Anton-Culver, H Eunjung, L Arndt, V Brenner, H Meindl, A Schmutzler, RK Brauch, H Hamann, U Aittomaki, K Blomqvist, C Ito, H Matsuo, K Bogdanova, N Dork, T Lindblom, A Margolin, S Kosma, VM Mannermaa, A Tseng, CC Wu, AH Lambrechts, D Wildiers, H Chang-Claude, J Rudolph, A Peterlongo, P Radice, P Olson, JE Giles, GG Milne, RL Haiman, CA Henderson, BE Goldberg, MS Teo, SH Yip, CH Nord, S Borresen-Dale, AL Kristensen, V Long, J Zheng, W Pylkas, K Winqvist, R Andrulis, IL Knight, JA Devilee, P Seynaeve, C Figueroa, J Sherman, ME Czene, K Darabi, H Hollestelle, A van den Ouweland, AMW Humphreys, K Gao, YT Shu, XO Cox, A Cross, SS Blot, W Cai, Q Ghoussaini, M Perkins, BJ Shah, M Choi, JY Kang, D Lee, SC Hartman, M Kabisch, M Torres, D Jakubowska, A Lubinski, J Brennan, P Sangrajrang, S Ambrosone, CB Toland, AE Shen, CY Wu, PE Orr, N Swerdlow, A McGuffog, L Healey, S Lee, A Kapuscinski, M John, EM Terry, MB Daly, MB Goldgar, DE Buys, SS Janavicius, R Tihomirova, L Tung, N Dorfling, CM van Rensburg, EJ Neuhausen, SL Ejlertsen, B Hansen, TVO Osorio, A Benitez, J Rando, R Weitzel, JN Bonanni, B Peissel, B Manoukian, S Papi, L Ottini, L Konstantopoulou, I Apostolou, P Garber, J Rashid, MU Frost, D Izatt, L Ellis, S Godwin, AK Arnold, N Niederacher, D Rhiem, K Bogdanova-Markov, N Sagne, C Stoppa-Lyonnet, D Damiola, F Sinilnikova, OM Mazoyer, S Isaacs, C Claes, KBM De Leeneer, K De la Hoya, M Caldes, T Nevanlinna, H Khan, S Mensenkamp, AR Hooning, MJ Rookus, MA Kwong, A Olah, E Diez, O Brunet, J Pujana, MA Gronwald, J Huzarski, T Barkardottir, RB Laframboise, R Soucy, P Montagna, M Agata, S Teixeira, MR Park, SK Lindor, N Couch, FJ Tischkowitz, M Foretova, L Vijai, J Offit, K Singer, CF Rappaport, C Phelan, CM Greene, MH Mai, PL Rennert, G Imyanitov, EN Hulick, PJ Phillips, KA Piedmonte, M Mulligan, AM Glendon, G Bojesen, A Thomassen, M Caligo, MA Yoon, SY Friedman, E Laitman, Y Borg, A Von Wachenfeldt, A Ehrencrona, H Rantala, J Olopade, OI Ganz, PA Nussbaum, RL Gayther, SA Nathanson, KL Domchek, SM Arun, BK Mitchell, G Karlan, BY Lester, J Maskarinec, G Woolcott, C Scott, C Stone, J Apicella, C Tamimi, R Luben, R Khaw, KT Helland, A Haakensen, V Dowsett, M Pharoah, PDP Simard, J Hall, P Garcia-Closas, M Vachon, C Chenevix-Trench, G Antoniou, AC Easton, DF Edwards, SL AF Dunning, Alison M. Michailidou, Kyriaki Kuchenbaecker, Karoline B. Thompson, Deborah French, Juliet D. Beesley, Jonathan Healey, Catherine S. Kar, Siddhartha Pooley, Karen A. Lopez-Knowles, Elena Dicks, Ed Barrowdale, Daniel Sinnott-Armstrong, Nicholas A. Sallari, Richard C. Hillman, Kristine M. Kaufmann, Susanne Sivakumaran, Haran Marjaneh, Mahdi Moradi Lee, Jason S. Hills, Margaret Jarosz, Monika Drury, Suzie Canisius, Sander Bolla, Manjeet K. Dennis, Joe Wang, Qin Hopper, John L. Southey, Melissa C. Broeks, Annegien Schmidt, Marjanka K. Lophatananon, Artitaya Muir, Kenneth Beckmann, Matthias W. Fasching, Peter A. dos-Santos-Silva, Isabel Peto, Julian Sawyer, Elinor J. Tomlinson, Ian Burwinkel, Barbara Marme, Frederik Guenel, Pascal Truong, Therese Bojesen, Stig E. Flyger, Henrik Gonzalez-Neira, Anna Perez, Jose I. A. Anton-Culver, Hoda Eunjung, Lee Arndt, Volker Brenner, Hermann Meindl, Alfons Schmutzler, Rita K. Brauch, Hiltrud Hamann, Ute Aittomaki, Kristiina Blomqvist, Carl Ito, Hidemi Matsuo, Keitaro Bogdanova, Natasha Dork, Thilo Lindblom, Annika Margolin, Sara Kosma, Veli-Matti Mannermaa, Arto Tseng, Chiu-chen Wu, Anna H. Lambrechts, Diether Wildiers, Hans Chang-Claude, Jenny Rudolph, Anja Peterlongo, Paolo Radice, Paolo Olson, Janet E. Giles, Graham G. Milne, Roger L. Haiman, Christopher A. Henderson, Brian E. Goldberg, Mark S. Teo, Soo H. Yip, Cheng Har Nord, Silje Borresen-Dale, Anne-Lise Kristensen, Vessela Long, Jirong Zheng, Wei Pylkas, Katri Winqvist, Robert Andrulis, Irene L. Knight, Julia A. Devilee, Peter Seynaeve, Caroline Figueroa, Jonine Sherman, Mark E. Czene, Kamila Darabi, Hatef Hollestelle, Antoinette van den Ouweland, Ans M. W. Humphreys, Keith Gao, Yu-Tang Shu, Xiao-Ou Cox, Angela Cross, Simon S. Blot, William Cai, Qiuyin Ghoussaini, Maya Perkins, Barbara J. Shah, Mitul Choi, Ji-Yeob Kang, Daehee Lee, Soo Chin Hartman, Mikael Kabisch, Maria Torres, Diana Jakubowska, Anna Lubinski, Jan Brennan, Paul Sangrajrang, Suleeporn Ambrosone, Christine B. Toland, Amanda E. Shen, Chen-Yang Wu, Pei-Ei Orr, Nick Swerdlow, Anthony McGuffog, Lesley Healey, Sue Lee, Andrew Kapuscinski, Miroslav John, Esther M. Terry, Mary Beth Daly, Mary B. Goldgar, David E. Buys, Saundra S. Janavicius, Ramunas Tihomirova, Laima Tung, Nadine Dorfling, Cecilia M. van Rensburg, Elizabeth J. Neuhausen, Susan L. Ejlertsen, Bent Hansen, Thomas V. O. Osorio, Ana Benitez, Javier Rando, Rachel Weitzel, Jeffrey N. Bonanni, Bernardo Peissel, Bernard Manoukian, Siranoush Papi, Laura Ottini, Laura Konstantopoulou, Irene Apostolou, Paraskevi Garber, Judy Rashid, Muhammad Usman Frost, Debra Izatt, Louise Ellis, Steve Godwin, Andrew K. Arnold, Norbert Niederacher, Dieter Rhiem, Kerstin Bogdanova-Markov, Nadja Sagne, Charlotte Stoppa-Lyonnet, Dominique Damiola, Francesca Sinilnikova, Olga M. Mazoyer, Sylvie Isaacs, Claudine Claes, Kathleen B. M. De Leeneer, Kim De la Hoya, Miguel Caldes, Trinidad Nevanlinna, Heli Khan, Sofia Mensenkamp, Arjen R. Hooning, Maartje J. Rookus, Matti A. Kwong, Ava Olah, Edith Diez, Orland Brunet, Joan Pujana, Miquel Angel Gronwald, Jacek Huzarski, Tomasz Barkardottir, Rosa B. Laframboise, Rachel Soucy, Penny Montagna, Marco Agata, Simona Teixeira, Manuel R. Park, Sue Kyung Lindor, Noralane Couch, Fergus J. Tischkowitz, Marc Foretova, Lenka Vijai, Joseph Offit, Kenneth Singer, Christian F. Rappaport, Christine Phelan, Catherine M. Greene, Mark H. Mai, Phuong L. Rennert, Gad Imyanitov, Evgeny N. Hulick, Peter J. Phillips, Kelly-Anne Piedmonte, Marion Mulligan, Anna Marie Glendon, Gord Bojesen, Anders Thomassen, Mads Caligo, Maria A. Yoon, Sook-Yee Friedman, Eitan Laitman, Yael Borg, Ake Von Wachenfeldt, Anna Ehrencrona, Hans Rantala, Johanna Olopade, Olufunmilayo I. Ganz, Patricia A. Nussbaum, Robert L. Gayther, Simon A. Nathanson, Katherine L. Domchek, Susan M. Arun, Banu K. Mitchell, Gillian Karlan, Beth Y. Lester, Jenny Maskarinec, Gertraud Woolcott, Christy Scott, Christopher Stone, Jennifer Apicella, Carmel Tamimi, Rulla Luben, Robert Khaw, Kay-Tee Helland, Aslaug Haakensen, Vilde Dowsett, Mitch Pharoah, Paul D. P. Simard, Jacques Hall, Per Garcia-Closas, Montserrat Vachon, Celine Chenevix-Trench, Georgia Antoniou, Antonis C. Easton, Douglas F. Edwards, Stacey L. CA EMBRACE GEMO Study Collaborators HEBON KConFab Investigators TI Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170 SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; BRCA2 MUTATION CARRIERS; BONE-MINERAL DENSITY; MAMMOGRAPHIC DENSITY; SUSCEPTIBILITY LOCUS; METAANALYSIS; EXPRESSION; MODIFIERS; REVEALS; DISEASE AB We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor a) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER+ or ER-) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER-tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression. C1 [Dunning, Alison M.; Healey, Catherine S.; Kar, Siddhartha; Dicks, Ed; Ghoussaini, Maya; Perkins, Barbara J.; Shah, Mitul; Pharoah, Paul D. P.; Easton, Douglas F.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. [Michailidou, Kyriaki; Kuchenbaecker, Karoline B.; Thompson, Deborah; Pooley, Karen A.; Barrowdale, Daniel; Bolla, Manjeet K.; Dennis, Joe; Wang, Qin; McGuffog, Lesley; Lee, Andrew; Frost, Debra; Ellis, Steve; Pharoah, Paul D. P.; Antoniou, Antonis C.; Easton, Douglas F.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [French, Juliet D.; Beesley, Jonathan; Hillman, Kristine M.; Kaufmann, Susanne; Sivakumaran, Haran; Marjaneh, Mahdi Moradi; Lee, Jason S.; Healey, Sue; Chenevix-Trench, Georgia; Edwards, Stacey L.] QIMR Berghofer Med Res Inst, Canc Div, Brisbane, Qld, Australia. [Lopez-Knowles, Elena; Jarosz, Monika; Drury, Suzie; Dowsett, Mitch] Breakthrough Breast Canc Res Ctr, Breast Canc Res, London, England. [Lopez-Knowles, Elena; Hills, Margaret; Jarosz, Monika; Drury, Suzie; Dowsett, Mitch] Royal Marsden Hosp, Acad Biochem, London SW3 6JJ, England. [Sinnott-Armstrong, Nicholas A.] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA. [Sallari, Richard C.] MIT, Comp Sci & Artificial Intelligence Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Canisius, Sander; Broeks, Annegien; Schmidt, Marjanka K.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands. [Hopper, John L.; Giles, Graham G.; Milne, Roger L.; Apicella, Carmel] Univ Melbourne, Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, Melbourne, Vic, Australia. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia. [Lophatananon, Artitaya; Muir, Kenneth] Univ Warwick, Warwick Med Sch, Div Hlth Sci, Coventry CV4 7AL, W Midlands, England. [Muir, Kenneth] Univ Manchester, Inst Populat Hlth, Manchester, Lancs, England. [Beckmann, Matthias W.; Fasching, Peter A.] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Dept Gynecol & Obstet, Comprehens Canc Ctr Erlangen Nuremberg Metropolit, D-91054 Erlangen, Germany. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Div Hematol & Oncol, Dept Med, Los Angeles, CA 90095 USA. [dos-Santos-Silva, Isabel; Peto, Julian] London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London WC1, England. [Sawyer, Elinor J.] Kings Coll London, Guys Hosp, Div Canc Studies, Res Oncol, London, England. [Tomlinson, Ian] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Tomlinson, Ian] Univ Oxford, Oxford Biomed Res Ctr, Oxford, England. [Burwinkel, Barbara] German Canc Res Ctr, Div Mol Genet Epidemiol, Heidelberg, Germany. [Burwinkel, Barbara] German Canc Res Ctr, Mol Epidemiol Grp, Heidelberg, Germany. [Marme, Frederik] Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany. [Marme, Frederik] Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany. [Guenel, Pascal; Truong, Therese] INSERM, Ctr Res Epidemiol & Populat Hlth, Environm Epidemiol Canc, Villejuif, France. [Guenel, Pascal; Truong, Therese] Univ Paris Sud, Villejuif, France. [Bojesen, Stig E.] Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, Herlev, Denmark. [Bojesen, Stig E.] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Herlev, Denmark. [Bojesen, Stig E.] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark. 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[Ambrosone, Christine B.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Toland, Amanda E.] Ohio State Univ, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. [Shen, Chen-Yang] China Med Univ, Sch Publ Hlth, Taichung, Taiwan. [Shen, Chen-Yang; Wu, Pei-Ei] Acad Sinica, Inst Biomed Sci, Taiwan Biobank, Taipei, Taiwan. [Orr, Nick; Garcia-Closas, Montserrat] Inst Canc Res, Breakthrough Breast Canc Res Ctr, Div Canc Studies, London SW3 6JB, England. [Swerdlow, Anthony; Garcia-Closas, Montserrat] Inst Canc Res, Div Genet & Epidemiol, London SW3 6JB, England. [Swerdlow, Anthony] Inst Canc Res, Div Breast Canc Res, London SW3 6JB, England. [Kapuscinski, Miroslav] Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia. [John, Esther M.] Canc Prevent Inst Calif, Dept Epidemiol, Fremont, CA USA. [Terry, Mary Beth] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY USA. [Daly, Mary B.] Fox Chase Canc Ctr, Dept Clin Genet, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Goldgar, David E.] Univ Utah, Sch Med, Dept Dermatol, Huntsman Canc Inst, Salt Lake City, UT USA. [Buys, Saundra S.] Univ Utah, Sch Med, Dept Med, Huntsman Canc Inst, Salt Lake City, UT USA. [Janavicius, Ramunas] State Res Inst Ctr Innovat Med, Vilnius, Lithuania. [Tihomirova, Laima] Latvian Biomed Res & Study Ctr, Riga, Latvia. [Tung, Nadine] Beth Israel Deaconess Med Ctr, Dept Med Oncol, Boston, MA 02215 USA. [Dorfling, Cecilia M.; van Rensburg, Elizabeth J.] Univ Pretoria, Dept Genet, ZA-0002 Pretoria, South Africa. [Neuhausen, Susan L.] Beckman Res Inst City Hope, Dept Populat Sci, Duarte, CA USA. [Ejlertsen, Bent] Copenhagen Univ Hosp, Rigshosp, Dept Oncol, Copenhagen, Denmark. [Hansen, Thomas V. O.] Copenhagen Univ Hosp, Rigshosp, Ctr Genom Med, Copenhagen, Denmark. [Osorio, Ana; Benitez, Javier] Spanish Natl Canc Ctr CNIO, Human Genet Grp, Madrid, Spain. [Osorio, Ana; Benitez, Javier] Biomed Network Rare Dis CIBERER, Madrid, Spain. [Benitez, Javier] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Program, Human Genotyping CEGEN Unit, Madrid, Spain. [Rando, Rachel] City Hope Clin Canc Genom Community Res Network, Duarte, CA USA. [Weitzel, Jeffrey N.] City Hope Natl Med Ctr, Clin Canc Genet, Duarte, CA USA. [Bonanni, Bernardo] Ist Europeo Oncol, Div Canc Prevent & Genet, Milan, Italy. [Peissel, Bernard; Manoukian, Siranoush] Ist Nazl Tumori, Fdn Ist Ricovero & Cura Carattere Sci, Dept Prevent & Predict Med, Unit Med Genet, Via Venezian 1, I-20133 Milan, Italy. [Papi, Laura] Univ Florence, Dept Biomed Expt & Clin Sci, Unit Med Genet, Florence, Italy. [Ottini, Laura] Univ Roma La Sapienza, Dept Mol Med, Piazzale Aldo Moro 5, I-00185 Rome, Italy. [Konstantopoulou, Irene; Apostolou, Paraskevi] Aghia Paraskevi Attikis, Natl Ctr Sci Res Demokritos, INRASTES Inst Nucl & Radiol Sci & Technol, Mol Diagnost Lab, Athens, Greece. [Garber, Judy] Dana Farber Canc Inst, Canc Risk & Prevent Clin, Boston, MA 02115 USA. [Rashid, Muhammad Usman] Shaukat Khanum Mem Canc Hosp & Res Ctr, Dept Basic Sci, Lahore, Pakistan. [Izatt, Louise] Guys & St Thomas Natl Hlth Serv NHS Fdn Trust, Clin Genet, London, England. [Godwin, Andrew K.] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66103 USA. [Arnold, Norbert] Univ Kiel, Univ Hosp Schleswig Holstein, Dept Gynaecol & Obstet, Campus Kiel, Kiel, Germany. [Niederacher, Dieter] Univ Dusseldorf, Dusseldorf, Germany. [Rhiem, Kerstin] Univ Hosp Cologne, Ctr Mol Med Cologne, Dept Obstet & Gynaecol, Ctr Familial Breast & Ovarian Canc, Cologne, Germany. [Rhiem, Kerstin] Univ Hosp Cologne, Ctr Mol Med Cologne, Ctr Integrated Oncol, Cologne, Germany. [Bogdanova-Markov, Nadja] Univ Munster, Inst Human Genet, D-48149 Munster, Germany. [Sagne, Charlotte; Damiola, Francesca; Sinilnikova, Olga M.; Mazoyer, Sylvie] Univ Lyon 1, CNRS UMR 5286, INSERM U1052, Ctr Rech Cancerol Lyon, F-69365 Lyon, France. [Stoppa-Lyonnet, Dominique] Inst Curie, Dept Tumour Biol, Paris, France. [Stoppa-Lyonnet, Dominique] Univ Paris 05, Sorbonne Paris Cite, Paris, France. [Sinilnikova, Olga M.] Hosp Civils Lyon, Ctr Leon Berard, Unite Mixte Genet Constitutionnelle Canc Frequent, Lyon, France. [Isaacs, Claudine] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. [Claes, Kathleen B. M.; De Leeneer, Kim] Univ Ghent, Ctr Med Genet, B-9000 Ghent, Belgium. [De la Hoya, Miguel; Caldes, Trinidad] Hosp Clin San Carlos, IdISSC, Mol Oncol Lab, Madrid, Spain. [Nevanlinna, Heli; Khan, Sofia] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland. [Nevanlinna, Heli; Khan, Sofia] Univ Helsinki, Cent Hosp, Helsinki, Finland. [Mensenkamp, Arjen R.] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands. [Hooning, Maartje J.] Erasmus Univ, Med Ctr, Family Canc Clin, Dept Med Oncol, Rotterdam, Netherlands. [Rookus, Matti A.] Netherlands Canc Inst, Dept Epidemiol, Amsterdam, Netherlands. [Kwong, Ava] Hong Kong Sanat & Hosp, Canc Genet Ctr, Hong Kong Hereditary Breast Canc Family Registry, Hong Kong, Hong Kong, Peoples R China. [Kwong, Ava] Univ Hong Kong, Dept Surg, Hong Kong, Hong Kong, Peoples R China. [Olah, Edith] Natl Inst Oncol, Dept Mol Genet, Budapest, Hungary. [Diez, Orland] Vall dHebron Univ Hosp, VHIO, Oncogenet Lab, Barcelona, Spain. [Brunet, Joan] Catalan Inst Oncol, IDIBGI, Hereditary Canc Program, Genet Counseling Unit, Girona, Spain. [Pujana, Miquel Angel] Catalan Inst Oncol, IDIBELL Bellvitge Biomed Res Inst, Breast Canc & Syst Biol Unit, Barcelona, Spain. [Barkardottir, Rosa B.] Univ Iceland, Fac Med, Landspitali Univ Hosp, Dept Pathol, Reykjavik, Iceland. [Barkardottir, Rosa B.] Univ Iceland, Fac Med, Biomed Ctr BMC, Reykjavik, Iceland. [Laframboise, Rachel] Ctr Hosp Univ Quebec, Div Med Genet, Quebec City, PQ, Canada. [Laframboise, Rachel; Soucy, Penny; Simard, Jacques] Univ Laval, Quebec City, PQ, Canada. [Soucy, Penny; Simard, Jacques] Ctr Hosp Univ Quebec, Quebec City, PQ, Canada. [Montagna, Marco; Agata, Simona] IRCCS, IOV, Immunol & Mol Oncol Unit, Padua, Italy. [Teixeira, Manuel R.] Portuguese Oncol Inst, Dept Genet, Oporto, Portugal. [Teixeira, Manuel R.] Univ Porto, Biomed Sci Inst ICBAS, Rua Campo Alegre 823, P-4100 Oporto, Portugal. [Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Tischkowitz, Marc] McGill Univ, Program Canc Genet, Montreal, PQ, Canada. [Foretova, Lenka] Masaryk Univ, Masaryk Mem Canc Inst, Brno, Czech Republic. [Foretova, Lenka] Masaryk Univ, Fac Med, Brno, Czech Republic. [Vijai, Joseph; Offit, Kenneth] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. [Singer, Christian F.; Rappaport, Christine] Med Univ Vienna, Ctr Comprehens Canc, Dept Obstet & Gynecol, Vienna, Austria. [Phelan, Catherine M.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Canc Epidemiol, Tampa, FL 33682 USA. [Greene, Mark H.; Mai, Phuong L.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, US NIH, Rockville, MD USA. [Rennert, Gad] Carmel Hosp, Dept Community Med & Epidemiol, Haifa, Israel. [Rennert, Gad] Technion Israel Inst Technol, Bruce Rappaport Fac Med, POB 9649, IL-31096 Haifa, Israel. [Rennert, Gad] Clalit Natl Israeli Canc Control Ctr, Haifa, Israel. [Imyanitov, Evgeny N.] NN Petrov Oncol Res Inst, St Petersburg, Russia. [Hulick, Peter J.] NorthShore Univ Hlth Syst, Ctr Med Genet, Evanston, IL USA. [Phillips, Kelly-Anne] Peter MacCallum Canc Ctr, Div Canc Med, East Melbourne, Vic, Australia. [Piedmonte, Marion] Roswell Pk Canc Inst, Stat & Data Management Ctr, NRG Oncol, Buffalo, NY 14263 USA. [Mulligan, Anna Marie] Univ Hlth Network, Lab Med Program, Toronto, ON, Canada. [Mulligan, Anna Marie] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada. [Bojesen, Anders] Vejle Hosp, Dept Clin Genet, Vejle, Denmark. [Thomassen, Mads] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense, Denmark. [Caligo, Maria A.] Univ Pisa, Dept Lab Med, Sect Genet Oncol, Pisa, Italy. [Caligo, Maria A.] Univ Hosp Pisa, Pisa, Italy. [Yoon, Sook-Yee] Univ Malaya, Univ Malaya Med Ctr, Fac Med, Univ Malaya Canc Res Inst, Kuala Lumpur, Malaysia. [Friedman, Eitan; Laitman, Yael] Chaim Sheba Med Ctr, Susanne Levy Gertner Oncogenet Unit, IL-52621 Tel Hashomer, Israel. [Borg, Ake] Lund Univ, Dept Oncol, Lund, Sweden. [Ehrencrona, Hans] Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden. [Ehrencrona, Hans] Univ Lund Hosp, Dept Clin Genet, S-22185 Lund, Sweden. [Rantala, Johanna] Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden. [Olopade, Olufunmilayo I.] Univ Chicago, Med Ctr, Ctr Clin Canc Genet & Global Hlth, Chicago, IL 60637 USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Sch Med, Johnsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, Los Angeles, CA USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Sch Publ Hlth, Johnsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, Los Angeles, CA USA. [Nussbaum, Robert L.] Univ Calif San Francisco, Dept Med & Genet, San Francisco, CA 94143 USA. [Nathanson, Katherine L.; Domchek, Susan M.] Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA. [Arun, Banu K.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Mitchell, Gillian] Peter MacCallum Canc Ctr, Familial Canc Ctr, Melbourne, Vic, Australia. [Mitchell, Gillian] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Melbourne, Vic, Australia. [Karlan, Beth Y.; Lester, Jenny] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA. [Maskarinec, Gertraud] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Woolcott, Christy] Dalhousie Univ, Dept Obstet Gynaecol & Pediat, Halifax, NS, Canada. [Stone, Jennifer] Univ Western Australia, Ctr Genet Origins Hlth & Dis, Perth, WA 6009, Australia. [Tamimi, Rulla] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Tamimi, Rulla] Harvard Univ, Sch Med, Boston, MA USA. [Tamimi, Rulla] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Tamimi, Rulla] Harvard Univ, Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, 665 Huntington Ave, Boston, MA 02115 USA. [Luben, Robert; Khaw, Kay-Tee] Univ Cambridge, Dept Publ Hlth & Primary Care, Clin Gerontol, Cambridge, England. RP Dunning, AM; Easton, DF; Edwards, SL (reprint author), Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England.; Easton, DF (reprint author), Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England.; Edwards, SL (reprint author), QIMR Berghofer Med Res Inst, Canc Div, Brisbane, Qld, Australia. EM amd24@medschl.cam.ac.uk; dfe20@medschl.cam.ac.uk; stacey.edwards@qimrberghofer.edu.au RI Gronwald, Jacek/A-4576-2017; Brenner, Hermann/B-4627-2017; manoukian, siranoush/E-7132-2017; Peissel, Bernard/E-8187-2017; montagna, marco/E-2225-2012; Helland, Aslaug/H-3910-2015; Andrulis, Irene/E-7267-2013; Edwards, Stacey/A-4980-2011; Zheng, Wei/O-3351-2013; Nord, Silje/R-5212-2016; Arnold, Norbert/E-3012-2010; Jansen van Rensburg, Elizabeth (Lizette)/B-9104-2011; Osorio, Ana/I-4324-2014; Lee, Jason/M-7522-2016; Dork, Thilo/J-8620-2012; Yip, Cheng-Har/B-1909-2010; Teo, Soo-hwang/H-2353-2014; Knight, Julia/A-6843-2012 OI Dunning, Alison Margaret/0000-0001-6651-7166; Matsuo, Keitaro/0000-0003-1761-6314; Evans, Gareth/0000-0002-8482-5784; Gronwald, Jacek/0000-0002-3643-2871; Brenner, Hermann/0000-0002-6129-1572; manoukian, siranoush/0000-0002-6034-7562; Peissel, Bernard/0000-0001-9233-3571; montagna, marco/0000-0002-4929-2150; Ehrencrona, Hans/0000-0002-5589-3622; Phillips, Kelly-Anne/0000-0002-0475-1771; Barrowdale, Daniel/0000-0003-1661-3939; Khan, Sofia/0000-0003-4185-8882; Brunet, Joan/0000-0003-1945-3512; Sivakumaran, Haran/0000-0002-4691-4989; Dowsett, Mitch/0000-0003-4122-744X; Helland, Aslaug/0000-0002-5520-0275; Zheng, Wei/0000-0003-1226-070X; Nord, Silje/0000-0002-3271-5356; Arnold, Norbert/0000-0003-4523-8808; Osorio, Ana/0000-0001-8124-3984; Lee, Jason/0000-0003-0879-934X; FU National Institute for Health Research (NIHR); European Community [223175 (HEALTH-F2-2009-223175)]; Cancer Research UK [C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565]; US National Institutes of Health (NIH) [CA128978, CA192393, CA116167, CA176785]; US National Institutes of Health (NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer) [CA116201]; Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]; Post-Cancer GWAS initiative (GAME-ON initiative); US Department of Defense [W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR); Komen Foundation for the Cure; Breast Cancer Research Foundation; Ovarian Cancer Research Fund FX We thank all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out. This study would not have been possible without the contributions of the following: A. Berchuck (OCAC), R.A. Eeles, A. A. Al Olama, Z. Kote-Jarai and S. Benlloch (PRACTICAL), C. Luccarini and the staff of the Centre for Genetic Epidemiology Laboratory, the staff of the CNIO genotyping unit, D.C. Tessier, F. Bacot, D. Vincent, S. LaBoissiere, F. Robidoux and the staff of the McGill University and Genome Quebec Innovation Centre, S. F. Nielsen, B.G. Nordestgaard and the staff of the Copenhagen DNA laboratory, and J.M. Cunningham, S. A. Windebank, C. A. Hilker, J. Meyer and the staff of the Mayo Clinic Genotyping Core Facility. Normal human tissues from the Susan G. Komen for the Cure Tissue Bank at the Indiana University Simon Cancer Center (Indianapolis) were used in this study. We thank the contributors, including Indiana University who collected samples used in this study, as well as the donors and their families, whose help and participation made this work possible. We also acknowledge National Institute for Health Research (NIHR) support to the Royal Marsden Biomedical Research Centre. Funding for the iCOGS infrastructure came from the European Community's Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692 and C8197/A16565), the US National Institutes of Health (NIH; CA128978, CA192393, CA116167, CA176785 and an NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201)) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112, the GAME-ON initiative), the US Department of Defense (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, the Komen Foundation for the Cure, the Breast Cancer Research Foundation and the Ovarian Cancer Research Fund. Full acknowledgments are given in the Supplementary Note. NR 46 TC 7 Z9 7 U1 6 U2 27 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD APR PY 2016 VL 48 IS 4 BP 374 EP + DI 10.1038/ng.3521 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA DH6NZ UT WOS:000372908800009 PM 26928228 ER PT J AU Hessell, AJ Jaworski, JP Epson, E Matsuda, K Pandey, S Kahl, C Reed, J Sutton, WF Hammond, KB Cheever, TA Barnette, PT Legasse, AW Planer, S Stanton, JJ Pegu, A Chen, XJ Wang, KY Siess, D Burke, D Park, BS Axthelm, MK Lewis, A Hirsch, VM Graham, BS Mascola, JR Sacha, JB Haigwood, NL AF Hessell, Ann J. Jaworski, J. Pablo Epson, Erin Matsuda, Kenta Pandey, Shilpi Kahl, Christoph Reed, Jason Sutton, William F. Hammond, Katherine B. Cheever, Tracy A. Barnette, Philip T. Legasse, Alfred W. Planer, Shannon Stanton, Jeffrey J. Pegu, Amarendra Chen, Xuejun Wang, Keyun Siess, Don Burke, David Park, Byung S. Axthelm, Michael K. Lewis, Anne Hirsch, Vanessa M. Graham, Barney S. Mascola, John R. Sacha, Jonah B. Haigwood, Nancy L. TI Early short-term treatment with neutralizing human monoclonal antibodies halts SHIV infection in infant macaques SO NATURE MEDICINE LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; HIGHLY PATHOGENIC SIV; IN-VIVO; VAGINAL TRANSMISSION; HIV-1 TRANSMISSION; NEONATAL MACAQUES; RHESUS-MONKEYS; MUCOSAL; PROTECTION; VIREMIA AB Prevention of mother-to-child transmission (MTCT) of HIV remains a major objective where antenatal care is not readily accessible. We tested HIV-1-specific human neutralizing monoclonal antibodies (NmAbs) as a post-exposure therapy in an infant macaque model for intrapartum MTCT. One-month-old rhesus macaques were inoculated orally with the simian-human immunodeficiency virus SHIVSF162P3. On days 1, 4, 7 and 10 after virus exposure, we injected animals subcutaneously with NmAbs and quantified systemic distribution of NmAbs in multiple tissues within 24 h after antibody administration. Replicating virus was found in multiple tissues by day 1 in animals that were not treated. All NmAb-treated macaques were free of virus in blood and tissues at 6 months after exposure. We detected no anti-SHIV T cell responses in blood or tissues at necropsy, and no virus emerged after CD8(+) T cell depletion. These results suggest that early passive immunotherapy can eliminate early viral foci and thereby prevent the establishment of viral reservoirs. C1 [Hessell, Ann J.; Jaworski, J. Pablo; Epson, Erin; Pandey, Shilpi; Kahl, Christoph; Sutton, William F.; Cheever, Tracy A.; Barnette, Philip T.; Legasse, Alfred W.; Planer, Shannon; Stanton, Jeffrey J.; Siess, Don; Burke, David; Park, Byung S.; Axthelm, Michael K.; Lewis, Anne; Sacha, Jonah B.; Haigwood, Nancy L.] Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Beaverton, OR USA. [Hessell, Ann J.; Reed, Jason; Hammond, Katherine B.; Axthelm, Michael K.; Sacha, Jonah B.; Haigwood, Nancy L.] Oregon Hlth & Sci Univ, Vaccine & Gene Therapy Inst, Beaverton, OR USA. [Matsuda, Kenta; Hirsch, Vanessa M.] NIAID, Lab Mol Microbiol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Pegu, Amarendra; Chen, Xuejun; Wang, Keyun; Graham, Barney S.; Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Haigwood, NL (reprint author), Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Beaverton, OR USA.; Haigwood, NL (reprint author), Oregon Hlth & Sci Univ, Vaccine & Gene Therapy Inst, Beaverton, OR USA. EM haigwoon@ohsu.edu OI Jaworski, Juan Pablo/0000-0002-1311-060X FU NIH [R01-HD080459, P51-OD011092]; Elizabeth Glaser Pediatric AIDS Foundation; American Foundation for AIDS Research (amfAR) [108823-55-RGRL]; intramural research program of the Vaccine Research Center; Laboratory of Molecular Microbiology, NIAID, NIH, Division of Health and Human Services, US Public Health Service FX We thank D. Malherbe for helpful discussions and C. Corbacci for graphic design work. We appreciate the expertise, dedication and thoughtful care provided to the infant macaques by H. Sidener and the ONPRC nursery animal care technicians. Titrated stocks of SHIVSF162P3 (passage 3) virus were obtained through the AIDS Research and Reference Reagent Program, Division of AIDS, National Institute of Allergy and Infectious Diseases NIAID), NIH (catalog number 6526; contributors J. Harouse, C. Cheng-Mayer and R. Pal) for each study. The SIVsmE660 stock was kindly provided by V.M. Hirsch. The linearized pBSII-SIVgag was kindly gifted by Michael Piatak, National Cancer Institute at the NIH. Funding was provided by US Public Health Service grants from the NIH (grant no. R01-HD080459 (N.L.H.), P51-OD011092 (J. Robertson), P51-OD011092 pilot funding (E.E.)), the Elizabeth Glaser Pediatric AIDS Foundation (N.L.H.) and the American Foundation for AIDS Research (amfAR) (grant no. 108823-55-RGRL; N.L.H.). This work was also funded, in part, by the intramural research program of the Vaccine Research Center (B.S.G. and J.R.M.) and the Laboratory of Molecular Microbiology, NIAID, NIH, Division of Health and Human Services, US Public Health Service (V.M.H.). NR 59 TC 16 Z9 16 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD APR PY 2016 VL 22 IS 4 BP 362 EP + DI 10.1038/nm.4063 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA DI4GF UT WOS:000373457700011 PM 26998834 ER PT J AU Francis, KR Ton, AN Xin, Y O'Halloran, PE Wassif, CA Malik, N Williams, IM Cluzeau, CV Trivedi, NS Pavan, WJ Cho, W Westphal, H Porter, FD AF Francis, Kevin R. Ton, Amy N. Xin, Yao O'Halloran, Peter E. Wassif, Christopher A. Malik, Nasir Williams, Ian M. Cluzeau, Celine V. Trivedi, Niraj S. Pavan, William J. Cho, Wonhwa Westphal, Heiner Porter, Forbes D. TI Modeling Smith-Lemli-Opitz syndrome with induced pluripotent stem cells reveals a causal role for Wnt/beta-catenin defects in neuronal cholesterol synthesis phenotypes SO NATURE MEDICINE LA English DT Article ID MEMBRANE-BINDING; NERVOUS-SYSTEM; DIFFERENTIATION; ACTIVATION; BRAIN; 7-DEHYDROCHOLESTEROL; MAINTENANCE; PROGENITORS; FIBROBLASTS; GENERATION AB Smith-Lemli-Opitz syndrome (SLOS) is a malformation disorder caused by mutations in DHCR7, which impair the reduction of 7-dehydrocholesterol (7DHC) to cholesterol. SLOS results in cognitive impairment, behavioral abnormalities and nervous system defects, though neither affected cell types nor impaired signaling pathways are fully understood. Whether 7DHC accumulation or cholesterol loss is primarily responsible for disease pathogenesis is also unclear. Using induced pluripotent stem cells (iPSCs) from subjects with SLOS, we identified cellular defects that lead to precocious neuronal specification within SLOS derived neural progenitors. We also demonstrated that 7DHC accumulation, not cholesterol deficiency, is critical for SLOS-associated defects. We further identified downregulation of Wnt/beta-catenin signaling as a key initiator of aberrant SLOS iPSC differentiation through the direct inhibitory effects of 7DHC on the formation of an active Wnt receptor complex. Activation of canonical Wnt signaling prevented the neural phenotypes observed in SLOS iPSCs, suggesting that Wnt signaling may be a promising therapeutic target for SLOS. C1 [Francis, Kevin R.; Ton, Amy N.; O'Halloran, Peter E.; Malik, Nasir; Westphal, Heiner] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD USA. [Francis, Kevin R.; Wassif, Christopher A.; Williams, Ian M.; Cluzeau, Celine V.; Porter, Forbes D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. [Xin, Yao; Cho, Wonhwa] Univ Illinois, Dept Chem, Chicago, IL USA. [Trivedi, Niraj S.] NHGRI, Computat & Stat Genom Branch, NIH, Bethesda, MD 20892 USA. [Pavan, William J.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Francis, KR (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD USA.; Francis, KR; Porter, FD (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. EM kevin.francis@sanfordhealth.org; fdporter@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Human Genome Research Institute (NHGRI); NIH Center for Regenerative Medicine; NIH [GM110128] FX This work was supported by the intramural research programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Human Genome Research Institute (NHGRI), a pilot award for iPSC research from the NIH Center for Regenerative Medicine, and NIH grant GM110128 (W.C.). We thank K. Perez, N. Khezri and G.F. Rodriguez for assistance with hESC and iPSC culture. We also thank C. Toth and A. Ely for assistance with mice and sequencing. We thank A. Dutra, E. Pak and the NHGRI Cytogenetics Core for assistance with hESC and iPSC karyotyping. We thank L. (Chip) Dye and the NICHD Microscopy and Imaging Core for electron microscopy assistance. We thank B.S. Mallon (National Institute of Neurological Disorders and Stroke, NIH Stem Cell Unit), S. Kuznetsov (National Institute of Dental and Craniofacial Research, NIDCR), and P.G. Robey (NIDCR, NIH Stem Cell Unit) for experimental advice and the i19 and i21 human iPSC lines. We thank G. Mostoslavksy (Boston University) for the kind gift of the STEMCCA plasmid. We thank D. Kotton (Boston University) for the kind gift of the Cre-IRES-PuroR plasmid. We thank F. Zhang (Massachusetts Institute of Technology) for the gift of the pX330-U6-Chimeric_BB-CBh-hSpCas9 plasmid. We thank J. Mills (Children's Hospital of Philadelphia) for experimental advice, the National Heart, Lung and Blood Institute iPSC Core Facility for assistance with lathosterolosis iPSC generation, and M. Rao and K. Pfeifer for critical discussions. Finally, we would like to thank the patients and guardians who participated in the NIH clinical program and contributed to this study. NR 51 TC 7 Z9 7 U1 9 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD APR PY 2016 VL 22 IS 4 BP 388 EP + DI 10.1038/nm.4067 PG 13 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA DI4GF UT WOS:000373457700014 PM 26998835 ER PT J AU Gros, A Parkhurst, MR Tran, E Pasetto, A Robbins, PF Ilyas, S Prickett, TD Gartner, JJ Crystal, JS Roberts, IM Trebska-McGowan, K Wunderlich, JR Yang, JC Rosenberg, SA AF Gros, Alena Parkhurst, Maria R. Tran, Eric Pasetto, Anna Robbins, Paul F. Ilyas, Sadia Prickett, Todd D. Gartner, Jared J. Crystal, Jessica S. Roberts, Ilana M. Trebska-McGowan, Kasia Wunderlich, John R. Yang, James C. Rosenberg, Steven A. TI Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients SO NATURE MEDICINE LA English DT Article ID ENHANCED ANTITUMOR-ACTIVITY; REACTIVE T-CELLS; CANCER-IMMUNOTHERAPY; METASTATIC MELANOMA; UNTREATED MELANOMA; PD-1 BLOCKADE; TUMOR; ANTIGENS; RNA; IPILIMUMAB AB Detection of lymphocytes that target tumor-specific mutant neoantigens-derived from products encoded by mutated genes in the tumor-is mostly limited to tumor-resident lymphocytes(1,2), but whether these lymphocytes often occur in the circulation is unclear. We recently reported that intratumoral expression of the programmed cell death 1 (PD-1) receptor can guide the identification of the patient-specific repertoire of tumor-reactive CD8(+) lymphocytes that reside in the tumor3. In view of these findings, we investigated whether PD-1 expression on peripheral blood lymphocytes could be used as a biomarker to detect T cells that target neoantigens. By using a high-throughput personalized screening approach, we identified neoantigenspecific lymphocytes in the peripheral blood of three of four melanoma patients. Despite their low frequency in the circulation, we found that CD8(+) PD-1(+), but not CD8(+) PD-1-, cell populations had lymphocytes that targeted 3, 3 and 1 unique, patient-specific neoantigens, respectively. We show that neoantigen-specific T cells and gene-engineered lymphocytes expressing neoantigen-specific T cell receptors (TCRs) isolated from peripheral blood recognized autologous tumors. Notably, the tumor-antigen specificities and TCR repertoires of the circulating and tumor-infiltrating CD8(+) PD-1(+) cells appeared similar, implying that the circulating CD8(+) PD-1(+) lymphocytes could provide a window into the tumor-resident antitumor lymphocytes. Thus, expression of PD-1 identifies a diverse and patient-specific antitumor T cell response in peripheral blood, providing a novel noninvasive strategy to develop personalized therapies using neoantigen-reactive lymphocytes or TCRs to treat cancer. C1 [Gros, Alena; Parkhurst, Maria R.; Tran, Eric; Pasetto, Anna; Robbins, Paul F.; Ilyas, Sadia; Prickett, Todd D.; Gartner, Jared J.; Crystal, Jessica S.; Roberts, Ilana M.; Trebska-McGowan, Kasia; Wunderlich, John R.; Yang, James C.; Rosenberg, Steven A.] NCI, Surg Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Rosenberg, SA (reprint author), NCI, Surg Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM SAR@nih.gov OI Gros, Alena/0000-0002-1207-1880 FU Center for Cancer Research intramural research program of the NCI, US National Institutes of Health (NIH) FX This work was supported by the Center for Cancer Research intramural research program of the NCI, US National Institutes of Health (NIH). We thank the members of the Surgery branch for helpful discussions, R. Somerville and members of the tumor-infiltrating lymphocytes (TIL) lab for technical support, and L. Liu for kindly providing the PD-1-specific AMP-514 antibody. This work used the computational resources of the NIH High-Performance Computing (HPC) Biowulf cluster (http://hpc.nih.gov). NR 40 TC 41 Z9 42 U1 14 U2 34 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD APR PY 2016 VL 22 IS 4 BP 433 EP + DI 10.1038/nm.4051 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA DI4GF UT WOS:000373457700020 PM 26901407 ER PT J AU Zhang, W Zhang, LF Liang, B Schroeder, D Zhang, ZW Cox, GA Li, Y Lin, DT AF Zhang, Wen Zhang, Lifeng Liang, Bo Schroeder, David Zhang, Zhong-wei Cox, Gregory A. Li, Yun Lin, Da-Ting TI Hyperactive somatostatin interneurons contribute to excitotoxicity in neurodegenerative disorders SO NATURE NEUROSCIENCE LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; FRONTOTEMPORAL LOBAR DEGENERATION; MOTOR CORTEX INHIBITION; TDP-43; ALS; MUTATIONS; NEURONS; MICE; RNA AB Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping neurodegenerative disorders whose pathogenesis remains largely unknown. Using TDP-43(A315T) mice, an ALS and FTD model with marked cortical pathology, we found that hyperactive somatostatin interneurons disinhibited layer 5 pyramidal neurons (L5-PNs) and contributed to their excitotoxicity. Focal ablation of somatostatin interneurons efficiently restored normal excitability of L5-PNs and alleviated neurodegeneration, suggesting a new therapeutic target for ALS and FTD. C1 [Zhang, Wen; Zhang, Lifeng; Liang, Bo; Li, Yun; Lin, Da-Ting] NIDA, Intramural Res Program, NIH, Baltimore, MD USA. [Schroeder, David; Zhang, Zhong-wei; Cox, Gregory A.; Lin, Da-Ting] Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. RP Li, Y; Lin, DT (reprint author), NIDA, Intramural Res Program, NIH, Baltimore, MD USA.; Lin, DT (reprint author), Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. EM yunlijax@gmail.com; lind3@mail.nih.gov RI Zhang, Wen/B-2671-2009; OI Zhang, Wen/0000-0001-5166-0736; Zhang, Zhong-wei/0000-0001-7165-6216 FU Jackson Lab Startup Funds [1R21 NS075382-01A1]; Intramural Research Program of the National Institute on Drug Abuse FX This research was supported by Jackson Lab Startup Funds (D.-T.L.), 1R21 NS075382-01A1 (Y.L. and G.A.C.), and the Intramural Research Program of the National Institute on Drug Abuse (D.-T.L.). NR 30 TC 13 Z9 13 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 EI 1546-1726 J9 NAT NEUROSCI JI Nat. Neurosci. PD APR PY 2016 VL 19 IS 4 BP 557 EP + DI 10.1038/nn.4257 PG 5 WC Neurosciences SC Neurosciences & Neurology GA DH6OI UT WOS:000372909800010 PM 26900927 ER PT J AU Steeg, PS AF Steeg, Patricia S. TI Targeting metastasis SO NATURE REVIEWS CANCER LA English DT Review ID BREAST-CANCER CELLS; RESISTANT PROSTATE-CANCER; ENDOTHELIAL GROWTH-FACTOR; KINASE INHIBITOR SARACATINIB; RANDOMIZED PHASE-II; OXALIPLATIN-BASED CHEMOTHERAPY; PLACEBO-CONTROLLED TRIAL; PANCREATIC-CANCER; COLORECTAL-CANCER; BRAIN METASTASIS AB Tumour metastasis, the movement of tumour cells from a primary site to progressively colonize distant organs, is a major contributor to the deaths of cancer patients. Therapeutic goals are the prevention of an initial metastasis in high-risk patients, shrinkage of established lesions and prevention of additional metastases in patients with limited disease. Instead of being autonomous, tumour cells engage in bidirectional interactions with metastatic microenvironments to alter antitumour immunity, the extracellular milieu, genomic stability, survival signalling, chemotherapeutic resistance and proliferative cycles. Can targeting of these interactions significantly improve patient outcomes? In this Review preclinical research, combination therapies and clinical trial designs are re-examined. C1 [Steeg, Patricia S.] NCI, Womens Malignancies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Steeg, PS (reprint author), NCI, Womens Malignancies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM steegp@mail.nih.gov NR 257 TC 30 Z9 30 U1 25 U2 61 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X EI 1474-1768 J9 NAT REV CANCER JI Nat. Rev. Cancer PD APR PY 2016 VL 16 IS 4 BP 201 EP 218 DI 10.1038/nrc.2016.25 PG 18 WC Oncology SC Oncology GA DH5AI UT WOS:000372796700004 PM 27009393 ER PT J AU Stracquadanio, G Wang, XT Wallace, MD Grawenda, AM Zhang, P Hewitt, J Zeron-Medina, J Castro-Giner, F Tomlinson, I Goding, CR Cygan, KJ Fairbrother, WG Thomas, LF Soetrom, P Gemignani, F Landi, S Schuster-Boeckler, B Bell, DA Bond, GL AF Stracquadanio, Giovanni Wang, Xuting Wallace, Marsha D. Grawenda, Anna M. Zhang, Ping Hewitt, Juliet Zeron-Medina, Jorge Castro-Giner, Francesc Tomlinson, Ianp. Goding, Colin R. Cygan, Kamil J. Fairbrother, William G. Thomas, Laurent F. Soetrom, Pal Gemignani, Federica Landi, Stefano Schuster-Boeckler, Benjamin Bell, Douglas A. Bond, Gareth L. TI The importance of p53 pathway genetics in inherited and somatic cancer genomes SO NATURE REVIEWS CANCER LA English DT Article ID AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME; TUMOR-SUPPRESSOR PROTEIN; CYCLIN D1; ATAXIA-TELANGIECTASIA; CASPASE-8 GENE; PARKINSONS-DISEASE; THERAPEUTIC TARGET; DEFICIENT MICE; BREAST-CANCER; FAS MUTATIONS AB Decades of research have shown that mutations in the p53 stress response pathway affect the incidence of diverse cancers more than mutations in other pathways. However, most evidence is limited to somatic mutations and rare inherited mutations. Using newly abundant genomic data, we demonstrate that commonly inherited genetic variants in the p53 pathway also affect the incidence of a broad range of cancers more than variants in other pathways. The cancer-associated single nucleotide polymorphisms (SNPs) of the p53 pathway have strikingly similar genetic characteristics to well-studied p53 pathway cancer-causing somatic mutations. Our results enable insights into p53-mediated tumour suppression in humans and into p53 pathway-based cancer surveillance and treatment strategies. C1 [Stracquadanio, Giovanni; Wallace, Marsha D.; Grawenda, Anna M.; Zhang, Ping; Hewitt, Juliet; Goding, Colin R.; Schuster-Boeckler, Benjamin; Bond, Gareth L.] Univ Oxford, Ludwig Inst Canc Res, Nuffield Dept Clin Med, Old Rd Campus Res Bldg, Oxford OX3 7DQ, England. [Wang, Xuting; Bell, Douglas A.] NIEHS, Environm Genom Grp, Genome Integr & Struct Biol, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Zeron-Medina, Jorge] Vall dHebron Univ Hosp, Dept Oncol, Passeig Vall DHebron 119, Barcelona 08035, Spain. [Castro-Giner, Francesc; Tomlinson, Ianp.] Univ Oxford, Wellcome Trust Ctr Human Genet, Mol & Populat Genet Lab, Oxford OX3 7BN, England. [Cygan, Kamil J.; Fairbrother, William G.] Brown Univ, Ctr Computat Mol Biol, 115 Waterman St, Providence, RI 02912 USA. [Cygan, Kamil J.; Fairbrother, William G.] Brown Univ, Dept Mol Biol Cell Biol & Biochem, 70 Ship St, Providence, RI 02903 USA. [Thomas, Laurent F.; Soetrom, Pal] Norwegian Univ Sci & Technol, Dept Canc Res & Mol Med, Oslo, Norway. [Soetrom, Pal] Norwegian Univ Sci & Technol, Dept Comp & Informat Sci, NO-7491 Trondheim, Norway. [Gemignani, Federica; Landi, Stefano] Univ Pisa, Dept Biol, Genet, Via Derna 1, I-56126 Pisa, Italy. RP Bond, GL (reprint author), Univ Oxford, Ludwig Inst Canc Res, Nuffield Dept Clin Med, Old Rd Campus Res Bldg, Oxford OX3 7DQ, England.; Bell, DA (reprint author), NIEHS, Environm Genom Grp, Genome Integr & Struct Biol, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM bell1@niehs.nih.gov; gareth.bond@ndm.ox.ac.uk RI Zeron-Medina, Jorge/E-2480-2013; OI Zeron-Medina, Jorge/0000-0001-5030-3219; Castro-Giner, Francesc/0000-0001-6111-0754; Thomas, Laurent/0000-0003-0548-2486; Wang, Xuting/0000-0001-6781-8008; Saetrom, Pal/0000-0001-8142-7441; Stracquadanio, Giovanni/0000-0001-9819-3645; Schuster-Bockler, Benjamin/0000-0002-8892-5133 FU Ludwig Institute for Cancer Research; Nuffield Department of Medicine; Development Fund, Oxford Cancer Research Centre, University of Oxford, UK; National Institute of Environmental Health Sciences, US National Institutes of Health [Z01ES100475, Z01ES46008] FX This work was funded in part by the Ludwig Institute for Cancer Research, the Nuffield Department of Medicine, the Development Fund, Oxford Cancer Research Centre, University of Oxford, UK, and by the Intramural Research Program of the National Institute of Environmental Health Sciences, US National Institutes of Health (projects: Z01ES100475 and Z01ES46008). We thank J. S. Bader, M. Muers, M. Resnick and B. A. Merrick for their critical reading of the manuscript. NR 118 TC 8 Z9 8 U1 5 U2 24 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X EI 1474-1768 J9 NAT REV CANCER JI Nat. Rev. Cancer PD APR PY 2016 VL 16 IS 4 BP 251 EP 265 DI 10.1038/nrc.2016.15 PG 15 WC Oncology SC Oncology GA DH5AI UT WOS:000372796700007 PM 27009395 ER PT J AU Gharwan, H Groninger, H AF Gharwan, Helen Groninger, Hunter TI Kinase inhibitors and monoclonal antibodies in oncology: clinical implications SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Review ID CHRONIC MYELOID-LEUKEMIA; RENAL-CELL CARCINOMA; SUNITINIB-INDUCED HYPOTHYROIDISM; DERMATOLOGICAL ADVERSE EVENTS; IMATINIB MESYLATE TREATMENT; INTERSTITIAL LUNG-DISEASE; ENDOTHELIAL GROWTH-FACTOR; QUALITY-OF-LIFE; POSTERIOR LEUKOENCEPHALOPATHY SYNDROME; ADVANCED HEPATOCELLULAR-CARCINOMA AB Molecularly targeted cancer therapies, such as small-molecule kinase inhibitors and monoclonal antibodies, constitute a rapidly growing and an important part of the oncology armamentarium. Unlike conventional (cytotoxic) chemotherapeutics, targeted therapies were designed to disrupt cancer cell pathogenesis at specific biological points essential for the development and progression of the tumour. These agents were developed to disrupt specific targets with the aim of minimizing treatment burden compared with conventional chemotherapy. Nevertheless the increasingly common use of targeted therapies has revealed some unanticipated, often clinically significant toxic effects, as well as compromising effective palliative and end-of-life management approaches. Although patients and clinicians welcome improvements in cancer prognosis, these changes can also impact patient quality-of-life. Therefore, as demand for oncology expertise increases, physicians need to apprise themselves of targeted therapies and their clinical implications, including drug-specific side effects, impact on quality of life, and cost issues, especially in relation to end-of-life care. This Review provides a useful summary and guide for professionals treating patients with malignant diseases. C1 [Gharwan, Helen] NCI, Med Oncol, NIH, 10 Ctr Dr,Bldg 10,Room 12N226, Bethesda, MD 20892 USA. [Groninger, Hunter] MedStar Washington Hosp Ctr, Dept Med, Sect Palliat Care, 110 Irving St NW,Room 2A-68, Washington, DC 20008 USA. RP Gharwan, H (reprint author), NCI, Med Oncol, NIH, 10 Ctr Dr,Bldg 10,Room 12N226, Bethesda, MD 20892 USA. EM hgh7@hotmail.com NR 247 TC 9 Z9 10 U1 12 U2 26 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4774 EI 1759-4782 J9 NAT REV CLIN ONCOL JI Nat. Rev. Clin. Oncol. PD APR PY 2016 VL 13 IS 4 BP 209 EP 227 DI 10.1038/nrclinonc.2015.213 PG 19 WC Oncology SC Oncology GA DH4DF UT WOS:000372735000004 PM 26718105 ER PT J AU Gilliland, CT Zuk, D Kocis, P Johnson, M Hay, S Hajduch, M Bietrix, F Aversa, G Austin, CP Ussi, AE AF Gilliland, C. Taylor Zuk, Dorit Kocis, Petr Johnson, Mike Hay, Stewart Hajduch, Marian Bietrix, Florence Aversa, Gregorio Austin, Christopher P. Ussi, Anton E. TI Putting translational science on to a global stage SO NATURE REVIEWS DRUG DISCOVERY LA English DT Editorial Material C1 [Gilliland, C. Taylor; Zuk, Dorit; Austin, Christopher P.] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20817 USA. [Kocis, Petr] Alzheon Inc, Framingham, MA 01701 USA. [Kocis, Petr; Hajduch, Marian; Bietrix, Florence; Ussi, Anton E.] European Infrastruct Translat Med, EATRIS ERIC, NL-1081 HZ Amsterdam, Netherlands. [Johnson, Mike] MRC Technol, London WC1H 9LT, England. [Hay, Stewart] Therapeut Innovat Australia, Melbourne, Vic 2000, Australia. [Hajduch, Marian] Palacky Univ, Fac Med & Dent, Inst Mol & Translat Med, CR-77147 Olomouc, Czech Republic. [Aversa, Gregorio] Ctr Drug Res & Dev, Vancouver, BC V6T 1Z3, Canada. RP Ussi, AE (reprint author), European Infrastruct Translat Med, EATRIS ERIC, NL-1081 HZ Amsterdam, Netherlands. EM antonussi@eatris.eu RI Hajduch, Marian/J-4015-2014 FU Intramural NIH HHS [Z01 HG200319-05] NR 0 TC 0 Z9 0 U1 2 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 EI 1474-1784 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD APR PY 2016 VL 15 IS 4 BP 217 EP + DI 10.1038/nrd.2016.33 PG 3 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA DI0ZM UT WOS:000373225800001 PM 27032820 ER PT J AU Abitbol, CL Moxey-Mims, M AF Abitbol, Carolyn L. Moxey-Mims, Mania TI Low birth weight and the global burden of kidney disease SO NATURE REVIEWS NEPHROLOGY LA English DT News Item ID RISK C1 [Abitbol, Carolyn L.] Univ Miami, Miller Sch Med, Holtz Childrens Hosp, Div Pediat Nephrol,Dept Pediat, POB 016960 M-714, Miami, FL 33101 USA. [Moxey-Mims, Mania] NIDDK, Div Kidney Urol & Hematol, NIH, 6707 Democracy Blvd, Bethesda, MD 20892 USA. RP Abitbol, CL (reprint author), Univ Miami, Miller Sch Med, Holtz Childrens Hosp, Div Pediat Nephrol,Dept Pediat, POB 016960 M-714, Miami, FL 33101 USA. EM cabitbol@med.miami.edu NR 10 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 1759-5061 EI 1759-507X J9 NAT REV NEPHROL JI Nat. Rev. Nephrol. PD APR PY 2016 VL 12 IS 4 BP 199 EP 200 DI 10.1028/nrneph.2016.19 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA DI1IF UT WOS:000373249100002 PM 26898625 ER PT J AU Grobman, WA Bailit, J Lai, YL Reddy, UM Wapner, RJ Varner, MW Caritis, SN Prasad, M Tita, ATN Saade, G Sorokin, Y Rouse, DJ Blackwell, SC Tolosa, JE AF Grobman, William A. Bailit, Jennifer Lai, Yinglei Reddy, Uma M. Wapner, Ronald J. Varner, Michael W. Caritis, Steve N. Prasad, Mona Tita, Alan T. N. Saade, George Sorokin, Yoram Rouse, Dwight J. Blackwell, Sean C. Tolosa, Jorge E. CA Eunice Kennedy Shriver Natl Inst C TI Association of the Duration of Active Pushing With Obstetric Outcomes SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID PROLONGED 2ND-STAGE; NEONATAL OUTCOMES; LABOR; WOMEN AB OBJECTIVE: To estimate the associations between the duration of active pushing during the second stage of labor and maternal and neonatal outcomes. METHODS: We performed an observational study in which data were obtained by trained abstractors from maternal and neonatal charts of deliveries at 25 hospitals over a 3-year period. In this secondary analysis, women with no prior cesarean delivery who had a term, singleton, cephalic gestation and reached complete dilation were analyzed. The duration of pushing, defined as the time from initiation of pushing to either vaginal delivery or the decision to proceed with a cesarean delivery, was determined. The primary maternal outcome was cesarean delivery and the primary neonatal outcome was a composite that included: mechanical ventilation, proven sepsis, brachial plexus palsy, clavicular fracture, skull fracture, other fracture, seizures, hypoxic-ischemic encephalopathy, or death. Nulliparous and parous women were analyzed separately in univariable and then multivariable analyses. RESULTS: A total of 53,285 women were analyzed. In both nulliparous and parous women, longer duration of pushing was associated with increased odds of both cesarean delivery and the neonatal adverse outcome composite. Nevertheless, even after 4 hours of pushing, approximately 78% of nulliparous women who continued with active pushing had a vaginal delivery and more than 97% did not have the composite adverse neonatal outcome. Similarly, after more than 2 hours of pushing, approximately 82% of parous women who continued active pushing delivered vaginally and more than 97% did not have the adverse neonatal outcome. CONCLUSION: A longer duration of pushing is associated with an increased relative risk, but small absolute difference in risk, of neonatal complications. Approximately 78% of nulliparous women delivered vaginally even after 4 hours of pushing. C1 Northwestern Univ, Dept Obstet, Chicago, IL 60611 USA. Northwestern Univ, Dept Gynecol, Chicago, IL 60611 USA. Case Western Reserve Univ, MetroHlth Med Ctr, Cleveland, OH 44106 USA. Columbia Univ, New York, NY USA. Univ Utah, Hlth Sci Ctr, Salt Lake City, UT USA. Univ Pittsburgh, Pittsburgh, PA USA. Ohio State Univ, Columbus, OH 43210 USA. Univ Alabama Birmingham, Birmingham, AL USA. Wayne State Univ, Detroit, MI USA. Brown Univ, Providence, RI 02912 USA. Univ Texas Hlth Sci Ctr Houston, Childrens Mem Hermann Hosp, Houston, TX 77030 USA. Oregon Hlth & Sci Univ, Portland, OR 97201 USA. George Washington Univ, Ctr Biostat, Washington, DC USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Grobman, WA (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Obstet & Gynecol, 250 East Super St,Suite 03-2303, Chicago, IL 60611 USA. EM w-grobman@northwestern.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) [HD21410, HD27869, HD27915, HD27917, HD34116, HD34208, HD36801, HD40500, HD40512, HD40544, HD40545, HD40560, HD40485, HD53097, HD53118]; National Center for Research Resources [UL1 RR024989, 5UL1 RR025764] FX Supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (HD21410, HD27869, HD27915, HD27917, HD34116, HD34208, HD36801, HD40500, HD40512, HD40544, HD40545, HD40560, HD40485, HD53097, HD53118) and the National Center for Research Resources (UL1 RR024989; 5UL1 RR025764). NR 8 TC 8 Z9 8 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD APR PY 2016 VL 127 IS 4 BP 667 EP 673 DI 10.1097/AOG.0000000000001354 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DH4YF UT WOS:000372791000007 PM 26959213 ER PT J AU Rice, MM Landon, MB Varner, MW Casey, BM Reddy, UM Wapner, RJ Rouse, DJ Biggio, JR Thorp, JM Chien, EK Saade, G Peaceman, AM Blackwell, SC VanDorsten, JP AF Rice, Madeline Murguia Landon, Mark B. Varner, Michael W. Casey, Brian M. Reddy, Uma M. Wapner, Ronald J. Rouse, Dwight J. Biggio, Joseph R., Jr. Thorp, John M., Jr. Chien, Edward K. Saade, George Peaceman, Alan M. Blackwell, Sean C. VanDorsten, J. Peter CA Eunice Kennedy Shriver Natl Inst C Maternal-Fetal Med Units Network M TI Pregnancy-Associated Hypertension in Glucose-Intolerant Pregnancy and Subsequent Metabolic Syndrome SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID CARDIOVASCULAR RISK-FACTORS; DIABETES-MELLITUS; CHRONIC DISEASE; CHILD HEALTH; LATER LIFE; PREECLAMPSIA; COMPLICATIONS; COHORT; DISORDERS AB OBJECTIVE:To evaluate whether pregnancy-associated hypertension (preeclampsia or gestational hypertension) among women with varying degrees of glucose intolerance during pregnancy is associated with maternal metabolic syndrome 5-10 years later.METHODS:This was an observational cohort study of women previously enrolled in a treatment trial of mild gestational diabetes mellitus or an observational study of lesser degrees of glucose intolerance evaluated 5-10 years after their index pregnancy. At follow-up, women underwent anthropometric and blood pressure measurements and analysis of fasting glucose and serum lipids.RESULTS:A total of 825 women (47% of eligible women from the original study) were included in this analysis and evaluated at a median 7 years after their index pregnancy at a median age of 35 years. Overall, 239 (29%) had subsequent metabolic syndrome. The frequency of metabolic syndrome and its components was highest in the women who had pregnancy-associated hypertension and delivered preterm. After adjusting for confounding factors, pregnancy-associated hypertension in women who delivered preterm was associated with subsequent hypertension (130/85 mm Hg or greater; relative risk 3.06, 95% confidence interval [CI] 1.95-4.80, P<.001), high triglycerides (150 mg/dL or greater; relative risk 1.82, 95% CI 1.06-3.14, P=.03), and metabolic syndrome (per the American Heart Association and National Heart Lung and Blood Institute Scientific Statement; relative risk 1.78, 95% CI 1.14-2.78, P=.01) compared with women who remained normotensive throughout their index pregnancy and were delivered at term.CONCLUSION:Women with varying degrees of glucose intolerance who experienced pregnancy-associated hypertension and then delivered preterm had a higher frequency of subsequent hypertension, high triglycerides, and metabolic syndrome 5-10 years later. C1 George Washington Univ, Ctr Biostat, Washington, DC USA. Ohio State Univ, Dept Obstet, Columbus, OH 43210 USA. Ohio State Univ, Dept Gynecol, Columbus, OH 43210 USA. Univ Utah, Hlth Sci Ctr, Salt Lake City, UT USA. Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. Columbia Univ, New York, NY USA. Brown Univ, Providence, RI 02912 USA. Univ Alabama Birmingham, Birmingham, AL USA. Univ N Carolina, Chapel Hill, NC USA. Case Western Reserve Univ, MetroHlth Med Ctr, Cleveland, OH 44106 USA. Univ Texas Med Branch, Galveston, TX 77555 USA. Northwestern Univ, Chicago, IL 60611 USA. Univ Texas Hlth Sci Ctr Houston, Childrens Mem Hermann Hosp, Houston, TX 77030 USA. Med Univ S Carolina, Charleston, SC 29425 USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Rice, MM (reprint author), George Washington Univ, Ctr Biostat, Epidemiol & Biostat, 6110 Execut Blvd,Suite 750, Rockville, MD 20852 USA. EM mrice@bsc.gwu.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) [HD27915, HD36801, HD34208, HD34116, HD40485, HD40500, HD27869, HD40560, HD40544, HD53097, HD40512, HD40545]; National Institutes of Health's National Center for Advancing Translational Sciences [UL1TR001070, UL1TR000439] FX Supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (HD27915, HD36801, HD34208, HD34116, HD40485, HD40500, HD27869, HD40560, HD40544, HD53097, HD40512, HD40545) and the National Institutes of Health's National Center for Advancing Translational Sciences (UL1TR001070, UL1TR000439). NR 28 TC 1 Z9 1 U1 2 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD APR PY 2016 VL 127 IS 4 BP 771 EP 779 DI 10.1097/AOG.0000000000001353 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DH4ZC UT WOS:000372793500002 PM 26959208 ER PT J AU Joseph, RM O'Shea, TM Allred, EN Heeren, T Hirtz, D Jara, H Leviton, A Kuban, KCK AF Joseph, Robert M. O'Shea, Thomas M. Allred, Elizabeth N. Heeren, Tim Hirtz, Deborah Jara, Hernan Leviton, Alan Kuban, Karl C. K. CA ELGAN Study Investigators TI Neurocognitive and Academic Outcomes at Age 10 Years of Extremely Preterm Newborns SO PEDIATRICS LA English DT Article ID LOW-BIRTH-WEIGHT; CHILDREN BORN; WHITE-MATTER; EXECUTIVE FUNCTION; GESTATIONAL-AGE; SCHOOL-AGE; PROCESSING SPEED; ADOLESCENTS BORN; GROWTH; BRAIN AB BACKGROUND AND OBJECTIVE: Despite reductions in mortality and morbidity among children born extremely preterm, they remain at high risk of neurocognitive deficits, with up to 40% having significant cognitive deficits at school age. We assessed the rate of neurocognitive impairment in a contemporary US cohort of 873 children aged 10 years who were born <28 weeks' gestation. METHODS: The families of 889 of 966 (92%) children enrolled from 2002 to 2004 at 14 sites in 5 states returned at age 10 years for a comprehensive assessment of IQ, language, attention, executive function, processing speed, visual perception, visual-motor function, and academic achievement. RESULTS: A total of 873 children were assessed with well-validated tests of cognitive and academic function. Distributions of test scores were consistently and markedly shifted below normative expectation, with one-third to two-thirds of children performing >1 SD below age expectation. The most extreme downward shifts were on measures of executive control and processing speed. Multivariate analyses, adjusted for socioeconomic status, growth restriction, and other potential confounders, revealed that the risk of poor outcome was highest at the lowest gestational age across all 18 measures. CONCLUSIONS: More than half of our extremely preterm cohort exhibited moderate or severe neurocognitive deficits at age 10 years, with the most extensive impairments found among those born at the lowest gestational age. Children born extremely preterm continue to be at significant risk of persistent impairments in neurocognitive function and academic achievement, underscoring the need for monitoring and remediating such outcomes beginning in early childhood. C1 [Joseph, Robert M.] Boston Univ, Sch Med, Dept Anat & Neurobiol, 72 East Concord St,L-816, Boston, MA 02118 USA. [Jara, Hernan] Boston Univ, Sch Med, Dept Radiol, Boston, MA 02118 USA. [Heeren, Tim] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [O'Shea, Thomas M.] Univ N Carolina, Dept Pediat, Chapel Hill, NC USA. [Allred, Elizabeth N.; Leviton, Alan] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Allred, Elizabeth N.; Leviton, Alan] Boston Childrens Hosp, Dept Neurol, Neuroepidemiol Unit, Boston, MA USA. [Hirtz, Deborah] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Kuban, Karl C. K.] Boston Med Ctr, Dept Pediat, Boston, MA USA. RP Joseph, RM (reprint author), Boston Univ, Sch Med, Dept Anat & Neurobiol, 72 East Concord St,L-816, Boston, MA 02118 USA. EM rmjoseph@bu.edu FU National Institute of Neurologic Disorders and Stroke [5U01NS040069-05, 2R01NS040069-06A2]; National Institute of Child Health and Human Development [5P30HD018655-28]; National Institutes of Health (NIH) FX This study was supported by grants from the National Institute of Neurologic Disorders and Stroke (5U01NS040069-05, 2R01NS040069-06A2) and the National Institute of Child Health and Human Development (5P30HD018655-28). Funded by the National Institutes of Health (NIH). NR 48 TC 2 Z9 2 U1 6 U2 10 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 APR PY 2016 VL 137 IS 4 AR e20154343 DI 10.1542/peds.2015-4343 PG 9 WC Pediatrics SC Pediatrics GA DI0OU UT WOS:000373197500056 ER PT J AU Keil, MF Zametkin, A Ryder, C Lodish, M Stratakis, CA AF Keil, Margaret F. Zametkin, Alan Ryder, Celia Lodish, Maya Stratakis, Constantine A. TI Cases of Psychiatric Morbidity in Pediatric Patients After Remission of Cushing Syndrome SO PEDIATRICS LA English DT Article ID QUALITY-OF-LIFE; LONG-TERM CURE; TRANSSPHENOIDAL SURGERY; COGNITIVE IMPAIRMENTS; HORMONE-LEVELS; DISEASE; CHILDREN; CORTISOL; ADOLESCENTS; HYPERCORTISOLISM AB Endogenous Cushing syndrome (CS) may have different effects in children than what has been described in adults. Previous studies of children and adolescents with CS have identified cognitive decline despite reversal of brain atrophy after remission of CS. Although the observations of parents of children and adolescents with CS support personality changes, significant psychopathology has not been described in the literature. We report 9 children who underwent successful surgery (transsphenoidal surgery [TSS] or resection of bronchial carcinoid) for treatment of CS and subsequently developed significant affective pathology. Affective symptoms included anger-rage outbursts, suicidal ideation, irritability, anxiety, and depression. One child, who committed suicide 60 months after TSS, had recently discontinued antidepressant medication. She had a history of anxiety during active CS and was treated with an anxiolytic. The 7 patients with onset of symptoms within 7 months of TSS were on glucocorticoid replacement, and 1-year follow-up evaluation showed recovery of hypothalamic-pituitary-adrenal axis and biochemical evidence of remission. The 2 patients who presented with onset of symptoms at 48 months or later underwent endocrine evaluation that showed biochemical evidence of remission and normal anterior pituitary hormone levels. This is the first report of affective symptoms and behavioral dysregulation, including suicidal ideation, in a subgroup of children and adolescents after remission of CS. Health care providers caring for children with CS who have been cured should continue to screen for mental illness, monitor for changes in behavior, and refer as appropriate to mental health professionals. C1 [Keil, Margaret F.; Lodish, Maya; Stratakis, Constantine A.] NICHHD, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Keil, Margaret F.; Lodish, Maya; Stratakis, Constantine A.] NICHHD, Pediat Endocrinol Interinst Training Program, NIH, Bethesda, MD 20892 USA. [Ryder, Celia] NIH, Clin Ctr Nursing Dept, Bldg 10, Bethesda, MD 20892 USA. RP Keil, MF (reprint author), NIH, Clin Res Ctr, 10 Ctr Dr,Bldg 10,Room 1-3330,MSC1103, Bethesda, MD 20892 USA. EM keilm@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health (NIH) [Z01-HD-000642-04] FX Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Funded by the National Institutes of Health (NIH) Intramural project Z01-HD-000642-04 to Dr. Stratakis. NR 45 TC 0 Z9 0 U1 2 U2 4 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 APR PY 2016 VL 137 IS 4 AR e20152234 DI 10.1542/peds.2015-2234 PG 6 WC Pediatrics SC Pediatrics GA DI0OU UT WOS:000373197500015 ER PT J AU Nelson, CP Hoberman, A Shaikh, N Keren, R Mathews, R Greenfi, SP Mattoo, TK Gotman, N Ivanova, A Moxey-Mims, M Carpenter, MA Chesney, RW AF Nelson, Caleb P. Hoberman, Alejandro Shaikh, Nader Keren, Ron Mathews, Ranjiv Greenfi, Saul P. Mattoo, Tej K. Gotman, Nathan Ivanova, Anastasia Moxey-Mims, Marva Carpenter, Myra A. Chesney, Russell W. TI Antimicrobial Resistance and Urinary Tract Infection Recurrence SO PEDIATRICS LA English DT Article ID VESICOURETERAL REFLUX; ANTIBIOTIC-PROPHYLAXIS; CHILDREN; MULTICENTER; TRIAL AB BACKGROUND: The Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial found that recurrent urinary tract infections (rUTI) with resistant organisms were more common in the trimethoprim-sulfamethoxazole prophylaxis (TSP) arm. We describe factors associated with trimethoprim-sulfamethoxazole (TMP-SMX) resistance of rUTIs in RIVUR. METHODS: Children aged 2 to 71 months with first or second UTI (index UTI) and grade I to IV vesicoureteral reflux (VUR) were randomized to TSP or placebo and followed for 2 years. Factors associated with TMP-SMX-resistant rUTI were evaluated. RESULTS: Among 571 included children, 48% were <12 months old, 43% had grade II VUR, and 38% had grade III VUR. Recurrent UTI occurred in 34 of 278 children receiving TSP versus 67 of 293 children receiving placebo. Among those with rUTI, 76% (26/34) of subjects receiving TSP had TMP-SMX-resistant organisms versus 28% (19/67) of subjects receiving placebo (P<.001). The proportion of TMP-SMX-resistant rUTI decreased over time: in the TSP arm, 96% were resistant during the initial 6 months versus 38% resistant during the final 6 months; corresponding proportions for the placebo arm were 32% and 11%. Among children receiving TSP, 7 (13%) of 55 with TMP-SMX-resistant index UTI had rUTI, whereas 27 (12%) of 223 with TMP-SMX-susceptible index UTI had rUTI (adjusted hazard ratio 1.38, 95% confidence interval 0.54-3.56). Corresponding proportions in placebo arm were 17 (26%) of 65 and 50 (22%) of 228 (adjusted hazard ratio 1.33, 95% confidence interval 0.74-2.38). CONCLUSIONS: Although TMP-SMX resistance is more common among children treated with TSP versus placebo, resistance decreased over time. Among children treated with TSP, there was no significant difference in UTI recurrence between those with TMP-SMX-resistant index UTI versus TMP-SMX-susceptible UTI. C1 [Nelson, Caleb P.] Boston Childrens Hosp, Dept Urol, 300 Longwood Ave, Boston, MA 02115 USA. [Hoberman, Alejandro; Shaikh, Nader] Childrens Hosp Pittsburgh, Dept Pediat, Pittsburgh, PA 15213 USA. [Keren, Ron] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. [Mathews, Ranjiv] Johns Hopkins Sch Med, Dept Urol, Baltimore, MD USA. [Greenfi, Saul P.] Women & Childrens Hosp Buffalo, Dept Pediat Urol, Buffalo, NY USA. [Mattoo, Tej K.] Childrens Hosp Michigan, Dept Pediat, Detroit, MI 48201 USA. [Gotman, Nathan; Ivanova, Anastasia; Carpenter, Myra A.] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Moxey-Mims, Marva] NIDDK, NIH, Bethesda, MD 20892 USA. [Chesney, Russell W.] Univ Tennessee, Hlth Sci Ctr, Dept Pediat, Memphis, TN USA. RP Nelson, CP (reprint author), Boston Childrens Hosp, Dept Urol, 300 Longwood Ave, Boston, MA 02115 USA. EM caleb.nelson@childrens.harvard.edu FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services [U01 DK074059, U01 DK074053, U01 DK074082, U01 DK074064, U01 DK074062, U01 DK074063]; University of Pittsburgh Clinical and Translational Science Award from National Center for Advancing Translational Sciences, National Institutes of Health [UL1RR024153, UL1TR000005]; Children's Hospital of Philadelphia Clinical and Translational Science Award from National Center for Advancing Translational Sciences, National Institutes of Health [UL1TR000003]; National Institute of Diabetes and Digestive and Kidney Diseases [K23-DK088943]; National Institutes of Health (NIH) FX Supported by grants U01 DK074059, U01 DK074053, U01 DK074082, U01 DK074064, U01 DK074062, and U01 DK074063 from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services. This trial was also supported by the University of Pittsburgh Clinical and Translational Science Award (UL1RR024153 and UL1TR000005) and the Children's Hospital of Philadelphia Clinical and Translational Science Award (UL1TR000003), both from the National Center for Research Resources, now at the National Center for Advancing Translational Sciences, National Institutes of Health. Dr Nelson is supported by grant K23-DK088943 from the National Institute of Diabetes and Digestive and Kidney Diseases. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Diabetes and Digestive and Kidney Diseases or the National Institutes of Health. Funded by the National Institutes of Health (NIH). NR 13 TC 3 Z9 3 U1 2 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 APR PY 2016 VL 137 IS 4 AR e20152490 DI 10.1542/peds.2015-2490 PG 9 WC Pediatrics SC Pediatrics GA DI0OU UT WOS:000373197500021 ER PT J AU Kahana, SY Jenkins, RA Bruce, D Fernandez, MI Hightow-Weidman, LB Bauermeister, JA AF Kahana, Shoshana Y. Jenkins, Richard A. Bruce, Douglas Fernandez, Maria I. Hightow-Weidman, Lisa B. Bauermeister, Jose A. CA Adolescent Med Trials Network HIV TI Structural Determinants of Antiretroviral Therapy Use, HIV Care Attendance, and Viral Suppression among Adolescents and Young Adults Living with HIV SO PLOS ONE LA English DT Article ID UNITED-STATES; RESIDENTIAL SEGREGATION; RACIAL DISPARITIES; RISK BEHAVIORS; HEALTH; ADHERENCE; PEOPLE; YOUTH; NONADHERENCE; HIV/AIDS AB Background The authors examined associations between structural characteristics and HIV disease management among a geographically diverse sample of behaviorally and perinatally HIV-infected adolescents and young adults in the United States. Methods The sample included 1891 adolescents and young adults living with HIV (27.8% perinatally infected; 72.2% behaviorally infected) who were linked to care through 20 Adolescent Medicine Trials Network for HIV/AIDS Interventions Units. All completed audio computer-assisted self-interview surveys. Chart abstraction or blood draw provided viral load data. Geographic-level variables were extracted from the United States Census Bureau (e.g., socioeconomic disadvantage, percent of Black and Latino households, percent rural) and Esri Crime (e.g., global crime index) databases as Zip Code Tabulation Areas. AIDSVu data (e.g., prevalence of HIV among youth) were extracted at the county-level. Using HLM v.7, the authors conducted means-as-outcomes random effects multi-level models to examine the association between structural-level and individual-level factors and (1) being on antiretroviral therapy (ART) currently; (2) being on ART for at least 6 months; (3) missed HIV care appointments (not having missed any vs. having missed one or more appointments) over the past 12 months; and (4) viral suppression (defined by the corresponding assay cutoff for the lower limit of viral load at each participating site which denoted nondetectability vs. detectability). Results Frequencies for the 4 primary outcomes were as follows: current ART use (n = 1120, 59.23%); ART use for >= 6 months (n = 861, 45.53%); at least one missed HIV care appointment (n = 936, 49.50); and viral suppression (n = 577, 30.51%). After adjusting for individual-level factors, youth living in more disadvantaged areas (defined by a composite score derived from 2010 Census indicators including percent poverty, percent receiving public assistance, percent of female, single-headed households, percent unemployment, and percent of people with less than a high school degree) were less likely to report current ART use (OR: 0.85, 95% CI: 0.72-1.00, p = .05). Among current ART users, living in more disadvantaged areas was associated with greater likelihood of having used ART for >= 6 months. Participants living in counties with greater HIV prevalence among 13-24 year olds were more likely to report current ART use (OR: 1.32, 95% CI: 1.05-1.65, p = .02), >= 6 months ART use (OR: 1.32, 95% CI: 1.05-1.65, p = .02), and to be virally suppressed (OR: 1.50, 95% CI: 1.20-1.87, p = .001); however, youth in these areas were also more likely to report missed medical appointments (OR: 1.32, 95% CI: 1.07-1.63, p = .008). Conclusions The findings underscore the multi-level and structural factors associated with ART use, missed HIV care appointments, and viral suppression for adolescents and young adults in the United States. Consideration of these factors is strongly recommended in future intervention, clinical practice, and policy research that seek to understand the contextual influences on individuals' health behaviors. C1 [Kahana, Shoshana Y.; Jenkins, Richard A.] NIDA, Div Epidemiol Serv & Prevent Res, NIH, Bethesda, MD 20892 USA. [Bruce, Douglas] Depaul Univ, Dept Hlth Sci, Chicago, IL 60604 USA. [Fernandez, Maria I.] Nova SE Univ, Dept Prevent Med, Coll Osteopath Med, Ft Lauderdale, FL 33314 USA. [Fernandez, Maria I.] Nova SE Univ, Dept Publ Hlth Program, Coll Osteopath Med, Ft Lauderdale, FL 33314 USA. [Hightow-Weidman, Lisa B.] Univ N Carolina, Dept Med, Div Infect Dis, Chapel Hill, NC USA. [Bauermeister, Jose A.] Univ Michigan, Sch Publ Hlth, Dept Hlth Behav & Hlth Educ, Ann Arbor, MI 48109 USA. RP Kahana, SY (reprint author), NIDA, Div Epidemiol Serv & Prevent Res, NIH, Bethesda, MD 20892 USA. EM kahanas@mail.nih.gov OI Bauermeister, Jose/0000-0002-9276-2306 FU Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) from National Institutes of Health through National Institute of Child Health and Human Development [U01 HD 040533, U01 HD 040474]; National Institutes on Drug Abuse and 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, with supplemental funding from the National Institutes on Drug Abuse and Mental Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 TC 1 Z9 1 U1 4 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 APR 1 PY 2016 VL 11 IS 4 AR e0151106 DI 10.1371/journal.pone.0151106 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI0QF UT WOS:000373201200006 PM 27035905 ER PT J AU Pagliaccio, D Luking, KR Anokhin, AP Gotlib, IH Hayden, EP Olino, TM Peng, CZ Hajcak, G Barch, DM AF Pagliaccio, David Luking, Katherine R. Anokhin, Andrey P. Gotlib, Ian H. Hayden, Elizabeth P. Olino, Thomas M. Peng, Chun-Zi Hajcak, Greg Barch, Deanna M. TI Revising the BIS/BAS Scale to Study Development: Measurement Invariance and Normative Effects of Age and Sex From Childhood Through Adulthood SO PSYCHOLOGICAL ASSESSMENT LA English DT Article DE BIS/BAS; confirmatory factor analysis; exploratory factor analysis; invariance; development ID ACTIVATION SYSTEM SCALES; OF-FIT INDEXES; BEHAVIORAL-INHIBITION; PSYCHOMETRIC EVALUATION; NEURAL RESPONSE; REINFORCEMENT SENSITIVITY; DEPRESSIVE SYMPTOMS; ADOLESCENT GIRLS; LARGE-SAMPLE; HUMAN BRAIN AB Carver and White's (1994) Behavioral Inhibition System/Behavioral Activation System (BIS/BAS) Scales have been useful tools for studying individual differences in reward-punishment sensitivity; however, their factor structure and invariance across development have not been well tested. In the current study, we examined the factor structure of the BIS/BAS Scales across 5 age groups: 6- to 10-year-old children (N = 229), 11- to 13-year-old early adolescents (N = 311), 14-to 16-year-old late adolescents (N = 353), 18- to 22-year-old young adults (N = 844), and 30- to 45-year-old adults (N = 471). Given poor fit of the standard 4-factor model (BIS, Reward Responsivity, Drive, Fun Seeking) in the literature, we conducted exploratory factor analyses in half of the participants and identified problematic items across age groups. The 4-factor model showed poor fit in our sample, whereas removing the BAS Fun Seeking subscale and problematic items from the remaining subscales improved fit in confirmatory factor analyses conducted with the second half of the participants. The revised model showed strict invariance across age groups and by sex, indicating consistent factor structure, item loadings, thresholds, and unique or residual variances. Additionally, in our cross-sectional data, we observed nonlinear relations between age and subscale scores, where scores tended to be higher in young adulthood than in childhood and later adulthood. Furthermore, sex differences emerged across development; adolescent and adult females had higher BIS scores than males in this age range, whereas sex differences were not observed in childhood. These differences may help us to understand the rise in internalizing psychopathology in adolescence, particularly in females. Future developmental studies are warranted to examine the impact of rewording problematic items. C1 [Pagliaccio, David; Luking, Katherine R.] Washington Univ, Program Neurosci, St Louis, MO 63130 USA. [Anokhin, Andrey P.; Peng, Chun-Zi] Washington Univ, Dept Psychiat, St Louis, MO 63130 USA. [Gotlib, Ian H.] Stanford Univ, Dept Psychol, Stanford, CA 94305 USA. [Hayden, Elizabeth P.] Western Univ, Dept Psychol, Toronto, ON, Canada. [Olino, Thomas M.] Temple Univ, Dept Psychol, Philadelphia, PA 19122 USA. [Luking, Katherine R.; Hajcak, Greg] SUNY Stony Brook, Dept Psychol, Stony Brook, NY USA. [Barch, Deanna M.] Washington Univ, Dept Psychol, St Louis, MO 63130 USA. [Pagliaccio, David] NIMH, Emot & Dev Branch, Rockville, MD 20857 USA. RP Pagliaccio, D (reprint author), NIMH, Emot & Dev Branch, Rockville, MD 20857 USA.; Pagliaccio, D (reprint author), Washington Univ, One Brookings Dr,Box 1125, St Louis, MO 63130 USA. EM david.pagliaccio@wustl.edu OI Pagliaccio, David/0000-0002-1214-1965 FU National Institute of Mental Health [MH097335, MH74849, MH092603, MH097767]; National Institute on Drug Abuse [DA018899, DA027096, DA007261]; National Institute of General Medical Sciences [5T32GM081739]; National Alliance for Research on Schizophrenia and Depression; Canadian Institute of Health Research [MOP 86458]; Social Sciences and Humanities Research Council of Canada FX The studies from which participants were drawn for the current study were supported by grants from the National Institute of Mental Health (MH097335 [Katherine R. Luking], MH74849 [Ian H. Gotlib], MH092603 [Thomas M. Olino], MH097767 [Greg Hajcak]); the National Institute on Drug Abuse (DA018899 [Andrey P. Anokhin], DA027096 [Andrey P. Anokhin], DA018899 [Chun-Zi Peng], DA007261 [Chun-Zi Peng]); the National Institute of General Medical Sciences (5T32GM081739 [David Pagliaccio and Katherine R. Luking]); the National Alliance for Research on Schizophrenia and Depression (Deanna M. Barch); the Canadian Institute of Health Research (MOP 86458 [Elizabeth P. Hayden]); and the Social Sciences and Humanities Research Council of Canada (Elizabeth P. Hayden). The funding agencies had no further role in the design and conduct of the current study, analysis, and interpretation of data or preparation, review, or approval of the manuscript. The authors have no financial interest(s) or conflicts to disclose. David Pagliaccio and Katherine R. Luking had full access to all study data and take responsibility for the integrity of the data and accuracy of the data analysis. We thank all the participants and their families who provided the time and effort to make this study possible. David Pagliaccio and Katherine R. Luking contributed equally to this work. NR 74 TC 2 Z9 2 U1 7 U2 14 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1040-3590 EI 1939-134X J9 PSYCHOL ASSESSMENT JI Psychol. Assess. PD APR PY 2016 VL 28 IS 4 BP 429 EP 442 DI 10.1037/pas0000186 PG 14 WC Psychology, Clinical SC Psychology GA DH7JC UT WOS:000372968600010 PM 26302106 ER PT J AU Siciliano, CA Calipari, ES Yorgason, JT Lovinger, DM Mateo, Y Jimenez, VA Helms, CM Grant, KA Jones, SR AF Siciliano, Cody A. Calipari, Erin S. Yorgason, Jordan T. Lovinger, David M. Mateo, Yolanda Jimenez, Vanessa A. Helms, Christa M. Grant, Kathleen A. Jones, Sara R. TI Increased presynaptic regulation of dopamine neurotransmission in the nucleus accumbens core following chronic ethanol self-administration in female macaques SO PSYCHOPHARMACOLOGY LA English DT Article DE Autoreceptor; Monkey; Nonhuman primate; Kappa opioid receptor; Voltammetry; Drinking ID UNITED-STATES; INDUCED PLASTICITY; SEX-DIFFERENCES; FIRING-RATE; RAT-BRAIN; ALCOHOL; RELEASE; WITHDRAWAL; DEPENDENCE; ADDICTION AB Hypofunction of striatal dopamine neurotransmission, or hypodopaminergia, is a consequence of excessive ethanol use and is hypothesized to be a critical component of alcoholism, driving alcohol intake in an attempt to restore dopamine levels; however, the neurochemical mechanisms involved in these dopaminergic deficiencies are not fully understood. Here we examined the specific dopaminergic adaptations that produce hypodopaminergia and contribute to alcohol use disorders using direct, sub-second measurements of dopamine signaling in nonhuman primates following chronic ethanol self-administration. Female rhesus macaques completed 1 year of daily (22 h/day) ethanol self-administration. Subsequently, fast-scan cyclic voltammetry was used in nucleus accumbens core brain slices to determine alterations in dopamine terminal function, including release and uptake kinetics, and sensitivity to quinpirole (D2/D3 dopamine receptor agonist) and U50,488 (kappa opioid receptor agonist) induced inhibition of dopamine release. Ethanol drinking greatly increased uptake rates, which were positively correlated with lifetime ethanol intake. Furthermore, the sensitivity of dopamine D2/D3 autoreceptors and kappa opioid receptors, which both act as negative regulators of presynaptic dopamine release, was moderately and robustly enhanced in ethanol drinkers. Greater uptake rates and sensitivity to D2-type autoreceptor and kappa opioid receptor agonists could converge to drive a hypodopaminergic state, characterized by reduced basal dopamine and an inability to mount appropriate dopaminergic responses to salient stimuli. Together, we outline the specific alterations to dopamine signaling that may drive ethanol-induced hypofunction of the dopamine system and suggest that the dopamine and dynorphin/kappa opioid receptor systems may be efficacious pharmacotherapeutic targets in the treatment of alcohol use disorders. C1 [Siciliano, Cody A.; Calipari, Erin S.; Yorgason, Jordan T.; Jones, Sara R.] Wake Forest Sch Med, Dept Physiol & Pharmacol, Med Ctr Blvd, Winston Salem, NC 27157 USA. [Calipari, Erin S.] Icahn Sch Med Mt Sinai, Fishberg Dept Neurosci, Friedman Brain Inst, New York, NY 10029 USA. [Lovinger, David M.; Mateo, Yolanda] NIAAA, Lab Integrat Neurosci, Sect Synapt Pharmacol, NIH, Rockville, MD 20852 USA. [Jimenez, Vanessa A.; Helms, Christa M.; Grant, Kathleen A.] Oregon Hlth & Sci Univ, Div Neurosci, Oregon Natl Primate Res Ctr, Beaverton, OR 97006 USA. RP Jones, SR (reprint author), Wake Forest Sch Med, Dept Physiol & Pharmacol, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM srjones@wakehealth.edu OI Siciliano, Cody/0000-0001-9871-2089; Jones, Sara/0000-0002-3424-7576 FU NIH [U01 AA014091, P01 AA021099, F31 DA031533, F31 DA037710, T32 AA007565, F31 AA020439, P51 OD011092, R24 AA019431, P60 AA10760]; Division of Intramural Clinical and Biomedical Research NIAAA; Integrative Neuroscience Initiative on Alcoholism [AA 13510] FX This work was funded by NIH grants U01 AA014091, P01 AA021099 (SRJ), F31 DA031533 (ESC), F31 DA037710, T32 AA007565 (CAS), F31 AA020439 (JTY), P51 OD011092, R24 AA019431, P60 AA10760 (KAG), Division of Intramural Clinical and Biomedical Research NIAAA (DML), and Integrative Neuroscience Initiative on Alcoholism AA 13510 (KAG). NR 47 TC 2 Z9 2 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 EI 1432-2072 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD APR PY 2016 VL 233 IS 8 BP 1435 EP 1443 DI 10.1007/s00213-016-4239-4 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DI1BC UT WOS:000373230000011 PM 26892380 ER PT J AU Patel, N Vytal, K Pavletic, N Stoodley, C Pine, DS Grillon, C Ernst, M AF Patel, Nilam Vytal, Katherine Pavletic, Nevia Stoodley, Catherine Pine, Daniel S. Grillon, Christian Ernst, Monique TI Interaction of threat and verbal working memory in adolescents SO PSYCHOPHYSIOLOGY LA English DT Article DE Cognitive load; Adolescence; Threat; Anxiety; Working memory ID ANXIETY DISORDERS; ATTENTIONAL BIAS; INHIBITORY CONTROL; COGNITIVE CONTROL; SACCADE TASK; PERFORMANCE; STARTLE; CONTINGENCIES; INDIVIDUALS; MATURATION AB Threat induces a state of sustained anxiety that can disrupt cognitive processing, and, reciprocally, cognitive processing can modulate an anxiety response to threat. These effects depend on the level of cognitive engagement, which itself varies as a function of task difficulty. In adults, we recently showed that induced anxiety impaired working memory accuracy at low and medium but not high load. Conversely, increasing the task load reduced the physiological correlates of anxiety (anxiety-potentiated startle). The present work examines such threat-cognition interactions as a function of age. We expected threat to more strongly impact working memory in younger individuals by virtue of putatively restricted cognitive resources and weaker emotion regulation. This was tested by examining the influence of age on the interaction of anxiety and working memory in 25 adolescents (10 to 17 years) and 25 adults (22 to 46 years). Working memory load was manipulated using a verbal n-back task. Anxiety was induced using the threat of an aversive loud scream and measured via eyeblink startle. Findings revealed that, in both age groups, accuracy was lower during threat than safe conditions at low and medium but not high load, and reaction times were faster during threat than safe conditions at high load but did not differ at other loads. Additionally, anxiety-potentiated startle was greater during low and medium than high load. Thus, the interactions of anxiety with working memory appear similar in adolescents and adults. Whether these similarities reflect common neural mechanisms would need to be assessed using functional neuroimaging. C1 [Patel, Nilam; Stoodley, Catherine] Amer Univ, Dept Psychol, Washington, DC 20016 USA. [Patel, Nilam; Vytal, Katherine; Pavletic, Nevia; Pine, Daniel S.; Grillon, Christian; Ernst, Monique] NIMH, NIH, 15K North Dr,MSC 2670, Bethesda, MD 20892 USA. RP Ernst, M (reprint author), NIMH, NIH, 15K North Dr,MSC 2670, Bethesda, MD 20892 USA. EM ernstm@mail.nih.gov RI Stoodley, Catherine/P-2081-2016 OI Stoodley, Catherine/0000-0003-2629-0213 FU Intramural Research Program of the National Institute of Mental Health [MH002798, 1ziamh002781] FX This study was funded by the Intramural Research Program of the National Institute of Mental Health (grants MH002798 and 1ziamh002781). NR 46 TC 3 Z9 3 U1 9 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0048-5772 EI 1469-8986 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD APR PY 2016 VL 53 IS 4 BP 518 EP 526 DI 10.1111/psyp.12582 PG 9 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA DH6GN UT WOS:000372889100010 PM 26589772 ER PT J AU Yang, JM Lynch, KF Uusitalo, UM Foterek, K Hummel, S Silvis, K Aronsson, CA Riikonen, A Rewers, M She, JX Ziegler, AG Simell, OG Toppari, J Hagopian, WA Lernmark, A Akolkar, B Krischer, JP Norris, JM Virtanen, SM Johnson, SB AF Yang, Jimin Lynch, Kristian F. Uusitalo, Ulla M. Foterek, Kristina Hummel, Sandra Silvis, Katherine Aronsson, Carin Andren Riikonen, Anne Rewers, Marian She, Jin-Xiong Ziegler, Anette G. Simell, Olli G. Toppari, Jorma Hagopian, William A. Lernmark, Ake Akolkar, Beena Krischer, Jeffrey P. Norris, Jill M. Virtanen, Suvi M. Johnson, Suzanne B. CA TEDDY Study Grp TI Factors associated with longitudinal food record compliance in a paediatric cohort study SO PUBLIC HEALTH NUTRITION LA English DT Article DE Dietary assessment; Food record compliance; Longitudinal study; Paediatrics; TEDDY ID DIETARY ASSESSMENT METHODS; ENVIRONMENTAL DETERMINANTS; FOLLOW-UP; CHILDREN; PARTICIPANTS; MULTICENTER; YOUNG; TEDDY; BIAS AB Objective Non-compliance with food record submission can induce bias in nutritional epidemiological analysis and make it difficult to draw inference from study findings. We examined the impact of demographic, lifestyle and psychosocial factors on such non-compliance during the first 3 years of participation in a multidisciplinary prospective paediatric study. Design The Environmental Determinants of Diabetes in the Young (TEDDY) study collects a 3 d food record quarterly during the first year of life and semi-annually thereafter. High compliance with food record completion was defined as the participating families submitting one or more days of food record at every scheduled clinic visit. Setting Three centres in the USA (Colorado, Georgia/Florida and Washington) and three in Europe (Finland, Germany and Sweden). Subjects Families who finished the first 3 years of TEDDY participation (n 8096). Results High compliance was associated with having a single child, older maternal age, higher maternal education and father responding to study questionnaires. Families showing poor compliance were more likely to be living far from the study centres, from ethnic minority groups, living in a crowded household and not attending clinic visits regularly. Postpartum depression, maternal smoking behaviour and mother working outside the home were also independently associated with poor compliance. Conclusions These findings identified specific groups for targeted strategies to encourage completion of food records, thereby reducing potential bias in multidisciplinary collaborative research. C1 [Yang, Jimin; Lynch, Kristian F.; Uusitalo, Ulla M.; Krischer, Jeffrey P.] Univ S Florida, Dept Pediat, Morsani Coll Med, Pediat Epidemiol Ctr, 3650 Spectrum Blvd,Suite 100, Tampa, FL 33612 USA. [Foterek, Kristina] Res Inst Child Nutr, Dortmund, Germany. [Hummel, Sandra] Helmholtz Zentrum Munchen, Diabet Res Inst, Neuherberg, Germany. [Hummel, Sandra] Tech Univ Munich, Forschergrp Diabet, Klinikum Rechts Isar, Neuherberg, Germany. [Hummel, Sandra] Forschergrp Diabet eV, Neuherberg, Germany. [Silvis, Katherine; She, Jin-Xiong] Georgia Regents Univ, Med Coll Georgia, Ctr Biotechnol & Genom Med, Augusta, GA USA. [Aronsson, Carin Andren; Lernmark, Ake] Lund Univ, Skane Univ Hosp, Dept Clin Sci, CRC, Malmo, Sweden. [Riikonen, Anne] Natl Inst Hlth & Welf, Terveystieteiden Yksikko, Tampereen Yliopisto, Finland. [Rewers, Marian] Univ Colorado, Sch Med, Barbara Davis Ctr Childhood Diabet, Aurora, CO USA. [Simell, Olli G.] Turku Univ Hosp, Dept Pediat, FIN-20520 Turku, Finland. [Toppari, Jorma] Univ Turku, Dept Physiol & Pediat, Turku, Finland. [Hagopian, William A.] Pacific Northwest Diabet Res Inst, Seattle, WA USA. [Akolkar, Beena] NIDDK, Bethesda, MD 20892 USA. [Norris, Jill M.] Colorado Sch Publ Hlth, Dept Epidemiol, Aurora, CO USA. [Virtanen, Suvi M.] Natl Inst Hlth & Welf, Nutr Unit, Helsinki, Finland. [Johnson, Suzanne B.] Florida State Univ, Coll Med, Dept Med Humanities & Social Sci, Tallahassee, FL 32306 USA. RP Yang, JM (reprint author), Univ S Florida, Dept Pediat, Morsani Coll Med, Pediat Epidemiol Ctr, 3650 Spectrum Blvd,Suite 100, Tampa, FL 33612 USA. EM jimin.yang@epi.usf.edu FU Environmental Determinants of Diabetes in the Young (TEDDY) [U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [HHSN267200700014C]; National Institute of Allergy and Infectious Diseases (NIAID); National Institute of Child Health and Human Development (NICHD); National Institute of Environmental Health Sciences (NIEHS); Juvenile Diabetes Research Foundation (JDRF); Centers for Disease Control and Prevention (CDC); NIH/NCATS Clinical and Translational Science [UL1 TR000064]; University of Colorado [UL1 TR001082] FX Acknowledgements: The authors thank the entire TEDDY study group for their contribution in project development and protocol implementation. The participation of all families is gratefully acknowledged. Financial support: The Environmental Determinants of Diabetes in the Young (TEDDY) study is funded by grants (numbers U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836 and UC4 DK95300) and a contract (number HHSN267200700014C) from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute of Child Health and Human Development (NICHD), the National Institute of Environmental Health Sciences (NIEHS), the Juvenile Diabetes Research Foundation (JDRF) and the Centers for Disease Control and Prevention (CDC). This work supported in part by the NIH/NCATS Clinical and Translational Science Awards to the University of Florida (grant number UL1 TR000064) and the University of Colorado (grant number UL1 TR001082). The sponsors of this study were represented on the Steering Committee and played a role in the study design, its execution and the plans for publication. The corresponding author had the final decision to submit this manuscript for publication. NR 19 TC 0 Z9 0 U1 2 U2 7 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 1368-9800 EI 1475-2727 J9 PUBLIC HEALTH NUTR JI Public Health Nutr. PD APR PY 2016 VL 19 IS 5 BP 804 EP 813 DI 10.1017/S1368980015001883 PG 10 WC Public, Environmental & Occupational Health; Nutrition & Dietetics SC Public, Environmental & Occupational Health; Nutrition & Dietetics GA DH5IM UT WOS:000372820100005 PM 26088478 ER PT J AU Mirabelli, MC Preisser, JS Loehr, LR Agarwal, SK Barr, RG Couper, DJ Hankinson, JL Hyun, N Folsom, AR London, SJ AF Mirabelli, Maria C. Preisser, John S. Loehr, Laura R. Agarwal, Sunil K. Barr, R. Graham Couper, David J. Hankinson, John L. Hyun, Noorie Folsom, Aaron R. London, Stephanie J. TI Lung function decline over 25 years of follow-up among black and white adults in the ARIC study cohort SO RESPIRATORY MEDICINE LA English DT Article DE Aging; Epidemiology; Lung function tests; Respiratory; Spirometry ID OBSTRUCTIVE PULMONARY-DISEASE; ATHEROSCLEROSIS RISK; LONGITUDINAL DATA; GENDER-DIFFERENCES; UNITED-STATES; SMOKING; MORTALITY; HEALTH; COMMUNITIES; ATTRITION AB Background: Interpretation of longitudinal information about lung function decline from middle to older age has been limited by loss to follow-up that may be correlated with baseline lung function or the rate of decline. We conducted these analyses to estimate age-related decline in lung function across groups of race, sex, and smoking status while accounting for dropout from the Atherosclerosis Risk in Communities Study. Methods: We analyzed data from 13,896 black and white participants, aged 45-64 years at the 1987-1989 baseline clinical examination. Using spirometry data collected at baseline and two follow-up visits, we estimated annual population-averaged mean changes in forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) by race, sex, and smoking status using inverse-probability-weighted independence estimating equations conditioning-on-being-alive. Results: Estimated rates of FEV1 decline estimated using inverse-probability-weighted independence estimating equations conditioning on being alive were higher among white than black participants at age 45 years (e.g., male never smokers: black: -29.5 ml/year; white: -51.9 ml/year), but higher among black than white participants by age 75 (black: -51.2 ml/year; white: -26). Observed differences by race were more pronounced among men than among women. By smoking status, FEV1 declines were larger among current than former or never smokers at age 45 across all categories of race and sex. By age 60, FEV1 decline was larger among former and never than current smokers. Estimated annual declines generated using unweighted generalized estimating equations were smaller for current smokers at younger ages in all four groups of race and sex compared with results from weighted analyses that accounted for attrition. Conclusions: Using methods accounting for dropout from an approximately 25-year health study, estimated rates of lung function decline varied by age, race, sex, and smoking status, with largest declines observed among current smokers at younger ages. Published by Elsevier Ltd. C1 [Mirabelli, Maria C.] Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Div Environm Hazards & Hlth Effects, Air Pollut & Resp Hlth Branch, 4770 Buford Highway NE,Mailstop F-60, Atlanta, GA 30341 USA. [Preisser, John S.; Couper, David J.; Hyun, Noorie] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Biostat, 3101 McGavran Greenberg Hall,CB 7420,135 Dauer Dr, Chapel Hill, NC 27599 USA. [Loehr, Laura R.] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, 170 Rosenau Hall,CB 7400,135 Dauer Dr, Chapel Hill, NC 27599 USA. [Agarwal, Sunil K.] Johns Hopkins Univ, Dept Med, 2020 E Monument St,Room B-321, Baltimore, MD 21287 USA. [Barr, R. Graham] Columbia Univ, Med Ctr, Coll Phys & Surg, Dept Med, 630 W 168th St, New York, NY 10032 USA. [Hankinson, John L.] Hankinson Consulting Inc, 1860 Barnett Shoals Rd,Suite 103,PMB 505, Athens, GA 30605 USA. [Folsom, Aaron R.] Univ Minnesota, Div Epidemiol & Community Hlth, 1300 S 2nd St,Suite 300, Minneapolis, MN 55454 USA. [London, Stephanie J.] NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, 111 TW Alexander Dr,POB 12233,MD A3-05, Res Triangle Pk, NC 27709 USA. RP Mirabelli, MC (reprint author), Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Div Environm Hazards & Hlth Effects, Air Pollut & Resp Hlth Branch, 4770 Buford Highway NE,Mailstop F-60, Atlanta, GA 30341 USA. EM mmirabelli@cdc.gov OI Mirabelli, Maria/0000-0002-3540-0085; London, Stephanie/0000-0003-4911-5290 FU National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C]; NIH, National Institute of Environmental Health Sciences FX The Atherosclerosis Risk in Communities 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). Dr. London is supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention. NR 35 TC 2 Z9 2 U1 1 U2 3 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0954-6111 EI 1532-3064 J9 RESP MED JI Respir. Med. PD APR PY 2016 VL 113 BP 57 EP 64 DI 10.1016/j.rmed.2016.02.003 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System SC Cardiovascular System & Cardiology; Respiratory System GA DH8ZO UT WOS:000373085700009 PM 26905512 ER PT J AU Lamichhane, TN Arimbasseri, AG Rijal, K Iben, JR Wei, FY Tomizawa, K Maraia, RJ AF Lamichhane, Tek N. Arimbasseri, Aneeshkumar G. Rijal, Keshab Iben, James R. Wei, Fan Yan Tomizawa, Kazuhito Maraia, Richard J. TI Lack of tRNA-i6A modification causes mitochondrial-like metabolic deficiency in S-pombe by limiting activity of cytosolic tRNA(Tyr), not mito-tRNA SO RNA LA English DT Article DE mitochondria ID SACCHAROMYCES-CEREVISIAE; CODON USAGE; SCHIZOSACCHAROMYCES-POMBE; TRANSLATION ELONGATION; FISSION YEAST; PROTEIN TRANSLATION; ANTICODON LOOP; GENES; ISOPENTENYLADENOSINE; EFFICIENCY AB tRNA-isopentenyl transferases (IPTases) are highly conserved enzymes that form isopentenyl-N-6-A37 (i6A37) on subsets of tRNAs, enhancing their translation activity. Nuclear-encoded IPTases modify select cytosolic (cy-) and mitochondrial (mt-) tRNAs. Mutation in human IPTase, TRIT1, causes disease phenotypes characteristic of mitochondrial translation deficiency due to mt-tRNA dysfunction. Deletion of the Schizosaccharomyces pombe IPTase (tit1-Delta) causes slow growth in glycerol, as well as in rapamycin, an inhibitor of TOR kinase that maintains metabolic homeostasis. Schizosaccharomyces pombe IPTase modifies three different cy-tRNAs(Ser) as well as cy-tRNA(Tyr), cy-tRNA(Trp), and mt-tRNA(Trp). We show that lower ATP levels in tit1-Delta relative to tit1(+) cells are also more decreased by an inhibitor of oxidative phosphorylation, indicative of mitochondrial dysfunction. Here we asked if the tit1-Delta phenotypes are due to hypomodification of cy-tRNA or mt-tRNA. A cytosol-specific IPTase that modifies cy-tRNA, but not mt-tRNA, fully rescues the tit1-Delta phenotypes. Moreover, overexpression of cy-tRNAs also rescues the phenotypes, and cy-tRNA(Tyr) alone substantially does so. Bioinformatics indicate that cy-tRNA(Tyr) is most limiting for codon demand in tit1-Delta cells and that the cytosolic mRNAs most loaded with Tyr codons encode carbon metabolilizing enzymes, many of which are known to localize to mitochondria. Thus, S. pombe i6A37 hypomodification-associated metabolic deficiency results from hypoactivity of cy-tRNA, mostly tRNA(Tyr), and unlike human TRIT1-deficiency does not impair mitochondrial translation due to mt-tRNA hypomodification. We discuss species-specific aspects of i6A37. Specifically relevant to mitochondria, we show that its hypermodified version, ms2i6A37 (2-methylthiolated), which occurs on certain mammalian mt-tRNAs (but not cy-tRNAs), is not found in yeast. C1 [Lamichhane, Tek N.; Arimbasseri, Aneeshkumar G.; Rijal, Keshab; Maraia, Richard J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol & Cell Biol, NIH, Bethesda, MD 20892 USA. [Iben, James R.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Genet Lab, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Wei, Fan Yan; Tomizawa, Kazuhito] Kumamoto Univ, Fac Life Sci, Dept Mol Physiol, Kumamoto 8600862, Japan. [Maraia, Richard J.] US PHS, Commissioned Corps, Rockville, MD 20016 USA. [Lamichhane, Tek N.] Univ Maryland, Fischell Dept Bioengn, College Pk, MD 20742 USA. RP Maraia, RJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol & Cell Biol, NIH, Bethesda, MD 20892 USA.; Maraia, RJ (reprint author), US PHS, Commissioned Corps, Rockville, MD 20016 USA. EM maraiar@mail.nih.gov OI Arimbasseri, Gopalakrishnan Aneeshkumar/0000-0001-5266-2688 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [HD000412-24 PGD] FX We thank Marty Blum (NICHD) for media preparation and Tom Dever (NICHD), Christopher Herbert, Nate Blewett, and members of the Maraia laboratory for discussion and comments on the manuscript. This work was supported by the Intramural Research Program (HD000412-24 PGD) of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 63 TC 1 Z9 1 U1 2 U2 5 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1355-8382 EI 1469-9001 J9 RNA JI RNA PD APR PY 2016 VL 22 IS 4 BP 583 EP 596 DI 10.1261/rna.054064.115 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DH4PA UT WOS:000372766700009 PM 26857223 ER PT J AU Davis, BA Nagarajan, A Forrest, LR Singh, SK AF Davis, Bruce A. Nagarajan, Anu Forrest, Lucy R. Singh, Satinder K. TI Mechanism of Paroxetine (Paxil) Inhibition of the Serotonin Transporter SO SCIENTIFIC REPORTS LA English DT Article ID TRANSMEMBRANE DOMAIN-I; SPECIES-SCANNING MUTAGENESIS; ANTIDEPRESSANT BINDING-SITE; HIGH-AFFINITY RECOGNITION; NEUROTRANSMITTER TRANSPORTERS; NOREPINEPHRINE TRANSPORTERS; STRUCTURAL DETERMINANTS; DOPAMINE TRANSPORTER; BACTERIAL HOMOLOG; MEMBRANE-PROTEINS AB The serotonin transporter (SERT) is an integral membrane protein that exploits preexisting sodium-, chloride-, and potassium ion gradients to catalyze the thermodynamically unfavorable movement of synaptic serotonin into the presynaptic neuron. SERT has garnered significant clinical attention partly because it is the target of multiple psychoactive agents, including the antidepressant paroxetine (Paxil), the most potent selective serotonin reuptake inhibitor known. However, the binding site and orientation of paroxetine in SERT remain controversial. To provide molecular insight, we constructed SERT homology models based on the Drosophila melanogaster dopamine transporter and docked paroxetine to these models. We tested the predicted binding configurations with a combination of radioligand binding and flux assays on wild-type and mutant SERTs. Our data suggest that the orientation of paroxetine, specifically its fluorophenyl ring, in SERT's substrate binding site directly depends on this pocket's charge distribution, and thereby provide an avenue toward understanding and enhancing high-affinity antidepressant activity. C1 [Davis, Bruce A.; Singh, Satinder K.] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, 333 Cedar St, New Haven, CT 06520 USA. [Nagarajan, Anu; Forrest, Lucy R.] Natl Inst Neurol Disorders & Stroke, Computat Struct Biol Sect, 35 Convent Dr, Bethesda, MD 20892 USA. RP Singh, SK (reprint author), Yale Univ, Sch Med, Dept Cellular & Mol Physiol, 333 Cedar St, New Haven, CT 06520 USA. EM satinder.k.singh@yale.edu FU Alfred P. Sloan Foundation; Brain & Behavior Research Foundation; NIH/NIMH [R00MH083050, R01MH100688]; Goodman-Gilman Yale Scholar Award; Intramural Research Program of the National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke FX We thank Gary Rudnick and Suraj Adhikary for helpful comments and discussions. We thank Randy D. Blakely for the plasmids encoding the SERTs from human and Drosophila melanogaster. We are grateful to the NIMH Chemical Synthesis and Drug Supply Program for the paroxetine used throughout this study and to technical support from the LoBoS system administrators and the Molecular Modeling Interest Group at NIH. This work was supported by the Alfred P. Sloan Foundation (S.K.S.), the Brain & Behavior Research Foundation (S.K.S.), the NIH/NIMH (R00MH083050 [S.K.S.] and R01MH100688 [S.K.S.]), a Goodman-Gilman Yale Scholar Award (S.K.S.), and the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke (A.N. and L.R.F.). NR 74 TC 2 Z9 2 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD APR 1 PY 2016 VL 6 AR 23789 DI 10.1038/srep23789 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI0QR UT WOS:000373202500001 PM 27032980 ER PT J AU Wells, KJ Winters, PC Jean-Pierre, P Warren-Mears, V Post, D Van Duyn, MAS Fiscella, K Darnell, J Freund, KM AF Wells, Kristen J. Winters, Paul C. Jean-Pierre, Pascal Warren-Mears, Victoria Post, Douglas Van Duyn, Mary Ann S. Fiscella, Kevin Darnell, Julie Freund, Karen M. CA Patient Navigation Res Program TI Effect of patient navigation on satisfaction with cancer-related care SO SUPPORTIVE CARE IN CANCER LA English DT Article DE Patient navigation; Patient satisfaction; Cancer-related care; Disparities; Patient navigator ID RANDOMIZED CONTROLLED-TRIAL; QUALITY-OF-LIFE; RESEARCH-PROGRAM; DIAGNOSTIC RESOLUTION; FOLLOW-UP; RELIABILITY-ANALYSIS; HEALTH DISPARITIES; ABNORMAL MAMMOGRAM; CASE-MANAGEMENT; CLINICAL-TRIAL AB Purpose Despite growing popularity of patient navigation (PN) as a means to improve cancer care quality and reduce cancer-related disparities, there are few well-designed controlled trials assessing the impact of PN on patient outcomes like satisfaction with care. The present controlled study examined effect of PN on satisfaction with cancer-related care. Methods Patients who presented with a symptom or abnormal screening test (n= 1788) or definitive diagnosis (n= 445) of breast, cervical, colorectal, or prostate cancer from eight Patient Navigator Research Program sites were included in one of two groups: intervention (PN) or comparison (usual care or usual care plus cancer educational materials). Trained patient navigators met with intervention group participants to help them assess and identify resources to address barriers to cancer diagnostic or treatment care. Using a validated instrument, we assessed participants' satisfaction with their cancer diagnostic or treatment care up to 3 months after diagnostic resolution of a cancer-related abnormality or within 3 months of initiation of cancer treatment. Results Overall, patients reported high satisfaction with diagnostic care and cancer treatment. There were no statistically significant differences between PN and control groups in satisfaction with cancer-related care (p> 0.05). Hispanic and African American participants were less likely to report high satisfaction with cancer care when compared to White patients. Middle-aged participants with higher education, higher household income, private insurance, owning their own home, working full-time, and those whose primary language is English had higher satisfaction with cancer-related diagnostic care. Conclusions PN had no statistically significant effect on patients' satisfaction with cancer-related care. Further research is needed to define the patient populations who might benefit from PN, content of PN that is most useful, and services that might enhance PN. C1 [Wells, Kristen J.] San Diego State Univ, Dept Psychol, 6363 Alvarado Court,Suite 103, San Diego, CA 92120 USA. [Wells, Kristen J.] Univ Calif San Diego, Moores Canc Ctr, 6363 Alvarado Court,Suite 103, San Diego, CA 92120 USA. [Winters, Paul C.; Fiscella, Kevin] Univ Rochester, Med Ctr, Family Med Res Programs, 1381 South Ave, Rochester, NY 14620 USA. [Jean-Pierre, Pascal] Univ Notre Dame, Dept Psychol, 109 Haggar Hall, Notre Dame, IN 46556 USA. [Warren-Mears, Victoria] Northwest Portland Area Indian Hlth Board, 2121 SW Broadway Suite 300, Portland, OR 97201 USA. [Post, Douglas] Ohio State Univ, 1590 North High St,Suite 525, Columbus, OH 43201 USA. [Van Duyn, Mary Ann S.] NCI, NIH, 9609 Med Ctr Dr,Room 6W118, Bethesda, MD 20892 USA. [Darnell, Julie] Univ Illinois, Sch Publ Hlth, Div Hlth Policy& Adm, 1603 W Taylor St,Room 758, Chicago, IL 60612 USA. [Freund, Karen M.] Tufts Univ, Sch Med, Tufts Med Ctr, Inst Clin Res & Hlth Policy Studies, 800 Washington St 63, Boston, MA 02111 USA. RP Wells, KJ (reprint author), San Diego State Univ, Dept Psychol, 6363 Alvarado Court,Suite 103, San Diego, CA 92120 USA.; Wells, KJ (reprint author), Univ Calif San Diego, Moores Canc Ctr, 6363 Alvarado Court,Suite 103, San Diego, CA 92120 USA. EM kwells@mail.sdsu.edu OI Swain, Sandra/0000-0002-1320-3830 FU Center to Reduce Cancer Health Disparities, National Cancer Institute, National Institutes of Health [5U01CA116875, 5U01CA116885, 5U01CA116924, 5U01CA116892, 5U01CA116937, 5U01CA116903, 5U01CA117281, 5U01CA116925]; American Cancer Society [SIRSG-05-253-01, CRP-12-219-01-CPPB]; Avon Foundation; NCI [R25CA090314] FX Study data resulted from the collaborative efforts of the following sites, the National Cancer Institute's (NCI's) Center to Reduce Cancer Health Disparities (CRCHD), and the NCI Program Evaluation Contractor (NOVA Research Company). The Patient Navigation Research Program Investigators include NCI, CRCHD: Martha Hare, Mollie Howerton, Ken Chu, Emmanuel Taylor, Mary Ann Van Duyn; NOVA Research: Paul Young, Frederick Snyder, Kathy Parillo; Boston Medical Center and Boston University: PI-Karen Freund, Co-PI-Tracy Battaglia, Sharon Bak, Bonnie Sherman, Sarah Karon, Richard Kalish, Nisha Thrakar, James Taylor, Stephen Tringale, Patrick Egan, Barbara Lottero, Walter Phinney; Denver Health and Hospital Authority: PI-Peter Raich, Co-PI-Elizabeth Whitley, Patricia Valverde, Diane Fairclough, William Thorland, Lina Escobar, Kristin Kilbourn, Besty Risendahl, Rachel Everhart, Evelinn Borrayo, Tim Byers, Hermenia Arambula, Inna Pines, Carol Spitz, Jesus Tovar; George Washington University Cancer Institute: PI-Steven Patierno, Lisa Alexander, Paul Levine, Heather Young, Heather Hoffman, Nancy LaVerda, Larisa Caicedo, William Funderburk, Elmer Huerta, Jeanne Mandelblatt, Jennifer Eng-Wong, Sandra Swain, Wayne Frederick, Felicia Buadoo-Adade; H. Lee Moffitt Cancer Center and Research Institute: PI-Richard Roetzheim, Cathy Meade, Kristen Wells, Ercilia Calcano, Ji-Hyun Lee, William Fulp, Marlene Rivera; Northwest Portland Area Indian Health Board: PI-Victoria Warren-Mears, Matthew Town, Jenine Dankovchik, Meagan Cahn; Northwestern University Robert H. Lurie Comprehensive Cancer Center: PI-Steven Rosen, Melissa Simon, Narissa Nonzee, June McKoy; Ohio State University Comprehensive Cancer Center: PI-Electra Paskett, Douglas Post, Mira Katz, David Murray, Cathy Tatum, Cecilia DeGraffinreid, Gregory Young, Melissa Gorsline; University of Illinois at Chicago and Access Community Health Center: PI-Elizabeth Calhoun, Julie Darnell, Julia Shklovskaya, Mickey Eder, Young Cho, Talar Markossian; University of Rochester: PI-Kevin Fiscella, Samantha Hendren, Jennifer Carroll, Ronald Epstein, Jennifer Griggs, Sharon Humiston, Pascal Jean-Pierre, Starlene Loader, Vi Luong, Sally Rousseau, Charcy Salamone, Michele Sanders, Bonnie Schwartzbauer, Amanat Yosha; University of Texas Health Science Center at San Antonio Cancer Therapy and Research Center: PI-Donald Dudley, Joan Drake, Kevin Hall, Alan Holden, Anand Karnard, Amelie Ramirez, Jennie Quinlan, Pam Saegert. This project was supported by grants 5U01CA116875, 5U01CA116885, 5U01CA116924, 5U01CA116892, 5U01CA116937, 5U01CA116903, 5U01CA117281, 5U01CA116925 from the Center to Reduce Cancer Health Disparities, National Cancer Institute, National Institutes of Health; and # SIRSG-05-253-01 and #CRP-12-219-01-CPPB from the American Cancer Society and the Avon Foundation. Dr. Wells' contribution was also funded by a grant from NCI (R25CA090314; Paul Jacobsen, Ph.D., Principal Investigator). The content of the paper is solely the responsibility of the authors and does not necessarily represent the official views of the American Cancer Society or the CRCHD at the NCI. NR 45 TC 1 Z9 1 U1 3 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-4355 EI 1433-7339 J9 SUPPORT CARE CANCER JI Support. Care Cancer PD APR PY 2016 VL 24 IS 4 BP 1729 EP 1753 DI 10.1007/s00520-015-2946-8 PG 25 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA DI0BE UT WOS:000373159000034 PM 26438146 ER PT J AU Fricks-Gleason, AN German, CL Hoonakker, AJ Friend, DM Ganesh, KK Carver, AS Hanson, GR Fleckenstein, AE Keefe, KA AF Fricks-Gleason, Ashley N. German, Christopher L. Hoonakker, Amanda J. Friend, Danielle M. Ganesh, Kamala K. Carver, Aaron S. Hanson, Glen R. Fleckenstein, Annette E. Keefe, Kristen A. TI An Acute, Epitope-Specific Modification in the Dopamine Transporter Associated With Methamphetamine-Induced Neurotoxicity SO SYNAPSE LA English DT Article DE immunohistochemistry; N-terminus; striatum; rodent; toxicity ID PROTEIN-KINASE-C; BRAIN-SEROTONIN TRANSPORTER; STRIATAL DOPAMINE; ABSTINENT METHAMPHETAMINE; PARKINSONS-DISEASE; SYNTAXIN 1A; DOWN-REGULATION; RAT STRIATUM; PHOSPHORYLATION; AMPHETAMINE AB Preclinical studies demonstrate that repeated, high-dose methamphetamine administrations rapidly decrease plasmalemmal dopamine uptake, which may contribute to aberrant dopamine accumulation, reactive species generation, and long-term dopaminergic deficits. The present study extends these findings by demonstrating a heretofore unreported, epitope-specific modification in the dopamine transporter caused by a methamphetamine regimen that induces these deficits. Specifically, repeated, high-dose methamphetamine injections (4 x 10 mg/kg/injection, 2-h intervals) rapidly decreased immunohistochemical detection of striatal dopamine transporter as assessed 1 h after the final methamphetamine exposure. In contrast, neither a single high dose (1 x 10 mg/kg) nor repeated injections of a lower dose (4 x 2 mg/kg/injection) induced this change. The high-dose regimen-induced alteration was only detected using antibodies directed against the N-terminus. Immunohistochemical staining using antibodies directed against the C-terminus did not reveal any changes. The high-dose regimen also did not alter dopamine transporter expression as assessed using [I-125] RTI-55 autoradiography. These data suggest that the repeated, high-dose methamphetamine regimen alters the N-terminus of the dopamine transporter. Further, these data may be predictive of persistent dopamine deficits caused by the stimulant. Future studies of the signaling cascades involved should provide novel insight into potential mechanisms underlying the physiological and pathophysiological regulation of the dopamine transporter. (C) 2016 Wiley Periodicals, Inc. C1 [Fricks-Gleason, Ashley N.] Regis Univ, Dept Psychol & Neurosci, Denver, CO 80221 USA. [German, Christopher L.; Hoonakker, Amanda J.; Hanson, Glen R.; Fleckenstein, Annette E.] Univ Utah, Sch Dent, Salt Lake City, UT 84108 USA. [Friend, Danielle M.] Natl Inst Diabet & Digest & Kidney Dis, Eating & Addict Sect, Bethesda, MD 20892 USA. [Friend, Danielle M.; Hanson, Glen R.; Fleckenstein, Annette E.; Keefe, Kristen A.] Univ Utah, Interdept Program Neurosci, Salt Lake City, UT 84112 USA. [Ganesh, Kamala K.; Carver, Aaron S.; Keefe, Kristen A.] Univ Utah, Dept Pharmacol & Toxicol, Salt Lake City, UT 84112 USA. RP Keefe, KA (reprint author), Univ Utah, Coll Pharm, Dept Pharmacol & Toxicol, 30 South 2000 East,Rm 201, Salt Lake City, UT 84112 USA. EM k.keefe@utah.edu FU [DA019447]; [DA011367]; [DA000869]; [DA031523]; [DA031883]; [DA013367] FX Contract grant sponsor: DA019447, DA011367, and DA000869 (to A.E.F.); DA031523 (to A.F.G.); DA031883 (to G.R.H.), and DA013367 (to K.A.K.). NR 56 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0887-4476 EI 1098-2396 J9 SYNAPSE JI Synapse PD APR PY 2016 VL 70 IS 4 BP 139 EP 146 DI 10.1002/syn.21891 PG 8 WC Neurosciences SC Neurosciences & Neurology GA DI0NK UT WOS:000373193200001 PM 26799527 ER PT J AU Mozzachio, K Moore, AB Kissling, GE Dixon, D AF Mozzachio, Kristie Moore, Alicia B. Kissling, Grace E. Dixon, Darlene TI Immunoexpression of Steroid Hormone Receptors and Proliferation Markers in Uterine Leiomyoma and Normal Myometrial Tissues from the Miniature Pig, Sus scrofa SO TOXICOLOGIC PATHOLOGY LA English DT Article DE miniature pig; uterine leiomyoma; fibroid; steroid hormone receptors; proliferation markers; immunoexpression ID X-CHROMOSOME INACTIVATION; ESTROGEN-RECEPTOR; STEM-CELLS; PREMENOPAUSAL WOMEN; REPRODUCTIVE-TRACT; FIBROIDS; MODEL; PROGESTERONE; EXPRESSION; ESTRADIOL AB Uterine leiomyomas in miniature pet pigs occur similarly to those in women with regard to frequency, age, parity, and cycling. Clinical signs, gross, and histologic features of the porcine tumors closely resemble uterine leiomyomas (fibroids) in women. Although fibroids are hormonally responsive in women, the roles of estrogen and progesterone have not been fully elucidated. In this study, immunohistochemistry was used to assess the expression of the steroid hormone receptors, estrogen receptor alpha (ER-), estrogen receptor beta (ER-) and progesterone receptor (PR), and cell proliferation markers, proliferating cell nuclear antigen (PCNA) and Ki-67 in tumor and matched myometrial tissues sampled from miniature pigs. A quickscore method was used to determine receptor expression and labeling indices were calculated for the markers. ER-/ and PR were localized to the nuclei of smooth muscle cells in both tissues. PR expression was intense and diffuse throughout all tissues, with correlation between tumors and matched myometria. Conversely, ER- expression was variable between the myometrial and tumor tissues, as well as between animals. ER- expression was low. PCNA and Ki-67 were localized to the nucleus and expression varied among tumors; however, normal tissues were overall negative. These findings support further investigation into the use of the miniature pig as a model of fibroids in women. C1 [Mozzachio, Kristie] Mozzachio Vet Serv, Hillsborough, NC USA. [Moore, Alicia B.; Dixon, Darlene] NTPL, Mol Pathogenesis Grp, Div NTP, Res Triangle Pk, NC USA. [Kissling, Grace E.] NIEHS, Biostat Branch, NIH, US Dept HHS, POB 12233, Res Triangle Pk, NC 27709 USA. RP Dixon, D (reprint author), NIEHS, Natl Toxicol Program, POB 12233,Bldg 101,MD B3-06,Rm B341, Res Triangle Pk, NC 27709 USA. EM dixon@niehs.nih.gov FU Intramural NIH HHS [ZIA ES021196-22, ZIA ES021196-23, Z01 ES021196-15] NR 51 TC 1 Z9 1 U1 1 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 EI 1533-1601 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD APR PY 2016 VL 44 IS 3 SI SI BP 450 EP 457 DI 10.1177/0192623315621414 PG 8 WC Pathology; Toxicology SC Pathology; Toxicology GA DI0VI UT WOS:000373215000018 PM 26692562 ER PT J AU Chen, YL Sakamuru, S Huang, RL Reese, DH Xia, MH AF Chen, Yanling Sakamuru, Srilatha Huang, Ruili Reese, David H. Xia, Menghang TI Identification of compounds that modulate retinol signaling using a cell-based qHTS assay SO TOXICOLOGY IN VITRO LA English DT Article DE Retinol signaling; Developmental toxicant; High-throughput screening; Stem cell; LOPAC; Tox21 ID EMBRYONAL CARCINOMA-CELLS; VITAMIN-A; STEM-CELLS; NUCLEAR RECEPTORS; CANCER-CELLS; HL-60 CELLS; NEURONAL DIFFERENTIATION; ENVIRONMENTAL CHEMICALS; GENE-EXPRESSION; ACID RECEPTORS AB In vertebrates, the retinol (vitamin A) signaling pathway (RSP) controls the biosynthesis and catabolism of all trans retinoic acid (atRA), which regulates transcription of genes essential for embryonic development. Chemicals that interfere with the RSP to cause abnormal intracellular levels of atRA are potential developmental toxicants. To assess chemicals for the ability to interfere with retinol signaling, we have developed a cell-based RARE (Retinoic Acid Response Element) reporter gene assay to identify RSP disruptors. To validate this assay in a quantitative high-throughput screening (qHTS) platform, we screened the Library of Pharmacologically Active Compounds (LOPAC) in both agonist and antagonist modes. The screens detected known RSP agonists, demonstrating assay reliability, and also identified novel RSP agonists including kenpaullone, niclosamide, PD98059 and SU4312, and RSP antagonists including Bay 11-7085, LY294002, 3,4-Methylenedioxy-beta-nitrostyrene, and topoisomerase inhibitors (camptothecin, topotecan, amsacrine hydrochloride, and idarubicin). When evaluated in the P19 pluripotent cell, these compounds were found to affect the expression of the Hoxa1 gene that is essential for embryo body patterning. These results show that the RARE assay is an effective qHTS approach for screening large compound libraries to identify chemicals that have the potential to adversely affect embryonic development through interference with retinol signaling. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Chen, Yanling; Reese, David H.] US FDA, Div Mol Biol, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. [Sakamuru, Srilatha; Huang, Ruili; Xia, Menghang] NIH, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. RP Chen, YL (reprint author), US FDA, 8301 Muirkirk Rd, Laurel, MD 20708 USA. EM yanling.chen@fda.hhs.gov FU National Institute of Environmental Health Sciences/Division of the National Toxicology Program [NTR 12003] FX This work was supported in part through the interagency agreement IAG #NTR 12003 from the National Institute of Environmental Health Sciences/Division of the National Toxicology Program to the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH). This project was also supported in part by the appointment of Dr. Yanling Chen to the Research Participation Program at the Center for Food Safety and Applied Nutrition administrated by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration (U.S. FDA). This research does not necessarily reflect the statements, opinions, views, conclusions, or policies of the NCATS, the NIH, U.S. FDA, or the United States government. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. NR 83 TC 0 Z9 0 U1 2 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0887-2333 J9 TOXICOL IN VITRO JI Toxicol. Vitro PD APR PY 2016 VL 32 BP 287 EP 296 DI 10.1016/j.tiv.2016.01.011 PG 10 WC Toxicology SC Toxicology GA DH4MU UT WOS:000372760900032 PM 26820057 ER PT J AU Wang, T Cunningham, A Houston, K Sharma, AM Chen, LD Dokun, AO Lye, RJ Spolski, R Leonard, WJ Annex, BH AF Wang, Tao Cunningham, Alexis Houston, Kevin Sharma, Aditya M. Chen, Lingdan Dokun, Ayotunde O. Lye, R. John Spolski, Rosanne Leonard, Warren J. Annex, Brian H. TI Endothelial interleukin-21 receptor up-regulation in peripheral artery disease SO VASCULAR MEDICINE LA English DT Article DE endothelial cells; IL-2R; interleukin-21 receptor; ischemia; PAD; peripheral artery disease ID HINDLIMB ISCHEMIA; SKELETAL-MUSCLE; ANGIOGENESIS; CELLS; PREVALENCE AB In most patients with symptomatic peripheral artery disease (PAD), severe stenosis in or occlusion of the major blood vessels that supply the legs make the amount of distal blood flow dependent on the capacity to induce angiogenesis and collateral vessel formation. Currently, there are no medications that improve perfusion to the ischemic limb, and thus directly treat the primary problem of PAD. A recent report from our group in a pre-clinical mouse PAD model showed that interleukin-21 receptor (IL-21R) is up-regulated in the endothelial cells from ischemic hindlimb muscle. We further showed that loss of IL-21R resulted in impaired perfusion recovery in this model. In our study, we sought to determine whether IL-21R is present in the endothelium from ischemic muscle of patients with PAD. Using human gastrocnemius muscle biopsies, we found increased levels of IL-21R in the skeletal muscle endothelial cells of patients with PAD compared to control individuals. Interestingly, PAD patients had approximately 1.7-fold higher levels of circulating IL-21. These data provide direct evidence that the IL-21R pathway is indeed up-regulated in patients with PAD. This pathway may serve as a therapeutic target for modulation. C1 [Wang, Tao; Cunningham, Alexis; Houston, Kevin; Chen, Lingdan; Dokun, Ayotunde O.; Lye, R. John; Annex, Brian H.] Univ Virginia, Robert M Berne Cardiovasc Res Ctr, Charlottesville, VA USA. [Sharma, Aditya M.; Annex, Brian H.] Univ Virginia, Dept Med, Div Cardiovasc Med, Charlottesville, VA USA. [Spolski, Rosanne; Leonard, Warren J.] NHLBI, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. [Spolski, Rosanne; Leonard, Warren J.] NHLBI, Ctr Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Annex, BH (reprint author), Div Cardiovasc Med, POB 800158, Charlottesville, VA 22908 USA. EM annex@virginia.edu RI WANG, TAO/B-1888-2013 FU Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH; [RO1HL16455]; [RO1HL121635] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: WJL and RS are supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH. This work was supported by RO1HL16455 and RO1HL121635 to BHA. NR 19 TC 1 Z9 1 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1358-863X EI 1477-0377 J9 VASC MED JI Vasc. Med. PD APR PY 2016 VL 21 IS 2 BP 99 EP 104 DI 10.1177/1358863X15621798 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DH6LB UT WOS:000372901000002 PM 26705256 ER PT J AU McDermott, MM Guralnik, JM Ferrucci, L Tian, L Kibbe, MR Greenland, P Green, D Liu, K Zhao, LH Wilkins, JT Huffman, MD Shah, SJ Liao, YH Gao, Y Lloyd-Jones, DM Criqui, MH AF McDermott, Mary M. Guralnik, Jack M. Ferrucci, Luigi Tian, Lu Kibbe, Melina R. Greenland, Philip Green, David Liu, Kiang Zhao, Lihui Wilkins, John T. Huffman, Mark D. Shah, Sanjiv J. Liao, Yihua Gao, Ying Lloyd-Jones, Donald M. Criqui, Michael H. TI Community walking speed, sedentary or lying down time, and mortality in peripheral artery disease SO VASCULAR MEDICINE LA English DT Article DE cardiovascular mortality; cardiovascular risk factors; intermittent claudication; modifiable behaviors; peripheral artery disease; physical activity; sedentary; six-minute walk test ID ANKLE-BRACHIAL INDEX; ALL-CAUSE MORTALITY; SLEEP DURATION; PHYSICAL-ACTIVITY; FUNCTIONAL PERFORMANCE; CARDIOVASCULAR EVENTS; DIABETES-MELLITUS; RISK; METAANALYSIS; ASSOCIATION AB We studied whether slower community walking speed and whether greater time spent lying down or sleeping were associated with higher mortality in people with lower extremity peripheral artery disease (PAD). Participants with an ankle-brachial index (ABI) < 0.90 were identified from Chicago medical centers. At baseline, participants reported their usual walking speed outside their home and the number of hours they spent lying down or sleeping per day. Cause of death was adjudicated using death certificates and medical record review. Analyses were adjusted for age, sex, race, comorbidities, ABI, and other confounders. Of 1314 PAD participants, 189 (14.4%) died, including 63 cardiovascular disease (CVD) deaths. Mean follow-up was 34.9 months +/- 18.1. Relative to average or normal pace (2-3 miles/hour), slower walking speed was associated with greater CVD mortality: no walking at all: hazard ratio (HR) = 4.17, 95% confidence interval (CI) = 1.46-11.89; casual strolling (0-2 miles/hour): HR = 2.24, 95% CI = 1.16-4.32; brisk or striding (>3 miles/hour): HR = 0.55, 95% CI = 0.07-4.30. These associations were not significant after additional adjustment for the six-minute walk. Relative to sleeping or lying down for 8-9 hours, fewer or greater hours sleeping or lying down were associated with higher CVD mortality: 4-7 hours: HR = 2.08, 95% CI = 1.06-4.05; 10-11 hours: HR = 4.07, 95% CI = 1.86-8.89; 12 hours: HR = 3.75, 95% CI = 1.47-9.62. These associations were maintained after adjustment for the six-minute walk. In conclusion, slower walking speed outside the home and less than 8 hours or more than 9 hours lying down per day are potentially modifiable behaviors associated with increased CVD mortality in patients with PAD. C1 [McDermott, Mary M.; Green, David; Wilkins, John T.; Huffman, Mark D.; Shah, Sanjiv J.; Lloyd-Jones, Donald M.] Northwestern Univ, Feinberg Sch Med, Dept Med, 750 N Lake Shore Dr,10th Floor, Chicago, IL 60611 USA. [McDermott, Mary M.; Greenland, Philip; Liu, Kiang; Zhao, Lihui; Wilkins, John T.; Huffman, Mark D.; Liao, Yihua; Gao, Ying; Lloyd-Jones, Donald M.] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Guralnik, Jack M.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD USA. [Ferrucci, Luigi] NIA, Bethesda, MD 20892 USA. [Tian, Lu] Stanford Univ, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Kibbe, Melina R.] Northwestern Univ, Feinberg Sch Med, Dept Surg, Chicago, IL 60611 USA. [Kibbe, Melina R.] Jesse Brown Vet Affairs Med Ctr, Chicago, IL USA. [Criqui, Michael H.] Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. RP McDermott, MM (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Med, 750 N Lake Shore Dr,10th Floor, Chicago, IL 60611 USA. EM mdm608@northwestern.edu OI Huffman, Mark/0000-0001-7412-2519 FU National Heart, Lung, and Blood Institute [R01-HL071223, R01-HL076298, R01-HL109244, R01-HL083064, R01-HL64739, R01-HL089619]; Intramural Research Program, National Institute on Aging, NIH FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: grants # R01-HL071223, R01-HL076298, R01-HL109244, R01-HL083064, R01-HL64739 and R01-HL089619 from the National Heart, Lung, and Blood Institute. Supported in part by the Intramural Research Program, National Institute on Aging, NIH. NR 31 TC 1 Z9 1 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1358-863X EI 1477-0377 J9 VASC MED JI Vasc. Med. PD APR PY 2016 VL 21 IS 2 BP 120 EP 129 DI 10.1177/1358863X15626521 PG 10 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DH6LB UT WOS:000372901000005 PM 26873873 ER PT J AU Mason, SM Tobias, DK Clark, CJ Zhang, CL Hu, FB Rich-Edwards, JW AF Mason, Susan M. Tobias, Deirdre K. Clark, Cari J. Zhang, Cuilin Hu, Frank B. Rich-Edwards, Janet W. TI Abuse in Childhood or Adolescence and Gestational Diabetes A Retrospective Cohort Study SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID SEXUAL-ABUSE; GLUCOSE-TOLERANCE; CESAREAN-SECTION; BIRTH-WEIGHT; WOMEN; RISK; HEALTH; DEPRESSION; OBESITY; PREDICTOR AB Introduction: Early life abuse has been linked to later Type 2 diabetes, but its association with gestational diabetes has not been examined. The aim of this study was to examine the association between childhood and adolescent abuse victimization and risk of gestational diabetes in the Nurses' Health Study II. Methods: Participants were asked about experiences of physical and sexual abuse in childhood or adolescence in 2001 and about history of pregnancy complications in 2009. Mothers of singleton live births who provided information on their abuse history comprised the study sample. Modified Poisson regression was used to estimate risk ratios and 95% CIs for gestational diabetes as a function of physical and sexual abuse victimization. Analyses were conducted in 2014-2015. Results: Of 45,550 women in the analysis, 8% reported severe physical abuse and 11% reported forced sexual activity in childhood or adolescence. Approximately 3% (n=3,181) of pregnancies were complicated by gestational diabetes. In adjusted models, severe physical abuse was associated with a 42% greater gestational diabetes risk (risk ratio=1.42, 95% CI=1.21, 1.66) relative to no physical abuse. Forced sexual activity was associated with a 30% greater risk (95% CI=1.14, 1.49). Women with histories of both physical and sexual abuse were at higher risk than women exposed to a single type of abuse. These associations were not explained by overweight status in early adulthood or prior to pregnancy. Conclusions: Childhood and adolescent victimization is associated with increased risk of gestational diabetes in adult women. (C) 2016 American Journal of Preventive Medicine C1 [Mason, Susan M.; Clark, Cari J.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, 1300 South 2nd St,Suite 300, Minneapolis, MN 55419 USA. [Mason, Susan M.; Hu, Frank B.] Brigham & Womens Hosp, Channing Div Network, 75 Francis St, Boston, MA 02115 USA. [Mason, Susan M.; Tobias, Deirdre K.; Hu, Frank B.; Rich-Edwards, Janet W.] Harvard Univ, Sch Med, Boston, MA USA. [Tobias, Deirdre K.] Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Tobias, Deirdre K.; Hu, Frank B.] Harvard Univ, Dept Nutr, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Clark, Cari J.] Univ Minnesota, Sch Med, Dept Med, Minneapolis, MN 55419 USA. [Zhang, Cuilin] NICHD, Epidemiol Branch, Div Intramural Populat Hlth Res, Bethesda, MD USA. [Hu, Frank B.; Rich-Edwards, Janet W.] Harvard Univ, Dept Epidemiol, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. Brigham & Womens Hosp, Connors Ctr Womens Hlth & Gender Biol, 75 Francis St, Boston, MA 02115 USA. RP Mason, SM (reprint author), Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, 1300 South 2nd St,Suite 300, Minneapolis, MN 55419 USA. EM smmason@umn.edu FU Eunice Kennedy Shriver National Institutes of Child Health and Human Development (NICHD) [K12HD055887]; NICHD [R03HD068045]; NIH [RO1HL081557, UM1CA176726] FX Dr. Mason's time is supported by the Building Interdisciplinary Research Careers in Women's Health Grant (K12HD055887) from the Eunice Kennedy Shriver National Institutes of Child Health and Human Development (NICHD), the Office of Research on Women's Health, and the National Institute on Aging, NIH, administered by the University of Minnesota Deborah E. Powell Center for Women's Health. The content is solely the responsibility of the authors and does not necessarily represent the office views of the NICHD or NIH. Dr. Clark is supported by grant R03HD068045 from NICHD. Additional support was provided by grant RO1HL081557 from NIH. Nurses' Health Study II infrastructure is supported by grant UM1CA176726 from NIH. NR 40 TC 0 Z9 0 U1 4 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD APR PY 2016 VL 50 IS 4 BP 436 EP 444 DI 10.1016/j.amepre.2015.08.033 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA DH1RP UT WOS:000372562900002 PM 26547539 ER PT J AU Boudreaux, ED Camargo, CA Arias, SA Sullivan, AF Allen, MH Goldstein, AB Manton, AP Espinola, JA Miller, IW AF Boudreaux, Edwin D. Camargo, Carlos A., Jr. Arias, Sarah A. Sullivan, Ashley F. Allen, Michael H. Goldstein, Amy B. Manton, Anne P. Espinola, Janice A. Miller, Ivan W. TI Improving Suicide Risk Screening and Detection in the Emergency Department SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID FOLLOW-UP; IDEATION; MULTICENTER; PREVENTION; VISITS; TRENDS AB Introduction: The Emergency Department Safety Assessment and Follow-up Evaluation Screening Outcome Evaluation examined whether universal suicide risk screening is feasible and effective at improving suicide risk detection in the emergency department (ED). Methods: A three-phase interrupted time series design was used: Treatment as Usual (Phase 1), Universal Screening (Phase 2), and Universal Screening + Intervention (Phase 3). Eight EDs from seven states participated from 2009 through 2014. Data collection spanned peak hours and 7 days of the week. Chart reviews established if screening for intentional self-harm ideation/behavior (screening) was documented in the medical record and whether the individual endorsed intentional self-harm ideation/behavior (detection). Patient interviews determined if the documented intentional self-harm was suicidal. In Phase 2, universal suicide risk screening was implemented during routine care. In Phase 3, improvements were made to increase screening rates and fidelity. Chi-square tests and generalized estimating equations were calculated. Data were analyzed in 2014. Results: Across the three phases (N=236,791 ED visit records), documented screenings rose from 26% (Phase 1) to 84% (Phase 3) (chi(2) [2, n=236,789]=71,000, p < 0.001). Detection rose from 2.9% to 5.7% (chi(2) [2, n=236,789]=902, p < 0.001). The majority of detected intentional self-harm was confirmed as recent suicidal ideation or behavior by patient interview. Conclusions: Universal suicide risk screening in the ED was feasible and led to a nearly twofold increase in risk detection. If these findings remain true when scaled, the public health impact could be tremendous, because identification of risk is the first and necessary step for preventing suicide. (C) 2016 American Journal of Preventive Medicine C1 [Boudreaux, Edwin D.] Univ Massachusetts, Sch Med, Dept Emergency Med, Worcester, MA 01655 USA. [Boudreaux, Edwin D.] Univ Massachusetts, Sch Med, Dept Psychiat, Worcester, MA 01655 USA. [Boudreaux, Edwin D.] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Worcester, MA 01655 USA. [Camargo, Carlos A., Jr.; Sullivan, Ashley F.; Espinola, Janice A.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Arias, Sarah A.; Miller, Ivan W.] Brown Univ, Dept Psychiat & Human Behav, Butler Hosp, Providence, RI 02912 USA. [Arias, Sarah A.; Miller, Ivan W.] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. [Allen, Michael H.] Univ Colorado, Depress Ctr, Aurora, CO USA. [Allen, Michael H.] Rocky Mt Crisis Partners, Aurora, CO USA. [Goldstein, Amy B.] NIMH, Div Serv & Intervent Res, NIH, Bethesda, MD 20892 USA. [Manton, Anne P.] Cape Cod Hosp, Ctr Behav Hlth, Cape Cod, MA USA. RP Boudreaux, ED (reprint author), Univ Massachusetts, Sch Med, Emergency Med, LA-189,55 Lake Ave North, Worcester, MA 01655 USA. EM edwin.boudreaux@umassmed.edu RI Allen, Michael/A-8776-2011 FU NIMH [U01MH088278]; NIMH FX The project described was supported by Award Number U01MH088278 from NIMH. This grant was funded as a cooperative award by NIMH. NIMH was represented on the Emergency Department Safety Assessment and Follow-up Evaluation (ED-SAFE) Steering Committee by Amy Goldstein, PhD. She collaborated with the other committee members and investigators to oversee the conduct of the study, data collection, analysis, and interpretation. NIMH provided Data and Safety Monitoring Board (DSMB) oversight of the study. The NIMH DSMB liaison was Adam Haim, PhD. NR 25 TC 5 Z9 5 U1 2 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD APR PY 2016 VL 50 IS 4 BP 445 EP 453 DI 10.1016/j.amepre.2015.09.029 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA DH1RP UT WOS:000372562900003 PM 26654691 ER PT J AU Fisher, DE Ward, MM Hoffman, HJ Li, CM Cotch, MF AF Fisher, Diana E. Ward, Michael M. Hoffman, Howard J. Li, Chuan-Ming Cotch, Mary Frances TI Impact of Sensory Impairments on Functional Disability in Adults With Arthritis SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID EXAMINATION SURVEY NHANES; OLDER-ADULTS; HEARING IMPAIRMENT; VISION IMPAIRMENT; RHEUMATOID-ARTHRITIS; PHYSICAL-ACTIVITY; NATIONAL-HEALTH; ASSOCIATION; INFLAMMATION; PREVALENCE AB Introduction: Mobility is reduced in people with sensory impairments and those with arthritis. The combined impact of these conditions may be underappreciated. This study examines the associations between impairments in vision, hearing, and balance and functional ability in adults with versus without arthritis. Methods: Using National Health and Nutrition Examination Survey data from 1999-2004, arthritis status, functional ability, and sensory impairments (vision, hearing, and balance) were assessed from self-reported responses by 6,654 individuals aged >= 50 years (mean age, 63.4 years; 46.3% male). Multivariable regression analyses, conducted in 2014, assessed the associations between sensory impairment and arthritis on functional ability and mobility. Results: Among study participants, 41.8% reported having arthritis; of these, 27.1%, 44.9%, and 35.1% reported impaired vision, hearing, or balance, respectively. Having multiple sensory impairments was significantly associated with reduced functional ability in people with arthritis; individuals with three sensory impairments reported the highest levels of disability for all functional domains (compared with no impairment; lower extremity mobility, 80.2% vs 39.1%; general physical activities, 94.7% vs 75.9%; activities of daily living, 69.7% vs 27.2%; instrumental activities of daily living, 77.2% vs 37.4%; leisure and social activities, 66.3% vs 30.6%; impaired gait speed, 48.1% vs 16.3%; all p < 0.001). Importantly, visual deficits, in combination with arthritis, had the greatest impact on mobility, with odds of impaired mobility at least twice as high as for individuals without arthritis. Conclusions: Addressing sensory deficits, especially difficulties with vision, may improve functional ability, which may be particularly helpful for adults with arthritis. Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Fisher, Diana E.; Cotch, Mary Frances] NEI, Div Epidemiol & Clin Applicat, Intramural Res Program, NIH, Bldg 10-CRC,Room 3-2521, Bethesda, MD 20892 USA. [Ward, Michael M.] NIAMSD, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Hoffman, Howard J.; Li, Chuan-Ming] Natl Inst Deafness & Other Commun Disorders, Epidemiol & Stat Program, Div Sci Programs, NIH, Bethesda, MD USA. RP Fisher, DE (reprint author), NEI, Div Epidemiol & Clin Applicat, Intramural Res Program, NIH, Bldg 10-CRC,Room 3-2521, Bethesda, MD 20892 USA. EM diana.fisher@nih.gov OI Cotch, Mary Frances/0000-0002-2046-4350 FU NIH Intramural Research Programs of the National Eye Institute [ZIAEY000402]; National Institute of Arthritis and Musculoskeletal and Skin Diseases [ZIAAR041153]; Division of Scientific Programs of the National Institute on Deafness and Other Communication Disorders [Y01 DC802809]; National Center for Health Statistics, CDC, IAA [02-430-G67-HOT-99] FX This study was supported by the NIH Intramural Research Programs of the National Eye Institute (ZIAEY000402) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (ZIAAR041153), as well as the Division of Scientific Programs of the National Institute on Deafness and Other Communication Disorders (Interagency Agreement No. Y01 DC802809 with National Center for Health Statistics, CDC, IAA No. 02-430-G67-HOT-99). NR 47 TC 0 Z9 0 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD APR PY 2016 VL 50 IS 4 BP 454 EP 462 DI 10.1016/j.amepre.2015.07.014 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA DH1RP UT WOS:000372562900004 PM 26410186 ER PT J AU McKinnon, RA Siddiqi, SM Chaloupka, FJ Mancino, L Prasad, K AF McKinnon, Robin A. Siddiqi, Sameer M. Chaloupka, Frank J. Mancino, Lisa Prasad, Kislaya TI Obesity-Related Policy/Environmental Interventions A Systematic Review of Economic Analyses SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Review ID NUTRITION EDUCATION-PROGRAM; BODY-MASS INDEX; COST-EFFECTIVENESS; PREVENTION PROGRAM; EXPANDED FOOD; NATURAL EXPERIMENT; PHYSICAL-ACTIVITY; UNITED-STATES; CARE COSTS; HEALTH AB Context: Policy and environmental changes to support and encourage individual-level nutrition and physical activity behavior are underway in many parts of the U.S. and around the world at national, state, and local levels. Yet, to the authors' knowledge, no summary of the cost-benefit or cost-effectiveness studies of obesity-related policy/environmental interventions exists. Evidence acquisition: The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta Analyses) statement guidelines were followed to identify, screen, and describe the protocols used in this systematic review. In 2014, a unique search was conducted of titles and abstracts in MEDLINE, EconLit, SCOPUS, and Web of Science databases that were published from January 2002 through January 2014 in English-language, peer-reviewed journals. The search terms described obesity, physical activity, and diet in combination with economic evaluation. Evidence synthesis: In 2014 and 2015, the results were analyzed. A total of 27 studies met the inclusion criteria, of which 26 described separate interventions. Of the 27 included studies, eight focused on the community and built environment, seven assessed nutrition-related changes, nine reported on the school environment, and three evaluated social marketing and media interventions. The vast majority of included studies reported beneficial economic outcomes of the interventions. Conclusions: Given the large and growing literature on the health and behavioral outcomes of policy and environmental interventions, the relatively low number of located cost-beneft and cost-effectiveness economic assessments appears to indicate a prime opportunity for the research community to address. Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [McKinnon, Robin A.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [McKinnon, Robin A.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Siddiqi, Sameer M.] Johns Hopkins Univ, Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Chaloupka, Frank J.] Univ Illinois, Inst Hlth Res & Policy, Ctr Hlth Policy, Chicago, IL USA. [Mancino, Lisa] Econ Res Serv, USDA, Washington, DC USA. [Prasad, Kislaya] Univ Maryland, Robert H Smith Sch Business, College Pk, MD 20742 USA. RP McKinnon, RA (reprint author), US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM robin.mckinnon@fda.hhs.gov FU Robert Wood Johnson Foundation FX The authors are grateful to Penny Randall-Levy for expert referencing support. Funding for Frank J. Chaloupka's time was supported by the Robert Wood Johnson Foundation's grant to the University of Illinois at Chicago for the Bridging the Gap program. NR 56 TC 1 Z9 1 U1 9 U2 33 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD APR PY 2016 VL 50 IS 4 BP 543 EP 549 DI 10.1016/j.amepre.2015.10.021 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA DH1RP UT WOS:000372562900014 PM 26707464 ER PT J AU White, A Danis, M Gillece, J AF White, Amina Danis, Marion Gillece, Joan TI Abuse survivor perspectives on trauma inquiry in obstetrical practice SO ARCHIVES OF WOMENS MENTAL HEALTH LA English DT Article DE Abuse; Disclosure; Trauma inquiry; Obstetrics; Survivor perspectives ID INTIMATE PARTNER VIOLENCE; POSTTRAUMATIC-STRESS; CHILDHOOD ABUSE; WOMEN; CHILDBIRTH; POSTPARTUM; NEGLECT; HEALTH AB The objective of this study was to explore abuse survivor perspectives on optimal physician approaches to trauma inquiry in prenatal care. Focus group involving six adult female abuse survivors. Five themes emerged for framing "safe" trauma inquiry: (1) a clear definition of trauma, (2) clear purpose for inquiry, (3) reassurance that inquiry was routine, (4) confidentiality, and (5) mention of helpful resources other than psychiatric therapy. Explaining the purpose of trauma inquiry may be important for effectively engaging abuse survivors in obstetrics. C1 [White, Amina; Danis, Marion] NIH, Ctr Clin, Dept Bioeth, 10 Ctr Dr,Bldg 10,Rm 1C118, Bethesda, MD 20892 USA. [Gillece, Joan] Natl Ctr Trauma Informed Care, Natl Assoc State Mental Hlth Program Directors, 66 Canal Ctr Plaza,Suite 302, Alexandria, VA 22314 USA. RP White, A (reprint author), NIH, Ctr Clin, Dept Bioeth, 10 Ctr Dr,Bldg 10,Rm 1C118, Bethesda, MD 20892 USA. EM amina.white@nih.gov FU Substance Abuse and Mental Health Services Administration; National Institutes of Health FX Funding for this study was provided by the Substance Abuse and Mental Health Services Administration. This research was also supported by the Intramural Research Program of the National Institutes of Health. NR 12 TC 0 Z9 0 U1 1 U2 4 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 1434-1816 EI 1435-1102 J9 ARCH WOMEN MENT HLTH JI Arch. Womens Ment. Health PD APR PY 2016 VL 19 IS 2 BP 423 EP 427 DI 10.1007/s00737-015-0547-7 PG 5 WC Psychiatry SC Psychiatry GA DH2GG UT WOS:000372601800025 PM 26189448 ER PT J AU Singh, RK Lee, KM Vujkovic-Cvijin, I Ucmak, D Farahnik, B Abrouk, M Nakamura, M Zhu, TH Bhutani, T Wei, M Liao, W AF Singh, Rasnik K. Lee, Kristina M. Vujkovic-Cvijin, Ivan Ucmak, Derya Farahnik, Benjamin Abrouk, Michael Nakamura, Mio Zhu, Tian Hao Bhutani, Tina Wei, Maria Liao, Wilson TI The role of IL-17 in vitiligo: A review SO AUTOIMMUNITY REVIEWS LA English DT Review DE Interleukin-17; IL-17; Vitiligo ID CD8(+) T-CELLS; COLLAGEN-INDUCED ARTHRITIS; GENOME-WIDE ASSOCIATION; TH17 CELLS; GENERALIZED VITILIGO; GROWTH-FACTOR; PSORIATIC-ARTHRITIS; SUSCEPTIBILITY LOCI; JOINT INFLAMMATION; DISEASE-ACTIVITY AB IL-17 is involved in the pathogenesis of several autoimmune diseases; however its role in vitiligo has not been well defined. Emerging human and mouse studies have demonstrated that systemic, tissue, and cellular levels of IL-17 are elevated in vitiligo. Many studies have also shown significant positive correlations between these levels and disease activity, extent, and severity. Treatments that improve vitiligo, such as ultraviolet B phototherapy, also modulate IL-17 levels. This review synthesizes our current understanding of how IL-17 may influence the pathogenesis of autoimmune vitiligo at the molecular level. This has implications for defining new vitiligo biomarkers and treatments. (C) 2016 Elsevier B.V. All rights reserved. C1 [Singh, Rasnik K.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Lee, Kristina M.; Ucmak, Derya; Bhutani, Tina; Wei, Maria; Liao, Wilson] Univ Calif San Francisco, Dept Dermatol, 2340 Sutter St Room N431,Box 0808, San Francisco, CA 94115 USA. [Vujkovic-Cvijin, Ivan] NIAID, Mucosal Immun Sect, NIH, Bethesda, MD 20892 USA. [Farahnik, Benjamin] Univ Vermont, Coll Med, Burlington, VT 05405 USA. [Abrouk, Michael] Univ Calif Irvine, Sch Med, Irvine, CA 92697 USA. [Nakamura, Mio] Univ Calif San Francisco, Dept Dermatol, Psoriasis & Skin Treatment Ctr, San Francisco, CA 94118 USA. [Zhu, Tian Hao] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. RP Singh, RK (reprint author), Univ Calif San Francisco, Dept Dermatol, 2340 Sutter St Room N431,Box 0808, San Francisco, CA 94115 USA. EM Rasnik.s@gmail.com OI Vujkovic-Cvijin, Ivan/0000-0002-8611-4900 FU NIH [R01AR065174, U01AI119125] FX Dr. Liao receives funding from the NIH (R01AR065174, U01AI119125) and serves as a research investigator for Abbvie, Janssen, and Novartis. NR 89 TC 2 Z9 3 U1 1 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-9972 EI 1873-0183 J9 AUTOIMMUN REV JI Autoimmun. Rev. PD APR PY 2016 VL 15 IS 4 BP 397 EP 404 DI 10.1016/j.autrev.2016.01.004 PG 8 WC Immunology SC Immunology GA DG9DV UT WOS:000372383900010 PM 26804758 ER PT J AU Zhang, W Wu, PL Li, F Tong, GS Chen, XY Zhu, ZH AF Zhang, Wei Wu, Peilin Li, Fang Tong, Guansheng Chen, Xiaoyuan Zhu, Zhaohui TI Potential Applications of Using 68Ga-Evans Blue PET/CT in the Evaluation of Lymphatic Disorder Preliminary Observations SO CLINICAL NUCLEAR MEDICINE LA English DT Article DE lymphedema, chylothorax, chyloperitoneum; Ga-68; chylothorax; Evans blue; PET/CT; chyloperitoneum; lymphoscintigraphy; lymphangioleiomyomatosis ID SENTINEL NODE BIOPSY; LYMPHOSCINTIGRAPHY SPECT/CT; CHYLOTHORAX; LYMPHEDEMA; DYE; CHYLOPERITONEUM; MODEL; LYMPHANGIOLEIOMYOMATOSIS; ALBUMIN; CANCER AB Purpose Potentials of Ga-68-NEB as a PET tracer in the evaluation of a variety of lymphatic drainage disorders were analyzed. Methods Ga-68-NEB was injected subcutaneously, and the PET/CT images were acquired in 13 patients with different suspected lymphatic drainage abnormality. The Ga-68-NEB PET/CT findings were compared with Tc-99m-SC lymphoscintigraphy. Results Ga-68-NEB activity could be clearly observed in the lymphatic route on the PET/CT images from all the patients. In 5 (38.5%) of 13 patients tested, Ga-68-NEB PET/CT provided more information than the Tc-99m-SC lymphoscintigraphy. Conclusions Ga-68-NEB PET/CT can be used as an alternative of Tc-99m-SC lymphoscintigraphy in the evaluation of lymphatic disorders, which enables fast results and might be more accurate than the conventional Tc-99m-SC lymphoscintigraphy. C1 [Zhang, Wei; Wu, Peilin; Li, Fang; Zhu, Zhaohui] Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Nucl Med, Beijing 100730, Peoples R China. [Zhang, Wei; Wu, Peilin; Li, Fang; Zhu, Zhaohui] Peking Union Med Coll, Beijing 100021, Peoples R China. [Tong, Guansheng] Capital Med Univ, Beijing Shijitan Hosp, Dept Nucl Med, Beijing, Peoples R China. [Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD USA. RP Zhu, ZH (reprint author), Beijing Union Med Coll Hosp, Dept Nucl Med, 1 Shuaifuyuan,Wangfujing St, Beijing 100730, Peoples R China.; Chen, XY (reprint author), NIH, 35A Convent Dr,GD937, Bethesda, MD 20892 USA. EM shawn.chen@nih.gov; zhuzhh@pumch.cn NR 31 TC 1 Z9 1 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0363-9762 EI 1536-0229 J9 CLIN NUCL MED JI Clin. Nucl. Med. PD APR PY 2016 VL 41 IS 4 BP 302 EP 308 DI 10.1097/RLU.0000000000001171 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DG6RT UT WOS:000372214500008 PM 26859218 ER PT J AU Luo, YP Li, NS Kiesewetter, DO Chen, XY Li, F AF Luo, Yaping Li, Naishi Kiesewetter, Dale O. Chen, Xiaoyuan Li, Fang TI 68Ga-NOTA-Exendin-4 PET/CT in Localization of an Occult Insulinoma and Appearance of Coexisting Esophageal Carcinoma SO CLINICAL NUCLEAR MEDICINE LA English DT Editorial Material DE esophageal carcinoma; PET/CT; glucagon-like peptide 1 receptor; insulinoma; exendin-4 ID EXPRESSION; TUMORS AB A 61-year-old woman with biochemically proven endogenous hyperinsulinemic hypoglycemia and negative conventional imaging underwent Ga-68-NOTA-exendin-4 PET/CT for localization of insulinoma. Focal intense radioactivity in the tail of the pancreas was observed that was subsequently confirmed as insulinoma pathologically after surgical resection. In addition, esophageal carcinoma with lymph node and hepatic metastases was found by FDG PET/CT in the same patient. Neither the primary carcinoma nor the metastases showed increased radioactivity on Ga-68-NOTA-exendin-4 PET/CT. C1 [Luo, Yaping; Li, Fang] Chinese Acad Med Sci, Dept Nucl Med, Minist Hlth, Beijing 100730, Peoples R China. [Li, Naishi] Chinese Acad Med Sci, Dept Endocrinol, Minist Hlth, Key Lab Endocrinol, Beijing 100730, Peoples R China. [Li, Naishi] Beijing Union Med Coll Hosp, Beijing, Peoples R China. [Kiesewetter, Dale O.; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD USA. RP Li, F (reprint author), Chinese Acad Med Sci, Dept Nucl Med, Beijing 100730, Peoples R China.; Li, F (reprint author), Peking Union Med Coll, Hosp Wangfujing, Beijing 100730, Peoples R China. EM lifang@pumch.cn FU Intramural NIH HHS [ZIA EB000073-06, Z99 EB999999] NR 9 TC 1 Z9 1 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0363-9762 EI 1536-0229 J9 CLIN NUCL MED JI Clin. Nucl. Med. PD APR PY 2016 VL 41 IS 4 BP 341 EP 343 DI 10.1097/RLU.0000000000001087 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DG6RT UT WOS:000372214500022 PM 26647001 ER PT J AU Johnson, RA Rid, A Emanuel, E Wendler, D AF Johnson, Rebecca A. Rid, Annette Emanuel, Ezekiel Wendler, David TI Risks of phase I research with healthy participants: A systematic review SO CLINICAL TRIALS LA English DT Review DE Ethics; phase I clinical trials; healthy volunteers; data transparency; research design ID CLINICAL-TRIALS; ADVERSE EVENTS; VOLUNTEERS; DRUGS; REGISTRATION; ACCESS AB Background/aims: Tragedies suggest that phase I trials in healthy participants may be highly risky. This possibility raises concern that phase I trials may exploit healthy participants to develop new therapies, making the translation of scientific discoveries ethically worrisome. Yet, few systematic data evaluate this concern. This article systematically reviews the risks of published phase I trials in healthy participants and evaluates trial features associated with increased risks. Methods: Data on adverse events and trial characteristics were extracted from all phase I trials published in PubMed, Embase, Cochrane, Scopus, and PsycINFO (1 January 2008-1 October 2012). Inclusion criteria were phase I studies that enrolled healthy participants of any age, provided quantitative adverse event data, and documented the number of participants enrolled. Exclusion criteria included (1) adverse event data not in English, (2) a challenge study in which participants were administered a pathogen, and (3) no quantitative information about serious adverse events. Data on the incidence of adverse events, duration of adverse event monitoring, trial agent tested, participant demographics, and trial location were extracted. Results: In 475 trials enrolling 27,185 participants, there was a median of zero serious adverse events (interquartile range=0-0) and a median of zero severe adverse events (interquartile range=0-0) per 1000 treatment group participants/day of monitoring. The rate of mild and moderate adverse events was a median of 1147.19 per 1000 participants (interquartile range=651.52-1730.9) and 46.07 per 1000 participants/adverse event monitoring day (interquartile range=17.80-77.19). Conclusion: We conclude that phase I trials do cause mild and moderate harms but pose low risks of severe harm. To ensure that this conclusion also applies to unpublished trials, it is important to increase trial transparency. C1 [Johnson, Rebecca A.] Princeton Univ, Dept Sociol, 117 Wallace Hall, Princeton, NJ 08540 USA. [Rid, Annette] Kings Coll London, Dept Social Sci Hlth & Med, London WC2R 2LS, England. [Emanuel, Ezekiel] Univ Penn, Dept Med Eth & Hlth Policy, Philadelphia, PA 19104 USA. [Wendler, David] NIH, Dept Bioeth, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. RP Johnson, RA (reprint author), Princeton Univ, Dept Sociol, 117 Wallace Hall, Princeton, NJ 08540 USA. EM raj2@princeton.edu FU Intramural NIH HHS [Z99 CL999999] NR 46 TC 4 Z9 4 U1 2 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD APR PY 2016 VL 13 IS 2 BP 149 EP 160 DI 10.1177/1740774515602868 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DG8AY UT WOS:000372306000005 PM 26350571 ER PT J AU Coronado, GD Retecki, S Schneider, J Taplin, SH Burdick, T Green, BB AF Coronado, Gloria D. Retecki, Sally Schneider, Jennifer Taplin, Stephen H. Burdick, Tim Green, Beverly B. TI Recruiting community health centers into pragmatic research: Findings from STOP CRC SO CLINICAL TRIALS LA English DT Article DE Clinic recruitment; pragmatic trial; colorectal cancer screening; federally qualified health centers; safety net clinics ID RANDOMIZED-CLINICAL-TRIAL; RE-AIM FRAMEWORK; CANCER; STRATEGIES; DESIGN; CARE AB Background: Challenges of recruiting participants into pragmatic trials, particularly at the level of the health system, remain largely unexplored. As part of Strategies and Opportunities to STOP Colon Cancer in Priority Populations (STOP CRC), we recruited eight separate community health centers (consisting of 26 individual safety net clinics) into a large comparative effectiveness pragmatic study to evaluate methods of raising the rates of colorectal cancer screening. Methods: In partnership with STOP CRC's advisory board, we defined criteria to identify eligible health centers and applied these criteria to a list of health centers in Washington, Oregon, and California affiliated with Oregon Community Health Information Network, a 16-state practice-based research network of federally sponsored health centers. Project staff contacted centers that met eligibility criteria and arranged in-person meetings of key study investigators with health center leadership teams. We used the Consolidated Framework for Implementation Research to thematically analyze the content of discussions during these meetings to identify major facilitators of and barriers to health center participation. Results: From an initial list of 41 health centers, 11 met the initial inclusion criteria. Of these, leaders at three centers declined and at eight centers (26 clinic sites) agreed to participate (73%). Participating and nonparticipating health centers were similar with respect to clinic size, percent Hispanic patients, and percent uninsured patients. Participating health centers had higher proportions of Medicaid patients and higher baseline colorectal cancer screening rates. Common facilitators of participation were perception by center leadership that the project was an opportunity to increase colorectal cancer screening rates and to use electronic health record tools for population management. Barriers to participation were concerns of center leaders about ability to provide fecal testing to and assure follow-up of uninsured patients, limited clinic capacity to prepare mailings required by the study protocol, discomfort with randomization, and concerns about delaying program implementation at some clinics due to the research requirements. Conclusion: Our findings address an important research gap and may inform future efforts to recruit community health centers into pragmatic research. C1 [Coronado, Gloria D.; Retecki, Sally; Schneider, Jennifer] Kaiser Permanente Northwest, Ctr Hlth Res, 3800 N Interstate Ave, Portland, OR 97227 USA. [Taplin, Stephen H.] NCI, Healthcare Delivery Res Program, Bethesda, MD 20892 USA. [Burdick, Tim] Oregon Hlth & Sci Univ, Dept Med Informat & Clin Epidemiol, Portland, OR 97201 USA. [Burdick, Tim] Oregon Hlth & Sci Univ, Dept Family Med, Portland, OR 97201 USA. [Burdick, Tim] Oregon Hlth & Sci Univ, Oregon Clin & Translat Res Inst, Portland, OR 97201 USA. [Green, Beverly B.] Grp Hlth Res Inst, Seattle, WA USA. RP Coronado, GD (reprint author), Kaiser Permanente Northwest, Ctr Hlth Res, 3800 N Interstate Ave, Portland, OR 97227 USA. EM Gloria.d.coronado@kpchr.org FU National Institutes of Health through the National Center for Complementary and Alternative Medicine [UH2AT007782]; National Cancer Institute [4UH3CA18864002] FX Research reported in this publication was supported by the National Institutes of Health through the National Center for Complementary and Alternative Medicine under Award Number UH2AT007782 and the National Cancer Institute under Award Number 4UH3CA18864002. NR 11 TC 0 Z9 0 U1 0 U2 5 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD APR PY 2016 VL 13 IS 2 BP 214 EP 222 DI 10.1177/1740774515608122 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DG8AY UT WOS:000372306000012 PM 26419905 ER PT J AU Kim, SYH Miller, FG AF Kim, Scott Y. H. Miller, Franklin G. TI Response to Magnus and Wilfond SO CLINICAL TRIALS LA English DT Letter C1 [Kim, Scott Y. H.] NIH, Dept Bioeth, Bldg 10, Bethesda, MD 20892 USA. [Miller, Franklin G.] Weill Cornell Med Coll, New York, NY USA. RP Kim, SYH (reprint author), NIH, Dept Bioeth, Bldg 10, Bethesda, MD 20892 USA. EM scott.kim@nih.gov 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 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD APR PY 2016 VL 13 IS 2 BP 244 EP 245 DI 10.1177/1740774515626149 PG 2 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DG8AY UT WOS:000372306000016 PM 26956113 ER PT J AU Evon, DM Wahed, AS Johnson, G Khalili, M Lisker-Melman, M Fontana, RJ Sarkar, S Reeve, BB Hoofnagle, JH AF Evon, Donna M. Wahed, Abdus S. Johnson, Geoffrey Khalili, Mandana Lisker-Melman, Mauricio Fontana, Robert J. Sarkar, Souvik Reeve, Bryce B. Hoofnagle, Jay H. TI Fatigue in Patients with Chronic Hepatitis B Living in North America: Results from the Hepatitis B Research Network (HBRN) SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article DE Liver; Mental health; Patient-reported outcomes; PROMIS; Symptoms ID QUALITY-OF-LIFE; INFORMATION-SYSTEM PROMIS; CHRONIC VIRAL-HEPATITIS; C VIRUS-INFECTION; ANTIVIRAL THERAPY; LIVER-DISEASE; HEALTH; OUTCOMES; SYMPTOMS; CIRRHOSIS AB Fatigue is a common symptom of liver disease but not well characterized in patients with chronic hepatitis B virus (HBV). We assessed the rate of fatigue using a validated instrument in patients with HBV and identified demographic, virologic, and clinical features associated with fatigue in a cross-sectional cohort study from the Hepatitis B Research Network. Participants were English- and Spanish-speaking adults with chronic HBV who were not pregnant nor on treatment. Fatigue was measured using the PROMISA (R) Fatigue 7-item Short Form. The sample included 948 adults: median age 42; 51 % female; 71 % Asian; 74 % college educated; 77 % employed; 41 % inactive HBV carriers; 36 % with active chronic disease; and 2 % with advanced fibrosis, defined as AST-platelet ratio index (APRI) > 1.50. Patients with chronic HBV had a mean fatigue T-score of 46.8 +/- A SD = 7.9, compared to a mean fatigue T-score of 50.0 +/- A 10 in the US general population (p < .0001). In univariate analyses, greater fatigue was associated with demographic and clinical features such as female sex, lower income, more comorbidities, higher APRI score, and poorer mental health (p < 0.05). In multivariate analysis, female sex (p < .001), poorer mental health (p < .001), APRI score (p = .005), and history of diabetes (p = .039) were the strongest independent predictors. The frequency of fatigue in this large cohort of North American chronic HBV patients may be equal to or lower than that reported in the US general population. Patients with advanced fibrosis, more comorbidities, and poorer mental health report worse fatigue. C1 [Evon, Donna M.] Univ N Carolina, Dept Med, Div Gastroenterol & Hepatol, CB 7584,8010 Burnett Womack, Chapel Hill, NC 27599 USA. [Wahed, Abdus S.; Johnson, Geoffrey] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. [Khalili, Mandana] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Lisker-Melman, Mauricio] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Fontana, Robert J.] Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA. [Sarkar, Souvik] Univ Calif Davis, Dept Med, Davis, CA 95616 USA. [Reeve, Bryce B.] Univ N Carolina, Dept Hlth Policy & Management, CB 7584,8010 Burnett Womack, Chapel Hill, NC 27599 USA. [Hoofnagle, Jay H.] NIDDK, Liver Dis Res Branch, Bethesda, MD 20892 USA. RP Evon, DM (reprint author), Univ N Carolina, Dept Med, Div Gastroenterol & Hepatol, CB 7584,8010 Burnett Womack, Chapel Hill, NC 27599 USA. EM donna_evon@med.unc.edu OI Wahed, Abdus/0000-0001-6911-7221 FU National Institute of Diabetes and Digestive and Kidney Diseases [DK 082843, DK082863, DK082864, DK082866, DK082867, DK082871, U01 DK082872, DK082874, DK082919, DK082923, DK082927, DK082943, U01 DK082944, A-DK-3002-001]; intramural program, NIDDK, NIH; Immunology Center (NIH/NIDDK Center of Molecular Studies in Digestive and Liver Diseases) [P30DK50306]; Immunology Center (NIH Public Health Service Research Grant) [M01-RR00040]; NCATS (National Center for Advancing Translational Sciences, NIH) [UL1TR000058]; CTSA Grant [UL1TR000004, UL1TR001111, UL1RR024986]; Gilead Sciences, Inc.,; Roche Molecular Systems via a CRADA through the NIDDK FX The HBRN was funded by a U01 grant from the National Institute of Diabetes and Digestive and Kidney Diseases to the following investigators Lewis R. Roberts, MB, ChB, PhD (DK 082843), Anna Suk-Fong Lok, MD (DK082863), Steven H. Belle, PhD, MScHyg (DK082864), Kyong-Mi Chang, MD (DK082866), Michael W. Fried, MD (DK082867), Adrian M. Di Bisceglie, MD (DK082871), William M. Lee, MD (U01 DK082872), Harry L. A. Janssen, MD, PhD (DK082874), Daryl T-Y Lau, MD, MPH (DK082919), Richard K. Sterling, MD, MSc (DK082923), Steven-Huy B. Han, MD (DK082927), Robert C. Carithers, MD (DK082943), Norah A. Terrault, MD, MPH (U01 DK082944), an interagency agreement with NIDDK: Lilia M. Ganova-Raeva, PhD (A-DK-3002-001), and support from the intramural program, NIDDK, NIH: Marc G. Ghany, MD. Additional funding to support this study was provided to Kyong-Mi Chang, MD, the Immunology Center (NIH/NIDDK Center of Molecular Studies in Digestive and Liver Diseases P30DK50306, NIH Public Health Service Research Grant M01-RR00040), Richard K. Sterling, MD, MSc (UL1TR000058, NCATS (National Center for Advancing Translational Sciences, NIH), Norah A. Terrault, MD, MPH (CTSA Grant Number UL1TR000004), Michael W. Fried, MD (CTSA Grant Number UL1TR001111), and Anna Suk-Fong Lok (CTSA Grant Number UL1RR024986). Additional support was provided by Gilead Sciences, Inc., and Roche Molecular Systems via a CRADA through the NIDDK. NR 44 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 EI 1573-2568 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD APR PY 2016 VL 61 IS 4 BP 1186 EP 1196 DI 10.1007/s10620-015-4006-0 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DG7ZJ UT WOS:000372301900034 PM 26831489 ER PT J AU Georgiev, D Dirnberger, G Wilkinson, L Limousin, P Jahanshahi, M AF Georgiev, Dejan Dirnberger, Georg Wilkinson, Leonora Limousin, Patricia Jahanshahi, Marjan TI In Parkinson's disease on a probabilistic Go/NoGo task deep brain stimulation of the subthalamic nucleus only interferes with withholding of the most prepotent responses SO EXPERIMENTAL BRAIN RESEARCH LA English DT Article DE Subthalamic nucleus (STN); Deep brain stimulation (DBS); Parkinson's disease (PD); Go/NoGo task; Prepotency; Load-dependent effects ID RANDOMIZED-TRIAL; DECISION-MAKING; INHIBITION; SELECTION; IMPULSIVITY; PERFORMANCE; MEDICATION; DISORDERS; CONFLICT; IMPACT AB The evidence on the impact of subthalamic nucleus deep brain stimulation (STN-DBS) on action restraint on Go/NoGO reaction time (RT) tasks in Parkinson's disease (PD) is inconsistent; with some studies reporting no effect and others finding that STN stimulation interferes with withholding of responses and results in more commission errors relative to STN-DBS off. We used a task in which the probability of Go stimuli varied from 100 % (simple RT task) to 80, 50 and 20 % (probabilistic Go/NoGo RT task), thus altering the prepotency of the response and the difficulty in withholding it on NoGo trials. Twenty PD patients with STN-DBS, ten unoperated PD patients and ten healthy controls participated in the study. All participants were tested twice; the order of on versus off stimulation for STN-DBS PD patients was counterbalanced. Both STN-DBS and unoperated PD patients were tested on medication. The results indicated that STN-DBS selectively decreased discriminability when the response was most prepotent (high-80 %, as compared to low Go probability trials-50 and 20 %). Movement times were faster with STN stimulation than with DBS off across different Go probability levels. There was neither an overall nor a selective effect of STN-DBS on RTs depending on the level of Go probability. Furthermore, compared to healthy controls, both STN-DBS and unoperated PD patients were more prone to making anticipatory errors; which was not influenced by STN stimulation. The results provide evidence for 'load-dependent' effects of STN stimulation on action restraint as a function of the prepotency of the Go response. C1 [Georgiev, Dejan; Limousin, Patricia; Jahanshahi, Marjan] UCL Inst Neurol, Sobell Dept Motor Neurosci & Movement Disorders, 33 Queen Sq, London WC1N 3BG, England. [Dirnberger, Georg] Danube Univ, Dept Clin Neurosci, Dr Karl Dorrek Str 30, A-3500 Krems, Austria. [Wilkinson, Leonora] NINDS, Behav Neurol Unit, NIH, 10 Ctr Dr,MSC 1440, Bethesda, MD 20892 USA. RP Jahanshahi, M (reprint author), UCL Inst Neurol, Sobell Dept Motor Neurosci & Movement Disorders, 33 Queen Sq, London WC1N 3BG, England. EM m.jahanshahi@ucl.ac.uk OI Georgiev, Dejan/0000-0003-1832-3441 NR 40 TC 1 Z9 1 U1 4 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0014-4819 EI 1432-1106 J9 EXP BRAIN RES JI Exp. Brain Res. PD APR PY 2016 VL 234 IS 4 BP 1133 EP 1143 DI 10.1007/s00221-015-4531-2 PG 11 WC Neurosciences SC Neurosciences & Neurology GA DG9VY UT WOS:000372433100019 PM 26758720 ER PT J AU Camargo, MC Kim, KM Matsuo, K Torres, J Liao, LM Morgan, DR Michel, A Waterboer, T Zabaleta, J Dominguez, RL Yatabe, Y Kim, S Rocha-Guevara, ER Lissowska, J Pawlita, M Rabkin, CS AF Camargo, M. Constanza Kim, Kyoung-Mee Matsuo, Keitaro Torres, Javier Liao, Linda M. Morgan, Douglas R. Michel, Angelika Waterboer, Tim Zabaleta, Jovanny Dominguez, Ricardo L. Yatabe, Yasushi Kim, Sung Rocha-Guevara, Erick R. Lissowska, Jolanta Pawlita, Michael Rabkin, Charles S. TI Anti-Helicobacter pylori Antibody Profiles in Epstein-Barr virus (EBV)-Positive and EBV-Negative Gastric Cancer SO HELICOBACTER LA English DT Article DE Epstein-Barr virus; gastric cancer; Helicobacter pylori; Interaction; serology ID MULTIPLEX SEROLOGY; EPITHELIAL-CELLS; ADENOCARCINOMA; PROTEINS; RISK; CARCINOGENESIS; ASSOCIATIONS; REACTIVATION; CARCINOMAS; FUSION AB BackgroundHelicobacter pylori is the primary cause of gastric cancer, but about 9% of cases harbor Epstein-Barr virus (EBV) in the tumor cells. There is limited evidence on the possible interaction or antagonism between these infectious agents in gastric carcinogenesis. MethodsWe compared H.pylori serologic profiles of EBV-positive (n=58) and EBV-negative (n=111) noncardia gastric cancer patients from the United States National Cancer Institute's International EBV-Gastric Cancer Consortium. EBV positivity of tumors was assessed by insitu hybridization. Serum levels of 15 antibodies to immunogenic proteins of H.pylori (Cad, CagA, Cag, CagM, Catalase, GroEL, HcpC, HP0231, HP0305, HpaA, HyuA, NapA, Omp, UreA, VacA) were assessed using bead-based multiplex serology. Logistic regression models were used to adjust odds ratios (OR) for country, age, sex, and year of diagnosis. ResultsSeropositivity to individual proteins ranged up to 90% overall. Antibodies to Catalase were borderline associated with tumor EBV positivity (adjusted OR=3.15, p=.0024, Bonferroni corrected p=.036). Distributions of other antibodies did not vary by tumor EBV status. ConclusionSimilarity of host-response indicates the essential etiological role of H.pylori in EBV-positive gastric cancer. C1 [Camargo, M. Constanza; Liao, Linda M.; Rabkin, Charles S.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Kim, Kyoung-Mee] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Pathol, Seoul, South Korea. [Matsuo, Keitaro] Aichi Canc Ctr Res Inst, Div Mol Med, Nagoya, Aichi, Japan. [Torres, Javier] Inst Mexicano Seguro Social, CMN SXXI, UMAE Pediat, Unidad Invest Enfermedades Infecciosas, Mexico City, DF, Mexico. [Morgan, Douglas R.] Vanderbilt Univ, Sch Med, Dept Med, Div Gastroenterol Hepatol & Nutr, 221 Kirkland Hall, Nashville, TN 37235 USA. [Michel, Angelika; Waterboer, Tim; Pawlita, Michael] German Canc Res Ctr DFKZ, Infect & Canc Program, Div Genome Modificat & Carcinogenesis, Heidelberg, Germany. [Zabaleta, Jovanny] Louisiana State Univ, Hlth Sci Ctr, Stanley S Scott Canc Ctr, New Orleans, LA USA. [Dominguez, Ricardo L.] Western Reg Hosp, Dept Med, Santa Rosa De Copan, Honduras. [Yatabe, Yasushi] Aichi Canc Ctr Hosp, Dept Pathol & Mol Diagnost, Nagoya, Aichi 464, Japan. [Kim, Sung] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Surg, Seoul, South Korea. [Rocha-Guevara, Erick R.] Inst Mexicano Seguro Social, CMN SXXI, Hosp Oncol, Mexico City, DF, Mexico. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr & Inst Oncol, Div Canc Epidemiol & Prevent, Warsaw, Poland. RP Camargo, MC (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr,Room 6E206, Rockville, MD 20892 USA. EM camargomc@mail.nih.gov RI Kim, Sung/G-4114-2014; Camargo, M. Constanza/R-9891-2016; Waterboer, Tim/G-1252-2010; OI Liao, Linda/0000-0002-1923-5294; Pawlita, Michael/0000-0002-4720-8306 FU Intramural Research Program of National Cancer Institute, National Institutes of Health, United States of America FX This study was funded by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, United States of America. NR 25 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1083-4389 EI 1523-5378 J9 HELICOBACTER JI Helicobacter PD APR PY 2016 VL 21 IS 2 BP 153 EP 157 DI 10.1111/hel.12249 PG 5 WC Gastroenterology & Hepatology; Microbiology SC Gastroenterology & Hepatology; Microbiology GA DH2YA UT WOS:000372652100009 PM 26251258 ER PT J AU Meaburn, KJ Agunloye, O Devine, M Leshner, M Roloff, GW True, LD Misteli, T AF Meaburn, Karen J. Agunloye, Olufunmilayo Devine, Michelle Leshner, Marc Roloff, Gregory W. True, Lawrence D. Misteli, Tom TI Tissue-of-origin-specific gene repositioning in breast and prostate cancer SO HISTOCHEMISTRY AND CELL BIOLOGY LA English DT Article DE Nuclear architecture; Spatial gene positioning; Breast cancer; Prostate cancer; Tissue specificity ID ORDER CHROMATIN ARRANGEMENTS; NUCLEAR LAMINA INTERACTIONS; INTERPHASE NUCLEI; HUMAN-CHROMOSOMES; CELL-NUCLEI; SPATIAL-ORGANIZATION; GENOME ORGANIZATION; INACTIVE GENES; TERRITORIES; DIFFERENTIATION AB Genes have preferential non-random spatial positions within the cell nucleus. The nuclear position of a subset of genes differ between cell types and some genes undergo repositioning events in disease, including cancer. It is currently unclear whether the propensity of a gene to reposition reflects an intrinsic property of the locus or the tissue. Using quantitative FISH analysis of a set of genes which reposition in cancer, we test here the tissue specificity of gene repositioning in normal and malignant breast or prostate tissues. We find tissue-specific organization of the genome in normal breast and prostate with 40 % of genes occupying differential positions between the two tissue types. While we demonstrate limited overlap between gene sets that repositioned in breast and prostate cancer, we identify two genes that undergo disease-related gene repositioning in both cancer types. Our findings indicate that gene repositioning in cancer is tissue-of-origin specific. C1 [Meaburn, Karen J.; Agunloye, Olufunmilayo; Devine, Michelle; Leshner, Marc; Roloff, Gregory W.; Misteli, Tom] NCI, NIH, Bethesda, MD 20892 USA. [True, Lawrence D.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. RP Meaburn, KJ; Misteli, T (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM meaburnk@mail.nih.gov; mistelit@mail.nih.gov OI Meaburn, Karen/0000-0002-1327-5957 FU Department of Defense Idea Awards [W81XWH-12-1-0224, W81XWH-12-1-0295]; NCI, National Institutes of Health (NIH) under award Pacific Northwest Prostate Cancer SPORE Grant [P50CA097186]; Intramural Research Program of the NIH, NCI, Center for Cancer Research FX This work was supported by a Department of Defense Idea Awards (W81XWH-12-1-0224 and W81XWH-12-1-0295), by NCI, National Institutes of Health (NIH) under award Pacific Northwest Prostate Cancer SPORE Grant (P50CA097186), and in part by the Intramural Research Program of the NIH, NCI, Center for Cancer Research. NR 41 TC 4 Z9 4 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0948-6143 EI 1432-119X J9 HISTOCHEM CELL BIOL JI Histochem. Cell Biol. PD APR PY 2016 VL 145 IS 4 BP 433 EP 446 DI 10.1007/s00418-015-1401-8 PG 14 WC Cell Biology; Microscopy SC Cell Biology; Microscopy GA DH2IQ UT WOS:000372608900008 PM 26791532 ER PT J AU Wang, HZ Leung, M Wandinger-Ness, A Hudson, LG Song, MZ AF Wang, Haizhou Leung, Ming Wandinger-Ness, Angela Hudson, Laurie G. Song, Mingzhou TI Constrained inference of protein interaction networks for invadopodium formation in cancer SO IET SYSTEMS BIOLOGY LA English DT Article ID GENETIC REGULATORY NETWORKS; FOCAL ADHESION KINASE; CELLULAR FUNCTIONS; PODOSOME FORMATION; C-ALPHA; CELLS; SRC; INTEGRIN; INVASION; ACTIN AB Integrating prior molecular network knowledge into interpretation of new experimental data is routine practice in biology research. However, a dilemma for deciphering interactome using Bayes' rule is the demotion of novel interactions with low prior probabilities. Here the authors present constrained generalised logical network (CGLN) inference to predict novel interactions in dynamic networks, respecting previously known interactions and observed temporal coherence. It encodes prior interactions as probabilistic logic rules called local constraints, and forms global constraints using observed dynamic patterns. CGLN finds constraint-satisfying trajectories by solving a k-stops problem in the state space of dynamic networks and then reconstructs candidate networks. They benchmarked CGLN on randomly generated networks, and CGLN outperformed its alternatives when 50% or more interactions in a network are given as local constraints. CGLN is then applied to infer dynamic protein interaction networks regulating invadopodium formation in motile cancer cells. CGLN predicted 134 novel protein interactions for their involvement in invadopodium formation. The most frequently predicted interactions centre around focal adhesion kinase and tyrosine kinase substrate TKS4, and 14 interactions are supported by the literature in molecular contexts related to invadopodium formation. As an alternative to the Bayesian paradigm, the CGLN method offers constrained network inference without requiring prior probabilities and thus can promote novel interactions, consistent with the discovery process of scientific facts that are not yet in common beliefs. C1 [Wang, Haizhou; Song, Mingzhou] New Mexico State Univ, Dept Comp Sci, Las Cruces, NM 88003 USA. [Leung, Ming] Duke Univ, Dept Biol, Durham, NC 27708 USA. [Leung, Ming] Duke Univ, Dept Comp Sci, Durham, NC 27708 USA. [Wandinger-Ness, Angela] Univ New Mexico, Dept Pathol, Albuquerque, NM 87131 USA. [Hudson, Laurie G.] Univ New Mexico, Dept Pharmaceut Sci, Albuquerque, NM 87131 USA. [Wang, Haizhou] SimQuest, Boston, MA 02109 USA. [Leung, Ming] NIAAA, NIH, Bethesda, MD 20892 USA. RP Song, MZ (reprint author), New Mexico State Univ, Dept Comp Sci, Las Cruces, NM 88003 USA. EM joemsong@cs.nmsu.edu OI Song, Mingzhou/0000-0002-6883-6547 FU New Mexico Cowboys for Cancer Research grant; US NIH [2P20GM103451-14]; New Mexico IDeA Networks of Biomedical Research Excellence; US NIH Mountain West Clinical Translational Research Grant [1U54GM104944-2]; US NSF MRI [CNS-1337884] FX The reported work was supported in part by a New Mexico Cowboys for Cancer Research grant to AWN, LGH, and MS and grants to MS under US NIH Grant 2P20GM103451-14 New Mexico IDeA Networks of Biomedical Research Excellence, US NIH Mountain West Clinical Translational Research Grant 1U54GM104944-2, and US NSF MRI Grant CNS-1337884. NR 48 TC 0 Z9 0 U1 0 U2 3 PU INST ENGINEERING TECHNOLOGY-IET PI HERTFORD PA MICHAEL FARADAY HOUSE SIX HILLS WAY STEVENAGE, HERTFORD SG1 2AY, ENGLAND SN 1751-8849 EI 1751-8857 J9 IET SYST BIOL JI IET Syst. Biol. PD APR PY 2016 VL 10 IS 2 BP 76 EP 85 DI 10.1049/iet-syb.2015.0009 PG 10 WC Cell Biology; Mathematical & Computational Biology SC Cell Biology; Mathematical & Computational Biology GA DH4IS UT WOS:000372749600004 ER PT J AU Gomes, MS Hugo, FN Hilgert, JB Sant'Ana, M Padilha, DMP Simonsick, EM Ferrucci, L Reynolds, MA AF Gomes, M. S. Hugo, F. N. Hilgert, J. B. Sant'Ana Filho, M. Padilha, D. M. P. Simonsick, E. M. Ferrucci, L. Reynolds, M. A. TI Apical periodontitis and incident cardiovascular events in the Baltimore Longitudinal Study of Ageing SO INTERNATIONAL ENDODONTIC JOURNAL LA English DT Article DE atherosclerosis; cardiovascular diseases; inflammation; oral-systemic diseases; risk factors ID CORONARY-HEART-DISEASE; ACUTE MYOCARDIAL-INFARCTION; BEAM COMPUTED-TOMOGRAPHY; PERIAPICAL RADIOGRAPHY; ORAL-HEALTH; INFLAMMATORY MARKERS; ASSOCIATION; RISK; MORTALITY; METAANALYSIS AB AimTo evaluate whether the presence of apical periodontitis (AP), root canal treatment (RCT) and endodontic burden (EB) - as the sum of AP and RCT sites - were associated with long-term risk of incident cardiovascular events (CVE), including cardiovascular-related mortality, using data on participants in the Baltimore Longitudinal Study of Ageing (BLSA). MethodologyThis retrospective cohort included 278 dentate participants in the BLSA with complete medical and dental examinations. Periodontal disease (PD) and missing teeth were recorded. The total number of AP and RCT sites was determined from panoramic radiographs. EB was calculated as the sum of AP and RCT sites. Oral inflammatory burden (OIB) was calculated combining PD and EB. The main outcome was incident CVE including angina, myocardial infarction and cardiovascular-related death. Participants were monitored for up to 44years (mean=17.411.1years) following dental examination. Relative risks (RRs) were calculated through Poisson regression models, estimating the relationship between AP, RCT, EB, PD, OIB and incident CVE. ResultsMean age at baseline was 55.016.8years and 51.4% were men. Sixty-two participants (22.3%) developed CVE. Bivariate analysis showed that PD, EB, number of teeth and OIB were associated with incident CVE. Multivariate models, adjusted for socio-demographic and medical variables, showed that age 60years (RR=3.07, 95% CI=1.68-5.62), hypertension (RR=2.0, 95% CI=1.16-3.46) and EB 3 (RR=1.77, 95% CI=1.04-3.02) were independently associated with incident CVE. The association between OIB and incident CVE was reduced to nonsignificance after adjustments (RR=1.97, 95% CI=0.83-4.70). ConclusionsEB in midlife was an independent predictor of CVE amongst community-dwelling participants in the BLSA. Prospective studies are required to evaluate cardiovascular risk reduction with the treatment of AP. View the pubcast on this paper at C1 [Gomes, M. S.] Mil Police Rio Grande Sul, Med & Dent Ctr, Rua Sete Setembro 372, BR-90000190 Porto Alegre, RS, Brazil. [Hugo, F. N.; Hilgert, J. B.; Padilha, D. M. P.] Univ Fed Rio Grande do Sul, Sch Dent, Dept Community Dent, Porto Alegre, RS, Brazil. [Sant'Ana Filho, M.] Univ Fed Rio Grande do Sul, Sch Dent, Postgrad Program, Porto Alegre, RS, Brazil. [Simonsick, E. M.; Ferrucci, L.] NIA, Translat Gerontol Branch, Intramural Res Program, Bethesda, MD 20892 USA. [Reynolds, M. A.] Univ Maryland, Sch Dent, Dept Periodont, Baltimore, MD 21201 USA. RP Gomes, MS (reprint author), Mil Police Rio Grande Sul, Med & Dent Ctr, Rua Sete Setembro 372, BR-90000190 Porto Alegre, RS, Brazil. EM endomax@gmail.com FU NIH/NIA, National Institute on Ageing; CAPES Foundation, Ministry of Education of Brazil [1433/11-3]; Military Police, State Government of Rio Grande do Sul, Brazil FX The authors thank Dr. Earl Jeffrey Metter and Dr. Angelo Bos for their invaluable help in providing and organizing the BLSA database. This study was supported by the Intramural Research Program of the NIH/NIA, National Institute on Ageing; the CAPES Foundation, Ministry of Education of Brazil, doctorate scholarship number 1433/11-3; and the Military Police, State Government of Rio Grande do Sul, Brazil. The authors deny any conflict of interests related to this study. NR 35 TC 5 Z9 5 U1 2 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0143-2885 EI 1365-2591 J9 INT ENDOD J JI Int. Endod. J. PD APR PY 2016 VL 49 IS 4 BP 334 EP 342 DI 10.1111/iej.12468 PG 9 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DH0YF UT WOS:000372509700003 PM 26011008 ER PT J AU Wenger, C Salvador, R Basser, PJ Miranda, PC AF Wenger, Cornelia Salvador, Ricardo Basser, Peter J. Miranda, Pedro C. TI Improving Tumor Treating Fields Treatment Efficacy in Patients With Glioblastoma Using Personalized Array Layouts SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID ALTERNATING ELECTRIC-FIELDS; WHITE-MATTER; ANISOTROPIC CONDUCTIVITY; NOVOTTF(TM)-100A SYSTEM; BRAIN; NOVOTTF-100A; STRENGTH; THERAPY; TISSUE; TRIAL AB Purpose: To investigate tumors of different size, shape, and location and the effect of varying transducer layouts on Tumor Treating Fields (TTFields) distribution in an anisotropic model. Methods and Materials: A realistic human head model was generated from MR images of 1 healthy subject. Four different virtual tumors were placed at separate locations. The transducer arrays were modeled to mimic the TTFields-delivering commercial device. For each tumor location, varying array layouts were tested. The finite element method was used to calculate the electric field distribution, taking into account tissue heterogeneity and anisotropy. Results: In all tumors, the average electric field induced by either of the 2 perpendicular array layouts exceeded the 1-V/cm therapeutic threshold value for TTFields effectiveness. Field strength within a tumor did not correlate with its size and shape but was higher in more superficial tumors. Additionally, it always increased when the array was adapted to the tumor's location. Compared with a default layout, the largest increase in field strength was 184%, and the highest average field strength induced in a tumor was 2.21 V/cm. Conclusions: These results suggest that adapting array layouts to specific tumor locations can significantly increase field strength within the tumor. Our findings support the idea of personalized treatment planning to increase TTFields efficacy for patients with GBM. (C) 2016 The Authors. Published by Elsevier Inc. C1 [Wenger, Cornelia; Salvador, Ricardo; Miranda, Pedro C.] Univ Lisbon, Fac Ciencias, Inst Biophys & Biomed Engn, P-1749016 Lisbon, Portugal. [Basser, Peter J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Tissue Biophys & Biomimet, NIH, Bethesda, MD USA. RP Wenger, C (reprint author), Univ Lisbon, Fac Ciencias, Inst Biophys & Biomed Engn, P-1749016 Lisbon, Portugal. EM cwenger@fc.ul.pt RI Miranda, Pedro/A-5643-2013; OI Miranda, Pedro/0000-0002-6793-8111; Wenger, Cornelia/0000-0001-7889-9093 FU Novocure; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; Foundation for Science and Technology, Portugal FX C.W. and P.C.M. were supported by Novocure. P.J.B. was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. P.C.M. and R.S. were supported in part by the Foundation for Science and Technology, Portugal. NR 21 TC 1 Z9 1 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD APR 1 PY 2016 VL 94 IS 5 BP 1137 EP 1143 DI 10.1016/j.ijrobp.2015.11.042 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DH1SI UT WOS:000372564800020 PM 26883559 ER PT J AU Chung, EJ McKay-Corkum, G Chung, S White, A Scroggins, BT Mitchell, JB Mulligan-Kehoe, MJ Citrin, D AF Chung, Eun Joo McKay-Corkum, Grace Chung, Su White, Ayla Scroggins, Bradley T. Mitchell, James B. Mulligan-Kehoe, Mary Jo Citrin, Deborah TI Truncated Plasminogen Activator Inhibitor-1 Protein Protects From Pulmonary Fibrosis Mediated by Irradiation in a Murine Model SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID INDUCED LUNG FIBROSIS; GROWTH-FACTOR-BETA; SENESCENT FIBROBLASTS; EXTRACELLULAR-MATRIX; MOLECULAR-MECHANISMS; THORACIC IRRADIATION; TRANSGENIC MICE; STEM-CELLS; INJURY; CANCER AB Purpose: To determine whether the delivery of recombinant truncated plasminogen activator inhibitor-1 (PAI-1) protein (rPAI-1(23)) would protect from the development of radiation-induced lung injury. Methods and Materials: C57Bl/6 mice received intraperitoneal injections of rPAI-123 (5.4 mu g/kg/d) or vehicle for 18 weeks, beginning 2 days before irradiation (IR) (5 daily fractions of 6 Gy). Cohorts of mice were followed for survival (n=8 per treatment) and tissue collection (n=3 per treatment and time point). Fibrosis in lung was assessed with Masson Trichrome staining and measurement of hydroxyproline content. Senescence was assessed with staining for beta-galactosidase activity in lung and primary pneumocytes. Results: Hydroxyproline content in irradiated lung was significantly reduced in mice that received rPAI-123 compared with mice that received vehicle (IR+vehicle: 84.97 mu g/lung; IR+rPAI-1(23): 56.2 mu g/lung, P=.001). C57Bl/6 mice exposed to IR+vehicle had dense foci of subpleural fibrosis at 19 weeks, whereas the lungs of mice exposed to IR+rPAI-1(23) were largely devoid of fibrotic foci. Cellular senescence was significantly decreased by rPAI-123 treatment in primary pneumocyte cultures and in lung at multiple time points after IR. Conclusions: These studies identify that rPAI-123 is capable of preventing radiation-induced fibrosis in murine lungs. These antifibrotic effects are associated with increased fibrin metabolism, enhanced matrix metalloproteinase-3 expression, and reduced senescence in type 2 pneumocytes. Thus, rPAI-123 is a novel therapeutic option for radiation-induced fibrosis. Published by Elsevier Inc. C1 [Chung, Eun Joo; McKay-Corkum, Grace; Chung, Su; White, Ayla; Scroggins, Bradley T.; Citrin, Deborah] NIH, Radiat Oncol Branch, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. [Mitchell, James B.] NIH, Radiat Biol Branch, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. [Mulligan-Kehoe, Mary Jo] Geisel Sch Med Dartmouth, Lebanon, NH USA. RP Citrin, D (reprint author), NCI, Radiat Oncol Branch, Bldg 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 in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 56 TC 2 Z9 2 U1 2 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD APR 1 PY 2016 VL 94 IS 5 BP 1163 EP 1172 DI 10.1016/j.ijrobp.2015.11.044 PG 10 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DH1SI UT WOS:000372564800023 PM 26883561 ER PT J AU De Bruycker, JJ Selleri, S Metras, ME Cros, G Saint-Cyr, C Lamarre, V Egerszegi, P Barsalou, J Merouani, A Alos, N Hatami, A Morin, MP Vincent, M Miron, MC Godin-Berthiaume, V Levasseur, MC Lemelin, M Fernandez, I Le Deist, F Lebon, P Haddad, E Goldbach-Mansky, R Decaluwe, H AF De Bruycker, Jean Jacques Selleri, Silvia Metras, Marie-Elaine Cros, Guilhem Saint-Cyr, Claire Lamarre, Valerie Egerszegi, Patricia Barsalou, Julie Merouani, Aicha Alos, Nathalie Hatami, Afshin Morin, Marie-Paule Vincent, Melanie Miron, Marie-Claude Godin-Berthiaume, Vanessa Levasseur, Marie-Claude Lemelin, Maude Fernandez, Isabel Le Deist, Francoise Lebon, Pierre Haddad, Elie Goldbach-Mansky, Raphaela Decaluwe, Helene TI RUXOLITINIB AS A SALVAGE TREATMENT FOR A SEVERE REFRACTORY INTERFERONOPATHY SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [De Bruycker, Jean Jacques; Selleri, Silvia; Metras, Marie-Elaine; Lamarre, Valerie; Egerszegi, Patricia; Barsalou, Julie; Merouani, Aicha; Alos, Nathalie; Hatami, Afshin; Morin, Marie-Paule; Vincent, Melanie; Miron, Marie-Claude; Godin-Berthiaume, Vanessa; Levasseur, Marie-Claude; Lemelin, Maude; Decaluwe, Helene] Univ Montreal, CHU St Justine, Montreal, PQ, Canada. [Cros, Guilhem; Saint-Cyr, Claire; Fernandez, Isabel; Haddad, Elie] Univ Montreal, Dept Pediat, CHU St Justine, Montreal, PQ H3C 3J7, Canada. [Le Deist, Francoise] CHU St Justine, Dept Pediat, Montreal, PQ, Canada. [Lebon, Pierre] Univ Paris 05, Hop St Vincent de Paul Cochin, Paris, France. [Goldbach-Mansky, Raphaela] NIAMSD, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 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 APR PY 2016 VL 36 IS 3 MA 4298 BP 240 EP 241 PG 2 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300022 ER PT J AU Toh, J Patel, PD Eisenfeld, M Madan, R Shliozberg, J Rubinstein, A Holland, SM AF Toh, Jennifer Patel, Payal D. Eisenfeld, Michelle Madan, Rebecca Shliozberg, Jenny Rubinstein, Arye Holland, Steven M. TI SPECIFIC ANTIBODY DEFICIENCY AND CHRONIC MUCOCUTANEOUS CANDIDIASIS IN STAT1 GAIN-OF-FUNCTION MUTATION SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Toh, Jennifer; Shliozberg, Jenny] Montefiore Med Ctr, Div Allergy & Immunol, 111 E 210th St, Bronx, NY 10467 USA. [Patel, Payal D.] Allergy Asthma Care PC, Portage, IN USA. [Eisenfeld, Michelle] Asthma & Allergy Associates Florida, Ft Lauderdale, FL USA. [Madan, Rebecca] Albert Einstein Coll Med, Div Infect Dis, Bronx, NY 10467 USA. [Rubinstein, Arye] Albert Einstein Coll Med, Div Allergy & Immunol, Pediat, Bronx, NY 10467 USA. [Rubinstein, Arye] Montefiore Hosp, Bronx, NY USA. [Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 APR PY 2016 VL 36 IS 3 MA 4305 BP 242 EP 242 PG 1 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300025 ER PT J AU Gallagher, JL Verbsky, JW Hartman, H Hintermeyer, MK Niemela, J Stoddard, JL Rosenzweig, SD Routes, JM AF Gallagher, Joel Louis Verbsky, James W. Hartman, Heather Hintermeyer, Mary K. Niemela, Julie Stoddard, Jennifer L. Rosenzweig, Sergio D. Routes, John M. TI THE WIDE PHENOTYPICAL SPECTRUM OF GAIN OF FUNCTION (GOF) MUTATIONS IN THE p110a CATALYTIC SUBUNIT OF THE PHOSPHATIDYLINOSITOL-3-OH (PIK3CD): ONE CENTER'S EXPERIENCE SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Gallagher, Joel Louis; Hartman, Heather; Routes, John M.] Med Coll Wisconsin, Dept Allergy & Clin Immunol, Milwaukee, WI 53226 USA. [Verbsky, James W.] Med Coll Wisconsin, Dept Pediat, Div Rheumatol, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. [Hintermeyer, Mary K.] Childrens Hosp Wisconsin, Allergy & Clin Immunol, Milwaukee, WI 53201 USA. [Niemela, Julie] NIH, Dept Lab Med, Bldg 10, Bethesda, MD 20892 USA. [Stoddard, Jennifer L.; Rosenzweig, Sergio D.] NIH, Immunol Serv, Dept Lab Med, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 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 APR PY 2016 VL 36 IS 3 MA 4364 BP 249 EP 250 PG 2 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300044 ER PT J AU Doshi, A Rosenzweig, SD Leonard, S AF Doshi, Ashmi Rosenzweig, Sergio D. Leonard, Stephanie TI A COMPLEX CASE OF HYPER IgM IMMUNODEFICIENCY AND LATE PRESENTATION OF ATAXIA TELANGIECTASIA WITHOUT NEUROLOGIC SIGNS SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Doshi, Ashmi; Leonard, Stephanie] Univ Calif San Diego, Div Allergy Immunol & Rheumatol, San Diego, CA 92103 USA. [Doshi, Ashmi; Leonard, Stephanie] Rady Childrens Hosp, San Diego, CA USA. [Rosenzweig, Sergio D.] NIH, Immunol Serv, Dept Lab Med, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 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 APR PY 2016 VL 36 IS 3 MA 4370 BP 251 EP 251 PG 1 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300047 ER PT J AU Ma, CS Wong, N Rao, G Avery, DT Warnatz, K Kobayashi, M Holland, SM Okada, S Bustamante, J Boisson-Dupuis, S Casanova, JL Uzel, G Tangye, SG AF Ma, Cindy S. Wong, Natalie Rao, Geetha Avery, Danielle T. Warnatz, Klaus Kobayashi, Masao Holland, Steven M. Okada, Satoshi Bustamante, Jacinta Boisson-Dupuis, Stephanie Casanova, Jean-Laurent Uzel, Gulbu Tangye, Stuart G. TI HUMAN T FOLLICULAR HELPER CELLS IN PRIMARY IMMUNODEFICIENCY: QUALITY JUST AS IMPORTANT AS QUANTITY SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Ma, Cindy S.; Tangye, Stuart G.] St Vincents Hosp, Garvan Inst Med Res, Immunol Div, Darlinghurst, NSW 2010, Australia. [Wong, Natalie] Garvan Inst Med Res, Immunol Program, Sydney, NS, Australia. [Rao, Geetha] Garvan Inst, Darlinghurst, NSW, Australia. [Warnatz, Klaus] Ctr Chron Immunodeficiency, Freiburg, Germany. [Holland, Steven M.; Uzel, Gulbu] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Okada, Satoshi; Boisson-Dupuis, Stephanie; Casanova, Jean-Laurent] Rockefeller Univ, St Giles Lab Human Genet Infect Dis, 1230 York Ave, New York, NY 10021 USA. [Bustamante, Jacinta] Inst Natl Sante & Rech Med, Lab Human Genet Infect Dis, Paris, France. RI Okada, Satoshi/B-8901-2011 OI Okada, Satoshi/0000-0002-4622-5657 NR 0 TC 0 Z9 0 U1 0 U2 1 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 APR PY 2016 VL 36 IS 3 MA 4400 BP 258 EP 258 PG 1 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300065 ER PT J AU Hussey, AA Agharahimi, A Shah, N Hickstein, DD Su, HC Sanchez, L DeZure, A Uzel, G Freeman, AF AF Hussey, Ashleigh A. Agharahimi, Anahita Shah, Nirali Hickstein, Dennis D. Su, Helen C. Sanchez, Lauren DeZure, Adam Uzel, Gulbu Freeman, Alexandra F. TI DOCK8 IMMUNODEFICIENCY ASSOCIATED WITH VASCULOPATHY SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Hussey, Ashleigh A.; Agharahimi, Anahita; Uzel, Gulbu; Freeman, Alexandra F.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Shah, Nirali] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Hickstein, Dennis D.] NCI, Expt Transplantat & Immunol Branch, Div Basic Sci, NIH, Bethesda, MD 20892 USA. [Su, Helen C.] NIAID, Host Def Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Sanchez, Lauren] NIAID, LCID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [DeZure, Adam] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 APR PY 2016 VL 36 IS 3 MA 4454 BP 269 EP 269 PG 1 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300093 ER PT J AU Rosen, LB Glowinski, RM Berger, M Browne, SK Holland, SM AF Rosen, Lindsey B. Glowinski, Rebecca M. Berger, Melvin Browne, Sarah K. Holland, Steven M. TI CHARACTERIZATION OF ANTICYTOKINE AUTOANTIBODIES IN INTRAVENOUS IMMUNOGLOBULIN (IVIG) PREPARATIONS SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Rosen, Lindsey B.; Glowinski, Rebecca M.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Berger, Melvin] CSL Behring LLC, Immunol R&D, King Of Prussia, PA USA. [Browne, Sarah K.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 APR PY 2016 VL 36 IS 3 MA 4457 BP 270 EP 271 PG 2 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300096 ER PT J AU Clarridge, KE Niemela, JE Hsu, AP Zerbe, CS Rosenzweig, S Shaw, D Holland, S AF Clarridge, Katherine E. Niemela, Julie E. Hsu, Amy P. Zerbe, Christa S. Rosenzweig, Sergio Shaw, Dawn Holland, Steven TI PERSISTENT, DISSEMINATED BORDETELLA HINZII INFECTION IN A PATIENT WITH INTERLEUKIN-12 RECEPTOR BETA 1 DEFICIENCY SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Clarridge, Katherine E.; Hsu, Amy P.; Zerbe, Christa S.; Rosenzweig, Sergio; Holland, Steven] NIAID, NIH, Bethesda, MD USA. [Niemela, Julie E.] NIH, Dept Lab Med, CC, Bldg 10, Bethesda, MD 20892 USA. [Shaw, Dawn] Leidos Biomedical Res INC, Clin Monitoring Res Program, Frederick Natl Lab, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 APR PY 2016 VL 36 IS 3 MA 4466 BP 273 EP 274 PG 2 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300104 ER PT J AU Jing, H Dove, C Zhang, Y Price, S Koneti, R Su, HC AF Jing, Huie Dove, Christopher Zhang, Yu Price, Susan Koneti, Rao Su, Helen C. TI NOVEL IMMUNODYSREGULATION DISORDER CAUSED BY LOSS-OF-FUNCTION MUTATIONS IN SBNO2 SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Jing, Huie; Dove, Christopher; Zhang, Yu; Su, Helen C.] NIAID, Host Def Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Price, Susan; Koneti, Rao] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 APR PY 2016 VL 36 IS 3 MA 4473 BP 275 EP 275 PG 1 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300107 ER PT J AU Lisco, A Niemela, J Stoddard, JL Rosenzweig, SD Hsu, AP Price, S MIcan, J Vanpouille, C Lo, B Maric, I Koneti, R Parenti, D Sheikh, V Sereti, I AF Lisco, Andrea Niemela, Julie Stoddard, Jennifer L. Rosenzweig, Sergio D. Hsu, Amy P. Price, Susan MIcan, JoAnn Vanpouille, Christophe Lo, Bernice Maric, Irina Koneti, Rao Parenti, David Sheikh, Virginia Sereti, Irini TI PERSISTENT CD4 LYMPHOPENIA LEADING TO A DIAGNOSIS OFAUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME (ALPS) CAUSED BYA NOVEL MUTATION IN THE FAS DEATH DOMAIN SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Lisco, Andrea; MIcan, JoAnn; Sheikh, Virginia; Sereti, Irini] NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Niemela, Julie; Maric, Irina] NIH, Dept Lab Med, Bldg 10, Bethesda, MD 20892 USA. [Stoddard, Jennifer L.; Rosenzweig, Sergio D.] NIH, Serv Immunol, Dept Lab Med, Bldg 10, Bethesda, MD 20892 USA. [Hsu, Amy P.; Price, Susan; Koneti, Rao] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Vanpouille, Christophe] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, Bethesda, MD USA. [Lo, Bernice] NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Parenti, David] George Washington Univ, Med Ctr, Div Infect Dis, Washington, DC 20037 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 APR PY 2016 VL 36 IS 3 MA 4480 BP 276 EP 276 PG 1 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300110 ER PT J AU Gernez, Y Smith, TD Tsuang, A Maglione, PJ Holland, SM Cunningham-Rundles, C AF Gernez, Yael Smith, Tukisa D. Tsuang, Angela Maglione, Paul J. Holland, Steve M. Cunningham-Rundles, Charlotte TI HIGH DOSE STEROID THERAPY FOR LIVER ABSCESS IN PATIENTS WITH CHRONIC GRANULOMATOUS DISEASE (CGD). SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Gernez, Yael; Smith, Tukisa D.; Tsuang, Angela; Maglione, Paul J.; Cunningham-Rundles, Charlotte] Icahn Sch Med Mt Sinai, Dept Med, Div Clin Immunol, New York, NY 10029 USA. [Holland, Steve M.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 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 APR PY 2016 VL 36 IS 3 MA 4497 BP 279 EP 279 PG 1 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300117 ER PT J AU Dobbs, K Tabellini, G Martinez, MP Al-Herz, W Bleesing, JJ Booth, C Cancrini, C Chou, J Cowan, M de la Morena, MT Geha, RS Gennery, A Giliani, S Holland, SM Kanariou, M King, A Kuijpers, T Lougaris, V Meyts, I Moratto, D Plebani, A Walter, JE Parolini, S Notarangelo, LD AF Dobbs, Kerry Tabellini, G. Martinez, Maria Paula Al-Herz, Waleed Bleesing, Jack J. Booth, Claire Cancrini, Caterina Chou, Janet Cowan, Morton de la Morena, M. Teresa Geha, Raif S. Gennery, Andrew Giliani, Silvia Holland, Steve M. Kanariou, Maria King, Alejandra Kuijpers, Taco Lougaris, Vassilios Meyts, Isabelle Moratto, Daniele Plebani, Alessandro Walter, Jolan E. Parolini, Silvia Notarangelo, Luigi D. TI NK CELLS FROM PATIENTS WITH RAG AND ARTEMIS DEFICIENCY HAVE AN IMMATURE PHENOTYPE AND DISPLAY INCREASED DEGRANULATION CAPACITY-IMPLICATIONS FOR HEMATOPOIETIC CELL TRANSPLANTATION SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Dobbs, Kerry; Martinez, Maria Paula] Boston Childrens Hosp, Div Immunol, Boston, MA USA. [Al-Herz, Waleed] Kuwait Univ, Fac Med, Dept Pediat, Kuwait, Kuwait. [Bleesing, Jack J.] Cincinnati Childrens Hosp Med Ctr, Div Bone Marrow Transplantat & Immune Deficiency, Cincinnati, OH 45229 USA. [Booth, Claire] Great Ormond St Hosp Sick Children, Dept Paediat Immunol, London, England. [Booth, Claire] Great Ormond St Hosp Sick Children, Dept Paediat Immunol, London, North Ireland. [Cancrini, Caterina] Childrens Hosp Bambino Gesu, Dept Pediat, Rome, Italy. [Cancrini, Caterina] Univ Roma Tor Vergata, Sch Med, Rome, Italy. [Chou, Janet; Geha, Raif S.] Harvard Univ, Sch Med, Dept Pediat, Immunol Div,Boston Childrens Hosp, Boston, MA 02115 USA. [Cowan, Morton] Univ Calif San Francisco, San Francisco, CA 94143 USA. [de la Morena, M. Teresa] UT Southwestern Med Ctr, Childrens Med Ctr Dallas, Dept Pediat, Dallas, TX USA. [Gennery, Andrew] Newcastle Upon Tyne Hosp, Dept Pediat Immunol, Newcastle Upon Tyne, Tyne & Wear, England. [Gennery, Andrew] Newcastle Upon Tyne Hosp, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England. [Gennery, Andrew] Newcastle Upon Tyne Hosp, Dept Pediat Immunol, Newcastle Upon Tyne, North Ireland. [Gennery, Andrew] Newcastle Upon Tyne Hosp, Inst Cellular Med, Newcastle Upon Tyne, North Ireland. [Giliani, Silvia] Univ Brescia, Dept Pathol, Dept Mol & Traslat Med, A Nocivelli Inst Mol Med, I-25121 Brescia, Italy. [Holland, Steve M.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Kanariou, Maria] Aghia Sophia Childrens Hosp, Dept Immunol Histocompatibil, Specialized Ctr, Athens, Greece. [Kanariou, Maria] Aghia Sophia Childrens Hosp, Referral Ctr Primary Immunodeficiencies Pediat Im, Athens, Greece. [King, Alejandra] Hosp Ninos Luis Calvo Mackenna, Div Pediat Immunol, Santiago, Chile. [Kuijpers, Taco] Univ Amsterdam, Acad Med Ctr, Emma Childrens Hosp, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [Lougaris, Vassilios; Plebani, Alessandro] Univ Brescia, Spedali Civili, Pediat Clin, Brescia, Italy. [Lougaris, Vassilios; Plebani, Alessandro] Univ Brescia, Spedali Civili, Dept Clin & Expt Sci, Inst Mol Med A Nocivelli, Brescia, Italy. [Meyts, Isabelle] Univ Hosp Leuven, Childhood Immunol, Leuven, Belgium. [Moratto, Daniele] Univ Brescia, A Nocivelli Inst Mol Med, Dept Pathol, Brescia, Italy. [Walter, Jolan E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis, Boston, MA USA. [Parolini, Silvia] Univ Brescia, Dipartimento Med Mol & Traslaz, Brescia, Italy. [Notarangelo, Luigi D.] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Immunol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 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 APR PY 2016 VL 36 IS 3 MA 4514 BP 283 EP 284 PG 2 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300127 ER PT J AU Falcone, EL Abusleme, L Swamydas, M Lionakis, MS Ding, L Hsu, AP Zelazny, A Moutsopoulos, N Kuhns, DB Deming, C Quinones, M Segre, JA Bryant, CE Holland, SM AF Falcone, Emilia Liana Abusleme, Loreto Swamydas, Muthulekha Lionakis, Michail S. Ding, Li Hsu, Amy P. Zelazny, Adrian Moutsopoulos, Niki Kuhns, Douglas B. Deming, Clay Quinones, Mariam Segre, Julia A. Bryant, Clare E. Holland, Steven M. TI COLITIS SUSCEPTIBILITY IN p47phox-/-MICE IS MEDIATED BY THE INTESTINAL MICROBIOME SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Falcone, Emilia Liana; Swamydas, Muthulekha; Lionakis, Michail S.; Ding, Li; Hsu, Amy P.; Zelazny, Adrian; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Abusleme, Loreto; Moutsopoulos, Niki] Natl Inst Dent & Craniofacial Res, Clin Res Core, NIH, Bethesda, MD USA. [Zelazny, Adrian] NIH, Microbiol Serv, Dept Lab Med, Bldg 10, Bethesda, MD 20892 USA. [Kuhns, Douglas B.] NCI Frederick, Leidos Biomed Res Inc, Frederick, MD USA. [Segre, Julia A.] NHGRI, Translat & Funct Genom Branch, NIH, Bethesda, MD 20892 USA. [Quinones, Mariam] NIAID, Bioinformat & Computat Biosci Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Bryant, Clare E.] Univ Cambridge, Dept Vet Med, Cambridge CB2 1TN, England. NR 0 TC 0 Z9 0 U1 0 U2 0 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 APR PY 2016 VL 36 IS 3 MA 4528 BP 288 EP 288 PG 1 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300137 ER PT J AU Freeman, AF Shah, N Su, HC Uzel, G Gea-Banacloche, J Cotton, S Holland, SM Hickstein, DD AF Freeman, Alexandra F. Shah, Nirali Su, Helen C. Uzel, Gulbu Gea-Banacloche, Juan Cotton, Stephanie Holland, Steven M. Hickstein, Dennis D. TI HAPLOIDENTICAL RELATED DONOR HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR DOCK8 DEFICIENCY SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Freeman, Alexandra F.; Uzel, Gulbu] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Shah, Nirali] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Su, Helen C.] NIAID, Lab Host Def, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Holland, Steven M.] NCI, Expt Transplantat & Immunol Branch, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 APR PY 2016 VL 36 IS 3 MA 4532 BP 289 EP 290 PG 2 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300140 ER PT J AU Barzaghi, F Passerini, L Sartirana, C Bejerano, G Floris, M Cesaro, S Cimaz, R Roncarolo, MG Santini, F Goldbach-Mansky, R Aiuti, A Bacchetta, R AF Barzaghi, Federica Passerini, Laura Sartirana, Claudia Bejerano, Gill Floris, Matteo Cesaro, Simone Cimaz, Rolando Roncarolo, Maria Grazia Santini, Ferruccio Goldbach-Mansky, Raphaela Aiuti, Alessandro Bacchetta, Rosa TI LIPOPOLYSACCHARIDE-RESPONSIVE AND BEIGE-LIKE ANCHOR (LRBA) PROTEIN DEFICIENCY MANIFESTING WITH LYPODISTROPHY AND ALPS-LIKE PHENOTYPE TREATED WITH LEPTIN AND RAPAMYCIN SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Barzaghi, Federica; Aiuti, Alessandro] IRCCS San Raffaele Sci Inst, San Raffaele Telethon Inst Gene Therapy, Dept Paediat Immunohematol, Milan, Italy. [Barzaghi, Federica; Passerini, Laura; Sartirana, Claudia; Aiuti, Alessandro] IRCCS San Raffaele Sci Inst, San Raffaele Telethon Inst Gene Therapy, Div Regenerat Med Stem Cells & Gene Therapy, Milan, Italy. [Bejerano, Gill] Stanford Univ, Dept Dev Biol, Dept Comp Sci, Stanford, CA 94305 USA. [Bejerano, Gill] Stanford Univ, Dept Pediat, Div Med Genet, Stanford, CA 94305 USA. [Floris, Matteo] Cittadella Univ Monserrato, IRGB CNR, Cagliari, Italy. [Floris, Matteo] Univ Sassari, Dept Biomed Sci, I-07100 Sassari, Italy. [Cesaro, Simone] Azienda Osped Univ Integrata, Dept Pediat, Pediat Hematol Oncol, Verona, Italy. [Cimaz, Rolando] Anna Meyer Children Hosp, Pediat Rheumatol, Florence, Italy. [Roncarolo, Maria Grazia; Bacchetta, Rosa] Stanford Univ, Dept Pediat, Div Stem Cell Transplantat & Regenerat Med, Sch Med, Stanford, CA 94305 USA. [Santini, Ferruccio] Univ Hosp Pisa, Obes Ctr, Endocrinol Unit, Pisa, Italy. [Goldbach-Mansky, Raphaela] NIAMSD, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 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 APR PY 2016 VL 36 IS 3 MA 4553 BP 293 EP 294 PG 2 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300149 ER PT J AU Dancy, EK Marciano, B Yockey, L Osgood, SM Barnhart, L Holland, SM Zerbe, CS AF Dancy, Ehren K. Marciano, Betty Yockey, Lynne Osgood, Sharon M. Barnhart, Lisa Holland, Steve M. Zerbe, Christa S. TI CHARACTERIZING IMMUNITY IN NORMAL PREGNANCY SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Dancy, Ehren K.; Marciano, Betty; Yockey, Lynne; Barnhart, Lisa; Holland, Steve M.; Zerbe, Christa S.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Osgood, Sharon M.] NCI, Dermatol Branch, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 APR PY 2016 VL 36 IS 3 MA 4559 BP 295 EP 295 PG 1 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300151 ER PT J AU Hsu, AP West, RR Calvo, K Kelly, SJ Ganson, NJ Parta, M Cuellar-Rodriguez, J Hershfield, M Hickstein, DD Holland, SM AF Hsu, Amy P. West, Robert R. Calvo, Katherine Kelly, Susan J. Ganson, Nancy J. Parta, Mark Cuellar-Rodriguez, Jennifer Hershfield, Michael Hickstein, Dennis D. Holland, Steven M. TI NOVEL CECR1 MUTATION MIMICKING GATA2 DEFICIENCY SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Hsu, Amy P.; Cuellar-Rodriguez, Jennifer; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [West, Robert R.] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. [Calvo, Katherine] NIH, Hematol Sect, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Kelly, Susan J.; Ganson, Nancy J.] Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA. [Parta, Mark] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Clin Res Directorate, Clin Monitoring Res Program, Frederick, MD USA. [Hershfield, Michael] Duke Univ, Sch Med, Dept Biochem, Durham, NC USA. [Hickstein, Dennis D.] NCI, Expt Transplantat & Immunol Branch, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 APR PY 2016 VL 36 IS 3 MA 4569 BP 297 EP 297 PG 1 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300156 ER PT J AU Hsu, AP Swamydas, M Lionakis, MS Szabolcs, P Steinberg, H Bonagura, VR Kuhns, DB Holland, SM AF Hsu, Amy P. Swamydas, Muthulekha Lionakis, Michail S. Szabolcs, Paul Steinberg, Harry Bonagura, Vincent R. Kuhns, Douglas B. Holland, Steven M. TI NOVEL HETEROZYGOUS RAC2 MUTATION PRESENTING AS COMBINED IMMUNODEFICIENCY SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Hsu, Amy P.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Swamydas, Muthulekha; Lionakis, Michail S.] NIAID, Fungal Pathogenesis Unit, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Szabolcs, Paul] Childrens Hosp Pittsburgh, Div Blood & Marrow Transplantat & Cellular Therap, Pittsburgh, PA 15213 USA. [Steinberg, Harry] N Shore Univ Hosp, Div Med Pulm Crit Care & Sleep Med, New Hyde Pk, NY USA. [Bonagura, Vincent R.] Cohen Childrens Med Ctr New York, Div Allergy & Immunol, Great Neck, NY USA. [Kuhns, Douglas B.] NCI, Leidos Biomed Res Inc, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 APR PY 2016 VL 36 IS 3 MA 4576 BP 298 EP 298 PG 1 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300159 ER PT J AU Sampaio, EP Ding, L Rose, S Cruz, P Hsu, AP Rosen, LB Tavella, T Ferrer, E Zerbe, CS Lionakis, M Holland, SM AF Sampaio, Elizabeth P. Ding, Li Rose, Stacey Cruz, Phillip Hsu, Amy P. Rosen, Lindsey B. Tavella, Tatyana Ferrer, Elise Zerbe, Christa S. Lionakis, Michail Holland, Steve M. TI NOVEL STAT1 GOF MUTATION AFFECTING PROTEIN SUMOYLATION SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Sampaio, Elizabeth P.; Ding, Li; Hsu, Amy P.; Rosen, Lindsey B.; Zerbe, Christa S.; Holland, Steve M.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Rose, Stacey] NIAID, Fungal Pathogenesis Unit, LCID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Cruz, Phillip] NIAID, Computat Biol Sect, OCICB, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NIH, LCID, Bethesda, MD USA. [Ferrer, Elise] NIH, Fungal Pathogenesis Unit, Lab Clin Infect Dis, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 APR PY 2016 VL 36 IS 3 MA 4582 BP 300 EP 300 PG 1 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300164 ER PT J AU Foldvari, Z Ujhazi, B Abolhassani, H Abraham, R Adeli, M Aghamohammadi, A Al-Herz, W Assaf-Casals, A Bertaina, A Bleesing, JJ Booth, C Buchbinder, D Cancrini, C Chen, K Chou, J Costa-Carvalho, BT Dbaibo, G DeRavin, SS Dilley, MA Dutmer, CM Eibl, MM Ferguson, PJ Geier, CB Geha, RS Gelfand, EW Hanna-Wakim, R Holland, SM Joshi, AY Kanariou, M Locatelli, F Lykopoulou, E Massaad, MJ Nicholas, SK Palma, P Patiroglu, T Puck, JM Reiff, A Schuetz, C Sleasman, J Unal, E Wolff, H Notarangelo, LD Walter, JE AF Foldvari, Zsofia Ujhazi, Boglarka Abolhassani, Hassan Abraham, Roshini Adeli, Mehdi Aghamohammadi, Asghar Al-Herz, Waleed Assaf-Casals, Aia Bertaina, Alice Bleesing, Jack J. Booth, Claire Buchbinder, David Cancrini, Caterina Chen, Karin Chou, Janet Costa-Carvalho, Beatriz Tavares Dbaibo, Ghassan DeRavin, Suk See Dilley, Meredith A. Dutmer, Cullen M. Eibl, Martha M. Ferguson, Polly J. Geier, Christoph B. Geha, Raif S. Gelfand, Erwin W. Hanna-Wakim, Rima Holland, Steven M. Joshi, Avni Y. Kanariou, Maria Locatelli, Franco Lykopoulou, E. Massaad, Michel J. Nicholas, Sarah Kogan Palma, Paolo Patiroglu, Turkan Puck, Jennifer M. Reiff, Andreas Schuetz, Catharina Sleasman, John Unal, Ekrem Wolff, Hermann Notarangelo, Luigi D. Walter, Jolan E. TI CLINICAL SPECTRUM AND OUTCOME OF TREATMENT FOR AUTOIMMUNE CYTOPENIAS IN RAG DEFICIENCY SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Foldvari, Zsofia] Univ Debrecen, Fac Med, Dept Immunol, Debrecen, Hungary. [Foldvari, Zsofia] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pediat Allergy & Immunol, Boston, MA USA. [Foldvari, Zsofia; Ujhazi, Boglarka; Walter, Jolan E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis, Boston, MA USA. [Ujhazi, Boglarka; Walter, Jolan E.] Massachusetts Gen Hosp Children, Div Pediat Allergy Immunol, Boston, MA USA. [Abolhassani, Hassan; Aghamohammadi, Asghar] Univ Tehran Med Sci, Childrens Med Ctr, Pediat Ctr Excellence, Res Ctr Immunodeficiencies, Tehran, Iran. [Abraham, Roshini] Mayo Clin, Lab Med & Pathol, Rochester, MN USA. [Adeli, Mehdi] Weill Cornell Med Coll Qatar, Pediat, Doha, Qatar. [Adeli, Mehdi] Sidra Med & Res Ctr, Allergy & Immunol, Doha, Qatar. [Adeli, Mehdi] Hamad Med Corp, Doha, Qatar. [Al-Herz, Waleed] Kuwait Univ, Fac Med, Dept Pediat, Safat 13060, Kuwait. [Assaf-Casals, Aia; Dbaibo, Ghassan; Hanna-Wakim, Rima] Amer Univ Beirut, Ctr Infect Dis Res, Dept Pediat & Adolescent Med, Beirut, Lebanon. [Bertaina, Alice] Bambino Gesu Pediat Hosp, Dept Oncohematol, Stem Cell Transplant Unit, Rome, Italy. [Bleesing, Jack J.] Cincinnati Childrens Hosp Med Ctr, Div Bone Marrow Transplantat & Immune Deficiency, Cincinnati, OH 45229 USA. [Bleesing, Jack J.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Booth, Claire] Great Ormond St Hosp Sick Children, Dept Paediat Immunol, London, England. [Booth, Claire] Great Ormond St Hosp Sick Children, Dept Paediat Immunol, London, North Ireland. [Buchbinder, David] UC Irvine, CHOC Childrens Hosp, Pediat Hematol, Orange, CA USA. [Cancrini, Caterina; Palma, Paolo] Childrens Hosp Bambino Gesu, Dept Pediat, Rome, Italy. [Cancrini, Caterina; Palma, Paolo] Univ Roma Tor Vergata, Sch Med, Rome, Italy. [Chen, Karin] Univ Utah, Dept Pediat, Div Allergy Immunol & Rheumatol, Salt Lake City, UT USA. [Chou, Janet; Geha, Raif S.; Massaad, Michel J.] Harvard Univ, Sch Med, Dept Pediat, Immunol Div,Boston Childrens Hosp, Boston, MA 02115 USA. [Costa-Carvalho, Beatriz Tavares] Univ Fed Sao Paulo, Dept Allergy Clin Immunol & Rheumatol, Sao Paulo, Brazil. [DeRavin, Suk See] NIAID, Host Def Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Dilley, Meredith A.] Boston Childrens Hosp, Dept Immunol, Boston, MA USA. [Dilley, Meredith A.] Harvard Univ, Sch Med, Boston, MA USA. [Dutmer, Cullen M.] Univ Colorado, Sch Med, Childrens Hosp Colorado, Div Allergy & Immunol, Boulder, CO 80309 USA. [Eibl, Martha M.; Geier, Christoph B.; Wolff, Hermann] Immunol Outpatient Clin, Vienna, Austria. [Ferguson, Polly J.] Univ Iowa, Dept Pediat, Carver Coll Med, Iowa City, IA 52242 USA. [Gelfand, Erwin W.] Natl Jewish Hlth, Dept Pediat, Div Pediat Allergy & Clin Immunol, Denver, CO USA. [Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Joshi, Avni Y.] Mayo Clin, Div Pediat Allergy Immunol, Rochester, MN USA. [Kanariou, Maria] Aghia Sophia Childrens Hosp, Specialized Ctr, Dept Immunol Histocompatibil, Athens, Greece. [Kanariou, Maria] Aghia Sophia Childrens Hosp, Referral Ctr Primary Immunodeficiencies Pediat Im, Athens, Greece. [Locatelli, Franco] Osped Pediat Bambino Gesu, Dept Pediat Hematol & Oncol, Rome, Italy. [Lykopoulou, E.] IRCCS Bambino Gesu Childrens Hosp, Dept Pediat Hematol & Oncol, Rome, Italy. [Nicholas, Sarah Kogan] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Nicholas, Sarah Kogan] Texas Childrens Hosp, Sect Allergy & Immunol, Houston, TX 77030 USA. [Patiroglu, Turkan; Unal, Ekrem] Erciyes Univ, Sch Med, Dept Pediat Hematol & Oncol, Kayseri, Turkey. [Patiroglu, Turkan] Erciyes Univ, Sch Med, Dept Pediat Immunol, Kayseri, Turkey. [Puck, Jennifer M.] Univ Calif San Fransisco, Pediat Immunol & Bone Marrow Transplantat, San Francisco, CA USA. [Reiff, Andreas] Childrens Hosp Los Angeles, USC Keck Sch Med, Los Angeles, CA 90027 USA. [Schuetz, Catharina] Univ Hosp Ulm, Dept Pediat & Adolescent Med, Ulm, Germany. [Sleasman, John] Duke Univ, Sch Med, Div Allergy & Immunol, Durham, NC USA. [Notarangelo, Luigi D.; Walter, Jolan E.] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Immunol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 2 U2 3 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 APR PY 2016 VL 36 IS 3 MA 4585 BP 301 EP 303 PG 3 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300167 ER PT J AU Kreuzburg, SA Shaw, D Darnell, D Daub, J Foruraghi, L Freeman, AF Mann, D Marciano, B Palmer, C Peterson, J Rump, A Snow, L Urban, A Uzel, G Yockey, L Holland, SM Zerbe, CS AF Kreuzburg, Samantha A. Shaw, Dawn Darnell, Dirk Daub, Janine Foruraghi, Ladan Freeman, Alexandra F. Mann, Daphne Marciano, Betty Palmer, Cindy Peterson, Joy Rump, Amy Snow, Laquita Urban, Amanda Uzel, Gulbu Yockey, Lynne Holland, Steve M. Zerbe, Christa S. TI PATIENT SATISFACTION USING THE NIH CLINICAL RESEARCH NURSING CARE DELIVERY MODEL SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Kreuzburg, Samantha A.; Daub, Janine; Foruraghi, Ladan; Freeman, Alexandra F.; Marciano, Betty; Uzel, Gulbu; Holland, Steve M.; Zerbe, Christa S.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Shaw, Dawn; Mann, Daphne; Peterson, Joy; Rump, Amy; Urban, Amanda] Leidos Biomed Res, Clin Monitoring Res Program, Frederick Natl Lab, Bethesda, MD USA. [Darnell, Dirk; Palmer, Cindy; Snow, Laquita; Yockey, Lynne] NIH, Dept Nursing, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 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 APR PY 2016 VL 36 IS 3 MA 4591 BP 304 EP 304 PG 1 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300171 ER PT J AU Urban, A Chang, R Oliver, K Darnell, D West, K Kolf, M Grimes, G Holland, SM Freeman, AF AF Urban, Amanda Chang, Richard Oliver, Kenneth Darnell, Dirk West, Kamille Kolf, Michael Grimes, George Holland, Steve M. Freeman, Alexandra F. TI INTRACAVITARY AMPHOTERICIN FOR ASPERGILLOMAS IN STAT3 MUTATED HYPER IgE SYNDROME SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Urban, Amanda] Leidos Biomed Res, Clin Monitoring Res Program, Frederick Natl Lab, Bethesda, MD USA. [Chang, Richard] NIH, Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Oliver, Kenneth] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Darnell, Dirk] NIH, Dept Nursing, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [West, Kamille] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Kolf, Michael; Grimes, George] NIH, Dept Pharm, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Holland, Steve M.; Freeman, Alexandra F.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 APR PY 2016 VL 36 IS 3 MA 4619 BP 313 EP 313 PG 1 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300191 ER PT J AU Marciano, B Olbrich, P Sampaio, EP Hsu, AP Zimmerman, O Uzel, G Zerbe, CS Holland, SM Freeman, AF AF Marciano, Betty Olbrich, Peter Sampaio, Elizabeth P. Hsu, Amy P. Zimmerman, Ofer Uzel, Gulbu Zerbe, Christa S. Holland, Steven M. Freeman, Alexandra F. TI BROAD CLINICAL PHENOTYPE IN PEDIATRIC PATIENTS WITH HETEROZYGOUS STAT1 MUTATIONS SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Marciano, Betty; Sampaio, Elizabeth P.; Hsu, Amy P.; Uzel, Gulbu; Zerbe, Christa S.; Holland, Steven M.; Freeman, Alexandra F.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Zimmerman, Ofer] NIAID, Immunopathogenesis Sect, NIH, LCID, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 APR PY 2016 VL 36 IS 3 MA 4627 BP 315 EP 315 PG 1 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300196 ER PT J AU Urban, AK Patel, NC Heimall, J Darnell, D Peterson, J Holland, SM Freeman, AF AF Urban, Amanda K. Patel, Niraj C. Heimall, Jennifer Darnell, Dirk Peterson, Joy Holland, Steve M. Freeman, Alexandra F. TI AUTOIMMUNITY IN STAT3 MUTATED HYPER IgE SYNDROME SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Urban, Amanda K.; Peterson, Joy] Leidos Biomed Res, Clin Monitoring Res Program, Frederick Natl Lab, Bethesda, MD USA. [Patel, Niraj C.] Carolinas Med Ctr, Pediat, Charlotte, NC 28203 USA. [Heimall, Jennifer] Childrens Hosp Philadelphia, Div Allergy & Immunol, Philadelphia, PA 19104 USA. [Darnell, Dirk] NIH, Dept Nursing, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Holland, Steve M.; Freeman, Alexandra F.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 APR PY 2016 VL 36 IS 3 MA 4632 BP 316 EP 316 PG 1 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300199 ER PT J AU Lyons, JJ Yu, XM Hughes, JD Le, QT Jamil, A Bai, Y Zhao, M Liu, YH O'Connell, MP Nelson, C DiMaggio, T Jones, N Lewis, K Arkwright, P Hong, C McElwee, J Rothenberg, ME Hohman, R Stone, K Metcalfe, DD Biesecker, LG Schwartz, LB Milner, JD AF Lyons, Jonathan J. Yu, Xiaomin Hughes, Jason D. Le, Quang T. Jamil, Ali Bai, Yun Zhao, Ming Liu, Yihui O'Connell, Michael P. Nelson, Celeste DiMaggio, Thomas Jones, Nina Lewis, Katie Arkwright, Peter Hong, Celine McElwee, Joshua Rothenberg, Marc E. Hohman, Robert Stone, Kelly Metcalfe, Dean D. Biesecker, Leslie G. Schwartz, Lawrence B. Milner, Joshua D. TI ALPHA TRYPTASEMIA TRAIT CAUSED BYALPHA TRYPTASE COPY NUMBER VARIATION SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Lyons, Jonathan J.; Yu, Xiaomin; Jamil, Ali; Bai, Yun; Liu, Yihui; O'Connell, Michael P.; Nelson, Celeste; DiMaggio, Thomas; Stone, Kelly; Metcalfe, Dean D.; Milner, Joshua D.] NIAID, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Hughes, Jason D.; McElwee, Joshua] Merck & Co Inc, Merck Res Labs, Boston, MA USA. [Le, Quang T.; Schwartz, Lawrence B.] Virginia Commonwealth Univ, Sch Med, Richmond, VA USA. [Zhao, Ming; Hohman, Robert] NIAID, Prot Chem Sect, RTB, NIH, Rockville, MD USA. [Jones, Nina] Leidos Biomed Res Inc, Clin Res Directorate, Clin Monitoring Res Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Lewis, Katie; Hong, Celine; Biesecker, Leslie G.] NHGRI, Genet Dis & Res Branch, NIH, Bethesda, MD 20892 USA. [Arkwright, Peter] Royal Manchester Childrens Hosp, Manchester M27 1HA, Lancs, England. [Arkwright, Peter] Royal Manchester Childrens Hosp, Manchester, North Ireland. [Rothenberg, Marc E.] Cincinnati Childrens Hosp Med Ctr, Div Allergy & Immunol, Cincinnati, OH 45229 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 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 APR PY 2016 VL 36 IS 3 MA 4651 BP 323 EP 323 PG 1 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300214 ER PT J AU Jesus, AA Hou, YF Deng, ZM Brooks, S Kim, H Huang, Y Montealegre, G Chapelle, D Marrero, B Malle, L Hashkes, P Nasrullayeva, G Terreri, MT Arabshahi, B Punaro, M Lilleby, V Morrthy, LN Reinhardt, A Goldbach-Mansky, R O'Neil, KM AF Jesus, Adriana A. Hou, Yanfeng Deng, Zuoming Brooks, Stephen Kim, Hanna Huang, Yan Montealegre, Gina Chapelle, Dawn Marrero, Bernadette Malle, Louise Hashkes, Philip Nasrullayeva, Gulnara Terreri, Maria Teresa Arabshahi, Bita Punaro, Marilynn Lilleby, Vibeke Nandini Morrthy, L. Reinhardt, Adam Goldbach-Mansky, Raphaela O'Neil, Kathleen M. TI STRATIFICATION OF PATIENTS WITH AUTOINFLAMMATORY DISEASES BY IFN SCORE SUGGESTS A NEW GROUP OF IFN MEDIATED DISEASES WITH OVERLAPPING CLINICAL PHENOTYPES SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Jesus, Adriana A.; Hou, Yanfeng; Marrero, Bernadette; Malle, Louise] NIAMS, Translat Autoinflammatory Dis Sect, NIH, Bethesda, MD USA. [Deng, Zuoming; Brooks, Stephen; Kim, Hanna; Huang, Yan; Montealegre, Gina; Chapelle, Dawn] NIAMS, NIH, Bethesda, MD USA. [Hashkes, Philip] Shaare Zedek Med Ctr Jerusalem, Shaare Zedek Unit Pediat Rheumatol, Jerusalem, Israel. [Nasrullayeva, Gulnara] Azerbaijan Med Univ, Dept Immunol, Baki, Azerbaijan. [Terreri, Maria Teresa] Univ Fed Sao Paulo, Pediat Rheumatol, Sao Paulo, Brazil. [Arabshahi, Bita] Inova Med Grp, Pediat Rheumatol, Fairfax, VA USA. [Punaro, Marilynn] Texas Scottish Rite Hosp Children, Pediat Rheumatol, Dallas, TX 75219 USA. [Lilleby, Vibeke] Oslo Univ Hosp, Rheumatol Res Grp, Oslo, Norway. [Nandini Morrthy, L.] Rutgers Robert Wood Johnson Med Sch, Div Pediat Rheumatol, New Brunswick, NJ USA. [Reinhardt, Adam] Childrens Hosp & Med Ctr, Pediat Rheumatol, Omaha, NE USA. [Reinhardt, Adam] Univ Nebraska, Omaha, NE 68182 USA. [Goldbach-Mansky, Raphaela] NIAMSD, NIH, Bethesda, MD 20892 USA. [O'Neil, Kathleen M.] Indiana Univ, Div Pediat Rheumatol, Indianapolis, IN 46204 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 APR PY 2016 VL 36 IS 3 MA 4659 BP 324 EP 325 PG 2 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300218 ER PT J AU Goyal, RK Uzel, G Pittaluga, S Sunseri, W Lindblad, D AF Goyal, Rakesh Kumar Uzel, Gulbu Pittaluga, Stefania Sunseri, Whitney Lindblad, Douglas TI PIK3CD IMMUNODEFICIENCY WITH COLITIS, PANCREATIC INSUFFICIENCY AND ASCITES SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Goyal, Rakesh Kumar] UPMC, Childrens Hosp Pittsburgh, Div Blood & Marrow Transplantat & Cellular Therap, Pittsburgh, PA USA. [Goyal, Rakesh Kumar] Univ Pittsburgh, Sch Med, Dept Pediat, Pittsburgh, PA 15261 USA. [Uzel, Gulbu] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Pittaluga, Stefania] NIH, Hematopathol Sect, Bldg 10, Bethesda, MD 20892 USA. [Sunseri, Whitney; Lindblad, Douglas] UPMC, Childrens Hosp Pittsburgh, Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 APR PY 2016 VL 36 IS 3 MA 4667 BP 327 EP 327 PG 1 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300223 ER PT J AU Gibson, AJ Hannibal, M Hsu, AP Holland, SM Harms, P Heider, A Blackwood, RA AF Gibson, Alison J. Hannibal, Mark Hsu, Amy P. Holland, Steven M. Harms, Paul Heider, Amer Blackwood, R. Alexander TI A CASE OF DISSEMINATED MUCO-CUTANEOUS MYCOBACTERIUM HAEMOPHILUM IN A CHILD WITH A MUTATION IN NFKBIA SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Gibson, Alison J.; Blackwood, R. Alexander] Univ Michigan, Pediat Infect Dis, Ann Arbor, MI 48109 USA. [Hannibal, Mark] Univ Michigan, Pediat Genet, Ann Arbor, MI 48109 USA. [Hsu, Amy P.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Harms, Paul; Heider, Amer] Univ Michigan, Pathol, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 APR PY 2016 VL 36 IS 3 MA 4673 BP 328 EP 329 PG 2 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300226 ER PT J AU Agharahimi, A Hussey, AA Pittaluga, S Raffeld, M Calvo, K Koh, C Heller, T Holland, SM Uzel, G Sullivan, K AF Agharahimi, Anahita Hussey, Ashleigh A. Pittaluga, Stefania Raffeld, Mark Calvo, Katherine Koh, Christopher Heller, Theo Holland, Steven M. Uzel, Gulbu Sullivan, Kathleen TI CHANGING DISEASE SPECTRUM IN ADULT X-LINKED AGAMMAGLOBULINEMIA (XLA) PATIENTS SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Agharahimi, Anahita; Hussey, Ashleigh A.; Holland, Steven M.; Uzel, Gulbu] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Pittaluga, Stefania] NIH, Hematopathol Sect, Bldg 10, Bethesda, MD 20892 USA. [Raffeld, Mark] NCI, Lab Pathol, Bethesda, MD 20892 USA. [Calvo, Katherine] Ctr Clin, Dept Lab Med, Hematol Serv, Bethesda, MD USA. [Koh, Christopher; Heller, Theo] NIDDK, Bethesda, MD 20892 USA. [Sullivan, Kathleen] Childrens Hosp Philadelphia, Div Allergy & Immunol, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 APR PY 2016 VL 36 IS 3 MA 4679 BP 330 EP 331 PG 2 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300231 ER PT J AU Sampaio, EP Marciano, B Hsu, AP Adamo, N Uzel, G Freeman, AF Zerbe, CS Holland, SM AF Sampaio, Elizabeth P. Marciano, Betty Hsu, Amy P. Adamo, Nick Uzel, Gulbu Freeman, Alexandra F. Zerbe, Christa S. Holland, Steven M. TI STAT1 GOF MUTATION IN THE SH2 DOMAIN SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Sampaio, Elizabeth P.; Marciano, Betty; Hsu, Amy P.; Adamo, Nick; Uzel, Gulbu; Freeman, Alexandra F.; Zerbe, Christa S.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 APR PY 2016 VL 36 IS 3 MA 4681 BP 332 EP 332 PG 1 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300233 ER PT J AU Uzel, G Ouyang, W Pittaluga, S Schindler, M Su, H Koneti, R Su, HC Agharahimi, A Hussey, AA Hsu, AP Meffre, E Holland, SM AF Uzel, Gulbu Ouyang, Weiming Pittaluga, Stefania Schindler, Matthew Su, Hua Koneti, Rao Su, Helen C. Agharahimi, Anahita Hussey, Ashleigh A. Hsu, Amy P. Meffre, Eric Holland, Steven M. TI MANY FACES OF CTLA-4 HAPLOINSUFFICIENCY; EXPANDING DISEASE SPECTRUM WITH PATHOLOGIC, IMMUNOLOGIC AND MOLECULAR FINDINGS IN A LARGE COHORT SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Uzel, Gulbu] NIAID, Lab Clin Infect Dis, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Ouyang, Weiming] US FDA, Lab Cell Biol, Div Monoclonal Antibodies, Off Biotechnol Prod,Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Pittaluga, Stefania] NIH, Hematopathol Sect, Bldg 10, Bethesda, MD 20892 USA. [Schindler, Matthew] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Su, Hua; Koneti, Rao; Hussey, Ashleigh A.; Hsu, Amy P.; Holland, Steven M.] NIAID, NIH, LCID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Su, Helen C.] NIAID, Lab Host Def, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Agharahimi, Anahita] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Meffre, Eric] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 APR PY 2016 VL 36 IS 3 MA 4683 BP 332 EP 332 PG 1 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300234 ER PT J AU Marciano, B Zerbe, CS Kreuzburg, SA Yockey, L Kuhns, DB Uzel, G Holland, SM AF Marciano, Betty Zerbe, Christa S. Kreuzburg, Samantha A. Yockey, Lynne Kuhns, Douglas B. Uzel, Gulbu Holland, Steven M. TI X-LINKED CARRIERS OF CHRONIC GRANULOMATOUS DISEASE SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Marciano, Betty; Zerbe, Christa S.; Kreuzburg, Samantha A.; Uzel, Gulbu; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Yockey, Lynne] NIH, Dept Nursing, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Kuhns, Douglas B.] NCI, Leidos Biomed Res Inc, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 APR PY 2016 VL 36 IS 3 MA 4687 BP 333 EP 334 PG 2 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300237 ER PT J AU Hoofnagle, JH AF Hoofnagle, Jay H. TI Hepatic decompensation during direct-acting antiviral therapy of chronic hepatitis C SO JOURNAL OF HEPATOLOGY LA English DT Editorial Material DE Hepatitis C; Cirrhosis; Mitochondrial injury; Lactic acidosis; Acute hepatic decompensation; Severe adverse events; Antiviral therapy; Sofosbuvir; Ribavirin ID HCV GENOTYPE 1; SOFOSBUVIR; INFECTION; RIBAVIRIN; ABT-450/R-OMBITASVIR; VELPATASVIR; LEDIPASVIR; DASABUVIR; CIRRHOSIS C1 [Hoofnagle, Jay H.] NIDDK, Liver Dis Res Branch, Div Digest Dis & Nutr, NIH, Bethesda, MD USA. RP Hoofnagle, JH (reprint author), NIDDK, JHH, LDRB, DDDN, Room 655,6707 Democracy Blvd, Bethesda, MD 20892 USA. EM Hoofnaglej@extra.niddk.nih.gov NR 18 TC 6 Z9 6 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 EI 1600-0641 J9 J HEPATOL JI J. Hepatol. PD APR PY 2016 VL 64 IS 4 BP 763 EP 765 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DH3IY UT WOS:000372681900002 PM 26795828 ER PT J AU Baranova, IN Souza, ACP Bocharov, AV Vishnyakova, TG Hu, XZ Vaisman, BL Amar, MJ Chen, ZG Kost, Y Remaley, AT Patterson, AP Yuen, PST Star, RA Eggerman, TL AF Baranova, Irina N. Souza, Ana C. P. Bocharov, Alexander V. Vishnyakova, Tatyana G. Hu, Xuzhen Vaisman, Boris L. Amar, Marcelo J. Chen, Zhigang Kost, Yana Remaley, Alan T. Patterson, Amy P. Yuen, Peter S. T. Star, Robert A. Eggerman, Thomas L. TI Human SR-BI and SR-BII Potentiate Lipopolysaccharide-Induced Inflammation and Acute Liver and Kidney Injury in Mice SO JOURNAL OF IMMUNOLOGY LA English DT Article ID RECEPTOR CLASS-B; HIGH-DENSITY-LIPOPROTEIN; TUBULAR EPITHELIAL-CELLS; NITRIC-OXIDE SYNTHASE; CHOLESTERYL ESTER UPTAKE; SERUM-AMYLOID-A; SCAVENGER RECEPTOR; INDUCED SEPSIS; IN-VIVO; GLUCOCORTICOID PRODUCTION AB The class B scavenger receptors BI (SR-BI) and BII (SR-BII) are high-density lipoprotein receptors that recognize various pathogens, including bacteria and their products. It has been reported that SR-BI/II null mice are more sensitive than normal mice to endotoxin-induced inflammation and sepsis. Because the SR-BI/II knockout model demonstrates multiple immune and metabolic disorders, we investigated the role of each receptor in the LPS-induced inflammatory response and tissue damage using transgenic mice with pLiv-11-directed expression of human SR-BI (hSR-BI) or human SR-BII (hSR-BII). At 6 h after i.p. LPS injection, transgenic hSR-BI and hSR-BII mice demonstrated markedly higher serum levels of proinflammatory cytokines and 2- to 3-fold increased expression levels of inflammatory mediators in the liver and kidney, compared with wild-type (WT) mice. LPS-stimulated inducible NO synthase expression was 3-to 6-fold higher in the liver and kidney of both transgenic strains, although serum NO levels were similar in all mice. Despite the lower high-density lipoprotein plasma levels, both transgenic strains responded to LPS by a 5-fold increase of plasma corticosterone levels, which were only moderately lower than in WT animals. LPS treatment resulted in MAPK activation in tissues of all mice; however, the strongest response was detected for hepatic extracellular signal-regulated protein kinase 1 and 2 and kidney JNK of both transgenic mice. Histological examination of hepatic and renal tissue from LPS-challenged mice revealed more injury in hSR-BII, but not hSR-BI, transgenic mice versus WT controls. Our findings demonstrate that hSR-BII, and to a lesser extent hSR-BI, significantly increase LPS-induced inflammation and contribute to LPS-induced tissue injury in the liver and kidney, two major organs susceptible to LPS toxicity. C1 [Baranova, Irina N.; Bocharov, Alexander V.; Vishnyakova, Tatyana G.; Chen, Zhigang; Kost, Yana; Patterson, Amy P.; Eggerman, Thomas L.] NIH, Dept Lab Med, Ctr Clin, Bldg 9,Room 1N128,9000 Rockville Pike, Bethesda, MD 20892 USA. [Souza, Ana C. P.; Hu, Xuzhen; Yuen, Peter S. T.; Star, Robert A.] NIDDK, Renal Diagnost & Therapeut Unit, NIH, Bethesda, MD 20892 USA. [Vaisman, Boris L.; Amar, Marcelo J.; Remaley, Alan T.; Patterson, Amy P.] NHLBI, NIH, Bethesda, MD 20892 USA. [Eggerman, Thomas L.] NIDDK, Div Diabet Endocrinol & Metab Dis, NIH, Bethesda, MD 20892 USA. RP Bocharov, AV (reprint author), NIH, Dept Lab Med, Ctr Clin, Bldg 9,Room 1N128,9000 Rockville Pike, Bethesda, MD 20892 USA. EM abocharov@cc.nih.gov; eggermant@niddk.nih.gov RI Yuen, Peter/B-1954-2008; OI Yuen, Peter/0000-0001-9557-3909; Vaisman, Boris/0000-0003-0495-2220 FU National Institutes of Health Intramural Research Programs at the Clinical Center; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute FX This work was supported by the National Institutes of Health Intramural Research Programs at the Clinical Center, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, and the National Heart, Lung, and Blood Institute. NR 87 TC 2 Z9 2 U1 4 U2 10 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD APR 1 PY 2016 VL 196 IS 7 BP 3135 EP 3147 DI 10.4049/jimmunol.1501709 PG 13 WC Immunology SC Immunology GA DG8MU UT WOS:000372339100024 PM 26936883 ER PT J AU Lee, EJ Brown, BR Vance, EE Snow, PE Silver, PB Heinrichs, D Lin, X Iwakura, Y Wells, CA Caspi, RR Rosenzweig, HL AF Lee, Ellen J. Brown, Brieanna R. Vance, Emily E. Snow, Paige E. Silver, Phyllis B. Heinrichs, David Lin, Xin Iwakura, Yoichiro Wells, Christine A. Caspi, Rachel R. Rosenzweig, Holly L. TI Mincle Activation and the Syk/Card9 Signaling Axis Are Central to the Development of Autoimmune Disease of the Eye SO JOURNAL OF IMMUNOLOGY LA English DT Article ID C-TYPE LECTIN; MYCOBACTERIAL CORD FACTOR; INNATE IMMUNE-RESPONSE; ANTIFUNGAL IMMUNITY; CANDIDA-ALBICANS; RECEPTOR; UVEITIS; CELLS; CARD9; UVEORETINITIS AB Uveitis, which occurs in association with systemic immunological diseases, presents a considerable medical challenge because of incomplete understanding of its pathogenesis. The signals that initiate T cells to target the eye, which may be of infectious or noninfectious origin, are poorly understood. Experimental autoimmune uveoretinitis (EAU) develops in mice immunized with the endogenous retinal protein interphotoreceptor retinoid binding protein in the presence of the adjuvant CFA. EAU manifests as posterior ocular inflammation consisting of vasculitis, granulomas, retinal damage, and invasion of self-reactive T cells, which are key clinical features of human uveitis. Our studies uncover Card9 as a critical genetic determinant for EAU. Card9 was responsible for Th17 polarization and Th17-associated Ag-specific responses, but not Th1-associated responses. Nonetheless, Card9 expression was essential for accumulation of both lineages within the eye. Consistent with its recently identified role as an intracellular signaling mediator for C-type lectin receptors (CLRs), a Card9-dependent transcriptional response in the neuroretina was observed involving genes encoding the CLRs Dectin-1, Dectin-2, and Mincle. Genetic deletion of these individual CLRs revealed an essential role for Mincle. Mincle activation was sufficient to generate the EAU phenotype, and this required activation of both Syk and Card9. In contrast, Dectin-1 contributed minimally and a possible repressive role was shown for Dectin-2. These findings extend our understanding of CLRs in autoimmune uveitis. The newly identified role of Mincle and Syk/Card9-coupled signaling axis in autoimmune uveitis could provide novel targets for treatment of patients with ocular inflammatory disease. C1 [Lee, Ellen J.; Brown, Brieanna R.; Vance, Emily E.; Snow, Paige E.; Heinrichs, David; Rosenzweig, Holly L.] VA Portland Hlth Care Syst, Portland, OR 97239 USA. [Lee, Ellen J.; Vance, Emily E.; Rosenzweig, Holly L.] Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97239 USA. [Silver, Phyllis B.; Caspi, Rachel R.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Lin, Xin] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA. [Iwakura, Yoichiro] Tokyo Univ Sci, Tokyo 2780022, Japan. [Wells, Christine A.] Univ Queensland, Brisbane, Qld 4072, Australia. RP Rosenzweig, HL (reprint author), Oregon Hlth & Sci Univ, VA Portland Hlth Care Syst, 3710 SW US Vet Hosp Rd,Bldg 103,Room E-221A, Portland, OR 97239 USA. EM rosenzwh@ohsu.edu RI Iwakura, Yoichiro/E-5457-2011; OI Iwakura, Yoichiro/0000-0002-9934-5775; Caspi, Rachel/0000-0002-7140-7671; Wells, Christine/0000-0003-3133-3628 FU National Institutes of Health [RO1 EY025250]; National Eye Institute [EY00184]; Department of Veterans Affairs Biomedical Laboratory Research and Development Service (Merit Review Award) [I01 BX002180] FX This work was supported by the National Institutes of Health (Grant RO1 EY025250), intramural funding from the National Eye Institute (Project EY00184), and by the Department of Veterans Affairs Biomedical Laboratory Research and Development Service (Merit Review Award I01 BX002180). NR 47 TC 7 Z9 7 U1 1 U2 26 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD APR 1 PY 2016 VL 196 IS 7 BP 3148 EP 3158 DI 10.4049/jimmunol.1502355 PG 11 WC Immunology SC Immunology GA DG8MU UT WOS:000372339100025 PM 26921309 ER PT J AU Wendler, D Wesley, B Pavlick, M Rid, A AF Wendler, David Wesley, Bob Pavlick, Mark Rid, Annette TI A new method for making treatment decisions for incapacitated patients: what do patients think about the use of a patient preference predictor? SO JOURNAL OF MEDICAL ETHICS LA English DT Article ID SERIOUSLY ILL PATIENTS; ADVANCE DIRECTIVES; MEDICAL DECISIONS; MAKING CAPACITY; CRITICALLY-ILL; OLDER-ADULTS; LIFE; END; SURROGATES; ACCURACY AB Background Surrogates frequently are unable to predict which treatment their charges would want and also can experience significant distress as a result of making treatment decisions. A new method, the patient preference predictor (PPP), has been proposed as a possible way to supplement the process of shared decision-making to address these two concerns. The PPP predicts which treatment the patient would want based on which treatment similar patients want in similar circumstances. The present article describes the results of the first evaluation to assess whether patients support the use of a PPP. Methods Self-administered survey of patients at a tertiary care centre. Results Overall, 1169 respondents completed the survey (response rate=59.8%). In the event that the respondent became unable to make decisions due to a car accident, 78.9% would want the PPP to be incorporated into the process of making treatment decisions for them. In contrast, 15.2% of respondents would not want the PPP to be used for them. Respondents who endorsed the PPP cited the possibility that its use could increase the chances that they receive the treatments they prefer and/or reduce the burdens on their surrogate decision-maker. Conclusions The majority of respondents endorsed the possibility of incorporating a PPP into the process of shared decision-making based on its potential to increase surrogates' predictive accuracy and/or reduce surrogate distress. These data provide strong patient support for further research to assess whether, in practice, the use of a PPP can increase the chances that incapacitated patients receive the treatments they prefer and reduce the burden of making decisions on their surrogates. C1 [Wendler, David] NIH, Ctr Clin, Dept Bioeth, Bldg 10, Bethesda, MD 20892 USA. [Wesley, Bob] NIH, Ctr Clin, Biostat & Clin Epidemiol Serv, Bldg 10, Bethesda, MD 20892 USA. [Pavlick, Mark] St Elizabeth Hosp, Washington, DC USA. [Rid, Annette] Kings Coll London, Dept Social Sci Hlth & Med, London WC2R 2LS, England. RP Wendler, D (reprint author), NIH, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM dwendler@nih.gov FU NIH Clinical Center FX NIH Clinical Center. NR 28 TC 1 Z9 1 U1 0 U2 4 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0306-6800 EI 1473-4257 J9 J MED ETHICS JI J. Med. Ethics PD APR PY 2016 VL 42 IS 4 BP 235 EP 241 DI 10.1136/medethics-2015-103001 PG 7 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA DH2BC UT WOS:000372588100007 PM 26825474 ER PT J AU Rulli, T Millum, J AF Rulli, Tina Millum, Joseph TI Rescuing the duty to rescue SO JOURNAL OF MEDICAL ETHICS LA English DT Article ID MEDICAL RESEARCHERS; ANCILLARY-CARE; CLINICAL CARE; MORAL DUTY; RULE; RESPONSIBILITIES; EQUIPOISE; ETHICS; OWE AB Clinicians and health researchers frequently encounter opportunities to rescue people. Rescue cases can generate a moral duty to aid those in peril. As such, bioethicists have leveraged a duty to rescue for a variety of purposes. Yet, despite its broad application, the duty to rescue is underanalysed. In this paper, we assess the state of theorising about the duty to rescue. There are large gaps in bioethicists' understanding of the force, scope and justification of the two most cited duties to rescue-the individual duty of easy rescue and the institutional rule of rescue. We argue that the duty of easy rescue faces unresolved challenges regarding its force and scope, and the rule of rescue is indefensible. If the duty to rescue is to help solve ethical problems, these theoretical gaps must be addressed. We identify two further conceptions of the duty to rescue that have received less attention-an institutional duty of easy rescue and the professional duty to rescue. Both provide guidance in addressing force and scope concerns and, thereby, traction in answering the outstanding problems with the duty to rescue. We conclude by proposing research priorities for developing accounts of duties to rescue in bioethics. C1 [Rulli, Tina; Millum, Joseph] NIH, Ctr Clin, Dept Bioeth, 10 Ctr Dr,Bldg 10,Room 1C118, Bethesda, MD 20892 USA. [Millum, Joseph] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. RP Rulli, T (reprint author), NIH, Ctr Clin, Dept Bioeth, 10 Ctr Dr,Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM tinarulli@gmail.com FU National Institutes of Health Clinical Center FX This work was supported, in part, by intramural funds from the National Institutes of Health Clinical Center. NR 29 TC 4 Z9 4 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0306-6800 EI 1473-4257 J9 J MED ETHICS JI J. Med. Ethics PD APR PY 2016 VL 42 IS 4 BP 260 EP 264 DI 10.1136/medethics-2013-101643 PG 5 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA DH2BC UT WOS:000372588100012 PM 24790055 ER PT J AU Bigelow, RT Semenov, YR du Lac, S Hoffman, HJ Agrawal, Y AF Bigelow, Robin T. Semenov, Yevgeniy R. du Lac, Sascha Hoffman, Howard J. Agrawal, Yuri TI Vestibular vertigo and comorbid cognitive and psychiatric impairment: the 2008 National Health Interview Survey SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Article ID BALANCE DISORDERS; LEARNING-DISABILITIES; GENERAL-POPULATION; PREVALENCE; DIZZINESS; ANXIETY; IMPACT; EPIDEMIOLOGY; DISTURBANCE; COMMUNITY AB Background/aims Patients with vestibular disease have been observed to have concomitant cognitive and psychiatric dysfunction. We evaluated the association between vestibular vertigo, cognitive impairment and psychiatric conditions in a nationally representative sample of US adults. Methods We performed a cross-sectional analysis using the 2008 National Health Interview Survey (NHIS), which included a Balance and Dizziness Supplement, and questions about cognitive function and psychiatric comorbidity. We evaluated the association between vestibular vertigo, cognitive impairment (memory loss, difficulty concentrating, confusion) and psychiatric diagnoses (depression, anxiety and panic disorder). Results We observed an 8.4% 1-year prevalence of vestibular vertigo among US adults. In adjusted analyses, individuals with vestibular vertigo had an eightfold increased odds of 'serious difficulty concentrating or remembering' (OR 8.3, 95% CI 4.8 to 14.6) and a fourfold increased odds of activity limitation due to difficulty remembering or confusion (OR 3.9, 95% CI 3.1 to 5.0) relative to the rest of the US adults. Individuals with vestibular vertigo also had a threefold increased odds of depression (OR 3.4, 95% CI 2.9 to 3.9), anxiety (OR 3.2, 95% CI 2.8 to 3.6) and panic disorder (OR 3.4, 95% CI 2.9 to 4.0). Conclusions Our findings indicate that vestibular impairment is associated with increased risk of cognitive and psychiatric comorbidity. The vestibular system is anatomically connected with widespread regions of the cerebral cortex, hippocampus and amygdala. Loss of vestibular inputs may lead to impairment of these cognitive and affective circuits. Further longitudinal research is required to determine if these associations are causal. C1 [Bigelow, Robin T.; Semenov, Yevgeniy R.; du Lac, Sascha; Agrawal, Yuri] Johns Hopkins Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21287 USA. [du Lac, Sascha] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21287 USA. [Hoffman, Howard J.] Natl Inst Deafness & Other Commun Disorders NIDCD, Epidemiol & Stat Program, Div Sci Programs, NIH, Bethesda, MD USA. RP Bigelow, RT (reprint author), Johns Hopkins Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21287 USA. EM rbigelow@jhmi.edu FU National Institute on Deafness and Other Communication Disorders (NIDCD); NIH/NIDCD [K23 DC013056, 5T32DC000023-30] FX The Balance and Dizziness Supplement of the 2008 NHIS was supported by funding from the National Institute on Deafness and Other Communication Disorders (NIDCD). Funding support also received from NIH/NIDCD K23 DC013056 (YA) and NIH/NIDCD 5T32DC000023-30 (RTB). NR 38 TC 4 Z9 4 U1 1 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-3050 EI 1468-330X J9 J NEUROL NEUROSUR PS JI J. Neurol. Neurosurg. Psychiatry PD APR PY 2016 VL 87 IS 4 BP 367 EP 372 DI 10.1136/jnnp-2015-310319 PG 6 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA DG7WI UT WOS:000372294000005 PM 25886779 ER PT J AU Saccone, PA Zelenock, KA Lindsey, AM Sulima, A Rice, KC Prinssen, EP Wichmann, J Woods, JH AF Saccone, Phillip A. Zelenock, Kathy A. Lindsey, Angela M. Sulima, Agnieszka Rice, Kenner C. Prinssen, Eric P. Wichmann, Juergen Woods, James H. TI Characterization of the Discriminative Stimulus Effects of a NOP Receptor Agonist Ro 64-6198 in Rhesus Monkeys SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID NOCICEPTIN/ORPHANIN FQ RECEPTOR; SYNTHETIC AGONIST; PEPTIDE RECEPTORS; OPIOID RECEPTORS; ORPHANIN-FQ; DELTA; MU; ORL1; NOCICEPTION; RO64-6198 AB Nociceptin/orphanin FQ receptor (NOP) agonists have been reported to produce antinociceptive effects in rhesus monkeys with comparable efficacy to m-opioid receptor (MOP) agonists, but without their limiting side effects. There are also known to be species differences between rodents and nonhuman primates (NHPs) in the behavioral effects of NOP agonists. The aims of this study were the following: 1) to determine if the NOP agonist Ro 64-6198 could be trained as a discriminative stimulus; 2) to evaluate its pharmacological selectivity as a discriminative stimulus; and 3) to establish the order of potency with which Ro 64-6198 produces discriminative stimulus effects compared with analgesic effects in NHPs. Two groups of rhesus monkeys were trained to discriminate either fentanyl or Ro 646198 from vehicle. Four monkeys were trained in the warm-water tail-withdrawal procedure to measure antinociception. Ro 64-6198 produced discriminative stimulus effects that were blocked by the NOP antagonist J-113397 and not by naltrexone. The discriminative stimulus effects of Ro 64-6198 partially generalized to diazepam, but not to fentanyl, SNC 80, ketocyclazocine, buprenorphine, phencyclidine, or chlorpromazine. Fentanyl produced stimulus effects that were blocked by naltrexone and not by J-113397, and Ro 64-6198 did not produce fentanyl-appropriate responding in fentanyl-trained animals. In measures of antinociception, fentanyl, but not Ro 64-6198, produced dose-dependent increases in tail-withdrawal latency. Together, these results demonstrate that Ro 64-6198 produced stimulus effects in monkeys that are distinct from other opioid receptor agonists, but may be somewhat similar to diazepam. In contrast to previous findings, Ro 64-6198 did not produce antinociception in the majority of animals tested even at doses considerably greater than those that produced discriminative stimulus effects. C1 [Saccone, Phillip A.; Zelenock, Kathy A.; Lindsey, Angela M.; Woods, James H.] Univ Michigan, Sch Med, Dept Pharmacol, 1301 MSRB 3,1150 W Med Ctr Dr, Ann Arbor, MI 48109 USA. [Sulima, Agnieszka; Rice, Kenner C.] NIDA, Bethesda, MD 20892 USA. [Sulima, Agnieszka; Rice, Kenner C.] NIAAA, Bethesda, MD USA. [Prinssen, Eric P.; Wichmann, Juergen] Hoffman La Roche Ltd, Basel, Switzerland. RP Saccone, PA (reprint author), Univ Michigan, Sch Med, Dept Pharmacol, 1301 MSRB 3,1150 W Med Ctr Dr, Ann Arbor, MI 48109 USA. EM sacconep@umich.edu FU National Institutes of Health National Institute on Drug Abuse [F31-DA038488, T32-DA007281]; National Institutes of Health National Institute on Alcohol Abuse and Alcoholism; National Institutes of Health National Institute on Drug Abuse Intramural Research Programs; National Institutes of Health Intramural Research Programs of the National Institute on Drug Abuse; National Institute of Alcohol Abuse and Alcoholism FX This study was supported by the National Institutes of Health National Institute on Drug Abuse [Grants F31-DA038488 and T32-DA007281]. A portion of this work was supported by the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism and the National Institutes of Health National Institute on Drug Abuse Intramural Research Programs. The work of the Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute on Drug Abuse, and National Institute of Alcohol Abuse and Alcoholism was supported by the National Institutes of Health Intramural Research Programs of the National Institute on Drug Abuse and National Institute of Alcohol Abuse and Alcoholism. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the National Institute on Drug Abuse. NR 29 TC 0 Z9 0 U1 0 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 EI 1521-0103 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD APR PY 2016 VL 357 IS 1 BP 17 EP 23 DI 10.1124/jpet.115.231134 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DG5TX UT WOS:000372142800003 PM 26801398 ER PT J AU Janowsky, A Tosh, DK Eshleman, AJ Jacobson, KA AF Janowsky, Aaron Tosh, Dilip K. Eshleman, Amy J. Jacobson, Kenneth A. TI Rigid Adenine Nucleoside Derivatives as Novel Modulators of the Human Sodium Symporters for Dopamine and Norepinephrine SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID ADENOSINE RECEPTOR ACTIVATION; BIOGENIC-AMINE TRANSPORTERS; MONOAMINE TRANSPORTERS; ALLOSTERIC MODULATORS; SUBSTRATE-BINDING; COCAINE; SITES; 2-ARYLETHYNYL; SUBSTITUTIONS; ASSOCIATION AB Thirty-two congeneric rigid adenine nucleoside derivatives containing a North (N)-methanocarba ribose substitution and a 2-arylethynyl group either enhanced (up to 760% of control) or inhibited [I-125] methyl (1R,2S,3S)-3-(4-iodophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate (RTI-55) binding at the human dopamine (DA) transporter (DAT) and inhibited DA uptake. Several nucleosides also enhanced [H-3]mazindol[(+/-)-5-(4-chlorophenyl)-3,5-dihydro-2H-imidazo[2,1-a]isoindol-5-ol] binding to the DAT. The combination of binding enhancement and functional inhibition suggests possible allosteric interaction with the tropanes. The structure-activity relationship of this novel class of DAT ligands was explored: small N-6-substition (methyl or ethyl) was favored, while the N1 of the adenine ring was essential. Effective terminal aryl groups include thien-2-yl (compounds 9 and 16), with EC50 values of 35.1 and 9.1 nM, respectively, in [I-125] RTI-55 binding enhancement, and 3,4-difluorophenyl as in the most potent DA uptake inhibitor (compound 6) with an IC50 value of 92 nM (3-fold more potent than cocaine), but not nitrogen heterocycles. Several compounds inhibited or enhanced binding at the norepinephrine transporter (NET) and serotonin transporter (SERT) and inhibited function in the micromolar range; truncation at the 49-position in compound 23 allowed for weak inhibition of the SERT. We have not yet eliminated adenosine receptor affinity from this class of DAT modulators, but we identified modifications that remove DAT inhibition as an off-target effect of potent adenosine receptor agonists. Thus, we have identified a new class of allosteric DAT ligands, rigidified adenosine derivatives, and explored their initial structural requirements. They display a very atypical pharmacological profile, i.e., either enhancement by increasing affinity or inhibition of radioligand binding at the DAT, and in some cases the NET and SERT, and inhibition of neurotransmitter uptake. C1 [Janowsky, Aaron; Eshleman, Amy J.] Oregon Hlth & Sci Univ, VA Portland Hlth Care Syst, Res Serv R&D 22, Portland, OR 97201 USA. [Janowsky, Aaron; Eshleman, Amy J.] Oregon Hlth & Sci Univ, Dept Psychiat, Portland, OR 97201 USA. [Janowsky, Aaron; Eshleman, Amy J.] Oregon Hlth & Sci Univ, Dept Behav Neurosci, Portland, OR 97201 USA. [Tosh, Dilip K.; Jacobson, Kenneth A.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Janowsky, A (reprint author), VA Portland Hlth Care Syst, Res Serv R&D 22, 3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM janowsky@ohsu.edu RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural Research Program of the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [ZIA DK031117]; National Institute of Mental Health's Psychoactive Drug Screening Program [HHSN-271-2008-00025-C]; National Institutes of Health National Institute on Drug Abuse/Veterans Association Interagency Agreement [ADA12013]; Methamphetamine Abuse Research Center [P50 DA018165-06]; Department of Veterans Affairs Research Career Scientist Program FX This work was supported by the Intramural Research Program of the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant ZIA DK031117] and the National Institute of Mental Health's Psychoactive Drug Screening Program [Contract HHSN-271-2008-00025-C]. This work was also supported by National Institutes of Health National Institute on Drug Abuse/Veterans Association Interagency Agreement ADA12013, the Methamphetamine Abuse Research Center [Grant P50 DA018165-06], and the Department of Veterans Affairs Research Career Scientist Program. NR 41 TC 3 Z9 3 U1 0 U2 4 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 EI 1521-0103 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD APR PY 2016 VL 357 IS 1 BP 24 EP 35 DI 10.1124/jpet.115.229666 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DG5TX UT WOS:000372142800004 PM 26813929 ER PT J AU Miller, AC AF Miller, Andrew C. TI Opinions on the Legitimacy of Brain Death Among Sunni and Shi'a Scholars SO JOURNAL OF RELIGION & HEALTH LA English DT Article DE Death; Brain death; Islam; Medical ethics; End of life ID OF-LIFE CARE; ORGAN DONATION; ISLAMIC BIOETHICS; SAUDI-ARABIA; 10-YEAR EXPERIENCE; HISTORY; ADULTS; END; TRANSPLANTATION; VARIABILITY AB The concept of brain death poses a great challenge to clinicians who may be required to bridge the interface of culture, religion, law, and medicine. This review discusses and applies Islamic jurisprudence to the question of whether brain death is accepted as true death under Islamic law. Among the five sources of Islamic law, the Qur'an and Sunnah do not directly address brain death. Scholarly consensus (IjmA') does not exist, and Qiya does not apply. When applying Ijtihad, the identified collection of non-binding fatwA offer conflicting results. Debate continues as to the validity of brain-death criteria within Islamic circles. C1 [Miller, Andrew C.] W Virginia Univ, Dept Emergency Med, Sch Med, 1 Med Ctr Dr, Morgantown, WV 26506 USA. [Miller, Andrew C.] NIH, Dept Crit Care Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. RP Miller, AC (reprint author), W Virginia Univ, Dept Emergency Med, Sch Med, 1 Med Ctr Dr, Morgantown, WV 26506 USA.; Miller, AC (reprint author), NIH, Dept Crit Care Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM Taqwa1@gmail.com OI Miller, Andrew/0000-0001-8474-5090 NR 37 TC 2 Z9 2 U1 3 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0022-4197 EI 1573-6571 J9 J RELIG HEALTH JI J. Relig. Health PD APR PY 2016 VL 55 IS 2 BP 394 EP 402 DI 10.1007/s10943-015-0157-8 PG 9 WC Public, Environmental & Occupational Health; Religion SC Public, Environmental & Occupational Health; Religion GA DG7ST UT WOS:000372284700005 PM 26581553 ER PT J AU Sandeep, N Uchida, Y Ratnayaka, K McCarter, R Hanumanthaiah, S Bangoura, A Zhao, Z Oliver-Danna, J Leatherbury, L Kanter, J Mukouyama, YS AF Sandeep, Nefthi Uchida, Yutaka Ratnayaka, Kanishka McCarter, Robert Hanumanthaiah, Sridhar Bangoura, Aminata Zhao, Zhen Oliver-Danna, Jacqueline Leatherbury, Linda Kanter, Joshua Mukouyama, Yoh-suke TI Characterizing the angiogenic activity of patients with single ventricle physiology and aortopulmonary collateral vessels SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article DE single ventricle; aortopulmonary collateral; congenital heart disease ID ENDOTHELIAL GROWTH-FACTOR; CONGENITAL HEART-DISEASE; PULMONARY COLLATERALS; RISK-FACTORS; IN-VITRO; FONTAN; CXCL12; EXPRESSION; OPERATION; CHILDREN AB Objectives: Patients with single ventricle congenital heart disease often form aortopulmonary collateral vessels via an unclear mechanism. To gain insights into the pathogenesis of aortopulmonary collateral vessels, we correlated angiogenic factor levels with in vitro activity and angiographic aortopulmonary collateral assessment and examined whether patients with single ventricle physiology have increased angiogenic factors that can stimulate endothelial cell sprouting in vitro. Methods: In patients with single ventricle physiology (n = 27) and biventricular acyanotic control patients (n = 21), hypoxia-inducible angiogenic factor levels were measured in femoral venous and arterial plasma at cardiac catheterization. To assess plasma angiogenic activity, we used a 3-dimensional in vitro cell sprouting assay that recapitulates angiogenic sprouting. Aortopulmonary collateral angiograms were graded using a 4-point scale. Results: Compared with controls, patients with single ventricle physiology had increased vascular endothelial growth factor (artery: 58.7 +/- 1.2 pg/mL vs 35.3 +/- 1.1 pg/mL, P < .01; vein: 34.8 +/- 1.1 pg/mL vs 21 +/- 1.2 pg/mL, P < .03), stromal-derived factor 1-alpha (artery: 1901.6 +/- 1.1 pg/mL vs 1542.6 +/- 1.1 pg/mL, P < .03; vein: 2092.8 pg/mL +/- 1.1 vs 1752.9 +/- 1.1 pg/mL, P < .02), and increased arterial soluble fms-like tyrosine kinase-1, a regulatory vascular endothelial growth factor receptor (612.3 +/- 1.2 pg/mL vs 243.1 +/- 1.2 pg/mL, P < .003). Plasma factors and sprout formation correlated poorly with aortopulmonary collateral severity. Conclusions: We are the first to correlate plasma angiogenic factor levels with angiography and in vitro angiogenic activity in patients with single ventricle disease with aortopulmonary collaterals. Patients with single ventricle disease have increased stromal-derived factor 1-alpha and soluble fms-like tyrosine kinase-1, and their roles in aortopulmonary collateral formation require further investigation. Plasma factors and angiogenic activity correlate poorly with aortopulmonary collateral severity in patients with single ventricles, suggesting complex mechanisms of angiogenesis. C1 [Sandeep, Nefthi; Uchida, Yutaka; Mukouyama, Yoh-suke] NHLBI, Lab Stem Cell & Neurovasc Biol, Genet & Dev Biol Ctr, NIH, Bldg 10,Room 6C103,MSC1583,10 Ctr Dr, Bethesda, MD 20892 USA. [Zhao, Zhen; Oliver-Danna, Jacqueline] NHLBI, Dept Lab Med, NIH, Bldg 10, Bethesda, MD 20892 USA. [Sandeep, Nefthi; Ratnayaka, Kanishka; Hanumanthaiah, Sridhar; Bangoura, Aminata; Leatherbury, Linda; Kanter, Joshua] Childrens Natl Hlth Syst, Div Pediat Cardiol, Washington, DC USA. [McCarter, Robert] Childrens Natl Hlth Syst, Dept Biostat & Informat, Washington, DC USA. RP Mukouyama, YS (reprint author), NHLBI, Lab Stem Cell & Neurovasc Biol, Genet & Dev Biol Ctr, NIH, Bldg 10,Room 6C103,MSC1583,10 Ctr Dr, Bethesda, MD 20892 USA. EM mukoyamay@mail.nih.gov FU Ruth L. Kirschstein National Research Service Award [T32]; National Center for Advancing Translational Sciences [UL1TR000075]; Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health [HL006116-05] FX N.S was supported by an institutional Ruth L. Kirschstein National Research Service Award (T32) and National Center for Advancing Translational Sciences (UL1TR000075). This work was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health (HL006116-05 [Y.-s.M.]). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Center for Advancing Translational Sciences or the National Institutes of Health. NR 33 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 EI 1097-685X J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD APR PY 2016 VL 151 IS 4 BP 1126 EP 1135 DI 10.1016/j.jtcvs.2015.10.001 PG 10 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA DG9XK UT WOS:000372436900065 PM 26611747 ER PT J AU Koester, SE Insel, TR AF Koester, S. E. Insel, T. R. TI Understanding how non-coding genomic polymorphisms affect gene expression SO MOLECULAR PSYCHIATRY LA English DT Article ID TRANSCRIPTOME AB The NIH Common Fund GTEx project is designed to serve as a data and post-mortem tissue resource to the research community. The project is testing the role of genomic variation in altering gene expression across a wide array of tissues in a large number of human post-mortem donors. Both data and tissue samples are available to the research community for additional studies. C1 [Koester, S. E.; Insel, T. R.] NIMH, Div Neurosci & Basic Behav Sci, NIH, 6001 Execut Blvd,Room 7205, Bethesda, MD 20892 USA. RP Koester, SE (reprint author), NIMH, Div Neurosci & Basic Behav Sci, NIH, 6001 Execut Blvd,Room 7205, Bethesda, MD 20892 USA. EM koesters@mail.nih.gov NR 6 TC 2 Z9 2 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD APR PY 2016 VL 21 IS 4 BP 448 EP 449 DI 10.1038/mp.2015.226 PG 2 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA DG9RM UT WOS:000372421500002 PM 26809843 ER PT J AU Belin-Rauscent, A Daniel, ML Puaud, M Jupp, B Sawiak, S Howett, D McKenzie, C Caprioli, D Besson, M Robbins, TW Everitt, BJ Dalley, JW Belin, D AF Belin-Rauscent, A. Daniel, M-L Puaud, M. Jupp, B. Sawiak, S. Howett, D. McKenzie, C. Caprioli, D. Besson, M. Robbins, T. W. Everitt, B. J. Dalley, J. W. Belin, D. TI From impulses to maladaptive actions: the insula is a neurobiological gate for the development of compulsive behavior SO MOLECULAR PSYCHIATRY LA English DT Article ID SCHEDULE-INDUCED-POLYDIPSIA; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; COCAINE-DEPENDENT INDIVIDUALS; CONDITIONED PLACE PREFERENCE; REACTION-TIME-TASK; NUCLEUS-ACCUMBENS; DECISION-MAKING; ANTERIOR INSULA; NEUROCOGNITIVE ENDOPHENOTYPES; TRAIT IMPULSIVITY AB Impulsivity is an endophenotype of vulnerability for compulsive behaviors. However, the neural mechanisms whereby impulsivity facilitates the development of compulsive disorders, such as addiction or obsessive compulsive disorder, remain unknown. We first investigated, in rats, anatomical and functional correlates of impulsivity in the anterior insular (AI) cortex by measuring both the thickness of, and cellular plasticity markers in, the AI with magnetic resonance imaging and in situ hybridization of the immediate early gene zif268, respectively. We then investigated the influence of bilateral AI cortex lesions on the high impulsivity trait, as measured in the five-choice serial reaction time task (5-CSRTT), and the associated propensity to develop compulsivity as measured by high drinking levels in a schedule-induced polydipsia procedure (SIP). We demonstrate that the AI cortex causally contributes to individual vulnerability to impulsive-compulsive behavior in rats. Motor impulsivity, as measured by premature responses in the 5-CSRTT, was shown to correlate with the thinness of the anterior region of the insular cortex, in which highly impulsive (HI) rats expressed lower zif268 mRNA levels. Lesions of AI reduced impulsive behavior in HI rats, which were also highly susceptible to develop compulsive behavior as measured in a SIP procedure. AI lesions also attenuated both the development and the expression of SIP. This study thus identifies the AI as a novel neural substrate of maladaptive impulse control mechanisms that may facilitate the development of compulsive disorders. C1 [Belin-Rauscent, A.; Howett, D.; McKenzie, C.; Belin, D.] Univ Cambridge, Dept Pharmacol, Tennis Court Rd, Cambridge CB2 1PD, England. [Belin-Rauscent, A.; Puaud, M.; Jupp, B.; Sawiak, S.; Robbins, T. W.; Everitt, B. J.; Dalley, J. W.; Belin, D.] Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 1PD, England. [Daniel, M-L] Univ Poitiers, Inserm CIC 1402, Poitiers, France. [Jupp, B.; Robbins, T. W.; Everitt, B. J.; Dalley, J. W.] Univ Cambridge, Dept Psychol, Cambridge CB2 1PD, England. [Caprioli, D.] Natl Inst Drug Abuse, Behav Neurosci Branch, Intramural Res Program, NIH, Baltimore, MD USA. [Besson, M.] Inst Pasteur, Neurobiol Integrat Syst Cholinerg, Paris, France. [Dalley, J. W.] Univ Cambridge, Dept Psychiat, Cambridge CB2 1PD, England. RP Belin-Rauscent, A (reprint author), Univ Cambridge, Dept Pharmacol, Tennis Court Rd, Cambridge CB2 1PD, England. EM bdb26@cam.ac.uk RI Sawiak, Stephen/I-8944-2012 OI Sawiak, Stephen/0000-0003-4210-9816 FU INSERM AVENIR grant; FYSSEN foundation grant; PhD fellowship from the Fondation pour la Recherche Medicale (FRM); post-doctoral fellowship from the INSERM; United Kingdom Medical Research Council (MRC) [9536855] FX This research was carried out within the Department of Psychology and the Department of Pharmacology of the University of Cambridge, as well as the INSERM AVENIR team Psychobiology of Compulsive Disorders of the University of Poitiers. It was supported by an INSERM AVENIR grant and a FYSSEN foundation grant to DB. M-LD was supported by a PhD fellowship from the Fondation pour la Recherche Medicale (FRM) and AB-R was supported by a post-doctoral fellowship from the INSERM. BJE was supported by the United Kingdom Medical Research Council (MRC) grant 9536855. NR 71 TC 5 Z9 5 U1 6 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD APR PY 2016 VL 21 IS 4 BP 491 EP 499 DI 10.1038/mp.2015.140 PG 9 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA DG9RM UT WOS:000372421500007 PM 26370145 ER PT J AU Nim, S Jeon, J Corbi-Verge, C Seo, MH Ivarsson, Y Moffat, J Tarasova, N Kim, PM AF Nim, Satra Jeon, Jouhyun Corbi-Verge, Carles Seo, Moon-Hyeong Ivarsson, Ylva Moffat, Jason Tarasova, Nadya Kim, Philip M. TI Pooled screening for antiproliferative inhibitors of protein-protein interactions SO NATURE CHEMICAL BIOLOGY LA English DT Article ID LENTIVIRAL VECTOR; FRET MICROSCOPY; CANCER-THERAPY; GENE DELIVERY; PHAGE DISPLAY; IN-VIVO; PEPTIDE; P53; APOPTOSIS; CELLS AB Protein-protein interactions (PPIs) are emerging as a promising new class of drug targets. Here, we present a novel high-throughput approach to screen inhibitors of PPIs in cells. We designed a library of 50,000 human peptide-binding motifs and used a pooled lentiviral system to express them intracellularly and screen for their effects on cell proliferation. We thereby identified inhibitors that drastically reduced the viability of a pancreatic cancer line (RWP1) while leaving a control line virtually unaffected. We identified their target interactions computationally, and validated a subset in experiments. We also discovered their potential mechanisms of action, including apoptosis and cell cycle arrest. Finally, we confirmed that synthetic lipopeptide versions of our inhibitors have similarly specific and dosage-dependent effects on cancer cell growth. Our screen reveals new drug targets and peptide drug leads, and it provides a rich data set covering phenotypes for the inhibition of thousands of interactions. C1 [Nim, Satra; Jeon, Jouhyun; Corbi-Verge, Carles; Seo, Moon-Hyeong; Moffat, Jason; Kim, Philip M.] Univ Toronto, Terrence Donnelly Ctr Cellular & Biomol Res, Toronto, ON, Canada. [Ivarsson, Ylva] Uppsala Univ, Dept Chem, Biomed Ctr BMC, Uppsala, Sweden. [Moffat, Jason; Kim, Philip M.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Moffat, Jason] Canadian Inst Adv Res, Toronto, ON, Canada. [Tarasova, Nadya] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD USA. [Kim, Philip M.] Univ Toronto, Dept Comp Sci, Toronto, ON, Canada. RP Kim, PM (reprint author), Univ Toronto, Terrence Donnelly Ctr Cellular & Biomol Res, Toronto, ON, Canada.; Kim, PM (reprint author), Univ Toronto, Dept Mol Genet, Toronto, ON, Canada.; Kim, PM (reprint author), Univ Toronto, Dept Comp Sci, Toronto, ON, Canada. EM pi@kimlab.org OI Corbi Verge, Carles/0000-0002-7654-4405; Ivarsson, Ylva/0000-0002-7081-3846 FU Canadian Institute of Health Research (CIHR) [MOP-123526]; Innovation Grant from the Canadian Cancer Society Research Institute (CCSRI) [702884]; Intramural Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX We thank the members of the Moffat laboratory for valuable technical assistance with lentiviral screening technology, usage of reagents and equipment. We thank A. Emili, T. Hughes and M. Garton for helpful comments on the manuscript. We thank A. Musacchio (Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology) for providing us with the INCENP cDNA clone. We thank F. Sicheri (Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto) for use of the ITC machine. P.M.K. acknowledges an Operating Grant from the Canadian Institute of Health Research (CIHR MOP-123526) and an Innovation Grant from the Canadian Cancer Society Research Institute (CCSRI# 702884). J.M. is a Tier 2 Canada Research Chair in Functional Genomics of Cancer. The research was supported in part by the Intramural Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (N.I.T.). NR 49 TC 3 Z9 3 U1 2 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 EI 1552-4469 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD APR PY 2016 VL 12 IS 4 BP 275 EP + DI 10.1038/NCHEMBIO.2026 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DH2DA UT WOS:000372593200016 PM 26900867 ER PT J AU Shivatare, SS Chang, SH Tsai, TI Tseng, SY Shivatare, VS Lin, YS Cheng, YY Ren, CT Lee, CCD Pawar, S Tsai, CS Shih, HW Zeng, YF Liang, CH Kwong, PD Burton, DR Wu, CY Wong, CH AF Shivatare, Sachin S. Chang, Shih-Huang Tsai, Tsung-I Tseng, Susan Yu Shivatare, Vidya S. Lin, Yih-Shyan Cheng, Yang-Yu Ren, Chien-Tai Lee, Chang-Chun David Pawar, Sujeet Tsai, Charng-Sheng Shih, Hao-Wei Zeng, Yi-Fang Liang, Chi-Hui Kwong, Peter D. Burton, Dennis R. Wu, Chung-Yi Wong, Chi-Huey TI Modular synthesis of N-glycans and arrays for the hetero-ligand binding analysis of HIV antibodies SO NATURE CHEMISTRY LA English DT Article ID EFFICIENT CHEMOENZYMATIC SYNTHESIS; CARBOHYDRATE-PROTEIN INTERACTIONS; COATED GLASS SLIDES; VACCINE DESIGN; GALACTOSIDE ALPHA-2,3-SIALYLTRANSFERASE; OLIGOSACCHARIDE MICROARRAYS; NEUTRALIZING ANTIBODIES; GLYCOSYLATION PROFILES; ENVELOPE GLYCOPROTEINS; RECOGNITION AB A new class of broadly neutralizing antibodies (bNAbs) from HIV donors has been reported to target the glycans on gp120-a glycoprotein found on the surface of the virus envelope-thus renewing hope of developing carbohydrate-based HIV vaccines. However, the version of gp120 used in previous studies was not from human T cells and so the glycosylation pattern could be somewhat different to that found in the native system. Moreover, some antibodies recognized two different glycans simultaneously and this cannot be detected with the commonly used glycan microarrays on glass slides. Here, we have developed a glycan microarray on an aluminium-oxide-coated glass slide containing a diverse set of glycans, including homo- and mixed N-glycans (high-mannose, hybrid and complex types) that were prepared by modular chemo-enzymatic methods to detect the presence of hetero-glycan binding behaviours. This new approach allows rapid screening and identification of optimal glycans recognized by neutralizing antibodies, and could speed up the development of HIV-1 vaccines targeting cell surface glycans. C1 [Shivatare, Sachin S.; Chang, Shih-Huang; Tseng, Susan Yu; Shivatare, Vidya S.; Cheng, Yang-Yu; Ren, Chien-Tai; Lee, Chang-Chun David; Pawar, Sujeet; Liang, Chi-Hui; Wu, Chung-Yi; Wong, Chi-Huey] Acad Sinica, Genom Res Ctr, 128 Acad Rd,Sect 2, Taipei 115, Taiwan. [Shivatare, Sachin S.; Pawar, Sujeet] Acad Sinica, Taiwan Int Grad Program, Chem Biol & Mol Biophys, Taipei 115, Taiwan. [Shivatare, Sachin S.; Chang, Shih-Huang] Natl Taiwan Univ, Inst Biochem Sci, 1 Roosevelt Rd,Sect 4, Taipei 106, Taiwan. [Shivatare, Sachin S.; Lin, Yih-Shyan; Tsai, Charng-Sheng; Shih, Hao-Wei; Zeng, Yi-Fang] CHO Pharma Inc, Pk St, Taipei 11503, Taiwan. [Tsai, Tsung-I; Liang, Chi-Hui; Burton, Dennis R.; Wong, Chi-Huey] Scripps Res Inst, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA. [Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Wu, CY; Wong, CH (reprint author), Acad Sinica, Genom Res Ctr, 128 Acad Rd,Sect 2, Taipei 115, Taiwan.; Wong, CH (reprint author), Scripps Res Inst, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA. EM cyiwu@gate.sinica.edu.tw; chwong@gate.sinica.edu.tw OI Tseng, Susan/0000-0002-5710-6960 FU National Science Council [NSC101-2321-B-001-024]; Academia Sinica; National Institutes of Health; International Aids Vaccine Initiative (IAVI) FX The authors thank D. Chiang and C.-N. Hsiao for their internal coordination within The Thin Film Technology Division, Instrument Technology Research Center (ITRC) and National Applied Research Laboratories, Hsinchu Science Park, Taiwan. The authors also thank W.-H. Cho of ITRC for the vapour deposition polymerization coating of aluminium-coated glass slides as well as the ellipsometry characterization work, N.-N. Chu and C.-Y. Su of ITRC for their work on SEM and AFM instrumental measurements, and L.-W. Lo of GRC for help with the use of various microscopy instruments, especially the confocal microscope (Leica SP5). Special thanks go to N.-H. Lin, L.-M. Wang and C.-C. Huang of CHO PHARMA Inc. This work was supported by the National Science Council (grant no. NSC101-2321-B-001-024), Academia Sinica, the National Institutes of Health and the International Aids Vaccine Initiative (IAVI). NR 59 TC 10 Z9 10 U1 11 U2 34 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1755-4330 EI 1755-4349 J9 NAT CHEM JI Nat. Chem. PD APR PY 2016 VL 8 IS 4 BP 338 EP 346 DI 10.1038/NCHEM.2463 PG 9 WC Chemistry, Multidisciplinary SC Chemistry GA DH0WT UT WOS:000372505500012 PM 27001729 ER PT J AU Xin, A Masson, F Liao, Y Preston, S Guan, TX Gloury, R Olshansky, M Lin, JX Li, P Speed, TP Smyth, GK Ernst, M Leonard, WJ Pellegrini, M Kaech, SM Nutt, SL Shi, W Belz, GT Kallies, A AF Xin, Annie Masson, Frederick Liao, Yang Preston, Simon Guan, Tianxia Gloury, Renee Olshansky, Moshe Lin, Jian-Xin Li, Peng Speed, Terence P. Smyth, Gordon K. Ernst, Matthias Leonard, Warren J. Pellegrini, Marc Kaech, Susan M. Nutt, Stephen L. Shi, Wei Belz, Gabrielle T. Kallies, Axel TI A molecular threshold for effector CD8(+) T cell differentiation controlled by transcription factors Blimp-1 and T-bet SO NATURE IMMUNOLOGY LA English DT Article ID CUTTING EDGE; MEMORY CELLS; EXPRESSION; EOMESODERMIN; EXPANSION; IL-2; ID2; AFFINITY; VIRUS; GENE AB T cell responses are guided by cytokines that induce transcriptional regulators, which ultimately control differentiation of effector and memory T cells. However, it is unknown how the activities of these molecular regulators are coordinated and integrated during the differentiation process. Using genetic approaches and transcriptional profiling of antigen-specific CD8(+) T cells, we reveal a common program of effector differentiation that is regulated by IL-2 and IL-12 signaling and the combined activities of the transcriptional regulators Blimp-1 and T-bet. The loss of both T-bet and Blimp-1 leads to abrogated cytotoxic function and ectopic IL-17 production in CD8(+) T cells. Overall, our data reveal two major overlapping pathways of effector differentiation governed by the availability of Blimp-1 and T-bet and suggest a model for cytokine-induced transcriptional changes that combine, quantitatively and qualitatively, to promote robust effector CD8(+) T cell differentiation. C1 [Xin, Annie; Masson, Frederick; Liao, Yang; Preston, Simon; Gloury, Renee; Olshansky, Moshe; Speed, Terence P.; Smyth, Gordon K.; Ernst, Matthias; Pellegrini, Marc; Nutt, Stephen L.; Shi, Wei; Belz, Gabrielle T.; Kallies, Axel] Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Parkville, Vic 3050, Australia. [Xin, Annie; Masson, Frederick; Liao, Yang; Preston, Simon; Gloury, Renee; Ernst, Matthias; Pellegrini, Marc; Nutt, Stephen L.; Belz, Gabrielle T.; Kallies, Axel] Univ Melbourne, Dept Med Biol, Parkville, Vic 3052, Australia. [Guan, Tianxia] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT USA. [Olshansky, Moshe; Kaech, Susan M.] Univ Melbourne, Dept Comp & Informat Syst, Parkville, Vic 3052, Australia. [Lin, Jian-Xin; Li, Peng; Leonard, Warren J.] NHLBI, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. [Lin, Jian-Xin; Li, Peng; Leonard, Warren J.] NHLBI, Ctr Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. [Speed, Terence P.; Smyth, Gordon K.; Shi, Wei] Univ Melbourne, Dept Math & Stat, Parkville, Vic 3052, Australia. [Kaech, Susan M.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Masson, Frederick; Ernst, Matthias] Olivia Newton John Canc Res Inst, Heidelberg, Vic, Australia. [Masson, Frederick; Ernst, Matthias] La Trobe Univ, Sch Canc Med, Heidelberg, Vic, Australia. RP Kallies, A (reprint author), Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Parkville, Vic 3050, Australia.; Kallies, A (reprint author), Univ Melbourne, Dept Med Biol, Parkville, Vic 3052, Australia. EM kallies@wehi.edu.au RI Smyth, Gordon/B-5276-2008; Guan, Tianxia/B-5559-2017 OI Smyth, Gordon/0000-0001-9221-2892; Guan, Tianxia/0000-0001-6187-5431 FU National Health and Medical Research Council of Australia [1054618, 1058892, 1023454, 637345, 1042582, 603122]; Sylvia and Charles Viertel Foundation; Australian Research Council; US National Institutes of Health (NIH) [R01AI066232, R0O1AI074699]; Howard Hughes Medical Institute; Howard Hughes Medical Institute International Student Fellowship; Division of Intramural Research; DNA Sequencing Core, National Heart, Lung, and Blood Institute, NIH; Australian Academy of Science; NIH; Victorian State Government Operational Infrastructure Support; Australian Government NHMRC Independent Research Institute Infrastructure Support scheme FX We thank M. Camilleri and L. Mackiewicz for technical support, and M. Ghisi (Peter MacCallum Cancer Centre) for assistance with MetaCore bioinformatics analysis. Supported by the National Health and Medical Research Council of Australia (program grant 1054618 to T.P.S. and G.K.S.; fellowship 1058892 to G.K.S.; project grant 1023454 to G.K.S. and W.S.; project grant 637345 to A.K. and G.T.B.; project grant 1042582 to G.T.B. and M.P.; project grant 603122 to M.E.), the Sylvia and Charles Viertel Foundation (A.K. and G.T.B.), the Australian Research Council (S.L.N., G.T.B. and A.K.), the US National Institutes of Health (NIH) (R01AI066232 and R0O1AI074699 to S.M.K.), the Howard Hughes Medical Institute (S.M.K.), the Howard Hughes Medical Institute International Student Fellowship (T.G.), the Division of Intramural Research and the DNA Sequencing Core, National Heart, Lung, and Blood Institute, NIH (W.J.L.), the Adam J. Berry Memorial Fund, jointly provided by the Australian Academy of Science and NIH (A.X.) and the Victorian State Government Operational Infrastructure Support and Australian Government NHMRC Independent Research Institute Infrastructure Support scheme. NR 64 TC 10 Z9 10 U1 3 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD APR PY 2016 VL 17 IS 4 BP 422 EP + DI 10.1038/ni.3410 PG 13 WC Immunology SC Immunology GA DH0XR UT WOS:000372508000016 PM 26950239 ER PT J AU Imtiaz, A Maqsood, A Rehman, AU Morell, RJ Holt, JR Friedman, TB Naz, S AF Imtiaz, Ayesha Maqsood, Azra Rehman, Atteeq U. Morell, Robert J. Holt, Jeffrey R. Friedman, Thomas B. Naz, Sadaf TI Recessive mutations of TMC1 associated with moderate to severe hearing loss SO NEUROGENETICS LA English DT Article DE TMC1; Mechanosensory transduction; DFNB7/11; Moderate or severe hearing loss ID MAMMALIAN INNER-EAR; HAIR-CELLS; DEAFNESS; PROTEIN; GENE; CHANNEL; DFNA36; MOUSE; MECHANOTRANSDUCTION; DOMINANT AB TMC1 encodes a protein required for the normal function of mechanically activated channels that enable sensory transduction in auditory and vestibular hair cells. TMC1 protein is localized at the tips of the hair cell stereocilia, the site of conventional mechanotransduction. In many populations, loss-of-function recessive mutations of TMC1 are associated with profound deafness across all frequencies tested. In six families reported here, variable moderate-to-severe or moderate-to-profound hearing loss co-segregated with STR (short tandem repeats) markers at the TMC1 locus DFNB7/11. Massively parallel and Sanger sequencing of genomic DNA revealed each family co-segregating hearing loss with a homozygous TMC1 mutation: two reported mutations (p.R34X and p.R389Q) and three novel mutations (p.S596R, p.N199I, and c.1404 + 1G > T). TMC1 cDNA sequence from affected subjects homozygous for the donor splice site transversion c.1404 + 1G > T revealed skipping of exon 16, deleting 60 amino acids from the TMC1 protein. Since the mutations in our study cause less than profound hearing loss, we speculate that there is hypo-functional TMC1 mechanotransduction channel activity and that other even less damaging variants of TMC1 may be associated with more common mild-to-severe sensorineural hearing loss. C1 [Imtiaz, Ayesha; Maqsood, Azra; Naz, Sadaf] Univ Punjab, Sch Biol Sci, Quaid I Azam Campus, Lahore 54590, Pakistan. [Imtiaz, Ayesha; Rehman, Atteeq U.; Morell, Robert J.; Friedman, Thomas B.] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA. [Holt, Jeffrey R.] Harvard Univ, Sch Med, FM Kirby Neurobiol Ctr, Dept Otolaryngol,Boston Childrens Hosp, Boston, MA 02114 USA. RP Naz, S (reprint author), Univ Punjab, Sch Biol Sci, Quaid I Azam Campus, Lahore 54590, Pakistan. EM naz.sbs@pu.edu.pk FU National Institute of Deafness and Other Communication Disorders, National Institute of Health, USA [R01DC01352103]; National Institute of Deafness and Other Communication Disorders, National Institutes of Health, USA [DC000039-19]; Fogarty International Center, NIH [R01TW007608]; National Institute on Deafness and Other Communication Disorders, NIH FX We thank the participants in this study and the Special Education Schools, Punjab, for their help. We are grateful to Drs. C. Brewer and A.J. Griffith for review of this manuscript. The help of Dr. A.J. Griffith is also acknowledged for providing many of the primers to amplify and sequence TMC1. This work was supported by grant R01DC01352103 to Jeffery R Holt from the National Institute of Deafness and Other Communication Disorders, National Institute of Health, USA, and intramural funds DC000039-19 to Thomas B Friedman from the National Institute of Deafness and Other Communication Disorders, National Institutes of Health, USA, and grant R01TW007608 to Sadaf Naz from the Fogarty International Center, NIH and National Institute on Deafness and Other Communication Disorders, NIH. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf.nih.gov), and also the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov). NR 40 TC 1 Z9 1 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1364-6745 EI 1364-6753 J9 NEUROGENETICS JI Neurogenetics PD APR PY 2016 VL 17 IS 2 BP 115 EP 123 DI 10.1007/s10048-016-0477-1 PG 9 WC Genetics & Heredity; Clinical Neurology SC Genetics & Heredity; Neurosciences & Neurology GA DH4LN UT WOS:000372757600004 PM 26879195 ER PT J AU Ahrens, KA Silver, RM Mumford, SL Sjaarda, LA Perkins, NJ Wactawski-Wende, J Galai, N Townsend, JM Lynch, AM Lesher, LL Faraggi, D Zarek, S Schisterman, EF AF Ahrens, Katherine A. Silver, Robert M. Mumford, Sunni L. Sjaarda, Lindsey A. Perkins, Neil J. Wactawski-Wende, Jean Galai, Noya Townsend, Janet M. Lynch, Anne M. Lesher, Laurie L. Faraggi, David Zarek, Shvetha Schisterman, Enrique F. TI Complications and Safety of Preconception Low-Dose Aspirin Among Women With Prior Pregnancy Losses SO OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 27th Annual Meeting of the Society-for-Pediatric-and-Perinatal-Epidemiologic-Research CY JUN 24-27, 2014 CL Seattle, WA SP Soc Pediat & Perinatal Epidemiol Res ID PERSISTENT PULMONARY-HYPERTENSION; RANDOMIZED-TRIAL; FOLLOW-UP; GASTROSCHISIS; METAANALYSIS; PREVENTION; GUIDELINES; OUTCOMES; NEWBORN; RISK AB OBJECTIVE: To evaluate complications and safety of preconception low-dose aspirin in 1,228 U.S. women (2007-2011). METHODS: Evaluation of the safety of low-dose aspirin in the participants and their fetuses was a planned secondary analysis of the Effects of Aspirin in Gestation and Reproduction trial, a multicenter, block-randomized, double-blind, placebo-controlled trial investigating the effect of low-dose aspirin on the incidence of live birth. Women aged 18-40 years with a history of one to two pregnancy losses trying to conceive were randomized to daily low-dose aspirin (81 mg, n=615) or placebo (n=613) and were followed for up to six menstrual cycles or through gestation if they became pregnant. Emergency care visits and possible aspirin-related symptoms were assessed at each study follow-up using standardized safety interviews. In addition, complications for both the participant and her fetus or neonate were captured prospectively using case report forms, interviews conducted during pregnancy and postpartum, and medical records. RESULTS: The proportion of women with at least one possible aspirin-related symptom during the trial was similar between treatment arms (456 [74%] low-dose aspirin compared with 447 [73%] placebo, P=.65) as was the proportion with at least one emergency care visit (104 [17%] low-dose aspirin compared with 99 [16%] placebo, P=.76). Maternal complications were evenly distributed by treatment arm with the exception of vaginal bleeding, which was more commonly reported in the low-dose aspirin arm (22% compared with 17%, P=.02). The distribution of fetal and neonatal complications-which included three stillbirths, three neonatal deaths, and 10 neonates with birth defect(s)-was similar between treatment arms. CONCLUSION: Although rare but serious complications resulting from low-dose aspirin cannot be ruled out, preconception low-dose aspirin appears to be well tolerated by women trying to conceive, women who become pregnant, and by their fetuses and neonates. C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Epidemiol Branch, Rockville, MD 20854 USA. Univ Utah, Hlth Sci Ctr, Dept Obstet & Gynecol, Salt Lake City, UT USA. SUNY Buffalo, Dept Epidemiol & Environm Hlth, Buffalo, NY 14260 USA. Univ Haifa, Dept Stat, IL-31999 Haifa, Israel. Commonwealth Med Coll, Dept Family Community & Rural Hlth, Scranton, PA USA. Univ Colorado, Dept Obstet & Gynecol, Aurora, CO USA. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, 6100 Executive 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 NIH HHS [Z01 HD008795-01, Z01 HD008795-02]; PHS HHS [HHSN267200603423, HHSN267200603424, HHSN267200603426] NR 25 TC 0 Z9 0 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD APR PY 2016 VL 127 IS 4 BP 689 EP 698 DI 10.1097/AOG.0000000000001301 PG 10 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DH4YJ UT WOS:000372791400001 PM 26959198 ER PT J AU Wiley, HE Thompson, DJS Bailey, C Chew, EY Cukras, CA Jaffe, GJ Lee, RWJ Loken, EK Meyerle, CB Wong, W Ferris, FL AF Wiley, Henry E. Thompson, Darby J. S. Bailey, Clare Chew, Emily Y. Cukras, Catherine A. Jaffe, Glenn J. Lee, Richard W. J. Loken, Erin K. Meyerle, Catherine B. Wong, Wai Ferris, Frederick L., III TI A Crossover Design for Comparative Efficacy A 36-Week Randomized Trial of Bevacizumab and Ranibizumab for Diabetic Macular Edema SO OPHTHALMOLOGY LA English DT Article ID DIABETIC MACULAR EDEMA; RANDOMIZED CLINICAL-TRIAL; SINGLE INTRAVITREAL INJECTION; INTRAOCULAR PHARMACOKINETICS; CHOROIDAL NEOVASCULARIZATION; RANIBIZUMAB; BEVACIZUMAB; DEGENERATION; AFLIBERCEPT; AVASTIN AB Purpose: To investigate the comparative efficacy of bevacizumab (Avastin) and ranibizumab (Lucentis; both Genentech, Inc, South San Francisco, CA) for diabetic macular edema (DME) using a crossover study design. Design: Randomized, double-masked, 36-week, 3-period crossover clinical trial. Participants: Fifty-six subjects with DME involving the center of the macula in one or both eyes. Methods: Monthly intravitreous injections of bevacizumab (1.25 mg) or ranibizumab (0.3 mg). Main Outcome Measures: Comparison of mean changes in visual acuity and central retinal thickness, tested using a linear mixed-effects model. Results: Based on the linear mixed-effects model, the 3-month estimated mean improvement in visual acuity was 5.3 letters for bevacizumab and 6.6 letters for ranibizumab (difference, 1.3 letters; P = 0.039). Estimated change in optical coherence tomography (OCT) central subfield mean thickness (CSMT) was -89 mu m for bevacizumab and -137 mu m for ranibizumab (difference, 48 mu m; P < 0.001). Incorporating cumulative treatment benefit, the model yielded a predicted 36-week (9-month) average improvement in visual acuity of 7.1 letters (95% confidence interval [CI], 5.0-9.2) for bevacizumab and 8.4 letters (95% CI, 6.3-10.5) for ranibizumab, and a change in OCT CSMT of -128 mu m (95% CI, -155 to -100) for bevacizumab and -176 mu m (95% CI, -202 to -149) for ranibizumab. There was no significant treatment-by-period interaction (i.e., treatment difference was constant in all 3 periods), nor was there a significant differential carryover effect from one period to the next. Conclusions: This trial demonstrated a statistically significant but small relative clinical benefit of ranibizumab compared with bevacizumab for treatment of DME, using a markedly reduced sample size relative to a full comparative efficacy study. The effects on visual acuity and central retinal thickness for the 2 drugs are consistent with those reported at 1 year for the concurrent parallel-group trial by the Diabetic Retinopathy Clinical Research Network testing bevacizumab, ranibizumab, and aflibercept for DME. The 3-period crossover design allowed for meaningful and efficient comparison, suggesting that this approach may be useful for future comparative efficacy studies of anti-vascular endothelial growth factor drugs for DME. (C) 2016 Published by Elsevier on behalf of the American Academy of Ophthalmology. C1 [Wiley, Henry E.; Chew, Emily Y.; Cukras, Catherine A.; Wong, Wai; Ferris, Frederick L., III] NEI, NIH, 10 Ctr Dr,Bldg 10 CRC Room 3-2531, Bethesda, MD 20892 USA. [Thompson, Darby J. S.; Loken, Erin K.] Emmes Corp, Rockville, MD USA. [Bailey, Clare; Lee, Richard W. J.] Univ Hosp Bristol Natl Hlth Serv Fdn Trust, Bristol, Avon, England. [Jaffe, Glenn J.] Duke Reading Ctr, Durham, NC USA. [Lee, Richard W. J.] Univ Bristol, Sch Clin Sci, Bristol, Avon, England. [Lee, Richard W. J.] Natl Hlth Serv Fdn Trust, Moorfields Eye Hosp, Natl Inst Hlth Res, Biomed Res Ctr, London, England. [Lee, Richard W. J.] UCL, Inst Ophthalmol, London, England. [Meyerle, Catherine B.] Johns Hopkins Univ Hosp, Wilmer Eye Inst, Baltimore, MD 21287 USA. RP Wiley, HE (reprint author), NEI, NIH, 10 Ctr Dr,Bldg 10 CRC Room 3-2531, Bethesda, MD 20892 USA. EM wileyhe@nei.nih.gov RI Lee, Richard/A-3116-2017 OI Lee, Richard/0000-0002-9480-6843 FU National Eye Institute, National Institutes of Health, Bethesda, Maryland [HHSN263201200001C]; National Institute for Health Research's Clinical Research Network West of England; Moorfields Biomedical Research Center, Universities and National Institutes Transatlantic Eye Consortium (UNITE) FX Supported by the National Eye Institute, National Institutes of Health, Bethesda, Maryland (contract no.: HHSN263201200001C). Patient recruitment and clinical research staff costs were also supported in the United Kingdom by the National Institute for Health Research's Clinical Research Network West of England and Moorfields Biomedical Research Center as part of the Universities and National Institutes Transatlantic Eye Consortium (UNITE). NR 40 TC 1 Z9 1 U1 2 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD APR PY 2016 VL 123 IS 4 BP 841 EP 849 DI 10.1016/j.ophtha.2015.11.021 PG 9 WC Ophthalmology SC Ophthalmology GA DH3WU UT WOS:000372718300028 PM 26875003 ER PT J AU Al-Holou, SN Tucker, WR Agron, E Clemons, TE Sperduto, RD Ferris, FL Chew, EY AF Al-Holou, Shaza N. Tucker, William R. Agron, Elvira Clemons, Traci E. Sperduto, Robert D. Ferris, Frederick L., III Chew, Emily Y. CA AREDS2 Res Grp TI The Association of Statin Use with Cataract Progression and Cataract Surgery: The AREDS2 Report Number 8 SO OPHTHALMOLOGY LA English DT Editorial Material C1 [Al-Holou, Shaza N.; Agron, Elvira; Ferris, Frederick L., III; Chew, Emily Y.] NEI, Clin Trials Branch, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Tucker, William R.] NEI, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Clemons, Traci E.; Sperduto, Robert D.] EMMES Corp, Rockville, MD USA. RP Chew, EY (reprint author), NEI, NIH, Bldg 10,CRC Room 3-2531,10 Ctr Dr,MSC 1204, Bethesda, MD 20892 USA. EM echew@nei.nih.gov NR 5 TC 1 Z9 1 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD APR PY 2016 VL 123 IS 4 BP 916 EP 917 PG 2 WC Ophthalmology SC Ophthalmology GA DH3WU UT WOS:000372718300036 ER PT J AU Taddei, F Falcinelli, C Balistreri, L Henys, P Baruffaldi, F Sigurdsson, S Gudnason, V Harris, TB Dietzel, R Armbrecht, G Boutroy, S Schileo, E AF Taddei, F. Falcinelli, C. Balistreri, L. Henys, P. Baruffaldi, F. Sigurdsson, S. Gudnason, V. Harris, T. B. Dietzel, R. Armbrecht, G. Boutroy, S. Schileo, E. TI Left-right differences in the proximal femur's strength of post-menopausal women: a multicentric finite element study SO OSTEOPOROSIS INTERNATIONAL LA English DT Article DE Computed tomography; Finite element; Multicentric study; Post-menopausal women; Proximal femur's strength; Side differences ID BONE-MINERAL DENSITY; HIP FRACTURE; GENE/ENVIRONMENT SUSCEPTIBILITY; BILATERAL ASYMMETRY; FEMORAL STRENGTH; CLINICAL CT; MODELS; QCT; MEN; AGE AB The strength of both femurs was estimated in 198 post-menopausal women through subject-specific finite element models. Important random differences between contralateral femurs were found in a significant number of subjects, pointing to the usefulness of further studies to understand if strength-based classification of patients at risk of fracture can be affected by laterality issues. Significant, although small, differences exist in mineral density and anatomy of contralateral proximal femurs. These differences, and their combined effect, may result in a side difference in femurs' strength. However, this has never been tested on a large sample of a homogenous population. The strength of both femurs was estimated in 198 post-menopausal women through CT-derived finite element models, built using a validated procedure, in sideways fall conditions. The impact of the resulting asymmetry on the classification of subjects at risk of fracture was analysed. The small difference observed between sides (the right femur on average 4 % stronger than the left) was statistically significant but mechanically negligible. In contrast, higher random differences (absolute difference between sides with respect to mean value) were found: on average close to 15 % (compared to 9.2 % for areal bone mineral density (aBMD) alone), with high scatter among the subjects. When using a threshold-based classification, the right and left femurs were discordant up to over 20 % of cases (K always lower than 0.60) but the left femur was concordant (mean K = 0.84) with the minimum strength between right and left. Considering both femurs may be important when trying to classify subjects at risk of failure with strength estimates. Future studies including fracture assessment would be necessary to quantify the real impact. C1 [Taddei, F.; Falcinelli, C.; Balistreri, L.; Henys, P.; Baruffaldi, F.; Schileo, E.] Ist Ortoped Rizzoli, Lab Bioingn Computaz, Bologna, Italy. [Falcinelli, C.] Univ Roma Tor Vergata, Rome, Italy. [Henys, P.] Tech Univ Liberec, Liberec, Czech Republic. [Sigurdsson, S.; Gudnason, V.] Icelandic Heart Assoc, Kopavogur, Iceland. [Dietzel, R.; Armbrecht, G.] Charite, Ctr Muscle & Bone Res, D-13353 Berlin, Germany. [Boutroy, S.] INSERM, Res Unit 1033, F-69008 Lyon, France. [Boutroy, S.] Univ Lyon, Lyon, France. [Gudnason, V.] Univ Iceland, Reykjavik, Iceland. [Harris, T. B.] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Taddei, F.] Ist Ortoped Rizzoli, Lab Tecnol Med, Via Barbiano 1-10, I-40136 Bologna, Italy. RP Taddei, F (reprint author), Ist Ortoped Rizzoli, Lab Bioingn Computaz, Bologna, Italy.; Taddei, F (reprint author), Ist Ortoped Rizzoli, Lab Tecnol Med, Via Barbiano 1-10, I-40136 Bologna, Italy. EM taddei@tecno.ior.it; falcinelli@tecno.ior.it; petr.henys@tul.cz; siggi@hjarta.is; villi@hjarta.is; harrista@nia.nih.gov; gabi.armbrecht@charite.de; stephanie.boutroy@inserm.fr OI Henys, Petr/0000-0002-8700-0163 FU EU [FP7-2008-ICT-223865, FP7-2011-ICT-269978]; national Emilia Romagna Region University Research Program; Italian Program for Donation "5 per mille"; NIH [N01-AG-1-2100]; NIA Intramural Research Program; Icelandic Heart Association; Althingi (the Icelandic Parliament) FX The authors would like to thank Luigi Lena for the illustrations, Mauro Ansaloni for the support in image processing and Barbara Bordini for the support in the statistical analysis. This work has partially been funded by EU projects VPHOP (The Osteoporotic Virtual Physiological Human, FP7-2008-ICT-223865) and VPH-SHARE (Virtual Physiological Human: Sharing for Healthcare-A Research Environment, FP7-2011-ICT-269978), by the national Emilia Romagna Region University Research Program 2007-2009 and by the Italian Program for Donation "5 per mille 2011". The AGES-Reykjavik study was funded by NIH contract N01-AG-1-2100, the NIA Intramural Research Program, the Icelandic Heart Association and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee, VSN:00-063. NR 35 TC 0 Z9 0 U1 1 U2 2 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0937-941X EI 1433-2965 J9 OSTEOPOROSIS INT JI Osteoporosis Int. PD APR PY 2016 VL 27 IS 4 BP 1519 EP 1528 DI 10.1007/s00198-015-3404-7 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DG8AI UT WOS:000372304400016 PM 26576543 ER PT J AU Alderete, E Gregorich, SE Monteban, M Kaplan, CP Mejia, R Livaudais-Toman, J Perez-Stable, EJ AF Alderete, Ethel Gregorich, Steven E. Monteban, Madalena Kaplan, Celia P. Mejia, Raul Livaudais-Toman, Jennifer Perez-Stable, Eliseo J. TI Effect of appreciation for Indigenous cultures and exposure to racial insults on alcohol and drug use initiation among multiethnic Argentinean youth SO PREVENTIVE MEDICINE LA English DT Article DE Culture; Racism; Substance use; Youth; Indigenous; Latin America ID SUBSTANCE USE; PERCEIVED DISCRIMINATION; LINGUISTIC ACCULTURATION; PROBLEM DRINKING; CRITICAL PERIOD; MARIJUANA USE; RISK-FACTORS; ADOLESCENTS; MEXICAN; GENDER AB Objectives. This study evaluated the effect of factors reflecting appreciation of Indigenous culture and racial insults on alcohol and drug use initiation among multi-ethnic youth in Jujuy, Argentina. Methods. Students were surveyed from 27 secondary schools that were randomly selected to represent the province. A total of 3040 eligible students in 10th grade, age 14 to 18 years were surveyed in 2006 and 2660 of these same students completed surveys in 1 lth grade in 2007. Multivariate logistic regression models assessed the effect of appreciation for Indigenous cultures and repotted exposure to racial insults in 10th grade on incident current alcohol drinking in previous 30 days, binge drinking (5 drinks at one sitting), and lifetime drug use (marijuana, inhalants or cocaine) in 11th grade among students not reporting these behaviors in 2006. Results. In 2006, 63% of respondents reported high appreciation for Indigenous cultures and 39% had ever experienced racial insults. In 2007, incident current drinking was 24.4%, binge drinking 14.8%, and any drug use initiation was 4.1%. Exposure W racial insults increased the likelihood of binge drinking (OR 1.6; 95% Cl 1.2-2.1) but was not significant for any drug use. Appreciation for Indigenous cultures reduced the risk of any drug use initiation (OR 0.5, 95% CI 0.3-0.7) but had no effect for alcohol drinking outcomes. These effects were independent of Indigenous ethnicity. Conclusions. Enhancing appreciation for Indigenous cultures and decreasing racial insults are achievable goals that can be incorporated into programs to prevent youth substance use. Published by Elsevier Inc. C1 [Alderete, Ethel] Univ Nacl Jujuy, Consejo Nacl Invest Cient & Tecn, San Salvador De Jujuy, Argentina. [Alderete, Ethel] Inst Ciencia & Tecnol Reg ICTER, San Salvador De Jujuy, Argentina. [Gregorich, Steven E.; Kaplan, Celia P.; Livaudais-Toman, Jennifer; Perez-Stable, Eliseo J.] Univ Calif San Francisco, Med Effectiveness Res Ctr Diverse Populat, Dept Med, Div Gen Internal Med, San Francisco, CA 94143 USA. [Monteban, Madalena] Univ Georgia, Dept Anthropol, Athens, GA 30602 USA. [Kaplan, Celia P.] UCSF, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA. [Mejia, Raul; Perez-Stable, Eliseo J.] Ctr Estudios Estado & Soc, Buenos Aires, DF, Argentina. [Mejia, Raul] Univ Buenos Aires, Buenos Aires, DF, Argentina. [Perez-Stable, Eliseo J.] Natl Inst Minor Hlth & Hlth Dispar, Bethesda, MD USA. RP Perez-Stable, EJ (reprint author), 6707 Democracy Blvd,Suite 800, Bethesda, MD 20892 USA. EM eliseo.perez-stable@nih.gov FU Tobacco Research Network Program [TW05935]; Fogarty International Center; National Cancer Institute; National Institute of Drug Abuse; National Institutes of Health; Research on International Tobacco Control, International Development Research Center, Canada [001726-037]; Cecilia Populus-Eudave FX This research was funded by Grant no. TW05935 from the Tobacco Research Network Program, Fogarty International Center, National Cancer Institute, National Institute of Drug Abuse, National Institutes of Health and by Grant no. 001726-037 from Research on International Tobacco Control, International Development Research Center, Canada. The administrative and research support of Cecilia Populus-Eudave and the research staff in Jujuy made this study possible. NR 61 TC 1 Z9 1 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 0091-7435 EI 1096-0260 J9 PREV MED JI Prev. Med. PD APR PY 2016 VL 85 BP 60 EP 68 DI 10.1016/j.ypmed.2016.12.017 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA DH1NS UT WOS:000372552300010 PM 26763165 ER PT J AU McMahon, FJ AF McMahon, Francis J. TI PREDICTING BIPOLAR SO SCIENTIFIC AMERICAN LA English DT Letter C1 [McMahon, Francis J.] NIMH, Human Genet Branch, Bethesda, MD 20892 USA. [McMahon, Francis J.] Int Soc Psychiat Genet, London, England. RP McMahon, FJ (reprint author), NIMH, Human Genet Branch, Bethesda, MD 20892 USA.; McMahon, FJ (reprint author), Int Soc Psychiat Genet, London, England. 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 0036-8733 J9 SCI AM JI Sci.Am. PD APR PY 2016 VL 314 IS 4 BP 6 EP 6 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH0NX UT WOS:000372482000002 ER PT J AU Imperiale, A Battini, S Averous, G Mutter, D Goichot, B Bachellier, P Pacak, K Taieb, D Namer, IJ AF Imperiale, Alessio Battini, Stephanie Averous, Gerlinde Mutter, Didier Goichot, Bernard Bachellier, Philippe Pacak, Karel Taieb, David Namer, Izzie-Jacques TI In vivo detection of catecholamines by magnetic resonance spectroscopy: A potential specific biomarker for the diagnosis of pheochromocytoma SO SURGERY LA English DT Editorial Material ID PARAGANGLIOMA C1 [Imperiale, Alessio; Namer, Izzie-Jacques] Univ Hosp Strasbourg, Dept Biophys & Nucl Med, Strasbourg, France. Univ Strasbourg, CNRS, UMR 7357, ICube, Strasbourg, France. [Imperiale, Alessio; Battini, Stephanie; Namer, Izzie-Jacques] Univ Hosp Strasbourg, FMTS, Strasbourg, France. [Averous, Gerlinde] Univ Hosp Strasbourg, Dept Pathol, Fac Med Strasbourg, Strasbourg, France. [Mutter, Didier] Univ Hosp Strasbourg, IRCAD IHU, Dept Gen Digest & Endocrine Surg, Strasbourg, France. [Goichot, Bernard] Univ Hosp Strasbourg, Dept Internal Med Diabet & Metab Disorders, Strasbourg, France. [Bachellier, Philippe] Univ Hosp Strasbourg, Dept Visceral Surg & Transplantat, Strasbourg, France. [Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Taieb, David] Aix Marseille Univ, CERIMED, La Timone Univ Hosp, Dept Nucl Med, Marseille, France. [Taieb, David] Inst Paoli Calmettes, INSERM, UMR1068, Marseille Cancerol Res Ctr, Marseille, France. RP Imperiale, A (reprint author), Hop Hautepierre, Serv Biophys & Med Nucl, 1 Ave Moliere, F-67098 Strasbourg, France. EM alessio.imperiale@chru-strasbourg.fr NR 9 TC 0 Z9 0 U1 1 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD APR PY 2016 VL 159 IS 4 BP 1231 EP 1233 DI 10.1016/j.surg.2015.03.012 PG 3 WC Surgery SC Surgery GA DG9FM UT WOS:000372388200028 PM 26116050 ER PT J AU Therkelsen, KE Pedley, A Hoffmann, U Fox, CS Murabito, JM AF Therkelsen, Kate E. Pedley, Alison Hoffmann, Udo Fox, Caroline S. Murabito, Joanne M. TI Intramuscular fat and physical performance at the Framingham Heart Study SO AGE LA English DT Article DE Epidemiology; Muscle; Adipose tissue; Physical function ID TRUNK MUSCLE COMPOSITION; METABOLIC RISK-FACTORS; HUMAN SKELETAL-MUSCLE; GAIT-SPEED DECLINE; OLDER-ADULTS; BODY-COMPOSITION; MOBILITY LIMITATION; BACK-PAIN; HEALTH; STRENGTH AB Intramuscular fat may mediate associations between obesity and physical disability. We examined the associations between muscle attenuation, a proxy for intramuscular fat, and physical function. Paraspinous muscle computed tomography attenuation was obtained on a Framingham Heart Study subgroup (n = 1152, 56% women, mean age 66 years). Regressions modeled cross-sectional associations between muscle attenuation and mobility disability, grip strength, and walking speed with standard covariates; models additionally adjusted for body mass index (BMI) and visceral adipose tissue (VAT). Separate models investigated associations between VAT and subcutaneous adipose tissue (SAT) and physical function. Per 1 standard deviation decrement in muscle attenuation (i.e., more muscle fat), we observed 1.29 (95 % CI=1.11, 1.50; p = 0.0009) increased odds of walking speed <= 1 m/s in women and men. This persisted after separate BMI and VAT adjustments (p < 0.02). In men, there was a 1.29 kg (95 % CI= 0.57, 2.01; p = 0.0005) decrement in grip strength, which persisted after BMI and VAT adjustments (p <= 0.0004). For VAT and SAT, similar associations were not observed. Intramuscular fat is associated with increased odds of walking speed <= 1 m/s in both sexes and lower grip strength in men. There were no similar associations for VAT and SAT, highlighting the specificity of intramuscular fat in association with physical function. C1 [Therkelsen, Kate E.; Pedley, Alison; Fox, Caroline S.; Murabito, Joanne M.] Natl Heart Lung & Blood Inst Framingham Heart Stu, 73 Mt Wayte Ave Suite 2, Framingham, MA 01702 USA. [Therkelsen, Kate E.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Hoffmann, Udo] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Fox, Caroline S.] NHLBI, Div Intra Mural Res, Framingham, MA USA. [Fox, Caroline S.] Ctr Populat Studies, Framingham, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol & Metab, 75 Francis St, Boston, MA 02115 USA. [Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Murabito, Joanne M.] Boston Univ, Sch Med, Gen Internal Med Sect, Boston, MA 02118 USA. RP Murabito, JM (reprint author), Natl Heart Lung & Blood Inst Framingham Heart Stu, 73 Mt Wayte Ave Suite 2, Framingham, MA 01702 USA. EM murabito@bu.edu FU [N01-HC-25195]; [HHSN268201500001I]; [R0129451] FX The Framingham Heart Study of the National Heart, Lung and Blood Institute is supported by contract N01-HC-25195 and HHSN268201500001I. Dr Joanne Murabito is supported by R0129451. NR 46 TC 2 Z9 2 U1 1 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0161-9152 EI 1574-4647 J9 AGE JI Age PD APR PY 2016 VL 38 IS 2 AR 31 DI 10.1007/s11357-016-9893-2 PG 12 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA DG7GM UT WOS:000372252800003 PM 26899132 ER PT J AU Fannin, RD Gerrish, K Sieber, SO Bushel, PR Watkins, PB Paules, RS AF Fannin, R. D. Gerrish, K. Sieber, S. O. Bushel, P. R. Watkins, P. B. Paules, R. S. TI Blood Transcript Immune Signatures Distinguish a Subset of People With Elevated Serum ALT From Others Given Acetaminophen SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID INDUCED LIVER-INJURY; DENDRITIC CELLS; INDUCED HEPATOTOXICITY; WHOLE-BLOOD; GENOME-WIDE; T-CELLS; HUMANS; ACTIVATION; DIFFERENTIATION; IL-10 AB The diagnosis of drug-induced liver injury is hindered by the limited utility of clinical chemistries. We have shown that hepatotoxicants can produce peripheral blood transcriptome "signatures" (PBTS) in rodents and humans. In this study, 42 adults were treated with acetaminophen (APAP; 1 g every 6 hours) for seven days, followed by three days of placebo. Eleven subjects received only placebo. After five days, 12 subjects (30%) had increases in serum alanine aminotransferase (ALT) levels ("responders"). PBTS of 707 and 760 genes, respectively, could distinguish responders and nonresponders from placebos. Functional analysis of the responder PBTS revealed increased expression of genes involved in TH2-mediated and innate immune responses, whereas the nonresponders demonstrated increased gene expression consistent with a tolerogenic immune response. Taken together, these observations suggest that the clinical subjects with transient increases in serum ALT failed to maintain or intensify a hepatic tolerogenic immune response. C1 [Fannin, R. D.; Gerrish, K.; Sieber, S. O.] NIEHS, Mol Genom Core, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Bushel, P. R.] NIEHS, Biostat & Computat Biol Branch, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Watkins, P. B.] Univ N Carolina, Hamner, Inst Drug Safety Sci, Res Triangle Pk, NC USA. [Paules, R. S.] NIEHS, Natl Toxicol Program, Biomol Screening Branch, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RP Fannin, RD (reprint author), NIEHS, Mol Genom Core, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM fannin@niehs.nih.gov FU Intramural Research Program of the National Institute of Environmental Health Science, NIH; Intramural Research Program of the National Institute of Environmental Health Science, National Institute of Environmental Health Sciences [P30ES10126]; NIH [R37 GM38149, K23 RR21857-01]; University of North Carolina General Clinical Research Center [M000046] FX This research was supported (in part) by the Intramural Research Program of the National Institute of Environmental Health Sciences, NIH, and National Institute of Environmental Health Sciences grant P30ES10126, NIH grants R37 GM38149 and K23 RR21857-01, and The University of North Carolina General Clinical Research Center grant M000046. NR 48 TC 1 Z9 1 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD APR PY 2016 VL 99 IS 4 BP 432 EP 441 DI 10.1002/cpt.328 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DG3GA UT WOS:000371956300025 PM 26690555 ER PT J AU Berg, RA Nadkarni, VM Clark, AE Moler, F Meert, K Harrison, RE Newth, CJL Sutton, RM Wessel, DL Berger, JT Carcillo, J Dalton, H Heidemann, S Shanley, TP Zuppa, AF Doctor, A Tamburro, RF Jenkins, TL Dean, JM Holubkov, R Pollack, MM AF Berg, Robert A. Nadkarni, Vinay M. Clark, Amy E. Moler, Frank Meert, Kathleen Harrison, Rick E. Newth, Christopher J. L. Sutton, Robert M. Wessel, David L. Berger, John T. Carcillo, Joseph Dalton, Heidi Heidemann, Sabrina Shanley, Thomas P. Zuppa, Athena F. Doctor, Allan Tamburro, Robert F. Jenkins, Tammara L. Dean, J. Michael Holubkov, Richard Pollack, Murray M. CA Eunice Kennedy Shriver Natl Inst C TI Incidence and Outcomes of Cardiopulmonary Resuscitation in PICUs SO CRITICAL CARE MEDICINE LA English DT Article DE cardiac arrest; cardiopulmonary resuscitation; children; incidence; intensive care; survival ID PEDIATRIC INTENSIVE-CARE; AMERICAN-HEART-ASSOCIATION; HOSPITAL CARDIAC ARRESTS; FUNCTIONAL STATUS SCALE; THERAPEUTIC HYPOTHERMIA; UNITED-STATES; SURVIVAL; INFANTS; GUIDELINES; CATEGORY AB Objectives: To determine the incidence of cardiopulmonary resuscitation in PICUs and subsequent outcomes. Design, Setting, and Patients: Multicenter prospective observational study of children younger than 18 years old randomly selected and intensively followed from PICU admission to hospital discharge in the Collaborative Pediatric Critical Care Research Network December 2011 to April 2013. Results: Among 10,078 children enrolled, 139 (1.4%) received cardiopulmonary resuscitation for more than or equal to 1 minute and/or defibrillation. Of these children, 78% attained return of circulation, 45% survived to hospital discharge, and 89% of survivors had favorable neurologic outcomes. The relative incidence of cardiopulmonary resuscitation events was higher for cardiac patients compared with non-cardiac patients (3.4% vs 0.8%, p <0.001), but survival rate to hospital discharge with favorable neurologic outcome was not statistically different (41% vs 39%, respectively). Shorter duration of cardiopulmonary resuscitation was associated with higher survival rates: 66% (29/44) survived to hospital discharge after 1-3 minutes of cardiopulmonary resuscitation versus 28% (9/32) after more than 30 minutes (p < 0.001). Among survivors, 90% (26/29) had a favorable neurologic outcome after 1-3 minutes versus 89% (8/9) after more than 30 minutes of cardiopulmonary resuscitation. Conclusions: These data establish that contemporary PICU cardiopulmonary resuscitation, including long durations of cardiopulmonary resuscitation, results in high rates of survival-to-hospital discharge (45%) and favorable neurologic outcomes among survivors (89%). Rates of survival with favorable neurologic outcomes were similar among cardiac and noncardiac patients. The rigorous prospective, observational study design avoided the limitations of missing data and potential selection biases inherent in registry and administrative data. C1 [Berg, Robert A.; Nadkarni, Vinay M.; Sutton, Robert M.; Zuppa, Athena F.] Childrens Hosp Philadelphia, Dept Anesthesiol & Crit Care, Philadelphia, PA 19104 USA. [Berg, Robert A.; Nadkarni, Vinay M.; Sutton, Robert M.; Zuppa, Athena F.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Clark, Amy E.; Dean, J. Michael; Holubkov, Richard] Univ Utah, Sch Med, Dept Pediat, Salt Lake City, UT USA. [Moler, Frank; Shanley, Thomas P.] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA. [Meert, Kathleen; Heidemann, Sabrina] Childrens Hosp Michigan, Dept Pediat, Detroit, MI 48201 USA. [Harrison, Rick E.] Univ Calif Los Angeles, Dept Pediat, Los Angeles, CA 90024 USA. [Newth, Christopher J. L.] Childrens Hosp Los Angeles, Dept Anesthesiol & Crit Care Med, Los Angeles, CA 90027 USA. [Wessel, David L.; Berger, John T.] Childrens Natl Med Ctr, Dept Pediat, Washington, DC 20010 USA. [Carcillo, Joseph] Childrens Hosp Pittsburgh, Dept Crit Care Med, Pittsburgh, PA 15213 USA. [Dalton, Heidi] Phoenix Childrens Hosp, Dept Child Hlth, Phoenix, AZ USA. [Dalton, Heidi] Univ Arizona, Coll Med Phoenix, Phoenix, AZ USA. [Doctor, Allan] Washington Univ, Sch Med, Dept Pediat, St Louis, MO USA. [Tamburro, Robert F.; Jenkins, Tammara L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Branch Trauma & Crit Illness, NIH, Bethesda, MD USA. [Pollack, Murray M.] George Washington Univ, Sch Med, Childrens Natl Med Ctr, Dept Pediat, Washington, DC USA. RP Berg, RA (reprint author), Childrens Hosp Philadelphia, Dept Anesthesiol & Crit Care, Philadelphia, PA 19104 USA. EM bergra@email.chop.edu FU Department of Health and Human Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH) [U10HD050096, U10HD049981, U10HD049983, U10HD050012, U10HD063108, U10HD063106, U10HD063114, U01HD049934] FX Supported, in part, by cooperative agreements from the Department of Health and Human Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH): U10HD050096, U10HD049981, U10HD049983, U10HD050012, U10HD063108, U10HD063106, U10HD063114, and U01HD049934. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. NR 31 TC 7 Z9 7 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD APR PY 2016 VL 44 IS 4 BP 798 EP 808 DI 10.1097/CCM.0000000000001484 PG 11 WC Critical Care Medicine SC General & Internal Medicine GA DG1NU UT WOS:000371835600018 PM 26646466 ER PT J AU Cortes-Puch, I Natanson, C Sweeney, DA AF Cortes-Puch, Irene Natanson, Charles Sweeney, Daniel A. TI Measuring Impact: Citation Rates and the Quest to Identify Meaningful Clinical Research in Critical Care Medicine SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE citation rate; critical care; industry sponsorship; randomized clinical trial ID INTENSIVE INSULIN THERAPY; GOAL-DIRECTED RESUSCITATION; EARLY SEPTIC SHOCK; SEVERE SEPSIS; ILL PATIENTS; TRIAL; HYDROCORTISONE; MULTICENTER C1 [Cortes-Puch, Irene; Natanson, Charles] NIH, Dept Crit Care Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Sweeney, Daniel A.] Univ Calif San Diego, Div Pulm Crit Care & Sleep Med, Dept Internal Med, San Diego, CA 92103 USA. RP Cortes-Puch, I (reprint author), NIH, Dept Crit Care Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 CL999999] NR 24 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD APR PY 2016 VL 44 IS 4 BP 844 EP 845 DI 10.1097/CCM.0000000000001536 PG 2 WC Critical Care Medicine SC General & Internal Medicine GA DG1NU UT WOS:000371835600024 PM 26974447 ER PT J AU Dodson, A Zabaglo, L Martins, V Yeo, B Hayes, D McShane, L Leung, S Neilsen, T Dowsett, M AF Dodson, A. Zabaglo, L. Martins, V. Yeo, B. Hayes, D. McShane, L. Leung, S. Neilsen, T. Dowsett, M. TI Between-lab variability in Ki67 scoring by a standardised method in core-cuts has little impact on risk estimates by the IHC4+Clinical (IHC4+C) Score. A study presented on behalf of the International Ki67 in Breast Cancer Working Group of the Breast International Group SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 10th European Breast Cancer Conference (EBCC) CY MAR 09-11, 2016 CL Amsterdam, NETHERLANDS C1 [Dodson, A.; Dowsett, M.] Royal Marsden Hosp, Acad Dept Biochem, London SW3 6JJ, England. [Dodson, A.; Martins, V.; Dowsett, M.] Breast Canc Res, Inst Canc Res, London, England. [Zabaglo, L.] BreakThrough Toby Robins Breast Canc Res Ctr, Inst Canc Res, London, England. [Yeo, B.] Royal Marsden Hosp, Dept Med, London SW3 6JJ, England. [Hayes, D.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [McShane, L.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Leung, S.; Neilsen, T.] Univ British Columbia, Pathol & Lab Med, Vancouver, BC V5Z 1M9, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD APR PY 2016 VL 57 SU 2 MA 491 BP S142 EP S143 PG 2 WC Oncology SC Oncology GA DG0TV UT WOS:000371779500409 ER PT J AU Sonnenblick, A Agbor-Tarh, D Bradbury, I Di Cosimo, S Zujewski, JA Azim, HA Judith, J Andersson, M Cufer, T Simon, S Salman, P Toi, M Harris, L Gralow, J Macoon, K Moreno-Aspitia, A Piccart, M De Azambuja, E AF Sonnenblick, A. Agbor-Tarh, D. Bradbury, I. Di Cosimo, S. Zujewski, J. A. Azim, H. A., Jr. Judith, J. Andersson, M. Cufer, T. Simon, S. Salman, P. Toi, M. Harris, L. Gralow, J. Macoon, K. Moreno-Aspitia, A. Piccart, M. De Azambuja, E. TI The impact of diabetes and metformin usage on the outcome of HER2 positive primary breast cancer patients. Analysis from the ALTTO phase III randomized trial SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 10th European Breast Cancer Conference (EBCC) CY MAR 09-11, 2016 CL Amsterdam, NETHERLANDS C1 [Sonnenblick, A.; Azim, H. A., Jr.; Piccart, M.; De Azambuja, E.] Inst Jules Bordet, Br EAST Data Ctr, B-1000 Brussels, Belgium. [Sonnenblick, A.] Hadassah Hebrew Univ, Med Ctr, Sharett Inst Oncol, Oncol, Jerusalem, Israel. [Agbor-Tarh, D.; Bradbury, I.] Frontier Sci Scotland Ltd, Frontier Sci, Kingussie, Scotland. [Zujewski, J. A.] NCI, Bethesda, MD 20892 USA. [Judith, J.] Dutch Breast Canc Trialists Grp, BOOG, Amsterdam, Netherlands. [Andersson, M.] Danish Breast Canc Cooperat Grp, DBCG, Odense, Denmark. [Cufer, T.] EORTC, Breast Grp, Brussels, Belgium. [Simon, S.] Brazilian Breast Canc Study, GBECAM, Brasilia, DF, Brazil. [Salman, P.] Chilean Cooperat Grp Oncol Res, GOCCHI, Santiago, Chile. [Toi, M.] Japan Breast Canc Res Grp, Tokyo, Japan. [Sonnenblick, A.; Azim, H. A., Jr.; Piccart, M.; De Azambuja, E.] CALGB, New York, NY USA. [Gralow, J.] SWOG, New York, NY USA. [Macoon, K.] Ireland Cooperat Oncol Res Grp, Dublin, Ireland. [Moreno-Aspitia, A.] Mayo Clin, Oncol, Jacksonville, FL USA. [Di Cosimo, S.] Fdn IRCCS, Ist Nazl Tumori, Milan, Italy. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD APR PY 2016 VL 57 SU 2 MA 126 BP S28 EP S28 PG 1 WC Oncology SC Oncology GA DG0TV UT WOS:000371779500055 ER PT J AU Matsumoto, S Koba, Y Kohno, R Lee, C Bolch, WE Kai, M AF Matsumoto, Shinnosuke Koba, Yusuke Kohno, Ryosuke Lee, Choonsik Bolch, Wesley E. Kai, Michiaki TI SECONDARY NEUTRON DOSES TO PEDIATRIC PATIENTS DURING INTRACRANIAL PROTON THERAPY: MONTE CARLO SIMULATION OF THE NEUTRON ENERGY SPECTRUM AND ITS ORGAN DOSES SO HEALTH PHYSICS LA English DT Article DE dose; organ; Monte Carlo; pediatrics; radiation therapy ID RADIATION-THERAPY; PHANTOMS; EQUIVALENT; ION AB Proton therapy has the physical advantage of a Bragg peak that can provide a better dose distribution than conventional x-ray therapy. However, radiation exposure of normal tissues cannot be ignored because it is likely to increase the risk of secondary cancer. Evaluating secondary neutrons generated by the interaction of the proton beam with the treatment beam-line structure is necessary; thus, performing the optimization of radiation protection in proton therapy is required. In this research, the organ dose and energy spectrum were calculated from secondary neutrons using Monte Carlo simulations. The Monte Carlo code known as the Particle and Heavy Ion Transport code System (PHITS) was used to simulate the transport proton and its interaction with the treatment beam-line structure that modeled the double scattering body of the treatment nozzle at the National Cancer Center Hospital East. The doses of the organs in a hybrid computational phantom simulating a 5-y-old boy were calculated. In general, secondary neutron doses were found to decrease with increasing distance to the treatment field. Secondary neutron energy spectra were characterized by incident neutrons with three energy peaks: 1x10(-7), 1, and 100 MeV. A block collimator and a patient collimator contributed significantly to organ doses. In particular, the secondary neutrons from the patient collimator were 30 times higher than those from the first scatter. These results suggested that proactive protection will be required in the design of the treatment beam-line structures and that organ doses from secondary neutrons may be able to be reduced. C1 [Matsumoto, Shinnosuke; Kai, Michiaki] Oita Univ Nursing & Hlth Sci, Grad Sch, Oita, Oita 8701201, Japan. [Matsumoto, Shinnosuke; Koba, Yusuke] Natl Inst Radiol Sci, Med Exposure Res Project, Chiba, Chiba 2638555, Japan. [Kohno, Ryosuke] Natl Canc Ctr Hosp East, Div Particle Therapy, Kashiwa, Chiba 2778577, Japan. [Lee, Choonsik] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA. [Bolch, Wesley E.] Univ Florida, Dept Radiol, Gainesville, FL 32611 USA. RP Matsumoto, S (reprint author), Natl Inst Radiol Sci, Inage Ku, 4-9-1 Anagawa, Chiba, Chiba 2638555, Japan. EM shimatsu@nirs.go.jp NR 20 TC 0 Z9 0 U1 1 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD APR PY 2016 VL 110 IS 4 BP 380 EP 386 DI 10.1097/HP.0000000000000461 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA DG1MZ UT WOS:000371833500006 PM 26910030 ER PT J AU Bustos-Arriaga, J Mita-Mendoza, NK Lopez-Gonzalez, M Garcia-Cordero, J Juarez-Delgado, FJ Gromowski, GD Mendez-Cruz, RA Fairhurst, RM Whitehead, SS Cedillo-Barron, L AF Bustos-Arriaga, Jose Mita-Mendoza, Neida K. Lopez-Gonzalez, Moises Garcia-Cordero, Julio Juarez-Delgado, Francisco J. Gromowski, Gregory D. Mendez-Cruz, Rene A. Fairhurst, Rick M. Whitehead, Stephen S. Cedillo-Barron, Leticia TI Soluble mediators produced by the crosstalk between microvascular endothelial cells and dengue-infected primary dermal fibroblasts inhibit dengue virus replication and increase leukocyte transmigration SO IMMUNOLOGIC RESEARCH LA English DT Article DE Dengue; Innate immunity; Skin; Cellular crosstalk; Fibroblast and endothelial cells ID HUMAN SKIN FIBROBLASTS; HUMAN DENDRITIC CELLS; NATURAL-KILLER-CELLS; HUMAN UMBILICAL VEIN; HEMORRHAGIC-FEVER; GENE POLYMORPHISMS; CLINICAL-OUTCOMES; NK CELLS; IN-VITRO; ACTIVATION AB When dengue virus (DENV)-infected mosquitoes use their proboscis to probe into human skin during blood feeding, both saliva and virus are released. During this process, cells from the epidermis and dermis layers of the skin, along with small blood vessels, may get exposed to or infected with DENV. In these microenvironments of the skin, the presence of DENV initiates a complex interplay among the DENV-infected and non-infected neighboring cells at the initial bite site. Previous studies suggested that DENV-infected human dermal fibroblasts (HDFs) participate in the immune response against DENV by secreting soluble mediators of innate immunity. In the present study, we investigated whether DENV-infected HDFs activate human dermal microvascular endothelial cells (HDMECs) in co-cultures. Our results suggest that co-cultures of DENV-infected HDFs and HDMECs elicit soluble mediators that are sufficient to reduce viral replication, activate HDMECs, and induce leukocyte migration through HDMEC monolayers. These effects were partly dependent on HDF donor and DENV serotype, which may provide novel insights into the natural variation in host susceptibility to DENV disease. C1 [Bustos-Arriaga, Jose; Lopez-Gonzalez, Moises; Garcia-Cordero, Julio; Cedillo-Barron, Leticia] Inst Politecn Nacl, Ctr Invest & Estudios Avanzados, Dept Biomed Mol, Mexico City, DF, Mexico. [Bustos-Arriaga, Jose; Gromowski, Gregory D.; Whitehead, Stephen S.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Mita-Mendoza, Neida K.; Fairhurst, Rick M.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Juarez-Delgado, Francisco J.] Hosp Gen Ticoman SS, Dept Cirugia, Mexico City, DF, Mexico. [Mendez-Cruz, Rene A.] Univ Autonoma Mexico, FES Iztacala, Lab Inmunol UMF, Mexico City, DF, Mexico. RP Cedillo-Barron, L (reprint author), Inst Politecn Nacl, Ctr Invest & Estudios Avanzados, Dept Biomed Mol, Mexico City, DF, Mexico. EM lcedillo@cinvestav.mx FU National Council for Science and Technology (CONACyT) [154270]; Intramural Research Program of the NIH, NIAID; CONACyT FX This work was supported by the National Council for Science and Technology (CONACyT, Grant no. 154270) and the Intramural Research Program of the NIH, NIAID. JB-A and ML-G received fellowships from CONACyT. LC-B, JB-A, and JG-C are members of the National System of Researchers. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 0 Z9 0 U1 3 U2 7 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0257-277X EI 1559-0755 J9 IMMUNOL RES JI Immunol. Res. PD APR PY 2016 VL 64 IS 2 BP 392 EP 403 DI 10.1007/s12026-015-8675-8 PG 12 WC Immunology SC Immunology GA DG6YH UT WOS:000372231500006 PM 26130295 ER PT J AU Bao, XH Chandramohan, V Reynolds, RP Norton, JN Wetsel, WC Rodriguiz, RM Aryal, DK McLendon, RE Levin, ED Petry, NA Zalutsky, MR Burnett, BK Kuan, CT Pastan, IH Bigner, DD AF Bao, Xuhui Chandramohan, Vidyalakshmi Reynolds, Randall P. Norton, John N. Wetsel, William C. Rodriguiz, Ramona M. Aryal, Dipendra K. McLendon, Roger E. Levin, Edward D. Petry, Neil A. Zalutsky, Michael R. Burnett, Bruce K. Kuan, Chien-Tsun Pastan, Ira H. Bigner, Darell D. TI Preclinical toxicity evaluation of a novel immunotoxin, D2C7-(scdsFv)-PE38KDEL, administered via intracerebral convection-enhanced delivery in rats SO INVESTIGATIONAL NEW DRUGS LA English DT Article DE D2C7-(scdsFv)-PE38KDEL; Immunotoxin; Convection-enhanced delivery; Toxicity; Rat ID BRAIN-TUMORS; MALIGNANT GLIOMAS; THERAPY; TOXIN AB D2C7-(scdsFv)-PE38KDEL (D2C7-IT) is a novel immunotoxin that reacts with wild-type epidermal growth factor receptor (EGFRwt) and mutant EGFRvIII proteins overexpressed in glioblastomas. This study assessed the toxicity of intracerebral administration of D2C7-IT to support an initial Food and Drug Administration Investigational New Drug application. After the optimization of the formulation and administration, two cohorts (an acute and chronic cohort necropsied on study days 5 and 34) of Sprague-Dawley (SD) rats (four groups of 5 males and 5 females) were infused with the D2C7-IT formulation at total doses of 0, 0.05, 0.1, 0.4 mu g (the acute cohort) and 0, 0.05, 0.1, 0.35 mu g (the chronic cohort) for approximately 72 h by intracerebral convection-enhanced delivery using osmotic pumps. Mortality was observed in the 0.40 mu g (5/10 rats) and 0.35 mu g (4/10 rats) high-dose groups of each cohort. Body weight loss and abnormal behavior were only revealed in the rats treated with high doses of D2C7-IT. No dose-related effects were observed in clinical laboratory tests in either cohort. A gross pathologic examination of systemic tissues from the high-dose and control groups in both cohorts exhibited no dose-related or drug-related pathologic findings. Brain histopathology revealed the frequent occurrence of dose-related encephalomalacia, edema, and demyelination in the high-dose groups of both cohorts. In this study, the maximum tolerated dose of D2C7-IT was determined to be between 0.10 and 0.35 mu g, and the no-observed-adverse-effect-level was 0.05 mu g in SD rats. Both parameters were utilized to design the Phase I/II D2C7-IT clinical trial. C1 [Bao, Xuhui; Chandramohan, Vidyalakshmi; McLendon, Roger E.; Zalutsky, Michael R.; Kuan, Chien-Tsun; Bigner, Darell D.] Duke Univ, Preston Robert Tisch Brain Tumor Ctr Duke, Med Ctr, 177 MSRB 1,203 Res Dr,Box 3156, Durham, NC USA. [Bao, Xuhui; Chandramohan, Vidyalakshmi; McLendon, Roger E.; Zalutsky, Michael R.; Kuan, Chien-Tsun; Bigner, Darell D.] Duke Univ, Med Ctr, Dept Pathol, 177 MSRB 1,203 Res Dr,Box 3156, Durham, NC 27710 USA. [Reynolds, Randall P.; Norton, John N.] Duke Univ, Med Ctr, Div Lab Anim Resources, 177 MSRB 1,203 Res Dr,Box 3156, Durham, NC USA. [Wetsel, William C.; Rodriguiz, Ramona M.; Aryal, Dipendra K.; Levin, Edward D.] Duke Univ, Dept Psychiat & Behav Sci, Med Ctr, Durham, NC USA. [Wetsel, William C.; Rodriguiz, Ramona M.; Aryal, Dipendra K.] Duke Univ, Mouse Behav & Neuroendocrine Anal Core Facil, Med Ctr, Durham, NC USA. [Wetsel, William C.] Duke Univ, Med Ctr, Dept Neurobiol, Durham, NC 27710 USA. [Wetsel, William C.] Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA. [Petry, Neil A.; Zalutsky, Michael R.] Duke Univ, Med Ctr, Dept Radiol, Durham, NC 27710 USA. [Burnett, Bruce K.] Duke Translat Med Inst, Regulatory Affairs Off, Durham, NC USA. [Burnett, Bruce K.] Duke Univ, Sch Med, Durham, NC USA. [Pastan, Ira H.] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. RP Bigner, DD (reprint author), Duke Univ, Preston Robert Tisch Brain Tumor Ctr Duke, Med Ctr, 177 MSRB 1,203 Res Dr,Box 3156, Durham, NC USA.; Bigner, DD (reprint author), Duke Univ, Med Ctr, Dept Pathol, 177 MSRB 1,203 Res Dr,Box 3156, Durham, NC 27710 USA. EM darell.bigner@duke.edu FU National Institutes of Health (NIH) of the United States [P01-CA154291-03]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX We thank Terri Lucas and Lena Perdue for coordinating the study, Charles Pegram, David Soule, and Xiao-Guang Zhao for the formulation preparation, and Colleen Herbst, Meredith Weksler, and Fernando Orozco for their surgical assistance. We wish to thank Christopher Means and Theo Rhodes for their detailed assessment of the animals for the Functional Observation Battery (FOB) and assistance in preparing and analyzing the FOB data. We also thank Jenna Lewis for her editorial assistance. The study was funded by the following grant from the National Institutes of Health (NIH) of the United States: P01-CA154291-03 (to D.D. Bigner). This research was also supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 25 TC 2 Z9 2 U1 1 U2 6 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6997 EI 1573-0646 J9 INVEST NEW DRUG JI Invest. New Drugs PD APR PY 2016 VL 34 IS 2 BP 149 EP 158 DI 10.1007/s10637-015-0318-3 PG 10 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA DG7RC UT WOS:000372280400002 PM 26728879 ER PT J AU Deming, DA Cavalcante, LL Lubner, SJ Mulkerin, DL LoConte, NK Eickhoff, JC Kolesar, JM Fioravanti, S Greten, TF Compton, K Doyle, AG Wilding, G Duffy, A Liu, G AF Deming, Dustin A. Cavalcante, Ludmila L. Lubner, Sam J. Mulkerin, Daniel L. LoConte, Noelle K. Eickhoff, Jens C. Kolesar, Jill M. Fioravanti, Suzanne Greten, Tim F. Compton, Kathryn Doyle, Austin G. Wilding, George Duffy, Austin Liu, Glenn TI A phase I study of selumetinib (AZD6244/ARRY-142866), a MEK1/2 inhibitor, in combination with cetuximab in refractory solid tumors and KRAS mutant colorectal cancer SO INVESTIGATIONAL NEW DRUGS LA English DT Article DE Selumetinib; AZD6244; Cetuximab; Phase I; KRAS; Colon cancer ID KINASE KINASE-1/2 INHIBITOR; AZD6244 ARRY-142886; BRAF; PANITUMUMAB; MUTATIONS; SURVIVAL; POTENT AB Background KRAS mutations are clinically important predictors of resistance to EGFR-directed therapies in colorectal cancer (CRC). Oncogenic activation of the RAS/RAF/MEK/ERK signaling cascade mediates proliferation independent of growth factor signaling. We hypothesized that targeting MEK with selumetinib could overcome resistance to cetuximab in KRAS mutant CRC. Methods A phase I study (NCT01287130) was undertaken to determine the tolerability, and pharmacokinetic profiles of the combination of selumetinib and cetuximab, with an expanded cohort in KRAS-mutant CRC. Results 15 patients were treated in the dose escalation cohort and 18 patients were treated in the expansion cohort. Two dose-limiting toxicities were observed. One grade 3 acneiform rash and one grade 4 hypomagnesemia occurred. The most common grade 1 and 2 adverse events included rash, nausea/vomiting, diarrhea, and fatigue. The maximum tolerated dose was established at selumetinib 75 mg PO BID and cetuximab 250 mg/m(2) weekly following a 400 mg/m(2) load. Best clinical response in the dose escalation group included 1 unconfirmed partial response in a patient with CRC and stable disease (SD) in 5 patients (1 squamous cell carcinoma of the tonsil, 1 non-small cell lung cancer, and 3 CRC), and in the KRAS-mutant CRC dose expansion cohort, of the 14 patients who were evaluable for response, 5 patients had SD and 9 patients had progressive disease. Conclusions The combination of selumetinib and cetuximab is safe and well tolerated. Minimal anti-tumor activity was observed in KRAS-mutant refractory metastatic CRC. Further investigations might be warranted in other cancer subtypes. C1 [Deming, Dustin A.; Cavalcante, Ludmila L.; Lubner, Sam J.; Mulkerin, Daniel L.; LoConte, Noelle K.; Eickhoff, Jens C.; Kolesar, Jill M.; Wilding, George; Liu, Glenn] Univ Wisconsin, Madison Carbone Canc Ctr, 600 Highland Ave,K6-544 CSC, Madison, WI 53792 USA. [Doyle, Austin G.] NCI, Canc Therapy Evaluat Program, Bethesda, MD USA. [Fioravanti, Suzanne; Greten, Tim F.; Compton, Kathryn; Duffy, Austin] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. RP Deming, DA (reprint author), Univ Wisconsin, Madison Carbone Canc Ctr, 600 Highland Ave,K6-544 CSC, Madison, WI 53792 USA. EM ddeming@medicine.wisc.edu FU National Cancer Institute [U01 CA062491, P30 CA014520] FX This study was supported by grants from the National Cancer Institute: U01 CA062491to Glenn Liu and P30 CA014520 to University of Wisconsin-Madison Carbone Cancer Center. We gratefully acknowledge the support of AstraZeneca who provided the selumetinib for this clinical trial. NR 17 TC 4 Z9 4 U1 1 U2 5 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6997 EI 1573-0646 J9 INVEST NEW DRUG JI Invest. New Drugs PD APR PY 2016 VL 34 IS 2 BP 168 EP 175 DI 10.1007/s10637-015-0314-7 PG 8 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA DG7RC UT WOS:000372280400004 PM 26666244 ER PT J AU Nichols, SL Bethel, J Kapogiannis, BG Li, TD Woods, SP Patton, ED Ren, WJ Thornton, SE Major-Wilson, HO Puga, AM Sleasman, JW Rudy, BJ Wilson, CM Garvie, PA AF Nichols, Sharon L. Bethel, James Kapogiannis, Bill G. Li, Tiandong Woods, Steven P. Patton, E. Doyle Ren, Weijia Thornton, Sarah E. Major-Wilson, Hanna O. Puga, Ana M. Sleasman, John W. Rudy, Bret J. Wilson, Craig M. Garvie, Patricia A. CA Adolescent Med Trials Network HIV TI Antiretroviral treatment initiation does not differentially alter neurocognitive functioning over time in youth with behaviorally acquired HIV SO JOURNAL OF NEUROVIROLOGY LA English DT Article DE HIV; Neurocognitive functioning; Adolescent; Youth; Antiretroviral therapy; HIV-associated neurocognitive disorder ID VISUOSPATIAL MEMORY TEST; NEUROPSYCHOLOGICAL CHANGE; MICROBIAL TRANSLOCATION; NORMATIVE DATA; THERAPY; RELIABILITY; IMPAIRMENT; DISORDERS; ACTIVATION; EFAVIRENZ AB Although youth living with behaviorally acquired HIV (YLWH) are at risk for cognitive impairments, the relationship of impairments to HIV and potential to improve with antiretroviral therapy (ART) are unclear. This prospective observational study was designed to examine the impact of initiation and timing of ART on neurocognitive functioning in YLWH in the Adolescent Medicine Trials Network for HIV/AIDS Interventions. Treatment na < ve YLWH age 18-24 completed baseline and four additional assessments of attention/working memory, complex executive, and motor functioning over 3 years. Group 1 co-enrolled in an early ART initiation study and initiated ART at enrollment CD4 > 350 (n = 56); group 2 had CD4 > 350 and were not initiating ART (n = 66); group 3 initiated ART with CD4 < 350 (n = 59) per standard of care treatment guidelines at the time. Treatment was de-intensified to boosted protease inhibitor monotherapy at 48 weeks for those in group 1 with suppressed viral load. Covariates included demographic, behavioral, and medical history variables. Analyses used hierarchical linear modeling. All groups showed improved performance with peak at 96 weeks in all three functional domains. Trajectories of change were not significantly associated with treatment, timing of treatment initiation, or ART de-intensification. Demographic variables and comorbidities were associated with baseline functioning but did not directly interact with change over time. In conclusion, YLWH showed improvement in neurocognitive functioning over time that may be related to practice effects and nonspecific impact of study participation. Neither improvement nor decline in functioning was associated with timing of ART initiation or therapy de-intensification. C1 [Nichols, Sharon L.] Univ Calif San Diego, Dept Neurosci, 9500 Gilman Dr,0935, San Diego, CA 92093 USA. [Bethel, James; Li, Tiandong; Ren, Weijia; Thornton, Sarah E.] Westat Corp, Rockville, MD USA. [Kapogiannis, Bill G.] NIH, Bethesda, MD USA. [Woods, Steven P.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92093 USA. [Patton, E. Doyle; Puga, Ana M.; Garvie, Patricia A.] Childrens Diagnost & Treatment Ctr Inc, Ft Lauderdale, FL USA. [Major-Wilson, Hanna O.] Univ Miami, Dept Pediat, Miami, FL 33152 USA. [Sleasman, John W.] Duke Univ, Div Allergy & Immunol, Durham, NC USA. [Rudy, Bret J.] NYU, Dept Pediat, New York, NY 10016 USA. [Wilson, Craig M.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA. RP Nichols, SL (reprint author), Univ Calif San Diego, Dept Neurosci, 9500 Gilman Dr,0935, San Diego, CA 92093 USA. EM slnichols@ucsd.edu FU NICHD NIH HHS [5 U01 HD 40474, 5 U01 HD40533, U01 HD040474, U01 HD040533] NR 34 TC 0 Z9 0 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 EI 1538-2443 J9 J NEUROVIROL JI J. Neurovirol. PD APR PY 2016 VL 22 IS 2 BP 218 EP 230 DI 10.1007/s13365-015-0389-0 PG 13 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA DG2WD UT WOS:000371929900010 PM 26463526 ER PT J AU Merbah, M Onkar, S Grivel, JC Vanpouille, C Biancotto, A Bonar, L Sanders-Buell, E Kijak, G Michael, N Robb, M Kim, JH Tovanabutra, S Chenine, AL AF Merbah, Melanie Onkar, Sayali Grivel, Jean-Charles Vanpouille, Christophe Biancotto, Angelique Bonar, Lydia Sanders-Buell, Eric Kijak, Gustavo Michael, Nelson Robb, Merlin Kim, Jerome H. Tovanabutra, Sodsai Chenine, Agnes-Laurence TI Standardization of a cytometric p24-capture bead-assay for the detection of main HIV-1 subtypes SO JOURNAL OF VIROLOGICAL METHODS LA English DT Article DE HIV-1; p24; Detection; Multi-subtype; Multiplex assay ID CELLS; REPLICATION; SUPPRESSION; INFECTION; PROTEIN; P24 AB The prevailing method to assess HIV-1 replication and infectivity is to measure the production of p24 Gag protein by enzyme-linked immunosorbent assay (ELISA). Since fluorescent bead-based technologies offer a broader dynamic range and higher sensitivity, this study describes a p24 capture Luminex assay capable of detecting HIV-1 subtypes A-D, circulating recombinant forms (CRF) CRF01_AE and CRF02_AG, which together are responsible for over 90% of HIV-1 infections worldwide. The success of the assay lies in the identification and selection of a cross-reactive capture antibody (clone 183-H12-5C). Fifty-six isolates that belonged to six HIV-1 subtypes and CRFs were successfully detected with p-values below 0.021; limits of detection ranging from 3.7 to 3 x 104 pg/ml. The intra- and inter-assay variation gave coefficient of variations below 6 and 14%, respectively. The 183-bead Luminex assay also displayed higher sensitivity of 91% and 98% compared to commercial p24 ELISA and a previously described Luminex assay. The p24 concentrations measured by the 183 bead Luminex assay showed a significant correlation (R=0.92, p < 0.0001) with the data obtained from quantitative real time PCR. This newly developed p24 assay leverages the advantages of the Luminex platform, which include smaller sample volume and simultaneous detection of up to 500 analytes in a single sample, and delivers a valuable tool for the field. (C) 2016 Elsevier B.V. All rights reserved. C1 [Merbah, Melanie; Onkar, Sayali; Bonar, Lydia; Sanders-Buell, Eric; Kijak, Gustavo; Michael, Nelson; Robb, Merlin; Kim, Jerome H.; Tovanabutra, Sodsai; Chenine, Agnes-Laurence] Walter Reed Army Inst Res, US Mil HIV Res Program, Silver Spring, MD 20910 USA. [Merbah, Melanie; Onkar, Sayali; Bonar, Lydia; Sanders-Buell, Eric; Kijak, Gustavo; Robb, Merlin; Tovanabutra, Sodsai; Chenine, Agnes-Laurence] Henry M Jackson Fdn Adv Mil Med, Bethesda, MD USA. [Grivel, Jean-Charles; Vanpouille, Christophe] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD USA. [Biancotto, Angelique] NIH, Ctr Human Immunol Autoimmun & Inflammat, Bldg 10, Bethesda, MD 20892 USA. RP Merbah, M (reprint author), Walter Reed Army Inst Res, MHRP, 503 Robert Grant Ave,Room 2N11, Silver Spring, MD 20910 USA.; Merbah, M (reprint author), Walter Reed Army Inst Res, Henry M Jackson Fdn Adv Mil Med HJF, 503 Robert Grant Ave,Room 2N11, Silver Spring, MD 20910 USA. EM mmerbah@hivresearch.org; sonkar@hivresearch.org; jgrivel@sidra.org; vanpouic@mail.nih.gov; biancoa@nhlbi.nih.gov; lbonar@hivresearch.org; esanders-buell@hivresearch.org; gkijak@hivresearch.org; nmichael@hivresearch.org; mrobb@hivresearch.org; jerome.kim@ivi.int; stovanabutra@hivresearch.org; achenine@hivresearch.org OI Merbah, Melanie/0000-0002-5641-8612 FU Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. [W81XWH-11-2-0174]; U.S. Department of Defense (DoD) [W81XWH-11-2-0174] 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, Inc., and the U.S. Department of Defense (DoD). The views expressed are those of the authors and should not be construed to represent the positions of the United States Departments of the Army, Defense, or Health and Human Services. NR 24 TC 0 Z9 0 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-0934 EI 1879-0984 J9 J VIROL METHODS JI J. Virol. Methods PD APR PY 2016 VL 230 BP 45 EP 52 DI 10.1016/j.jviromet.2016.01.009 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Virology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Virology GA DG3DS UT WOS:000371950300008 PM 26808359 ER PT J AU Graus, F Titulaer, MJ Balu, R Benseler, S Bien, CG Cellucci, T Cortese, I Dale, RC Gelfand, JM Geschwind, M Glaser, CA Honnorat, J Hoftberger, R Iizuka, T Irani, SR Lancaster, E Leypoldt, F Pruss, H Rae-Grant, A Reindl, M Rosenfeld, MR Rostasy, K Saiz, A Venkatesan, A Vincent, A Wandinger, KP Waters, P Dalmau, J AF Graus, Francesc Titulaer, Maarten J. Balu, Ramani Benseler, Susanne Bien, Christian G. Cellucci, Tania Cortese, Irene Dale, Russell C. Gelfand, Jeffrey M. Geschwind, Michael Glaser, Carol A. Honnorat, Jerome Hoeftberger, Romana Iizuka, Takahiro Irani, Sarosh R. Lancaster, Eric Leypoldt, Frank Pruess, Harald Rae-Grant, Alexander Reindl, Markus Rosenfeld, Myrna R. Rostasy, Kevin Saiz, Albert Venkatesan, Arun Vincent, Angela Wandinger, Klaus-Peter Waters, Patrick Dalmau, Josep TI A clinical approach to diagnosis of autoimmune encephalitis SO LANCET NEUROLOGY LA English DT Review ID D-ASPARTATE RECEPTOR; HERPES-SIMPLEX ENCEPHALITIS; ACUTE DISSEMINATED ENCEPHALOMYELITIS; GLUTAMIC-ACID DECARBOXYLASE; BRAIN-STEM ENCEPHALITIS; PARANEOPLASTIC NEUROLOGICAL SYNDROMES; MYELIN OLIGODENDROCYTE GLYCOPROTEIN; LIMBIC ENCEPHALITIS; MULTIPLE-SCLEROSIS; CASE SERIES AB Encephalitis is a severe inflammatory disorder of the brain with many possible causes and a complex differential diagnosis. Advances in autoimmune encephalitis research in the past 10 years have led to the identification of new syndromes and biomarkers that have transformed the diagnostic approach to these disorders. However, existing criteria for autoimmune encephalitis are too reliant on antibody testing and response to immunotherapy, which might delay the diagnosis. We reviewed the literature and gathered the experience of a team of experts with the aims of developing a practical, syndrome-based diagnostic approach to autoimmune encephalitis and providing guidelines to navigate through the differential diagnosis. Because autoantibody test results and response to therapy are not available at disease onset, we based the initial diagnostic approach on neurological assessment and conventional tests that are accessible to most clinicians. Through logical differential diagnosis, levels of evidence for autoimmune encephalitis (possible, probable, or definite) are achieved, which can lead to prompt immunotherapy. C1 [Graus, Francesc; Rosenfeld, Myrna R.; Saiz, Albert; Dalmau, Josep] Inst Invest Biomed August Pi & Sunyer, Neuroimmunol Program, Barcelona, Spain. [Graus, Francesc; Saiz, Albert] Hosp Clin Barcelona, Serv Neurol, Barcelona, Spain. [Titulaer, Maarten J.] Erasmus MC, Dept Neurol, Rotterdam, Netherlands. [Balu, Ramani; Lancaster, Eric; Dalmau, Josep] Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA. [Benseler, Susanne] Alberta Children Hosp, Dept Pediat, Calgary, AB, Canada. [Bien, Christian G.] Krankenhaus Mara, Epilepsy Ctr Bethel, Bielefeld, Germany. [Cellucci, Tania] McMaster Univ, Dept Pediat, McMaster Childrens Hosp, Hamilton, ON, Canada. [Cortese, Irene] NINDS, Neuroimmunol Clin, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Dale, Russell C.] Univ Sydney, Neuroimmunol Grp, Childrens Hosp Westmead, Sydney, NSW 2006, Australia. [Gelfand, Jeffrey M.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Glaser, Carol A.] Kaiser Permanente, Div Pediat Infect Dis, Oakland Med Ctr, San Francisco, CA USA. [Glaser, Carol A.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Honnorat, Jerome] Univ Lyon 1, French Reference Ctr Paraneoplast Neurol Syndrome, Hosp Civils Lyon, Hop Neurol,Inserm U1028,CNRS UMR 5292,Lyons Neuro, F-69365 Lyon, France. [Hoeftberger, Romana] Med Univ Vienna, Inst Neurol, Vienna, Austria. [Iizuka, Takahiro] Kitasato Univ, Sch Med, Dept Neurol, Sagamihara, Kanagawa, Japan. [Irani, Sarosh R.; Vincent, Angela; Waters, Patrick] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Neurosci, Oxford OX3 9DU, England. [Leypoldt, Frank] Univ Med Ctr Schleswig Holstein, Inst Clin Chem, Neuroimmunol, Kiel, Germany. [Leypoldt, Frank] Univ Med Ctr Schleswig Holstein, Dept Neurol, Kiel, Germany. [Pruess, Harald] Charite, Dept Neurol, D-13353 Berlin, Germany. [Pruess, Harald] German Ctr Neurodegenerat Disorders Berlin, Berlin, Germany. [Rae-Grant, Alexander] Cleveland Clin Fdn, Dept Neurol, 9500 Euclid Ave, Cleveland, OH 44195 USA. [Reindl, Markus] Med Univ Innsbruck, Dept Clin Neurol, A-6020 Innsbruck, Austria. [Rostasy, Kevin] Univ Witten Herdecke, Childrens Hosp Datteln, Dept Pediat Neurol, Datteln, Germany. [Venkatesan, Arun] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Wandinger, Klaus-Peter] Univ Hosp Schleswig Holstein, Inst Clin Chem, Lubeck, Germany. [Wandinger, Klaus-Peter] Univ Hosp Schleswig Holstein, Dept Neurol, Lubeck, Germany. [Dalmau, Josep] ICREA, Barcelona, Spain. RP Graus, F; Dalmau, J (reprint author), Univ Barcelona, Inst Invest Biomed August Pi & Sunyer Hosp Clin, E-08036 Barcelona, Spain. EM fgraus@clinic.ub.es; jdalmau@clinic.ub.es OI Reindl, Markus/0000-0003-2817-1402; Irani, Sarosh/0000-0002-7667-9748; Rosenfeld, Myrna/0000-0001-5095-2534; Dalmau, Josep/0000-0001-5856-2813 FU Fundacio la Marato TV3 [20141830]; Erasmus fellowship, the Netherlands Organisation for Scientific Research (Veni-incentive); Dutch Epilepsy Foundations (NEF) [14-19]; National Health and Medical Research Council; Tourette Syndrome Association; University of Sydney; Petre Foundation; National Institute on Aging; CurePSP; Tau Consortium; National Health Service National Specialised Commissioning Group for Neuromyelitis Optica, UK; National Institute for Health Research Oxford Biomedical Research Centre; Guthy-Jackson Charitable Foundation; Instituto Carlos III [FIS 14/00203]; National Institutes of Health [RO1NS077851]; Fundacio Cellex; MS Research Australia; Grand Round Lectures, and the Michael J Homer Family Fund FX We thank the Autoimmune Encephalitis Alliance (USA), the Encephalitis Society (UK), the Anti-NMDA Receptor Encephalitis Foundation Inc (Canada), and the Anti-NMDA Receptor Encephalitis Patient Initiative (Germany) for disseminating information, helping patients and families, and promoting research in autoimmune encephalitis. FG was supported in part by grant 20141830 Fundacio la Marato TV3. MJT has been supported by an Erasmus fellowship, the Netherlands Organisation for Scientific Research (Veni-incentive), and a grant from the Dutch Epilepsy Foundations (NEF project 14-19). RCD has received research funding from the National Health and Medical Research Council, MS Research Australia, the Tourette Syndrome Association, the University of Sydney, and the Petre Foundation. MG receives grants from the National Institute on Aging; has received grants from CurePSP and the Tau Consortium; and has received speaker's fees and research funding from Grand Round Lectures, and the Michael J Homer Family Fund. PW is supported by the National Health Service National Specialised Commissioning Group for Neuromyelitis Optica, UK, and the National Institute for Health Research Oxford Biomedical Research Centre, and has received travel grants from the Guthy-Jackson Charitable Foundation. JD was supported by the Instituto Carlos III (FIS 14/00203) grant, National Institutes of Health RO1NS077851 grant, and Fundacio Cellex. NR 109 TC 58 Z9 65 U1 17 U2 37 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 EI 1474-4465 J9 LANCET NEUROL JI Lancet Neurol. PD APR PY 2016 VL 15 IS 4 BP 391 EP 404 DI 10.1016/S1474-4422(15)00401-9 PG 14 WC Clinical Neurology SC Neurosciences & Neurology GA DG3MP UT WOS:000371974000019 PM 26906964 ER PT J AU Verdurand, M Chauveau, F Daoust, A Morel, AL Bonnefoi, F Liger, F Berod, A Zimmer, L AF Verdurand, Mathieu Chauveau, Fabien Daoust, Alexia Morel, Anne-Laure Bonnefoi, Frederic Liger, Francois Berod, Anne Zimmer, Luc TI Differential effects of amyloid-beta 1-40 and 1-42 fibrils on 5-HT1A serotonin receptors in rat brain SO NEUROBIOLOGY OF AGING LA English DT Article DE Alzheimer's disease; Amyloid-beta peptides; Serotonin; 5-HT1A receptors; Positron emission tomography ID MILD COGNITIVE IMPAIRMENT; ALZHEIMERS-DISEASE; MESSENGER-RNA; CEREBRAL-CORTEX; IN-VITRO; HIPPOCAMPUS; BINDING; LOCALIZATION; NEUROGENESIS; DEPOSITION AB Evidence accumulates suggesting a complex interplay between neurodegenerative processes and serotonergic neurotransmission. We have previously reported an overexpression of serotonin 5-HT1A receptors (5-HT1AR) after intrahippocampal injections of amyloid-beta 1-40 (A beta 40) fibrils in rats. This serotonergic reactivity paralleled results from clinical positron emission tomography studies with [F-18] MPPF revealing an overexpression of 5-HT1AR in the hippocampus of patients with mild cognitive impairment. Because A beta 40 and A beta 42 isoforms are found in amyloid plaques, we tested in this study the hypothesis of a peptide-and region-specific 5-HT1AR reactivity by injecting them, separately, into the hippocampus or striatum of rats. [F-18] MPPF in vitro autoradiography revealed that A beta 40 fibrils, but not A beta 42, were triggering an overexpression of 5-HT1AR in the hippocampus and striatum of rat brains after 7 days. Immunohistochemical approaches targeting neuronal precursor cells, mature neurons, and astrocytes showed that A beta 42 fibrils caused more pathophysiological damages than A beta 40 fibrils. The mechanisms of A beta 40 fibrilseinduced 5-HT1AR expression remains unknown, but hypotheses including neurogenesis, glial expression, and axonal sprouting are discussed. (C) 2016 Elsevier Inc. All rights reserved. C1 [Verdurand, Mathieu; Chauveau, Fabien; Daoust, Alexia; Morel, Anne-Laure; Berod, Anne; Zimmer, Luc] Univ Lyon, Lyon, France. [Verdurand, Mathieu; Chauveau, Fabien; Daoust, Alexia; Morel, Anne-Laure; Berod, Anne; Zimmer, Luc] CNRS, Lyon Neurosci Res Ctr, UMR5292, Lyon, France. [Verdurand, Mathieu; Chauveau, Fabien; Daoust, Alexia; Morel, Anne-Laure; Berod, Anne; Zimmer, Luc] Univ Lyon 1, INSERM, U1028, F-69365 Lyon, France. [Bonnefoi, Frederic; Liger, Francois; Zimmer, Luc] CERMEP Imaging Platform, Lyon, France. [Zimmer, Luc] Hosp Civils Lyon, Lyon, France. [Daoust, Alexia] NINDS, NIH, LFMI, FMMS, 10 Ctr Dr,Bldg 10,Room 1D48, Bethesda, MD 20892 USA. RP Verdurand, M (reprint author), CERMEP Imagerie Vivant, Equipe BIORAN, Ctr Rech Neurosci Lyon, 59 Blvd Pinel, F-69677 Bron, France. EM verdurand@cermep.fr; zimmer@univ-lyon1.fr RI Chauveau, Fabien/I-9722-2014; OI Chauveau, Fabien/0000-0002-4177-741X; Verdurand, Mathieu/0000-0003-2619-3907 FU Fondation Plan Alzheimer (Paris); LABEX PRIMES of Universite de Lyon, within the program "Investissements d'Avenir" [ANR-11-IDEX-0007]; Fondation Caisse d'Epargne Rhone-Alpes FX Dr. Mathieu Verdurand was supported by a Young Researcher Grant from the Fondation Plan Alzheimer (Paris). Elisabeth Errazuriz-Cerda is acknowledged for her assistance in Transmission Electronic Microscopy acquisition and interpretation (Centre d'Imagerie Quantitative Lyon-Est). Catherine Rey from "ProfileXpert" platform of Lyon 1 University is acknowledged for the qRT-PCR experiments. This work was performed within the framework of the LABEX PRIMES (ANR-11-LABX-0063) of Universite de Lyon, within the program "Investissements d'Avenir" (ANR-11-IDEX-0007) operated by the French National Research Agency (ANR) and thanks to a research grant with Fondation Caisse d'Epargne Rhone-Alpes. NR 63 TC 2 Z9 2 U1 2 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD APR PY 2016 VL 40 BP 11 EP 21 DI 10.1016/j.neurobiolaging.2015.12.008 PG 11 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA DG2OZ UT WOS:000371908400002 PM 26973100 ER PT J AU Cuevas, CA Tapia-Pizarro, A Salvatierra, AM Munroe, DJ Velasquez, L Croxatto, HB AF Cuevas, Catherina A. Tapia-Pizarro, Alejandro Maria Salvatierra, Ana Munroe, David J. Velasquez, Luis Croxatto, Horacio B. TI Effect of single post-ovulatory administration of mifepristone (RU486) on transcript profile during the receptive period in human endometrium SO REPRODUCTION LA English DT Article ID EARLY LUTEAL-PHASE; UTERINE EPITHELIAL PROLIFERATION; HUMAN PROGESTERONE-RECEPTOR; ENDOTHELIAL GROWTH-FACTOR; FACTOR-BINDING PROTEIN-1; GENE-EXPRESSION; MENSTRUAL-CYCLE; INDIAN HEDGEHOG; MOUSE UTERUS; CLINICAL-APPLICATIONS AB Progesterone regulates uterine function during the luteal phase and is essential for the acquisition of endometrial receptivity. The objective of the present study was to identify endometrial transcripts whose expression is altered during the window of implantation after the administration of 200 mg of the antiprogestin mifepristone, 48 h after the LH peak (LH+2, LH+0=LH peak), and to determine the relationship of these transcripts with those regulated during the acquisition of receptivity. Endometrial samples were obtained in LH+7 from seven women of proven fertility, each one contributing with one cycle treated with placebo and another with mifepristone. Additionally, endometrial samples were obtained in LH+2 and LH+7 during a single untreated spontaneous cycle from seven normal fertile women as a reference. DNA microarrays were used to identify transcripts significantly regulated (defined as >= 2.0-fold change with false discovery rate below 1% using t-test) with the administration of mifepristone vs placebo, or during the transition from pre-receptive to receptive (LH+2 vs LH+7). Approximately 2000 transcripts were significantly regulated in both comparisons (mifepristone vs placebo and LH+2 vs LH+7), but only 777 of them were coincident and displayed opposite regulation except for 25. The mRNA level for eight selected genes regulated by mifepristone was confirmed by real-time RT-PCR. We conclude that not all changes in endometrial transcript levels occurring in the transition from LH+2 to LH+7 seem to be regulated by the progesterone receptor and similar to 37% of the genes whose transcript levels changed by effect of mifepristone could be associated with the acquisition of receptivity. C1 [Cuevas, Catherina A.] Univ Santiago Chile, Santiago, Chile. [Tapia-Pizarro, Alejandro] Univ Chile, Inst Maternal & Child Res IDIMI, Santiago, Chile. [Maria Salvatierra, Ana] Inst Chileno Med Reproduct ICMER, Santiago, Chile. [Munroe, David J.] NCI, Lab Mol Technol, Sci Applicat Int Corp, Frederick, MD 21701 USA. [Velasquez, Luis; Croxatto, Horacio B.] Univ Andres Bello, Ctr Integrat Med & Innovat Sci, Fac Med, Santiago, Chile. RP Tapia-Pizarro, A (reprint author), Univ Chile, Inst Maternal & Child Res IDIMI, Santiago, Chile. EM atapiap@med.uchile.cl OI Cuevas, Catherina/0000-0002-6511-4020 FU Millenium Institute for Fundamental and Applied Biology (MIFAB); National Fund for Scientific and Technological Development; Government of Chile (FONDECYT) [11100443, 1140614] FX This work was supported by the Millenium Institute for Fundamental and Applied Biology (MIFAB), the National Fund for Scientific and Technological Development and the Government of Chile (FONDECYT grant numbers 11100443 and 1140614). NR 102 TC 1 Z9 2 U1 0 U2 2 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1470-1626 J9 REPRODUCTION JI Reproduction PD APR PY 2016 VL 151 IS 4 BP 331 EP 349 DI 10.1530/REP-15-0458 PG 19 WC Developmental Biology; Reproductive Biology SC Developmental Biology; Reproductive Biology GA DG5BR UT WOS:000372088100006 PM 26755688 ER PT J AU Siegel, M Masur, H Kovacs, J AF Siegel, Marc Masur, Henry Kovacs, Joseph TI Pneumocystis jirovecii Pneumonia in Human Immunodeficiency Virus Infection SO SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Review DE Pneumocystis jirovecii; pneumonia; acquired immunodeficiency syndrome; human immunodeficiency virus; trimethoprim-sulfamethoxazole ID DIHYDROPTEROATE SYNTHASE GENE; RECONSTITUTION INFLAMMATORY SYNDROME; POLYMERASE-CHAIN-REACTION; ACTIVE ANTIRETROVIRAL THERAPY; PATIENTS RECEIVING INHIBITORS; BRONCHOALVEOLAR LAVAGE FLUID; HIGH-RESOLUTION CT; REAL-TIME PCR; CARINII-PNEUMONIA; TRIMETHOPRIM-SULFAMETHOXAZOLE AB The presentation of Pneumocystis pneumonia (PCP) in previously healthymen having sex with men (MSM) in San Francisco and New York City in 1981 heralded the beginning of the human immunodeficiency virus (HIV) pandemic. Despite a decreasing incidence of PCP among patients with HIV/AIDS (acquired immunodeficiency syndrome) since the advent of combination antiretroviral therapy in the mid-1990s, PCP remains one of the most common AIDS-defining opportunistic infections in the United States and Western Europe. Newer molecular diagnostic tests in conjunction with standard immunofluorescent or colorimetric tests have allowed for more rapid and accurate diagnosis. Although several effective oral and intravenous therapies exist to treat PCP, mortality rates in HIV-infected individuals remain unacceptably high, especially in those with advanced AIDS. The identification of specific mutations in Pneumocystis genes targeted by trimethoprim-sulfamethoxazole has raised concerns about the development of resistance to the drug of choice and may ultimately lead to greater utilization of alternative therapies to treat PCP in the future. C1 [Siegel, Marc] George Washington Univ, Sch Med & Hlth Sci, Div Infect Dis, 2150 Penn Ave NW,Suite 8-436, Washington, DC 20037 USA. [Masur, Henry; Kovacs, Joseph] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Siegel, M (reprint author), George Washington Univ, Sch Med & Hlth Sci, Div Infect Dis, 2150 Penn Ave NW,Suite 8-436, Washington, DC 20037 USA. EM msiegel@mfa.gwu.edu NR 161 TC 1 Z9 1 U1 1 U2 4 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1069-3424 EI 1098-9048 J9 SEMIN RESP CRIT CARE JI Semin. Respir. Crit. Care Med. PD APR PY 2016 VL 37 IS 2 BP 243 EP 256 DI 10.1055/s-0036-1579556 PG 14 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DG4VK UT WOS:000372071000009 PM 26974301 ER PT J AU Beck, DE Lv, W Abdelmalak, M Plescia, CB Agama, K Marchand, C Pommier, Y Cushman, M AF Beck, Daniel E. Lv, Wei Abdelmalak, Monica Plescia, Caroline B. Agama, Keli Marchand, Christophe Pommier, Yves Cushman, Mark TI Synthesis and biological evaluation of new fluorinated and chlorinated indenoisoquinoline topoisomerase I poisons SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Topoisomerase I; Indenoisoquinoline; Anticancer; Cytotoxicity; Tyrosyl DNA phosphodiesterase 1; Tyrosyl DNA phosphodiesterase 2 ID DNA PHOSPHODIESTERASE I; CLEAVAGE COMPLEXES; ANTICANCER AGENTS; NITRATED INDENOISOQUINOLINES; MJ-III-65 NSC-706744; INDIMITECAN LMP776; INDOTECAN LMP400; INHIBITORS; CAMPTOTHECIN; IDENTIFICATION AB Fluorine and chlorine are metabolically stable, but generally less active replacements for a nitro group at the 3-position of indenoisoquinoline topoisomerase IB (Top1) poisons. A number of strategies were employed in the present investigation to enhance the Top1 inhibitory potencies and cancer cell growth inhibitory activities of halogenated indenoisoquinolines. In several cases, the new compounds' activities were found to rival or surpass those of similarly substituted 3-nitroindenoisoquinolines, and several unusually potent analogs were discovered through testing in human cancer cell cultures. A hydroxyethylaminopropyl side chain on the lactam nitrogen of two halogenated indenoisoquinoline Top1 inhibitors was found to also impart inhibitory activity against tyrosyl DNA phosphodiesterases 1 and 2 (TDP1 and TDP2), which are enzymes that participate in the repair of DNA damage induced by Top1 poisons. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Beck, Daniel E.; Lv, Wei; Cushman, Mark] Purdue Univ, Coll Pharm, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. [Beck, Daniel E.; Lv, Wei; Cushman, Mark] Purdue Univ, Purdue Ctr Canc Res, W Lafayette, IN 47907 USA. [Abdelmalak, Monica; Plescia, Caroline B.; Agama, Keli; Marchand, Christophe; Pommier, Yves] NCI, Dev Therapeut Branch, Bethesda, MD 21892 USA. [Abdelmalak, Monica; Plescia, Caroline B.; Agama, Keli; Marchand, Christophe; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 21892 USA. RP Cushman, M (reprint author), Purdue Univ, Coll Pharm, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA.; Cushman, M (reprint author), Purdue Univ, Purdue Ctr Canc Res, W Lafayette, IN 47907 USA. EM cushman@purdue.edu FU National Institutes of Health (NIH) [U01CA089566, P30CA023168]; Developmental Therapeutics Program at National Cancer Institute [NO1-CO-56000]; NIH Intramural Research Program [Z01 BC006161] FX This work was made possible by the National Institutes of Health (NIH) through support with Research Grants U01CA089566 and P30CA023168. In vitro cytotoxicity testing was performed by the Developmental Therapeutics Program at the National Cancer Institute, under contract NO1-CO-56000. Work done in the NCI Intramural Program, Center for Cancer Research was supported by the NIH Intramural Research Program (Z01 BC006161). NR 37 TC 2 Z9 2 U1 4 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 EI 1464-3391 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD APR 1 PY 2016 VL 24 IS 7 BP 1469 EP 1479 DI 10.1016/j.bmc.2016.02.015 PG 11 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA DG0RC UT WOS:000371772300006 PM 26906474 ER PT J AU Kable, JA O'Connor, MJ Olson, HC Paley, B Mattson, SN Anderson, SM Riley, EP AF Kable, Julie A. O'Connor, Mary J. Olson, Heather Carmichael Paley, Blair Mattson, Sarah N. Anderson, Sally M. Riley, Edward P. TI Neurobehavioral Disorder Associated with Prenatal Alcohol Exposure (ND-PAE): Proposed DSM-5 Diagnosis SO CHILD PSYCHIATRY & HUMAN DEVELOPMENT LA English DT Review DE ND-PAE; Fetal alcohol spectrum disorders; Prenatal alcohol exposure; Psychiatric diagnosis ID ATTENTION-DEFICIT-HYPERACTIVITY; ATTENUATES BEHAVIORAL ALTERATIONS; MATERNAL RISK-FACTORS; FETAL ALCOHOL; SPECTRUM DISORDERS; ETHANOL EXPOSURE; EXECUTIVE FUNCTION; SOUTH-AFRICA; YOUNG-ADULT; DEFICIT/HYPERACTIVITY DISORDER AB Over the past 40 years, a significant body of animal and human research has documented the teratogenic effects of prenatal alcohol exposure (PAE). Neurobehavioral Disorder associated with PAE is proposed as a new clarifying term, intended to encompass the neurodevelopmental and mental health symptoms associated with PAE. Defining this disorder is a necessary step to adequately characterize these symptoms and allow clinical assessment not possible using existing physically-based diagnostic schemes. Without appropriate diagnostic guidelines, affected individuals are frequently misdiagnosed and treated inappropriately (often to their considerable detriment) by mental health, educational, and criminal justice systems. Three core areas of deficits identified from the available research, including neurocognitive, self-regulation, and adaptive functioning impairments, are discussed and information regarding associated features and disorders, prevalence, course, familial patterns, differential diagnosis, and treatment of the proposed disorder are also provided. C1 [Kable, Julie A.] Emory Univ, Sch Med, Dept Psychiat & Behav Sci, Atlanta, GA 30329 USA. [Kable, Julie A.] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA 30329 USA. [O'Connor, Mary J.; Paley, Blair] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA 90095 USA. [Olson, Heather Carmichael] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Mattson, Sarah N.; Riley, Edward P.] San Diego State Univ, Ctr Behav Teratol, Dept Psychol, San Diego, CA 92120 USA. [Anderson, Sally M.] NIAAA, Bethesda, MA USA. RP Kable, JA (reprint author), Emory Univ, Sch Med, Dept Psychiat & Behav Sci, Atlanta, GA 30329 USA.; Kable, JA (reprint author), Emory Univ, Sch Med, Dept Pediat, Atlanta, GA 30329 USA. EM jkabl01@emory.edu RI Mattson, Sarah/G-5344-2011; OI Mattson, Sarah/0000-0001-8499-9605; Kable, Julie/0000-0001-5008-0887 NR 157 TC 7 Z9 7 U1 8 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-398X EI 1573-3327 J9 CHILD PSYCHIAT HUM D JI Child Psychiat. Hum. Dev. PD APR PY 2016 VL 47 IS 2 BP 335 EP 346 DI 10.1007/s10578-015-0566-7 PG 12 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA DF8KN UT WOS:000371606700016 PM 26202432 ER PT J AU Gardner, TW Chew, EY AF Gardner, Thomas W. Chew, Emily Y. TI Future opportunities in diabetic retinopathy research SO CURRENT OPINION IN ENDOCRINOLOGY DIABETES AND OBESITY LA English DT Review DE intraocular drug delivery; metabolism; diabetic retinopathy; neurodegeneration ID BLOOD-GLUCOSE CONTROL; RANDOMIZED CLINICAL-TRIAL; MACULAR EDEMA; COMPLICATIONS TRIAL; RETINAL VASODILATOR; GLYCEMIC CONTROL; C-PEPTIDE; PROGRESSION; RANIBIZUMAB; DYSFUNCTION AB Purpose of review The risk of vision loss from diabetic retinopathy has fallen dramatically over the past 3 decades with improvements in diabetes and blood pressure treatments, and with advances in laser surgery and intraocular drug delivery. Nevertheless, diabetes continues to be a major cause of blindness. This study summarizes the state of the art in diabetic retinopathy research and provides a perspective on opportunities for future investigations. Recent findings New insights into the pathophysiology of diabetes and diabetic retinopathy will improve metabolic control. Structure-function analyses are revealing new details of diabetic retinopathy. Intraocular drug therapy provides improved visual outcomes. Together these steps will yield better means to detect and quantify vision loss, and to develop patient-specific treatments to preserve vision for persons with diabetes. Retinopathy is one of the most successfully treated complications of diabetes and will continue to be an important area of research for patients and their families. C1 [Gardner, Thomas W.] Univ Michigan, Sch Med, Dept Ophthalmol & Visual Sci, WK Kellogg Eye Ctr, 1000 Wall St, Ann Arbor, MI 48105 USA. [Chew, Emily Y.] NEI, Bethesda, MD 20892 USA. RP Gardner, TW (reprint author), Univ Michigan, Sch Med, Dept Ophthalmol & Visual Sci, WK Kellogg Eye Ctr, 1000 Wall St, Ann Arbor, MI 48105 USA. EM tomwgard@umich.edu OI Gardner, Thomas/0000-0002-5112-5810 FU JDRF; A. Alfred Taubman Medical Research Institute at the University of Michigan; [R01EY20582]; [DP3DK094292] FX This work was supported by R01EY20582, DP3DK094292, JDRF, and the A. Alfred Taubman Medical Research Institute at the University of Michigan (T.W.G.). NR 66 TC 0 Z9 0 U1 2 U2 15 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1752-296X EI 1752-2978 J9 CURR OPIN ENDOCRINOL JI Curr. Opin. Endocrinol. Diabetes Obes. PD APR PY 2016 VL 23 IS 2 BP 91 EP 96 DI 10.1097/MED.0000000000000238 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DF7OL UT WOS:000371546900001 PM 26915035 ER PT J AU Kreitchmann, R Coelho, DF Kakehasi, FM Hofer, CB Read, JS Losso, M Haberer, JE Siberry, GK Harris, DR Yu, QL AF Kreitchmann, Regis Coelho, Debora Fernandes Kakehasi, Fabiana Maria Hofer, Cristina Barroso Read, Jennifer S. Losso, Marcelo Haberer, Jessica E. Siberry, George K. Harris, D. Robert Yu, Qilu TI Long-term postpartum adherence to antiretroviral drugs among women in Latin America SO INTERNATIONAL JOURNAL OF STD & AIDS LA English DT Article DE HIV; AIDS; treatment; women; antiretroviral; adherence; postpartum; mother-to-child transmission ID HUMAN-IMMUNODEFICIENCY-VIRUS; SELF-REPORTED ADHERENCE; TO-CHILD TRANSMISSION; HIV-INFECTED PATIENTS; MEDICATION ADHERENCE; THERAPY ADHERENCE; INTERAGENCY HIV; PREGNANT-WOMEN; UNITED-STATES; METAANALYSIS AB Antiretroviral adherence in the postpartum period is crucial for maternal health and decreasing the risk of mother-to-child HIV transmission and transmission to sexual partners. Self-reported antiretroviral adherence was examined between 6- to 12-weeks and 30 months postpartum among 270 HIV-infected women enrolled in a prospective cohort study from 2008 to 2010 at multiple sites in Latin America. Adherence data were collected at each study visit to quantify the proportion of prescribed antiretrovirals taken during the previous three days, assess the timing of the last missed dose, and identify predictors of adherence. Mean adherence rates were 89.5% at 6-12 weeks and 92.4% at 30 months; the proportions with perfect adherence were 80.3% and 83.6%, respectively. The overall trend for perfect adherence was not significant (p=0.71). In adjusted regression modelling, younger age was associated with an increased probability of non-perfect adherence at 18 and 24 months postpartum. Other factors associated with increased probability of non-perfect adherence were higher parity, current use of alcohol and tobacco, and more advanced HIV disease. Women with perfect adherence had lower viral loads. Interventions for alcohol and tobacco use cessation, and support for young women and those with advanced HIV disease should be considered to improve postpartum adherence. C1 [Kreitchmann, Regis; Coelho, Debora Fernandes] Irmandade Santa Casa Misericordia Porto Alegre, Prof Annes Dias 285, BR-90020090 Porto Alegre, RS, Brazil. [Kreitchmann, Regis; Coelho, Debora Fernandes] Univ Fed Ciencias Saude Porto Alegre, Porto Alegre, RS, Brazil. [Kakehasi, Fabiana Maria] Univ Fed Minas Gerais, Belo Horizonte, MG, Brazil. [Hofer, Cristina Barroso] Univ Fed Rio de Janeiro, Inst Puericultura & Pediat Martagao Gesteira, Rio De Janeiro, Brazil. [Hofer, Cristina Barroso] Univ Fed Rio de Janeiro, Dept Prevent Med, Rio De Janeiro, Brazil. [Read, Jennifer S.; Siberry, George K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, Bethesda, MD USA. [Read, Jennifer S.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Losso, Marcelo] Hosp Gen Agudos Jose Maria Ramos Mejia, Buenos Aires, DF, Argentina. [Haberer, Jessica E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Harris, D. Robert; Yu, Qilu] WESTAT Corp, Rockville, MD 20850 USA. RP Kreitchmann, R (reprint author), Irmandade Santa Casa Misericordia Porto Alegre, Prof Annes Dias 285, BR-90020090 Porto Alegre, RS, Brazil. EM regis.kr@terra.com.br OI Harris, Donald/0000-0002-8262-3716 FU NICHD [N01-HD-3-3345, HHSN267200800001C, HHSN275201300003C] 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 NICHD Contracts N01-HD-3-3345 (2002-2007), HHSN267200800001C (2007-2012), and HHSN275201300003C (2012-2017). NR 34 TC 1 Z9 1 U1 2 U2 6 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0956-4624 EI 1758-1052 J9 INT J STD AIDS JI Int. J. STD AIDS PD APR PY 2016 VL 27 IS 5 BP 377 EP 386 DI 10.1177/0956462415584483 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DF8SO UT WOS:000371629200006 PM 25931238 ER PT J AU Sui, YJ Lee, EM Wang, YC Hogg, A Frey, B Venzon, D Pal, R Berzofsky, JA AF Sui, Yongjun Lee, Eun Mi Wang, Yichuan Hogg, Alison Frey, Blake Venzon, David Pal, Ranajit Berzofsky, Jay A. TI Early SIV Dissemination After Intrarectal SIVmac251 Challenge Was Associated With Proliferating Virus-Susceptible Cells in the Colorectum SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE intrarectal inoculation; viral target cells; viral loads; eclipse time; SIV; AIDS virus transmission ID SIMIAN/HUMAN IMMUNODEFICIENCY VIRUS; HIV-1 INFECTION; TYPE-1 INFECTION; RHESUS MACAQUES; TRANSMISSION; ACTIVATION; VACCINE; REPLICATION; MONKEYS AB Objective: Few studies have examined the eclipse time of simian immunodeficiency virus/HIV infection through the anal route. We aimed to measure the eclipse time after SIVmac251 intrarectal inoculation, and to investigate the factor(s) associated with early dissemination. Design: Forty macaques were intrarectally challenged with SIVmac251 3 times at 2-week intervals. Methods: Plasma viral RNA was monitored at 4, 7, 11, 14, 21, and 28 days after infection. Rectal/vaginal tissues were obtained and tissue viral loads (VLs) were measured at day 14 postinfection. Results: Of 40 macaques 26 (65%) had first detectable viral RNAs in the plasma at day 7 after the challenge that led to productive infection. Strikingly, 6 animals (15%) had detectable viral RNA in the plasma as early as at day 4. The Ki67(+) viral target CD4(+) T cells in the colorectal tissues were significantly higher in the early or middle-transmitter groups than those in the late-transmitter group. The rectal VL did not correlate with plasma VL at 14-day postinoculation, but did positively correlate with plasma VLs at days 21 and 28 postinfection. Conclusions: The median eclipse time after intrarectal challenge was 7 days, with a few early transmitters at 4 days. More rapid viral dissemination was associated with a high frequency of colorectal Ki67(+)CCR5(+)CD4(+)T cells, which fuel the local viral replication. Furthermore, local viral replication in the colorectal tissue during the early stage might affect the plasma VL in a delayed manner. Therefore, to reduce/limit these target cells at the portal of viral entry is essential. C1 [Sui, Yongjun; Wang, Yichuan; Hogg, Alison; Frey, Blake; Berzofsky, Jay A.] NCI, NIH, Vaccine Branch, 41 Medlars Dr, Bethesda, MD 20892 USA. [Lee, Eun Mi; Pal, Ranajit] Adv BioSci Labs Inc, Rockville, MD USA. [Venzon, David] NCI, NIH, Biostat & Data Management Sect, Bethesda, MD 20892 USA. RP Sui, YJ (reprint author), NCI, NIH, Vaccine Branch, 41 Medlars Dr, Bethesda, MD 20892 USA. EM suiy@mail.nih.gov FU NCI [ZO1 SC 004020] FX J.A.B. is currently receiving NCI intramural funding ZO1 SC 004020, this work was performed under contract awarded to Advanced BioScience Labs, Inc. The remaining authors have no funding or conflicts of interest to disclose. NR 20 TC 1 Z9 1 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD APR 1 PY 2016 VL 71 IS 4 BP 353 EP 358 DI 10.1097/QAI.0000000000000890 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DG0II UT WOS:000371748100001 PM 26545123 ER PT J AU Hattori, J Shiino, T Gatanaga, H Mori, H Minami, R Uchida, K Sadamasu, K Kondo, M Sugiura, W AF Hattori, Junko Shiino, Teiichiro Gatanaga, Hiroyuki Mori, Haruyo Minami, Rumi Uchida, Kazue Sadamasu, Kenji Kondo, Makiko Sugiura, Wataru CA Japanese Drug Resistance HIV-1 Sur TI Characteristics of Transmitted Drug-Resistant HIV-1 in Recently Infected Treatment-Naive Patients in Japan SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE Japan; BED assay; recent infection; transmitted drug-resistant HIV ID CAPTURE ENZYME-IMMUNOASSAY; ANTIRETROVIRAL THERAPY; MUTATIONS; SURVEILLANCE; INDIVIDUALS; PREVALENCE; ADHERENCE; SELECTION; HAART AB Objectives: Progress in antiretroviral treatment has led to fewer virological failure cases, but 10%-20% of treatment-naive HIV/AIDS cases are reported to harbor drug-resistant strains, suggesting transmission of drug-resistant HIV. We aimed to determine the trend in prevalence of transmitted drug-resistant (TDR) HIV in Japan, particularly in recently infected patients. Methods: Drug-resistance test was performed on 3904 HIV-1-infected cases newly diagnosed between 2007 and 2012. The number of cases infected within 6 months [recent seroconverters (RS)] was estimated by BED assay of 2700 plasma samples. Characteristics of RS cases were further analyzed. Results: The overall prevalence of TDR was 9.1%, ranging from 7.3% in 2008% to 12.5% in 2010. Among 1403 subtype B/E/D cases with >50 CD4(+) T cell counts and >1000 HIV copies per milliliter, 468 (33.4%) were estimated to be RS. The prevalence of RS was significantly higher among cases who were male, Japanese, and men who have sex with men. The prevalence of TDR did not differ significantly between recent and long-term seroconverters (8.5% vs. 9.2%, respectively, P = 0.68). Common mutations in both groups were M46I/L and T215 revertants. Furthermore, sequences with these mutations, K103N and D30N/N88D formed clusters on phylogenetic trees. Conclusion: Our study clarified an increase in prevalence of TDR in Japan from 2007 to 2012. The phylogenetic clustering of cases with M46I/L or T215 revertants suggests that HIV with these mutations have become circulating strains. Furthermore, detailed analyses showed that Japanese men who have sex with men are more aware of their risk of HIV infection. C1 [Hattori, Junko; Sugiura, Wataru] Natl Hosp Org, Nagoya Med Ctr, Clin Res Ctr, Nagoya, Aichi, Japan. [Hattori, Junko] NCI, NIH, HIV Dynam & Replicat Program, Bethesda, MD 20892 USA. [Shiino, Teiichiro] Natl Inst Infect Dis, Infect Dis Surveillance Ctr, Tokyo, Japan. [Gatanaga, Hiroyuki] Natl Ctr Global Hlth & Med, Tokyo, Japan. [Mori, Haruyo] Osaka Prefectural Inst Publ Hlth, Osaka 537, Japan. [Minami, Rumi] Natl Hosp Org, Kyushu Med Ctr, Fukuoka, Japan. [Uchida, Kazue] Saitama Inst Publ Hlth, Tokyo, Japan. [Sadamasu, Kenji] Tokyo Metropolitan Inst Publ Hlth, Tokyo, Japan. [Kondo, Makiko] Kanagawa Prefectural Inst Publ Hlth, 1-3-1 Shimomachiya, Chigasaki, Kanagawa 2530087, Japan. [Sugiura, Wataru] Nagoya Univ, Grad Sch Med, Div Basic Med, Nagoya, Aichi 4648601, Japan. [Sugiura, Wataru] GlaxoSmithKline KK, Tokyo, Japan. RP Sugiura, W (reprint author), 4-6-15 Sendagaya, Tokyo 1518566, Japan. EM wataru.2.sugiura@gsk.com FU Ministry of Health, Labour and Welfare of Japan [H25-AIDS-004] FX Supported by a Grant-in-Aid for AIDS research from the Ministry of Health, Labour and Welfare of Japan (H25-AIDS-004). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the article. NR 30 TC 0 Z9 0 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD APR 1 PY 2016 VL 71 IS 4 BP 367 EP 373 DI 10.1097/QAI.0000000000000861 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DG0II UT WOS:000371748100003 PM 26428230 ER PT J AU Chen, M Jen, I Sharp, GB Chen, YMA AF Chen, Marcelo Jen, Ian Sharp, Gerald B. Chen, Yi-Ming Arthur TI The Incidence Rates and Standardized Incidence Ratios of Cancer in Hemophilic HIV/AIDS Patients in Taiwan SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Letter ID ANTIRETROVIRAL THERAPY; MORTALITY; DEATH C1 [Chen, Marcelo; Jen, Ian; Chen, Yi-Ming Arthur] Kaohsiung Med Univ, Ctr Infect Dis & Canc Res, Kaohsiung, Taiwan. [Chen, Marcelo] Mackay Mem Hosp, Dept Urol, Taipei, Taiwan. [Chen, Marcelo] Mackay Jr Coll Med Nursing & Management, Dept Cosmet Applicat & Management, Taipei, Taiwan. [Jen, Ian] Natl Yang Ming Univ, Dept & Inst Publ Hlth, Taipei 112, Taiwan. [Sharp, Gerald B.] NIAID, Epidemiol Branch, Basic Sci Program,Div AIDS, Natl Inst Hlth, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Chen, Yi-Ming Arthur] Kaohsiung Med Univ, Dept Microbiol, Kaohsiung, Taiwan. [Chen, Yi-Ming Arthur] Kaohsiung Med Univ, Inst Med Res, Coll Med, Kaohsiung, Taiwan. RP Chen, M (reprint author), Kaohsiung Med Univ, Ctr Infect Dis & Canc Res, Kaohsiung, Taiwan. FU NIAID NIH HHS [U01AI069907, U01 AI069907] NR 16 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD APR 1 PY 2016 VL 71 IS 4 BP e114 EP e115 DI 10.1097/QAI.0000000000000903 PG 2 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DG0IJ UT WOS:000371748200004 PM 26579984 ER PT J AU Brown, VB Oluwatosin, OA Akinyemi, JO Adeyemo, AA AF Brown, V. B. Oluwatosin, O. A. Akinyemi, J. O. Adeyemo, A. A. TI Effects of Community Health Nurse-Led Intervention on Childhood Routine Immunization Completion in Primary Health Care Centers in Ibadan, Nigeria SO JOURNAL OF COMMUNITY HEALTH LA English DT Article DE Cellphone reminder/recall; Childhood; Immunization; Vaccine-preventable-diseases ID ADOLESCENT IMMUNIZATIONS; INFLUENZA VACCINATION; RATES; POPULATION; COVERAGE; CHILDREN; TRIAL AB Immunization coverage of vulnerable children is often sub-optimal in many low- and middle-income countries. The use of a reminder/recall (R/R) system has been one of the strategies shown to be effective in improving immunization rates. In the resent study, we evaluated the effect of R/R and Primary Health Care Immunization Providers' Training (PHCIPT) intervention on routine immunization completion among 595 infants in Ibadan, Nigeria. The design was a group randomized controlled trial with Local Government Area (LGA) being the unit of randomization. Four randomly selected LGAs were randomized to receive a cellphone R/R only (A), a PHCIPT only (B); combined R/R and PHCIPT (C) intervention or serve as a control group (D). Children aged 0-12 weeks were consecutively recruited into each group and followed up for 12 months. The primary outcome measure was routine immunization completion at 12 months of age. At the study endpoint, immunization completion rates were: group A, 98.6 %; group B, 70 %; group C, 97.3 %; and group D, 57.3 %. Compared to the control group, the cellphone R/R group was 72 % (RR 1.72, 95 % CI 1.50-1.98) and the combined RR/PHCIPT group 70 % (RR 1.70, 95 % CI 1.47-1.95) more likely to complete immunization. In contrast, immunization completion in the PHCIPT group was marginally different from the control group (RR 1.22, 95 % CI 1.03-1.45). These findings remained robust to adjustment for potential predictors of immunization completion as covariates. In conclusion, cellphone reminder/recall was effective in improving immunization completion in this Nigerian setting. Its use is recommended for large scale implementation. C1 [Brown, V. B.] Univ Coll Hosp, Sch Nursing, Ibadan, Nigeria. [Oluwatosin, O. A.] Univ Ibadan, Dept Nursing, Fac Clin Sci, Coll Med, Ibadan, Nigeria. [Akinyemi, J. O.] Univ Ibadan, Fac Publ Hlth, Dept Epidemiol & Biostat, Coll Med, Ibadan, Nigeria. [Adeyemo, A. A.] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Brown, VB (reprint author), Univ Coll Hosp, Sch Nursing, Ibadan, Nigeria. EM vicbrown2010@gmail.com RI Emchi, Karma/Q-1952-2016; OI Brown, Victoria/0000-0001-6601-4307 NR 29 TC 1 Z9 1 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0094-5145 EI 1573-3610 J9 J COMMUN HEALTH JI J. Community Health PD APR PY 2016 VL 41 IS 2 BP 265 EP 273 DI 10.1007/s10900-015-0092-3 PG 9 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA DG0ZB UT WOS:000371793700009 PM 26395786 ER PT J AU Akinyemiju, T Waterbor, JW Pisu, M Moore, JX Altekruse, SF AF Akinyemiju, Tomi Waterbor, John W. Pisu, Maria Moore, Justin Xavier Altekruse, Sean F. TI Availability of Healthcare Resources and Colorectal Cancer Outcomes Among Non-Hispanic White and Non-Hispanic Black Adults SO JOURNAL OF COMMUNITY HEALTH LA English DT Article DE Colorectal cancer; Healthcare access; Disparities; Residential area; Cancer ID SOCIOECONOMIC-STATUS; ETHNIC DISPARITIES; ACCESS; MORTALITY; SYSTEM; AREA; ASSOCIATION; RACE; SATISFACTION; MAMMOGRAPHY AB This study aims to examine if access to healthcare, measured through the availability of medical resources at the neighborhood level, influences colorectal cancer (CRC) stage, treatment and survival using the Surveillance Epidemiology and Ends Result (SEER) dataset (November 2012), linked with the 2004 Area Resource File. A cross-sectional study was conducted to determine the association between availability of healthcare resources and CRC outcomes among non-Hispanic Black (n = 9162) and non-Hispanic White patients (n = 97,264). CRC patients were identified using the SEER*Stat program, and individual socio-demographic, clinical, and county-level healthcare access variables were obtained for each patient. Among NH-W patients, residence in counties with lower number of oncology hospitals was associated with increased odds of late stage diagnosis (OR 1.09, 95 % CI 1.04-1.14), reduced odds of receiving surgery (OR 0.83, 95 % CI 0.74-0.92) and higher hazard rates (HR 1.09, 95 % CI 1.06-1.12). There were no significant associations among NH-B patients. Increased availability of healthcare resources improves CRC outcomes among NH-W patients. However, future studies are required to better understand healthcare utilization patterns in NH-B neighborhoods, and identify other important dimensions of healthcare access such as affordability, acceptability and accommodation. C1 [Akinyemiju, Tomi; Waterbor, John W.; Moore, Justin Xavier] Univ Alabama Birmingham, Dept Epidemiol, 1720 2nd Ave S RPHB Rm 210, Birmingham, AL 35294 USA. [Akinyemiju, Tomi; Waterbor, John W.] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35294 USA. [Pisu, Maria] Univ Alabama Birmingham, Div Prevent Med, Birmingham, AL 35294 USA. [Moore, Justin Xavier] Univ Alabama Birmingham, Dept Emergency Med, Birmingham, AL 35294 USA. [Altekruse, Sean F.] NCI, Canc Stat Branch, Div Canc Control & Populat Sci, Bethesda, MD USA. RP Akinyemiju, T (reprint author), Univ Alabama Birmingham, Dept Epidemiol, 1720 2nd Ave S RPHB Rm 210, Birmingham, AL 35294 USA.; Akinyemiju, T (reprint author), Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35294 USA. EM tomiakin@uab.edu OI Moore, Justin/0000-0002-5496-752X FU NCI NIH HHS [U54 CA118948] NR 31 TC 0 Z9 0 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0094-5145 EI 1573-3610 J9 J COMMUN HEALTH JI J. Community Health PD APR PY 2016 VL 41 IS 2 BP 296 EP 304 DI 10.1007/s10900-015-0096-z PG 9 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA DG0ZB UT WOS:000371793700013 PM 26446012 ER PT J AU Sepanlou, SG Sharafkhah, M Poustchi, H Malekzadeh, MM Etemadi, A Khademi, H Islami, F Pourshams, A Pharoah, PD Abnet, CC Brennan, P Boffetta, P Dawsey, SM Esteghamati, A Kamangar, F Malekzadeh, R AF Sepanlou, S. G. Sharafkhah, M. Poustchi, H. Malekzadeh, M. M. Etemadi, A. Khademi, H. Islami, F. Pourshams, A. Pharoah, P. D. Abnet, C. C. Brennan, P. Boffetta, P. Dawsey, S. M. Esteghamati, A. Kamangar, F. Malekzadeh, R. TI Hypertension and mortality in the Golestan Cohort Study: A prospective study of 50 000 adults in Iran SO JOURNAL OF HUMAN HYPERTENSION LA English DT Article ID CORONARY HEART-DISEASE; COMPARATIVE RISK-ASSESSMENT; DIASTOLIC BLOOD-PRESSURE; PULSE PRESSURE; ESOPHAGEAL CANCER; GLOBAL BURDEN; CARDIOVASCULAR-DISEASES; PRACTICE GUIDELINES; NORTHERN IRAN; PREVALENCE AB High blood pressure has been the second most important determinant of disease burden in Iran since the 1990s. Despite well-recognized evidence on the association of high blood pressure and mortality in other countries, this relationship has not been fully investigated in the demographic setting of Iran. The current study is the first large-scale longitudinal study of this association in Iran. Briefly, 50 045 subjects between 40 and 75 years of age have been recruited and followed. Blood pressure measurements were carried out at baseline. Causes of death were reported and verified by verbal autopsy throughout the follow-up period. The outcomes of interest were all-cause deaths and deaths due to ischemic heart disease (IHD) or stroke. Cox proportional hazards regression models were used to estimate hazard ratios (HRs). A total of 46 674 subjects free from cardiovascular disease at baseline were analyzed. Absolute mortality rates increased along with increasing systolic or diastolic blood pressure above 120 and 80mmHg, respectively. Adjusted HRs (95% confidence intervals) for each 20 mmHg increase in systolic blood pressure in all age groups were 1.18 (1.13-1.23) for all-cause mortality, 1.21 (1.13-1.31) for deaths due to IHD and 1.50 (1.39-1.63) for deaths due to stroke. Unadjusted and adjusted HRs were higher in younger subjects and decreased with increasing age of the participants. High blood pressure is a serious threat to the health of Iranians. The entire health-care system of Iran should be involved in a comprehensive action plan for controlling blood pressure. C1 [Sepanlou, S. G.; Sharafkhah, M.; Poustchi, H.; Malekzadeh, M. M.; Etemadi, A.; Khademi, H.; Islami, F.; Pourshams, A.; Kamangar, F.; Malekzadeh, R.] Univ Tehran Med Sci, Shariati Hosp, Digest Dis Res Inst, Tehran 1411713135, Iran. [Etemadi, A.; Abnet, C. C.; Dawsey, S. M.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Islami, F.] Amer Canc Soc, Surveillance & Hlth Serv Res, Atlanta, GA 30329 USA. [Pharoah, P. D.] Univ Cambridge, Dept Oncol, Cambridge, England. [Pharoah, P. D.] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Brennan, P.] Int Agcy Res Canc, 150 Cours Albert Thomas, F-69372 Lyon, France. [Boffetta, P.] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA. [Boffetta, P.] Icahn Sch Med Mt Sinai, Inst Translat Epidemiol, New York, NY 10029 USA. [Esteghamati, A.] Univ Tehran Med Sci, Vali Asr Hosp, Endocrinol & Metab Res Ctr, Tehran 1411713135, Iran. [Kamangar, F.] Morgan State Univ, Dept Publ Hlth Anal, Sch Community Hlth & Policy, Baltimore, MD 21239 USA. RP Malekzadeh, R (reprint author), Univ Tehran Med Sci, Digest Dis Res Inst, Med, Shariati Hosp, Tehran 1411713135, Iran. EM dr.reza.malekzadeh@gmail.com RI Sepanlou, Sadaf/H-9343-2016; Abnet, Christian/C-4111-2015 OI Sepanlou, Sadaf/0000-0002-3669-5129; Abnet, Christian/0000-0002-3008-7843 FU Division of Cancer Epidemiology and Genetics of the National Cancer Institute, NIH; Digestive Disease Research Institute of Tehran University of Medical Sciences [82-603]; Cancer Research UK (CRUK); International Agency for Research on Cancer FX This study was supported in part by the intramural research program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute, NIH, by the Digestive Disease Research Institute of Tehran University of Medical Sciences (grant No 82-603), by Cancer Research UK (CRUK) and by the International Agency for Research on Cancer. We sincerely thank the Golestan Cohort study staff for their valuable helps. We also thank the study participants for their cooperation and health workers (Behvarz) in the study area for their help. NR 35 TC 2 Z9 2 U1 4 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9240 EI 1476-5527 J9 J HUM HYPERTENS JI J. Hum. Hypertens. PD APR PY 2016 VL 30 IS 4 SI SI BP 260 EP 267 DI 10.1038/jhh.2015.57 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DG1BQ UT WOS:000371800500009 PM 26063561 ER PT J AU Berlin, I Singleton, EG Heishman, SJ AF Berlin, Ivan Singleton, Edward G. Heishman, Stephen J. TI Craving and Withdrawal Symptoms During Smoking Cessation: Comparison of Pregnant and Non-Pregnant Smokers SO JOURNAL OF SUBSTANCE ABUSE TREATMENT LA English DT Article DE Pregnant smokers; Non-pregnant female smokers; Craving to smoke; Withdrawal symptoms; Smoking cessation ID NICOTINE DEPENDENCE; TOBACCO WITHDRAWAL; FAGERSTROM TEST; CIGARETTE DEPENDENCE; PARENTAL SMOKING; FRENCH VERSION; QUESTIONNAIRE; INTERVENTIONS; EXPOSURE; COTININE AB Although pregnant smokers are aware of the negative peri- and postnatal health consequences of smoking, the cessation rate in pregnancy is low, raising the question of why pregnant smokers have difficulty quitting. Reasons might be that pregnant smokers experience more intense craving and withdrawal symptoms than non-pregnant smokers. We compared craving and withdrawal in 306 pregnant smokers versus 93 non-pregnant women using data from two smoking cessation trials. Complete data were analyzed using pre-quit and post-quit (2 weeks after quit date) craving and withdrawal measured by the 12-item French Tobacco Craving Questionnaire (FTCQ-12) and French Minnesota Nicotine Withdrawal Scale (FMNWS). Pregnant smokers started smoking and smoked regularly earlier and succeeded far less at quitting smoking by week 2 than the general population of smokers (11% versus 43%). Post-quit date FTCQ-12 general score was higher in pregnant smokers compared to comparison groups, and was driven by elevated emotionality and expectancy. FMNWS decreased significantly less among pregnant smokers than among non-pregnant smokers. Insufficient reduction of craving and withdrawal symptoms in response to a quit attempt may partially explain why pregnant smokers may have more difficulty quitting than non-pregnant smokers. Because this was a historical comparison, findings are preliminary; however, they might foster further investigation of differences in craving and withdrawal symptoms in pregnant versus non-pregnant smokers. (C) 2015 Elsevier Inc. All rights reserved. C1 [Berlin, Ivan] Univ Paris 06, Hop La Pitie Salpetriere, AP HP, Fac Med,INSERM,U1178, Paris, France. [Singleton, Edward G.] Interact Profess Serv, Catonsville, MD USA. [Heishman, Stephen J.] NIDA, Intramural Res Program, NIH, Baltimore, MD USA. RP Berlin, I (reprint author), Hop La Pitie Salpetriere, Dept Pharmacol, 47 Bd Hop, F-75013 Paris, France. EM ivan.berlin@aphp.fr FU French Ministry of Health Programme Hospitalier de Recherche Clinique Loco-regional [AOR04001//P040406, 050558]; Agence francaise de securite sanitaire des produits de sante, Convention Pharmacologie Clinique et Therapeutique [RAF02020]; Ministry of Health, France [MA05 001050]; National Institute on Drug Abuse, Intramural Research Program FX The ADONIS study was supported by the French Ministry of Health Programme Hospitalier de Recherche Clinique Loco-regional 2004 (AOR04001//P040406, registration number: 050558) by the Agence francaise de securite sanitaire des produits de sante, Convention Pharmacologie Clinique et Therapeutique 2003, RAF02020. The SNIPP study was funded by the Ministry of Health, France, Grant Number MA05 001050. E. G. Singleton was partly funded by the same research grant. S. J. Heishman was supported by the National Institute on Drug Abuse, Intramural Research Program. The funding sources had no other role than financial support. NR 53 TC 0 Z9 0 U1 2 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0740-5472 J9 J SUBST ABUSE TREAT JI J. Subst. Abus. Treat. PD APR PY 2016 VL 63 BP 18 EP 24 DI 10.1016/j.jsat.2015.12.008 PG 7 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA DG0KA UT WOS:000371752500003 PM 26806411 ER PT J AU You, IJ Wright, SR Garcia-Garcia, AL Tapper, AR Gardner, PD Koob, GF Leonardo, ED Bohn, LM Wee, S AF You, In-Jee Wright, Sherie R. Garcia-Garcia, Alvaro L. Tapper, Andrew R. Gardner, Paul D. Koob, George F. Leonardo, E. David Bohn, Laura M. Wee, Sunmee TI 5-HT1A Autoreceptors in the Dorsal Raphe Nucleus Convey Vulnerability to Compulsive Cocaine Seeking SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID CORTICOTROPIN-RELEASING-FACTOR; PROGRESSIVE RATIO SCHEDULE; INDUCED LOCOMOTOR-ACTIVITY; PROTEIN-COUPLED RECEPTORS; VOLUNTARY ETHANOL INTAKE; EXTENDED ACCESS; MEDIAN RAPHE; SEROTONIN-1A AUTORECEPTORS; BEHAVIORAL SENSITIZATION; INDUCED REINSTATEMENT AB Cocaine addiction and depression are comorbid disorders. Although it is well recognized that 5-hydroxytryptamine (5-HT; serotonin) plays a central role in depression, our understanding of its role in addiction is notably lacking. The 5-HT system in the brain is carefully controlled by a combined process of regulating 5-HT neuron firing through 5-HT autoreceptors, neurotransmitter release, enzymatic degradation, and reuptake by transporters. This study tests the hypothesis that activation of 5-HT1A autoreceptors, which would lessen 5-HT neuron firing, contributes to cocaine-seeking behaviors. Using 5-HT neuron-specific reduction of 5-HT1A autoreceptor gene expression in mice, we demonstrate that 5-HT1A autoreceptors are necessary for cocaine conditioned place preference. In addition, using designer receptors exclusively activated by designer drugs (DREADDs) technology, we found that stimulation of the serotonergic dorsal raphe nucleus (DRN) afferents to the nucleus accumbens (NAc) abolishes cocaine reward and promotes antidepressive-like behaviors. Finally, using a rat model of compulsive-like cocaine self-administration, we found that inhibition of dorsal raphe 5-HT1A autoreceptors attenuates cocaine self-administration in rats with 6 h extended access, but not 1 h access to the drug. Therefore, our findings suggest an important role for 5-HT1A autoreceptors, and thus DRN -> NAc 5-HT neuronal activity, in the etiology and vulnerability to cocaine reward and addiction. Moreover, our findings support a strategy for antagonizing 5-HT1A autoreceptors for treating cocaine addiction. C1 [You, In-Jee; Tapper, Andrew R.; Gardner, Paul D.] Univ Massachusetts, Sch Med, Dept Psychiat, Brudnick Neuropsychiat Res Inst, Worcester, MA 01604 USA. [You, In-Jee; Wright, Sherie R.; Bohn, Laura M.; Wee, Sunmee] Scripps Res Inst Florida, Dept Mol Therapeut, Jupiter, FL USA. [Garcia-Garcia, Alvaro L.; Leonardo, E. David] Columbia Univ, Dept Psychiat, New York, NY USA. [Koob, George F.] Scripps Res Inst, Comm Neurobiol Addict Disorders, La Jolla, CA 92037 USA. [Koob, George F.] NIAAA, Rockville, MD 20852 USA. [Leonardo, E. David] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. RP You, IJ (reprint author), Univ Massachusetts, Sch Med, Dept Psychiat, Brudnick Neuropsychiat Res Inst, Worcester, MA 01604 USA. EM In-Jee.You@umassmed.edu RI koob, george/P-8791-2016 FU National Institutes of Health [DA025785, DA004398, DA035371, MH91427]; Spanish Ministry of Science postdoctoral fellowship; Scripps Research Institute FX We gratefully acknowledge Yanabel Grant and Christine Lynch for their excellent technical assistance. We also thank Jeffrey Sobrieraj and James Heu, undergraduate student interns from the University of California, San Diego, Tara Patton, a National Institute on Drug Abuse undergraduate summer intern, The Scripps FL Mouse Behavior Core, and Maria Mavrikaki, a postdoctoral scholar from The Scripps Research Institute. National Institutes of Health grants DA025785 (to SW), DA004398 (to GFK), DA035371 (to ART and PDG), and MH91427 (to EDL) supported this study. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. ALG-G is a recipient of a Spanish Ministry of Science postdoctoral fellowship. NR 85 TC 3 Z9 3 U1 3 U2 13 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD APR PY 2016 VL 41 IS 5 BP 1210 EP 1222 DI 10.1038/npp.2015.268 PG 13 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DG1BW UT WOS:000371801200004 PM 26324408 ER PT J AU Sharpe, MJ Clemens, KJ Morris, MJ Westbrook, RF AF Sharpe, M. J. Clemens, K. J. Morris, M. J. Westbrook, R. F. TI Daily Exposure to Sucrose Impairs Subsequent Learning About Food Cues: A Role for Alterations in Ghrelin Signaling and Dopamine D2 Receptors SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID NUCLEUS-ACCUMBENS; COGNITIVE CONTROL; OBESITY; REWARD; RATS; ATTENTION; STIMULI; COCAINE; MEMORY; SENSITIZATION AB The prevalence of hedonic foods and associated advertising slogans has contributed to the rise of the obesity epidemic in the modern world. Research has shown that intake of these foods disrupt dopaminergic systems. It may be that a disruption of these circuits produces aberrant learning about food-cue relationships. We found that rodents given 28 days of intermittent access to sucrose exhibited a deficit in the ability to block learning about a stimulus when it is paired in compound with food and another stimulus that has already been established as predictive of the food outcome. This deficit was characterized by an approach to a cue signaling food delivery that is usually blocked by prior learning, an effect dependent on dopaminergic prediction-error signaling in the midbrain. Administering the D-2 agonist quinpirole during learning restored blocking in animals with a prior history of sucrose exposure. Further, repeated central infusions of ghrelin produced a deficit in blocking in the same manner as sucrose exposure. We argue that changes in dopaminergic systems resulting from sucrose exposure are mediated by a disruption of ghrelin signaling as rodents come to anticipate delivery of the highly palatable sucrose outside of normal feeding schedules. This suggestion is supported by our finding that both sucrose and ghrelin treatments resulted in increases in amphetamine-induced locomotor responding. Thus, for the first time, we have provided evidence of a potential link between alterations in D-2 receptors caused by the intake of hedonic foods and aberrant learning about cue-food relationships capable of promoting inappropriate feeding habits. In addition, we have found preliminary evidence to suggest that this is mediated by changes in ghrelin signaling, a finding that should stimulate further research into modulation of ghrelin activity to treat obesity. C1 [Sharpe, M. J.; Clemens, K. J.; Westbrook, R. F.] UNSW, Sch Psychol, Sydney, NSW, Australia. [Morris, M. J.] UNSW, Med Sci, Dept Pharmacol, Sydney, NSW, Australia. RP Sharpe, MJ (reprint author), UNSW, Sch Psychol, Sydney, NSW, Australia.; Sharpe, MJ (reprint author), NIDA, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM melissa.sharpe@nih.gov FU National Health and Medical Research Council of Australia FX This research was supported by a project grant from the National Health and Medical Research Council of Australia to MJM and RFW. The authors declare no conflict of interest. NR 43 TC 4 Z9 4 U1 3 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD APR PY 2016 VL 41 IS 5 BP 1357 EP 1365 DI 10.1038/npp.2015.287 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DG1BW UT WOS:000371801200018 PM 26365954 ER PT J AU Urban, DJ Zhu, H Marcinkiewcz, CA Michaelides, M Oshibuchi, H Rhea, D Aryal, DK Farrell, MS Lowery-Gionta, E Olsen, RHJ Wetsel, WC Kash, TL Hurd, YL Tecott, LH Roth, BL AF Urban, Daniel J. Zhu, Hu Marcinkiewcz, Catherine A. Michaelides, Michael Oshibuchi, Hidehiro Rhea, Darren Aryal, Dipendra K. Farrell, Martilias S. Lowery-Gionta, Emily Olsen, Reid H. J. Wetsel, William C. Kash, Thomas L. Hurd, Yasmin L. Tecott, Laurence H. Roth, Bryan L. TI Elucidation of The Behavioral Program and Neuronal Network Encoded by Dorsal Raphe Serotonergic Neurons SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; PROTEIN-COUPLED RECEPTORS; MAJOR DEPRESSION; ANTICIPATORY ANXIETY; REMOTE-CONTROL; RAT-BRAIN; NUCLEUS; FLUOXETINE; CIRCUIT; ANTIDEPRESSANTS AB Elucidating how the brain's serotonergic network mediates diverse behavioral actions over both relatively short (minutes-hours) and long period of time (days-weeks) remains a major challenge for neuroscience. Our relative ignorance is largely due to the lack of technologies with robustness, reversibility, and spatio-temporal control. Recently, we have demonstrated that our chemogenetic approach (eg, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)) provides a reliable and robust tool for controlling genetically defined neural populations. Here we show how short-and long-term activation of dorsal raphe nucleus (DRN) serotonergic neurons induces robust behavioral responses. We found that both short-and long-term activation of DRN serotonergic neurons induce antidepressant-like behavioral responses. However, only short-term activation induces anxiogenic-like behaviors. In parallel, these behavioral phenotypes were associated with a metabolic map of whole brain network activity via a recently developed non-invasive imaging technology DREAMM (DREADD Associated Metabolic Mapping). Our findings reveal a previously unappreciated brain network elicited by selective activation of DRN serotonin neurons and illuminate potential therapeutic and adverse effects of drugs targeting DRN neurons. C1 [Urban, Daniel J.; Zhu, Hu; Farrell, Martilias S.; Olsen, Reid H. J.; Roth, Bryan L.] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC USA. [Urban, Daniel J.; Zhu, Hu; Farrell, Martilias S.; Olsen, Reid H. J.; Roth, Bryan L.] NIMH, Psychoact Drug Screening Program, Chapel Hill, NC USA. [Marcinkiewcz, Catherine A.; Lowery-Gionta, Emily; Kash, Thomas L.] Univ N Carolina, Sch Med, Bowles Ctr Alcohol Studies, Chapel Hill, NC USA. [Marcinkiewcz, Catherine A.; Lowery-Gionta, Emily; Kash, Thomas L.] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC USA. [Michaelides, Michael; Hurd, Yasmin L.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Michaelides, Michael; Hurd, Yasmin L.] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA. [Oshibuchi, Hidehiro; Rhea, Darren; Tecott, Laurence H.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Aryal, Dipendra K.; Wetsel, William C.] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC USA. [Aryal, Dipendra K.; Wetsel, William C.] Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA. [Aryal, Dipendra K.; Wetsel, William C.] Duke Univ, Med Ctr, Dept Neurobiol, Durham, NC 27710 USA. RP Tecott, LH (reprint author), Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA.; Roth, BL (reprint author), Univ N Carolina, Sch Med, NIMH Psychoact Drug Screening Program, Dept Pharmacol, Chapel Hill, NC 27599 USA. EM bryan_roth@med.unc.edu FU National Institute of Mental Health [R01MH61887, U19MH82441, U01MH105892, R21 MH079145]; National Institute of Alcohol Abuse and Alcoholism [AA11034, AA07574, AA07611]; National Institue on Drug Abuse (NIDA) [DA030359, DA015446]; National Institute of Child Health and Human Development [P30 HD03110]; NIDA Postdoctoral Training Program at Mount Sinai [DA007135] FX This work was supported by the National Institute of Mental Health (R01MH61887, U19MH82441, and U01MH105892, R21 MH079145), National Institute of Alcohol Abuse and Alcoholism (Grants AA11034, AA07574, AA07611), National Institue on Drug Abuse (NIDA, DA030359, DA015446) and the National Institute of Child Health and Human Development (Grant no. P30 HD03110). MM was supported by the NIDA Postdoctoral Training Program at Mount Sinai (DA007135). BLR has consulted for Otsuka Pharmaceuticals, Merck, Sunovion, Albany Molecular Research, Pfizer Pharmaceuticals, Finnegan, Henderson, Farabow, Garrett and Dunner, and Venrock. BLR receives compensation for serving as Associate Editor of the Journal of Clinical Investigation. The authors declare no conflict of interest. NR 45 TC 8 Z9 8 U1 5 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD APR PY 2016 VL 41 IS 5 BP 1404 EP 1415 DI 10.1038/npp.2015.293 PG 12 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DG1BW UT WOS:000371801200023 PM 26383016 ER PT J AU Scherma, M Dessi, C Muntoni, AL Lecca, S Satta, V Luchicchi, A Pistis, M Panlilio, LV Fattore, L Goldberg, SR Fratta, W Fadda, P AF Scherma, Maria Dessi, Christian Muntoni, Anna Lisa Lecca, Salvatore Satta, Valentina Luchicchi, Antonio Pistis, Marco Panlilio, Leigh V. Fattore, Liana Goldberg, Steven R. Fratta, Walter Fadda, Paola TI Adolescent Delta(9)-Tetrahydrocannabinol Exposure Alters WIN55,212-2 Self-Administration in Adult Rats SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID MESOLIMBIC DOPAMINE TRANSMISSION; POSITRON-EMISSION-TOMOGRAPHY; CANNABIS USE; SEX-DIFFERENCES; NERVOUS-SYSTEM; ENDOCANNABINOID SYSTEM; PROTEIN EXPRESSION; NUCLEUS-ACCUMBENS; MESSENGER-RNA; DRUG-USE AB Cannabis is the most commonly used illicit drug worldwide, and use is typically initiated during adolescence. The endocannabinoid system has an important role in formation of the nervous system, from very early development through adolescence. Cannabis exposure during this vulnerable period might lead to neurobiological changes that affect adult brain functions and increase the risk of cannabis use disorder. The aim of this study was to investigate whether exposure to Delta(9)-tetrahydrocannabinol (THC) in adolescent rats might enhance reinforcing effects of cannabinoids in adulthood. Male adolescent rats were treated with increasing doses of THC (or its vehicle) twice/day for 11 consecutive days (PND 45-55). When the animals reached adulthood, they were tested by allowing them to intravenously self-administer the cannabinoid CB1-receptor agonist WIN55,212-2. In a separate set of animals given the same THC (or vehicle) treatment regimen, electrophysiological and neurochemical experiments were performed to assess possible modifications of the mesolimbic dopaminergic system, which is critically involved in cannabinoid-induced reward. Behavioral data showed that acquisition of WIN55,212-2 self administration was enhanced in THC-exposed rats relative to vehicle-exposed controls. Neurophysiological data showed that THC-exposed rats displayed a reduced capacity for WIN55,212-2 to stimulate firing of dopamine neurons in the ventral tegmental area and to increase dopamine levels in the nucleus accumbens shell. These findings-that early, passive exposure to THC can produce lasting alterations of the reward system of the brain and subsequently increase cannabinoid self-administration in adulthood-suggest a mechanism by which adolescent cannabis exposure could increase the risk of subsequent cannabis dependence in humans. C1 [Scherma, Maria; Dessi, Christian; Lecca, Salvatore; Satta, Valentina; Luchicchi, Antonio; Pistis, Marco; Fratta, Walter; Fadda, Paola] Univ Cagliari, Div Neurosci & Clin Pharmacol, Dept Biomed Sci, Cagliari, Italy. [Muntoni, Anna Lisa; Pistis, Marco; Fattore, Liana] Natl Res Council Italy, Sect Cagliari, Neurosci Inst, Cagliari, Italy. [Muntoni, Anna Lisa; Pistis, Marco; Fattore, Liana; Fratta, Walter; Fadda, Paola] Univ Cagliari, Ctr Excellence Neurobiol Dependence, Cagliari, Italy. [Panlilio, Leigh V.; Goldberg, Steven R.] NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, Intramural Res Program,Dept Hlth & Human Serv,NIH, Baltimore, MD USA. RP Fadda, P (reprint author), Univ Cagliari, Sect Neurosci & Clin Pharmacol, Dept Biomed Sci, Cittadella Univ Monserrato, SS554,Km 4,500, I-09042 Cagliari, Italy. EM pfadda@unica.it FU Compagnia di San Paolo; Department of Biomedical Sciences Project; University of Cagliari; Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, USA FX This study was supported by funds from Compagnia di San Paolo (2008), by the Department of Biomedical Sciences Project (2013), University of Cagliari, and by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, USA. The authors declare no conflict of interest. NR 64 TC 1 Z9 1 U1 4 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD APR PY 2016 VL 41 IS 5 BP 1416 EP 1426 DI 10.1038/npp.2015.295 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DG1BW UT WOS:000371801200024 PM 26388146 ER PT J AU Racicot, K Kwon, JY Aldo, P Abrahams, V El-Guindy, A Romero, R Mor, G AF Racicot, Karen Kwon, Ja Young Aldo, Paulomi Abrahams, Vikki El-Guindy, Ayman Romero, Roberto Mor, Gil TI Type I Interferon Regulates the Placental Inflammatory Response to Bacteria and is Targeted by Virus: Mechanism of Polymicrobial Infection-Induced Preterm Birth SO AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY LA English DT Article DE Bacteria; infection; interferon; polymicrobial; pregnancy; trophoblast; virus ID VIRAL-INFECTION; AMNIOTIC-FLUID; GENE-EXPRESSION; CEREBRAL-PALSY; LABOR; INTERVENTIONS; INTERLEUKIN-6; EPIDEMIOLOGY; SUPPRESSION; MORTALITY AB ProblemPreterm birth (PTB) affects approximately 12% of pregnancies and at least 50% of cases have no known risk factors. We hypothesize that subclinical viral infections of the placenta are a factor sensitizing women to intrauterine bacterial infection. Specifically, we propose that viral-induced placental IFN- inhibition results in a robust inflammatory response to low concentrations of bacteria. MethodsHuman trophoblast SW.71, C57BL/6, and interferon (IFN) receptor knockout animals were used to determine IFN function. Illumina and Bio-Rad microarrays identified pathways. ResultsInhibiting the IFN- pathway resulted in a significant increase in inflammatory cytokines such as IL-1B in response to LPS. Twist was positively correlated with IFN- expression and STAT3 phosphorylation and overexpressing Twist reduced IL-1B. Treating IFNAR-/- mice with low-dose LPS at E15.5 caused preterm birth. ConclusionIFN- was identified as a key modulator of placental inflammation and, importantly, is commonly affected by viruses. We propose dysregulation of IFN- is a major determinant for preterm birth associated with polymicrobial infection. C1 [Racicot, Karen; Kwon, Ja Young; Aldo, Paulomi; Abrahams, Vikki; Mor, Gil] Yale Univ, Sch Med, Dept Obstet Gynecol & Reprod Sci, New Haven, CT USA. [Racicot, Karen] Michigan State Univ, Coll Human Med, Dept OB GYN, Grand Rapids, MI USA. [Kwon, Ja Young] Yonsei Univ, Coll Med, Inst Womens Life Med Sci, Dept OB GYN, Seoul 120749, South Korea. [El-Guindy, Ayman] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. [Romero, Roberto] DHHS, NIH, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Detroit, MI USA. RP Mor, G (reprint author), Yale Univ, Sch Med, Dept OB GYN, 333 Cedar St LSOG 305A, New Haven, CT 06520 USA. EM gil.mor@yale.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services [P01HD054713, 3N01 HD23342] FX This study is in part funded by grants P01HD054713 and 3N01 HD23342 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services. We are grateful to A. F. Parlow, Scientific Director at Los Angeles Biomedical Research Institute National Hormone & Peptide Program for the Pregnant Mare Serum Gonadotropin (PMSG) used for superovulation protocols for embryo transfer experiments. Also, we extend our gratitude to JoAnn Bilyard for the careful editing of this manuscript. NR 47 TC 6 Z9 6 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1046-7408 EI 1600-0897 J9 AM J REPROD IMMUNOL JI Am. J. Reprod. Immunol. PD APR PY 2016 VL 75 IS 4 BP 451 EP 460 DI 10.1111/aji.12501 PG 10 WC Immunology; Reproductive Biology SC Immunology; Reproductive Biology GA DF7IR UT WOS:000371531900006 PM 26892235 ER PT J AU Hughes, MS Zager, J Faries, M Alexander, HR Royal, RE Wood, B Choi, J McCluskey, K Whitman, E Agarwala, S Siskin, G Nutting, C Toomey, MA Webb, C Beresnev, T Pingpank, JF AF Hughes, Marybeth S. Zager, Jonathan Faries, Mark Alexander, H. Richard Royal, Richard E. Wood, Bradford Choi, Junsung McCluskey, Kevin Whitman, Eric Agarwala, Sanjiv Siskin, Gary Nutting, Charles Toomey, Mary Ann Webb, Carole Beresnev, Tatiana Pingpank, James F. TI Results of a Randomized Controlled Multicenter Phase III Trial of Percutaneous Hepatic Perfusion Compared with Best Available Care for Patients with Melanoma Liver Metastases SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID ISOLATED LIMB INFUSION; SINGLE-INSTITUTION EXPERIENCE; ADVANCED EXTREMITY MELANOMA; UVEAL MELANOMA; OCULAR MELANOMA; REGIONAL THERAPY; SURVIVAL BENEFIT; MELPHALAN; SAFETY; IMMUNOEMBOLIZATION AB There is no consensus for the treatment of melanoma metastatic to the liver. Percutaneous hepatic perfusion with melphalan (PHP-Mel) is a method of delivering regional chemotherapy selectively to the liver. In this study, we report the results of a multicenter, randomized controlled trial comparing PHP-Mel with best alternative care (BAC) for patients with ocular or cutaneous melanoma metastatic to the liver. A total of 93 patients were randomized to PHP-Mel (n = 44) or BAC (n = 49). On the PHP-Mel arm, melphalan was delivered via the hepatic artery, and the hepatic effluent captured and filtered extracorporeally prior to return to the systemic circulation via a venovenous bypass circuit. PHP-Mel was repeatable every 4-8 weeks. The primary endpoint was hepatic progression-free survival (hPFS), and secondary endpoints included overall PFS (oPFS), overall survival (OS), hepatic objective response (hOR), and safety. hPFS was 7.0 months for PHP-Mel and 1.6 months for BAC (p < 0.0001), while oPFS was 5.4 months for PHP-Mel and 1.6 months for BAC (p < 0.0001). Median OS was not significantly different (PHP-Mel 10.6 months vs. BAC 10.0 months), likely due to crossover to PHP-Mel treatment (57.1 %) from the BAC arm, and the hOR was 36.4 % for PHP-Mel and 2.0 % for BAC (p < 0.001). The majority of adverse events were related to bone marrow suppression. Four deaths were attributed to PHP-Mel, three in the primary PHP-Mel group, and one post-crossover to PHP-Mel from BAC. This randomized, phase III study demonstrated the efficacy of the PHP-Mel procedure. hPFS, oPFS, and hOR were significantly improved with PHP-Mel. PHP with melphalan should provide a new treatment option for unresectable metastatic melanoma in the liver. C1 [Hughes, Marybeth S.; Toomey, Mary Ann; Webb, Carole; Beresnev, Tatiana] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Zager, Jonathan; Choi, Junsung] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Faries, Mark] Providence St Johns Hlth Ctr, John Wayne Canc Inst, Santa Monica, CA USA. [Alexander, H. Richard] Univ Maryland, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Royal, Richard E.] Univ Texas Houston, MD Anderson Canc Ctr, 1515 Holcombe Blvd, Houston, TX 77030 USA. [Wood, Bradford] NIH, Ctr Intervent Oncol, Bldg 10, Bethesda, MD 20892 USA. [McCluskey, Kevin; Pingpank, James F.] Univ Pittsburgh, Med Ctr, Univ Pittsburgh Sch Hlth Sci, Pittsburgh, PA USA. [Whitman, Eric] Atlantic Hlth Syst, Carol G Simon Canc Ctr, Morristown, NJ USA. [Agarwala, Sanjiv] St Lukes Canc Ctr, Bethlehem, PA USA. [Siskin, Gary] Albany Med Neurosci Inst, Albany, NY USA. [Nutting, Charles] RIA Endovascular, Greenwood Village, CO USA. [Pingpank, James F.] UPMC, Div Hepatobiliary Surg, Surg Oncol Serv, Hillman Canc Ctr, Pittsburgh, PA USA. RP Pingpank, JF (reprint author), Univ Pittsburgh, Med Ctr, Univ Pittsburgh Sch Hlth Sci, Pittsburgh, PA USA.; Pingpank, JF (reprint author), UPMC, Div Hepatobiliary Surg, Surg Oncol Serv, Hillman Canc Ctr, Pittsburgh, PA USA. EM pingpankjf@upmc.edu FU Intramural NIH HHS NR 29 TC 4 Z9 4 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD APR PY 2016 VL 23 IS 4 BP 1309 EP 1319 DI 10.1245/s10434-015-4968-3 PG 11 WC Oncology; Surgery SC Oncology; Surgery GA DF4QA UT WOS:000371333200035 PM 26597368 ER PT J AU Racz, S Saha, S Trent, M Adger, H Bradshaw, CP Goldweber, A Cauffman, E AF Racz, Sarah Jensen Saha, Shonali Trent, Maria Adger, Hoover Bradshaw, Catherine P. Goldweber, Asha Cauffman, Elizabeth TI Polysubstance Use Among Minority Adolescent Males Incarcerated for Serious Offenses SO CHILD & YOUTH CARE FORUM LA English DT Article DE Juvenile offenders; Polysubstance use; Risk factors; Aggression ID SUBSTANCE USE DISORDERS; NATIONALLY REPRESENTATIVE SAMPLE; MALE JUVENILE-OFFENDERS; HIGH-RISK YOUTHS; MULTISYSTEMIC TREATMENT; PSYCHIATRIC-DISORDERS; VIOLENT BEHAVIOR; ABUSE TREATMENT; MENTAL-HEALTH; UNITED-STATES AB Adolescent juvenile offenders are at high risk for problems associated with drug use, including polysubstance use (i.e., use of a variety of drugs). The combination of juvenile offending and polysubstance use presents a significant public and child health concern. This study explored polysubstance use among a sample of youth incarcerated for serious offenses. We examined several risk factors for substance use and delinquency (i.e., early and frequent substance use, prior history of arrests, school expulsion, Black ethnicity), as well as the association between aggression and polysubstance use. Data were collected via questionnaires from 373 serious male juvenile offenders upon intake into a secure locked facility. Youth were on average 16 years old, and minority youth were overrepresented (28.1 % Black, 53.1 % Latino). Poisson regressions were used to assess the associations between the risk factors, aggression, and polysubstance use. Consistent with the literature, Black youth reported less polysubstance use and later age of drug use onset than White and Latino youth. Findings suggest that Latino juvenile offenders and those with an early and problematic pattern of substance use are at heightened risk for polysubstance use. Aggression was not significantly related to polysubstance use, over and above the risk factors. Given that Latino youth experience low rates of treatment for substance use, the development of culturally-sensitive interventions for these youth is needed. Interventions should also be multifaceted to address the multitude of risk factors associated with polysubstance use among juvenile offenders. C1 [Racz, Sarah Jensen] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, 6705 Rockledge Dr Suite 8030, Bethesda, MD 20892 USA. [Saha, Shonali; Trent, Maria; Adger, Hoover] Johns Hopkins Sch Med, Baltimore, MD USA. [Trent, Maria; Bradshaw, Catherine P.; Goldweber, Asha] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Bradshaw, Catherine P.] Univ Virginia, Charlottesville, VA USA. [Cauffman, Elizabeth] Univ Calif Irvine, Irvine, CA USA. RP Racz, S (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, 6705 Rockledge Dr Suite 8030, Bethesda, MD 20892 USA. EM sarah.racz@nih.gov FU NICHD [T32-HD052459]; NIMH [T32 MH19545-21, K01MH01791-01A]; HRSA MCH [T71MC08054] FX Preparation of this manuscript was supported by the following Grants: NICHD T32-HD052459, NIMH T32 MH19545-21 and HRSA MCH T71MC08054. The original study was supported by a grant to the last author from NIMH (K01MH01791-01A). NR 67 TC 0 Z9 0 U1 6 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1053-1890 EI 1573-3319 J9 CHILD YOUTH CARE FOR JI Child Youth Care Forum PD APR PY 2016 VL 45 IS 2 BP 205 EP 220 DI 10.1007/s10566-015-9334-x PG 16 WC Psychology, Developmental SC Psychology GA DF3LX UT WOS:000371246800002 ER PT J AU Kongnyuy, M George, AK Rastinehad, AR Pinto, PA AF Kongnyuy, Michael George, Arvin K. Rastinehad, Ardeshir R. Pinto, Peter A. TI Magnetic Resonance Imaging-Ultrasound Fusion-Guided Prostate Biopsy: Review of Technology, Techniques, and Outcomes SO CURRENT UROLOGY REPORTS LA English DT Review DE Prostate cancer; Transrectal ultrasound; Magnetic resonance imaging; Biopsy ID TRANSRECTAL ULTRASOUND; ACTIVE SURVEILLANCE; TARGETED BIOPSY; ULTRASONOGRAPHY FUSION; CANCER DETECTION; MRI; TIME; GUIDANCE; SYSTEM; MEN AB Transrectal ultrasound (TRUS)-guided (12-14 core) systematic biopsy of the prostate is the recommended standard for patients with suspicion of prostate cancer (PCa). Advances in imaging have led to the application of magnetic resonance imaging (MRI) for the detection of PCa with subsequent development of software-based co-registration allowing for the integration of MRI with real-time TRUS during prostate biopsy. A number of fusion-guided methods and platforms are now commercially available with common elements in image and analysis and planning. Implementation of fusion-guided prostate biopsy has now been proven to improve the detection of clinically significant PCa in appropriately selected patients. C1 [Kongnyuy, Michael; George, Arvin K.; Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, 10 Ctr Dr, Bethesda, MD 20814 USA. [Rastinehad, Ardeshir R.] Icahn Sch Med Mt Sinai, 625 Madison Ave, New York, NY 10029 USA. RP George, AK (reprint author), NCI, Urol Oncol Branch, NIH, 10 Ctr Dr, Bethesda, MD 20814 USA. EM michael.kongnyuy@nih.gov; arvinkgeorge@gmail.com; art.rastinehad@mountsinai.org; pintop@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 69 TC 6 Z9 6 U1 2 U2 15 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 APR PY 2016 VL 17 IS 4 AR 32 DI 10.1007/s11934-016-0589-z PG 9 WC Urology & Nephrology SC Urology & Nephrology GA DF2MS UT WOS:000371178100006 PM 26902626 ER PT J AU Brown, JR Schwartz, CL Heumann, JM Dawson, SC Hoenger, A AF Brown, Joanna R. Schwartz, Cindi L. Heumann, Johil. M. Dawson, Scott C. Hoenger, Andreas TI A detailed look at the cytoskeletal architecture of the Giardia lamblia ventral disc SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE Giardia lamblia ventral disc; Cryo-electron microscopy; Cryo-electron tomography; Microtubules; Microtubule-associated proteins (MAPs); Volume averaging ID CRYOELECTRON TOMOGRAPHY; CELL-DIVISION; INTESTINALIS; ATTACHMENT; FLAGELLAR; BIOLOGY; PROTEIN; CYTOKINESIS; MICROSCOPY AB Giardia lamblia is a protistan parasite that infects and colonizes the small intestine of mammals. It is widespread and particularly endemic in the developing world. Here we present a detailed structural study by 3-D negative staining and cryo-electron tomography of a unique Giardia organelle, the ventral disc. The disc is composed of a regular array of microtubules and associated sheets, called microribbons that form a large spiral, held together by a myriad of mostly unknown associated proteins. In a previous study we analyzed by cryo-electron tomography the central microtubule portion (here called disc body) of the ventral disc and found a large portion of microtubule associated inner (MIPs) and outer proteins (MAPs) that render these microtubules hyper-stable. With this follow-up study we expanded our 3-D analysis to different parts of the disc such as the ventral and dorsal areas of the overlap zone, as well as the outer disc margin. There are intrinsic location-specific characteristics in the composition of microtubule-associated proteins between these regions, as well as large differences between the overall architecture of microtubules and microribbons. The lateral packing of microtubule-microribbon complexes varies substantially, and closer packing often comes with contracted lateral tethers that seem to hold the disc together. It appears that the marginal microtubule-microribbon complexes function as outer, laterally contractible lids that may help the cell to clamp onto the intestinal microvilli. Furthermore, we analyzed length, quantity, curvature and distribution between different zones of the disc, which we found to differ from previous publications. (C) 2016 Elsevier Inc. All rights reserved. C1 [Brown, Joanna R.; Schwartz, Cindi L.; Heumann, Johil. M.; Hoenger, Andreas] Univ Colorado, Dept MCD Biol, Boulder, CO 80309 USA. [Dawson, Scott C.] Univ Calif Davis, Dept Microbiol & Mol Genet, Davis, CA 95616 USA. [Brown, Joanna R.] Univ Edinburgh, Ctr Regenerat Med, MRC, Edinburgh Bioquarter EH16 4UU, Scotland. [Schwartz, Cindi L.] NIAID, Res Technol Branch, Microscopy Unit, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. RP Hoenger, A (reprint author), Univ Colorado, Dept MCD Biol, Boulder, CO 80309 USA. EM Hoenger@colorado.edu OI Hoenger, Andreas/0000-0001-9176-6658 FU National Institutes of Health-National Center for Research Resources grant [NCRR: P41RR000592, NIGMS: P41GM103431-43, P41GM103431-43S1]; NSF [0801680] FX The authors would like to thank David Mastronarde for valuable discussion on sub-volume averaging, and Christopher Nosala (UCD) for carefully reading the manuscript. This work was funded in part by National Institutes of Health-National Center for Research Resources grant (NCRR: P41RR000592 and since 05/02/12: NIGMS: P41GM103431-43, and P41GM103431-43S1) to A.H. J.B. received support from an NSF IGERT-COSY training grant (award ID: 0801680, PI: Rafael Piestun, Engineering Univ. of Colorado, Boulder; Co-PI: AH). NR 39 TC 1 Z9 1 U1 4 U2 17 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1047-8477 EI 1095-8657 J9 J STRUCT BIOL JI J. Struct. Biol. PD APR PY 2016 VL 194 IS 1 BP 38 EP 48 DI 10.1016/j.jsb.2016.01.011 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA DF2SH UT WOS:000371193600005 PM 26821343 ER PT J AU Severinov, K Shmakov, S Abudayyeh, O Makarova, K Wolf, Y Semenova, E Minakhin, L Gootenberg, J Zhang, F Koonin, E AF Severinov, Konstantin Shmakov, Sergei Abudayyeh, Omar Makarova, Kira Wolf, Yuri Semenova, Ekaterina Minakhin, Leonid Gootenberg, Jonathan Zhang, Feng Koonin, Eugene TI A pipeline approach for discovery of novel CRISRP-Cas systems SO TRANSGENIC RESEARCH LA English DT Meeting Abstract DE CRISPR-Cas; Cas9; bioinformatics C1 [Severinov, Konstantin; Shmakov, Sergei] Skolkovo Inst Sci & Technol, Moscow, Russia. [Severinov, Konstantin; Semenova, Ekaterina; Minakhin, Leonid; Koonin, Eugene] Waksman Inst Microbiol, Piscataway, NJ USA. [Severinov, Konstantin; Semenova, Ekaterina; Minakhin, Leonid; Koonin, Eugene] NIH, Beteshda, MD USA. [Severinov, Konstantin; Semenova, Ekaterina; Minakhin, Leonid; Koonin, Eugene] MIT, 77 Massachusetts Ave, Cambridge, MA 02139 USA. NR 0 TC 0 Z9 0 U1 5 U2 15 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-8819 EI 1573-9368 J9 TRANSGENIC RES JI Transgenic Res. PD APR PY 2016 VL 25 IS 2 BP 207 EP 208 PG 2 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA DF2FD UT WOS:000371155900023 ER PT J AU Zetsche, B Gootenberg, JS Abudayyeh, OO Slaymaker, IM Makarova, KS Essletzbichler, P Volz, S Joung, J van der Oost, J Regev, A Koonin, EV Zhang, F AF Zetsche, Bernd Gootenberg, Jonathan S. Abudayyeh, Omar O. Slaymaker, Ian M. Makarova, Kira S. Essletzbichler, Patrick Volz, Sara Joung, Julia van der Oost, John Regev, Aviv Koonin, Eugene V. Zhang, Feng TI Cpf1 is a single-RNA-guided endonuclease of a Class 2 CRISPR-Cas system SO TRANSGENIC RESEARCH LA English DT Meeting Abstract DE CRISPR; Cpf1; genome editing C1 [Zetsche, Bernd; Gootenberg, Jonathan S.; Abudayyeh, Omar O.; Slaymaker, Ian M.; Essletzbichler, Patrick; Volz, Sara; Joung, Julia; Regev, Aviv; Zhang, Feng] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Zetsche, Bernd; Gootenberg, Jonathan S.; Abudayyeh, Omar O.; Slaymaker, Ian M.; Essletzbichler, Patrick; Volz, Sara; Joung, Julia; Zhang, Feng] MIT, McGovern Inst Brain Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Zetsche, Bernd; Gootenberg, Jonathan S.; Abudayyeh, Omar O.; Slaymaker, Ian M.; Essletzbichler, Patrick; Volz, Sara; Joung, Julia; Zhang, Feng] MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA. [Zetsche, Bernd; Gootenberg, Jonathan S.; Abudayyeh, Omar O.; Slaymaker, Ian M.; Essletzbichler, Patrick; Volz, Sara; Joung, Julia; Zhang, Feng] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Zetsche, Bernd] Bonn Med Sch, Inst Pathol, Dept Dev Pathol, Sigmund Freud St 25, D-53127 Bonn, Germany. [Gootenberg, Jonathan S.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Makarova, Kira S.; Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [van der Oost, John] Wageningen Univ, Microbiol Lab, Dept Agrotechnol & Food Sci, Dreijenpl 10, NL-6703 HB Wageningen, Netherlands. [Regev, Aviv] MIT, Howard Hughes Med Inst, Dept Biol, Cambridge, MA 02139 USA. NR 0 TC 0 Z9 0 U1 8 U2 30 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-8819 EI 1573-9368 J9 TRANSGENIC RES JI Transgenic Res. PD APR PY 2016 VL 25 IS 2 BP 207 EP 207 PG 1 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA DF2FD UT WOS:000371155900022 ER PT J AU Bronstad, A Newcomer, CE Decelle, T Everitt, JI Guillen, J Laber, K AF Bronstad, Aurora Newcomer, Christian E. Decelle, Thierry Everitt, Jeffrey I. Guillen, Javier Laber, Kathy TI The AALAS-FELASA Working Group on Harm-Benefit analysis of animal studies SO TRANSGENIC RESEARCH LA English DT Meeting Abstract DE harm-benefit; ethical evaluation; animal experiments; animal etics C1 [Bronstad, Aurora] Univ Bergen, Dept Clin Med, N-5020 Bergen, Norway. [Newcomer, Christian E.] AAALAC Int, Frederick, MD USA. [Decelle, Thierry] Sanofi, Paris, France. [Everitt, Jeffrey I.] GlaxoSmithKline, Dept Lab Anim Sci, Philadelphia, PA USA. [Guillen, Javier] AAALAC Int, Madrid, Spain. [Laber, Kathy] NIEHS, Comparat Med Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-8819 EI 1573-9368 J9 TRANSGENIC RES JI Transgenic Res. PD APR PY 2016 VL 25 IS 2 BP 211 EP 211 PG 1 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA DF2FD UT WOS:000371155900032 ER PT J AU Saligan, LN Luckenbaugh, DA Slonena, EE Machado-Vieira, R Zarate, CA AF Saligan, Leorey N. Luckenbaugh, David A. Slonena, Elizabeth E. Machado-Vieira, Rodrigo Zarate, Carlos A., Jr. TI An assessment of the anti-fatigue effects of ketamine from a double-blind, placebo-controlled, crossover study in bipolar disorder SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Fatigue; Ketamine; Depression; Glutamate; New therapeutics ID CANCER-RELATED FATIGUE; RESISTANT MAJOR DEPRESSION; D-ASPARTATE ANTAGONIST; MULTIPLE-SCLEROSIS; ANTIDEPRESSANT EFFICACY; INTRAVENOUS KETAMINE; BREAST-CANCER; TRIAL; MODAFINIL; NOREPINEPHRINE AB Background: Fatigue is a multidimensional condition that is difficult to treat with standard monoaminergic antidepressants. Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist produces rapid and robust improvements in depressive symptoms in treatment-resistant depression. However, there is a dearth of literature examining the anti-fatigue effects of ketamine. We hypothesize that ketamine will rapidly improve fatigue symptoms in treatment-resistant depressed patients. Methods: This is an exploratory analysis of data obtained from two double-blind, randomized, placebo controlled, crossover trials. A total of 36 participants with treatment-resistant bipolar I or II disorder in a depressive episode (maintained on therapeutic levels of lithium or valproate) received a single infusion of ketamine hydrochloride intravenously (0.5 mg/kg over 40 min) or placebo. A post-hoc analysis compared fatigue scores on ketamine vs. placebo at 10 time points from baseline through 14 days post-treatment using the National Institute of Health-Brief Fatigue Inventory. Results: A linear mixed model showed that ketamine significantly lowered fatigue scores compared to placebo from 40 min post-treatment to Day 14 with the exception of Day 7. The largest difference in anti fatigue effects between placebo and ketamine was at day 2 (d=0.58, p < 0.05). The effect remained significant after controlling for changes in non-fatigue depressive symptoms. Limitation: The retrospective nature and a small sample size are study limitations. Conclusions: Ketamine rapidly improved fatigue relative to placebo in a group of individuals with treatment-resistant bipolar depression. NMDAR is a glutamate receptor; hence, glutamate may represent a valuable target to study the clinical efficacy of new anti-fatigue approaches in multiple disorders. Published by Elsevier B.V. C1 [Saligan, Leorey N.] NINR, Div Intramural Res, NIH, 31 Ctr Dr,MSC 2178, Bethesda, MD USA. [Luckenbaugh, David A.; Slonena, Elizabeth E.; Machado-Vieira, Rodrigo; Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, 10 Ctr Dr,Rm 4N222,MSC 1381, Bethesda, MD 20892 USA. RP Saligan, LN (reprint author), NINR, NIH, 3 Ctr Dr,Bldg 3,Room 5E14, Bethesda, MD 20892 USA. EM saliganl@mail.nih.gov; luckenbd@mail.nih.gov; elizabeth.slonena@nih.gov; rodrigo.machadovieira@nih.gov; zaratec@mail.nih.gov RI MACHADO-VIEIRA, RODRIGO/D-8293-2012 OI MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190 FU Intramural NIH HHS [Z99 NR999999] NR 46 TC 2 Z9 2 U1 7 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 EI 1573-2517 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD APR PY 2016 VL 194 BP 115 EP 119 DI 10.1016/j.jad.2016.01.009 PG 5 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DE6DP UT WOS:000370724200017 PM 26807672 ER PT J AU Foran, E Kwon, DY Nofziger, JH Arnold, ES Hall, MD Fischbeck, KH Burnett, BG AF Foran, Emily Kwon, Deborah Y. Nofziger, Jonathan H. Arnold, Eveline S. Hall, Matthew D. Fischbeck, Kenneth H. Burnett, Barrington G. TI CNS uptake of bortezomib is enhanced by P-glycoprotein inhibition: implications for spinal muscular atrophy SO NEUROBIOLOGY OF DISEASE LA English DT Article DE Spinal muscular atrophy (SMA); Survival motor neuron (SMN); P-glycoprotein (P-gp); Blood brain barrier (BBB); Bortezomib; Tariquidar; Proteasome ID BLOOD-BRAIN-BARRIER; CANCER RESISTANCE PROTEIN; ADVANCED MULTIPLE-MYELOMA; MOUSE MODEL; CELL-LINE; PROTEASOME INHIBITORS; TUMOR-CELLS; GENE; SMN; EXPRESSION AB The development of therapeutics for neurological disorders is constrained by limited access to the central nervous system (CNS). ATP-binding cassette (ABC) transporters, particularly P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), are expressed on the luminal surface of capillaries in the CNS and transport drugs out of the endothelium back into the blood against the concentration gradient. Survival motor neuron (SMN) protein, which is deficient in spinal muscular atrophy (SMA), is a target of the ubiquitin proteasome system. Inhibiting the proteasome in a rodent model of SMA with bortezomib increases SMN protein levels in peripheral tissues but not the CNS, because bortezomib has poor CNS penetrance. We sought to determine if we could inhibit SMN degradation in the CNS of SMA mice with a combination of bortezomib and the ABC transporter inhibitor tariquidar. In cultured cells we show that bortezomib is a substrate of P-gp. Mass spectrometry analysis demonstrated that intraperitoneal co-administration of tariquidar increased the CNS penetrance of bortezomib, and reduced proteasome activity in the brain and spinal cord. This correlated with increased SMN protein levels and improved survival and motor function of SMA mice. These findings show that CNS penetrance of treatment for this neurological disorder can be improved by inhibiting drug efflux at the blood-brain barrier. (C) 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license. C1 [Foran, Emily; Kwon, Deborah Y.; Nofziger, Jonathan H.; Arnold, Eveline S.; Fischbeck, Kenneth H.] NIDDK, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Kwon, Deborah Y.] Brown Univ, Dept Neurosci, Providence, RI 02912 USA. [Hall, Matthew D.] NCI, CE Lab Cell Biol, NIH, Bethesda, MD 20892 USA. [Burnett, Barrington G.] Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. RP Foran, E (reprint author), 35 Convent Dr,2A1010 Bldg 35, Bethesda, MD 20892 USA. EM Emily.Carifi@nih.gov FU NINDS [1ZIANS003038-09] FX We thank Robert Innis and Jeih-San Liow (NIMH, NIH)) for their kind gift of the P-gp1a/b-/-:BCRP-/-mice. We thank Michael Gottesman and Robert Robey (NCI, NIH) for their kind gift of the P-gp and BCRP transfected HEK cells and the drug selected MCF-7 cells. The work was supported by intramural research funds from NINDS (1ZIANS003038-09). NR 40 TC 3 Z9 3 U1 2 U2 22 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 EI 1095-953X J9 NEUROBIOL DIS JI Neurobiol. Dis. PD APR PY 2016 VL 88 BP 118 EP 124 DI 10.1016/j.nbd.2016.01.008 PG 7 WC Neurosciences SC Neurosciences & Neurology GA DE8TH UT WOS:000370909100011 PM 26792401 ER PT J AU Arnold, MA Anderson, JR Gastier-Foster, JM Barr, FG Skapek, SX Hawkins, DS Raney, RB Parham, DM Teot, LA Rudzinski, ER Walterhouse, DO AF Arnold, Michael A. Anderson, James R. Gastier-Foster, Julie M. Barr, Frederic G. Skapek, Stephen X. Hawkins, Douglas S. Raney, R. Beverly, Jr. Parham, David M. Teot, Lisa A. Rudzinski, Erin R. Walterhouse, David O. TI Histology, Fusion Status, and Outcome in Alveolar Rhabdomyosarcoma With Low-Risk Clinical Features: A Report From the Children's Oncology Group SO PEDIATRIC BLOOD & CANCER LA English DT Article DE alveolar rhabdomyosarcoma; D9602; D9803; embryonal rhabdomyosarcoma; fusion status; histology; low risk; outcomes; rhabdomyosarcoma ID TISSUE SARCOMA COMMITTEE; INTERGROUP RHABDOMYOSARCOMA; EMBRYONAL RHABDOMYOSARCOMA; CLASSIFICATION; GENE; MUTATIONS AB BackgroundDistinguishing alveolar rhabdomyosarcoma (ARMS) from embryonal rhabdomyosarcoma (ERMS) is of prognostic and therapeutic importance. Criteria for classifying these entities evolved significantly from 1995 to 2013. ARMS is associated with inferior outcome; therefore, patients with alveolar histology have generally been excluded from low-risk therapy. However, patients with ARMS and low-risk stage and group (Stage 1, Group I/II/orbit III; or Stage 2/3, Group I/II) were eligible for the Children's Oncology Group (COG) low-risk rhabdomyosarcoma (RMS) study D9602 from 1997 to 1999. The characteristics and outcomes of these patients have not been previously reported, and the histology of these cases has not been reviewed using current criteria. ProcedureWe re-reviewed cases that were classified as ARMS on D9602 using current histologic criteria, determined PAX3/PAX7-FOXO1 fusion status, and compared these data with outcome for this unique group of patients. ResultsThirty-eight patients with ARMS were enrolled onto D9602. Only one-third of cases with slides available for re-review (11/33) remained classified as ARMS by current histologic criteria. Most cases were reclassified as ERMS (17/33, 51.5%). Cases that remained classified as ARMS were typically fusion-positive (8/11, 73%), therefore current classification results in a similar rate of fusion-positive ARMS for all clinical risk groups. In conjunction with data from COG intermediate-risk treatment protocol D9803, our data demonstrate excellent outcomes for fusion-negative ARMS with otherwise low-risk clinical features. ConclusionsPatients with fusion-positive RMS with low-risk clinical features should be classified and treated as intermediate risk, while patients with fusion-negative ARMS could be appropriately treated with reduced intensity therapy. C1 [Arnold, Michael A.; Gastier-Foster, Julie M.] Nationwide Childrens Hosp, Dept Pathol & Lab Med, 700 Childrens Dr, Columbus, OH 43205 USA. [Arnold, Michael A.; Gastier-Foster, Julie M.] Ohio State Univ, Coll Med, Dept Pathol, Columbus, OH 43210 USA. [Anderson, James R.] Frontier Sci & Technol Res Fdn Inc, Madison, WI USA. [Barr, Frederic G.] NCI, Pathol Lab, Bldg 10, Bethesda, MD 20892 USA. [Skapek, Stephen X.] Univ Texas SW Med Ctr Dallas, Dept Hematol & Oncol, Dallas, TX 75390 USA. [Hawkins, Douglas S.] Seattle Childrens Hosp, Dept Pediat, Seattle, WA USA. [Hawkins, Douglas S.] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. [Hawkins, Douglas S.] Univ Washington, Seattle, WA 98195 USA. [Raney, R. Beverly, Jr.] Univ Texas MD Anderson Canc Ctr, Childrens Canc Hosp, Houston, TX 77030 USA. [Raney, R. Beverly, Jr.] Univ Texas MD Anderson Canc Ctr, Div Pediat, Houston, TX 77030 USA. [Parham, David M.] Univ So Calif, Childrens Hosp Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA USA. [Parham, David M.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Teot, Lisa A.] Boston Childrens Hosp, Dept Pathol, Boston, MA USA. [Rudzinski, Erin R.] Seattle Childrens Hosp, Dept Labs, Seattle, WA USA. [Walterhouse, David O.] Northwestern Univ, Feinberg Sch Med, Ann & Robert H Lurie Childrens Hosp Chicago, Div Hematol Oncol & Stem Cell Transplantat, Chicago, IL 60611 USA. RP Arnold, MA (reprint author), Nationwide Childrens Hosp, Dept Pathol & Lab Med, 700 Childrens Dr, Columbus, OH 43205 USA. EM Michael.Arnold@NationwideChildrens.org OI Arnold, Michael/0000-0002-6921-3720 FU St. Baldrick's Foundation Consortium Research Grant [244660]; National Cancer Institute [U10CA180886, U10CA180899, U10CA098543, U10CA098413]; Intramural Research Program of the National Cancer Institute FX This study was supported by St. Baldrick's Foundation Consortium Research Grant (244660), and National Cancer Institute grants U10CA180886, U10CA180899, U10CA098543, and U10CA098413. FGB was supported by the Intramural Research Program of the National Cancer Institute. All studies were conducted in accordance with institutional review board approved protocols. NR 15 TC 2 Z9 2 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD APR PY 2016 VL 63 IS 4 BP 634 EP 639 DI 10.1002/pbc.25862 PG 6 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA DE2ZR UT WOS:000370497100011 PM 26756883 ER PT J AU Yan, YT Cummings, CA Sutton, D Yu, LD Castro, L Moore, AB Gao, XH Dixon, D AF Yan, Yitang Cummings, Connie A. Sutton, Deloris Yu, Linda Castro, Lysandra Moore, Alicia B. Gao, Xiaohua Dixon, Darlene TI Immunogold electron microscopy and confocal analyses reveal distinctive patterns of histone H3 phosphorylation during mitosis in MCF-7 cells SO GENES CHROMOSOMES & CANCER LA English DT Article ID PHOSPHOHISTONE H3; TRANSFORMATION; SERINE-10; KINASE; INDUCTION; JNK AB Histone phosphorylation has a profound impact on epigenetic regulation of gene expression, chromosome condensation and segregation, and maintenance of genome integrity. Histone H3 Serine 10 is evolutionally conserved and heavily phosphorylated during mitosis. To examine Histone H3 Serine 10 phosphorylation (H3S10ph) dynamics in mitosis, we applied immunogold labeling and confocal microscopy to visualize H3S10ph expression in MCF-7 cells. Confocal observations showed that MCF-7 cells had abundant H3S10ph expression in prophase and metaphase. In anaphase, the H3S10ph expression was significantly decreased and displayed only sparsely localized staining that mainly associated with the chromatid tips. We showed that immunogold bead density distribution followed the H3S10ph expression patterns observed in confocal analysis. At a higher magnification in metaphase, the immunogold beads were readily visible and the bead distribution along the condensed chromosomes was distinctive, indicating the specificity and reliability of the immunogold staining procedure. In anaphase, the beads were found to distribute focally in specific regions of chromatids, reinforcing the confocal observations of differential H3 phosphorylation. To our knowledge, this is the first report to show the specific H3S10ph expression with an immunogold technique and transmission electron microscopy. Additionally, with confocal microscopy, we analyzed H3S10ph expression in an immortalized cell line derived from benign uterine smooth muscle tumor cells. H3S10ph epitope was expressed more abundantly during anaphase in the benign tumor cells, and there was no dramatic differential expression within the condensed chromatid clusters as observed in MCF-7 cells. The differences in H3S10ph expression pattern and dynamics may contribute to the differential proliferative potential between benign tumor cells and MCF-7 cells. Published 2016. This article is a U.S. Government work and is in the public domain in the USA C1 [Yan, Yitang; Yu, Linda; Castro, Lysandra; Moore, Alicia B.; Gao, Xiaohua; Dixon, Darlene] NIEHS, Natl Toxicol Program Lab, Mol Pathogenesis Grp, Div NTP DNTP,NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Cummings, Connie A.; Sutton, Deloris] NIEHS, Cellular & Mol Pathol Branch, Pathol Support Grp, DNTP,NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RP Dixon, D (reprint author), NIEHS, Natl Toxicol Program, POB 12233,MD B3-06,111 TW Alexander Dr,Bldg 101, Res Triangle Pk, NC 27709 USA. EM dixon@niehs.nih.gov FU Intramural Research Program of the NIH; DNTP; NIEHS FX Supported by: The Intramural Research Program of the NIH, NIEHS, and DNTP. NR 19 TC 0 Z9 0 U1 2 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1045-2257 EI 1098-2264 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD APR PY 2016 VL 55 IS 4 BP 397 EP 406 DI 10.1002/gcc.22343 PG 10 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA DD8HW UT WOS:000370168100011 PM 26799600 ER PT J AU Inoue-Choi, M Sinha, R Gierach, GL Ward, MH AF Inoue-Choi, Maki Sinha, Rashmi Gierach, Gretchen L. Ward, Mary H. TI Red and processed meat, nitrite, and heme iron intakes and postmenopausal breast cancer risk in the NIH-AARP Diet and Health Study SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE red meat; processed meat; breast cancer; nitrite; heme iron ID N-NITROSO COMPOUNDS; FOOD-FREQUENCY QUESTIONNAIRE; RETIRED-PERSONS DIET; NATIONAL-INSTITUTES; AMERICAN-ASSOCIATION; OVARIAN-CANCER; HOT DOGS; NITRATE; COHORT; CONSUMPTION AB Previous studies have shown inconsistent associations between red and processed meat intake and breast cancer risk. N-nitroso compounds and heme iron have been hypothesized as contributing factors. We followed 193,742 postmenopausal women in the NIH-AARP Diet and Health Study and identified 9,305 incident breast cancers (1995-2006). Dietary intake was assessed using a food frequency questionnaire at baseline. We adjusted daily intakes of meat, nitrite and heme iron for energy intake using the nutrient density method. We estimated multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) by quintiles of dietary exposures for all breast cancer, by stage (in-situ, localized, regional/distant) and by estrogen/progesterone receptor (ER/PR) status using Cox proportional hazards regression. Total red meat intake was positively associated with risk of regional/distant cancer (p-trend = 0.02). The risk was 25% higher in the highest vs. lowest intake quintile (95% CI = 1.03-1.52). Higher processed red meat intake (Q5 vs. Q1) was associated with 27% higher risk of localized breast cancer (95% CI = 1.01-1.27, p-trend = 0.03) and a 19% higher risk of regional/distant cancer (95% CI = 0.98-1.44, p-trend = 0.10). In addition, higher nitrite intake from processed red meat was positively associated with localized cancer (HR for Q5 vs. Q1 = 1.23, 95% CI = 1.09-1.39, p-trend < 0.0001). Heme iron intake was positively associated with breast cancer risk overall and all cancer stages (p-trend = 0.02-0.05). No heterogeneity was observed in risk associations by hormone receptor status. Our findings suggest that high consumption of red meat and processed meat may increase risk of postmenopausal breast cancer. Added nitrite and heme iron may partly contribute to these observed associations. C1 [Inoue-Choi, Maki; Ward, Mary H.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr,6E-640, Bethesda, MD 20892 USA. [Inoue-Choi, Maki] Natl Inst Minor Hlth & Hlth Dispar, Div Intramural Res, NIH, Bethesda, MD USA. [Sinha, Rashmi] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr,6E-640, Bethesda, MD 20892 USA. [Gierach, Gretchen L.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr,6E-640, Bethesda, MD 20892 USA. RP Inoue-Choi, M (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr,6E-640, Bethesda, MD 20892 USA.; Inoue-Choi, M (reprint author), Natl Inst Minor Hlth & Hlth Dispar, Div Intramural Res, NIH, Bethesda, MD USA. EM maki.inoue-choi@nih.gov RI Gierach, Gretchen/E-1817-2016 OI Gierach, Gretchen/0000-0002-0165-5522 FU Intramural Research Program of the National Cancer Institute FX Grant sponsor: Intramural Research Program of the National Cancer Institute NR 48 TC 3 Z9 3 U1 8 U2 41 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD APR 1 PY 2016 VL 138 IS 7 BP 1609 EP 1618 DI 10.1002/ijc.29901 PG 10 WC Oncology SC Oncology GA DD7SX UT WOS:000370125500005 PM 26505173 ER PT J AU Karami, S Colt, JS Stewart, PA Schwartz, K Davis, FG Ruterbusch, JJ Chow, WH Wacholder, S Graubard, BI Purdue, MP Moore, LE AF Karami, Sara Colt, Joanne S. Stewart, Patricia A. Schwartz, Kendra Davis, Faith G. Ruterbusch, Julie J. Chow, Wong-Ho Wacholder, Sholom Graubard, Barry I. Purdue, Mark P. Moore, Lee E. TI A case-control study of occupational sunlight exposure and renal cancer risk SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE sunlight; occupational UV; kidney cancer; race ID VITAMIN-D; UNITED-STATES; 25-HYDROXYVITAMIN D; CELL CARCINOMA; KIDNEY CANCER; SKIN; RADIATION; MORTALITY AB Epidemiological evidence of a relationship between vitamin D and kidney cancer risk has been inconsistent despite experimental data indicating that vitamin D and its metabolites may inhibit carcinogenesis. Previously we reported an inverse association between renal cell carcinoma (RCC) risk and occupational ultraviolet (UV) exposure among European men. In this study, we examined the association between occupational UV exposure and RCC risk among US residents and investigated whether this association varied by race and sex. Lifetime occupational data for 1,217 RCC cases and 1,235 controls in a population-based case-control study, conducted from 2002 to 2007, were assessed for occupational UV exposure. We evaluated exposure metrics in quartiles based on control exposure levels and calculated associations between RCC risk and occupational UV exposure using unconditional logistic regression adjusted for sex, race, body mass index, smoking, hypertension, center, education, family history of cancer and dietary vitamin D intake. A general pattern of decreasing RCC risk with increasing UV exposure was observed. Cases had significantly lower cumulative occupational UV exposure than controls (fourth quartile vs. first: odds ratio = 0.74 [95% confidence interval = 0.56-0.99], p-trend = 0.03). Similar results were observed for other UV exposure metrics. The association with occupational UV exposure was stronger for women than for men, but did not differ by race. Our findings suggest an inverse association between occupational UV exposure and RCC, particularly among women. Given the sex finding discrepancies in this study versus our previous study, additional research is need to clarify whether the protective effects of occupational UV exposure and RCC risk are real. C1 [Karami, Sara; Colt, Joanne S.; Chow, Wong-Ho; Wacholder, Sholom; Graubard, Barry I.; Purdue, Mark P.; Moore, Lee E.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Rockville, MD USA. [Stewart, Patricia A.] Stewart Exposure Assessments LLC, Arlington, VA USA. [Schwartz, Kendra; Ruterbusch, Julie J.] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Davis, Faith G.] Univ Illinois, Chicago, IL USA. RP Karami, S (reprint author), NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, 9609 Med Ctr Dr,6E624, Rockville, MD 20850 USA. EM karamis@mail.nih.gov FU Intramural Research Program of the NCI, Division of Cancer Epidemiology and Genetics, National Institutes of Health FX Grant sponsor: Intramural Research Program of the NCI, Division of Cancer Epidemiology and Genetics, National Institutes of Health Patricia A. Stewart was formerly with: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD NR 25 TC 1 Z9 1 U1 4 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD APR 1 PY 2016 VL 138 IS 7 BP 1626 EP 1633 DI 10.1002/ijc.29902 PG 8 WC Oncology SC Oncology GA DD7SX UT WOS:000370125500007 PM 26505275 ER PT J AU Kovacs, W Weisenthal, S Folio, L Li, QY Summers, RM Yao, JH AF Kovacs, William Weisenthal, Samuel Folio, Les Li, Qiaoyi Summers, Ronald M. Yao, Jianhua TI Retrieval, visualization, and mining of large radiation dosage data SO INFORMATION RETRIEVAL LA English DT Article DE Radiation dose; Clinical PACS; Data retrieval; Data visualization ID COMPUTED-TOMOGRAPHY; SUBSEQUENT RISK; OPTIMIZATION; EXPOSURE; SYSTEM; PROTECTION; COHORT AB Radiation dose monitoring has become an essential service that hospitals must perform. Depending on the system in place, this can result in the collection of large quantities of data, ripe for analysis. These data should include a wide variety of variables for each study because assessment of the propriety of the patient's dose is dependent on many factors, including patient age and size, as well as the body section that is being scanned. Moreover, the scanners themselves have many properties that affect patient dose, such as model, pitch and kVp. In this paper, we propose an engine that seamlessly integrated with a clinical PACS to retrieve radiation dosage data. We devised several schemes to analyze these data through visualization and mining techniques that examine it at different scopes. We demonstrate the utility of such visual methods at examining large, noisy, and multi-dimensional data, which is embodied in the collected radiation data. C1 [Kovacs, William; Weisenthal, Samuel; Folio, Les; Li, Qiaoyi; Summers, Ronald M.; Yao, Jianhua] NIH, Clin Image Proc Serv, Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. RP Kovacs, W (reprint author), NIH, Clin Image Proc Serv, Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM william.kovacs@nih.gov FU Intramural Research Program of NIH, Clinical Center FX This research was supported by the Intramural Research Program of NIH, Clinical Center. The opinions expressed herein are those of the authors and do not necessarily represent those of the NIH. The authors would like to thank the radiation monitoring and dose reduction team and the CT technologists for their help with setting up the experiments and their rapid responses to questions about aberrations in the data. NR 27 TC 1 Z9 1 U1 3 U2 17 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1386-4564 EI 1573-7659 J9 INFORM RETRIEVAL JI Inf. Retr. PD APR PY 2016 VL 19 IS 1-2 SI SI BP 38 EP 58 DI 10.1007/s10791-015-9265-z PG 21 WC Computer Science, Information Systems SC Computer Science GA DC1UM UT WOS:000369002500003 ER PT J AU Roberts, K Simpson, M Demner-Fushman, D Voorhees, E Hersh, W AF Roberts, Kirk Simpson, Matthew Demner-Fushman, Dina Voorhees, Ellen Hersh, William TI State-of-the-art in biomedical literature retrieval for clinical cases: a survey of the TREC 2014 CDS track SO INFORMATION RETRIEVAL LA English DT Article DE Biomedical information retrieval; Clinical decision support; Information retrieval evaluation ID PERFORMANCE; INFORMATION; DISEASES; DATABASE; MEDLINE; CARE AB Providing access to relevant biomedical literature in a clinical setting has the potential to bridge a critical gap in evidence-based medicine. Here, our goal is specifically to provide relevant articles to clinicians to improve their decision-making in diagnosing, treating, and testing patients. To this end, the TREC 2014 Clinical Decision Support Track evaluated a system's ability to retrieve relevant articles in one of three categories (Diagnosis, Treatment, Test) using an idealized form of a patient medical record . Over 100 submissions from over 25 participants were evaluated on 30 topics, resulting in over 37k relevance judgments. In this article, we provide an overview of the task, a survey of the information retrieval methods employed by the participants, an analysis of the results, and a discussion on the future directions for this challenging yet important task. C1 [Roberts, Kirk; Simpson, Matthew; Demner-Fushman, Dina] Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, NIH, Bethesda, MD USA. [Voorhees, Ellen] NIST, Gaithersburg, MD 20899 USA. [Hersh, William] Oregon Hlth & Sci Univ, Dept Med Informat & Clin Epidemiol, Portland, OR 97201 USA. RP Roberts, K (reprint author), Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, NIH, Bethesda, MD USA. EM kirk.roberts@nih.gov OI Hersh, William/0000-0002-4114-5148 FU intramural research program at U.S. National Library of Medicine, National Institutes of Health FX Kirk Roberts, Matthew Simpson, and Dina Demner-Fushman were supported by the intramural research program at the U.S. National Library of Medicine, National Institutes of Health. The authors would also like to thank the following participants for providing feedback and clarifications: Raymond Wan, Paul McNamee, Jean Garcia-Gathright, Joao Palotti, Eva D'hondt, Dawit Girmay, Afshin Deroie, Sungbin Choi, Luca Soldaini, Joe McCarthy, and Yi-Shu Wei. NR 75 TC 3 Z9 3 U1 1 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1386-4564 EI 1573-7659 J9 INFORM RETRIEVAL JI Inf. Retr. PD APR PY 2016 VL 19 IS 1-2 SI SI BP 113 EP 148 DI 10.1007/s10791-015-9259-x PG 36 WC Computer Science, Information Systems SC Computer Science GA DC1UM UT WOS:000369002500006 ER PT J AU Sajgo, S Ali, S Popescu, O Badea, TC AF Sajgo, Szilard Ali, Seid Popescu, Octavian Badea, Tudor Constantin TI Dynamic expression of transcription factor Brn3b during mouse cranial nerve development SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE cranial nerves; transcription; optic nerve; trigeminal nerve; facial nerve; glossopharyngeal nerve; vagus nerve; POU domain Brn3b ID RETINAL GANGLION-CELLS; MOTOR-NEURON DIFFERENTIATION; RHOMBOMERE-SPECIFIC ORIGIN; SUPERIOR OLIVARY COMPLEX; DORSAL-ROOT GANGLION; HOMEOBOX GENE PHOX2B; HORSERADISH-PEROXIDASE; SOMATOSENSORY NEURONS; FACIAL-NERVE; BRAIN-STEM AB During development, transcription factor combinatorial codes define a large variety of morphologically and physiologically distinct neurons. Such a combinatorial code has been proposed for the differentiation of projection neurons of the somatic and visceral components of cranial nerves. It is possible that individual neuronal cell types are not specified by unique transcription factors but rather emerge through the intersection of their expression domains. Brn3a, Brn3b, and Brn3c, in combination with each other and/or transcription factors of other families, can define subgroups of retinal ganglion cells (RGC), spiral and vestibular ganglia, inner ear and vestibular hair cell neurons in the vestibuloacoustic system, and groups of somatosensory neurons in the dorsal root ganglia. The present study investigates the expression and potential role of the Brn3b transcription factor in cranial nerves and associated nuclei of the brainstem. We report the dynamic expression of Brn3b in the somatosensory component of cranial nerves II, V, VII, and VIII and visceromotor nuclei of nerves VII, IX, and X as well as other brainstem nuclei during different stages of development into adult stage. We find that genetically identified Brn3b(KO) RGC axons show correct but delayed pathfinding during the early stages of embryonic development. However, loss of Brn3b does not affect the anatomy of the other cranial nerves normally expressing this transcription factor. J. Comp. Neurol. 524:1033-1061, 2016. (c) 2015 Wiley Periodicals, Inc. C1 [Sajgo, Szilard; Ali, Seid; Badea, Tudor Constantin] NEI, NIH, Bldg 6, Bethesda, MD 20892 USA. [Sajgo, Szilard; Popescu, Octavian] Univ Babes Bolyai, Ctr Mol Biol, Interdisciplinary Res Inst Bionanosci, Cluj Napoca 400084, Romania. [Popescu, Octavian] Romanian Acad, Inst Biol, Bucharest 060031, Romania. RP Badea, TC (reprint author), NEI, NIH, Bldg 6, Bethesda, MD 20892 USA. EM badeatc@mail.nih.gov FU National Eye Institute Intramural Funding FX Grant sponsor: National Eye Institute Intramural Funding (to T.C.B.). NR 118 TC 0 Z9 0 U1 1 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9967 EI 1096-9861 J9 J COMP NEUROL JI J. Comp. Neurol. PD APR 1 PY 2016 VL 524 IS 5 BP 1033 EP 1061 DI 10.1002/cne.23890 PG 29 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA DC3XP UT WOS:000369153400008 PM 26356988 ER PT J AU Kruszka, P Addissie, YA Yarnell, CMP Hadley, DW Sacoto, MJG Platte, P Paelecke, Y Collmann, H Snow, N Schweitzer, T Boyadjiev, SA Aravidis, C Hall, SE Mulliken, JB Roscioli, T Muenke, M AF Kruszka, Paul Addissie, Yonit A. Yarnell, Colin M. P. Hadley, Donald W. Sacoto, Maria J. Guillen Platte, Petra Paelecke, Yvonne Collmann, Hartmut Snow, Nicole Schweitzer, Tilmann Boyadjiev, Simeon A. Aravidis, Christos Hall, Samantha E. Mulliken, John B. Roscioli, Tony Muenke, Maximilian TI Muenke syndrome: An international multicenter natural history study SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE Muenke syndrome; FGFR3-related craniosynostosis; craniosynostosis ID GROWTH-FACTOR RECEPTOR-3; CORONAL CRANIOSYNOSTOSIS; MUTATIONS; PHENOTYPE; GENE; PREVALENCE; SYNOSTOSIS; MECHANISMS; EXPANSION; CHILDREN AB Muenke syndrome is an autosomal dominant disorder characterized by coronal suture craniosynostosis, hearing loss, developmental delay, carpal, and calcaneal fusions, and behavioral differences. Reduced penetrance and variable expressivity contribute to the wide spectrum of clinical findings. Muenke syndrome constitutes the most common syndromic form of craniosynostosis, with an incidence of 1 in 30,000 births and is defined by the presence of the p.Pro250Arg mutation in FGFR3. Participants were recruited from international craniofacial surgery and genetic clinics. Affected individuals, parents, and their siblings, if available, were enrolled in the study if they had a p.Pro250Arg mutation in FGFR3. One hundred and six patients from 71 families participated in this study. In 51 informative probands, 33 cases (64.7%) were inherited. Eighty-five percent of the participants had craniosynostosis (16 of 103 did not have craniosynostosis), with 47.5% having bilateral and 28.2% with unilateral synostosis. Females and males were similarly affected with bicoronal craniosynostosis, 50% versus 44.4% (P=0.84), respectively. Clefting was rare (1.1%). Hearing loss was identified in 70.8%, developmental delay in 66.3%, intellectual disability in 35.6%, attention deficit/hyperactivity disorder in 23.7%, and seizures in 20.2%. In patients with complete skeletal surveys (upper and lower extremity x-rays), 75% of individuals were found to have at least a single abnormal radiographical finding in addition to skull findings. This is the largest study of the natural history of Muenke syndrome, adding valuable clinical information to the care of these individuals including behavioral and cognitive impairment data, vision changes, and hearing loss. (c) 2016 Wiley Periodicals, Inc. C1 [Kruszka, Paul; Addissie, Yonit A.; Yarnell, Colin M. P.; Hadley, Donald W.; Sacoto, Maria J. Guillen; Muenke, Maximilian] NIH, Med Genet Branch, Natl Human Genome Res Inst, 35 Convent Dr,Room 1B203, Bethesda, MD 20892 USA. [Platte, Petra; Paelecke, Yvonne] Univ Wurzburg, Clin Psychol & Psychotherapy, Dept Biol Psychol, Wurzburg, Germany. [Collmann, Hartmut; Schweitzer, Tilmann; Roscioli, Tony] Univ Wurzburg, Dept Neurosurg, Sect Pediat Neurosurg, Wurzburg, Germany. [Snow, Nicole; Roscioli, Tony] Univ New S Wales, Sydney Childrens Hosp, Sydney, NSW, Australia. [Snow, Nicole] Garvan Inst, Kinghorn Ctr Clin Gen, Sydney, NSW, Australia. [Boyadjiev, Simeon A.] Univ Calif Davis, Genet Sect, Dept Pediat, Sacramento, CA 95817 USA. [Aravidis, Christos] Akad Univ Hosp, Dept Clin Genet, Uppsala, Sweden. [Hall, Samantha E.; Mulliken, John B.] Boston Childrens Hosp, Dept Plast & Oral Surg, Boston, MA USA. RP Muenke, M (reprint author), NIH, Med Genet Branch, Natl Human Genome Res Inst, 35 Convent Dr,Room 1B203, Bethesda, MD 20892 USA. EM mamuenke@mail.nih.gov NR 35 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD APR PY 2016 VL 170 IS 4 BP 918 EP 929 DI 10.1002/ajmg.a.37528 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA DH9EN UT WOS:000373099300014 PM 26740388 ER PT J AU VanderMeer, JE Carter, TC Pangilinan, F Mitchell, A Kurnat-Thoma, E Kirke, PN Troendle, JF Molloy, AM Munger, RG Feldkamp, ML Mansilla, MA Mills, JL Murray, JC Brody, LC AF VanderMeer, Julia E. Carter, Tonia C. Pangilinan, Faith Mitchell, Adam Kurnat-Thoma, Emma Kirke, Peadar N. Troendle, James F. Molloy, Anne M. Munger, Ronald G. Feldkamp, Marcia L. Mansilla, Maria A. Mills, James L. Murray, Jeff C. Brody, Lawrence C. TI Evaluation of proton-coupled folate transporter (SLC46A1) polymorphisms as risk factors for neural tube defects and oral clefts SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE folate; folic acid; folate transport; proton-coupled folate transporter; neural tube; oral clefts; cleft lip; cleft palate ID FOLIC-ACID; OROFACIAL CLEFTS; SPINA-BIFIDA; GENE POLYMORPHISMS; BIRTH-DEFECTS; CARRIER A80G; METHYLENETETRAHYDROFOLATE REDUCTASE; VITAMIN SUPPLEMENTATION; WIDE ASSOCIATION; IRISH POPULATION AB Many folate-related genes have been investigated for possible causal roles in neural tube defects (NTDs) and oral clefts. However, no previous reports have examined the major gene responsible for folate uptake, the proton-coupled folate transporter (SLC46A1). We tested for association between these birth defects and single nucleotide polymorphisms in the SLC46A1 gene. The NTD study population included 549 complete and incomplete case-family triads, and 999 controls from Ireland. The oral clefts study population comprised a sample from Utah (495 complete and incomplete case-family triads and 551 controls) and 221 Filipino multiplex cleft families. There was suggestive evidence of increased NTD case risk with the rs17719944 minor allele (odds ratio (OR): 1.29; 95% confidence intervals (CI): [1.00-1.67]), and decreased maternal risk of an NTD pregnancy with the rs4795436 minor allele (OR: 0.62; [0.39-0.99]). In the Utah sample, the rs739439 minor allele was associated with decreased case risk for cleft lip with cleft palate (genotype relative risk (GRR): 0.56 [0.32-0.98]). Additionally, the rs2239907 minor allele was associated with decreased case risk for cleft lip with cleft palate in several models, and with cleft palate only in a recessive model (OR: 0.41; [0.20-0.85]). These associations did not remain statistically significant after correcting for multiple hypothesis testing. Nominal associations between SLC46A1 polymorphisms and both Irish NTDs and oral clefts in the Utah population suggest some role in the etiology of these birth defects, but further investigation in other populations is needed. (c) 2016 Wiley Periodicals, Inc. C1 [VanderMeer, Julia E.; Pangilinan, Faith; Mitchell, Adam; Kurnat-Thoma, Emma; Brody, Lawrence C.] NHGRI, Sect Mol Pathogenesis, Med Genom & Metab Genet Branch, Bldg 50,Room 5306,50 South Dr,MSC 8004, Bethesda, MD 20892 USA. [Carter, Tonia C.; Mills, James L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Dept Hlth & Human Serv, NIH, Bethesda, MD USA. [Kirke, Peadar N.] Hlth Res Board, Unit Child Hlth Epidemiol, Dublin, Ireland. [Troendle, James F.] NHLBI, Off Biostat Res, Dept Hlth & Human Serv, NIH, Bldg 10, Bethesda, MD 20892 USA. [Molloy, Anne M.] Trinity Coll Dublin, Dept Clin Med, Dublin, Ireland. [Munger, Ronald G.] Utah State Univ, Dept Nutr Dietet & Food Sci, Logan, UT 84322 USA. [Feldkamp, Marcia L.] Univ Utah, Sch Med, Dept Pediat, Div Med Genet, Salt Lake City, UT USA. [Mansilla, Maria A.; Murray, Jeff C.] Univ Iowa, Dept Pediat, Div Neonatol, Iowa City, IA 52242 USA. RP Brody, LC (reprint author), NHGRI, Sect Mol Pathogenesis, Med Genom & Metab Genet Branch, Bldg 50,Room 5306,50 South Dr,MSC 8004, Bethesda, MD 20892 USA. EM lbrody@mail.nih.gov FU Eunice Kennedy Shriver NICHD; NHGRI; National Institute of Dental and Craniofacial Research; U.S. Centers for Disease Control and Prevention; Health Research Board, Dublin, Ireland FX Grant sponsor: Intramural Research Program of the Eunice Kennedy Shriver NICHD; Grant sponsor: Intramural Research Program of NHGRI; Grant sponsor: National Institute of Dental and Craniofacial Research; Grant sponsor: U.S. Centers for Disease Control and Prevention; Grant sponsor: Health Research Board, Dublin, Ireland. NR 52 TC 1 Z9 1 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD APR PY 2016 VL 170 IS 4 BP 1007 EP 1016 DI 10.1002/ajmg.a.37539 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA DH9EN UT WOS:000373099300024 PM 26789141 ER PT J AU Nailor, A Walker, DA Jacques, TS Warren, KE Brem, H Kearns, PR Greenwood, J Penny, JI Pilkington, GJ Carcaboso, AM Fleischhack, G Macarthur, D Slavc, I Meijer, L Gill, S Lowis, S van Vuurden, DG Pearl, MS Clifford, SC Morrissy, S Ivanov, DP Beccaria, K Gilbertson, RJ Straathof, K Green, JJ Smith, S Rahman, R Kilday, JP AF Nailor, Audrey Walker, David A. Jacques, Thomas S. Warren, Kathy E. Brem, Henry Kearns, Pamela R. Greenwood, John Penny, Jeffrey I. Pilkington, Geoffrey J. Carcaboso, Angel M. Fleischhack, Gudrun Macarthur, Donald Slavc, Irene Meijer, Lisethe Gill, Steven Lowis, Stephen van Vuurden, Dannis G. Pearl, Monica S. Clifford, Steven C. Morrissy, Sorana Ivanov, Delyan P. Beccaria, Kevin Gilbertson, Richard J. Straathof, Karin Green, Jordan J. Smith, Stuart Rahman, Ruman Kilday, John-Paul TI Highlights of Children with Cancer UK's Workshop on Drug Delivery in Paediatric Brain Tumours SO ECANCERMEDICALSCIENCE LA English DT Article DE drug delivery; translational medicine; paediatrics; brain tumours; glioma; medulloblastoma; CNS involvement; blood-brain barrier AB The first Workshop on Drug Delivery in Paediatric Brain Tumours was hosted in London by the charity Children with Cancer UK. The goals of the workshop were to break down the barriers to treating central nervous system (CNS) tumours in children, leading to new collaborations and further innovations in this under-represented and emotive field. These barriers include the physical delivery challenges presented by the blood-brain barrier, the underpinning reasons for the intractability of CNS cancers, and the practical difficulties of delivering cancer treatment to the brains of children. Novel techniques for overcoming these problems were discussed, new models brought forth, and experiences compared. C1 [Nailor, Audrey] Canc Intelligence, 154 Cheltenham Rd, Bristol BS6 5RL, Avon, England. [Walker, David A.] Univ Nottingham, Childrens Brain Tumour Res Ctr, Nottingham Childrens Hosp, Queens Med Ctr, Room EE 1833a, Nottingham NG7 2UH, England. [Jacques, Thomas S.] UCL, Inst Child Hlth, 30 Guilford St, London WC1N 1EH, England. [Warren, Kathy E.] NCI, Bldg 10 Hatfield CRC, Bethesda, MD 20892 USA. [Brem, Henry] Johns Hopkins Univ, 600 N Wolfe St, Baltimore, MD USA. [Kearns, Pamela R.] Univ Birmingham, Canc Res UK Clin Trials Unit, Birmingham B15 2TT, W Midlands, England. [Greenwood, John] UCL, 11-43 Bath St, London EC1V 9EL, England. [Penny, Jeffrey I.] Univ Manchester, Stopford Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England. [Pilkington, Geoffrey J.] Univ Portsmouth, Winston Churchill Ave, Portsmouth PO1 2UP, Hants, England. [Carcaboso, Angel M.] Hosp St Joan de Deu, Inst Recerca, Barcelona, Spain. [Fleischhack, Gudrun] Essen Univ Hosp, Paediat 3, Hufelandstr 55, D-45147 Essen, Germany. [Macarthur, Donald; Meijer, Lisethe] Univ Nottingham Hosp, Derby Rd, Nottingham NG7 2UH, England. [Slavc, Irene] Med Univ Vienna, Spitalgasse 23, A-1090 Vienna, Austria. [Meijer, Lisethe] Univ Med Ctr Groningen, 1 Hanzepl, NL-9713 GZ Groningen, Netherlands. [Gill, Steven; Lowis, Stephen] Bristol Royal Hosp Children, Upper Maudlin St, Bristol BS2 8BJ, Avon, England. [van Vuurden, Dannis G.] Vrije Univ Amsterdam Med Ctr, Boelelaan 1118, NL-1081 HZ Amsterdam, Netherlands. [Pearl, Monica S.] Johns Hopkins Univ, Sch Med, 1800 Orleans St,Bloomberg Bldg 7218, Baltimore, MD 21287 USA. [Clifford, Steven C.] Univ Newcastle, Royal Victoria Infirm, Queen Victoria Rd, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England. [Morrissy, Sorana] Hosp Sick Children, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. [Ivanov, Delyan P.] Univ Nottingham Hosp, Derby Rd, Nottingham NG7 2UH, England. [Beccaria, Kevin] Hop La Pitie Salpetriere, AP HP, 27 Rue Chaligny, F-75012 Paris, France. [Gilbertson, Richard J.] Cambridge Canc Ctr, 120 Cambridge Rd, Cambridge CB22 5JT, England. [Straathof, Karin] UCL, Inst Child Hlth, 30 Guilford St, London WC1N 1EH, England. [Green, Jordan J.] Johns Hopkins Univ, Sch Med, Translat Tissue Engn Ctr, Inst NanoBioTechnol, 400 N Broadway,Smith Bldg Room 5017, Baltimore, MD 21231 USA. [Smith, Stuart; Rahman, Ruman] Univ Nottingham Hosp, Derby Rd, Nottingham NG7 2UH, England. [Kilday, John-Paul] Royal Manchester Childrens Hosp, Oxford Rd, Manchester M13 9WL, Lancs, England. RP Nailor, A (reprint author), Canc Intelligence, 154 Cheltenham Rd, Bristol BS6 5RL, Avon, England. EM audrey@ecancer.org OI Van Vuurden, Dannis/0000-0002-1364-9007; Carcaboso, Angel/0000-0002-8485-426X; Ivanov, Delyan/0000-0001-5515-5251 FU NCI NIH HHS [P01 CA096832] NR 1 TC 0 Z9 0 U1 2 U2 2 PU CANCER INTELLIGENCE LTD PI BRISTOL PA 11 ALMA VALE RD,, BRISTOL, BS8 2HL, ENGLAND SN 1754-6605 J9 ECANCERMEDICALSCIENC JI eCancerMedicalScience PD MAR 31 PY 2016 VL 10 AR 630 DI 10.3332/ecancer.2016.630 PG 13 WC Oncology SC Oncology GA DK7PA UT WOS:000375117000001 PM 27110286 ER PT J AU Little, MP Hendry, JH Puskin, JS AF Little, Mark P. Hendry, Jolyon H. Puskin, Jerome S. TI Lack of Correlation between Stem-Cell Proliferation and Radiation-or Smoking-Associated Cancer Risk SO PLOS ONE LA English DT Article ID GENOMIC INSTABILITY; COLON-CANCER; RELATIVE RISK; CARCINOGENESIS; MODEL; MORTALITY; EXPOSURE; LUNG; MUTATIONS; ARMITAGE AB Background A recent paper by Tomasetti and Vogelstein (Science 2015 347 78-81) suggested that the variation in natural cancer risk was largely explained by the total number of stem-cell divisions, and that most cancers arose by chance. They proposed an extra-risk score as way of distinguishing the effects of the stochastic, replicative component of cancer risk from other causative factors, specifically those due to the external environment and inherited mutations. Objectives We tested the hypothesis raised by Tomasetti and Vogelstein by assessing the degree of correlation of stem cell divisions and their extra-risk score with radiation-and tobacco-associated cancer risk. Methods We fitted a variety of linear and log-linear models to data on stem cell divisions per year and cumulative stem cell divisions over lifetime and natural cancer risk, some taken from the paper of Tomasetti and Vogelstein, augmented using current US lifetime cancer risk data, and also radiation-and tobacco-associated cancer risk. Results The data assembled by Tomasetti and Vogelstein, as augmented here, are inconsistent with the power-of-age relationship commonly observed for cancer incidence and the predictions of a multistage carcinogenesis model, if one makes the strong assumption of homogeneity of numbers of driver mutations across cancer sites. Analysis of the extra-risk score and various other measures (number of stem cell divisions per year, cumulative number of stem cell divisions over life) considered by Tomasetti and Vogelstein suggests that these are poorly predictive of currently available estimates of radiation- or smoking-associated cancer risk-for only one out of 37 measures or logarithmic transformations thereof is there a statistically significant correlation (p<0.05) with radiation-or smoking-associated risk. Conclusions The data used by Tomasetti and Vogelstein are in conflict with predictions of a multistage model of carcinogenesis, under the assumption of homogeneity of numbers of driver mutations across most cancer sites. Their hypothesis that if the extra-risk score for a tissue type is high then one would expect that environmental factors would play a relatively more important role in that cancer's risk is in conflict with the lack of correlation between the extra-risk score and other stem-cell proliferation indices and radiation-or smoking-related cancer risk. C1 [Little, Mark P.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Rockville, MD USA. [Hendry, Jolyon H.] Christie Hosp, Christie Med Phys & Engn, Manchester, Lancs, England. [Hendry, Jolyon H.] Univ Manchester, Manchester, Lancs, England. [Puskin, Jerome S.] US EPA, Radiat Protect Div, Washington, DC 20460 USA. RP Little, MP (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Rockville, MD USA. EM mark.little@nih.gov OI Matsuo, Keitaro/0000-0003-1761-6314 FU Intramural Research Program of the National Institutes of Health, the National Cancer Institute, Division of Cancer Epidemiology and Genetics FX The work of MPL was supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute, Division of Cancer Epidemiology and Genetics. NR 38 TC 4 Z9 4 U1 3 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 31 PY 2016 VL 11 IS 3 AR e0150335 DI 10.1371/journal.pone.0150335 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH9NC UT WOS:000373121800006 PM 27031507 ER PT J AU Milutinovic, S Heynen-Genel, S Chao, E Dewing, A Solano, R Milan, L Barron, N He, M Diaz, PW Matsuzawa, S Reed, JC Hassig, CA AF Milutinovic, Snezana Heynen-Genel, Susanne Chao, Elizabeth Dewing, Antimone Solano, Ricardo Milan, Loribelle Barron, Nikki He, Min Diaz, Paul W. Matsuzawa, Shuichi Reed, John C. Hassig, Christian A. TI Cardiac Glycosides Activate the Tumor Suppressor and Viral Restriction Factor Promyelocytic Leukemia Protein (PML) SO PLOS ONE LA English DT Article ID NUCLEAR-BODY FORMATION; ARSENIC TRIOXIDE; CARDIOTONIC STEROIDS; INDUCED APOPTOSIS; INHIBITION; ATPASE; RAR; THERAPY; BODIES; GENE AB Cardiac glycosides (CGs), inhibitors of Na+/K+-ATPase (NKA), used clinically to treat heart failure, have garnered recent attention as potential anti-cancer and anti-viral agents. A high-throughput phenotypic screen designed to identify modulators of promyelocytic leukemia protein (PML) nuclear body (NB) formation revealed the CG gitoxigenin as a potent activator of PML. We demonstrate that multiple structurally distinct CGs activate the formation of PML NBs and induce PML protein SUMOylation in an NKA-dependent fashion. CG effects on PML occur at the post-transcriptional level, mechanistically distinct from previously described PML activators and are mediated through signaling events downstream of NKA. Curiously, genomic deletion of PML in human cancer cells failed to abrogate the cytotoxic effects of CGs and other apoptotic stimuli such as ceramide and arsenic trioxide that were previously shown to function through PML in mice. These findings suggest that alternative pathways can compensate for PML loss to mediate apoptosis in response to CGs and other apoptotic stimuli. C1 [Milutinovic, Snezana; Heynen-Genel, Susanne; Chao, Elizabeth; Dewing, Antimone; Solano, Ricardo; Milan, Loribelle; Matsuzawa, Shuichi; Reed, John C.; Hassig, Christian A.] Sanford Burnham Prebys Med Discovery Inst, 10901 N Torrey Pines Rd, La Jolla, CA 92037 USA. [Barron, Nikki] Bemer USA LLC, Carlsbad, CA USA. [He, Min] NCI, Bethesda, MD 20892 USA. [Diaz, Paul W.] P William Diaz Pharmaceut Consulting, Riverside, CA USA. [Reed, John C.] Roche, Grenzacherstr 124, CH-4070 Basel, Switzerland. RP Hassig, CA (reprint author), Sanford Burnham Prebys Med Discovery Inst, 10901 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM chassig@sbpdiscovery.org FU National Cancer Institute NExT Program, National Institutes of Health [HHSN261200800001E] FX National Cancer Institute NExT Program, National Institutes of Health, under contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government.; We are grateful to members of the Reed laboratory and the Conrad Prebys Center for Chemical Genomics for assistance with assay optimization and screening. This project was supported in part by federal funds from the National Cancer Institute NExT Program, National Institutes of Health, under contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. NR 34 TC 1 Z9 1 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 31 PY 2016 VL 11 IS 3 AR e0152692 DI 10.1371/journal.pone.0152692 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH9NC UT WOS:000373121800120 PM 27031987 ER PT J AU Pava, MJ Makriyannis, A Lovinger, DM AF Pava, Matthew J. Makriyannis, Alexandros Lovinger, David M. TI Endocannabinoid Signaling Regulates Sleep Stability SO PLOS ONE LA English DT Article ID ACID AMIDE HYDROLASE; BICYCLIC CANNABINOID ANALOGS; PENTOBARBITAL-INDUCED SLEEP; INCREASES REM-SLEEP; C-FOS EXPRESSION; RAT-BRAIN; RECEPTOR ANTAGONIST; KNOCKOUT MICE; TOLERANCE DEVELOPMENT; LATERAL HYPOTHALAMUS AB The hypnogenic properties of cannabis have been recognized for centuries, but endogenous cannabinoid (endocannabinoid) regulation of vigilance states is poorly characterized. We report findings from a series of experiments in mice measuring sleep with polysomnography after various systemic pharmacological manipulations of the endocannabinoid system. Rapid, unbiased scoring of vigilance states was achieved using an automated algorithm that we devised and validated. Increasing endocannabinoid tone with a selective inhibitor of monoacyglycerol lipase (JZL184) or fatty acid amide hydrolase (AM3506) produced a transient increase in non-rapid eye movement (NREM) sleep due to an augmentation of the length of NREM bouts (NREM stability). Similarly, direct activation of type 1 cannabinoid (CB1) receptors with CP47,497 increased NREM stability, but both CP47,497 and JZL184 had a secondary effect that reduced NREM sleep time and stability. This secondary response to these drugs was similar to the early effect of CB1 blockade with the antagonist/inverse agonist AM281, which fragmented NREM sleep. The magnitude of the effects produced by JZL184 and AM281 were dependent on the time of day this drug was administered. While activation of CB1 resulted in only a slight reduction in gamma power, CB1 blockade had dramatic effects on broadband power in the EEG, particularly at low frequencies. However, CB1 blockade did not significantly reduce the rebound in NREM sleep following total sleep deprivation. These results support the hypothesis that endocannabinoid signaling through CB1 is necessary for NREM stability but it is not necessary for sleep homeostasis. C1 [Pava, Matthew J.; Lovinger, David M.] NIAAA, Sect Synapt Pharmacol, Lab Integrat Neurosci, Div Intramural Biol & Clin Res,NIH, Rockville, MD 20852 USA. [Makriyannis, Alexandros] Northeastern Univ, Ctr Drug Discovery, Boston, MA 02115 USA. [Makriyannis, Alexandros] Northeastern Univ, Dept Chem & Chem Biol, Boston, MA 02115 USA. [Makriyannis, Alexandros] Northeastern Univ, Dept Pharmaceut Sci, Boston, MA 02115 USA. RP Lovinger, DM (reprint author), NIAAA, Sect Synapt Pharmacol, Lab Integrat Neurosci, Div Intramural Biol & Clin Res,NIH, Rockville, MD 20852 USA. EM lovindav@mail.nih.gov FU United States National Institutes of Health; National Institute on Alcohol Abuse and Alcoholism's Division of Intramural Clinical and Biological Research [ZIA AA000416]; National Institute on Drug Abuse Grant [DA003801] FX This work was supported by the United States National Institutes of Health. DML and MJP received support from the National Institute on Alcohol Abuse and Alcoholism's Division of Intramural Clinical and Biological Research, award number ZIA AA000416 (http://www.niaaa.nih.gov/). AM received support from National Institute on Drug Abuse Grant DA003801 (http://www.drugabuse.gov/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 86 TC 1 Z9 1 U1 3 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 31 PY 2016 VL 11 IS 3 AR e0152473 DI 10.1371/journal.pone.0152473 PG 47 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH9NC UT WOS:000373121800080 PM 27031992 ER PT J AU Liu, ZZ Cheng, TTK Shi, ZY Liu, ZR Lei, Y Wang, CD Shi, WL Chen, XF Qi, XF Cai, DQ Feng, B Deng, Y Chen, YL Zhao, H AF Liu, Zhongzhen Cheng, Tina Tsz Kwan Shi, Zhaoying Liu, Ziran Lei, Yong Wang, Chengdong Shi, Weili Chen, Xiongfeng Qi, Xufeng Cai, Dongqing Feng, Bo Deng, Yi Chen, Yonglong Zhao, Hui TI Efficient genome editing of genes involved in neural crest development using the CRISPR/Cas9 system in Xenopus embryos SO CELL AND BIOSCIENCE LA English DT Article DE Genome editing; Cas9; Neural crest; Gene disruption; Segmental deletion/inversion; Multiplex deletion; Xenopus ID EFFECTOR NUCLEASES TALENS; ZINC-FINGER NUCLEASES; ONE-STEP GENERATION; HUMAN-CELLS; CHROMOSOMAL DELETIONS; TARGETED MUTAGENESIS; CRISPR-CAS9 SYSTEM; TROPICALIS EMBRYOS; CAS SYSTEMS; RNA AB Background: The RNA guided CRISPR/Cas9 nucleases have been proven to be effective for gene disruption in various animal models including Xenopus tropicalis. The neural crest (NC) is a transient cell population during embryonic development and contributes to a large variety of tissues. Currently, loss-of-function studies on NC development in X. tropicalis are largely based on morpholino antisense oligonucleotide. It is worthwhile establishing targeted gene knockout X. tropicails line using CRISPR/Cas9 system to study NC development. Methods: We utilized CRISPR/Cas9 to disrupt genes that are involved in NC formation in X. tropicalis embryos. A single sgRNA and Cas9 mRNA synthesized in vitro, were co-injected into X. tropicalis embryos at one-cell stage to induce single gene disruption. We also induced duplex mutations, large segmental deletions and inversions in X. tropicalis by injecting Cas9 and a pair of sgRNAs. The specificity of CRISPR/Cas9 was assessed in X. tropicalis embryos and the Cas9 nickase was used to reduce the off-target cleavages. Finally, we crossed the G0 mosaic frogs with targeted mutations to wild type frogs and obtained the germline transmission. Results: Total 16 target sites in 15 genes were targeted by CRISPR/Cas9 and resulted in successful indel mutations at 14 loci with disruption efficiencies in a range from 9.3 to 57.8 %. Furthermore, we demonstrated the feasibility of generation of duplex mutations, large segmental deletions and inversions by using Cas9 and a pair of sgRNAs. We observed that CRISPR/Cas9 displays obvious off-target effects at some loci in X. tropicalis embryos. Such off-target cleavages was reduced by using the D10A Cas9 nickase. Finally, the Cas9 induced indel mutations were efficiently passed to G1 offspring. Conclusion: Our study proved that CRISPR/Cas9 could mediate targeted gene mutation in X. tropicalis with high efficiency. This study expands the application of CRISPR/Cas9 platform in X. tropicalis and set a basis for studying NC development using genetic approach. C1 [Liu, Zhongzhen; Cheng, Tina Tsz Kwan; Liu, Ziran; Lei, Yong; Wang, Chengdong; Shi, Weili; Feng, Bo; Zhao, Hui] Chinese Univ Hong Kong, Sch Biomed Sci, Key Lab Regenerat Med, Minist Educ,Fac Med, Hong Kong, Hong Kong, Peoples R China. [Shi, Zhaoying; Deng, Yi; Chen, Yonglong] South Univ Sci & Technol China, Shenzhen Key Lab Cell Microenvironm, Dept Biol, Shenzhen 518055, Guangdong, Peoples R China. [Chen, Xiongfeng] NCI, Adv Biomed Comp Ctr, NIH, Frederick, MD 21702 USA. [Qi, Xufeng; Cai, Dongqing] Ji Nan Univ, Key Lab Regenerat Med, Minist Educ, Guangzhou 510632, Guangdong, Peoples R China. [Liu, Zhongzhen; Zhao, Hui] KIZ CUHK Joint Lab Bioresources & Mol Res Common, Hong Kong, Hong Kong, Peoples R China. [Qi, Xufeng; Cai, Dongqing] Ji Nan Univ, Coll Life Sci & Technol, Dept Dev & Regenerat Biol, Guangzhou 510632, Guangdong, Peoples R China. RP Zhao, H (reprint author), Chinese Univ Hong Kong, Sch Biomed Sci, Key Lab Regenerat Med, Minist Educ,Fac Med, Hong Kong, Hong Kong, Peoples R China.; Chen, YL (reprint author), South Univ Sci & Technol China, Shenzhen Key Lab Cell Microenvironm, Dept Biol, Shenzhen 518055, Guangdong, Peoples R China.; Zhao, H (reprint author), KIZ CUHK Joint Lab Bioresources & Mol Res Common, Hong Kong, Hong Kong, Peoples R China. EM chenyl@sustc.edu.cn; zhaohui@cuhk.edu.hk RI Zhao, Hui/B-8429-2016 FU Research Grants Council of Hong Kong [CUHK413/12, CUHK24100414]; National Natural Science Foundation of China [31471367, 31271554]; National Basic Research Program of China [81200566]; Fundamental Research Funds for the Central Universities (Ji Nan University) [11614601]; Shenzhen Key Laboratory of Cell Microenvironment [ZDSYS20140509142721429]; Chinese University of Hong Kong FX The authors thank Prof. George M Church, Feng Zhang, James A. Thomason, and Erik J. Sontheimer, and Addgene for making the plasmids available to research community. The authors are in debt to those colleagues whose work could not be cited due to space constraint. This work is supported by Grants from the Research Grants Council of Hong Kong CUHK413/12 and CUHK24100414 to HZ, by 31471367 and 31271554 of National Natural Science Foundation of China to YC, by fund of 81200566 from the National Basic Research Program of China to YD, and the Fundamental Research Funds for the Central Universities (Ji Nan University) (11614601) to HZ and XFQ. YC and YD are also supported by Shenzhen Key Laboratory of Cell Microenvironment (ZDSYS20140509142721429). ZZL and TKC are supported by the Graduate Studentships from The Chinese University of Hong Kong. We thank colleagues in our laboratories for helpful discussion on this project. NR 53 TC 1 Z9 1 U1 4 U2 14 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 MAR 31 PY 2016 VL 6 AR 22 DI 10.1186/s13578-016-0088-4 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DI0NI UT WOS:000373193000001 PM 27042291 ER PT J AU Mandelkow, H de Zwart, JA Duyn, JH AF Mandelkow, Hendrik de Zwart, Jacco A. Duyn, Jeff H. TI Linear Discriminant Analysis Achieves High Classification Accuracy for the BOLD fMRI Response to Naturalistic Movie Stimuli SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE BOLD fMRI; multivariate pattern analysis (MVPA); classification; movies; naturalistic stimuli; linear discriminant analysis (LDA); Gaussian Naive Bayes (GNB); nearest-neighbor ID VENTRAL TEMPORAL CORTEX; HUMAN BRAIN; FUNCTIONAL ARCHITECTURE; PATTERN-CLASSIFICATION; VISION; REPRESENTATION; COMMUNICATION; CLASSIFIERS; SCENES; SPACE AB Naturalistic stimuli like movies evoke complex perceptual processes, which are of great interest in the study of human cognition by functional MRI (fMRI). However, conventional fMRI analysis based on statistical parametric mapping (SPM) and the general linear model (GLM) is hampered by a lack of accurate parametric models of the BOLD response to complex stimuli. In this situation, statistical machine-learning methods, a.k.a. multivariate pattern analysis (MVPA), have received growing attention for their ability to generate stimulus response models in a data-driven fashion. However, machine-learning methods typically require large amounts of training data as well as computational resources. In the past, this has largely limited their application to fMRI experiments involving small sets of stimulus categories and small regions of interest in the brain. By contrast, the present study compares several classification algorithms known as Nearest Neighbor (NN), Gaussian Naive Bayes (GNB), and (regularized) Linear Discriminant Analysis (LDA) in terms of their classification accuracy in discriminating the global fMRI response patterns evoked by a large number of naturalistic visual stimuli presented as a movie. Results show that LDA regularized by principal component analysis (RCA) achieved high classification accuracies, above 90% on average for single fMRI volumes acquired 2 s apart during a 300 s movie (chance level 0.7% = 2 s/300 s). The largest source of classification errors were autocorrelations in the BOLD signal compounded by the similarity of consecutive stimuli. All classifiers performed best when given input features from a large region of interest comprising around 25% of the voxels that responded significantly to the visual stimulus. Consistent with this, the most informative principal components represented widespread distributions of co-activated brain regions that were similar between subjects and may represent functional networks. In light of these results, the combination of naturalistic movie stimuli and classification analysis in fMRI experiments may prove to be a sensitive tool for the assessment of changes in natural cognitive processes under experimental manipulation. C1 [Mandelkow, Hendrik; de Zwart, Jacco A.; Duyn, Jeff H.] NINDS, Adv MRI Sect, Lab Funct & Mol Imaging, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Mandelkow, H (reprint author), NINDS, Adv MRI Sect, Lab Funct & Mol Imaging, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM hendrik.mandelkow@nih.gov FU intramural research program of the National Institute of Neurological Disorders and Stroke (NINDS) FX Great thanks for fantastic volunteer management and scan support go to Steven Newman and Susan Guttman. Likewise, the authors thank Dr. Catie Chang for inspiring discussions. This research was supported by the intramural research program of the National Institute of Neurological Disorders and Stroke (NINDS). NR 34 TC 2 Z9 2 U1 4 U2 8 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD MAR 31 PY 2016 VL 10 AR 128 DI 10.3389/fnhum.2016.00128 PG 12 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA DI2PE UT WOS:000373338000001 PM 27065832 ER PT J AU Zhu, X Sundby, K Bjork, JM Momenan, R AF Zhu, Xi Sundby, Kelsey Bjork, James M. Momenan, Reza TI Alcohol Dependence and Altered Engagement of Brain Networks in Risky Decisions SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE decision-making; risk; ICA; alcohol-dependence; salience network ID STATE FUNCTIONAL CONNECTIVITY; PREFRONTAL CORTEX; INSULAR CORTEX; DRUG-ADDICTION; NEURAL SYSTEMS; REWARD; ACTIVATION; TASK; CINGULATE; DEFICITS AB Alcohol dependence is associated with heightened risk tolerance and altered decision making. This raises the question as to whether alcohol dependent patients (ADP) are incapable of proper risk assessment. We investigated how healthy controls (HC) and ADP engage neural networks to cope with the increased cognitive demands of risky decisions. We collected fMRI data while 34 HC and 16 ADP played a game that included "safe" and "risky" trials. In safe trials, participants accrued money at no risk of a penalty. In risky trials, reward and risk simultaneously increased as participants were instructed to decide when to stop a reward accrual period. If the participant failed to stop before an undisclosed time, the trial would "bust" and participants would not earn the money from that trial. Independent Component Analysis was used to identify networks engaged during the anticipation and the decision execution of risky compared with safe trials. Like HC, ADP demonstrated distinct network engagement for safe and risky trials at anticipation. However, at decision execution, ADP exhibited severely reduced discrimination in network engagement between safe and risky trials. Although ADP behaviorally responded to risk they failed to appropriately modify network engagement as the decision continued, leading ADP to assume similar network engagement regardless of risk prospects. This may reflect disorganized network switching and a facile response strategy uniformly adopted by ADP across risk conditions. We propose that aberrant salience network (SN) engagement in ADP might contribute to ineffective network switching and that the role of the SN in risky decisions warrants further investigation. C1 [Zhu, Xi; Sundby, Kelsey; Momenan, Reza] NIAAA, Clin NeuroImaging Res Core, Bethesda, MD USA. [Bjork, James M.] Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA USA. RP Momenan, R (reprint author), NIAAA, Clin NeuroImaging Res Core, Bethesda, MD USA. EM rezam@mail.nih.gov FU National Institute on Alcohol Abuse; Alcoholism intramural funding FX This research was supported by the National Institute on Alcohol Abuse and Alcoholism intramural funding. NR 42 TC 1 Z9 1 U1 6 U2 8 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD MAR 31 PY 2016 VL 10 AR 142 DI 10.3389/fnhum.2016.00142 PG 11 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA DI2PG UT WOS:000373338200004 PM 27064561 ER PT J AU Parks, CG D'Aloisio, AA Sandler, DP AF Parks, Christine G. D'Aloisio, Aimee A. Sandler, Dale P. TI Early Life Factors Associated with Adult-Onset Systemic Lupus Erythematosus in Women SO FRONTIERS IN IMMUNOLOGY LA English DT Article DE lifecourse epidemiology; pesticide exposure; birthweight; preterm birth; autoimmune disease ID RHEUMATOID-ARTHRITIS; RISK-FACTORS; DISEASE; HEALTH; POPULATION; EXPOSURES; BIRTH; DISPARITIES; MORTALITY; ORIGINS AB Background: Exposure early in life can influence adult disease and immunity, but the role of early life exposures in risk of systemic lupus erythematosus (SLE) is not established. Methods: Women in a national cohort (ages 35-74) provided data on perinatal, maternal, and sociodemographic factors, longest residence to age 14, and residential farm history of at least 12 months to age 18. Cases (N = 124) reported SLE diagnosed age 16 years or older with use of disease modifying antirheumatic drugs. Non-cases (N = 50,465) did not report lupus. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by logistic regression adjusting for age and race/ethnicity. Results: SLE was associated with low birthweight (data on 84 cases and 36,477 non cases; <2,500 versus 3,000 to <3,500 g OR = 2.2; 95%CI 1.2, 3.9) and preterm birth (57 cases and 22,784 non-cases; >= 1 month early versus full-term OR = 3.4; 95%CI 1.6, 7.4). Considering longest childhood residence to age 14, SLE was associated with more frequent pesticide use (e.g., at least monthly OR = 2.3; 95%CI 1.3, 4.1). SLE was associated with having an early and extended childhood farm residence (i.e., prenatal/maternal farm exposure and longest childhood farm residence OR = 1.8; 95%CI 1.1, 3.0 versus neither). In those with a childhood-only farm residence of 12+ months, agricultural pesticide use was associated with SLE, with the strongest associations for direct personal exposures. Conclusion: The association of SLE with preterm birth is consistent with studies in other populations and with an observed association with low birthweight. The associations of SLE with childhood exposure to residential and agricultural pesticides warrant further study. C1 [Parks, Christine G.; D'Aloisio, Aimee A.; Sandler, Dale P.] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [D'Aloisio, Aimee A.] Social & Sci Syst Inc, Durham, NC USA. RP Parks, CG (reprint author), NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. EM parks1@mail.nih.gov OI Parks, Christine/0000-0002-5734-3456 FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES044005] FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01 ES044005). NR 34 TC 1 Z9 1 U1 1 U2 2 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD MAR 31 PY 2016 VL 7 AR 103 DI 10.3389/fimmu.2016.00103 PG 7 WC Immunology SC Immunology GA DI2PT UT WOS:000373339600002 PM 27064771 ER PT J AU Bernstock, JD Budinich, CS Cohen, LG Awosika, OO AF Bernstock, Joshua D. Budinich, Craig S. Cohen, Leonardo G. Awosika, Oluwole O. TI Recrudescence of Focal stroke symptoms during pain Management with Hydromorphone SO FRONTIERS IN NEUROLOGY LA English DT Article DE stroke; pain management; opioids; plasticity; recrudescence of symptoms ID NEUROLOGICAL DEFICITS; MIDAZOLAM CHALLENGE; OPIOID RECEPTORS; NALOXONE; RECOVERY; REVERSAL; MEMORY AB Patients who have recovered from a prior stroke may experience a reemergence of their original stroke syndrome secondary to metabolic derangements, sedation, infection, and/or fatigue. Critically, the molecular/cellular mechanisms mediating symptom recurrence after exposure to analgesic agents remain unknown. Accordingly, herein, we report a unique case of a patient with hydromorphone-induced recrudescence 30 years after her initial stroke event(s) and in so doing propose a putative mechanism related to post-infarction functional neuroplasticity. C1 [Bernstock, Joshua D.] NINDS, Stroke Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Budinich, Craig S.] Dwight D Eisenhower Army Med Ctr, Dept Anesthesiol, Ft Gordon, GA USA. [Cohen, Leonardo G.; Awosika, Oluwole O.] NINDS, Human Cort Physiol & Stroke Neurorehabil Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Awosika, OO (reprint author), NINDS, Human Cort Physiol & Stroke Neurorehabil Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM awosikaoo@ninds.nih.gov FU Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health (NINDS/NIH) 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 of the National Institute of Neurological Disorders and Stroke, National Institutes of Health (NINDS/NIH). NR 18 TC 0 Z9 0 U1 1 U2 2 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-2295 J9 FRONT NEUROL JI Front. Neurol. PD MAR 31 PY 2016 VL 7 AR 50 DI 10.3389/fneur.2016.00050 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DI0IH UT WOS:000373178400001 PM 27064505 ER PT J AU Craddock, RC Margulies, DS Bellec, P Nichols, BN Alcauter, S Barrios, FA Burnod, Y Cannistraci, CJ Cohen-Adad, J De Leener, B Dery, S Downar, J Dunlop, K Franco, AR Froehlich, CS Gerber, AJ Ghosh, SS Grabowski, TJ Hill, S Heinsfeld, AS Hutchison, RM Kundu, P Laird, AR Liew, SL Lurie, DJ McLaren, DG Meneguzzi, F Mennes, M Mesmoudi, S O'Connor, D Pasaye, EH Peltier, S Poline, JB Prasad, G Pereira, RF Quirion, PO Rokem, A Saad, ZS Shi, YG Strother, SC Toro, R Uddin, LQ Van Horn, JD Van Meter, JW Welsh, RC Xu, T AF Craddock, R. Cameron Margulies, Daniel S. Bellec, Pierre Nichols, B. Nolan Alcauter, Sarael Barrios, Fernando A. Burnod, Yves Cannistraci, Christopher J. Cohen-Adad, Julien De Leener, Benjamin Dery, Sebastien Downar, Jonathan Dunlop, Katharine Franco, Alexandre R. Froehlich, Caroline Seligman Gerber, Andrew J. Ghosh, Satrajit S. Grabowski, Thomas J. Hill, Sean Heinsfeld, Anibal Solon Hutchison, R. Matthew Kundu, Prantik Laird, Angela R. Liew, Sook-Lei Lurie, Daniel J. McLaren, Donald G. Meneguzzi, Felipe Mennes, Maarten Mesmoudi, Salma O'Connor, David Pasaye, Erick H. Peltier, Scott Poline, Jean-Baptiste Prasad, Gautam Pereira, Ramon Fraga Quirion, Pierre-Olivier Rokem, Ariel Saad, Ziad S. Shi, Yonggang Strother, Stephen C. Toro, Roberto Uddin, Lucina Q. Van Horn, John D. Van Meter, John W. Welsh, Robert C. Xu, Ting TI Brainhack: a collaborative workshop for the open neuroscience community SO GIGASCIENCE LA English DT Review DE Hackathon; Unconference; Open science; Neuroscience; Data sharing; Collaboration; Networking ID THICKNESS; MRI AB Brainhack events offer a novel workshop format with participant-generated content that caters to the rapidly growing open neuroscience community. Including components from hackathons and unconferences, as well as parallel educational sessions, Brainhack fosters novel collaborations around the interests of its attendees. Here we provide an overview of its structure, past events, and example projects. Additionally, we outline current innovations such as regional events and post-conference publications. Through introducing Brainhack to the wider neuroscience community, we hope to provide a unique conference format that promotes the features of collaborative, open science. C1 [Craddock, R. Cameron; Margulies, Daniel S.; Bellec, Pierre; Nichols, B. Nolan; Franco, Alexandre R.; Froehlich, Caroline Seligman; Ghosh, Satrajit S.; Hutchison, R. Matthew; Kundu, Prantik; Liew, Sook-Lei; McLaren, Donald G.; Mennes, Maarten; Toro, Roberto; Uddin, Lucina Q.] Neuro Bur, D-04317 Leipzig, Germany. [Craddock, R. Cameron; Froehlich, Caroline Seligman] Nathan S Kline Inst Psychiat Res, Ctr Biomed Imaging & Neuromodulat, Computat Neuroimaging Lab, Orangeburg, NY 10962 USA. [Craddock, R. Cameron; O'Connor, David; Xu, Ting] Child Mind Inst, Ctr Dev Brain, New York, NY 10022 USA. [Margulies, Daniel S.] Max Planck Inst Human Cognit & Brain Sci, Max Planck Res Grp Neuroanat & Connect, D-04103 Leipzig, Germany. [Bellec, Pierre] Univ Montreal, Dept Informat & Rech Operat, Montreal, PQ H3W 1W5, Canada. [Bellec, Pierre; Cohen-Adad, Julien; Quirion, Pierre-Olivier] Inst Univ Geriatrie Montreal, Ctr Rech, Funct Neuroimaging Unit, Montreal, PQ H3W 1W5, Canada. [Nichols, B. Nolan] SRI Int, Ctr Hlth Sci, Menlo Pk, CA 94025 USA. [Nichols, B. Nolan] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. [Alcauter, Sarael; Barrios, Fernando A.; Pasaye, Erick H.] Univ Nacl Autonoma Mexico, Inst Neurobiol, Queretaro 76203, Mexico. [Burnod, Yves] Univ Paris 06, Univ Sorbonne, Lab Imagerie Biomed, F-75005 Paris, France. [Burnod, Yves; Mesmoudi, Salma] Inst Syst Complexes Paris Ile de France, F-75013 Paris, France. [Cannistraci, Christopher J.; Kundu, Prantik] Icahn Sch Med Mt Sinai, Translat & Mol Imaging Inst, New York, NY 10029 USA. [Cohen-Adad, Julien; De Leener, Benjamin] Ecole Polytech, Inst Biomed Engn, Montreal, PQ H3T 1J4, Canada. [Dery, Sebastien] McGill Univ, Montreal Neurol Inst, McConnell Brain Imaging Ctr, 3801 Univ St, Montreal, PQ H3A 2B4, Canada. [Downar, Jonathan; Dunlop, Katharine] Univ Hlth Network, MRI Guided rTMS Clin, Toronto, ON M5T 2S8, Canada. [Downar, Jonathan] Univ Toronto, Univ Hlth Network, Dept Psychiat, Toronto, ON M5T 2S8, Canada. [Downar, Jonathan; Dunlop, Katharine; Strother, Stephen C.] Univ Toronto, Inst Med Sci, 100 Coll St, Toronto, ON M5S 1A8, Canada. [Franco, Alexandre R.] Pontificia Univ Catolica Rio Grande do Sul, Fac Engn, BR-90619 Porto Alegre, RS, Brazil. [Franco, Alexandre R.] Pontificia Univ Catolica Rio Grande do Sul, Inst Cerebro Rio Grande do Sul, BR-90610 Porto Alegre, RS, Brazil. [Franco, Alexandre R.] Pontificia Univ Catolica Rio Grande do Sul, Fac Med, BR-90619 Porto Alegre, RS, Brazil. [Gerber, Andrew J.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Gerber, Andrew J.] Columbia Univ, Dept Psychiat, Div Child & Adolescent Psychiat, New York, NY 10032 USA. [Ghosh, Satrajit S.] MIT, McGovern Inst Brain Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Ghosh, Satrajit S.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Grabowski, Thomas J.] Univ Washington, Dept Radiol, Seattle, WA 98105 USA. [Grabowski, Thomas J.] Univ Washington, Dept Neurol, Seattle, WA 98105 USA. [Hill, Sean] Int Neuroinformat Coordinating Facil, S-17177 Stockholm, Sweden. [Hill, Sean] Karolinska Inst, S-17177 Stockholm, Sweden. [Heinsfeld, Anibal Solon; Meneguzzi, Felipe; Pereira, Ramon Fraga] Pontificia Univ Catolica Rio Grande do Sul, Fac Informat, BR-90619 Porto Alegre, RS, Brazil. [Hutchison, R. Matthew] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA. [Laird, Angela R.] Florida Int Univ, Dept Phys, Miami, FL 33199 USA. [Liew, Sook-Lei] Univ So Calif, Dept Neurol, Div Phys Therapy & Biokinesiol, Chan Div Occupat Sci & Occupat Therapy, Los Angeles, CA 90033 USA. [Liew, Sook-Lei; Van Horn, John D.] Univ So Calif, USC Mark & Mary Stevens Neuroimaging & Informat I, Los Angeles, CA 90033 USA. [Lurie, Daniel J.] Univ Calif Berkeley, Dept Psychol, Berkeley, CA 94720 USA. [McLaren, Donald G.] Biospective Inc, Montreal, PQ H4P 1K6, Canada. [McLaren, Donald G.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Mennes, Maarten] Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Ctr Cognit Neuroimaging, NL-6525 EN Nijmegen, Netherlands. [Mesmoudi, Salma] Univ Paris 01, Sorbonne Univ, Equipement Excellence MATRICE, F-75005 Paris, France. [Peltier, Scott] Univ Michigan, Funct MRI Lab, Ann Arbor, MI 48109 USA. [Poline, Jean-Baptiste] Univ Calif Berkeley, Helen Wills Neurosci Inst, Berkeley, CA 94720 USA. [Poline, Jean-Baptiste] Univ Calif Berkeley, Henry H Wheeler Jr Brain Imaging Ctr, Berkeley, CA 94709 USA. [Prasad, Gautam; Shi, Yonggang] Univ So Calif, Keck Sch Med, Stevens Neuroimaging & Informat Inst, Lab Neuro Imaging, Los Angeles, CA 90033 USA. [Rokem, Ariel] Univ Washington, ESci Inst, Seattle, WA 98195 USA. [Saad, Ziad S.] NIMH, Sci & Stat Comp Core, Bethesda, MD 20892 USA. [Strother, Stephen C.] Baycrest Hosp, Rotman Res Inst, Toronto, ON M6A 2E1, Canada. [Strother, Stephen C.] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 1L7, Canada. [Toro, Roberto] Inst Pasteur, Human Genet & Cognit Funct Unit, F-75015 Paris, France. [Toro, Roberto] Inst Pasteur, CNRS, Genes Synapses & Cognit, UMR 3571, F-75015 Paris, France. [Uddin, Lucina Q.] Univ Miami, Dept Psychol, Coral Gables, FL 33124 USA. [Uddin, Lucina Q.] Univ Miami, Neurosci Program, Miller Sch Med, Miami, FL 33136 USA. [Van Meter, John W.] Georgetown Univ, Med Ctr, Ctr Funct & Mol Imaging, Washington, DC 20007 USA. [Welsh, Robert C.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Welsh, Robert C.] Univ Michigan, Dept Radiol, Ann Arbor, MI 48109 USA. RP Craddock, RC (reprint author), Neuro Bur, D-04317 Leipzig, Germany. EM cameron.craddock@gmail.com RI Margulies, Daniel/L-4719-2016; OI Margulies, Daniel/0000-0002-8880-9204; Craddock, Cameron/0000-0002-4950-1303; Nichols, Nolan/0000-0003-1099-3328 FU Allen Institute for Brain Science (OHBM); Amazon Web Services (OHBM); Amazon Web Services (Boston); Amazon Web Services (Brainhack AMX); Athinoula A. Martinos Center for Biomedical Imaging (Boston); Child Mind Institute, Inc. (NYC); Child Mind Institute, Inc. (MX); FIU Division of Research (Miami); Frontiers (OHBM); Frontiers in Neuroscience (OHBM); International Neuroinformatics Coordinating Facility (OHBM); International Neuroinformatics Coordinating Facility (MX); MATRICE (Paris); Max Planck Institute for Cognitive and Brain Sciences (Leipzig); Microsoft Azure (OHBM); NIH BD2K Center [1U54EB020406-01]; Big Data for Discovery Science (USC, PI: Toga, LA); Enigma Center for Worldwide Medicine, Imaging, and Genomics (USC, PI: Thompson, LA); NIH BD2K [3U01AA021697-04S1, 5U01AA021697-04]; Organization for Human Brain Mapping (OHBM); Ontario Brain Institute (Toronto); Quebec Bio-Imaging Network (MTL); Siemens (Paris); University of Miami Flipse Funds (Miami) FX The authors would like to thank prior organizers and attendees of Brainhacks over the past four years. We would also like to thank our sponsors, whose funds have been used to enrich the educational experience at Brainhack and have provided travel support for attendees. These include (in alphabetical order): Allen Institute for Brain Science (OHBM 2013), Amazon Web Services (OHBM 2013, OHBM 2014, Boston 2014, Brainhack AMX 2015), Athinoula A. Martinos Center for Biomedical Imaging (Boston 2014), Child Mind Institute, Inc. (NYC 2014, NYC 2015, MX 2015), FIU Division of Research (Miami 2014), Frontiers (OHBM 2014), Frontiers in Neuroscience (OHBM 2013), International Neuroinformatics Coordinating Facility (OHBM 2013, OHBM 2014, OHBM 2015, MX 2015), MATRICE (Paris 2013), Max Planck Institute for Cognitive and Brain Sciences (Leipzig 2012), Microsoft Azure (OHBM 2015), NIH BD2K Center (1U54EB020406-01) Big Data for Discovery Science (USC, PI: Toga, LA 2015), NIH BD2K Center (1U54EB020403-01) Enigma Center for Worldwide Medicine, Imaging, and Genomics (USC, PI: Thompson, LA 2015), NIH BD2K Supplement for NCANDA (3U01AA021697-04S1) and NCANDA: Data Analysis Component (5U01AA021697-04) (SRI International, PI: Pohl, OHBM2015, MX 2015), Organization for Human Brain Mapping (OHBM 2013, OHBM 2014, OHBM 2015), Ontario Brain Institute (Toronto 2014), Quebec Bio-Imaging Network (MTL 2014, MTL 2015), Siemens (Paris 2013), and University of Miami Flipse Funds (Miami 2015). NR 13 TC 2 Z9 2 U1 4 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2047-217X J9 GIGASCIENCE JI GigaScience PD MAR 31 PY 2016 VL 5 AR 16 DI 10.1186/s13742-016-0121-x PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI1LR UT WOS:000373258100001 ER PT J AU Jensen, NF Agama, K Roy, A Smith, DH Pfister, TD Romer, MU Zhang, HL Doroshow, JH Knudsen, BR Stenvang, J Brunner, N Pommier, Y AF Jensen, Niels Frank Agama, Keli Roy, Amit Smith, David Hersi Pfister, Thomas D. Romer, Maria Unni Zhang, Hong-Liang Doroshow, James H. Knudsen, Birgitta R. Stenvang, Jan Bruenner, Nils Pommier, Yves TI Characterization of DNA topoisomerase I in three SN-38 resistant human colon cancer cell lines reveals a new pair of resistance-associated mutations SO JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH LA English DT Article DE DNA topoisomerase I; TOP1; SN-38; Irinotecan; Resistance; Colon cancer; Mutation ID ADVANCED COLORECTAL-CANCER; RANDOMIZED CONTROLLED-TRIAL; CAMPTOTHECIN RESISTANCE; ACTIVE-SITE; COMBINATION CHEMOTHERAPY; PREDICTIVE BIOMARKERS; MULTIDRUG-RESISTANCE; DRUG-SENSITIVITY; SINGLE MUTATION; COPY-NUMBER AB Background: DNA topoisomerase I (Top1) is a DNA unwinding protein and the specific target of the camptothecin class of chemotherapeutic drugs. One of these, irinotecan, acting through its active metabolite SN-38, is used in the treatment of metastatic colorectal cancer. However, resistance to irinotecan represents a major clinical problem. Since molecular alterations in Top1 may result in resistance to irinotecan, we characterized Top1 in three human colon cancer cell lines with acquired resistance to SN-38. Methods: Three SN-38 resistant (20-67 fold increased resistance) cell lines were generated and compared to wildtype parental cells with regards to: TOP1 gene copy number and gene sequence, Top1 expression (mRNA and protein), Top1 enzymatic activity in the absence and presence of drug, and Top1-DNA cleavage complexes in drug treated cells. TOP1 mutations were validated by PCR using mutant specific primers. Furthermore, cross-resistance to two indenoisoquinoline Top1-targeting drugs (NSC 725776 and NSC 743400) and two Top2-targeting drugs (epirubicin and etoposide) was investigated. Results: Two of three SN-38 resistant cell lines carried TOP1 gene copy number aberrations: A TOP1 gene copy gain and a loss of chromosome 20, respectively. One resistant cell line harbored a pair of yet unreported TOP1 mutations (R364K and G717R) in close proximity to the drug binding site. Mutant TOP1 was expressed at a markedly higher level than wild-type TOP1. None or very small reductions were observed in Top1 expression or Top1 activity in the absence of drug. In all three SN-38 resistant cell lines Top1 activity was maintained in the presence of high concentrations of SN-38. None or only partial cross-resistance were observed for etoposide and epirubicin, respectively. SN-38 resistant cells with wild-type TOP1 remained sensitive to NSC 743400, while cells with mutant TOP1 was fully cross-resistant to both indenoisoquinolines. Top1-DNA cleavage complex formation following drug treatment supported the other findings. Conclusions: This study adds to the growing knowledge about resistance mechanisms for Top1-targeting chemotherapeutic drugs. Importantly, two yet unreported TOP1 mutations were identified, and it was underlined that cross-resistance to the new indenoisoquinoline drugs depends on the specific underlying molecular mechanism of resistance to SN-38. C1 [Jensen, Niels Frank; Smith, David Hersi; Romer, Maria Unni; Stenvang, Jan; Bruenner, Nils] Univ Copenhagen, Fac Hlth & Med Sci, Sect Mol Dis Biol, Dept Vet Dis Biol, Strandblvd 49, DK-2100 Copenhagen, Denmark. [Agama, Keli; Zhang, Hong-Liang; Doroshow, James H.; Pommier, Yves] NCI, NIH, Ctr Canc Res, Mol Pharmacol Lab, 37 Convent Dr,Bldg 37,Room 5068, Bethesda, MD 20892 USA. [Roy, Amit; Knudsen, Birgitta R.] Aarhus Univ, Dept Mol Biol & Genet, CP Mollers Alle 3,Bldg 1130, DK-8000 Aarhus C, Denmark. [Roy, Amit] Natl Inst Pharmaceut Educ & Res NIPER, Dept Biotechnol, Hajipur 844102, Vaishali, India. [Smith, David Hersi] Dako Denmark AS, R&D, Prod Vej 42, DK-2600 Glostrup, Denmark. [Pfister, Thomas D.; Doroshow, James H.] Leidos Biomed Res Inc, Lab Human Toxicol & Pharmacol, Appl Dev Directorate, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Romer, Maria Unni] Frederiksberg Univ Hosp, Dept Clin Physiol & Nucl Med, Nordre Fasanvej 57, DK-2000 Frederiksberg C, Denmark. RP Stenvang, J (reprint author), Univ Copenhagen, Fac Hlth & Med Sci, Sect Mol Dis Biol, Dept Vet Dis Biol, Strandblvd 49, DK-2100 Copenhagen, Denmark. EM stenvang@sund.ku.dk FU Danish Council for Strategic Research; Danish Cancer Society; Simon Fougner Hartmanns Family Foundation; IMK Almene Foundation; Kathrine & Vigo Skovgaards Foundation; Fabrikant Einar Willumsens Memorial Trust; Danish Medical Research Council; Hede Nielsen Foundation; Director Ib Henriksens Foundation; Sawmill owner Jeppe Juhl and Wife Ovita Juhl Foundation; Aase and Ejnar Danielsen Foundation; Arvid Nilssons Foundation; Carlsberg Foundation; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported by The Danish Council for Strategic Research, The Danish Cancer Society, Simon Fougner Hartmanns Family Foundation, IMK Almene Foundation, Kathrine & Vigo Skovgaards Foundation, Fabrikant Einar Willumsens Memorial Trust, The Danish Medical Research Council, The Hede Nielsen Foundation, Director Ib Henriksens Foundation, Sawmill owner Jeppe Juhl and Wife Ovita Juhl Foundation, The Aase and Ejnar Danielsen Foundation, The Arvid Nilssons Foundation and The Carlsberg Foundation. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 69 TC 4 Z9 4 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-9966 J9 J EXP CLIN CANC RES JI J. Exp. Clin. Cancer Res. PD MAR 31 PY 2016 VL 35 AR 56 DI 10.1186/s13046-016-0335-x PG 14 WC Oncology SC Oncology GA DI3GY UT WOS:000373388300001 PM 27029323 ER PT J AU Volkow, ND McLellan, AT AF Volkow, Nora D. McLellan, A. Thomas TI Opioid Abuse in Chronic Pain - Misconceptions and Mitigation Strategies SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID DRUG-MONITORING PROGRAM; EMERGENCY-DEPARTMENT VISITS; CHRONIC NONCANCER PAIN; UNITED-STATES; OVERDOSE DEATHS; PRESCRIPTION OPIOIDS; INDUCED HYPERALGESIA; HEROIN-ADDICTION; CENTRAL AMYGDALA; PRIMARY-CARE C1 [Volkow, Nora D.] NIDA, NIH, 6001 Execut Blvd, Bethesda, MD 20892 USA. [McLellan, A. Thomas] Treatment Res Inst, Philadelphia, PA USA. RP Volkow, ND (reprint author), NIDA, NIH, 6001 Execut Blvd, Bethesda, MD 20892 USA. EM nvolkow@nida.nih.gov FU Indivior Pharmaceuticals FX Dr. McLellan reports receiving fees for serving on the board of directors of Indivior Pharmaceuticals. No other potential conflict of interest relevant to this article was reported. NR 120 TC 35 Z9 35 U1 17 U2 31 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 31 PY 2016 VL 374 IS 13 BP 1253 EP 1263 DI 10.1056/NEJMra1507771 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA DH8ZM UT WOS:000373085500008 PM 27028915 ER PT J AU Compton, WM Jones, CM Baldwin, GT AF Compton, Wilson M. Jones, Christopher M. Baldwin, Grant T. TI Nonmedical Prescription-Opioid Use and Heroin Use REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Compton, Wilson M.] Natl Inst Drug Abuse, Bethesda, MD USA. [Jones, Christopher M.] Dept Hlth & Human Serv, Washington, DC USA. [Baldwin, Grant T.] Ctr Dis Control & Prevent, Atlanta, GA USA. RP Compton, WM (reprint author), Natl Inst Drug Abuse, Bethesda, MD USA. EM wcompton@nida.nih.gov NR 5 TC 1 Z9 1 U1 4 U2 4 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 31 PY 2016 VL 374 IS 13 BP 1296 EP 1296 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA DH8ZM UT WOS:000373085500026 PM 27028930 ER PT J AU Leal, AR Cruz, R Bur, D Huesgen, PF Faro, R Manadas, B Wlodawer, A Faro, C Simoes, I AF Leal, Ana Rita Cruz, Rui Bur, Daniel Huesgen, Pitter F. Faro, Rosario Manadas, Bruno Wlodawer, Alexander Faro, Carlos Simoes, Isaura TI Enzymatic properties, evidence for in vivo expression, and intracellular localization of shewasin D, the pepsin homolog from Shewanella denitrificans SO SCIENTIFIC REPORTS LA English DT Article ID ACTIVE-SITE; PEPTIDE LIBRARIES; PROTEASES; SPECIFICITY; AMAZONENSIS; ACTIVATION; BACTERIA; DATABASE; TANDEM; NOV. AB The widespread presence of pepsin-like enzymes in eukaryotes together with their relevance in the control of multiple biological processes is reflected in the large number of studies published so far for this family of enzymes. By contrast, pepsin homologs from bacteria have only recently started to be characterized. The work with recombinant shewasin A from Shewanella amazonensis provided the first documentation of this activity in prokaryotes. Here we extend our studies to shewasin D, the pepsin homolog from Shewanella denitrificans, to gain further insight into this group of bacterial peptidases that likely represent ancestral versions of modern eukaryotic pepsin-like enzymes. We demonstrate that the enzymatic properties of recombinant shewasin D are strongly reminiscent of eukaryotic pepsin homologues. We determined the specificity preferences of both shewasin D and shewasin A using proteome-derived peptide libraries and observed remarkable similarities between both shewasins and eukaryotic pepsins, in particular with BACE-1, thereby confirming their phylogenetic proximity. Moreover, we provide first evidence of expression of active shewasin D in S. denitrificans cells, confirming its activity at acidic pH and inhibition by pepstatin. Finally, our results revealed an unprecedented localization for a family A1 member by demonstrating that native shewasin D accumulates preferentially in the cytoplasm. C1 [Leal, Ana Rita; Cruz, Rui; Faro, Rosario; Manadas, Bruno; Faro, Carlos; Simoes, Isaura] Univ Coimbra, CNC Ctr Neurosci & Cell Biol, P-3004517 Coimbra, Portugal. [Leal, Ana Rita; Cruz, Rui; Faro, Rosario; Manadas, Bruno; Faro, Carlos; Simoes, Isaura] Biotechnol Innovat Ctr, Biocant, P-3060197 Cantanhede, Portugal. [Bur, Daniel] Actel Pharmaceut Ltd, CH-4123 Allschwil, Switzerland. [Huesgen, Pitter F.] Forschungszentrum Julich, Cent Inst Engn Elect & Analyt, ZEA 3, D-52425 Julich, Germany. [Wlodawer, Alexander] NCI, Prot Struct Sect, Macromol Crystallog Lab, Ft Detrick, MD 21702 USA. [Leal, Ana Rita] Univ Nova Lisboa, Inst Tecnol Quim & Biol, P-2780157 Oeiras, Portugal. RP Simoes, I (reprint author), Univ Coimbra, CNC Ctr Neurosci & Cell Biol, P-3004517 Coimbra, Portugal.; Simoes, I (reprint author), Biotechnol Innovat Ctr, Biocant, P-3060197 Cantanhede, Portugal. EM isimoes@biocant.pt RI Manadas, Bruno/A-7667-2012; PTMS, RNEM/C-1589-2014; Simoes, Isaura/F-3239-2010 OI Manadas, Bruno/0000-0002-2087-4042; Simoes, Isaura/0000-0002-9331-6340 FU "COMPETE Programa Operacional Factores de Competitividade", QREN; European Union (FEDER - Fundo Europeu de Desenvolvimento Regional); National Mass Spectrometry Network (RNEM) [REDE/1506/REM/2005]; NIH, National Cancer Institute, Center for Cancer Research; [UID/NEU/04539/2013] FX The authors would like to thank Vironova AB, Stockholm, Sweden for immunogold labeling analysis. The authors would like to thank Vera Mendes for MS analysis. Authors would like to acknowledge grant UID/NEU/04539/2013, and co-financed by "COMPETE Programa Operacional Factores de Competitividade", QREN, the European Union (FEDER - Fundo Europeu de Desenvolvimento Regional) and by The National Mass Spectrometry Network (RNEM) under the contract REDE/1506/REM/2005. This work was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 34 TC 0 Z9 0 U1 2 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAR 31 PY 2016 VL 6 AR 23869 DI 10.1038/srep23869 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI0FM UT WOS:000373170500001 PM 27029611 ER PT J AU Shimabukuro, MK Langhi, LGP Cordeiro, I Brito, JM Batista, CMD Mattson, MP Coelho, VD AF Shimabukuro, Marilia Kimie Paranhos Langhi, Larissa Gutman Cordeiro, Ingrid Brito, Jose M. de Castro Batista, Claudia Maria Mattson, Mark P. Coelho, Valeria de Mello TI Lipid-laden cells differentially distributed in the aging brain are functionally active and correspond to distinct phenotypes SO SCIENTIFIC REPORTS LA English DT Article ID AGE-RELATED-CHANGES; SUBVENTRICULAR ZONE; PROINFLAMMATORY CYTOKINES; WHITE-MATTER; NEURODEGENERATIVE DISEASES; SECRETORY PHENOTYPE; ALZHEIMERS-DISEASE; CEREBRAL-CORTEX; NEURAL STEM; IN-VITRO AB We characterized cerebral Oil Red O-positive lipid-laden cells (LLC) of aging mice evaluating their distribution, morphology, density, functional activities and inflammatory phenotype. We identified LLC in meningeal, cortical and neurogenic brain regions. The density of cerebral LLC increased with age. LLC presenting small lipid droplets were visualized adjacent to blood vessels or deeper in the brain cortical and striatal parenchyma of aging mice. LLC with larger droplets were asymmetrically distributed in the cerebral ventricle walls, mainly located in the lateral wall. We also found that LLC in the subventricular region co-expressed beclin-1 or LC3, markers for autophagosome or autophagolysosome formation, and perilipin (PLIN), a lipid droplet-associated protein, suggesting lipophagic activity. Some cerebral LLC exhibited beta galactosidase activity indicating a senescence phenotype. Moreover, we detected production of the pro-inflammatory cytokine TNF-alpha in cortical PLIN+ LLC. Some cortical NeuN(+) neurons, GFAP(+) glia limitans astrocytes, Iba-1(+) microglia and S100 beta(+) ependymal cells expressed PLIN in the aging brain. Our findings suggest that cerebral LLC exhibit distinct cellular phenotypes and may participate in the age-associated neuroinflammatory processes. C1 [Shimabukuro, Marilia Kimie; Paranhos Langhi, Larissa Gutman; de Castro Batista, Claudia Maria; Coelho, Valeria de Mello] Univ Fed Rio de Janeiro, Immunophysiol Lab, Inst Biomed Sci, Hlth Sci Ctr, Ave Carlos Chagas Filho 373, BR-21941902 Rio De Janeiro, RJ, Brazil. [Cordeiro, Ingrid; Brito, Jose M.] Univ Fed Rio de Janeiro, Lab Cellular Proliferat & Differentiat, Inst Biomed Sci, Hlth Sci Ctr, Ave Carlos Chagas Filho 373, BR-21941902 Rio De Janeiro, RJ, Brazil. [Mattson, Mark P.] NIA, Neurosci Lab, NIH, Baltimore, MD 21224 USA. RP Coelho, VD (reprint author), Univ Fed Rio de Janeiro, Immunophysiol Lab, Inst Biomed Sci, Hlth Sci Ctr, Ave Carlos Chagas Filho 373, BR-21941902 Rio De Janeiro, RJ, Brazil. EM coelhova@histo.ufrj.br FU Research Support Foundation of the State of Rio de Janeiro/FAPERJ; National Council of Technological and Scientific Development/CNPq, Brazil; Intramural Research Program of the National Institute on Aging/NIH, USA FX This work was supported, in part, by the Research Support Foundation of the State of Rio de Janeiro/FAPERJ and the National Council of Technological and Scientific Development/CNPq, Brazil; and the Intramural Research Program of the National Institute on Aging/NIH, USA. NR 61 TC 0 Z9 0 U1 2 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAR 31 PY 2016 VL 6 AR 23795 DI 10.1038/srep23795 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI0EX UT WOS:000373169000001 PM 27029648 ER PT J AU Sekula, B Ruszkowski, M Malinska, M Dauter, Z AF Sekula, Bartosz Ruszkowski, Milosz Malinska, Maura Dauter, Zbigniew TI Structural Investigations of N-carbamoylputrescine Amidohydrolase from Medicago truncatula: Insights into the Ultimate Step of Putrescine Biosynthesis in Plants SO FRONTIERS IN PLANT SCIENCE LA English DT Article DE polyamine synthesis; amidase mechanism; cadaverine; 1,4-diaminobutane; crystal structure; octamer; carbamoyl hydrolysis; CPA ID AMINO-ACID AMIDOHYDROLASE; ARGININE DECARBOXYLASE PATHWAY; SITE-DIRECTED MUTAGENESIS; BETA-ALANINE SYNTHASE; CRYSTAL-STRUCTURE; POLYAMINE BIOSYNTHESIS; SUBSTRATE-SPECIFICITY; EXOGENOUS APPLICATION; STRUCTURE VALIDATION; TRANSGENIC RICE AB Putrescine, 1,4-diaminobutane, is an intermediate in the biosynthesis of more complexed polyamines, spermidine and spermine. Unlike other eukaryotes, plants have evolved a multistep pathway for putrescine biosynthesis that utilizes arginine. In the final reaction, N-carbamoylputrescine is hydrolyzed to putrescine by N-carbamoylputrescine amidohydrolase (CPA, EC 3.5.1.53). During the hydrolysis, consecutive nucleophilic attacks on the substrate by Cysl 58 and water lead to formation of putrescine and two by-products, ammonia and carbon dioxide. CPA from the model legume plant, Medicago truncatula (MtCPA), was investigated in this work. Four crystal structures were determined: the wild-type MtCPA in complex with the reaction intermediate, N-(dihydroxymethyl)putrescine as well as with cadaverine, which is a longer analog of putrescine; and also structures of MtCPA-C158S mutant unliganded and with putrescine. MtCPA assembles into octamers, which resemble an incomplete left-handed helical twist. The active site of MtCPA is funnel-like shaped, and its entrance is walled with a contribution of the neighboring protein subunits. Deep inside the catalytic cavity, Glu48, Lys121, and Cys158 form the catalytic triad. In this studies, we have highlighted the key residues, highly conserved among the plant kingdom, responsible for the activity and selectivity of MtCPA toward N-carbamoylputrescine. Moreover, since, according to previous reports, a close MtCPA relative from Arabidopsis thaliana, along with several other nitrilase-like proteins, are subjected to allosteric regulation by substrates, we have used the structural information to indicate a putative secondary binding site. Based on the docking experiment, we postulate that this site is adjacent to the entrance to the catalytic pocket. C1 [Sekula, Bartosz] Lodz Univ Technol, Fac Biotechnol & Food Sci, Inst Tech Biochem, Lodz, Poland. [Ruszkowski, Milosz; Malinska, Maura; Dauter, Zbigniew] NCI, Macromol Crystallog Lab, Synchrotron Radiat Res Sect, Argonne, IL USA. [Malinska, Maura] Univ Warsaw, Fac Chem, Warsaw, Poland. RP Ruszkowski, M (reprint author), NCI, Macromol Crystallog Lab, Synchrotron Radiat Res Sect, Argonne, IL USA. EM mruszkowski@anl.gov OI Malinska, Maura/0000-0002-7138-7041; Sekula, Bartosz/0000-0003-4008-4360 FU Intramural Research Program of the NCI, Center for Cancer Research; US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; Polish National Science Centre [2014/12/T/ST5/00136] FX This project supported in part by the Intramural Research Program of the NCI, Center for Cancer Research. Diffraction data were collected at the SER-CAT beamline 22-ID at the Advanced Photon Source, Argonne National Laboratory, supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract W-31-109-Eng-38. The research was conducted during the Ph.D. scholarship of B.S. (2014/12/T/ST5/00136) financed by Polish National Science Centre. We gratefully acknowledge Miroslawa Dauter for the valuable advice and assistance during crystallization of MtCPA. NR 82 TC 1 Z9 1 U1 2 U2 3 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-462X J9 FRONT PLANT SCI JI Front. Plant Sci. PD MAR 30 PY 2016 VL 7 AR 350 DI 10.3389/fpls.2016.00350 PG 15 WC Plant Sciences SC Plant Sciences GA DU1PO UT WOS:000381980800001 PM 27066023 ER PT J AU Binder, ZA Wilson, KM Salmasi, V Orr, BA Eberhart, CG Siu, IM Lim, M Weingart, JD Quinones-Hinojosa, A Bettegowda, C Kassam, AB Olivi, A Brem, H Riggins, GJ Gallia, GL AF Binder, Zev A. Wilson, Kelli M. Salmasi, Vafi Orr, Brent A. Eberhart, Charles G. Siu, I-Mei Lim, Michael Weingart, Jon D. Quinones-Hinojosa, Alfredo Bettegowda, Chetan Kassam, Amin B. Olivi, Alessandro Brem, Henry Riggins, Gregory J. Gallia, Gary L. TI Establishment and Biological Characterization of a Panel of Glioblastoma Multiforme (GBM) and GBM Variant Oncosphere Cell Lines SO PLOS ONE LA English DT Article ID STEM-CELLS; CROSS-CONTAMINATION; INITIATING CELLS; TUMOR; CANCER; RESISTANCE; CHEMOTHERAPY; GLIOSARCOMA; PHENOTYPE; GENOTYPE AB Objective Human tumor cell lines form the basis of the majority of present day laboratory cancer research. These models are vital to studying the molecular biology of tumors and preclinical testing of new therapies. When compared to traditional adherent cell lines, suspension cell lines recapitulate the genetic profiles and histologic features of glioblastoma multiforme (GBM) with higher fidelity. Using a modified neural stem cell culture technique, here we report the characterization of GBM cell lines including GBM variants. Methods Tumor tissue samples were obtained intra-operatively and cultured in neural stem cell conditions containing growth factors. Tumor lines were characterized in vitro using differentiation assays followed by immunostaining for lineage-specific markers. In vivo tumor formation was assayed by orthotopic injection in nude mice. Genetic uniqueness was confirmed via short tandem repeat (STR) DNA profiling. Results Thirteen oncosphere lines derived from GBM and GBM variants, including a GBM with PNET features and a GBM with oligodendroglioma component, were established. All unique lines showed distinct genetic profiles by STR profiling. The lines assayed demonstrated a range of in vitro growth rates. Multipotency was confirmed using in vitro differentiation. Tumor formation demonstrated histologic features consistent with high grade gliomas, including invasion, necrosis, abnormal vascularization, and high mitotic rate. Xenografts derived from the GBM variants maintained histopathological features of the primary tumors. Conclusions We have generated and characterized GBM suspension lines derived from patients with GBMs and GBM variants. These oncosphere cell lines will expand the resources available for preclinical study. C1 [Binder, Zev A.; Wilson, Kelli M.; Salmasi, Vafi; Siu, I-Mei; Lim, Michael; Weingart, Jon D.; Quinones-Hinojosa, Alfredo; Bettegowda, Chetan; Olivi, Alessandro; Brem, Henry; Riggins, Gregory J.; Gallia, Gary L.] Johns Hopkins Univ, Sch Med, Dept Neurosurg, Baltimore, MD 21205 USA. [Binder, Zev A.] Johns Hopkins Univ, Johns Hopkins Phys Sci Oncol Ctr, Baltimore, MD USA. [Binder, Zev A.] Johns Hopkins Univ, Inst NanoBioTechnol, Baltimore, MD USA. [Orr, Brent A.; Eberhart, Charles G.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Lim, Michael; Weingart, Jon D.; Quinones-Hinojosa, Alfredo; Bettegowda, Chetan; Olivi, Alessandro; Brem, Henry; Riggins, Gregory J.; Gallia, Gary L.] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Kassam, Amin B.] Aurora Neurosci Innovat Inst, Dept Neurosurg, Milwaukee, WI USA. [Binder, Zev A.] Univ Penn, Dept Neurosurg, Philadelphia, PA 19104 USA. [Wilson, Kelli M.] NIH, Div Preclin Innovat, Chem Genom Ctr, Natl Ctr Adv Translat Sci, Rockville, MD USA. [Salmasi, Vafi] Cleveland Clin, Inst Anesthesiol, Cleveland, OH 44106 USA. [Orr, Brent A.] St Jude Childrens Res Hosp, Dept Pathol, 332 N Lauderdale St, Memphis, TN 38105 USA. RP Gallia, GL (reprint author), Johns Hopkins Univ, Sch Med, Dept Neurosurg, Baltimore, MD 21205 USA.; Gallia, GL (reprint author), Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. EM ggallia1@jhmi.edu RI Olivi, Alessandro/K-6531-2016 OI Olivi, Alessandro/0000-0002-4489-7564 FU Brain Tumor Funding Collaborative; Virginia and D.K. Ludwig Fund for Cancer Research; National Institutes of Health [5R01NS070024]; Department of Neurosurgery at Johns Hopkins School of Medicine; Postdoctoral Training Program in Nanotechnology for Cancer Medicine - National Institutes of Health [T32CA130840] FX This work was supported by the Brain Tumor Funding Collaborative, http://www.braintumorfunders.org/, GJR), the Virginia and D.K. Ludwig Fund for Cancer Research, http://www.ludwigcancerresearch.org/, GJR), National Institutes of Health Grant 5R01NS070024, http://www.nih.gov/, AQH), the Department of Neurosurgery at Johns Hopkins School of Medicine, http://www.hopkinsmedicine.org/neurology_neurosurgery/, GJR, GLG), and the Postdoctoral Training Program in Nanotechnology for Cancer Medicine supported by National Institutes of Health grant T32CA130840, http://www.nih.gov/, (ZAB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 1 Z9 1 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 30 PY 2016 VL 11 IS 3 AR e0150271 DI 10.1371/journal.pone.0150271 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH9LB UT WOS:000373116500004 PM 27028405 ER PT J AU Hamilton, JP Glover, GH Bagarinao, E Chang, C Mackey, S Sacchet, MD Gotlib, IH AF Hamilton, J. Paul Glover, Gary H. Bagarinao, Epifanio Chang, Catie Mackey, Sean Sacchet, Matthew D. Gotlib, Ian H. TI Effects of salience-network-node neurofeedback training on affective biases in major depressive disorder SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Major depressive disorder; Neurofeedback; Functional magnetic resonance imaging; Salience network; Information processing biases ID REAL-TIME FMRI; BRAIN ACTIVATION; MEDIAL PULVINAR; CORTEX ACTIVITY; AMYGDALA; MODEL; CONNECTIVITY; INDIVIDUALS; STIMULI; EMOTION AB Neural models of major depressive disorder (MDD) posit that over-response of components of the brain's salience network (SN) to negative stimuli plays a crucial role in the pathophysiology of MDD. In the present proof-of-concept study, we tested this formulation directly by examining the affective consequences of training depressed persons to down-regulate response of SN nodes to negative material. Ten participants in the real neurofeedback group saw, and attempted to learn to down-regulate, activity from an empirically identified node of the SN. Ten other participants engaged in an equivalent procedure with the exception that they saw SN-node neurofeedback indices from participants in the real neurofeedback group. Before and after scanning, all participants completed tasks assessing emotional responses to negative scenes and to negative and positive self-descriptive adjectives. Compared to participants in the sham-neurofeedback group, from pre- to post-training, participants in the realneurofeedback group showed a greater decrease in SN-node response to negative stimuli, a greater decrease in self-reported emotional response to negative scenes, and a greater decrease in self-reported emotional response to negative self-descriptive adjectives. Our findings provide support for a neural formulation in which the SN plays a primary role in contributing to negative cognitive biases in MDD. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Hamilton, J. Paul] Linkoping Univ, Dept Clin & Expt Med, Ctr Social & Affect Neurosci, Linkoping, Sweden. [Glover, Gary H.] Stanford Univ, Dept Radiol, Stanford, CA 94305 USA. [Bagarinao, Epifanio; Mackey, Sean] Stanford Univ, Dept Anesthesiol, Stanford, CA 94305 USA. [Chang, Catie] NINDS, Adv MRI Sect, Lab Funct & Mol Imaging, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Sacchet, Matthew D.] Stanford Univ, Neurosci Program, Stanford, CA 94305 USA. [Gotlib, Ian H.] Stanford Univ, Dept Psychol, Stanford, CA 94305 USA. RP Hamilton, JP (reprint author), Linkoping Univ, Dept Clin & Expt Med, Ctr Social & Affect Neurosci, Linkoping, Sweden. EM paul.hamilton@liu.se RI Bagarinao, Epifanio/A-5002-2012 FU National Institutes of Health [P41 EB15891, F32 MH079651, R01 MH59259] FX The research presented here was made possible by National Institutes of Health Grants P41 EB15891 (GHG), F32 MH079651 (JPH), and R01 MH59259 (IHG). The authors gratefully acknowledge the support of Mirra Schwartz, Meghan Vinograd, Arkadiy Maksimovskiy, Melissa Henry, and Becka Johnson for their assistance in collecting the data presented here. The authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. None of the authors has a conflict of interest to report pertaining to the data presented in this manuscript. NR 34 TC 4 Z9 4 U1 4 U2 13 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 EI 1872-7506 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD MAR 30 PY 2016 VL 249 BP 91 EP 96 DI 10.1016/j.pscychresns.2016.01.016 PG 6 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DH1EG UT WOS:000372526600012 PM 26862057 ER PT J AU Chouinard, VA Pingali, SM Chouinard, G Henderson, DC Mallya, SG Cypess, AM Cohen, BM Ongur, D AF Chouinard, Virginie-Anne Pingali, Samira M. Chouinard, Guy Henderson, David C. Mallya, Sonal G. Cypess, Aaron M. Cohen, Bruce M. Oenguer, Dost TI Factors associated with overweight and obesity in schizophrenia, schizoaffective and bipolar disorders SO PSYCHIATRY RESEARCH LA English DT Article DE Schizophrenia; Bipolar; Affective; Overweight; Obesity; BMI ID BODY-MASS INDEX; QUALITY-OF-LIFE; SELF-REPORTED WEIGHT; DRUG-NAIVE PATIENTS; METABOLIC SYNDROME; I-DISORDER; CARDIOVASCULAR MORTALITY; DIABETES-MELLITUS; 1ST-EPISODE MANIA; SPECTRUM PATIENTS AB Evidence suggests abnormal bioenergetic status throughout the body in psychotic disorders. The present study examined predictors of elevated body mass index (BMI) across diagnostic categories of schizophrenia, schizoaffective and bipolar disorders. In a cross-sectional study, we studied demographic and clinical risk factors for overweight and obesity in a well-characterized sample of 262 inpatients and outpatients with schizophrenia (n=59), schizoaffective disorder (n=81) and bipolar I disorder (n=122). Across the three diagnostic categories, the prevalence of overweight (29.4%) and obesity (33.2%) combined was 62.6% (164/262). Logistic regression analyses, adjusted for age, sex and ethnicity, showed that schizoaffective disorder, lifetime major depressive episode, presence of prior suicide attempt, and more than 5 lifetime hospitalizations were significantly associated with BMI >= 25. Patients with schizophrenia had significantly lower risk for overweight and obesity. Overall, we found that affective components of illness were associated with elevated BMI in our cross-diagnostic sample. Our results show that patients with schizoaffective disorder have a greater risk for obesity. Identifying predictors of elevated BMI in patients with psychotic and mood disorders will help prevent obesity and related cardiovascular and cerebral complications. Future studies are needed to elucidate the mechanistic nature of the relationship between obesity and psychiatric illness. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Chouinard, Virginie-Anne; Pingali, Samira M.; Mallya, Sonal G.; Cohen, Bruce M.; Oenguer, Dost] McLean Hosp, Psychot Disorders Div, 115 Mill St,Mailstop 108, Belmont, MA 02478 USA. [Chouinard, Virginie-Anne; Henderson, David C.; Cohen, Bruce M.; Oenguer, Dost] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Chouinard, Guy] McGill Univ, Clin Pharmacol & Toxicol Program, Montreal, PQ, Canada. [Chouinard, Guy] Montreal Fernand Seguin Res Ctr, Mental Hlth Inst, Montreal, PQ, Canada. [Henderson, David C.] Massachusetts Gen Hosp, Schizophrenia Clin & Res Program, Boston, MA 02114 USA. [Henderson, David C.] Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Cypess, Aaron M.] NIDDK, Translat Physiol Sect, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. RP Chouinard, VA (reprint author), McLean Hosp, Psychot Disorders Div, 115 Mill St,Mailstop 108, Belmont, MA 02478 USA. EM vchouinard@mclean.harvard.edu FU Shervert Frazier Research Institute; National Institute of Mental Health [K23MH079982]; Harvard Catalyst I The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health) [UL1 TR001102]; Harvard University FX The authors would like to gratefully acknowledge patients who participated in this study. Funding for this study was provided from the Shervert Frazier Research Institute to Bruce M. Cohen and National Institute of Mental Health (K23MH079982) to Dost Ongur. This work was conducted with statistical support from Harvard Catalyst I The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR001102) and financial contributions from Harvard University and its affiliated Academic Healthcare Centers. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. NR 74 TC 4 Z9 4 U1 7 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD MAR 30 PY 2016 VL 237 BP 304 EP 310 DI 10.1016/j.psychres.2016.01.024 PG 7 WC Psychiatry SC Psychiatry GA DG2ZM UT WOS:000371939300047 PM 26805561 ER PT J AU Teng, C Otero, M Geraci, M Blair, RJR Pine, DS Grillon, C Blair, KS AF Teng, Cindy Otero, Marcela Geraci, Manilla Blair, R. J. R. Pine, Daniel S. Grillon, Christian Blair, Karina S. TI Abnormal decision-making in generalized anxiety disorder: Aversion of risk or stimulus-reinforcement impairment? SO PSYCHIATRY RESEARCH LA English DT Article DE GAD; Decision-making; Stimulus-reinforcement learning; Passive avoidance; Global assessment of functioning; Reward; Punishment ID VENTROMEDIAL PREFRONTAL CORTEX; POSTTRAUMATIC-STRESS-DISORDER; QUALITY-OF-LIFE; ANTERIOR CINGULATE; IMPLICIT REGULATION; SOCIAL PHOBIA; INDIVIDUALS; ATTENTION; AMYGDALA AB There is preliminary data indicating that patients with generalized anxiety disorder (GAD) show impairment on decision-making tasks requiring the appropriate representation of reinforcement value. The current study aimed to extend this literature using the passive avoidance (PA) learning task, where the participant has to learn to respond to stimuli that engender reward and avoid responding to stimuli that engender punishment. Six stimuli engendering reward and six engendering punishment are presented once per block for 10 blocks of trials. Thirty-nine medication-free patients with GAD and 29 age-, IQ and gender matched healthy comparison individuals performed the task. In addition, indexes of social functioning as assessed by the Global Assessment of Functioning (GAF) scale were obtained to allow for correlational analyzes of potential relations between cognitive and social impairments. The results revealed a Group-by-Error Type-by-Block interaction; patients with GAD committed significantly more commission (passive avoidance) errors than comparison individuals in the later blocks (blocks 7,8, and 9). In addition, the extent of impairment on these blocks was associated with their functional impairment as measured by the GAF scale. These results link GAD with anomalous decision-making and indicate that a potential problem in reinforcement representation may contribute to the severity of expression of their disorder. (C) 2016 Published by Elsevier Ireland Ltd. C1 [Teng, Cindy; Otero, Marcela; Geraci, Manilla; Blair, R. J. R.; Pine, Daniel S.; Grillon, Christian; Blair, Karina S.] NIMH, NIH, Dept Hlth & Human Serv, 15K North Dr,Rm 115A,MSC 2670, Bethesda, MD 20892 USA. RP Blair, KS (reprint author), NIMH, NIH, Dept Hlth & Human Serv, 15K North Dr,Rm 115A,MSC 2670, Bethesda, MD 20892 USA. OI Teng, Cindy/0000-0002-2611-1791 FU Intramural Research Program of the NIH, National Institute of Mental Health [1-ZIA-MH002860] FX This research was supported by the Intramural Research Program of the NIH, National Institute of Mental Health (Grant no. 1-ZIA-MH002860). The authors have no conflicts of interest or financial disclosures to report. NR 33 TC 1 Z9 1 U1 4 U2 12 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD MAR 30 PY 2016 VL 237 BP 351 EP 356 DI 10.1016/j.psychres.2015.12.031 PG 6 WC Psychiatry SC Psychiatry GA DG2ZM UT WOS:000371939300054 PM 26822065 ER PT J AU Kim, PS Kwilas, AR Xu, WX Alter, S Jeng, EK Wong, HC Schlom, J Hodge, JW AF Kim, Peter S. Kwilas, Anna R. Xu, Wenxin Alter, Sarah Jeng, Emily K. Wong, Hing C. Schlom, Jeffrey Hodge, James W. TI IL-15 superagonist/IL-15R alpha Sushi-Fc fusion complex (IL-15SA/IL-15R alpha Su-Fc; ALT-803) markedly enhances specific subpopulations of NK and memory CD8(+) T cells, and mediates potent anti-tumor activity against murine breast and colon carcinomas SO ONCOTARGET LA English DT Article DE IL-15; IL-15 superagonist; NK cells; immunotherapy ID NATURAL-KILLER-CELLS; IN-VIVO; CANCER; INTERLEUKIN-15; SUPERAGONIST; IMMUNOTHERAPY; MICE; ACTIVATION; SUBSETS; EOMESODERMIN AB Interleukin (IL)-15-N72D superagonist-complexed with IL-15R alpha Sushi-Fc fusion protein (IL-15SA/IL-15R alpha Su-Fc; ALT-803) has been reported to exhibit significant anti-tumor activity in murine myeloma, rat bladder cancer, and murine glioblastoma models. In this study, we examined the immunomodulatory and anti-tumor effects of IL-15SA/IL-15R alpha Su-Fc in tumor-free and highly metastatic tumor-bearing mice. Here, IL-15SA/IL-15R alpha Su-Fc significantly expanded natural killer (NK) and CD8(+) T cells. In examining NK cell subsets, the greatest significant increase was in highly cytotoxic and migrating (CD11b(+), CD27(hi); high effector) NK cells, leading to enhanced function on a per-cell basis. CD8(+) T cell subset analysis determined that IL-15SA/IL-15R alpha Su-Fc significantly increased IL-15 responding memory (CD122(+), CD44(+)) CD8+ T cells, in particular those having the innate (NKG2D(+), PD1(-)) phenotype. In 4T1 breast tumor-bearing mice, IL-15SA/IL-15R alpha Su-Fc induced significant anti-tumor activity against spontaneous pulmonary metastases, depending on CD8(+) T and NK cells, and resulting in prolonged survival. Similar anti-tumor activity was seen in the experimental pulmonary metastasis model of CT26 colon carcinoma cells, particularly when IL-15SA/IL-15R alpha Su-Fc was combined with a cocktail of checkpoint inhibitors, anti-CTLA-4 and anti-PD-L1. Altogether, these studies showed for the first time that IL-15SA/IL-15R alpha Su-Fc (1) promoted the development of high effector NK cells and CD8(+) T cell responders of the innate phenotype, (2) enhanced function of NK cells, and (3) played a vital role in reducing tumor metastasis and ultimately survival, especially in combination with checkpoint inhibitors. C1 [Kim, Peter S.; Kwilas, Anna R.; Schlom, Jeffrey; Hodge, James W.] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Xu, Wenxin; Alter, Sarah; Jeng, Emily K.; Wong, Hing C.] Altor BioSci Corp, Miramar, FL USA. RP Hodge, JW (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM jh241d@nih.gov RI Hodge, James/D-5518-2015 OI Hodge, James/0000-0001-5282-3154 FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health FX Laboratory of Tumor Immunology and Biology, NCI: Studies conducted in the Laboratory of Tumor Immunology and Biology were funded by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health. NR 50 TC 3 Z9 3 U1 0 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 MAR 29 PY 2016 VL 7 IS 13 BP 16130 EP 16145 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL5QW UT WOS:000375692900064 PM 26910920 ER PT J AU Zhang, LS Boufraqech, M Lake, R Kebebew, E AF Zhang, Lisa Boufraqech, Myriem Lake, Ross Kebebew, Electron TI Carfilzomib potentiates CUDC-101-induced apoptosis in anaplastic thyroid cancer SO ONCOTARGET LA English DT Article DE carfilzomib; CUDC-101; anaplastic thyroid cancer; combination therapy; apoptosis ID GROWTH-FACTOR RECEPTOR; PROTEASOME INHIBITORS; HISTONE DEACETYLASE; PHOSPHATIDYLINOSITOL 3-KINASE/AKT; MULTITARGETED INHIBITOR; THERAPEUTIC TARGET; CELL-MIGRATION; TUMOR-GROWTH; CARCINOMA; COMBINATION AB Anaplastic thyroid cancer (ATC) is one of the most aggressive human malignancies, with no effective treatment currently available. Previously, we identified agents active against ATC cells, both in vitro and in vivo, using quantitative high-throughput screening of 3282 clinically approved drugs and small molecules. Here, we report that combining two of these active agents, carfilzomib, a second-generation proteasome inhibitor, and CUDC-101, a histone deacetylase and multi-kinase inhibitor, results in increased, synergistic activity in ATC cells. The combination of carfilzomib and CUDC-101 synergistically inhibited cellular proliferation and caused cell death in multiple ATC cell lines harboring various driver mutations observed in human ATC tumors. This increased anti-ATC effect was associated with a synergistically enhanced G2/M cell cycle arrest and increased caspase 3/7 activity induced by the drug combination. Mechanistically, treatment with carfilzomib and CUDC-101 increased p21 expression and poly (ADP-ribose) polymerase protein cleavage. Our results suggest that combining carfilzomib and CUDC-101 would offer an effective therapeutic strategy to treat ATC. C1 [Zhang, Lisa; Boufraqech, Myriem; Kebebew, Electron] NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. [Lake, Ross] NCI, Lab Genitourinary Canc Pathogenesis, Bethesda, MD 20892 USA. RP Kebebew, E (reprint author), NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov FU intramural research program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This research was supported by the intramural research program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 45 TC 1 Z9 1 U1 0 U2 0 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAR 29 PY 2016 VL 7 IS 13 BP 16517 EP 16528 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL5QW UT WOS:000375692900094 PM 26934320 ER PT J AU Nakamura, Y Bernardo, M Nagaya, T Sato, K Harada, T Choyke, PL Kobayashi, H AF Nakamura, Yuko Bernardo, Marcelino Nagaya, Tadanobu Sato, Kazuhide Harada, Toshiko Choyke, Peter L. Kobayashi, Hisataka TI MR imaging biomarkers for evaluating therapeutic effects shortly after near infrared photoimmunotherapy SO ONCOTARGET LA English DT Article DE near infrared photoimmunotherapy; MRI; T2 relaxation time; diffusion weighted image; gadofosveset ID FLUORESCENCE-GUIDED SURGERY; KILLER-REPORTER ADENOVIRUS; CANCER-CELL; REAL-TIME; CAPILLARY-PERMEABILITY; LIVE MICE; DIFFUSION; BRAIN; DEATH; IRRADIATION AB Near infrared photoimmunotherapy (NIR-PIT) is a new cancer treatment that combines the specificity of antibodies for targeting tumors with the toxicity induced by photon absorbers after irradiation with NIR light. The purpose of this study was to determine if MR imaging can detect changes in the MR properties of tumor within several hours of NIR-PIT. A431 cells were injected subcutaneously in the right and left dorsi of 12 mice. Six days later, the mice were injected with a photon absorber, IR700, conjugated to panitumumab, an antibody targeting epidermal growth factor receptor. One day later, only right sided tumor was exposed to NIR light (treated tumor). MRI was performed 1 day before and 1-2 hours after NIR-PIT using gadofosveset for six mice and gadopentetate dimeglumine for another six mice. T2 relaxation times, the apparent diffusion coefficient (ADC) for the following combinations of b-values: 0-1000, 200-1000 and 500-1000 s/mm(2) and enhancement indices were compared before and after NIR-PIT using a two-sided paired t-test. For treated tumors, T2 relaxation time increased after NIR-PIT (p < 0.01) and all three ADC values decreased after NIR-PIT (p < 0.01). Moreover, the enhancement area under the curve (AUC) using gadofosveset increased after NIR-PIT (p = 0.02). In conclusion, prolongation of T2, reductions in ADC and increased enhancement using gadofosveset are seen within 2 hours of NIR-PIT treatment of tumors. Thus, MRI can be a useful imaging biomarker for detecting early therapeutic changes after NIR-PIT. C1 [Nakamura, Yuko; Nagaya, Tadanobu; Sato, Kazuhide; Harada, Toshiko; Choyke, Peter L.; Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, Bethesda, MD 20892 USA. [Bernardo, Marcelino] NCI, Res Technol Program, SAIC Frederick Inc, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, Bethesda, MD 20892 USA. EM kobayash@mail.nih.gov FU National Institute of Health, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the National Institute of Health, National Cancer Institute, Center for Cancer Research. NR 34 TC 0 Z9 0 U1 1 U2 5 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAR 29 PY 2016 VL 7 IS 13 BP 17254 EP 17264 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL5QW UT WOS:000375692900147 PM 26885619 ER PT J AU Bowen, EM Pfeiffer, RM Linet, MS Liu, WT Weisenburger, DD Freedman, DM Cahoon, EK AF Bowen, Emily M. Pfeiffer, Ruth M. Linet, Martha S. Liu, Wayne T. Weisenburger, Dennis D. Freedman, D. Michal Cahoon, Elizabeth K. TI Relationship between ambient ultraviolet radiation and Hodgkin lymphoma subtypes in the United States SO BRITISH JOURNAL OF CANCER LA English DT Article DE Hodgkin lymphoma; lymphoma; ultraviolet radiation; United States ID HEALTH-ORGANIZATION CLASSIFICATION; REGULATORY-T-CELLS; UV-RADIATION; EPIDEMIOLOGIC RESEARCH; 25-HYDROXYVITAMIN D; SUN EXPOSURE; VITAMIN-D; RISK; NEOPLASMS; CANCER AB Background: There are few modifiable risk factors for Hodgkin lymphoma (HL), the most common cancer among young adults in Western populations. Some studies have found a reduced risk with exposure to ultraviolet radiation (UVR), but findings have been inconsistent and limited to HL as a group or the most common subtypes. Methods: We evaluated UVR and incidence of HL subtypes using data from 15 population-based cancer registries in the United States from 2001 to 2010 (n = 20 021). Ground-based ambient UVR estimates were linked to county of diagnosis. Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were calculated for UVR quintiles using Poisson regression models adjusted for age, sex, race/ethnicity, diagnosis year, and registry. Results: Hodgkin lymphoma incidence was lower in the highest UVR quintile for nodular sclerosis (IRR = 0.84, 95% CI = 0.75-0.96, P-trendo0.01), mixed cellularity/lymphocyte-depleted (IRR = 0.66, 95% CI = 0.51-0.86, P-trend = 0.11), lymphocyte-rich (IRR = 0.71, 95% CI = 0.57-0.88, P-trendo0.01), and nodular lymphocyte predominant HL (IRR = 0.74, 95% CI = 0.56-0.97, P-trendo0.01), but 'not otherwise specified' HL (IRR = 1.19, 95% CI = 0.96-1.47, P-trend = 0.11). Conclusions: This is the largest study of UVR and HL subtypes covering a wide range of UVR levels; however, we lack information on personal UVR and other individual risk factors. These findings support an inverse association between UVR and HL. C1 [Bowen, Emily M.; Pfeiffer, Ruth M.; Linet, Martha S.; Liu, Wayne T.; Freedman, D. Michal; Cahoon, Elizabeth K.] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, 9609 Med Ctr Dr, Rockville, MD 20850 USA. [Weisenburger, Dennis D.] City Hope Natl Med Ctr, Dept Pathol, 1500 E Duarte Rd, Duarte, CA 91010 USA. RP Cahoon, EK (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM cahoonek@mail.nih.gov FU Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, US Department of Health and Human Services FX We thank Kimia Zarabian for computing support. This research was supported by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, US Department of Health and Human Services. NR 43 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD MAR 29 PY 2016 VL 114 IS 7 BP 826 EP 831 DI 10.1038/bjc.2015.383 PG 6 WC Oncology SC Oncology GA DI1RU UT WOS:000373274200017 PM 26889979 ER PT J AU Zhou, CK Sutcliffe, S Welsh, J Mackinnon, K Kuh, D Hardy, R Cook, MB AF Zhou, Cindy Ke Sutcliffe, Siobhan Welsh, Judith Mackinnon, Karen Kuh, Diana Hardy, Rebecca Cook, Michael B. TI Is birthweight associated with total and aggressive/lethal prostate cancer risks? A systematic review and meta-analysis SO BRITISH JOURNAL OF CANCER LA English DT Review DE birthweight; prostatic neoplasms; meta-analysis; review ID UMBILICAL-CORD BLOOD; GROWTH-FACTOR-I; RACIAL VARIATION; GESTATIONAL-AGE; HORMONE-LEVELS; FETAL-GROWTH; FOLLOW-UP; INSULIN; SIZE; ADULTHOOD AB Background: It has been hypothesised that intrauterine exposures are important for subsequent prostate cancer risk. Prior epidemiological studies have used birthweight as a proxy of cumulative intrauterine exposures to test this hypothesis, but results have been inconsistent partly because of limited statistical power. Methods: We investigated birthweight in relation to prostate cancer in the Medical Research Council (MRC) National Survey of Health and Development (NSHD) using Cox proportional hazards models. We then conducted a meta-analysis of birthweight in relation to total and aggressive/lethal prostate cancer risks, combining results from the NSHD analysis with 13 additional studies on this relationship identified from a systematic search in four major scientific literature databases through January 2015. Results: Random-effects models found that per kg increase in birthweight was positively associated with total (OR - 1.02, 95% confidence interval (95% CI) = 1.00, 1.05; I-2 = 13%) and aggressive/lethal prostate cancer (OR = 1.08, 95% CI = 0.99, 1.19; I-2 = 40%). Sensitivity analyses restricted to studies with birthweight extracted from medical records demonstrated stronger positive associations with total (OR = 1.11, 95% CI = 1.03, 1.19; I-2 = 0%) and aggressive/lethal (OR = 1.37, 95% CI = 1.09, 1.74; I-2 = 0%) prostate cancer. These studies heavily overlapped with those based in Nordic countries. Conclusions: This study provides evidence that heavier birthweight may be associated with modest increased risks of total and aggressive/lethal prostate cancer, which supports the hypothesis that intrauterine exposures may be related to subsequent prostate cancer risks. C1 [Zhou, Cindy Ke; Cook, Michael B.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, 9609 Med Ctr Dr,MSC 9774, Bethesda, MD 20892 USA. [Sutcliffe, Siobhan] Washington Univ, Sch Med, Div Publ Hlth Sci, St Louis, MO USA. [Sutcliffe, Siobhan] Washington Univ, Sch Med, Dept Surg, Siteman Canc Ctr, St Louis, MO 63110 USA. [Welsh, Judith] NIH, NIH Lib, Bldg 10, Bethesda, MD 20892 USA. [Mackinnon, Karen; Kuh, Diana; Hardy, Rebecca] UCL, MRC, Unit Lifelong Hlth & Ageing, London, England. RP Zhou, CK (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, 9609 Med Ctr Dr,MSC 9774, Bethesda, MD 20892 USA. EM ke.zhou@nih.gov RI Cook, Michael/A-5641-2009; Zhou, Cindy /H-2165-2015 OI Cook, Michael/0000-0002-0533-7302; Zhou, Cindy /0000-0003-4814-4305 FU Intramural Program of the National Cancer Institute at the National Institutes of Health; Department of Health and Human Services FX We thank Drs Johan G Erikson from the University of Helsinki, Finland; Virginia Lope from Carlos III Institute of Health, Spain; Clive Osmond from the University of Southampton, UK; Marie-Elise Parent from INRS-Institut Armand-Frappier, Canada; David Ulmert from Memorial Sloan-Kettering Cancer Center, USA as well as their colleagues for the additional information they generously provided about their publications on birth weight in relation to prostate cancer risks. We also thank Dr Barry I Graubard for his statistical consultation and support. This work was supported by the Intramural Program of the National Cancer Institute at the National Institutes of Health and Department of Health and Human Services. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the National Institutes of Health. NR 51 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD MAR 29 PY 2016 VL 114 IS 7 BP 839 EP 848 DI 10.1038/bjc.2016.38 PG 10 WC Oncology SC Oncology GA DI1RU UT WOS:000373274200019 PM 26930450 ER PT J AU Hu, X Myhr, C Huang, ZH Xiao, JB Barnaeva, E Ho, BA Agoulnik, IU Ferrer, M Marugan, JJ Southall, N Agoulnik, AI AF Hu, Xin Myhr, Courtney Huang, Zaohua Xiao, Jingbo Barnaeva, Elena Ho, Brian A. Agoulnik, Irina U. Ferrer, Marc Marugan, Juan J. Southall, Noel Agoulnik, Alexander I. TI Structural Insights into the Activation of Human Relaxin Family Peptide Receptor 1 by Small-Molecule Agonists SO BIOCHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTOR; CRYSTAL-STRUCTURE; FORCE-FIELD; BINDING; RXFP1; IDENTIFICATION; LIGAND; LGR7 AB The GPCR relaxin family peptide receptor 1 (RXFP1) mediates the action of relaxin peptide hormone, including its tissue remodeling and antifibrotic effects. The peptide has a short half-life in plasma, limiting its therapeutic utility. However, small-molecule agonists of human RXFP1 can overcome this limitation and may provide a useful therapeutic approach, especially for chronic diseases such as heart failure and fibrosis. The first small molecule agonists of RXFP1 were recently identified from a high-throughput screening, using a homogeneous cell-based cAMP assay. Optimization of the hit compounds resulted in a series of highly potent and RXFP1 selective agonists with low cytotoxicity, and excellent in vitro ADME and pharmacokinetic properties. Here, we undertook extensive site-directed mutagenesis studies in combination with computational modeling analysis to probe the molecular basis of the small-molecule binding to RXFP1. The results showed that the agonists bind to an allosteric site of RXFP1 in a manner that closely interacts with the seventh transmembrane domain (TM7) and "the third extracellular loop (ECL3). Several residues were determined to play an important role in the agonist binding and receptor activation, including a hydrophobic region at TM7 consisting of W664, F668, and L670. The G659/T660 motif within ECL3 "is crucial to the observed species selectivity of the agonists for RXFP1. The receptor binding and activation effects by the small molecule ML290 were compared with the-cognate ligand, relaxin, providing valuable insights on the structural basis and molecular mechanism of receptor activation and selectivity for RXFP1. C1 [Hu, Xin; Xiao, Jingbo; Barnaeva, Elena; Ferrer, Marc; Marugan, Juan J.; Southall, Noel] NIH, Natl Ctr Adv Translat Sci, NIH Chem Genom Ctr, Rockville, MD 20850 USA. [Myhr, Courtney; Huang, Zaohua; Ho, Brian A.; Agoulnik, Alexander I.] Florida Int Univ, Dept Human & Mol Genet, Miami, FL 33199 USA. [Agoulnik, Irina U.] Florida Int Univ, Herbert Wertheim Coll Med, Dept Cellular Biol & Pharmacol, Miami, FL 33199 USA. RP Agoulnik, AI (reprint author), Florida Int Univ, Dept Human & Mol Genet, Miami, FL 33199 USA. EM aagoulni@fiu.edu OI Agoulnik, Alexander/0000-0001-6587-6845 FU Florida Department of Health; James and Esther King Biomedical Research Program [3KFO1]; National Cancer Institute [1U01CA177711]; NIH/NIGMS fellowship [T34 GM083688] FX This research has been funded in part by the Florida Department of Health, the James and Esther King Biomedical Research Program (Grant 3KFO1), and the National Cancer Institute (Grant No. 1U01CA177711) (A.I.A.). B.A.H. was supported by NIH/NIGMS T34 GM083688 fellowship. NR 31 TC 0 Z9 0 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAR 29 PY 2016 VL 55 IS 12 BP 1772 EP 1783 DI 10.1021/acs.biochem.5b01195 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DI1HQ UT WOS:000373247600011 PM 26866459 ER PT J AU McReznolds, AC Karra, AS Li, Y Lopez, ED Turjanski, AG Dioum, E Lorenz, K Zaganjor, E Stippec, S McGlynn, K Earnest, S Cobb, MH AF McReznolds, Andrea C. Karra, Aroon S. Li, Yan Daniel Lopez, Elias Turjanski, Adrian G. Dioum, Elhadji Lorenz, Kristina Zaganjor, Elma Stippec, Steve McGlynn, Kathleen Earnest, Svetlana Cobb, Melanie H. TI Phosphorylation or Mutation of the ERK2 Activation Loop Alters Oligonucleotide Binding SO BIOCHEMISTRY LA English DT Article ID INSULIN GENE-TRANSCRIPTION; CARDIAC-HYPERTROPHY; PROTEIN-KINASES; MAP KINASES; IN-VITRO; DOCKING MOTIF; BETA-CELLS; RECEPTOR; PATHWAY; MECHANISM AB The mitogen-activated protein kinase ERK2 is able to elicit a wide range of context-specific responses to distinct stimuli, but the mechanisms underlying this versatility remain in question. Some cellular functions of ERK2 are mediated through regulation of gene expression. In addition to phosphorylating numerous transcriptional regulators, ERK2 is known to associate with chromatin and has been shown to bind oligonucleotides directly. ERK2 is activated by the upstream kinases MEK1/2, which phosphorylate both tyrosine 185 and threonine 183: ERK2 requires phosphorylation on both sites to be fully active. Some additional ERK2 phosphorylation sites have also been reported, including threonine 188. It has been suggested that this phospho form has distinct properties. We detected some ERK2 phosphorylated on T188 in bacterial preparations of ERK2 by mass spectrometry and further demonstrate that phosphomimetic substitution of this ERK2 residue impairs its kinase activity toward well-defined substrates and also affects its DNA binding. We used electrophoretic mobility shift assays with oligOnucleotides derived from the insulin gene promoter and other regions to examine effects of phosphorylation and mutations on the binding of ERK2 to DNA. We show that ERK2 can bind oligonucleotides directly. Phosphorylation and mutations alter DNA binding and support the idea that signaling functions may be influenced through an alternate phosphorylation site. C1 [McReznolds, Andrea C.; Karra, Aroon S.; Li, Yan; Dioum, Elhadji; Zaganjor, Elma; Stippec, Steve; McGlynn, Kathleen; Earnest, Svetlana; Cobb, Melanie H.] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA. [Daniel Lopez, Elias; Turjanski, Adrian G.] Univ Buenos Aires, Dept Biol Chem, Lab Struct Bioinformat, Buenos Aires, DF, Argentina. [Lorenz, Kristina] Leibniz Inst Analyt Wissensch ISAS eV, Dortmund, Germany. [Li, Yan] NINDS, Prot Peptide Sequencing Facil, Bethesda, MD 20824 USA. [Dioum, Elhadji] Nestle Inst, Lausanne, Switzerland. [Li, Yan] NINDS, Bethesda, MD 20824 USA. [Zaganjor, Elma] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Cobb, MH (reprint author), Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA. EM melanie.cobb@utsouthwestern.edu OI Cobb, Melanie/0000-0003-0833-5473 FU National Institutes of Health [R37 DK34128]; Welch Foundation Grant [I1243]; Deutsche Forschungsgemeinschaft grant (DFG) [Sonderforschungsbereich SFB688] FX These studies were supported by National Institutes of Health Grant R37 DK34128 and Welch Foundation Grant I1243 to M.H.C. and a Deutsche Forschungsgemeinschaft grant (DFG; Sonderforschungsbereich SFB688) to K.L. NR 49 TC 1 Z9 1 U1 2 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAR 29 PY 2016 VL 55 IS 12 BP 1909 EP 1917 DI 10.1021/acs.biochem.6b00096 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DI1HQ UT WOS:000373247600022 PM 26950759 ER PT J AU Wang, XX Galletta, BJ Cooper, JA Carlsson, AE AF Wang, Xinxin Galletta, Brian J. Cooper, John A. Carlsson, Anders E. TI Actin-Regulator Feedback Interactions during Endocytosis SO BIOPHYSICAL JOURNAL LA English DT Article ID CLATHRIN-MEDIATED ENDOCYTOSIS; YEAST ARP2/3 COMPLEX; DYNAMICS IN-VIVO; FISSION YEAST; SACCHAROMYCES-CEREVISIAE; PLASMA-MEMBRANE; BUDDING YEAST; N-WASP; FILAMENT TURNOVER; DISTINCT ROLES AB Endocytosis mediated by clathrin, a cellular process by which cells internalize membrane receptors and their extracellular ligands, is an important component of cell signaling regulation. Actin polymerization is involved in endocytosis in varying degrees depending on the cellular context. In yeast, clathrin-mediated endocytosis requires a pulse of polymerized actin and its regulators, which recruit and activate the Arp2/3 complex. In this article, we seek to identify the main protein-protein interactions that 1) cause actin and its regulators to appear in pulses, and 2) determine the effects of key mutations and drug treatments on actin and regulator assembly. We perform a joint modeling/experimental study of actin and regulator dynamics during endocytosis in the budding yeast Saccharomyces cerevisiae. We treat both a stochastic model that grows an explicit three-dimensional actin network, and a simpler two-variable Fitzhugh-Nagumo type model. The models include a negative-feedback interaction of F-actin onto the Arp2/3 regulators. Both models explain the pulse time courses and the effects of interventions on actin polymerization: the surprising increase in the peak F-actin count caused by reduced regulator branching activity, the increase in F-actin resulting from slowing of actin disassembly, and the increased Arp2/3 regulator lifetime resulting from latrunculin treatment. In addition, they predict that decreases in the regulator branching activity lead to increases in accumulation of regulators, and we confirmed this prediction with experiments on yeast harboring mutations in the Arp2/3 regulators, using quantitative fluorescence microscopy. Our experimental measurements suggest that the regulators act quasi-independently, in the sense that accumulation of a particular regulator is most strongly affected by mutations of that regulator, as opposed to the others. C1 [Wang, Xinxin; Carlsson, Anders E.] Washington Univ, Dept Phys, St Louis, MO 63130 USA. [Galletta, Brian J.] NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. [Cooper, John A.] Washington Univ, Sch Med, Dept Cell Biol & Physiol, St Louis, MO 63110 USA. RP Carlsson, AE (reprint author), Washington Univ, Dept Phys, St Louis, MO 63130 USA. EM aec@wustl.edu FU National Institutes of Health [R01 GM107667, R01 GM086882, R01 GM38542, R01 GM95509] FX This work was supported by the National Institutes of Health under grants No. R01 GM107667, R01 GM086882, R01 GM38542, and R01 GM95509. NR 81 TC 1 Z9 1 U1 2 U2 6 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 MAR 29 PY 2016 VL 110 IS 6 BP 1430 EP 1443 DI 10.1016/j.bpj.2016.02.018 PG 14 WC Biophysics SC Biophysics GA DI4RO UT WOS:000373487200024 PM 27028652 ER PT J AU Crowley, NA Bloodgood, DW Hardaway, JA Kendra, AM McCall, JG Al-Hasani, R McCall, NM Yu, W Schools, ZL Krashes, MJ Lowell, BB Whistler, JL Bruchas, MR Kash, TL AF Crowley, Nicole A. Bloodgood, Daniel W. Hardaway, J. Andrew Kendra, Alexis M. McCall, Jordan G. Al-Hasani, Ream McCall, Nora M. Yu, Waylin Schools, Zachary L. Krashes, Michael J. Lowell, Bradford B. Whistler, Jennifer L. Bruchas, Michael R. Kash, Thomas L. TI Dynorphin Controls the Gain of an Amygdalar Anxiety Circuit SO CELL REPORTS LA English DT Article ID KAPPA-OPIOID RECEPTOR; LONG-TERM DEPRESSION; STRIA TERMINALIS; BED NUCLEUS; PLACE AVERSION; DORSAL RAPHE; STRESS; ACTIVATION; DISORDERS; BEHAVIOR AB Kappa opioid receptors (KORs) are involved in a variety of aversive behavioral states, including anxiety. To date, a circuit-based mechanism for KOR-driven anxiety has not been described. Here, we show that activation of KORs inhibits glutamate release from basolateral amygdala (BLA) inputs to the bed nucleus of the stria terminalis (BNST) and occludes the anxiolytic phenotype seen with optogenetic activation of BLA-BNST projections. In addition, deletion of KORs from amygdala neurons results in an anxiolytic phenotype. Furthermore, we identify a frequency-dependent, optically evoked local dynorphin-induced heterosynaptic plasticity of glutamate inputs in the BNST. We also find that there is cell type specificity to the KOR modulation of the BLA-BNST input with greater KOR-mediated inhibition of BLA dynorphin-expressing neurons. Collectively, these results provide support for a model in which local dynorphin release can inhibit an anxiolytic pathway, providing a discrete therapeutic target for the treatment of anxiety disorders. C1 [Crowley, Nicole A.; Bloodgood, Daniel W.; Yu, Waylin] Univ N Carolina, Neurobiol Curriculum, Chapel Hill, NC 27599 USA. [Crowley, Nicole A.; Bloodgood, Daniel W.; Hardaway, J. Andrew; Kendra, Alexis M.; McCall, Nora M.; Yu, Waylin; Kash, Thomas L.] Univ N Carolina, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27599 USA. [McCall, Jordan G.; Bruchas, Michael R.] Washington Univ, Sch Med, Neurosci Program, Div Biol & Biomed Sci, St Louis, MO 63110 USA. [McCall, Jordan G.; Al-Hasani, Ream; Schools, Zachary L.; Bruchas, Michael R.] Washington Univ, Sch Med, Dept Anesthesiol, St Louis, MO 63110 USA. [McCall, Jordan G.; Al-Hasani, Ream; Bruchas, Michael R.] Washington Univ, Sch Med, Dept Neurosci, St Louis, MO 63110 USA. [Kash, Thomas L.] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Krashes, Michael J.; Lowell, Bradford B.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Endocrinol Diabet & Metab,Dept Med, Boston, MA 02215 USA. [Krashes, Michael J.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Krashes, Michael J.] NIDA, NIH, Baltimore, MD 21224 USA. [Lowell, Bradford B.] Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02215 USA. [Whistler, Jennifer L.] Univ Calif San Francisco, Ernest Gallo Clin, Emeryville, CA 94806 USA. [Whistler, Jennifer L.] Univ Calif San Francisco, Dept Neurol, Res Ctr, Emeryville, CA 94806 USA. RP Kash, TL (reprint author), Univ N Carolina, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27599 USA.; Kash, TL (reprint author), Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA. EM tkash@med.unc.edu FU NARSAD Young Investigator Award [U01AA020911]; BNORC Transgenic Core [P30 DK046200]; BADERC Transgenic Core [P30 DK57521]; McDonnell Center for Systems Neuroscience [R01DA033396]; [R01AA019454]; [R00AA017668]; [R01DK096010]; [R01DK089044]; [R01DK071051]; [R01DK075632]; [R37DK053477]; [F32 DK089710] FX This work was supported by the following grants: R01AA019454, R00AA017668, NARSAD Young Investigator Award, and U01AA020911 (to T.L.K.); F31AA02228001 (to N.A.C.); R01DK096010, R01DK089044, R01DK071051, R01DK075632, R37DK053477, BNORC Transgenic Core P30 DK046200, and BADERC Transgenic Core P30 DK57521 (to B.B.L.); F32 DK089710 (to M.J.K.); R01DA033396, and McDonnell Center for Systems Neuroscience (to M.R.B.). NR 47 TC 4 Z9 4 U1 2 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD MAR 29 PY 2016 VL 14 IS 12 BP 2774 EP 2783 DI 10.1016/j.celrep.2016.02.069 PG 10 WC Cell Biology SC Cell Biology GA DH5YX UT WOS:000372869300002 PM 26997280 ER PT J AU Albanese, E Matthews, KA Zhang, JL Jacobs, DR Whitmer, RA Wadley, VG Yaffe, K Sidney, S Launer, LJ AF Albanese, Emiliano Matthews, Karen A. Zhang, Julia Jacobs, David R., Jr. Whitmer, Rachel A. Wadley, Virginia G. Yaffe, Kristine Sidney, Stephen Launer, Lenore J. TI Hostile attitudes and effortful coping in young adulthood predict cognition 25 years later SO NEUROLOGY LA English DT Article ID ALZHEIMERS-DISEASE; PSYCHOLOGICAL DISTRESS; PSYCHOSOCIAL FACTORS; BLOOD-PRESSURE; JOHN-HENRYISM; PERSONALITY; RISK; LIFE; AGE; CARDIA AB Objective: We studied the relation of early-life (mean age 25 years) and mid-life (mean age 50 years) cognitive function to early measures of hostile attitudes and effortful coping. Methods: In 3,126 black and white men and women (born in 1955-1968) from the Coronary Artery Risk Development in Young Adults Study (CARDIA), we used linear regression to examine the association of hostile attitudes (Cook-Medley questionnaire) and effortful coping assessed at baseline (1985-1986) to cognitive ability measured in 1987 and to a composite cognitive Z score of tests of verbal memory, psychomotor speed, and executive function ascertained in midlife (2010-2011). Results: Baseline hostility and effortful coping were prospectively associated with lower cognitive function 25 years later, controlling for age, sex, race, education, long-term exposure to depression, discrimination, negative life events, and baseline cognitive ability. Compared to the lowest quartile, those in the highest quartile of hostility performed 0.21 SD units lower (95% confidence interval [CI] -0.39, -0.02). Those in the highest quartile of effortful coping performed 0.30 SD units lower (95% CI -0.48, -0.12) compared to those in the lowest quartile. Further adjustment for cumulative exposure to cardiovascular risk factors attenuated the association with the cognitive composite Z score for hostility. Conclusions: Worse cognition in midlife was independently associated with 2 psychological characteristics measured in young adulthood. This suggests that interventions that promote positive social interactions may have a role in reducing risk of late-age cognitive impairment. C1 [Albanese, Emiliano; Zhang, Julia; Launer, Lenore J.] NIA, NIH, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. [Albanese, Emiliano] Univ Geneva, Dept Psychiat, Sch Med, CH-1211 Geneva 4, Switzerland. [Matthews, Karen A.] Univ Pittsburgh, Dept Psychiat & Psychol, Pittsburgh, PA 15260 USA. [Jacobs, David R., Jr.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55455 USA. [Whitmer, Rachel A.; Sidney, Stephen] Kaiser Permanente, Div Res, Oakland, CA USA. [Wadley, Virginia G.] Univ Alabama Birmingham, Dept Med, Birmingham, AL USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat Neurol & Epidemiol & Biostat, San Francisco, CA 94143 USA. RP Launer, LJ (reprint author), NIA, NIH, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. EM launerl@nia.nih.gov FU National Heart, Lung, and Blood Institute (NHLBI); University of Alabama at Birmingham [HHSN268201300025C, HHSN268201300026C]; Northwestern University [HHSN268201300027C]; University of Minnesota [HHSN268201300028C]; Kaiser Foundation Research Institute [HHSN268201300029C]; Johns Hopkins University School of Medicine [HHSN268200900041C]; Intramural Research Program of the National Institute on Aging (NIA); [AG0005] FX The Coronary Artery Risk Development in Young Adults Study (CARDIA) is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with the University of Alabama at Birmingham (HHSN268201300025C and HHSN268201300026C), Northwestern University (HHSN268201300027C), University of Minnesota (HHSN268201300028C), Kaiser Foundation Research Institute (HHSN268201300029C), and Johns Hopkins University School of Medicine (HHSN268200900041C). CARDIA is also partially supported by the Intramural Research Program of the National Institute on Aging (NIA) and an intra-agency agreement between NIA and NHLBI (AG0005). The funding source had no role in the design of the study; analysis and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. This manuscript has been reviewed by CARDIA for scientific content. NR 40 TC 0 Z9 0 U1 4 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD MAR 29 PY 2016 VL 86 IS 13 BP 1227 EP 1234 DI 10.1212/WNL.0000000000002517 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA DH5SV UT WOS:000372853000009 PM 26935891 ER PT J AU Kennedy, MW Chalamalasetty, RB Thomas, S Garriock, RJ Jailwala, P Yamaguchi, TP AF Kennedy, Mark W. Chalamalasetty, Ravindra B. Thomas, Sara Garriock, Robert J. Jailwala, Parthav Yamaguchi, Terry P. TI Sp5 and Sp8 recruit beta-catenin and Tcf1-Lef1 to select enhancers to activate Wnt target gene transcription SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Sp5/Sp8; transcription; stem cells; Wnt; Tcf/Lef ID EMBRYONIC STEM-CELLS; WNT/BETA-CATENIN; PRESOMITIC MESODERM; SIGNALING PATHWAY; DIFFERENTIATION; REVEALS; SPECIFICATION; SEGMENTATION; MAINTENANCE; PROGENITORS AB The ancient, highly conserved, Wnt signaling pathway regulates cell fate in allmetazoans. We have previously shown that combined null mutations of the specificity protein (Sp) 1/Klf-like zinc-finger transcription factors Sp5 and Sp8 (i.e., Sp5/8) result in an embryonic phenotype identical to that observed when core components of the Wnt/beta-catenin pathway are mutated; however, their role in Wnt signal transduction is unknown. Here, we show in mouse embryos and differentiating embryonic stem cells that Sp5/8 are gene-specific transcriptional coactivators in the Wnt/beta-catenin pathway. Sp5/8 bind directly to GC boxes in Wnt target gene enhancers and to adjacent, or distally positioned, chromatin-bound T-cell factor (Tcf) 1/lymphoid enhancer factor (Lef) 1 to facilitate recruitment of beta-catenin to target gene enhancers. Because Sp5 is itself directly activated by Wnt signals, we propose that Sp5 is a Wnt/beta-catenin pathway-specific transcripton factor that functions in a feed-forward loop to robustly activate select Wnt target genes. C1 [Kennedy, Mark W.; Chalamalasetty, Ravindra B.; Thomas, Sara; Garriock, Robert J.; Yamaguchi, Terry P.] NCI, Canc & Dev Biol Lab, Ctr Canc Res, NIH, Frederick, MD 21701 USA. [Jailwala, Parthav] Frederick Natl Lab Canc Res, Leidos Biomed Res, Ctr Canc Res Collaborat Bioinformat Resource, Frederick, MD 21702 USA. RP Yamaguchi, TP (reprint author), NCI, Canc & Dev Biol Lab, Ctr Canc Res, NIH, Frederick, MD 21701 USA. EM yamagute@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX We thank David Wilkinson and Sally Dunwoodie, Steven Potter and Kenneth Campbell, and Mark Lewandoski, for kindly providing us with the Sp5lacz/LacZ, Sp8Flox/Flox and tetO-Sp8-ires-EGFP, and T-Cre mouse lines, respectively; Marian Waterman for the LEF1 deletion constructs; Susan Mackem, Mark Lewandoski, and Joseph Landry for comments on the manuscript; and Ruth Wolfe for excellent animal colony management. This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 37 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 MAR 29 PY 2016 VL 113 IS 13 BP 3545 EP 3550 DI 10.1073/pnas.1519994113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH6BQ UT WOS:000372876400052 PM 26969725 ER PT J AU Nicoli, ER Al Eisa, N Cluzeau, CVM Wassif, CA Gray, J Burkert, KR Smith, DA Morris, L Cologna, SM Peer, CJ Sissung, TM Uscatu, CD Figg, WD Pavan, WJ Vite, CH Porter, FD Platt, FM AF Nicoli, Elena-Raluca Al Eisa, Nada Cluzeau, Celine V. M. Wassif, Christopher A. Gray, James Burkert, Kathryn R. Smith, David A. Morris, Lauren Cologna, Stephanie M. Peer, Cody J. Sissung, Tristan M. Uscatu, Constantin-Daniel Figg, William D. Pavan, William J. Vite, Charles H. Porter, Forbes D. Platt, Frances M. TI Defective Cytochrome P450-Catalysed Drug Metabolism in Niemann-Pick Type C Disease SO PLOS ONE LA English DT Article ID PRIMARY BILIARY-CIRRHOSIS; RECEPTOR LXR-ALPHA; MOUSE MODEL; MITOCHONDRIAL-FUNCTION; URSODEOXYCHOLIC ACID; PARKINSONS-DISEASE; LIVER-DISEASE; CHOLESTEROL; MICE; EXPRESSION AB Niemann-Pick type C (NPC) disease is a neurodegenerative lysosomal storage disease caused by mutations in either the NPC1 or NPC2 gene. NPC is characterised by storage of multiple lipids in the late endosomal/lysosomal compartment, resulting in cellular and organ system dysfunction. The underlying molecular mechanisms that lead to the range of clinical presentations in NPC are not fully understood. While evaluating potential small molecule therapies in Npc1(-/-) mice, we observed a consistent pattern of toxicity associated with drugs metabolised by the cytochrome P450 system, suggesting a potential drug metabolism defect in NPC1 disease. Investigation of the P450 system in the context of NPC1 dysfunction revealed significant changes in the gene expression of many P450 associated genes across the full lifespan of Npc1(-/-) mice, decreased activity of cytochrome P450 reductase, and a global decrease of multiple cytochrome P450 catalysed dealkylation reactions. In vivo drug metabolism studies using a prototypic P450 metabolised drug, midazolam, confirmed dysfunction in drug clearance in the Npc1(-/-) mouse. Expression of the Phase II enzyme uridinediphosphate- glucuronosyltransferase (UGT) was also significantly reduced in Npc1(-/-) mice. Interestingly, reduced activity within the P450 system was also observed in heterozygous Npc1(+/-) mice. The reduced activity of P450 enzymes may be the result of bile acid deficiency/imbalance in Npc1(-/-) mice, as bile acid treatment significantly rescued P450 enzyme activity in Npc1(-/-) mice and has the potential to be an adjunctive therapy for NPC disease patients. The dysfunction in the cytochrome P450 system were recapitulated in the NPC1 feline model. Additionally, we present the first evidence that there are alterations in the P450 system in NPC1 patients. C1 [Nicoli, Elena-Raluca; Al Eisa, Nada; Wassif, Christopher A.; Gray, James; Smith, David A.; Morris, Lauren; Uscatu, Constantin-Daniel; Platt, Frances M.] Univ Oxford, Dept Pharmacol, S Parks Rd, Oxford OX1 3QT, England. [Cluzeau, Celine V. M.; Wassif, Christopher A.; Burkert, Kathryn R.; Cologna, Stephanie M.; Porter, Forbes D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Dysmorphol, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Peer, Cody J.; Sissung, Tristan M.; Figg, William D.] NCI, Clin Pharmacol Program, Med Oncol Branch, US Dept HHS, Bethesda, MD 20892 USA. [Uscatu, Constantin-Daniel] Univ Med & Pharm Craiova, Dept Cellular & Mol Biol, Craiova, Romania. [Pavan, William J.] NHGRI, Genet Dis Res Branch, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Vite, Charles H.] Univ Penn, Sch Vet Med, Philadelphia, PA 19104 USA. RP Platt, FM (reprint author), Univ Oxford, Dept Pharmacol, S Parks Rd, Oxford OX1 3QT, England.; Porter, FD (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Dysmorphol, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. EM fdporter@mail.nih.gov; Frances.platt@pharm.ox.ac.uk RI Figg Sr, William/M-2411-2016 FU Niemann-Pick Research Foundation (NPRF) UK; Action Medical Research; King Saud bin Abdulaziz University for Health Sciences; King Abdulaziz Medical City; National Guard Health Affairs; Saudi Ministry of Higher Education; NPRF; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Cancer Institute; Ara Parseghian Medical Research Foundation; Dana's Angels Research Trust; NIH [R01 NS073661, RR02512]; European Social Fund, Human Resources Development Operational Programme [POSDRU/159/1.5/136893]; NPRF (Niemann-Pick Research Foundation); NPUK (Niemann-Pick, UK); SOAR-NPC (support of accelerated research for Niemann-Pick Type C) FX The Npc1 mouse studies were funded by an infrastructure grant to FMP from the Niemann-Pick Research Foundation (NPRF) UK. ERN was supported by Action Medical Research. NA was supported by King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, National Guard Health Affairs and the Saudi Ministry of Higher Education. DS and LM were supported by NPRF. CAW, CVMC, KB, SMC and FDP were funded by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. CJP, TMS and WDF were all funded by the intramural research program of the National Cancer Institute. CHV was supported by the Ara Parseghian Medical Research Foundation, Dana's Angels Research Trust, and NIH (R01 NS073661 and RR02512). CDU was supported by European Social Fund, Human Resources Development Operational Programme 2007-2013, project no. POSDRU/159/1.5/136893. FMP was supported by NPRF (Niemann-Pick Research Foundation) and NPUK (Niemann-Pick, UK), SOAR-NPC (support of accelerated research for Niemann-Pick Type C). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 73 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 28 PY 2016 VL 11 IS 3 AR e0152007 DI 10.1371/journal.pone.0152007 PG 31 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH5EH UT WOS:000372807800026 PM 27019000 ER PT J AU Kapogiannis, BG Leister, E Siberry, GK Van Dyke, RB Rudy, B Flynn, P Williams, PL AF Kapogiannis, Bill G. Leister, Erin Siberry, George K. Van Dyke, Russell B. Rudy, Bret Flynn, Patricia Williams, Paige L. CA REACH Study PACTG 219 219C Study TI Prevalence of and progression to abnormal noninvasive markers of liver disease (aspartate aminotransferase-to-platelet ratio index and Fibrosis-4) among US HIV-infected youth SO AIDS LA English DT Article DE adolescents; HIV infection; noninvasive liver disease markers ID VIRUS TYPE-1 INFECTION; HEPATITIS-C; ANTIRETROVIRAL THERAPY; HIV/HCV COINFECTION; UNITED-STATES; CHILDREN; PREDICT; CELLS; AIDS; HCV AB Objective:To longitudinally characterize noninvasive markers of liver disease in HIV-infected youth.Design:HIV infection, without viral hepatitis coinfection, may contribute to liver disease. Noninvasive markers of liver disease [FIB-4 (Fibrosis-4) and APRI (aspartate aminotransferase-to-platelet ratio index)] have been evaluated in adults with concomitant HIV and hepatitis C, but are less studied in children.Methods:In prospective cohorts of HIV-infected and HIV-uninfected youth, we used linear regression models to compare log-transformed FIB-4 and APRI measures by HIV status based on a single visit at ages 15-20 years. We also longitudinally modeled trends in these measures in HIV-infected youth with two or more visits to compare those with behavioral vs. perinatal HIV infection (PHIV) using mixed effect linear regression, adjusting for age, sex, body mass index, and race/ethnicity.Results:Of 1785 participants, 41% were men, 57% black non-Hispanic, and 27% Hispanic. More HIV-infected than uninfected youth had an APRI score more than 0.5 (13 vs. 3%, P<0.001). Among 1307 HIV-infected participants with longitudinal measures, FIB-4 scores increased 6% per year (P<0.001) among all HIV-infected youth, whereas APRI scores increased 2% per year (P=0.007) only among PHIV youth. The incidence rates (95% confidence interval) of progression of APRI to more than 0.5 and more than 1.5 were 7.5 (6.5-8.7) and 1.4 (1.0-1.9) cases per 100 person-years of follow-up, respectively. The incidence of progression of FIB-4 to more than 1.5 and more than 3.25 were 1.6 (1.2-2.2) and 0.3 (0.2-0.6) cases per 100 person-years, respectively.Conclusion:APRI and FIB-4 scores were higher among HIV-infected youth. Progression to scores suggesting subclinical fibrosis or worse was common. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved. C1 [Kapogiannis, Bill G.; Siberry, George K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, 6100 Execut Blvd,Room 4B11J, Bethesda, MD 20892 USA. [Leister, Erin; Williams, Paige L.] Harvard Univ, TH Chan Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Van Dyke, Russell B.] Tulane Univ, Hlth Sci Ctr, New Orleans, LA 70118 USA. [Rudy, Bret] NYU, New York, NY USA. [Flynn, Patricia] St Jude Childrens Res Hosp, 332 N Lauderdale St, Memphis, TN 38105 USA. RP Kapogiannis, BG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, 6100 Execut Blvd,Room 4B11J, Bethesda, MD 20892 USA. EM kapogiannisb@mail.nih.gov FU Pediatric HIV/AIDS Cohort Study (PHACS) [U01HD052102, U01HD052104]; Adolescent Medicine HIV/AIDS Research Network (AMHARN) [U01HD32842]; PACTG; IMPAACT Group; National Institute of Allergy and Infectious Diseases (NIAID); Eunice Kennedy Shriver NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network - NICHD [N01-DK-9-001/HHSN267200800001C]; PACTG 219/219C; National Institute of Allergy and Infectious Diseases [U01 AI068632]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) International and Domestic Pediatric and Maternal HIV Clinical Trials Network; NICHD [N01-3-3345, HHSN267200800001C]; Statistical and Data Analysis Center at Harvard School of Public Health, under the National Institute of Allergy and Infectious Diseases [5 U01 AI41110]; Pediatric AIDS Clinical Trials Group (PACTG) [1 U01 AI068616]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development through the Adolescent Medicine HIV/AIDS Research Network (AMHARN) [U01HD32842]; Pediatric HIV/AIDS Cohort Study (PHACS) - Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute on Drug Abuse; National Institute of Allergy and Infectious Diseases; Office of AIDS Research; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; National Institute on Deafness and Other Communication Disorders; National Heart Lung and Blood Institute; National Institute of Dental and Craniofacial Research; National Institute on Alcohol Abuse and Alcoholism; Harvard T.H. Chan School of Public Health [HD052102]; Tulane University School of Medicine [HD052104]; NIH [1 U01 AI068616, U01 HD052102]; [U01AI068632]; [U01AI41110]; [U01 AI068616] FX We are indebted to the Pediatric HIV/AIDS Cohort Study (PHACS) that provided support for the conduct of this analysis (Dr George Seage, PI of Data and Operations Center, U01HD052102, and Dr Russell Van Dyke, PI of Clinical Coordinating Center, U01HD052104). REACH was supported by U01HD32842 through the Adolescent Medicine HIV/AIDS Research Network (AMHARN). The authors thank investigators and staff [listed in J Adolesc Health Sept 2001, Vol 29, Issue 3 (supplement 1): 5-6] of AMHARN (1994-2001) and the youth who participated in the REACH project for their valuable contributions. PACTG 219/219C was supported through the following cooperative agreements: Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) was provided by U01AI068632. The Statistical and Data Analysis Center at Harvard School of Public Health was supported under cooperative agreement U01AI41110 with the PACTG and under U01 AI068616 with the IMPAACT Group. Support of the sites was provided by the National Institute of Allergy and Infectious Diseases (NIAID) and the Eunice Kennedy Shriver NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network funded by NICHD (contract number N01-DK-9-001/HHSN267200800001C). The authors thank investigators and staff [listed in AIDS July 2013, Vol 27, Issue 12: 1959-1970] of the Pediatric AIDS Clinical Trials Group (PACTG) 219/219C protocols (1993-2007) and the youth who participated in these protocols for their valuable contributions. We also would like to thank all investigators from the Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN), PHACS, and IMPAACT who were involved in the review of this study for their invaluable expertise and input.; This work was supported by the following main entities: PACTG 219/219C.; Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases [U01 AI068632] and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) International and Domestic Pediatric and Maternal HIV Clinical Trials Network supported by the NICHD [contract N01-3-3345 and HHSN267200800001C]. Additional support was provided by the Statistical and Data Analysis Center at Harvard School of Public Health, under the National Institute of Allergy and Infectious Diseases cooperative agreement #5 U01 AI41110 with the Pediatric AIDS Clinical Trials Group (PACTG) and # 1 U01 AI068616 with the IMPAACT Group.; The REACH and PACTG 219/219C studies received support from the National Institute of Allergy and Infectious Diseases (NIAID), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institutes of Health.; REACH: The Reaching for Excellence in Adolescent Care and Heath cohort was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development [U01HD32842] through the Adolescent Medicine HIV/AIDS Research Network (AMHARN).; PHACS: The analyses for this work were funded by the Pediatric HIV/AIDS Cohort Study (PHACS), which was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) with cofunding from the National Institute on Drug Abuse, the National Institute of Allergy and Infectious Diseases, the Office of AIDS Research, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Institute on Deafness and Other Communication Disorders, the National Heart Lung and Blood Institute, the National Institute of Dental and Craniofacial Research, and the National Institute on Alcohol Abuse and Alcoholism, through cooperative agreements with the Harvard T.H. Chan School of Public Health [HD052102] and the Tulane University School of Medicine [HD052104].; R.B.V.D. NIH-funded investigator in PHACS and IMPAACT networks, including support to travel to network meetings; P.F. NIH-funded investigator in PHACS and IMPAACT networks; also receives support for consultancy to Merck's Safety Monitoring Committee and royalties for the publication of UpToDate; E.L., P.L.W. NIH-funded Data and Operations center for the Pediatric HIV/AIDS Cohort Study and IMPAACT, under cooperative agreements U01 HD052102 and # 1 U01 AI068616, respectively. The remaining authors had nothing to declare. NR 37 TC 1 Z9 1 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD MAR 27 PY 2016 VL 30 IS 6 BP 889 EP 898 DI 10.1097/QAD.0000000000001003 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DG2NZ UT WOS:000371905500008 PM 26959353 ER PT J AU Huang, CC Lu, ZY AF Huang, Chung-Chi Lu, Zhiyong TI Discovering biomedical semantic relations in PubMed queries for information retrieval and database curation SO DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION LA English DT Article ID KNOWLEDGE-BASE; ANNOTATION; EXPANSION AB Identifying relevant papers from the literature is a common task in biocuration. Most current biomedical literature search systems primarily rely on matching user keywords. Semantic search, on the other hand, seeks to improve search accuracy by understanding the entities and contextual relations in user keywords. However, past research has mostly focused on semantically identifying biological entities (e.g. chemicals, diseases and genes) with little effort on discovering semantic relations. In this work, we aim to discover biomedical semantic relations in PubMed queries in an automated and unsupervised fashion. Specifically, we focus on extracting and understanding the contextual information (or context patterns) that is used by PubMed users to represent semantic relations between entities such as 'CHEMICAL-1 compared to CHEMICAL-2.' With the advances in automatic named entity recognition, we first tag entities in PubMed queries and then use tagged entities as knowledge to recognize pattern semantics. More specifically, we transform PubMed queries into context patterns involving participating entities, which are subsequently projected to latent topics via latent semantic analysis (LSA) to avoid the data sparseness and specificity issues. Finally, we mine semantically similar contextual patterns or semantic relations based on LSA topic distributions. Our two separate evaluation experiments of chemical-chemical (CC) and chemical-disease (CD) relations show that the proposed approach significantly outperforms a baseline method, which simply measures pattern semantics by similarity in participating entities. The highest performance achieved by our approach is nearly 0.9 and 0.85 respectively for the CC and CD task when compared against the ground truth in terms of normalized discounted cumulative gain (nDCG), a standard measure of ranking quality. These results suggest that our approach can effectively identify and return related semantic patterns in a ranked order covering diverse bio-entity relations. To assess the potential utility of our automated top-ranked patterns of a given relation in semantic search, we performed a pilot study on frequently sought semantic relations in PubMed and observed improved literature retrieval effectiveness based on post-hoc human relevance evaluation. Further investigation in larger tests and in real-world scenarios is warranted. C1 [Huang, Chung-Chi; Lu, Zhiyong] NIH, Natl Lib Med, NCBI, 8600 Rockville Pike, Bethesda, MD 20894 USA. RP Lu, ZY (reprint author), NIH, Natl Lib Med, NCBI, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM Zhiyong.lu@nih.gov FU National Library of Medicine, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Library of Medicine, National Institutes of Health. NR 35 TC 0 Z9 0 U1 6 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1758-0463 J9 DATABASE-OXFORD JI Database PD MAR 25 PY 2016 AR baw025 DI 10.1093/database/baw025 PG 15 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA DJ3FR UT WOS:000374090700001 ER PT J AU Hanke-Gogokhia, C Wu, ZJ Gerstner, CD Frederick, JM Zhang, HB Baehr, W AF Hanke-Gogokhia, Christin Wu, Zhijian Gerstner, Cecilia D. Frederick, Jeanne M. Zhang, Houbin Baehr, Wolfgang TI Arf-like Protein 3 (ARL3) Regulates Protein Trafficking and Ciliogenesis in Mouse Photoreceptors SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE animal model; gene knock-out; lipid-binding protein; photoreceptor; protein trafficking (Golgi); retinal degeneration ID ROD OUTER SEGMENTS; CYCLIC-GMP PHOSPHODIESTERASE; COUPLED RECEPTOR KINASES; RETINITIS-PIGMENTOSA 2; PDE-DELTA; JOUBERT-SYNDROME; PRIMARY CILIUM; CGMP PHOSPHODIESTERASE; RETINAL DEGENERATION; CATALYTIC SUBUNITS AB Arf-like protein 3 (ARL3) is a ubiquitous small GTPase expressed in ciliated cells of plants and animals. Germline deletion of Arl3 in mice causes multiorgan ciliopathy reminiscent of Bardet-Biedl or Joubert syndromes. As photoreceptors are elegantly compartmentalized and have cilia, we probed the function of ARL3 (ADP-ribosylation factor (Arf)-like 3 protein) by generating rod photoreceptor-specific (prefix (rod)) and retina-specific (prefix (ret)) Arl3 deletions. In predegenerate (rod)Arl3(-/-) mice, lipidated phototransduction proteins showed trafficking deficiencies, consistent with the role of ARL3 as a cargo displacement factor for lipid-binding proteins. By contrast, (ret)Arl3(-/-) rods and cones expressing Cre recombinase during embryonic development formed neither connecting cilia nor outer segments and degenerated rapidly. Absence of cilia infers participation of ARL3 in ciliogenesis and axoneme formation. Ciliogenesis was rescued, and degeneration was reversed in part by subretinal injection of adeno-associated virus particles expressing ARL3-EGFP. The conditional knock-out phenotypes permitted identification of two ARL3 functions, both in the GTP-bound form as follows: one as a regulator of intraflagellar transport participating in photoreceptor ciliogenesis and the other as a cargo displacement factor transporting lipidated protein to the outer segment. Surprisingly, a farnesylated inositol polyphosphate phosphatase only trafficked from the endoplasmic reticulum to the Golgi, thereby excluding it from a role in photoreceptor cilia physiology. C1 [Hanke-Gogokhia, Christin; Gerstner, Cecilia D.; Frederick, Jeanne M.; Baehr, Wolfgang] Univ Utah, Sch Med, John A Moran Eye Ctr, Dept Ophthalmol & Visual Sci, 65 Mario Capecchi Dr, Salt Lake City, UT 84132 USA. [Baehr, Wolfgang] Univ Utah, Sch Med, Dept Neurobiol & Anat, 65 Mario Capecchi Dr, Salt Lake City, UT 84132 USA. [Hanke-Gogokhia, Christin] Univ Potsdam, Dept Biol & Biochem, D-14476 Golm, Germany. [Wu, Zhijian] NEI, NIH, Bethesda, MD 20892 USA. [Zhang, Houbin] Hosp Univ Elect Sci & Technol China, Inst Lab Med, Sichuan Prov Key Lab Human Dis Gene Study, Chengdu 610072, Sichuan, Peoples R China. [Zhang, Houbin] Sichuan Prov Peoples Hosp, Chengdu 610072, Sichuan, Peoples R China. [Zhang, Houbin] Univ Elect Sci & Technol China, Sch Med, Chengdu 610072, Sichuan, Peoples R China. [Baehr, Wolfgang] Univ Utah, Dept Biol, Salt Lake City, UT 84112 USA. RP Zhang, HB (reprint author), Hosp Univ Elect Sci & Technol China, Inst Lab Med, Sichuan Prov Key Lab Human Dis Gene Study, Chengdu 610072, Sichuan, Peoples R China.; Zhang, HB (reprint author), Sichuan Prov Peoples Hosp, Chengdu 610072, Sichuan, Peoples R China.; Baehr, W (reprint author), Univ Utah, Moran Eye Ctr, 65 Mario Capecchi Dr, Salt Lake City, UT 84132 USA. EM houbin.zhang@gmail.com; wbaehr@hsc.utah.edu FU National Institutes of Health [EY08123, EY019298]; NEI Core [EY014800-039003]; Research to Prevent Blindness (New York); National Science Foundation of China [81371030]; Science and Technology Department of Sichuan [2014HH0009] FX This work was supported in part by National Institutes of Health Grants EY08123 and EY019298 (to W. B.) and NEI Core Grant EY014800-039003, unrestricted grants to the University of Utah Department of Ophthalmology from Research to Prevent Blindness (New York), National Science Foundation of China Grant 81371030, and Science and Technology Department of Sichuan Grant 2014HH0009 (to H. Z.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 75 TC 7 Z9 7 U1 2 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 25 PY 2016 VL 291 IS 13 BP 7142 EP 7155 DI 10.1074/jbc.M115.710954 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DI2BC UT WOS:000373299700047 PM 26814127 ER PT J AU Hirasaka, K Mills, EM Haruna, M Bando, A Ikeda, C Abe, T Kohno, S Nowinski, SM Lago, CU Akagi, K Tochio, H Ohno, A Teshima-Kondo, S Okumura, Y Nikawa, T AF Hirasaka, Katsuya Mills, Edward M. Haruna, Marie Bando, Aki Ikeda, Chika Abe, Tomoki Kohno, Shohei Nowinski, Sara M. Lago, Cory U. Akagi, Ken-ichi Tochio, Hidehito Ohno, Ayako Teshima-Kondo, Shigetada Okumura, Yuushi Nikawa, Takeshi TI UCP3 is associated with Hax-1 in mitochondria in the presence of calcium ion SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Mitochondria; Uncoupling protein 3; Calcium ion; Folding ID ANTI-APOPTOTIC PROTEIN; INHIBITION; CELLS AB Uncoupling protein 3 (UCP3) is known to regulate energy dissipation, proton leakage, fatty acid oxidation, and oxidative stress. To identify the putative protein regulators of UCP3, we performed yeast two hybrid screens. Here we report that UCP3 interacted with HS-1 associated protein X-1 (Hax-1), an antiapoptotic protein that was localized in the mitochondria, and is involved in cellular responses to Ca2+. The hydrophilic sequences within loop 2, and the matrix-localized hydrophilic domain of mouse UCP3, were necessary for binding to Hax-1 at the C-terminal domain, adjacent to the mitochondrial inner membrane. Interestingly, interaction of these proteins occurred in a calcium-dependent manner. Moreover, the NMR spectrum of the C-terminal domain of Hax-1 was dramatically changed by removal of Ca2+, suggesting that the C-terminal domain of Hax-1 underwent a Ca2+-induced conformational change. In the Ca2+-free state, the C-terminal Hax-1 tended to unfold, suggesting that Ca2+ binding may induce protein folding of the Hax-1 C-terminus. These results suggested that the UCP3-Hax-1 complex may regulate mitochondrial functional changes caused by mitochondrial Ca2+. (C) 2016 Elsevier Inc. All rights reserved. C1 [Hirasaka, Katsuya] Nagasaki Univ, Grad Sch Fisheries & Environm Sci, 1-14 Bunkyo Machi, Nagasaki 8528521, Japan. [Hirasaka, Katsuya; Haruna, Marie; Bando, Aki; Ikeda, Chika; Abe, Tomoki; Ohno, Ayako; Teshima-Kondo, Shigetada; Nikawa, Takeshi] Univ Tokushima, Dept Nutr Physiol, Inst Hlth Biosci, Tokushima 770, Japan. [Mills, Edward M.; Kohno, Shohei; Nowinski, Sara M.] Univ Texas Austin, Div Pharmacol Toxicol, Austin, TX 78712 USA. [Lago, Cory U.] NHLBI, Translat Med Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Akagi, Ken-ichi] Natl Inst Biomed Innovat, Sect Lab Equipment, Osaka, Japan. [Tochio, Hidehito] Kyoto Univ, Grad Sch Engn, Kyoto, Japan. [Okumura, Yuushi] Sagami Womans Univ, Dept Nutr & Hlth, Sagamihara, Kanagawa, Japan. RP Hirasaka, K (reprint author), Nagasaki Univ, Grad Sch Fisheries & Environm Sci, 1-14 Bunkyo Machi, Nagasaki 8528521, Japan. EM hirasaka@nagasaki-u.ac.jp OI Nowinski, Sara/0000-0002-4744-6101 FU Ministry of Education, Culture, Sports, Science, and Technology, Japan [24700753, 26350148] FX This work was supported in part by Grant No. 24700753, 26350148 (K.H.) from a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan. NR 27 TC 0 Z9 0 U1 1 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 MAR 25 PY 2016 VL 472 IS 1 BP 108 EP 113 DI 10.1016/j.bbrc.2016.02.075 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA DI1HY UT WOS:000373248400016 PM 26915802 ER PT J AU Klaene, JJ Flarakos, C Glick, J Barret, JT Zarbl, H Vouros, P AF Klaene, Joshua J. Flarakos, Caroline Glick, James Barret, Jennifer T. Zarbl, Helmut Vouros, Paul TI Tracking matrix effects in the analysis of DNA adducts of polycyclic aromatic hydrocarbons SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE Matrix effects; Benzo[a]pyrene; DNA adducts; Ion suppression; Polycyclic aromatic hydrocarbons ID TANDEM MASS-SPECTROMETRY; LIQUID-CHROMATOGRAPHY; ELECTROSPRAY-IONIZATION; CYTOCHROMES P450; AFLATOXIN B-1; BLADDER CELLS; QUANTITATION; TISSUES; LIVER; QUANTIFICATION AB LC-MS using electrospray ionization is currently the method of choice in bio-organic analysis covering a wide range of applications in a broad spectrum of biological media. The technique is noted for its high sensitivity but one major limitation that hinders achievement of its optimal sensitivity is the signal suppression due to matrix inferences introduced by the presence of co-extracted compounds during the sample preparation procedure. The analysis of DNA adducts of common environmental carcinogens is particularly sensitive to such matrix effects as sample preparation is a multistep process which involves "contamination" of the sample due to the addition of enzymes and other reagents for digestion of the DNA in order to isolate the analyte(s). This problem is further exacerbated by the need to reach low levels of quantitation (LOQ in the ppb level) while also working with limited (2-5 mu g) quantities of sample. We report here on the systematic investigation of ion signal suppression contributed by each individual step involved in the sample preparation associated with the analysis of DNA adducts of polycyclic aromatic hydrocarbon (PAH) using as model analyte BaP-dG, the deoxyguanosine (dG) adduct of benzo[a]pyrene (BaP). The individual matrix contribution of each one of these sources to analyte signal was systematically addressed as were any interactive effects. The information was used to develop a validated analytical protocol for the target biomarker at levels typically encountered in vivo using as little as 2 mu g of DNA and applied to a dose response study using a metabolically competent cell line. (C) 2015 Elsevier B.V. All rights reserved. C1 [Klaene, Joshua J.; Flarakos, Caroline; Glick, James; Vouros, Paul] Northeastern Univ, Dept Chem & Chem Biol, Boston, MA 02115 USA. [Klaene, Joshua J.; Flarakos, Caroline; Glick, James; Vouros, Paul] Northeastern Univ, Barnett Inst, Boston, MA 02115 USA. [Barret, Jennifer T.; Zarbl, Helmut] Rutgers State Univ, Robert Wood Johnson Med Sch, Grad Sch Biomed Sci, Piscataway, NJ 08854 USA. [Barret, Jennifer T.; Zarbl, Helmut] Rutgers State Univ, Robert Wood Johnson Med Sch, Environm & Occupat Hlth Sci Inst, Piscataway, NJ 08854 USA. [Zarbl, Helmut] Rutgers State Univ, Robert Wood Johnson Med Sch, NIEHS Ctr Environm Exposures & Dis, Piscataway, NJ 08854 USA. [Zarbl, Helmut] Rutgers State Univ, Robert Wood Johnson Med Sch, Dept Environm & Occupat Med, Piscataway, NJ 08854 USA. RP Vouros, P (reprint author), Northeastern Univ, Dept Chem & Chem Biol, Boston, MA 02115 USA. EM p.vouros@neu.edu FU Public Health Services Grants: NIH [RO1CA112231, RO1 069390]; NIEHS Center Grant [P30ES005022]; Toxicology training grant [T32ES007148] FX This work was supported by Public Health Services Grants: NIH RO1CA112231 (P. Vouros, P.I.), NIH RO1 069390 (P. Vouros, RI.); NIEHS Center Grant P30ES005022 (H. Zarbl, P.I.) and Toxicology training grant T32ES007148 (H. Zarbl, P.I.) NR 46 TC 1 Z9 1 U1 7 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 EI 1873-3778 J9 J CHROMATOGR A JI J. Chromatogr. A PD MAR 25 PY 2016 VL 1439 BP 112 EP 123 DI 10.1016/j.chroma.2015.10.057 PG 12 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA DH3GS UT WOS:000372676100011 PM 26607319 ER PT J AU Sharma, A Liu, X Hadley, D Hagopian, W Liu, E Chen, WM Onengut-Gumuscu, S Simell, V Rewers, M Ziegler, AG Lernmarklo, A Simell, O Toppari, J Krischer, JP Akolkar, B Rich, SS Agardh, D She, JX AF Sharma, Ashok Liu, Xiang Hadley, David Hagopian, William Liu, Edwin Chen, Wei-Min Onengut-Gumuscu, Suna Simell, Ville Rewers, Marian Ziegler, Anette-G. Lernmarklo, Ake Simell, Olli Toppari, Jorma Krischer, Jeffrey P. Akolkar, Beena Rich, Stephen S. Agardh, Daniel She, Jin-Xiong CA TEDDY Study Grp TI Identification of Non-HLA Genes Associated with Celiac Disease and Country-Specific Differences in a Large, International Pediatric Cohort SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; RHEUMATOID-ARTHRITIS; TRANSGLUTAMINASE ANTIBODIES; MULTIPLE COMMON; RISK VARIANTS; CHILDREN; SUSCEPTIBILITY; PADI4; METAANALYSIS; POPULATION AB Objectives There are significant geographical differences in the prevalence and incidence of celiac disease that cannot be explained by HLA alone. More than 40 loci outside of the HLA region have been associated with celiac disease. We investigated the roles of these non-HLA genes in the development of tissue transglutaminase autoantibodies (tTGA) and celiac disease in a large international prospective cohort study. Methods A total of 424,788 newborns from the US and European general populations and first-degree relatives with type 1 diabetes were screened for specific HLA genotypes. Of these, 21,589 carried 1 of the 9 HLA genotypes associated with increased risk for type 1 diabetes and celiac disease; we followed 8676 of the children in a 15 y prospective follow-up study. Genotype analyses were performed on 6010 children using the Illumina ImmunoChip. Levels of tTGA were measured in serum samples using radio-ligand binding assays; diagnoses of celiac disease were made based on persistent detection of tTGA and biopsy analysis. Data were analyzed using Cox proportional hazards analyses. Results We found 54 single-nucleotide polymorphisms (SNPs) in 5 genes associated with celiac disease (TAGAP, IL18R1, RGS21, PLEK, and CCR9) in time to celiac disease analyses (10(-4)> P> 5.8x10(-6)). The hazard ratios (HR) for the SNPs with the smallest P values in each region were 1.59, 1.45, 2.23, 2.64, and 1.40, respectively. Outside of regions previously associated with celiac disease, we identified 10 SNPs in 8 regions that could also be associated with the disease (P< 10(-4)). A SNP near PKIA (rs117128341, P = 6.5x10(-8), HR = 2.8) and a SNP near PFKFB3 (rs117139146, P< 2.8x10(-7), HR = 4.9) reached the genome-wide association threshold in subjects from Sweden. Analyses of time to detection of tTGA identified 29 SNPs in 2 regions previously associated with celiac disease (CTLA4, P = 1.3x10(-6), HR = 0.76 and LPP, P = 2.8x10(-5), HR =.80) and 6 SNPs in 5 regions not previously associated with celiac disease (P< 10(-4)); non-HLA genes are therefore involved in development of tTGA. Conclusions In conclusion, using a genetic analysis of a large international cohort of children, we associated celiac disease development with 5 non-HLA regions previously associated with the disease and 8 regions not previously associated with celiac disease. We identified 5 regions associated with development of tTGA. Two loci associated with celiac disease progression reached a genome-wide association threshold in subjects from Sweden. C1 [Sharma, Ashok; She, Jin-Xiong] Georgia Regents Univ, Ctr Biotechnol & Genom Med, Augusta, GA USA. [Liu, Xiang; Hadley, David; Krischer, Jeffrey P.] Univ S Florida, Dept Pediat, Pediat Epidemiol Ctr, Tampa, FL 33620 USA. [Hadley, David] St Georges Univ London, Div Populat Hlth Sci & Educ, London, England. [Hagopian, William] Pacific Northwest Diabet Res Inst, Seattle, WA USA. [Liu, Edwin] Univ Colorado Denver, Childrens Hosp Colorado, Digest Hlth Inst, Aurora, CO USA. [Chen, Wei-Min; Onengut-Gumuscu, Suna; Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Simell, Ville; Simell, Olli; Toppari, Jorma] Univ Turku, Dept Pediat, Turku, Finland. [Rewers, Marian] Univ Colorado Denver, Barbara Davis Ctr Childhood Diabet, Aurora, CO USA. [Ziegler, Anette-G.] Tech Univ Munich, Diabet Res Inst, Helmholtz Zentrum Munchen, D-80290 Munich, Germany. [Ziegler, Anette-G.] Tech Univ Munich, Klinikum Rechts Isar, D-80290 Munich, Germany. [Ziegler, Anette-G.] Forschergrp Diabet eV, Munich, Germany. [Lernmarklo, Ake] Lund Univ CRC, Dept Clin Sci, Malmo, Sweden. [Akolkar, Beena] NIDDK, NIH, Bethesda, MD 20892 USA. [Agardh, Daniel] Lund Univ, Diabet & Celiac Dis Unit, Malmo, Sweden. RP She, JX (reprint author), Georgia Regents Univ, Ctr Biotechnol & Genom Med, Augusta, GA USA. EM jshe@gru.edu FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [HHSN267200700014C]; National Institute of Allergy and Infectious Diseases (NIAID); National Institute of Child Health and Human Development (NICHD); National Institute of Environmental Health Sciences (NIEHS); Juvenile Diabetes Research Foundation (JDRF); Centers for Disease Control and Prevention (CDC); [DK 63829]; [63861]; [63821]; [63865]; [63863]; [63836]; [63790]; [UC4DK095300] FX None of the authors listed has any financial or other conflicts to disclose relevant to this article. This study was funded by DK 63829, 63861, 63821, 63865, 63863, 63836, 63790 and UC4DK095300 and contract no. HHSN267200700014C from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Child Health and Human Development (NICHD), National Institute of Environmental Health Sciences (NIEHS), Juvenile Diabetes Research Foundation (JDRF), and Centers for Disease Control and Prevention (CDC). The complete TEDDY Study Group is listed in the Supplementary material. NR 44 TC 1 Z9 1 U1 4 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 MAR 25 PY 2016 VL 11 IS 3 AR e0152476 DI 10.1371/journal.pone.0152476 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH3TE UT WOS:000372708900069 PM 27015091 ER PT J AU Sinha, R Ahn, J Sampson, JN Shi, JX Yu, GQ Xiong, XQ Hayes, RB Goedert, JJ AF Sinha, Rashmi Ahn, Jiyoung Sampson, Joshua N. Shi, Jianxin Yu, Guoqin Xiong, Xiaoqin Hayes, Richard B. Goedert, James J. TI Fecal Microbiota, Fecal Metabolome, and Colorectal Cancer Interrelations SO PLOS ONE LA English DT Article ID HUMAN GUT MICROBIOME; CONJUGATED LINOLEIC-ACID; CATABACTER-HONGKONGENSIS; PERFORMANCE; IDENTIFICATION; INFLAMMATION; SEQUENCE; TWINS; RISK AB Background and Aims Investigation of microbe-metabolite relationships in the gut is needed to understand and potentially reduce colorectal cancer (CRC) risk. Methods Microbiota and metabolomics profiling were performed on lyophilized feces from 42 CRC cases and 89 matched controls. Multivariable logistic regression was used to identify statistically independent associations with CRC. First principal coordinate-component pair (PCo1-PC1) and false discovery rate (0.05)-corrected P-values were calculated for 116,000 Pearson correlations between 530 metabolites and 220 microbes in a sex*case/control meta-analysis. Results Overall microbe-metabolite PCo1-PC1 was more strongly correlated in cases than in controls (Rho 0.606 vs 0.201, P = 0.01). CRC was independently associated with lower levels of Clostridia, Lachnospiraceae, p-aminobenzoate and conjugated linoleate, and with higher levels of Fusobacterium, Porphyromonas, p-hydroxy-benzaldehyde, and palmitoyl-sphingomyelin. Through postulated effects on cell shedding (palmitoyl-sphingomyelin), inflammation (conjugated linoleate), and innate immunity (p-aminobenzoate), metabolites mediated the CRC association with Fusobacterium and Porphyromonas by 29% and 34%, respectively. Overall, palmitoyl-sphingomyelin correlated directly with abundances of Enterobacteriaceae (Gammaproteobacteria), three Actinobacteria and five Firmicutes. Only Parabacteroides correlated inversely with palmitoyl-sphingomyelin. Other lipids correlated inversely with Alcaligenaceae (Betaproteobacteria). Six Bonferroni-significant correlations were found, including low indolepropionate and threnoylvaline with Actinobacteria and high erythronate and an uncharacterized metabolite with Enterobacteriaceae. Conclusions Feces from CRC cases had very strong microbe-metabolite correlations that were predominated by Enterobacteriaceae and Actinobacteria. Metabolites mediated a direct CRC association with Fusobacterium and Porphyromonas, but not an inverse association with Clostridia and Lachnospiraceae. This study identifies complex microbe-metabolite networks that may provide insights on neoplasia and targets for intervention. C1 [Sinha, Rashmi; Sampson, Joshua N.; Shi, Jianxin; Yu, Guoqin; Goedert, James J.] NCI, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. [Ahn, Jiyoung; Hayes, Richard B.] NYU, Sch Med, Div Epidemiol, Dept Populat Hlth, 650 First Ave,518, New York, NY 10016 USA. [Xiong, Xiaoqin] Informat Management Serv Inc, 6110 Execut Blvd, Rockville, MD 20852 USA. RP Goedert, JJ (reprint author), NCI, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM goedertj@mail.nih..gov OI Hayes, Richard/0000-0002-0918-661X FU National Cancer Institute Intramural Research Program [R03CA159414, R01CA159036] FX This work was supported by the National Cancer Institute Intramural Research Program and grants R03CA159414 and R01CA159036. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; Funding.Supported by the National Cancer Institute Intramural Research Program and grants R03CA159414 and R01CA159036. NR 47 TC 3 Z9 4 U1 6 U2 32 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 25 PY 2016 VL 11 IS 3 AR e0152126 DI 10.1371/journal.pone.0152126 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH3TE UT WOS:000372708900041 PM 27015276 ER PT J AU Collins, FS Anderson, JM Austin, CP Battey, JF Birnbaum, LS Briggs, JP Clayton, JA Cuthbert, B Eisinger, RW Fauci, AS Gallin, JI Gibbons, GH Glass, RI Gottesman, MM Gray, PA Green, ED Greider, FB Hodes, R Hudson, KL Humphreys, B Katz, SI Koob, GF Koroshetz, WJ Lauer, MS Lorsch, JR Lowy, DR McGowan, JJ Murray, DM Nakamura, R Norris, A Perez-Stable, EJ Pettigrew, RI Riley, WT Rodgers, GP Sieving, PA Somerman, MJ Spong, CY Tabak, LA Volkow, ND Wilder, EL AF Collins, Francis S. Anderson, James M. Austin, Christopher P. Battey, James F. Birnbaum, Linda S. Briggs, Josephine P. Clayton, Janine A. Cuthbert, Bruce Eisinger, Robert W. Fauci, Anthony S. Gallin, John I. Gibbons, Gary H. Glass, Roger I. Gottesman, Michael M. Gray, Patricia A. Green, Eric D. Greider, Franziska B. Hodes, Richard Hudson, Kathy L. Humphreys, Betsy Katz, Stephen I. Koob, George F. Koroshetz, Walter J. Lauer, Michael S. Lorsch, Jon R. Lowy, Douglas R. McGowan, John J. Murray, David M. Nakamura, Richard Norris, Andrea Perez-Stable, Eliseo J. Pettigrew, Roderic I. Riley, William T. Rodgers, Griffin P. Sieving, Paul A. Somerman, Martha J. Spong, Catherine Y. Tabak, Lawrence A. Volkow, Nora D. Wilder, Elizabeth L. TI Basic science: Bedrock of progress SO SCIENCE LA English DT Letter C1 [Collins, Francis S.; Hudson, Kathy L.; Tabak, Lawrence A.] NIH, Off Director, Bldg 10, Bethesda, MD 20892 USA. [Anderson, James M.] NIH, Div Program Coordinat Planning & Strateg Initiat, Bldg 10, Bethesda, MD 20892 USA. [Austin, Christopher P.] NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Battey, James F.] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA. [Birnbaum, Linda S.] NIEHS, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Briggs, Josephine P.] NIH, Natl Ctr Complementary & Integrat Hlth, Bldg 10, Bethesda, MD 20892 USA. [Clayton, Janine A.] NIH, Off Res Womens Hlth, Bldg 10, Bethesda, MD 20892 USA. [Cuthbert, Bruce] NIMH, NIH, Bethesda, MD 20892 USA. [Eisinger, Robert W.] NIH, Off AIDS Res, Bldg 10, Bethesda, MD 20892 USA. [Fauci, Anthony S.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Gallin, John I.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Gibbons, Gary H.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Glass, Roger I.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Gottesman, Michael M.] NIH, Off Intramural Res, Bldg 10, Bethesda, MD 20892 USA. [Gray, Patricia A.] NINR, NIH, Bethesda, MD 20892 USA. [Green, Eric D.] NHGRI, NIH, Bethesda, MD 20892 USA. [Greider, Franziska B.] NIH, Off Res Infrastruct Programs, Bldg 10, Bethesda, MD 20892 USA. [Hodes, Richard] NIA, NIH, Bethesda, MD 20892 USA. [Humphreys, Betsy] NIH, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. [Katz, Stephen I.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Koob, George F.] NIAAA, NIH, Bethesda, MD 20892 USA. [Koroshetz, Walter J.] NINDS, NIH, Bethesda, MD 20892 USA. [Lauer, Michael S.] NIH, Off Extramural Res, Bldg 10, Bethesda, MD 20892 USA. [Lorsch, Jon R.] NIGMS, NIH, Bethesda, MD 20892 USA. [Lowy, Douglas R.] NCI, NIH, Bethesda, MD 20892 USA. [McGowan, John J.] NIH, Off Management, Bldg 10, Bethesda, MD 20892 USA. [Murray, David M.] NIH, Off Dis Prevent, Bldg 10, Bethesda, MD 20892 USA. [Nakamura, Richard] NIH, Ctr Sci Review, Bldg 10, Bethesda, MD 20892 USA. [Norris, Andrea] NIH, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. [Perez-Stable, Eliseo J.] Natl Inst Minor Hlth & Hlth Dispar, NIH, Bethesda, MD 20892 USA. [Pettigrew, Roderic I.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. [Riley, William T.] NIH, Off Behav & Social Sci Res, Bldg 10, Bethesda, MD 20892 USA. [Rodgers, Griffin P.] NIDDK, NIH, Bethesda, MD 20892 USA. [Sieving, Paul A.] NEI, NIH, Bethesda, MD 20892 USA. [Somerman, Martha J.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. [Spong, Catherine Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Volkow, Nora D.] NIDA, NIH, Bethesda, MD 20892 USA. [Wilder, Elizabeth L.] NIH, Off Strateg Coordinat, Bldg 10, Bethesda, MD 20892 USA. RP Collins, FS (reprint author), NIH, Off Director, Bldg 10, Bethesda, MD 20892 USA. EM collinsf@mail.nih.gov RI koob, george/P-8791-2016 NR 6 TC 2 Z9 2 U1 3 U2 11 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 MAR 25 PY 2016 VL 351 IS 6280 BP 1405 EP 1405 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH4KZ UT WOS:000372756200028 PM 27013720 ER PT J AU Kankanala, J Marchand, C Abdelmalak, M Aihara, H Pommier, Y Wang, ZQ AF Kankanala, Jayakanth Marchand, Christophe Abdelmalak, Monica Aihara, Hideki Pommier, Yves Wang, Zhengqiang TI Isoquinoline-1,3-diones as Selective Inhibitors of Tyrosyl DNA Phosphodiesterase II (TDP2) SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; TOPOISOMERASE-II; REPAIR PATHWAYS; VIRUS; TDP2/TTRAP; RESISTANCE; COMPLEXES; ADDUCTS; DOCKING; ENZYME AB Tyrosyl DNA phosphodiesterase II (TDP2) is a recently discovered enzyme that specifically repairs DNA damages induced by topoisomerase II (Top2) poisons and causes resistance to these drugs. Inhibiting TDP2 is expected to enhance the efficacy of clinically important Top2-targeting anticancer drugs. However, TDP2 as a therapeutic target remains poorly understood. We report herein the discovery of isoquinoline-1,3-dione as a viable chemotype for selectively inhibiting TDP2. The initial hit compound 43 was identified by screening our in-house collection of synthetic compounds. Further structure activity relationship (SAR) studies identified numerous analogues inhibiting TDP2 in low micromolar range without appreciable inhibition against the homologous TDP1 at the highest testing concentration (111 mu M). The best compound 64 inhibited recombinant TDP2 with an IC50 of 1.9 mu M. The discovery of this chemotype may provide a platform toward understanding TDP2 as a drug target. C1 [Kankanala, Jayakanth; Wang, Zhengqiang] Univ Minnesota, Acad Hlth Ctr, Ctr Drug Design, Minneapolis, MN 55455 USA. [Marchand, Christophe; Abdelmalak, Monica; Pommier, Yves] NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Aihara, Hideki] Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA. RP Wang, ZQ (reprint author), Univ Minnesota, Acad Hlth Ctr, Ctr Drug Design, Minneapolis, MN 55455 USA. EM wangx472@umn.edu FU Faculty Research Development Grant of the Academic Health Center, University of Minnesota; Intramural Research Program of the NIH, Center for Cancer Research, National Cancer Institute [Z01 BC 006161-17] FX This research was supported by the Faculty Research Development Grant (to H.A. and Z.W.) of the Academic Health Center, University of Minnesota, and in part by the Intramural Research Program of the NIH, Center for Cancer Research, National Cancer Institute (Z01 BC 006161-17), and the Minnesota Supercomputing Institute (MSI) for computational resources involving modeling. NR 32 TC 3 Z9 3 U1 4 U2 11 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 MAR 24 PY 2016 VL 59 IS 6 BP 2734 EP 2746 DI 10.1021/acs.jmedchem.5b01973 PG 13 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA DH7BP UT WOS:000372946500032 PM 26910725 ER PT J AU Miyazaki, K Yoshizaki, K Arai, C Yamada, A Saito, K Ishikawa, M Xue, H Funada, K Haruyama, N Yamada, Y Fukumoto, S Takahashi, I AF Miyazaki, Kanako Yoshizaki, Keigo Arai, Chieko Yamada, Aya Saito, Kan Ishikawa, Masaki Xue, Han Funada, Keita Haruyama, Naoto Yamada, Yoshihiko Fukumoto, Satoshi Takahashi, Ichiro TI Plakophilin-1, a Novel Wnt Signaling Regulator, Is Critical for Tooth Development and Ameloblast Differentiation SO PLOS ONE LA English DT Article ID SKIN FRAGILITY SYNDROME; OCULODENTODIGITAL DYSPLASIA; GJA1 MUTATIONS; MOUSE INCISOR; CELL-ADHESION; PKP1 GENE; MORPHOGENESIS; CONNEXIN-43; EXPRESSION; PHENOTYPE AB Tooth morphogenesis is initiated by reciprocal interactions between the ectoderm and neural crest-derived mesenchyme, and the Wnt signaling pathway is involved in this process. We found that Plakophilin (PKP) 1, which is associated with diseases such as ectodermal dysplasia/skin fragility syndrome, was highly expressed in teeth and skin, and was upregulated during tooth development. We hypothesized that PKP1 regulates Wnt signaling via its armadillo repeat domain in a manner similar to beta-catenin. To determine its role in tooth development, we performed Pkp1 knockdown experiments using ex vivo organ cultures and cell cultures. Loss of Pkp1 reduced the size of tooth germs and inhibited dental epithelial cell proliferation, which was stimulated by Wnt3a. Furthermore, transfected PKP1-emerald green fluorescent protein was translocated from the plasma membrane to the nucleus upon stimulation with Wnt3a and LiCl, which required the PKP1 N terminus (amino acids 161 to 270). Localization of PKP1, which is known as an adhesion-related desmosome component, shifted to the plasma membrane during ameloblast differentiation. In addition, Pkp1 knockdown disrupted the localization of Zona occludens 1 in tight junctions and inhibited ameloblast differentiation; the two proteins were shown to directly interact by immuno-precipitation. These results implicate the participation of PKP1 in early tooth morphogenesis as an effector of canonical Wnt signaling that controls ameloblast differentiation via regulation of the cell adhesion complex. C1 [Miyazaki, Kanako; Yoshizaki, Keigo; Arai, Chieko; Xue, Han; Funada, Keita; Haruyama, Naoto; Takahashi, Ichiro] Kyushu Univ, Sect Orthodont & Dentofacial Orthoped, Div Oral Hlth Growth & Dev, Fac Dent Sci, Fukuoka 812, Japan. [Yamada, Aya; Saito, Kan; Fukumoto, Satoshi] Tohoku Univ, Div Pediat Dent, Dept Oral Hlth & Dev Sci, Grad Sch Dent, Sendai, Miyagi 980, Japan. [Ishikawa, Masaki] Tohoku Univ, Operat Dent, Dept Restorat Dent, Grad Sch Dent, Sendai, Miyagi 980, Japan. [Yamada, Yoshihiko] Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD USA. RP Yoshizaki, K (reprint author), Kyushu Univ, Sect Orthodont & Dentofacial Orthoped, Div Oral Hlth Growth & Dev, Fac Dent Sci, Fukuoka 812, Japan.; Fukumoto, S (reprint author), Tohoku Univ, Div Pediat Dent, Dept Oral Hlth & Dev Sci, Grad Sch Dent, Sendai, Miyagi 980, Japan. EM yosizaki@dent.kyushu-u.ac.jp; fukumoto@dent.tohoku.ac.jp RI Haruyama, Naoto/D-1993-2011; OI Haruyama, Naoto/0000-0001-6225-5816; Saito, Kan/0000-0002-2151-6204 FU Ministry of Education, Science, and Culture of Japan [20679006, 26670880]; NEXT program [LS010]; Intramural Research Program of the National Institute of Dental and Craniofacial Research, NIH, USA [DE000720-08]; [15H05688]; [26670886] FX This work was supported in part by Grants-in-aid from the Ministry of Education, Science, and Culture of Japan (20679006 and 26670880 to SF) and the NEXT program (LS010 to SF), the Intramural Research Program of the National Institute of Dental and Craniofacial Research, NIH, USA (DE000720-08 to YY), and a Grant-in-Aid for Scientific Research (15H05688 and 26670886 to KY).; We thank Megumi Kiyota of the Research Support Center, Graduate School of Medical Sciences, Kyushu University for assistance with the microarray analysis. This work was supported in part by Grants-in-aid from the Ministry of Education, Science, and Culture of Japan (20679006 and 26670880 to SF) and the NEXT program (LS010 to SF), the Intramural Research Program of the National Institute of Dental and Craniofacial Research, NIH, USA (DE000720-08 to YY), and Grants-in-Aid for Scientific Research (15H05688 and 26670886 to KY). NR 47 TC 1 Z9 1 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 MAR 24 PY 2016 VL 11 IS 3 AR e0152206 DI 10.1371/journal.pone.0152206 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH3SV UT WOS:000372708000111 PM 27015268 ER PT J AU Reid, WC Casas, R Papadakis, GZ Muthusamy, S Lee, DE Ibrahim, WG Nair, A Koziol, D Maric, D Hammoud, DA AF Reid, William C. Casas, Rafael Papadakis, Georgios Z. Muthusamy, Siva Lee, Dianne E. Ibrahim, Wael G. Nair, Anand Koziol, Deloris Maric, Dragan Hammoud, Dima A. TI Neurobehavioral Abnormalities in the HIV-1 Transgenic Rat Do Not Correspond to Neuronal Hypometabolism on F-18-FDG-PET SO PLOS ONE LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; VITAMIN-A-DEFICIENCY; MOTOR DEFICITS; MODEL; EXPRESSION; BEHAVIOR; HABITUATION; DYSFUNCTION; DEMENTIA; MEMORY AB Motor and behavioral abnormalities are common presentations among individuals with HIV-1 associated neurocognitive disorders (HAND). We investigated whether longitudinal motor and behavioral performance in the HIV-1 transgenic rat (Tg), a commonly used neuro-HIV model, corresponded to in vivo neuronal death/dysfunction, by using rotarod and open field testing in parallel to [F-18] 2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET). We demonstrated that age-matched non-Tg wild type (WT) rats outperformed the HIV-1 Tg rats at most time points on rotarod testing. Habituation to rotarod occurred at 8 weeks of age (fifth weekly testing session) in the WT rats but it never occurred in the Tg rats, suggesting deficits in motor learning. Similarly, in open field testing, WT rats outperformed the Tg rats at most time points, suggesting defective exploratory/motor behavior and increased emotionality in the Tg rat. Despite the neurobehavioral abnormalities, there were no concomitant deficits in F-18-FDG uptake in Tg rats on PET compared to age-matched WT rats and no significant longitudinal loss of FDG uptake in either group. The negative PET findings were confirmed using C-14-Deoxy-D-glucose autoradiography in 32 week-old Tg and WT rats. We believe that the neuropathology in the HIV-1 Tg rat is more likely a consequence of neuronal dysfunction rather than overt neurodegeneration/neuronal cell death, similar to what is seen in HIV-positive patients in the post-ART era. C1 [Reid, William C.; Casas, Rafael; Papadakis, Georgios Z.; Lee, Dianne E.; Ibrahim, Wael G.; Nair, Anand; Hammoud, Dima A.] NIH, Ctr Infect Dis Imaging CIDI Radiol & Imaging Sci, Bldg 10, Bethesda, MD 20892 USA. [Koziol, Deloris] NIH, Biostat & Clin Epidemiol Serv, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Maric, Dragan] NINDS, DIR, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Hammoud, DA (reprint author), NIH, Ctr Infect Dis Imaging CIDI Radiol & Imaging Sci, Bldg 10, Bethesda, MD 20892 USA. EM hammoudd@cc.nih.gov FU Center of Infectious Disease Imaging (CIDI); Radiology and Imaging Sciences (RIS); Clinical Center, National Institutes of Health (Intramural Program) FX Center of Infectious Disease Imaging (CIDI), Radiology and Imaging Sciences (RIS), Clinical Center, National Institutes of Health (Intramural Program). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 1 Z9 1 U1 3 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 24 PY 2016 VL 11 IS 3 AR e0152265 DI 10.1371/journal.pone.0152265 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH3SV UT WOS:000372708000123 PM 27010205 ER PT J AU Tapocik, JD Ceniccola, K Mayo, CL Schwandtl, ML Solomon, M Wang, BD Luu, TV Olender, J Harrigan, T Maynard, TM Elmer, GI Lee, NH AF Tapocik, Jenica D. Ceniccola, Kristin Mayo, Cheryl L. Schwandtl, Melanie L. Solomon, Matthew Wang, Bi-Dar Luu, Truong V. Olender, Jacqueline Harrigan, Thomas Maynard, Thomas M. Elmer, Greg I. Lee, Norman H. TI MicroRNAs Are Involved in the Development of Morphine-Induced Analgesic Tolerance and Regulate Functionally Relevant Changes in Serpini1 SO FRONTIERS IN MOLECULAR NEUROSCIENCE LA English DT Article DE miR-27a; miR-9; Dicer; opioid; plasticity ID MU-OPIOID RECEPTOR; DIFFERENT BRAIN-REGIONS; GENE-EXPRESSION; INDUCED HYPERALGESIA; MESSENGER-RNA; SYNAPTIC PLASTICITY; HIPPOCAMPAL-NEURONS; INTERDOSE INTERVAL; CELL-PROLIFERATION; SURFACE EXPRESSION AB Long-term opioid treatment results in reduced therapeutic efficacy and in turn leads to an increase in the dose required to produce equivalent pain relief and alleviate break-through or insurmountable pain. Altered gene expression is a likely means for inducing long-term neuroadaptations responsible for tolerance. Studies conducted by our laboratory (lapocik et al., 2009) revealed a network of gene expression changes occurring in canonical pathways involved in neuroplasticity, and uncovered miRNA processing as a potential mechanism. In particular, the mRNA coding the protein responsible for processing miRNAs, Dicerl, was positively correlated with the development of analgesic tolerance. The purpose of the present study was to test the hypothesis that miRNAs play a significant role in the development of analgesic tolerance as measured by thermal nociception. Dicerl knockdown, miRNA profiling, bioinformatics, and confirmation of high value targets were used to test the proposition. Regionally targeted Dicerl knockdown (via shRNA) had the anticipated consequence of eliminating the development of tolerance in C57BL/6J (B6) mice, thus supporting the involvement of miRNAs in the development of tolerance. MiRNA expression profiling identified a core set of chronic morphine-regulated miRNAs (miR's 27a, 9, 483, 505, 146b, 202). Bioinformatics approaches were implemented to identify and prioritize their predicted target mRNAs. We focused our attention on miR27a and its predicted target serpin peptidase inhibitor Glade I (Serpinil) mRNA, a transcript known to be intricately involved in dendritic spine density regulation in a manner consistent with chronic morphine's consequences and previously found to be correlated with the development of analgesic tolerance. In vitro reporter assay confirmed the targeting of the Serpinil 3'-untranslated region by miR27a. Interestingly miR27a was found to positively regulate Serpinil mRNA and protein levels in multiple neuronal cell lines. Lastly. Serpinil knockout mice developed analgesic tolerance at a slower rate than wild-type mice thus confirming a role for the protein in analgesic tolerance. Overall, these results provide evidence to support a specific role for miR27a and Serpinil in the behavioral response to chronic opioid administration (COA) and suggest that miRNA expression and mRNA targeting may underlie the neuroadaptations that mediate tolerance to the analgesic effects of morphine. C1 [Tapocik, Jenica D.; Schwandtl, Melanie L.; Solomon, Matthew] NIAAA, NIH, Bethesda, MD USA. [Ceniccola, Kristin; Wang, Bi-Dar; Luu, Truong V.; Olender, Jacqueline; Harrigan, Thomas; Maynard, Thomas M.; Lee, Norman H.] George Washington Univ, Dept Physiol & Pharmacol, Washington, DC USA. [Mayo, Cheryl L.; Elmer, Greg I.] Univ Maryland, Sch Med, Dept Psychiat, Maryland Psychiat Res Ctr, Baltimore, MD 21201 USA. RP Lee, NH (reprint author), George Washington Univ, Dept Physiol & Pharmacol, Washington, DC USA.; Elmer, GI (reprint author), Univ Maryland, Sch Med, Dept Psychiat, Maryland Psychiat Res Ctr, Baltimore, MD 21201 USA. EM gelmer@mprc.umaryland.edu; nhlee@gwu.edu RI Schwandt, Melanie/L-9866-2016; Maynard, Thomas/I-9039-2012 OI Maynard, Thomas/0000-0001-6976-3936 FU National Institute on Drug Abuse, National Institutes of Health [DA015087, R21DA033803] FX This work was funded by National Institute on Drug Abuse, National Institutes of Health Grant DA015087 and R21DA033803 (G.I.E., N.H.L.). NR 111 TC 2 Z9 2 U1 1 U2 2 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5099 J9 FRONT MOL NEUROSCI JI Front. Molec. Neurosci. PD MAR 24 PY 2016 VL 9 AR 20 DI 10.3389/fnmol.2016.00020 PG 16 WC Neurosciences SC Neurosciences & Neurology GA DH4CP UT WOS:000372733400001 PM 27047334 ER PT J AU Ravindran, R Loebbermann, J Nakaya, HI Khan, N Ma, HL Gama, L Machiah, DK Lawson, B Hakimpour, P Wang, YC Li, SZ Sharma, P Kaufman, RJ Martinez, J Pulendran, B AF Ravindran, Rajesh Loebbermann, Jens Nakaya, Helder I. Khan, Nooruddin Ma, Hualing Gama, Leonardo Machiah, Deepa K. Lawson, Benton Hakimpour, Paul Wang, Yi-chong Li, Shuzhao Sharma, Prachi Kaufman, Randal J. Martinez, Jennifer Pulendran, Bali TI The amino acid sensor GCN2 controls gut inflammation by inhibiting inflammasome activation SO NATURE LA English DT Article ID LOW-PROTEIN DIET; DENDRITIC CELLS; EIF2-ALPHA KINASE; OXIDATIVE STRESS; TRANSGENIC MICE; TRANSLATION; AUTOPHAGY; PHOSPHORYLATION; DIFFERENTIATION; DEPRIVATION AB The integrated stress response (ISR) is a homeostatic mechanism by which eukaryotic cells sense and respond to stress-inducing signals, such as amino acid starvation. General controlled non-repressed (GCN2) kinase is a key orchestrator of the ISR, and modulates protein synthesis in response to amino acid starvation. Here we demonstrate in mice that GCN2 controls intestinal inflammation by suppressing inflammasome activation. Enhanced activation of ISR was observed in intestinal antigen presenting cells (APCs) and epithelial cells during amino acid starvation, or intestinal inflammation. Genetic deletion of Gcn2 (also known as Eif2ka4) in CD11c(+) APCs or intestinal epithelial cells resulted in enhanced intestinal inflammation and T helper 17 cell (T(H)17) responses, owing to enhanced inflammasome activation and interleukin (IL)-1 beta production. This was caused by reduced autophagy in Gcn2(-/-) intestinal APCs and epithelial cells, leading to increased reactive oxygen species (ROS), a potent activator of inflammasomes(1). Thus, conditional ablation of Atg5 or Atg7 in intestinal APCs resulted in enhanced ROS and T(H)17 responses. Furthermore, in vivo blockade of ROS and IL-1 beta resulted in inhibition of T(H)17 responses and reduced inflammation in Gcn2(-/-) mice. Importantly, acute amino acid starvation suppressed intestinal inflammation via a mechanism dependent on GCN2. These results reveal a mechanism that couples amino acid sensing with control of intestinal inflammation via GCN2. C1 [Ravindran, Rajesh; Loebbermann, Jens; Ma, Hualing; Hakimpour, Paul; Wang, Yi-chong; Li, Shuzhao; Pulendran, Bali] Yerkes Natl Primate Res Ctr, Emory Vaccine Ctr, 954 Gatewood Rd, Atlanta, GA 30329 USA. [Nakaya, Helder I.; Gama, Leonardo] Univ Sao Paulo, Sch Pharmaceut Sci, BR-05508 Sao Paulo, Brazil. [Khan, Nooruddin] Univ Hyderabad, Sch Life Sci, Dept Biotechnol & Bioinformat, Hyderabad 500046, Andhra Pradesh, India. [Machiah, Deepa K.; Sharma, Prachi] Yerkes Natl Primate Res Ctr, Div Pathol, 954 Gatewood Rd, Atlanta, GA 30329 USA. [Lawson, Benton] Emory Vaccine Ctr, Virol Core, 954 Gatewood Rd, Atlanta, GA 30329 USA. [Lawson, Benton] Yerkes Natl Primate Res Ctr, 954 Gatewood Rd, Atlanta, GA 30329 USA. [Kaufman, Randal J.] Sanford Burnham Prebys Med Discovery Inst, Degenerat Dis Program, 10901 N Torrey Pines Rd, La Jolla, CA 92037 USA. [Martinez, Jennifer] NIEHS, Mail Drop D2-01, Res Triangle Pk, NC 27709 USA. RP Pulendran, B (reprint author), Yerkes Natl Primate Res Ctr, Emory Vaccine Ctr, 954 Gatewood Rd, Atlanta, GA 30329 USA. EM bpulend@emory.edu RI Nakaya, Helder/A-1397-2010; Ma, Huailiang/C-3403-2017; CEPID, CRID/J-2644-2015 OI Nakaya, Helder/0000-0001-5297-9108; FU US National Institutes of Health (NIH) [R37 DK057665, R37 AI048638, U19 AI090023, U19 AI057266]; Bill & Melinda Gates Foundation; NIH [R01 DK088227, R37 DK042394, R01 DK103185]; Crohn's & Colitis Foundation of America Senior Fellow Award [3800]; Center for AIDS Research core at Yerkes Primate Research Center [P30-AI-50409] FX This work was supported by grants from the US National Institutes of Health (NIH; grants R37 DK057665, R37 AI048638, U19 AI090023, U19 AI057266) and from the Bill & Melinda Gates Foundation to B.P. R.J.K. was supported by NIH grants R01 DK088227, R37 DK042394, R01 DK103185 and the Crohn's & Colitis Foundation of America Senior Fellow Award 3800. We thank B. Cervasi and K. P. Gill for help with sorting and D. Levesque, D. Hampton, S. Weismann and colleagues for animal husbandry and veterinary support. We thank the Center for AIDS Research core at Yerkes Primate Research Center for help with qPCR (grant P30-AI-50409) and the Integrated Cellular Imaging Center at Winship Cancer Center, Emory University for help with confocal microscopy. We also thank the Yerkes Pathology Core for performing the immunofluorescence and histology analysis. We thank S. Virgin for his advice and review of the autophagy experiments. NR 35 TC 19 Z9 20 U1 5 U2 32 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD MAR 24 PY 2016 VL 531 IS 7595 BP 523 EP + DI 10.1038/nature17186 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH3QK UT WOS:000372701300045 PM 26982722 ER PT J AU Falk, MJ Decherney, A Kahn, JP AF Falk, Marni J. Decherney, Alan Kahn, Jeffrey P. TI Mitochondrial Replacement Techniques - Implications for the Clinical Community SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID DISEASES C1 [Falk, Marni J.] Childrens Hosp Philadelphia, Dept Pediat, Div Human Genet, Philadelphia, PA 19104 USA. [Falk, Marni J.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Decherney, Alan] NICHD, NIH, Bethesda, MD 20892 USA. [Kahn, Jeffrey P.] Johns Hopkins Univ, Johns Hopkins Berman Inst Bioeth, Baltimore, MD USA. RP Falk, MJ (reprint author), Childrens Hosp Philadelphia, Dept Pediat, Div Human Genet, Philadelphia, PA 19104 USA.; Falk, MJ (reprint author), Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. FU Intramural NIH HHS [Z99 HD999999]; NICHD NIH HHS [U54 HD086984] NR 5 TC 6 Z9 6 U1 4 U2 9 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 24 PY 2016 VL 374 IS 12 BP 1103 EP 1106 DI 10.1056/NEJMp1600893 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA DH2AA UT WOS:000372585100002 PM 26910290 ER PT J AU Stitziel, NO Stirrups, KE Masca, NGD Erdmann, J Ferrario, PG Konig, IR Weeke, PE Webb, TR Auer, PL Schick, UM Lu, YC Zhang, H Dube, MP Goel, A Farrall, M Peloso, GM Won, HH Do, R van Iperen, E Kanoni, S Kruppa, J Mahajan, A Scott, RA Willenborg, C Braund, PS van Capelleveen, JC Doney, ASF Donnelly, LA Asselta, R Merlini, PA Duga, S Marziliano, N Denny, JC Shaffer, CM El-Mokhtari, NE Franke, A Gottesman, O Heilmann, S Hengstenberg, C Hoffmann, P Holmen, OL Hveem, K Jansson, JH Jockel, KH Kessler, T Kriebel, J Laugwitz, KL Marouli, E Martinelli, N McCarthy, MI Van Zuydam, NR Meisinger, C Esko, T Mihailov, E Escher, SA Alver, M Moebus, S Morris, AD Muller-Nurasyid, M Nikpay, M Olivieri, O Perreault, LPL AlQarawi, A Robertson, NR Akinsanya, KO Reilly, DF Vogt, TF Yin, W Asselbergs, FW Kooperberg, C Jackson, RD Stahl, E Strauch, K Varga, TV Waldenberger, M Zeng, LY Kraja, AT Liu, CY Ehret, GB Newton-Cheh, C Chasman, DI Chowdhury, R Ferrario, M Ford, I Jukema, JW Kee, F Kuulasmaa, K Nordestgaard, BG Perola, M Saleheen, D Sattar, N Surendran, P Tregouet, D Young, R Howson, JMM Butterworth, AS Danesh, J Ardissino, D Bottinger, EP Erbel, R Franks, PW Girelli, D Hall, AS Hovingh, GK Kastrati, A Lieb, W Meitinger, T Kraus, WE Shah, SH McPherson, R Orho-Melander, M Melander, O Metspalu, A Palmer, CNA Peters, A Rader, DJ Reilly, MP Loos, RJF Reiner, AP Roden, DM Tardif, JC Thompson, JR Wareham, NJ Watkins, H Willer, CJ Kathiresan, S Deloukas, P Samani, NJ Schunkert, H AF Stitziel, Nathan O. Stirrups, Kathleen E. Masca, Nicholas G. D. Erdmann, Jeanette Ferrario, Paola G. Koenig, Inke R. Weeke, Peter E. Webb, Thomas R. Auer, Paul L. Schick, Ursula M. Lu, Yingchang Zhang, He Dube, Marie-Pierre Goel, Anuj Farrall, Martin Peloso, Gina M. Won, Hong-Hee Do, Ron van Iperen, Erik Kanoni, Stavroula Kruppa, Jochen Mahajan, Anubha Scott, Robert A. Willenborg, Christina Braund, Peter S. van Capelleveen, Julian C. Doney, Alex S. F. Donnelly, Louise A. Asselta, Rosanna Merlini, Piera A. Duga, Stefano Marziliano, Nicola Denny, Josh C. Shaffer, Christian M. El-Mokhtari, Nour Eddine Franke, Andre Gottesman, Omri Heilmann, Stefanie Hengstenberg, Christian Hoffmann, Per Holmen, Oddgeir L. Hveem, Kristian Jansson, Jan-Hakan Joeckel, Karl-Heinz Kessler, Thorsten Kriebel, Jennifer Laugwitz, Karl L. Marouli, Eirini Martinelli, Nicola McCarthy, Mark I. Van Zuydam, Natalie R. Meisinger, Christa Esko, Tonu Mihailov, Evelin Escher, Stefan A. Alver, Maris Moebus, Susanne Morris, Andrew D. Mueller-Nurasyid, Martina Nikpay, Majid Olivieri, Oliviero Perreault, Louis-Philippe Lemieux AlQarawi, Alaa Robertson, Neil R. Akinsanya, Karen O. Reilly, Dermot F. Vogt, Thomas F. Yin, Wu Asselbergs, Folkert W. Kooperberg, Charles Jackson, Rebecca D. Stahl, Eli Strauch, Konstantin Varga, Tibor V. Waldenberger, Melanie Zeng, Lingyao Kraja, Aldi T. Liu, Chunyu Ehret, Georg B. Newton-Cheh, Christopher Chasman, Daniel I. Chowdhury, Rajiv Ferrario, Marco Ford, Ian Jukema, J. Wouter Kee, Frank Kuulasmaa, Kari Nordestgaard, Borge G. Perola, Markus Saleheen, Danish Sattar, Naveed Surendran, Praveen Tregouet, David Young, Robin Howson, Joanna M. M. Butterworth, Adam S. Danesh, John Ardissino, Diego Bottinger, Erwin P. Erbel, Raimund Franks, Paul W. Girelli, Domenico Hall, Alistair S. Hovingh, G. Kees Kastrati, Adnan Lieb, Wolfgang Meitinger, Thomas Kraus, William E. Shah, Svati H. McPherson, Ruth Orho-Melander, Marju Melander, Olle Metspalu, Andres Palmer, Colin N. A. Peters, Annette Rader, Daniel J. Reilly, Muredach P. Loos, Ruth J. F. Reiner, Alex P. Roden, Dan M. Tardif, Jean-Claude Thompson, John R. Wareham, Nicholas J. Watkins, Hugh Willer, Cristen J. Kathiresan, Sekar Deloukas, Panos Samani, Nilesh J. Schunkert, Heribert TI Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID OF-FUNCTION MUTATIONS; LIPOPROTEIN-LIPASE; ARTERY-DISEASE; HEART-DISEASE; PCSK9; TRIGLYCERIDES; INHIBITION; VARIANT; APOC3; HDL AB BACKGROUND The discovery of low-frequency coding variants affecting the risk of coronary artery disease has facilitated the identification of therapeutic targets. METHODS Through DNA genotyping, we tested 54,003 coding-sequence variants covering 13,715 human genes in up to 72,868 patients with coronary artery disease and 120,770 controls who did not have coronary artery disease. Through DNA sequencing, we studied the effects of loss-of-function mutations in selected genes. RESULTS We confirmed previously observed significant associations between coronary artery disease and low-frequency missense variants in the genes LPA and PCSK9. We also found significant associations between coronary artery disease and low-frequency missense variants in the genes SVEP1 (p.D2702G; minor-allele frequency, 3.60%; odds ratio for disease, 1.14; P = 4.2x10(-10)) and ANGPTL4 (p.E40K; minor-allele frequency, 2.01%; odds ratio, 0.86; P = 4.0x10(-8)), which encodes angiopoietin-like 4. Through sequencing of ANGPTL4, we identified 9 carriers of loss-of-function mutations among 6924 patients with myocardial infarction, as compared with 19 carriers among 6834 controls (odds ratio, 0.47; P = 0.04); carriers of ANGPTL4 loss-of-function alleles had triglyceride levels that were 35% lower than the levels among persons who did not carry a loss-of-function allele (P = 0.003). ANGPTL4 inhibits lipoprotein lipase; we therefore searched for mutations in LPL and identified a loss-of-function variant that was associated with an increased risk of coronary artery disease (p.D36N; minor-allele frequency, 1.9%; odds ratio, 1.13; P = 2.0x10(-4)) and a gain-of-function variant that was associated with protection from coronary artery disease (p.S447*; minor-allele frequency, 9.9%; odds ratio, 0.94; P = 2.5x10(-7)). CONCLUSIONS We found that carriers of loss-of-function mutations in ANGPTL4 had triglyceride levels that were lower than those among noncarriers; these mutations were also associated with protection from coronary artery disease. C1 [Stitziel, Nathan O.] Washington Univ, Sch Med, Div Cardiovasc, Dept Med, St Louis, MO 63130 USA. [Stitziel, Nathan O.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63130 USA. [Stitziel, Nathan O.] Washington Univ, Sch Med, McDonnell Genome Inst, St Louis, MO 63130 USA. [Kraja, Aldi T.] Washington Univ, Sch Med, Div Stat Genom, Dept Genet, St Louis, MO 63130 USA. [Kraja, Aldi T.] Washington Univ, Sch Med, Ctr Genome Sci & Syst Biol, St Louis, MO 63130 USA. [Stirrups, Kathleen E.; Kanoni, Stavroula; Marouli, Eirini; Deloukas, Panos] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England. [Asselbergs, Folkert W.] UCL, Inst Cardiovasc Sci, Fac Populat Hlth Sci, London, England. [Stirrups, Kathleen E.] Univ Cambridge, Dept Haematol, Cambridge, England. [Braund, Peter S.; Chowdhury, Rajiv; Young, Robin; Howson, Joanna M. M.; Butterworth, Adam S.; Danesh, John] Univ Cambridge, Cardiovasc Epidemiol Unit, Dept Publ Hlth & Primary Care, Cambridge, England. [Danesh, John] Univ Cambridge, Natl Inst Hlth Res Blood & Transplant Res Unit Do, Cambridge, England. [Scott, Robert A.; Wareham, Nicholas J.] Addenbrookes Hosp, MRC, Epidemiol Unit, Inst Metab Sci, Cambridge, England. [Danesh, John] Wellcome Trust Sanger Inst, Cambridge, England. [Masca, Nicholas G. D.; Webb, Thomas R.; Braund, Peter S.; Samani, Nilesh J.] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England. [Thompson, John R.] Univ Leicester, Dept Hlth Sci, Leicester, Leics, England. [Masca, Nicholas G. D.; Webb, Thomas R.; Braund, Peter S.; Thompson, John R.; Samani, Nilesh J.] Glenfield Hosp, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England. [Goel, Anuj; Farrall, Martin; Watkins, Hugh] Univ Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford, England. [Goel, Anuj; Farrall, Martin; Mahajan, Anubha; McCarthy, Mark I.; Robertson, Neil R.; Watkins, Hugh] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [McCarthy, Mark I.; Van Zuydam, Natalie R.; Robertson, Neil R.] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [McCarthy, Mark I.] Churchill Hosp, Oxford Natl Inst Hlth Res, Biomed Res Ctr, Oxford OX3 7LJ, England. [Doney, Alex S. F.; Donnelly, Louise A.; Palmer, Colin N. A.] Univ Dundee, Ninewells Hosp & Med Sch, Med Res Inst, Dundee DD1 9SY, Scotland. [Morris, Andrew D.] Univ Edinburgh, Sch Med, Sch Mol Genet & Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Ford, Ian] Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland. [Sattar, Naveed] Univ Glasgow, British Heart Fdn, Glasgow Cardiovasc Res Ctr, Glasgow, Lanark, Scotland. [Hall, Alistair S.] Univ Leeds, Leeds Inst Genet Hlth & Therapeut, Leeds, W Yorkshire, England. [Erdmann, Jeanette; Willenborg, Christina] Med Univ Lubeck, Inst Integrat & Expt Genom, D-23538 Lubeck, Germany. [Erdmann, Jeanette; Ferrario, Paola G.; Koenig, Inke R.; Willenborg, Christina] DZHK German Ctr Cardiovasc Res, Partner Site Hamburg Lubeck Kiel, Lubeck, Germany. [Ferrario, Paola G.; Koenig, Inke R.; Kruppa, Jochen] Med Univ Lubeck, Inst Med Biometrie & Stat, D-23538 Lubeck, Germany. [Kruppa, Jochen] Univ Med Ctr Gottingen, Dept Med Stat, Gottingen, Germany. [El-Mokhtari, Nour Eddine] Kreiskrankenhaus Rendsburg, Innere Med Klin, Rendsburg, Germany. [Franke, Andre] Univ Kiel, Inst Clin Mol Biol, Kiel, Germany. [Lieb, Wolfgang] Univ Kiel, Inst Epidemiol & Biobank Popgen, Kiel, Germany. [Heilmann, Stefanie; Hoffmann, Per] Univ Bonn, Inst Human Genet, Bonn, Germany. [Heilmann, Stefanie; Hoffmann, Per] Univ Bonn, Dept Genom, Life & Brain Ctr, Bonn, Germany. [Hengstenberg, Christian; Kessler, Thorsten; Zeng, Lingyao; Kastrati, Adnan; Schunkert, Heribert] Tech Univ Munich, Deutsch Herzzentrum Munchen, D-80290 Munich, Germany. [Meitinger, Thomas] Tech Univ Munich, Inst Human Genet, D-80290 Munich, Germany. [Hengstenberg, Christian; Laugwitz, Karl L.; Mueller-Nurasyid, Martina; Meitinger, Thomas; Peters, Annette; Schunkert, Heribert] DZHK Partner Site Munich Heart Alliance, Munich, Germany. [Laugwitz, Karl L.] Tech Univ Munich, Klinikum Rechts Isar, Med Klin & Poliklin 1, D-80290 Munich, Germany. [Mueller-Nurasyid, Martina] Univ Munich, Dept Med 1, Munich, Germany. [Strauch, Konstantin] Univ Munich, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Joeckel, Karl-Heinz; Moebus, Susanne; Erbel, Raimund] Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany. [Kriebel, Jennifer; Waldenberger, Melanie] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Neuherberg, Germany. [Kriebel, Jennifer; Meisinger, Christa; Waldenberger, Melanie; Peters, Annette] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany. [Mueller-Nurasyid, Martina; Strauch, Konstantin] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Genet Epidemiol, Neuherberg, Germany. [Meitinger, Thomas] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Human Genet, Neuherberg, Germany. [Kriebel, Jennifer] German Ctr Diabet Res, Neuherberg, Germany. [Weeke, Peter E.; Denny, Josh C.; Shaffer, Christian M.; Roden, Dan M.] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA. [Denny, Josh C.] Vanderbilt Univ, Med Ctr, Dept Biomed Informat, Nashville, TN USA. [Roden, Dan M.] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA. [Weeke, Peter E.] Copenhagen Univ Hosp, Rigshosp, Mol Cardiol Lab, Dept Cardiol, Copenhagen, Denmark. [Nordestgaard, Borge G.] Copenhagen Univ Hosp, Copenhagen, Denmark. [Nordestgaard, Borge G.] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark. [Auer, Paul L.] Univ Wisconsin, Sch Publ Heath, Milwaukee, WI 53201 USA. [Schick, Ursula M.; Kooperberg, Charles; Reiner, Alex P.] Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA. [Reiner, Alex P.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Lu, Yingchang; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA. [Schick, Ursula M.; Lu, Yingchang; Do, Ron; Gottesman, Omri; Bottinger, Erwin P.; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA. [Do, Ron] Icahn Sch Med Mt Sinai, Ctr Stat Genet, New York, NY 10029 USA. [Do, Ron] Icahn Sch Med Mt Sinai, Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, Michael A Weiner Cardiovasc Inst, New York, NY 10029 USA. [Stahl, Eli] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. [Zhang, He; Willer, Cristen J.] Univ Michigan, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. [Willer, Cristen J.] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Willer, Cristen J.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Dube, Marie-Pierre; Tardif, Jean-Claude] Univ Montreal, Dept Med, Fac Med, Montreal, PQ H3C 3J7, Canada. [Dube, Marie-Pierre; Perreault, Louis-Philippe Lemieux; Tardif, Jean-Claude] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Nikpay, Majid; McPherson, Ruth] Univ Ottawa, Inst Heart, Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada. [Peloso, Gina M.; Won, Hong-Hee; Newton-Cheh, Christopher; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Peloso, Gina M.; Won, Hong-Hee; Newton-Cheh, Christopher; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Newton-Cheh, Christopher; Kathiresan, Sekar] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Peloso, Gina M.; Won, Hong-Hee; Newton-Cheh, Christopher; Kathiresan, Sekar] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Esko, Tonu] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Esko, Tonu] Boston Childrens Hosp, Div Endocrinol, Boston, MA USA. [Chasman, Daniel I.] Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Franks, Paul W.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Peloso, Gina M.; Won, Hong-Hee; Newton-Cheh, Christopher; Kathiresan, Sekar] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Esko, Tonu] Broad Inst Massachusetts Inst Technol & Harvard, Cambridge, MA USA. [Liu, Chunyu] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Won, Hong-Hee] Sungkyunkwan Univ, Samsung Med Ctr, SAIHST, Seoul, South Korea. [van Iperen, Erik] Univ Amsterdam, Acad Med Ctr, Dept Biostat, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [van Capelleveen, Julian C.; Hovingh, G. Kees] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [Asselbergs, Folkert W.] UMC Utrecht, Div Heart & Lungs, Dept Cardiol, Utrecht, Netherlands. [Asselbergs, Folkert W.] ICIN Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, Utrecht, Netherlands. [Jukema, J. Wouter] Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands. [Jukema, J. Wouter] Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands. [Asselta, Rosanna; Duga, Stefano] Humanitas Univ, Dept Biomed Sci, Milan, Italy. [Asselta, Rosanna; Duga, Stefano] Humanitas Clin & Res Ctr, Milan, Italy. [Merlini, Piera A.] Osped Niguarda Ca Granda, Div Cardiol, Milan, Italy. [Marziliano, Nicola; Ardissino, Diego] Univ Parma, Azienda Osped, Div Cardiol, I-43100 Parma, Italy. [Marziliano, Nicola; Ardissino, Diego] Assoc Studio Trombosi Cardiol, Pavia, Italy. [Marziliano, Nicola; Olivieri, Oliviero; Girelli, Domenico] Univ Verona, Sect Internal Med, Dept Med, I-37100 Verona, Italy. [Ferrario, Marco] Univ Insubria, EPIMED Res Ctr, Dept Clin & Expt Med, Varese, Italy. [Hoffmann, Per] Univ Basel, Div Med Genet, Dept Biomed, Basel, Switzerland. [Ehret, Georg B.] Univ Hosp Geneva, Dept Med, Div Cardiol, Geneva, Switzerland. [Holmen, Oddgeir L.; Hveem, Kristian] Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, HUNT Res Ctr, Levanger, Norway. [Hveem, Kristian] Nord Trondelag Hlth Trust Norway, Levanger Hosp, Dept Med, Levanger, Norway. [Holmen, Oddgeir L.] Univ Trondheim Hosp, St Olav Hosp, Trondheim, Norway. [Jansson, Jan-Hakan] Umea Univ, Res Unit Skelleftea, Dept Publ Hlth & Clin Med, Umea, Sweden. [Franks, Paul W.] Umea Univ Hosp, Dept Publ Hlth & Clin Med, S-90185 Umea, Sweden. [Escher, Stefan A.; Varga, Tibor V.; Franks, Paul W.] Lund Univ, Ctr Diabet, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden. [Orho-Melander, Marju; Melander, Olle] Lund Univ, Ctr Diabet, Clin Res Ctr, Skane Univ Hosp,Dept Clin Sci Malmo, Malmo, Sweden. [Esko, Tonu; Mihailov, Evelin; Alver, Maris; Metspalu, Andres] Univ Tartu, Estonian Genome Ctr, Ulikooli 18, EE-50090 Tartu, Estonia. [Alver, Maris; Metspalu, Andres] Inst Mol & Cell Biol, Tartu, Estonia. [AlQarawi, Alaa; Deloukas, Panos] King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah 21413, Saudi Arabia. [Akinsanya, Karen O.; Reilly, Dermot F.; Vogt, Thomas F.; Yin, Wu] Merck Sharp & Dohme Ltd, Pob 2000, Rahway, NJ 07065 USA. [Jackson, Rebecca D.] Ohio State Univ, Dept Med, Div Endocrinol Diabet & Metab, Columbus, OH USA. [Liu, Chunyu] NHLBI, Populat Sci Branch, Bldg 10, Bethesda, MD 20892 USA. [Ehret, Georg B.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Baltimore, MD USA. [Kee, Frank] Queens Univ Belfast, Belfast, Antrim, North Ireland. [Kuulasmaa, Kari; Perola, Markus] Natl Inst Hlth & Welf, Helsinki, Finland. [Saleheen, Danish] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Rader, Daniel J.] Univ Penn, Perelman Sch Med, Dept Genet, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Reilly, Muredach P.] Univ Penn, Perelman Sch Med, Dept Genet, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. [Saleheen, Danish] Ctr Noncommunicable Dis, Karachi, Pakistan. [Tregouet, David] Univ Paris 06, Sorbonne Univ, ICAN Inst Cardiometab & Nutr, Paris, France. [Kraus, William E.; Shah, Svati H.] Duke Univ, Duke Mol Physiol Inst, Durham, NC USA. [Kraus, William E.; Shah, Svati H.] Duke Univ, Dept Med, Div Cardiol, Durham, NC USA. RP Stitziel, NO (reprint author), Washington Univ, Sch Med, Div Cardiovasc, Dept Med, St Louis, MO 63130 USA.; Stitziel, NO (reprint author), Washington Univ, Sch Med, Dept Genet, St Louis, MO 63130 USA.; Stitziel, NO (reprint author), Washington Univ, Sch Med, McDonnell Genome Inst, St Louis, MO 63130 USA.; Deloukas, P (reprint author), Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England.; Samani, NJ (reprint author), Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England.; Samani, NJ (reprint author), Glenfield Hosp, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England.; Schunkert, H (reprint author), Tech Univ Munich, Deutsch Herzzentrum Munchen, D-80290 Munich, Germany.; Schunkert, H (reprint author), DZHK Partner Site Munich Heart Alliance, Munich, Germany.; Kathiresan, S (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.; Kathiresan, S (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.; Kathiresan, S (reprint author), Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA.; Kathiresan, S (reprint author), Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA.; Kathiresan, S (reprint author), Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.; Deloukas, P (reprint author), King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah 21413, Saudi Arabia. EM nstitziel@wustl.edu; skathiresan@partners.org; p.deloukas@qmul.ac.uk; njs@le.ac.uk; schunkert@dhm.mhn.de RI Erdmann, Jeanette/P-7513-2014; Martinelli, Nicola/J-5622-2016; Palmer, Colin/C-7053-2008; Study, GoDARTS/K-9448-2016; Tregouet, David-Alexandre/E-3961-2016; Webb, Tom/C-6237-2011; Waldenberger, Melanie/B-5355-2014; Peters, Annette/A-6117-2011; Deloukas, Panos/B-2922-2013; Dube, Marie-Pierre/B-9364-2008; Konig, Inke/A-4544-2009; Franke, Andre/B-2151-2010; Lieb, Wolfgang/C-1990-2012; OI Erdmann, Jeanette/0000-0002-4486-6231; Stitziel, Nathan/0000-0002-4963-8211; Meisinger, Christa/0000-0002-9026-6544; Kuulasmaa, Kari/0000-0003-2165-1411; Heilmann-Heimbach, Stefanie/0000-0003-1057-465X; Watkins, Hugh/0000-0002-5287-9016; Varga, Tibor/0000-0002-2383-699X; Peters, Annette/0000-0001-6645-0985; Martinelli, Nicola/0000-0001-6465-5119; Palmer, Colin/0000-0002-6415-6560; Waldenberger, Melanie/0000-0003-0583-5093; Deloukas, Panos/0000-0001-9251-070X; Dube, Marie-Pierre/0000-0001-8442-4393; Franke, Andre/0000-0003-1530-5811; Ferrario, Marco M/0000-0003-2741-7124 FU National Heart, Lung, and Blood Institute, National Institutes of Health (NIH) [K08HL114642]; Foundation for Barnes Jewish Hospital; National Heart, Lung, and Blood Institute of the NIH [K01HL125751]; Massachusetts General Hospital; Donovan Family Foundation; NIH [R01HL107816, R01HL127564]; Fondation Leducq; Merck; Italian Ministry of Health [RFPS-2007-3-644382]; Regione Emilia Romagna Area; Wellcome Trust [090532/Z/09/Z, 098381]; British Heart Foundation (BHF) Centre of Research Excellence; National Cancer Institute [R25CA094880]; EU FP7 AMP; Wellcome Trust Institutional; National Institute for Health Research (NIHR); British Heart Foundation; NIHR Leicester Cardiovascular Biomedical Research Unit (BRU); BRU; American Heart Association [15POST23280019]; European Union [261123]; Fondation Leducq (CADgenomics) [12CVD02]; German Federal Ministry of Education and Research e:Med program (e:AtheroSysMed and sysINFLAME); Deutsche Forschungsgemeinschaft cluster of excellence "Inflammation at Interfaces"; SFB [1123]; DZHK; BHF [RG/14/5/30893] FX Supported by a career development award from the National Heart, Lung, and Blood Institute, National Institutes of Health (NIH) (K08HL114642 to Dr. Stitziel) and by the Foundation for Barnes Jewish Hospital. Dr. Peloso is supported by the National Heart, Lung, and Blood Institute of the NIH (award number K01HL125751). Dr. Kathiresan is supported by a Research Scholar award from the Massachusetts General Hospital, the Donovan Family Foundation, grants from the NIH (R01HL107816 and R01HL127564), a grant from Fondation Leducq, and an investigator-initiated grant from Merck. Dr. Merlini was supported by a grant from the Italian Ministry of Health (RFPS-2007-3-644382). Drs. Ardissino and Marziliano were supported by Regione Emilia Romagna Area 1 Grants. Drs. Farrall and Watkins acknowledge the support of the Wellcome Trust core award (090532/Z/09/Z), the British Heart Foundation (BHF) Centre of Research Excellence. Dr. Schick is supported in part by a grant from the National Cancer Institute (R25CA094880). Dr. Goel acknowledges EU FP7 & Wellcome Trust Institutional strategic support fund. Dr. Deloukas's work forms part of the research themes contributing to the translational research portfolio of Barts Cardiovascular Biomedical Research Unit, which is supported and funded by the National Institute for Health Research (NIHR). Drs. Webb and Samani are funded by the British Heart Foundation, and Dr. Samani is an NIHR Senior Investigator. Dr. Masca was supported by the NIHR Leicester Cardiovascular Biomedical Research Unit (BRU), and this work forms part of the portfolio of research supported by the BRU. Dr. Won was supported by a postdoctoral award from the American Heart Association (15POST23280019). Dr. McCarthy is a Wellcome Trust Senior Investigator (098381) and an NIHR Senior Investigator. Dr. Danesh is a British Heart Foundation Professor, European Research Council Senior Investigator, and NIHR Senior Investigator. Drs. Erdmann, Webb, Samani, and Schunkert are supported by the FP7 European Union project CVgenes@target (261123) and the Fondation Leducq (CADgenomics, 12CVD02). Drs. Erdmann and Schunkert are also supported by the German Federal Ministry of Education and Research e:Med program (e:AtheroSysMed and sysINFLAME), and Deutsche Forschungsgemeinschaft cluster of excellence "Inflammation at Interfaces" and SFB 1123. Dr. Kessler received a DZHK Rotation Grant. The analysis was funded, in part, by a Programme Grant from the BHF (RG/14/5/30893 to Dr. Deloukas). Additional funding is listed in the Supplementary Appendix. NR 23 TC 21 Z9 21 U1 7 U2 21 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 24 PY 2016 VL 374 IS 12 BP 1134 EP 1144 DI 10.1056/NEJMoa1507652 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA DH2AA UT WOS:000372585100006 ER PT J AU Klima, M Toth, DJ Hexnerova, R Baumlova, A Chalupska, D Tykvart, J Rezabkova, L Sengupta, N Man, P Dubankova, A Humpolickova, J Nencka, R Veverka, V Balla, T Boura, E AF Klima, Martin Toth, Daniel J. Hexnerova, Rozalie Baumlova, Adriana Chalupska, Dominika Tykvart, Jan Rezabkova, Lenka Sengupta, Nivedita Man, Petr Dubankova, Anna Humpolickova, Jana Nencka, Radim Veverka, Vaclav Balla, Tamas Boura, Evzen TI Structural insights and in vitro reconstitution of membrane targeting and activation of human PI4KB by the ACBD3 protein SO SCIENTIFIC REPORTS LA English DT Article ID 4-KINASE III-BETA; PHOSPHATIDYLINOSITOL 4-KINASES; ENDOPLASMIC-RETICULUM; CRYSTAL-STRUCTURE; GOLGI PROTEIN; COMPLEX; REPLICATION; BINDING; PI4KIII-BETA; DOMAIN AB Phosphatidylinositol 4-kinase beta (PI4KB) is one of four human PI4K enzymes that generate phosphatidylinositol 4-phosphate (PI4P), a minor but essential regulatory lipid found in all eukaryotic cells. To convert their lipid substrates, PI4Ks must be recruited to the correct membrane compartment. PI4KB is critical for the maintenance of the Golgi and trans Golgi network (TGN) PI4P pools, however, the actual targeting mechanism of PI4KB to the Golgi and TGN membranes is unknown. Here, we present an NMR structure of the complex of PI4KB and its interacting partner, Golgi adaptor protein acyl-coenzyme A binding domain containing protein 3 (ACBD3). We show that ACBD3 is capable of recruiting PI4KB to membranes both in vitro and in vivo, and that membrane recruitment of PI4KB by ACBD3 increases its enzymatic activity and that the ACBD3:PI4KB complex formation is essential for proper function of the Golgi. C1 [Klima, Martin; Hexnerova, Rozalie; Baumlova, Adriana; Chalupska, Dominika; Tykvart, Jan; Dubankova, Anna; Humpolickova, Jana; Nencka, Radim; Veverka, Vaclav; Boura, Evzen] Inst Organ Chem & Biochem AS CR, Vvi, Flemingovo Nam 2, Prague 16610 6, Czech Republic. [Toth, Daniel J.; Sengupta, Nivedita; Balla, Tamas] NICHD, Sect Mol Signal Transduct, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. [Rezabkova, Lenka] Paul Scherrer Inst, Dept Biol & Chem, Lab Biomol Res, CH-5232 Villigen, Switzerland. [Man, Petr] Inst Microbiol AS CR, Vvi, Videnska 1083, Prague, Czech Republic. [Man, Petr] Charles Univ Prague, Fac Sci, Dept Biochem, Hlavova 8, Prague, Czech Republic. RP Boura, E (reprint author), Inst Organ Chem & Biochem AS CR, Vvi, Flemingovo Nam 2, Prague 16610 6, Czech Republic. EM boura@uochb.cas.cz RI Boura, Evzen/G-5275-2014; Nencka, Radim/G-5296-2014; Veverka, Vaclav/G-9174-2014; Tykvart, Jan/G-6770-2014; Man, Petr/H-2451-2014; OI Tykvart, Jan/0000-0002-6938-1513; Man, Petr/0000-0002-1485-2197; Balla, Tamas/0000-0002-9077-3335 FU Czech Science Foundation grant [15-21030Y]; Ministry of Education of the Czech Republic [LO1302, LK11205, LO1304, LO1509]; EMBO long-term fellowship; Marie Curie IEF fellowship; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health FX The work in the laboratory of E.B. is supported by the Czech Science Foundation grant number 15-21030Y and by Ministry of Education of the Czech Republic - LO1302. The work of R.H. and V.V. was supported by the Ministry of Education of the Czech Republic - LK11205 and LO1304. The work of PM was supported by a grant from the Ministry of Education of the Czech Republic-LO1509. LR acknowledges the receipt of EMBO long-term and Marie Curie IEF fellowships. The Academy of Sciences of the Czech Republic (RVO: 61388963) is also acknowledged. Confocal imaging of cells was performed at the Microscopy & Imaging Core of the National Institute of Child Health and Human Development, NIH with the kind assistance of Drs. Vincent Schram and James T. Russell. The research of D.T., N.S. and T.B. was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health. We are grateful to Prof. C. Machamer (Johns Hopkins University, Baltimore, MD) for sharing the ACBD3 encoding plasmid. We are grateful to Michael Downey and Edward Curtis for critical reading of the manuscript. NR 41 TC 8 Z9 8 U1 2 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAR 24 PY 2016 VL 6 AR 23641 DI 10.1038/srep23641 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH3PV UT WOS:000372699800001 PM 27009356 ER PT J AU Crawford, NPS AF Crawford, Nigel P. S. TI Deciphering the Dark Matter of Complex Genetic Inheritance SO CELL SYSTEMS LA English DT Editorial Material ID SYSTEMS GENETICS; DISEASE AB A multifaceted "systems genetics" strategy illuminates the relationship between genotype and coronary artery disease. C1 [Crawford, Nigel P. S.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Crawford, NPS (reprint author), NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. EM crawforn@mail.nih.gov NR 10 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2405-4712 EI 2405-4720 J9 CELL SYST JI Cell Syst. PD MAR 23 PY 2016 VL 2 IS 3 BP 144 EP 146 DI 10.1016/j.cels.2016.03.003 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EL1CT UT WOS:000394358800004 PM 27135361 ER PT J AU Romera-Cardenas, G Thomas, LM Lopez-Cobo, S Garcia-Cuesta, EM Long, EO Reyburn, HT AF Romera-Cardenas, Gema Thomas, L. Michael Lopez-Cobo, Sheila Garcia-Cuesta, Eva M. Long, Eric O. Reyburn, Hugh T. TI Ionomycin Treatment Renders NK Cells Hyporesponsive SO PLOS ONE LA English DT Article ID NATURAL-KILLER-CELLS; MHC CLASS-I; COMPLEX CLASS-I; SELF-TOLERANCE; T-CELLS; TRANSCRIPTIONAL ANALYSIS; MEDIATED CYTOTOXICITY; FUNCTIONAL-ANALYSIS; SIGNALING PATHWAYS; VIRAL-INFECTION AB Natural killer cells are cytotoxic lymphocytes important in immune responses to cancer and multiple pathogens. However, chronic activation of NK cells can induce a hyporesponsive state. The molecular basis of the mechanisms underlying the generation and maintenance of this hyporesponsive condition are unknown, thus an easy and reproducible mechanism able to induce hyporesponsiveness on human NK cells would be very useful to gain understanding of this process. Human NK cells treated with ionomycin lose their ability to degranulate and secrete IFN-gamma in response to a variety of stimuli, but IL-2 stimulation can compensate these defects. Apart from reductions in the expression of CD11a/CD18, no great changes were observed in the activating and inhibitory receptors expressed by these NK cells, however their transcriptional signature is different to that described for other hyporesponsive lymphocytes. C1 [Romera-Cardenas, Gema; Lopez-Cobo, Sheila; Garcia-Cuesta, Eva M.; Reyburn, Hugh T.] CSIC, CNB, Madrid, Spain. [Thomas, L. Michael; Long, Eric O.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Romera-Cardenas, Gema] Univ Porto, Inst Invest & Inovacao Saude i3S, Rua Campo Alegre 823, P-4100 Oporto, Portugal. RP Reyburn, HT (reprint author), CSIC, CNB, Madrid, Spain. EM htreyburn@cnb.csic.es RI Reyburn, Hugh/B-4338-2009 FU Fondo de Investigacion Sanitaria [PI11/00298, PI08/1701]; MINECO [SAF2014-58752-R]; CSIC; EMBO Short term fellowship; National Institutes of Health, National Institute of Allergy and Infectious Disease FX This work was supported by grants from the Fondo de Investigacion Sanitaria (PI11/00298 and PI08/1701), MINECO (SAF2014-58752-R) (to HTR), a JAE Predoc studentship from the CSIC and an EMBO Short term fellowship (to GRC) and the Intramural Research Program at the National Institutes of Health, National Institute of Allergy and Infectious Disease (to LMT and EOL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 1 Z9 1 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 23 PY 2016 VL 11 IS 3 AR e0150998 DI 10.1371/journal.pone.0150998 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH3QJ UT WOS:000372701200039 PM 27007115 ER PT J AU Wiers, CE Shokri-Kojori, E Cabrera, E Cunningham, S Wong, C Tomasi, D Wang, GJ Volkow, ND AF Wiers, Corinde E. Shokri-Kojori, Ehsan Cabrera, Elizabeth Cunningham, Samantha Wong, Christopher Tomasi, Dardo Wang, Gene -Jack Volkow, Nora D. TI Socioeconomic status is associated with striatal dopamine D2/D3 receptors in healthy volunteers but not in cocaine abusers SO NEUROSCIENCE LETTERS LA English DT Article DE Cocaine; Dopamine; PET; Socioeconomic status; Striatum ID POSITRON-EMISSION-TOMOGRAPHY; AGE-RELATED DECLINE; SOCIAL-STATUS; HUMAN BRAIN; AVAILABILITY; MONKEYS; BINDING; HUMANS; METABOLISM; ADDICTION AB Positron emission tomography (PET) studies in animals and humans have shown that social status is associated with striatal dopamine D2/D3 receptor (D2/D3R) availability. That is, higher social hierarchy and higher scores on questionnaires assessing social status correlated positively with striatal D2/D3R availability in animals and humans respectively. Furthermore, subordinate monkeys were vulnerable to cocaine self-administration, suggesting that alternations in social hierarchy can change D2/D3R availability and vulnerability to cocaine use. Here, we investigated whether socioeconomic status (SES) measured with the Hollingshead scale is associated with striatal D2D/3R availability using [C-11]raclopride PET in 38 cocaine abusers and 42 healthy controls matched for age and education. Compared to controls, cocaine abusers showed lower D2/D3R availability in the caudate, putamen and ventral striatum (all p <= 0.001). Despite matching groups for education, SES scores were lower in cocaine abusers than controls (p < 0.001). In the control group only, SES scores significantly correlated with D2/D3R in caudate (r = 0.35, p = 0.024) and putamen (r = 0.39, p = 0.011) but not in ventral striatum (p = 0.61); all corrected for age. The study confirms that SES is associated with striatal D2/D3R availability in healthy human volunteers. However, reductions in D2/D3R availability in cocaine abusers may be driven by factors other than SES such as chronic cocaine exposure. Published by Elsevier Ireland Ltd. C1 [Wiers, Corinde E.; Shokri-Kojori, Ehsan; Cabrera, Elizabeth; Cunningham, Samantha; Wong, Christopher; Tomasi, Dardo; Wang, Gene -Jack; Volkow, Nora D.] NIAAA, NIH, 10 Ctr Dr,Room B2L124, Bethesda, MD 20892 USA. [Volkow, Nora D.] NIDA, NIH, Bethesda, MD 20892 USA. RP Wiers, CE (reprint author), NIAAA, NIH, 10 Ctr Dr,Room B2L124, Bethesda, MD 20892 USA. EM corinde.wiers@nih.gov FU National Institutes of Health Intramural Research Program [Y1AA-3009]; German Research Foundation (DFG) FX The work was supported by the National Institutes of Health Intramural Research Program (Y1AA-3009 to NDV). CEW received a scholarship from the German Research Foundation (DFG). NR 32 TC 2 Z9 2 U1 2 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 EI 1872-7972 J9 NEUROSCI LETT JI Neurosci. Lett. PD MAR 23 PY 2016 VL 617 BP 27 EP 31 DI 10.1016/j.neulet.2016.01.056 PG 5 WC Neurosciences SC Neurosciences & Neurology GA DI5LB UT WOS:000373539400005 PM 26828302 ER PT J AU Rosenthal, ES Kottilil, S Polis, MA AF Rosenthal, Elana S. Kottilil, Shyam Polis, Michael A. TI Sofosbuvir and ledipasvir for HIV/HCV co-infected patients SO EXPERT OPINION ON PHARMACOTHERAPY LA English DT Editorial Material DE direct-acting antivirals; ledipasvir/sofosbuvir; HIV/HCV co-infection; Hepatitis C virus ID DRUG-DRUG INTERACTIONS; GENOTYPE 1 INFECTION; HEPATITIS-C; VIRUS-INFECTION; HCV; COINFECTION; DACLATASVIR; HIV-1 AB Introduction: Hepatitis C virus (HCV) is a chronic infection that disproportionately impacts people living with HIV. In the past, HCV therapy was less effective in individuals with HIV co-infection. However, the advent of direct-acting antivirals has revolutionized HCV treatment with high rates of success in patients both with and without HIV. Areas covered: In this paper, we review the evidence supporting the use of ledipasvir and sofosbuvir (LDV/SOF) for the treatment of HCV in patients with HIV co-infection. Articles searchable on MEDLINE/PubMed were reviewed to provide context for use of LDV/SOF in individuals with HCV and HIV co-infection. Expert opinion: This treatment is highly effective in achieving HCV cure or sustained virologic response, however further studies need to done to address efficacy of treatment in people with uncontrolled HIV, concerns regarding drug-interactions with antiretroviral therapy, and potential for shorter duration treatment. C1 [Rosenthal, Elana S.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Clin Monitoring Res Program, Clin Res Directorate, Frederick, MD USA. [Kottilil, Shyam] Univ Maryland, Inst Human Virol, Div Clin Care & Res, Baltimore, MD 21201 USA. [Polis, Michael A.] NIAID, Collaborat Clin Res Branch, Div Clin Res, NIH, Bethesda, MD USA. RP Rosenthal, ES (reprint author), NIH, Clin Monitoring Res Program, Leidos Biomed Res Inc, Support ICMOB, 5415 W Cedar Lane,Suite 203B, Bethesda, MD 20814 USA. EM elana.rosenthal@nih.gov OI Rosenthal, Elana/0000-0001-7234-4871 FU CCR NIH HHS [HHSN261200800001C]; Intramural NIH HHS; NCI NIH HHS [HHSN261200800001E]; PHS HHS [HHSN261200800001E] NR 33 TC 0 Z9 0 U1 3 U2 6 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1465-6566 EI 1744-7666 J9 EXPERT OPIN PHARMACO JI Expert Opin. Pharmacother. PD MAR 23 PY 2016 VL 17 IS 5 BP 743 EP 749 DI 10.1517/14656566.2016.1157580 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DH4AP UT WOS:000372728200005 PM 26898158 ER PT J AU Shamanna, RA Lu, HM Croteau, DL Arora, A Agarwal, D Ball, G Aleskandarany, MA Ellis, IO Pommier, Y Madhusudan, S Bohr, VA AF Shamanna, Raghavendra A. Lu, Huiming Croteau, Deborah L. Arora, Arvind Agarwal, Devika Ball, Graham Aleskandarany, Mohammed A. Ellis, Ian O. Pommier, Yves Madhusudan, Srinivasan Bohr, Vilhelm A. TI Camptothecin targets WRN protein: mechanism and relevance in clinical breast cancer SO ONCOTARGET LA English DT Article DE Werner syndrome; topoisomerase I; senescence; protein degradation; DNA damage response; breast cancer ID WERNER-SYNDROME PROTEIN; HUMAN RECQ HELICASES; DNA TOPOISOMERASE-I; CELLULAR SENESCENCE; DAMAGE; REPAIR; RESISTANCE; CELLS; BLM; REPLICATION AB Werner syndrome protein (WRN) is a RecQ helicase that participates in DNA repair, genome stability and cellular senescence. The five human RecQ helicases, RECQL1, Bloom, WRN, RECQL4 and RECQL5 play critical roles in DNA repair and cell survival after treatment with the anticancer drug camptothecin (CPT). CPT derivatives are widely used in cancer chemotherapy to inhibit topoisomerase I and generate DNA double-strand breaks during replication. Here we studied the effects of CPT on the stability and expression dynamics of human RecQ helicases. In the cells treated with CPT, we observed distinct effects on WRN compared to other human RecQ helicases. CPT altered the cellular localization of WRN and induced its degradation by a ubiquitin-mediated proteasome pathway. WRN knockdown cells as well as CPT treated cells became senescent and stained positive for senescence-associated beta-galactosidase at a higher frequency compared to control cells. However, the senescent phenotype was attenuated by ectopic expression of WRN suggesting functional implication of WRN degradation in CPT treated cells. Approximately 5-23% of breast cancer tumors are known to respond to CPT-based chemotherapy. Interestingly, we found that the extent of CPT-induced WRN degradation correlates with increasing sensitivity of breast cancer cells to CPT. The abundance of WRN decreased in CPT-treated sensitive cells; however, WRN remained relatively stable in CPT-resistant breast cancer cells. In a large clinical cohort of breast cancer patients, we find that WRN and topoisomerase I expression correlate with an aggressive tumor phenotype and poor prognosis. Our novel observations suggest that WRN abundance along with CPT-induced degradation could be a promising strategy for personalizing CPT-based cancer chemotherapeutic regimens. C1 [Shamanna, Raghavendra A.; Lu, Huiming; Croteau, Deborah L.; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. [Arora, Arvind; Aleskandarany, Mohammed A.; Ellis, Ian O.; Madhusudan, Srinivasan] Univ Nottingham, Sch Med, Acad Unit Oncol, Div Canc & Stem Cells, Nottingham, England. [Agarwal, Devika; Ball, Graham] Nottingham Trent Univ, Sch Sci & Technol, Clifton Campus, Nottingham, England. [Pommier, Yves] NCI, Dev Therapeut Branch, Bethesda, MD 20892 USA. [Pommier, Yves] NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. EM vbohr@nih.gov FU Intramural Program of the National Institute on Aging; National Cancer Institute, National Institutes of Health, USA FX Intramural Program of the National Institute on Aging and the National Cancer Institute, National Institutes of Health, USA. NR 43 TC 4 Z9 4 U1 5 U2 7 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAR 22 PY 2016 VL 7 IS 12 BP 13269 EP 13284 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL5OT UT WOS:000375687200001 PM 26959889 ER PT J AU Croglio, MP Haake, JM Ryan, CP Wang, VS Lapier, J Schlarbaum, JP Dayani, Y Artuso, E Prandi, C Koltai, H Agama, K Pommier, Y Chen, Y Tricoli, L LaRocque, JR Albanese, C Yarden, RI AF Croglio, Michael P. Haake, Jefferson M. Ryan, Colin P. Wang, Victor S. Lapier, Jennifer Schlarbaum, Jamie P. Dayani, Yaron Artuso, Emma Prandi, Cristina Koltai, Hinanit Agama, Keli Pommier, Yves Chen, Yu Tricoli, Lucas LaRocque, Jeannine R. Albanese, Christopher Yarden, Ronit I. TI Analogs of the novel phytohormone, strigolactone, trigger apoptosis and synergize with PARP inhibitors by inducing DNA damage and inhibiting DNA repair SO ONCOTARGET LA English DT Article DE strigolactone; small molecule; homology-directed repair; RAD51; PARP inhibitors ID POLY(ADP-RIBOSE) POLYMERASE INHIBITION; PROSTATE-CANCER CELLS; DOUBLE-STRAND BREAKS; HOMOLOGOUS RECOMBINATION; DRUG-RESISTANCE; TOPOISOMERASE-I; RAD51 OVEREXPRESSION; EPITHELIAL-CELLS; MAMMALIAN-CELLS; ROCK INHIBITOR AB Strigolactones are a novel class of plant hormones produced in roots that regulate shoot and root development. We previously reported that strigolactone analogs (SLs) induce G2/M cell cycle arrest and apoptosis in a variety of human cancer cells and inhibit tumor growth of human breast cancer xenografts in mice. SLs had no significant influences on non-transformed cells. Here we report for the first time that SLs induce DNA damage in the form of DNA double-strand breaks (DSBs) and activate the DNA damage response signaling by inducing phosphorylation of ATM, ATR and DNA-PKcs and co-localization of the DNA damage signaling protein, 53BP1, with yH2AX nuclear foci. We further report that in addition to DSBs induction, SLs simultaneously impair DSBs repair, mostly homology-directed repair (HDR) and to a lesser extent non-homologous end joining (NHEJ). In response to SLs, RAD51, the homologous DSB repair protein, is ubiquitinated and targeted for proteasomal degradation and it fails to co-localize with yH2AX foci. Interestingly, SLs synergize with DNA damaging agents-based therapeutics. The combination of PARP inhibitors and SLs showed an especially potent synergy, but only in BRCA1-proficient cells. No synergy was observed between SLs and PARP inhibitors in BRCA1-deficient cells, supporting a role for SLs in HDR impairment. Together, our data suggest that SLs increase genome instability and cell death by a unique mechanism of inducing DNA damage and inhibiting DNA repair. C1 [Croglio, Michael P.; Haake, Jefferson M.; Ryan, Colin P.; Wang, Victor S.; Lapier, Jennifer; Schlarbaum, Jamie P.; Dayani, Yaron; LaRocque, Jeannine R.; Yarden, Ronit I.] Georgetown Univ, Med Ctr, NHS, Dept Human Sci, Washington, DC 20007 USA. [Tricoli, Lucas; Albanese, Christopher; Yarden, Ronit I.] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. [Artuso, Emma; Prandi, Cristina] Univ Turin, Dept Chem, Turin, Italy. [Koltai, Hinanit] Agr Res Org, Volcani Ctr, Inst Plant Sci, IL-50250 Bet Dagan, Israel. [Agama, Keli; Pommier, Yves] NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Agama, Keli; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Chen, Yu] Mem Sloan Kettering Canc Ctr, New York, NY USA. [Albanese, Christopher] Georgetown Univ, Med Ctr, Dept Pathol, Washington, DC 20007 USA. RP Yarden, RI (reprint author), Georgetown Univ, Med Ctr, NHS, Dept Human Sci, Washington, DC 20007 USA.; Yarden, RI (reprint author), Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. EM riy2@georgetown.edu RI prandi, cristina/L-9290-2015 OI prandi, cristina/0000-0001-9510-8783 FU NIH [P30 CA051008]; Georgetown University; Georgetown University Undergraduate Research Opportunity Program (GUROP fellowship); Georgetown University Raines Fellowship to JMH; [1R15GM110454-01]; [NIH/NCAT TL1-TR001431]; [DOD-PC140268]; [DOD- W81XWH-13-1-0327 (CA)] FX This work was partially supported by NIH P30 CA051008 and Georgetown University internal funding to RIY, Georgetown University Undergraduate Research Opportunity Program (GUROP fellowship) provided to VSW, JPS and JL and Georgetown University Raines Fellowship to JMH. This work was supported by 1R15GM110454-01 (JRL) NIH/NCAT TL1-TR001431 (Sandberg) (CA and LT) (CA), DOD-PC140268 (CA), and DOD- W81XWH-13-1-0327 (CA). NR 64 TC 1 Z9 1 U1 5 U2 10 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAR 22 PY 2016 VL 7 IS 12 BP 13984 EP 14001 PG 18 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL5OT UT WOS:000375687200054 PM 26910887 ER PT J AU Ito, K Mitsunaga, M Nishimura, T Kobayashi, H Tajiri, H AF Ito, Kimihiro Mitsunaga, Makoto Nishimura, Takashi Kobayashi, Hisataka Tajiri, Hisao TI Combination photoimmunotherapy with monoclonal antibodies recognizing different epitopes of human epidermal growth factor receptor 2: an assessment of phototherapeutic effect based on fluorescence molecular imaging SO ONCOTARGET LA English DT Article DE molecular targeted therapy; photoimmunotherapy; HER2; trastuzumab; pertuzumab ID NEAR-INFRARED PHOTOIMMUNOTHERAPY; HUMAN GASTRIC-CANCER; BREAST-CANCER; IN-VIVO; OVARIAN-CANCER; PHOTO-IMMUNOTHERAPY; CELL DEATH; TRASTUZUMAB; CHEMOTHERAPY; PERTUZUMAB AB Photoimmunotherapy is a new class of molecular targeted cancer therapy based on a monoclonal antibody (mAb) conjugated to a photosensitizer and irradiation with near-infrared (NIR) light for both imaging and therapy. Here, we sought to determine the feasibility of combining photoimmunotherapy using conjugates of human epidermal growth factor receptor 2 (HER2)-specific mAb-photosensitizer IR700, trastuzumab-IR700 and pertuzumab-IR700. HER2-experessing and nonexpressing cells were treated with mAb-IR700 conjugates and irradiated with NIR light. Fluorescence imaging and cytotoxic effects were examined in cultured HER2-expressng cancer cell lines and in a mouse tumor xenograft model. Trastuzumab-IR700 and pertuzumab-IR700 could specifically bind to HER2 without competing, and the combination treatment of both agents yielded stronger HER2-specific IR700 fluorescence signals than with the treatment with either agent singly. A cytotoxicity assay showed that the combination treatment of both trastuzumab-IR700 and pertuzumab-IR700 followed by NIR light irradiation induced stronger cytotoxic effect than with treatment of either agent plus NIR light irradiation. Furthermore, the phototoxic and cytotoxic effects of mAb depended on HER2-specific IR700 signal intensities. Consistent with in vitro studies, in xenograft tumor models also, IR700 fluorescence imaging-guided NIR light irradiation after the combination treatment of trastuzumab-IR700 and pertuzumab-IR700 led to stronger antitumor effects than by treatment with either agent followed by NIR light irradiation. In conclusion, fluorescence molecular imaging can facilitate the assessment of treatment outcomes of molecular targeted photoimmunotherapy, which holds great potential in facilitating better outcomes in cancer patients. C1 [Ito, Kimihiro; Mitsunaga, Makoto; Nishimura, Takashi; Tajiri, Hisao] Jikei Univ, Sch Med, Dept Internal Med, Div Gastroenterol & Hepatol,Minato Ku, Tokyo 1058461, Japan. [Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, Bethesda, MD 20892 USA. RP Mitsunaga, M (reprint author), Jikei Univ, Sch Med, Dept Internal Med, Div Gastroenterol & Hepatol,Minato Ku, Tokyo 1058461, Japan. EM mit@jikei.ac.jp FU Uehara Memorial Foundation; Kato Memorial Bioscience Foundation,; Mochida Memorial Foundation for Medical and Pharmaceutical Research; Takeda Science Foundation; Kowa Life Science Foundation; Nakayama Cancer Research Institute; Jikei University Research Fund; Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; [JSPS KAKENHI 6710010] FX This study was supported by a Grant-in-Aid for Young Scientists (A) (JSPS KAKENHI 26710010), the Uehara Memorial Foundation, Kato Memorial Bioscience Foundation, Mochida Memorial Foundation for Medical and Pharmaceutical Research, Takeda Science Foundation, Kowa Life Science Foundation, Nakayama Cancer Research Institute, The Jikei University Research Fund (M. M.), and Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (H. K.). NR 31 TC 0 Z9 0 U1 2 U2 4 PU IMPACT JOURNALS LLC PI ORCHARD PARK PA 6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAR 22 PY 2016 VL 7 IS 12 BP 14143 EP 14152 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL5OT UT WOS:000375687200064 PM 26909859 ER PT J AU Sato, K Watanabe, R Hanaoka, H Nakajima, T Choyke, PL Kobayashi, H AF Sato, Kazuhide Watanabe, Rira Hanaoka, Hirofumi Nakajima, Takahito Choyke, Peter L. Kobayashi, Hisataka TI Comparative effectiveness of light emitting diodes (LEDs) and Lasers in near infrared photoimmunotherapy SO ONCOTARGET LA English DT Article DE near infrared photoimmunotherapy; light emitting diode (LED); light amplification by stimulated emission of radiation (Laser); epidermal growth factor receptor; super-enhanced permeability and retention (SUPR) effect ID IN-VIVO; PHOTODYNAMIC THERAPY; CANCER; METASTASES; TUMORS AB Near infrared photoimmunotherapy (NIR-PIT) is a new cancer treatment that combines the specificity of antibodies for targeting tumors with the toxicity induced by photosensitizers after exposure to near infrared (NIR) light. Herein we compare two NIR-light sources; light emitting diodes (LEDs) and Lasers, for their effectiveness in NIR-PIT. A photosensitizer, IRDye-700DX, conjugated to panitumumab (pan-IR700), was incubated with EGFR-expressing A431 and MDA-MB-468-luc cells. NIR-light was provided by LEDs or Lasers at the same light dose. Laser-light produced more cytotoxicity and greater reductions in IR700-fluorescence intensity than LED-light. Laser-light also produced more cytotoxicity in vivo in both cell lines. Assessment of super-enhanced permeability and retention (SUPR) effects were stronger with Laser than LED. These results suggest that Laser-light produced significantly more cytotoxic effects compared to LEDs. Although LED is less expensive, Laser-light produces superior results in NIR-PIT. C1 [Sato, Kazuhide; Watanabe, Rira; Hanaoka, Hirofumi; Nakajima, Takahito; Choyke, Peter L.; Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, Bethesda, MD 20892 USA. EM Kobayash@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 20 TC 0 Z9 0 U1 4 U2 4 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAR 22 PY 2016 VL 7 IS 12 BP 14324 EP 14335 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL5OT UT WOS:000375687200079 PM 26885688 ER PT J AU Kim, JH Lee, HS Lee, NCO Goncharov, NV Kumeiko, V Masumoto, H Earnshaw, WC Kouprina, N Larionov, V AF Kim, Jung-Hyun Lee, Hee-Sheung Lee, Nicholas C. O. Goncharov, Nikolay V. Kumeiko, Vadim Masumoto, Hiroshi Earnshaw, William C. Kouprina, Natalay Larionov, Vladimir TI Development of a novel HAC-based "gain of signal" quantitative assay for measuring chromosome instability (CIN) in cancer cells SO ONCOTARGET LA English DT Article DE chromosome instability; CIN; human artificial chromosome; HAC; anticancer drugs ID HUMAN ARTIFICIAL CHROMOSOME; CONDITIONAL CENTROMERE; CENP-E; MIS-SEGREGATION; MITOTIC DELAY; GENE DELIVERY; KINETOCHORE; MISSEGREGATION; EXPRESSION; ANEUPLOIDY AB Accumulating data indicates that chromosome instability (CIN) common to cancer cells can be used as a target for cancer therapy. At present the rate of chromosome mis-segregation is quantified by laborious techniques such as coupling clonal cell analysis with karyotyping or fluorescence in situ hybridization (FISH). Recently, a novel assay was developed based on the loss of a non-essential human artificial chromosome (HAC) carrying a constitutively expressed EGFP transgene ("loss of signal" assay). Using this system, anticancer drugs can be easily ranked on by their effect on HAC loss. However, it is problematic to covert this "loss of signal" assay into a high-throughput screen to identify drugs and mutations that increase CIN levels. To address this point, we re-designed the HAC-based assay. In this new system, the HAC carries a constitutively expressed shRNA against the EGFP transgene integrated into human genome. Thus, cells that inherit the HAC display no green fluorescence, while cells lacking the HAC do. We verified the accuracy of this "gain of signal" assay by measuring the level of CIN induced by known antimitotic drugs and added to the list of previously ranked CIN inducing compounds, two newly characterized inhibitors of the centromere-associated protein CENP-E, PF-2771 and GSK923295 that exhibit the highest effect on chromosome instability measured to date. The "gain of signal" assay was also sensitive enough to detect increase of CIN after siRNA depletion of known genes controlling mitotic progression through distinct mechanisms. Hence this assay can be utilized in future experiments to uncover novel human CIN genes, which will provide novel insight into the pathogenesis of cancer. Also described is the possible conversion of this new assay into a high-throughput screen using a fluorescence microplate reader to characterize chemical libraries and identify new conditions that modulate CIN level. C1 [Kim, Jung-Hyun; Lee, Hee-Sheung; Lee, Nicholas C. O.; Goncharov, Nikolay V.; Kouprina, Natalay; Larionov, Vladimir] NCI, Dev Therapeut Branch, NIH, Bethesda, MD 20892 USA. [Goncharov, Nikolay V.; Kumeiko, Vadim] Far Eastern Fed Univ, AV Zhirmunsky Inst Marine Biol, Sch Biomed, FEB RAS, Vladivostok, Russia. [Masumoto, Hiroshi] Kazusa DNA Res Inst, Dept Human Genome Res, Lab Cell Engn, Kisarazu, Japan. [Earnshaw, William C.] Univ Edinburgh, Wellcome Trust Ctr Cell Biol, Edinburgh, Midlothian, Scotland. RP Larionov, V (reprint author), NCI, Dev Therapeut Branch, NIH, Bethesda, MD 20892 USA. EM larionov@mail.nih.gov RI Lee, Nicholas/F-3668-2015 FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, USA; Wellcome Trust Principal Research Fellowship [073915]; MEXT KAKENHI [23114008]; Kazusa DNA Research Institute Foundation FX PF-2771 was kindly provided by Dr. B.W. Murray (Pfizer Worldwide Research and Development, La Jolla Laboratories, San Diego). The authors also would like to thank the CRC, LRBGE Fluorescence Imaging Facility (NIH) and personally Dr. Karpova and Dr. McNally for instructions, consultations and help with the usage of a DeltaVision microscopy imaging system. This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, USA (VL), a Wellcome Trust Principal Research Fellowship [grant number 073915] (WCE), MEXT KAKENHI [grant number 23114008] (HM) and the Kazusa DNA Research Institute Foundation (HM). NR 37 TC 2 Z9 2 U1 2 U2 2 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAR 22 PY 2016 VL 7 IS 12 BP 14841 EP 14856 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL5OT UT WOS:000375687200117 PM 26943579 ER PT J AU Gao, P Yang, CZ Nesvick, CL Feldman, MJ Sizdahkhani, S Liu, HL Chu, HY Yang, FX Tang, L Tian, J Zhao, SG Li, GH Heiss, JD Liu, Y Zhuang, ZP Xu, GW AF Gao, Peng Yang, Chunzhang Nesvick, Cody L. Feldman, Michael J. Sizdahkhani, Saman Liu, Huailei Chu, Huiying Yang, Fengxu Tang, Ling Tian, Jing Zhao, Shiguang Li, Guohui Heiss, John D. Liu, Yang Zhuang, Zhengping Xu, Guowang TI Hypotaurine evokes a malignant phenotype in glioma through aberrant hypoxic signaling SO ONCOTARGET LA English DT Article DE hypoxia; hypoxia-inducible factors; hypotaurine; metabolomics; glioma ID MOLECULAR-DYNAMICS SIMULATIONS; MAGNETIC-RESONANCE-SPECTROSCOPY; STEM-CELLS; IN-VITRO; H-1-NMR SPECTROSCOPY; METABOLIC PROFILES; INDUCIBLE FACTORS; TAURINE LEVELS; GLIOBLASTOMA; CANCER AB Metabolomics has shown significant potential in identifying small molecules specific to tumor phenotypes. In this study we analyzed resected tissue metabolites using capillary electrophoresis-mass spectrometry and found that tissue hypotaurine levels strongly and positively correlated with glioma grade. In vitro studies were conducted to show that hypotaurine activates hypoxia signaling through the competitive inhibition of prolyl hydroxylase domain-2. This leads to the activation of hypoxia signaling as well as to the enhancement of glioma cell proliferation and invasion. In contrast, taurine, the oxidation metabolite of hypotaurine, decreased intracellular hypotaurine and resulted in glioma cell growth arrest. Lastly, a glioblastoma xenograft mice model was supplemented with taurine feed and exhibited impaired tumor growth. Taken together, these findings suggest that hypotaurine is an aberrantly produced oncometabolite, mediating tumor molecular pathophysiology and progression. The hypotaurine metabolic pathway may provide a potentially new target for glioblastoma diagnosis and therapy. C1 [Gao, Peng; Yang, Fengxu; Tang, Ling; Liu, Yang; Xu, Guowang] Chinese Acad Sci, Dalian Inst Chem Phys, Key Lab Separat Sci Analyt Chem, Dalian, Peoples R China. [Yang, Chunzhang; Nesvick, Cody L.; Feldman, Michael J.; Sizdahkhani, Saman; Yang, Fengxu; Heiss, John D.; Zhuang, Zhengping] NINDS, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Liu, Huailei; Zhao, Shiguang] Harbin Med Univ, Affiliated Hosp 1, Dept Neurosurg, Harbin, Peoples R China. [Chu, Huiying; Li, Guohui] Chinese Acad Sci, Dalian Inst Chem Phys, State Key Lab Mol React Dynam, Lab Mol Modeling & Design, Dalian, Peoples R China. [Yang, Fengxu; Tian, Jing] Dalian Polytech Univ, Sch Bioengn, Dalian, Peoples R China. [Gao, Peng] Dalian Sixth Peoples Hosp, Clin Lab, Dalian, Peoples R China. [Yang, Chunzhang] NCI, Neurooncol Branch, NIH, Bethesda, MD 20892 USA. RP Xu, GW (reprint author), Chinese Acad Sci, Dalian Inst Chem Phys, Key Lab Separat Sci Analyt Chem, Dalian, Peoples R China.; Zhuang, ZP (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA.; Zhao, SG (reprint author), Harbin Med Univ, Affiliated Hosp 1, Dept Neurosurg, Harbin, Peoples R China.; Li, GH (reprint author), Chinese Acad Sci, Dalian Inst Chem Phys, State Key Lab Mol React Dynam, Lab Mol Modeling & Design, Dalian, Peoples R China. EM guangsz@hotmail.com; ghli@dicp.ac.cn; zhuangp@ninds.nih.gov; xugw@dicp.ac.cn FU National Natural Science Foundation of China [81372695, 81472374, 21435006, 81272788, 81402061]; National Natural Science Foundation of China (Creative Research Group Project) [21321064]; Ministry of Science and Technology of China [2012AA01A305, 2012CB721002]; Intramural Research Program at the National Institute of Neurological Disorders and Stroke at the National Institutes of Health (NIH) FX This work was supported by the National Natural Science Foundation of China (Foundation Grants 81372695, 81472374, 21435006, 81272788, 81402061), Creative Research Group Project Grant 21321064), the Ministry of Science and Technology of China (Grants 2012AA01A305, 2012CB721002), the Intramural Research Program at the National Institute of Neurological Disorders and Stroke at the National Institutes of Health (NIH) and the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer, Inc., The Doris Duke Charitable Foundation, The Alexandria Real Estate Equities, Inc. and Mr. and Mrs. Joel S. Marcus and the Howard Hughes Medical Institute, as well as other private donors. For a complete list, please visit the Foundation at: http://fnih.org/work/education-training-0/medical-research-scholarsprogr am. NR 59 TC 0 Z9 0 U1 4 U2 7 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAR 22 PY 2016 VL 7 IS 12 BP 15200 EP 15214 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL5OT UT WOS:000375687200141 PM 26934654 ER PT J AU Carlsten, M Levy, E Karambelkar, A Li, LH Reger, R Berg, M Peshwa, MV Childs, RW AF Carlsten, Mattias Levy, Emily Karambelkar, Amrita Li, Linhong Reger, Robert Berg, Maria Peshwa, Madhusudan V. Childs, Richard W. TI Efficient mRNA-Based Genetic Engineering of Human NK Cells with High-Affinity CD16 and CCR7 Augments Rituximab-Induced ADCC against Lymphoma and Targets NK Cell Migration toward the Lymph Node-Associated Chemokine CCL19 SO FRONTIERS IN IMMUNOLOGY LA English DT Article DE gene therapy; NK cells; NK cell immunotherapy; antibody -dependent cellular cytotoxicity; cellular migration ID NATURAL-KILLER-CELLS; T-CELLS; CANCER; POLYMORPHISMS; CYTOTOXICITY; MANIPULATION; MALIGNANCIES; ENHANCE AB For more than a decade, investigators have pursued methods to genetically engineer natural killer (NK) cells for use in clinical therapy against cancer. Despite considerable advances in viral transduction of hematopoietic stem cells and T cells, transduction efficiencies for NK cells have remained disappointingly low. Here, we show that NK cells can be genetically reprogramed efficiently using a cGMP-compliant mRNA electroporation method that induces rapid and reproducible transgene expression in nearly all transfected cells, without negatively influencing their viability, phenotype, and cytotoxic function. To study its potential therapeutic application, we used this approach to improve key aspects involved in efficient lymphoma targeting by adoptively infused ex vivo expanded NK cells. Electroporation of NK cells with mRNA coding for the chemokine receptor CCR7 significantly promoted migration toward the lymph node-associated chemokine CCL19. Further, introduction of mRNA coding for the high-affinity antibody-binding receptor CD16 (CD16-158V) substantially augmented NK cell cytotoxicity against rituximab-coated lymphoma cells. Based on these data, we conclude that this approach can be utilized to genetically modify multiple modalities of NK cells in a highly efficient manner with the potential to improve multiple facets of their in vivo tumor targeting, thus, opening a new arena for the development of more efficacious adoptive NK cell-based cancer immunotherapies. C1 [Carlsten, Mattias; Levy, Emily; Karambelkar, Amrita; Reger, Robert; Berg, Maria; Childs, Richard W.] NHLBI, Lab Transplantat Immunotherapy, Hematol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Li, Linhong; Peshwa, Madhusudan V.] MaxCyte Inc, Gaithersburg, MD USA. RP Carlsten, M (reprint author), NHLBI, Lab Transplantat Immunotherapy, Hematol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM mattlas.carlsten@nih.gov OI Carlsten, Mattias/0000-0001-9815-0012 FU Intramural Research Program at the National Heart, Lung, and Blood Institute, National Institutes of Health FX This research was supported by the Intramural Research Program at the National Heart, Lung, and Blood Institute, National Institutes of Health. NR 17 TC 3 Z9 4 U1 4 U2 6 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD MAR 22 PY 2016 VL 7 AR 105 DI 10.3389/fimmu.2016.00105 PG 9 WC Immunology SC Immunology GA DH6VF UT WOS:000372929500002 PM 27047492 ER PT J AU Rabin, BA Lewis, CC Norton, WE Neta, G Chambers, D Tobin, JN Brownson, RC Glasgow, RE AF Rabin, Borsika A. Lewis, Cara C. Norton, Wynne E. Neta, Gila Chambers, David Tobin, Jonathan N. Brownson, Ross C. Glasgow, Russell E. TI Measurement resources for dissemination and implementation research in health SO IMPLEMENTATION SCIENCE LA English DT Article DE Measurement; Dissemination; Implementation; Resources; Systematic review ID SCIENCE; FRAMEWORK AB Background: A 2-day consensus working meeting, hosted by the United States National Institutes of Health and the Veterans Administration, focused on issues related to dissemination and implementation (D&I) research in measurement and reporting. Meeting participants included 23 researchers, practitioners, and decision makers from the USA and Canada who concluded that the field would greatly benefit from measurement resources to enhance the ease, harmonization, and rigor of D&I evaluation efforts. This paper describes the findings from an environmental scan and literature review of resources for D&I measures. Findings: We identified a total of 17 resources, including four web-based repositories and 12 static reviews or tools that attempted to synthesize and evaluate existing measures for D&I research. Thirteen resources came from the health discipline, and 11 were populated from database reviews. Ten focused on quantitative measures, and all were generated as a resource for researchers. Fourteen were organized according to an established D&I theory or framework, with the number of constructs and measures ranging from 1 to more than 450. Measure metadata was quite variable with only six providing information on the psychometric properties of measures. Conclusions: Additional guidance on the development and use of measures are needed. A number of approaches, resources, and critical areas for future work are discussed. Researchers and stakeholders are encouraged to take advantage of a number of funding mechanisms supporting this type of work. C1 [Rabin, Borsika A.] Univ Calif San Diego, Sch Med, Dept Family Med & Publ Hlth, 8452 La Jolla Shores Dr, San Diego, CA 92037 USA. [Rabin, Borsika A.; Glasgow, Russell E.] Univ Colorado, Ctr Hlth Outcomes Res & Delivery Sci, Sch Med, Dept Family Med & Adult & Child, Mail Stop F496,Acad Off 1,12631 East 17th Ave, Aurora, CO 80045 USA. [Lewis, Cara C.] Indiana Univ, Dept Psychol & Brain Sci, 1101 E 10th St, Bloomington, IN 47405 USA. [Norton, Wynne E.; Neta, Gila; Chambers, David] NCI, Div Canc Control & Populat Sci, BG 9609 MSC 9760,9609 Med Ctr Dr, Bethesda, MD 20892 USA. [Tobin, Jonathan N.] Rockefeller Univ, Ctr Clin & Translat Sci, Clin Directors Network Inc CDN, 5 West 37th St 10th Floor, New York, NY 10018 USA. [Brownson, Ross C.] Washington Univ, Brown Sch, Prevent Res Ctr St Louis, St Louis, MO 63130 USA. [Brownson, Ross C.] Washington Univ, Sch Med, Dept Surg, Div Publ Hlth Sci, St Louis, MO 63110 USA. [Brownson, Ross C.] Washington Univ, Sch Med, Dept Surg, Alvin J Siteman Canc Ctr, St Louis, MO 63110 USA. RP Rabin, BA (reprint author), Univ Calif San Diego, Sch Med, Dept Family Med & Publ Hlth, 8452 La Jolla Shores Dr, San Diego, CA 92037 USA.; Rabin, BA (reprint author), Univ Colorado, Ctr Hlth Outcomes Res & Delivery Sci, Sch Med, Dept Family Med & Adult & Child, Mail Stop F496,Acad Off 1,12631 East 17th Ave, Aurora, CO 80045 USA. EM borsika.a.rabin@gmail.com FU National Institute of Mental Health of the National Institutes of Health [R01MH106510] FX Research reported in this publication was also supported by the National Institute of Mental Health of the National Institutes of Health under Award Number R01MH106510. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We would also like to thank Caitlin Dorsey and Abigail Melvin for their diligent work as raters that led to the summarization of measure resources and to W. Chase Cameron for his help with the review of the literature. NR 15 TC 2 Z9 2 U1 8 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-5908 J9 IMPLEMENT SCI JI Implement. Sci. PD MAR 22 PY 2016 VL 11 AR 42 DI 10.1186/s13012-016-0401-y PG 9 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA DI0JG UT WOS:000373181400003 PM 27000147 ER PT J AU Srikanth, S Kim, KD Gao, YY Woo, JS Ghosh, S Calmettes, G Paz, A Abramson, J Jiang, MS Gwack, Y AF Srikanth, Sonal Kim, Kyun-Do Gao, Yuanyuan Woo, Jin Seok Ghosh, Shubhamoy Calmettes, Guillaume Paz, Aviv Abramson, Jeff Jiang, Meisheng Gwack, Yousang TI A large Rab GTPase encoded by CRACR2A is a component of subsynaptic vesicles that transmit T cell activation signals SO SCIENCE SIGNALING LA English DT Article ID SYSTEM AUTOIMMUNE-DISEASE; IMMUNOLOGICAL SYNAPSE; RHO-GTPASES; EXPRESSION; PROTEIN; ORAI1; DIFFERENTIATION; MICROCLUSTERS; ATORVASTATIN; MODULATION AB More than 60 members of the Rab family of guanosine triphosphatases (GTPases) exist in the human genome. Rab GTPases are small proteins that are primarily involved in the formation, trafficking, and fusion of vesicles. We showed that CRACR2A (Ca2+ release-activated Ca2+ channel regulator 2A) encodes a lymphocyte-specific large Rab GTPase that contains multiple functional domains, including EF-hand motifs, a proline-rich domain (PRD), and a Rab GTPase domain with an unconventional prenylation site. Through experiments involving gene silencing in cells and knockout mice, we demonstrated a role for CRACR2A in the activation of the Ca2+ and c-Jun N-terminal kinase signaling pathways in response to T cell receptor (TCR) stimulation. Vesicles containing this Rab GTPase translocated from near the Golgi to the immunological synapse formed between a T cell and a cognate antigen-presenting cell to activate these signaling pathways. The interaction between the PRD of CRACR2A and the guanidine nucleotide exchange factor Vav1 was required for the accumulation of these vesicles at the immunological synapse. Furthermore, we demonstrated that GTP binding and prenylation of CRACR2A were associated with its localization near the Golgi and its stability. Our findings reveal a previously uncharacterized function of a large Rab GTPase and vesicles near the Golgi in TCR signaling. Other GTPases with similar domain architectures may have similar functions in T cells. C1 [Srikanth, Sonal; Kim, Kyun-Do; Gao, Yuanyuan; Woo, Jin Seok; Ghosh, Shubhamoy; Paz, Aviv; Abramson, Jeff; Gwack, Yousang] Univ Calif Los Angeles, David Geffen Sch Med, Dept Physiol, Los Angeles, CA 90095 USA. [Calmettes, Guillaume] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med Cardiol, Los Angeles, CA 90095 USA. [Jiang, Meisheng] Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. [Kim, Kyun-Do] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. [Gao, Yuanyuan] NIAID, Lab Immunogenet Virol & Cellular Immunol, NIH, Rockville, MD 20852 USA. [Ghosh, Shubhamoy] Univ Calif Los Angeles, Coll Life Sci, Dept Mol Cell & Dev Biol, Los Angeles, CA 90095 USA. RP Srikanth, S; Gwack, Y (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Physiol, Los Angeles, CA 90095 USA. EM ssrikanth@mednet.ucla.edu; ygwack@mednet.ucla.edu FU NIH [AI083432]; American Heart Association [12SDG12040188]; JCCC [P30 CA016042]; CFAR [5P30 AI028697] FX This work was supported by NIH grant AI083432 (Y. Gwack) and American Heart Association grant 12SDG12040188 (S.S.). Flow cytometry was performed in the UCLA Jonsson Comprehensive Cancer Center (JCCC) and Center for AIDS Research (CFAR) Flow Cytometry Core Facility, which is supported by JCCC grant P30 CA016042 and CFAR grant 5P30 AI028697. NR 41 TC 0 Z9 0 U1 2 U2 2 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1945-0877 EI 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD MAR 22 PY 2016 VL 9 IS 420 AR ra31 DI 10.1126/scisignal.aac9171 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DI0DN UT WOS:000373165400002 PM 27016526 ER PT J AU Zhang, HE Meltzer, PS Davis, SR AF Zhang, Hongen Meltzer, Paul S. Davis, Sean R. TI caOmicsV: an R package for visualizing multidimensional cancer genomic data SO BMC BIOINFORMATICS LA English DT Article DE Software; R package; Genomic data visualization; Multidimensional data visualization ID CIRCOS AB Background: Translational genomics research in cancers, e.g., International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), has generated large multidimensional datasets from high-throughput technologies. Data analysis at multidimensional level will greatly benefit clinical applications of genomic information in diagnosis, prognosis and therapeutics of cancers. To help, tools to effectively visualize integrated multidimensional data are important for understanding and describing the relationship between genomic variations and cancers. Results: We implemented the R package, caOmicsV, to provide methods under R environment to visualize multidimensional cancer genomic data in two layouts: matrix layout and combined biological network and circular layout. Both layouts support to display sample information, gene expression (e.g., RNA and miRNA), DNA methylation, DNA copy number variations, and summarized data. A set of supplemental functions are included in the caOmicsV package to help users in generation of plot data sets from multiple genomic datasets with given gene names and sample names. Default plot methods for both layouts for easy use are also implemented. Conclusion: caOmicsV package provides an easy and flexible way to visualize integrated multidimensional cancer genomic data under R environment. C1 [Zhang, Hongen; Meltzer, Paul S.; Davis, Sean R.] NCI, Genet Branch, Ctr Canc Res, NIH, Bldg 37,Room 6138,37 Convent Dr, Bethesda, MD 20892 USA. RP Davis, SR (reprint author), NCI, Genet Branch, Ctr Canc Res, NIH, Bldg 37,Room 6138,37 Convent Dr, Bethesda, MD 20892 USA. EM sdavis2@mail.nih.gov FU NCI intramural research funding in Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This work was supported by NCI intramural research funding in Center for Cancer Research, National Cancer Institute, National Institutes of Health, and the package was developed and tested on Helix system at the Center for Information Technology, National Institutes of Health, Bethesda, Maryland, USA. The data used for implementation and demo of caOmcisV package is based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov/. NR 14 TC 0 Z9 0 U1 2 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD MAR 22 PY 2016 VL 17 AR 141 DI 10.1186/s12859-016-0989-6 PG 5 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA DH0QE UT WOS:000372487900006 PM 27005934 ER PT J AU Ahlman, MA Raman, FS Pang, JN Zemrak, F Sandfort, V Penzak, SR Fan, ZY Liu, ST Li, DB Bluemke, DA AF Ahlman, Mark A. Raman, Fabio S. Pang, Jianing Zemrak, Filip Sandfort, Veit Penzak, Scott R. Fan, Zhaoyang Liu, Songtao Li, Debiao Bluemke, David A. TI Part 2-Coronary angiography with gadofosveset trisodium: a prospective intra-subject comparison for dose optimization for 100 % efficiency imaging SO BMC CARDIOVASCULAR DISORDERS LA English DT Article DE Gadofosveset trisodium; MS-325; Gadolinium-based intravascular contrast agent; Whole-heart coronary magnetic resonance angiography; Navigator-based angiography; 3.0 Tesla; Image quality; Respiratory motion correction ID MAGNETIC-RESONANCE ANGIOGRAPHY; MR-ANGIOGRAPHY; GADOBENATE DIMEGLUMINE; VISUALIZATION; GADOPENTETATE; DISEASE; SINGLE; MS-325; TRIAL; 3.0-T AB Background: Three tesla (3T) coronary magnetic resonance angiography (MRA) may be optimized using gadolinium-based contrast agents (GBCA) such as gadofosveset trisodium. The goal of this study was to evaluate if there is a qualitative or quantitative improvement in the coronary arteries with variation in contrast dose. Methods: Twenty-eight healthy volunteers were prospectively recruited for coronary MRA at 3T using a steady state injection technique for 3D radial whole-heart image acquisition with retrospective respiratory self-gating (ClinicalTrials.gov identifier: NCT01853592). Nineteen volunteers completed both single- and double-dose imaging instances (0.03 and 0.06 mmol/kg, respectively). Intra-individual comparison of image quality was assessed by measurement of apparent signal/contrast-to-noise ratio (aSNR/aCNR) and subjective evaluation of image quality by 2 independent reviewers. Results: The average duration of coronary MRA acquisition was 7.2 +/- 1.2 min. There was significantly higher (60 %, p < 0.001) aSNR of the aorta and right/left ventricle for the double dose compared to single dose injection scheme and aSNR of the coronary arteries increased by 70 % (p < 0.001) for the double dose injection. aCNR increased by +55 % and +60 % in the ventricles and coronary arteries, respectively (p < 0.001). Overall segmental artery visualization for single dose was possible 47 % of the time, which improved to 60 % with double dose (p = 0.019), predominantly driven by improvements in more distal segment visualization (+ 40 % improvement in mid arterial segments, p = 0.013). Conclusions: Gadofosveset trisodium dose of 0.06 mmol/kg significantly quantitatively and qualitatively improves the coronary artery image quality compared to 0.03 mmol/kg at 3T for moderate duration (6-8 min) steady state contrast enhanced coronary MRA. C1 [Ahlman, Mark A.; Raman, Fabio S.; Sandfort, Veit; Liu, Songtao; Bluemke, David A.] NIH, Radiol & Imaging Sci, Ctr Clin, 10 Ctr Dr,Bldg 10,Rm B1N264B-7, Bethesda, MD 20892 USA. [Raman, Fabio S.] Univ Alabama Birmingham, Med Scientist Training Program, Birmingham, AL USA. [Pang, Jianing; Fan, Zhaoyang; Li, Debiao] Cedars Sinai Med Ctr, Bioengn, Los Angeles, CA 90048 USA. [Zemrak, Filip] Barts & London Queen Marys Sch Med & Dent, Ctr Adv Cardiovasc Imaging, William Harvey Res Inst, London, England. [Penzak, Scott R.] Univ N Texas, Dept Pharmacotherapy, Ft Worth, TX USA. RP Ahlman, MA (reprint author), NIH, Radiol & Imaging Sci, Ctr Clin, 10 Ctr Dr,Bldg 10,Rm B1N264B-7, Bethesda, MD 20892 USA. EM mark.ahlman@gmail.com OI Raman, Fabio/0000-0003-2393-9937 FU NIH [R01 EB002623]; National Institutes of Health (NIH); imaging sciences training program FX JP, ZF, and DL acknowledge support of NIH R01 EB002623. Otherwise, the National Institutes of Health (NIH) intramural research program and the imaging sciences training program supported this research. We thank Jacquin Jones who provided scheduling and recruitment services for the work herein. NR 21 TC 0 Z9 0 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2261 J9 BMC CARDIOVASC DISOR JI BMC Cardiovasc. Disord. PD MAR 22 PY 2016 VL 16 AR 58 DI 10.1186/s12872-015-0152-8 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DH1SH UT WOS:000372564700002 PM 27004532 ER PT J AU Li, JY Bushel, PR AF Li, Jianying Bushel, Pierre R. TI EPIG-Seq: extracting patterns and identifying co-expressed genes from RNA-Seq data SO BMC GENOMICS LA English DT Article DE EPIG-Seq; Gene expression; RNA-Seq; Clustering; Pattern analysis; Toxicogenomics; Cancer ID DIFFERENTIAL EXPRESSION ANALYSIS; HUMAN BREAST-TUMORS; SEQUENCE COUNT DATA; MOLECULAR PORTRAITS; CANCER; NORMALIZATION; TRANSCRIPTOME; DISCOVERY; ALPHA AB Background: RNA sequencing (RNA-Seq) measures genome-wide gene expression. RNA-Seq data is count-based rendering normal distribution models for analysis inappropriate. Normalization of RNA-Seq data to transform the data has limitations which can adversely impact the analysis. Furthermore, there are a few count-based methods for analysis of RNA-Seq data but they are essentially for pairwise analysis of treatment groups or multiclasses but not pattern-based to identify co-expressed genes. Results: We adapted our extracting patterns and identifying genes methodology for RNA-Seq (EPIG-Seq) count data. The software uses count-based correlation to measure similarity between genes, quasi-Poisson modelling to estimate dispersion in the data and a location parameter to indicate magnitude of differential expression. EPIG-Seq is different than any other software currently available for pattern analysis of RNA-Seq data in that EPIG-Seq 1) uses count level data and supports cases of inflated zeros, 2) identifies statistically significant clusters of genes that are co-expressed across experimental conditions, 3) takes into account dispersion in the replicate data and 4) provides reliable results even with small sample sizes. EPIG-Seq operates in two steps: 1) extract the pattern profiles from data as seeds for clustering co-expressed genes and 2) cluster the genes to the pattern seeds and compute statistical significance of the pattern of co-expressed genes. EPIG-Seq provides a table of the genes with bootstrapped p-values and profile plots of the patterns of co-expressed genes. In addition, EPIG-Seq provides a heat map and principal component dimension reduction plot of the clustered genes as visual aids. We demonstrate the utility of EPIG-Seq through the analysis of toxicogenomics and cancer data sets to identify biologically relevant co-expressed genes. EPIG-Seq is available at: sourceforge.net/projects/epig-seq. Conclusions: EPIG-Seq is unlike any other software currently available for pattern analysis of RNA-Seq count level data across experimental groups. Using the EPIG-Seq software to analyze RNA-Seq count data across biological conditions permits the ability to extract biologically meaningful co-expressed genes associated with coordinated regulation. C1 [Li, Jianying] NIEHS, Integrat Bioinformat Grp, Res Triangle Pk, NC 27709 USA. [Li, Jianying; Bushel, Pierre R.] NIEHS, Microarray & Genome Informat Grp, Res Triangle Pk, NC 27709 USA. [Bushel, Pierre R.] NIEHS, Biostat & Computat Biol Branch, 111 TW Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. [Li, Jianying] Kelly Govt Solut, Res Triangle Pk, NC 27709 USA. RP Bushel, PR (reprint author), NIEHS, Microarray & Genome Informat Grp, Res Triangle Pk, NC 27709 USA.; Bushel, PR (reprint author), NIEHS, Biostat & Computat Biol Branch, 111 TW Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. EM bushel@niehs.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS) FX We thank the MicroArray Quality Control phase III (MAQC-III) Sequence Quality Control (SEQC) toxicogenomics working group members (TGxSEQC) Weida Tong, Charles Wang, Joshua Xu, Binsheng Gong and Zhenqiang Su for contributing the RNA-Seq mapped reads from the raw Toxicogenomics MOA data. We thank Raja Jothi and Oswaldo A. Lozoya for their critical review of the paper. The results published here are in whole or part based upon data generated by TCGA pilot project established by the NCI and NHGRI. Information about TCGA and the investigators and institutions who constitute the TCGA research network can be found at http://cancergenome.nih.gov. We acknowledge Jeff Chou for his insight to the details of EPIG and Joel Parker for help with obtaining the TCGA breast cancer subtype information. This research was supported, in part, by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS). NR 37 TC 0 Z9 0 U1 4 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD MAR 22 PY 2016 VL 17 AR 255 DI 10.1186/s12864-016-2584-7 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA DH1KX UT WOS:000372544000005 PM 27004791 ER PT J AU Finkel, TH Li, J Wei, Z Wang, W Zhang, HT Behrens, EM Reuschel, EL Limou, S Wise, C Punaro, M Becker, ML Munro, JE Flato, B Forre, O Thompson, SD Langefeld, CD Glass, DN Glessner, JT Kim, CE Frackelton, E Shivers, DK Thomas, KA Chiavacci, RM Hou, CP Xu, KX Snyder, J Qiu, HJ Mentch, F Wang, K Winkler, CA Lie, BA Ellis, JA Hakonarson, H AF Finkel, Terri H. Li, Jin Wei, Zhi Wang, Wei Zhang, Haitao Behrens, Edward M. Reuschel, Emma L. Limou, Sophie Wise, Carol Punaro, Marilynn Becker, Mara L. Munro, Jane E. Flato, Berit Forre, Oystein Thompson, Susan D. Langefeld, Carl D. Glass, David N. Glessner, Joseph T. Kim, Cecilia E. Frackelton, Edward Shivers, Debra K. Thomas, Kelly A. Chiavacci, Rosetta M. Hou, Cuiping Xu, Kexiang Snyder, James Qiu, Haijun Mentch, Frank Wang, Kai Winkler, Cheryl A. Lie, Benedicte A. Ellis, Justine A. Hakonarson, Hakon TI Variants in CXCR4 associate with juvenile idiopathic arthritis susceptibility SO BMC MEDICAL GENETICS LA English DT Article DE Juvenile idiopathic arthritis; Genome-wide association study; CXCR4; Targeted resequencing ID GENOME-WIDE ASSOCIATION; FIBROBLAST-LIKE SYNOVIOCYTES; RHEUMATOID-ARTHRITIS; GENE-EXPRESSION; AUTOIMMUNE-DISEASES; SEQUENCING DATA; UNITED-STATES; POPULATION; CXCL12; LOCUS AB Background: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease among children, the etiology of which involves a strong genetic component, but much of the underlying genetic determinants still remain unknown. Our aim was to identify novel genetic variants that predispose to JIA. Methods: We performed a genome-wide association study (GWAS) and replication in a total of 1166 JIA cases and 9500 unrelated controls of European ancestry. Correlation of SNP genotype and gene expression was investigated. Then we conducted targeted resequencing of a candidate locus, among a subset of 480 cases and 480 controls. SUM test was performed to evaluate the association of the identified rare functional variants. Results: The CXCR4 locus on 2q22.1 was found to be significantly associated with JIA, peaking at SNP rs953387. However, this result is subjected to subpopulation stratification within the subjects of European ancestry. After adjusting for principal components, nominal significant association remained (p < 10(-4)). Because of its interesting known function in immune regulation, we carried out further analyses to assess its relationship with JIA. Expression of CXCR4 was correlated with CXCR4 rs953387 genotypes in lymphoblastoid cell lines (p = 0.014) and T-cells (p = 0.0054). In addition, rare non-synonymous and stop-gain sequence variants in CXCR4, putatively damaging for CXCR4 function, were significantly enriched in JIA cases (p = 0.015). Conclusion: Our results suggest the association of CXCR4 variants with JIA, implicating that this gene may be involved in the pathogenesis of autoimmune disease. However, because this locus is subjected to population stratification within the subjects of European ancestry, additional replication is still necessary for this locus to be considered a true risk locus for JIA. This cell-surface chemokine receptor has already been targeted in other diseases and may serve as a tractable therapeutic target for a specific subset of pediatric arthritis patients with additional replication and functional validation of the locus. C1 [Finkel, Terri H.; Behrens, Edward M.; Reuschel, Emma L.; Shivers, Debra K.] Childrens Hosp Philadelphia, Div Rheumatol, Philadelphia, PA 19104 USA. [Finkel, Terri H.; Behrens, Edward M.; Reuschel, Emma L.; Hakonarson, Hakon] Univ Penn, Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. [Li, Jin; Zhang, Haitao; Glessner, Joseph T.; Kim, Cecilia E.; Frackelton, Edward; Thomas, Kelly A.; Chiavacci, Rosetta M.; Hou, Cuiping; Xu, Kexiang; Snyder, James; Qiu, Haijun; Mentch, Frank; Wang, Kai; Hakonarson, Hakon] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Wei, Zhi; Wang, Wei] New Jersey Inst Technol, Dept Comp Sci, Newark, NJ 07102 USA. [Limou, Sophie; Winkler, Cheryl A.] NCI, Basic Res Lab, Ctr Canc Res, Leidos Biomed Res Inc,Frederick Natl Lab, Ft Detrick, MD 21702 USA. [Wise, Carol] Texas Scottish Rite Hosp Children, Sarah M & Charles E Seay Ctr Musculoskeletal Res, Dallas, TX 75219 USA. [Punaro, Marilynn] Texas Scottish Rite Hosp Crippled Children, Div Rheumatol, Dallas, TX 75219 USA. [Becker, Mara L.] Childrens Mercy Kansas City, Div Rheumatol, Kansas City, MO 64108 USA. [Munro, Jane E.; Ellis, Justine A.] Murdoch Childrens Res Inst, Parkville, Vic 3052, Australia. [Munro, Jane E.] Royal Childrens Hosp, Paediat Rheumatol Unit, Parkville, Vic 3052, Australia. [Flato, Berit; Forre, Oystein] Natl Hosp Norway, Oslo Univ Hosp, Dept Rheumatol, Oslo, Norway. [Thompson, Susan D.; Glass, David N.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Langefeld, Carl D.] Wake Forest Sch Med, Ctr Publ Hlth Genom, Winston Salem, NC 27157 USA. [Langefeld, Carl D.] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC 27157 USA. [Wang, Kai] UUniv Southern Calif, Dept Psychiat & Behav Sci, Los Angeles, CA 90089 USA. [Lie, Benedicte A.] Natl Hosp Norway, Oslo Univ Hosp, Inst Immunol, N-0027 Oslo, Norway. [Ellis, Justine A.] Univ Melbourne, Dept Paediat, Melbourne, Vic 3010, Australia. [Hakonarson, Hakon] Childrens Hosp Philadelphia, Div Human Genet, Philadelphia, PA 19104 USA. [Hakonarson, Hakon] Nemours Childrens Hosp, Dept Pediat, Nemours Res Inst, Orlando, FL 32827 USA. RP Finkel, TH (reprint author), Childrens Hosp Philadelphia, Div Rheumatol, Philadelphia, PA 19104 USA.; Finkel, TH; Hakonarson, H (reprint author), Univ Penn, Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. EM tfinkel@nemours.org; hakonarson@email.chop.edu FU Institutional Development Funds from The Children's Hospital of Philadelphia [RC1AR058606, U01HG006830]; National Cancer Institute, National Institutes of Health [HHSN26120080001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX We gratefully thank all the children with JIA and their families at the participating study sites who were enrolled in this study and all the control subjects who donated blood samples to the Children's Hospital of Philadelphia (CHOP) for genetic research purposes. We thank the technical staff at the Center for Applied Genomics at CHOP for producing the genotypes used for analyses, and the nursing, medical assistant and medical staff for their help with recruitment of patient and control subjects for the study. This study was supported by Institutional Development Funds from The Children's Hospital of Philadelphia, RC1AR058606 and U01HG006830. The expression work reported in this project was funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E, and by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 52 TC 0 Z9 0 U1 2 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2350 J9 BMC MED GENET JI BMC Med. Genet. PD MAR 22 PY 2016 VL 17 AR 24 DI 10.1186/s12881-016-0285-3 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA DH1WO UT WOS:000372575800001 PM 27005825 ER PT J AU He, FH Wollscheid, HP Nowicka, U Biancospino, M Valentini, E Ehlinger, A Acconcia, F Magistrati, E Polo, S Walters, KJ AF He, Fahu Wollscheid, Hans-Peter Nowicka, Urszula Biancospino, Matteo Valentini, Eleonora Ehlinger, Aaron Acconcia, Filippo Magistrati, Elisa Polo, Simona Walters, Kylie J. TI Myosin VI Contains a Compact Structural Motif that Binds to Ubiquitin Chains SO CELL REPORTS LA English DT Article ID 63-LINKED POLYUBIQUITIN CHAINS; MEDIATED ENDOCYTOSIS; GRISCELLI-SYNDROME; AUTOPHAGY; PROTEINS; DOMAIN; MOTOR; RECOGNITION; MECHANISM; DEAFNESS AB Myosin VI is critical for cargo trafficking and sorting during early endocytosis and autophagosome maturation, and abnormalities in these processes are linked to cancers, neurodegeneration, deafness, and hypertropic cardiomyopathy. We identify a structured domain in myosin VI, myosin VI ubiquitin-binding domain (MyUb), that binds to ubiquitin chains, especially those linked via K63, K11, and K29. Herein, we solve the solution structure of MyUb and MyUb: K63-linked diubiquitin. MyUb folds as a compact helix-turn-helix-like motif and nestles between the ubiquitins of K63-linked diubiquitin, interacting with distinct surfaces of each. A nine-amino-acid extension at the C-terminal helix (Helix2) of MyUb is required for myosin VI interaction with endocytic and autophagic adaptors. Structure-guided mutations revealed that a functional MyUb is necessary for optineurin interaction. In addition, we found that an isoform-specific helix restricts MyUb binding to ubiquitin chains. This work provides fundamental insights into myosin VI interaction with ubiquitinated cargo and functional adaptors. C1 [He, Fahu; Nowicka, Urszula; Walters, Kylie J.] NCI, Prot Proc Sect, Struct Biophys Lab, Ctr Canc Res, Ft Detrick, MD 21702 USA. [Wollscheid, Hans-Peter; Biancospino, Matteo; Valentini, Eleonora; Acconcia, Filippo; Magistrati, Elisa; Polo, Simona] Fdn Ist FIRC Oncol Mol, IFOM, Via Adamello 16, I-20139 Milan, Italy. [Ehlinger, Aaron] Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA. [Polo, Simona] Univ Milan, Dipartimento Oncol & Ematooncol, DIPO, Via Rudini 8, I-20122 Milan, Italy. [Wollscheid, Hans-Peter] Inst Mol Biol, D-55128 Mainz, Germany. [Ehlinger, Aaron] Vanderbilt Univ, Struct Biol Ctr, Nashville, TN 37240 USA. [Acconcia, Filippo] Univ Rome ROMA TRE, I-00154 Rome, Italy. RP Walters, KJ (reprint author), NCI, Prot Proc Sect, Struct Biophys Lab, Ctr Canc Res, Ft Detrick, MD 21702 USA.; Polo, S (reprint author), Fdn Ist FIRC Oncol Mol, IFOM, Via Adamello 16, I-20139 Milan, Italy.; Polo, S (reprint author), Univ Milan, Dipartimento Oncol & Ematooncol, DIPO, Via Rudini 8, I-20122 Milan, Italy. EM simona.polo@ifom.eu; kylie.walters@nih.gov RI Acconcia, Filippo/K-4960-2016; Polo, Simona/P-3509-2014; OI Acconcia, Filippo/0000-0002-4651-2509 FU Intramural Research Program of the NIH, Center for Cancer Research; NIH [CA136472]; Association for International Cancer Research (AICR) [11-0051]; Italian Ministry of Education, Universities and Research (PRIN) [20108MXN2J] FX This research was funded by the Intramural Research Program of the NIH, Center for Cancer Research (to K.J.W.); by a grant from the NIH (CA136472) (to K.J.W.); by the Association for International Cancer Research (AICR, grant 11-0051) (to S.P.); and by the Italian Ministry of Education, Universities and Research (PRIN 20108MXN2J) (to S.P.). We are grateful to Dr. Janusz Koscielniak for his technical assistance with the NMR facility. NR 52 TC 6 Z9 6 U1 1 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD MAR 22 PY 2016 VL 14 IS 11 BP 2683 EP 2694 DI 10.1016/j.celrep.2016.01.079 PG 12 WC Cell Biology SC Cell Biology GA DH0UG UT WOS:000372499000017 PM 26971995 ER PT J AU Covacu, R Philip, H Jaronen, M Almeida, J Kenison, JE Darko, S Chao, CC Yaari, G Louzoun, Y Carmel, L Douek, DC Efroni, S Quintana, FJ AF Covacu, Ruxandra Philip, Hagit Jaronen, Merja Almeida, Jorge Kenison, Jessica E. Darko, Samuel Chao, Chun-Cheih Yaari, Gur Louzoun, Yoram Carmel, Liran Douek, Daniel C. Efroni, Sol Quintana, Francisco J. TI System-wide Analysis of the T Cell Response SO CELL REPORTS LA English DT Article ID ZEBRAFISH ANTIBODY REPERTOIRE; ANTIGEN RECEPTOR; CONVERGENT RECOMBINATION; IMMUNE-SYSTEM; GENE REARRANGEMENTS; ALPHA-CHAIN; INFECTION; RECOGNITION; DIVERSITY; SELECTION AB The T cell receptor (TCR) controls the cellular adaptive immune response to antigens, but our understanding of TCR repertoire diversity and response to challenge is still incomplete. For example, TCR clones shared by different individuals with minimal alteration to germline gene sequences (public clones) are detectable in all vertebrates, but their significance is unknown. Although small in size, the zebrafish TCR repertoire is controlled by processes similar to those operating in mammals. Thus, we studied the zebrafish TCR repertoire and its response to stimulation with self and foreign antigens. We found that cross-reactive public TCRs dominate the T cell response, endowing a limited TCR repertoire with the ability to cope with diverse antigenic challenges. These features of vertebrate public TCRs might provide a mechanism for the rapid generation of protective T cell immunity, allowing a short temporal window for the development of more specific private T cell responses. C1 [Covacu, Ruxandra; Jaronen, Merja; Kenison, Jessica E.; Chao, Chun-Cheih; Quintana, Francisco J.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ann Romney Ctr Neurol Dis, 77 Ave Louis Pasteur, Boston, MA 02115 USA. [Philip, Hagit; Efroni, Sol] Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, IL-52900 Ramat Gan, Israel. [Almeida, Jorge; Darko, Samuel; Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, US NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Yaari, Gur] Bar Ilan Univ, Fac Engn, Bioengn Program, IL-52900 Ramat Gan, Israel. [Louzoun, Yoram] Bar Ilan Univ, Dept Math, IL-52900 Ramat Gan, Israel. [Louzoun, Yoram] Bar Ilan Univ, Gonda Brain Res Ctr, IL-52900 Ramat Gan, Israel. [Carmel, Liran] Hebrew Univ Jerusalem, Fac Sci, Alexander Silberman Inst Life Sci, Dept Genet, Edmond J Safra Campus, IL-91904 Jerusalem, Israel. [Quintana, Francisco J.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. RP Quintana, FJ (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Ann Romney Ctr Neurol Dis, 77 Ave Louis Pasteur, Boston, MA 02115 USA.; Efroni, S (reprint author), Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, IL-52900 Ramat Gan, Israel.; Douek, DC (reprint author), NIAID, Human Immunol Sect, Vaccine Res Ctr, US NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.; Quintana, FJ (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. EM ddouek@mail.nih.gov; sol.efroni@biu.ac.il; fquintana@rics.bwh.harvard.edu FU NIH [AI075285, AI093903]; Harry Weaver Scholar Award; National Multiple Sclerosis Society [RG4111A1]; BSF [2011154]; Swedish Research Council; Sigrid Juselius fellowship; Paulo Foundation; Finnish Multiple Sclerosis Foundation; Orion-Farmos Research Foundation; Saastamoinen Foundation; intramural program of the National Institute of Allergy and Infectious Diseases, NIH FX This work was supported by grants AI075285 and AI093903 from the NIH and a Harry Weaver Scholar Award and grant RG4111A1 from the National Multiple Sclerosis Society to F.J.Q. and grant 2011154 from the BSF to F.J.Q. and S.E. F.J.Q. thanks Maria Ethel del Aguila for useful discussions and support. R.C. is supported by a postdoctoral fellowship from the Swedish Research Council. M.J. is supported by a Sigrid Juselius fellowship, The Paulo Foundation, The Finnish Multiple Sclerosis Foundation, Orion-Farmos Research Foundation, and the Saastamoinen Foundation. This work was funded in part through the intramural program of the National Institute of Allergy and Infectious Diseases, NIH. NR 62 TC 1 Z9 1 U1 3 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD MAR 22 PY 2016 VL 14 IS 11 BP 2733 EP 2744 DI 10.1016/j.celrep.2016.02.056 PG 12 WC Cell Biology SC Cell Biology GA DH0UG UT WOS:000372499000021 PM 26972015 ER PT J AU Fontana, M Pica, S Reant, P Abdel-Gadir, A Treibel, TA Banypersad, SM Maestrini, V Barcella, W Rosmini, S Bulluck, H Sayed, RH Patel, K Mamhood, S Bucciarelli-Ducci, C Whelan, CJ Herrey, AS Lachmann, HJ Wechalekar, AD Manisty, CH Schelbert, EB Kellman, P Gillmore, JD Hawkins, PN Moon, JC AF Fontana, Marianna Pica, Silvia Reant, Patricia Abdel-Gadir, Amna Treibel, Thomas A. Banypersad, Sanjay M. Maestrini, Viviana Barcella, William Rosmini, Stefania Bulluck, Heerajnarain Sayed, Rabya H. Patel, Ketna Mamhood, Shameem Bucciarelli-Ducci, Chiara Whelan, Carol J. Herrey, Anna S. Lachmann, Helen J. Wechalekar, Ashutosh D. Manisty, Charlotte H. Schelbert, Eric B. Kellman, Peter Gillmore, Julian D. Hawkins, Philip N. Moon, James C. TI Response to Letters Regarding Article, "Prognostic Value of Late Gadolinium Enhancement Cardiovascular Magnetic Resonance in Cardiac Amyloidosis" SO CIRCULATION LA English DT Letter C1 [Fontana, Marianna; Pica, Silvia; Reant, Patricia; Abdel-Gadir, Amna; Treibel, Thomas A.; Banypersad, Sanjay M.; Maestrini, Viviana; Barcella, William; Rosmini, Stefania; Bulluck, Heerajnarain; Herrey, Anna S.; Manisty, Charlotte H.; Moon, James C.] Heart Hosp, London, England. [Sayed, Rabya H.; Patel, Ketna; Mamhood, Shameem; Whelan, Carol J.; Lachmann, Helen J.; Wechalekar, Ashutosh D.; Gillmore, Julian D.; Hawkins, Philip N.] UCL, Natl Amyloidosis Ctr, Royal Free Hosp, London, England. [Bucciarelli-Ducci, Chiara] Univ Bristol, Bristol Heart Inst, Bristol, Avon, England. [Schelbert, Eric B.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Kellman, Peter] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Fontana, M (reprint author), Heart Hosp, London, England. OI moon, james/0000-0001-8071-1491; Bulluck, Heerajnarain/0000-0002-1985-1783; Bucciarelli-Ducci, Chiara/0000-0002-2515-0852 FU British Heart Foundation [FS/10/40/28260, FS/12/ 56/29723, FS/12/56/29723]; Department of Health [, DRF-2013-06-102]; Intramural NIH HHS [Z99 HL999999] NR 7 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 22 PY 2016 VL 133 IS 12 BP E450 EP E451 DI 10.1161/CIRCULATIONAHA.116.021162 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DG9ME UT WOS:000372406300006 PM 27002091 ER PT J AU Brooks, DLP Schwab, LP Krutilina, R Parke, DN Sethuraman, A Hoogewijs, D Schorg, A Gotwald, L Fan, MY Wenger, RH Seagroves, TN AF Brooks, Danielle L. Peacock Schwab, Luciana P. Krutilina, Raisa Parke, Deanna N. Sethuraman, Aarti Hoogewijs, David Schoerg, Alexandra Gotwald, Lauren Fan, Meiyun Wenger, Roland H. Seagroves, Tiffany N. TI ITGA6 is directly regulated by hypoxia-inducible factors and enriches for cancer stem cell activity and invasion in metastatic breast cancer models SO MOLECULAR CANCER LA English DT Article DE Hypoxia; Hypoxia-inducible factor (HIF); Breast cancer; CD49f; Cancer stem cells (CSC); Invasion; Metastasis ID EXTRACELLULAR-MATRIX; ALPHA-6 INTEGRIN; IX EXPRESSION; TUMOR HYPOXIA; SUBUNIT GENE; GROWTH; CARCINOMA; IDENTIFICATION; LINES; MECHANISMS AB Background: Hypoxia-inducible factors (HIFs) are well-established mediators of tumor growth, the epithelial to mesenchymal transition (EMT) and metastasis. In several types of solid tumors, including breast cancers, the HIFs play a critical role in maintaining cancer stem cell (CSC) activity. Thus, we hypothesized that HIFs may also regulate transcription of markers of breast CSC activity. One approach to enrich for breast cells with stem-like phenotypes is FACS sorting, in which sub-populations of live cells are gated based on the expression of cell surface antigens, including various integrin subunits. Integrin alpha 6 (ITGA6; CD49f) is routinely used in combination with other integrin subunits to enrich for breast stem cells by FACS. Integrins not only mediate interactions with the extracellular matrix (ECM), but also drive intracellular signaling events that communicate from the tumor microenvironment to inside of the tumor cell to alter phenotypes including migration and invasion. Methods: We used two models of metastatic breast cancer (MBC), polyoma middle T (MMTV-PyMT) and MDA-MB-231 cells, to compare the expression of ITGA6 in wild type and knockout (KO) or knockdown cells. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays verified that ITGA6 is a direct HIF transcriptional target. We also used FACS sorting to enrich for CD49f(+) cells to compare tumorsphere formation, tumor initiating cell activity, invasion and HIF activity relative to CD49f(neg) (or) (low) cells. Knockdown of ITGA6 significantly reduced invasion, whereas re-expression of ITGA6 in the context of HIF knockdown partially rescued invasion. A search of public databases also revealed that ITGA6 expression is an independent prognostic factor of survival in breast cancer patients. Results: We report that ITGA6 is a HIF-dependent target gene and that high ITGA6 expression enhances invasion and tumor-initiating cell activities in models of MBC. Moreover, cells that express high levels of ITGA6 are enriched for HIF-1 alpha expression and the expression of HIF-dependent target genes. Conclusions: Our data suggest that HIF-dependent regulation of ITGA6 is one mechanism by which sorting for CD49f (+) cells enhances CSC and metastatic phenotypes in breast cancers. Our results are particularly relevant to basal-like breast cancers which express higher levels of the HIF alpha subunits, core HIF-dependent target genes and ITGA6 relative to other molecular subtypes. C1 [Brooks, Danielle L. Peacock; Schwab, Luciana P.; Krutilina, Raisa; Parke, Deanna N.; Sethuraman, Aarti; Gotwald, Lauren; Fan, Meiyun; Seagroves, Tiffany N.] Univ Tennessee, Hlth Sci Ctr, Ctr Canc Res, Memphis, TN 38163 USA. [Brooks, Danielle L. Peacock; Schwab, Luciana P.; Krutilina, Raisa; Parke, Deanna N.; Sethuraman, Aarti; Gotwald, Lauren; Fan, Meiyun; Seagroves, Tiffany N.] Univ Tennessee, Hlth Sci Ctr, Dept Pathol & Lab Med, Memphis, TN 38163 USA. [Hoogewijs, David; Schoerg, Alexandra; Wenger, Roland H.] Univ Zurich, Inst Physiol, CH-8057 Zurich, Switzerland. [Hoogewijs, David; Schoerg, Alexandra; Wenger, Roland H.] Univ Zurich, Zurich Ctr Integrat Human Physiol, CH-8057 Zurich, Switzerland. [Brooks, Danielle L. Peacock] NCI, Ctr Canc Res, Womens Malignancies Branch, Bethesda, MD 20892 USA. [Hoogewijs, David] Univ Duisburg Essen, Inst Physiol, D-45122 Essen, Germany. RP Seagroves, TN (reprint author), Univ Tennessee, Hlth Sci Ctr, Ctr Canc Res, Memphis, TN 38163 USA.; Seagroves, TN (reprint author), Univ Tennessee, Hlth Sci Ctr, Dept Pathol & Lab Med, Memphis, TN 38163 USA. EM tseagro1@uthsc.edu RI Hoogewijs, David/L-5144-2016 FU NCI [CA138488]; Department of Defense [BC083846]; West Cancer Center in Memphis, TN; Swiss National Science Foundation grant [31003A_146203] FX This work was supported by the NCI (CA138488, L.P.S., D.L.P., T.N.S.), the Department of Defense (BC083846, D.L.P., T.N.S.), a pilot project award from The West Cancer Center in Memphis, TN (to T.N.S.) and a Swiss National Science Foundation grant (31003A_146203 to R.H.W.). None of the funding bodies played a role in data collection, analysis or interpretation of data, in the writing of the manuscript, or the decision to submit the manuscript for publication. We thank Dr. Dan Rosson and Dr. Tony Marion of the UTHSC Flow Cytometry and Cell Sorting Core for expert technical assistance. These studies were also supported by resources maintained at the Molecular Resource Center of Excellence core facility at UTHSC and the Cancer Research Building confocal microscopy core managed by Ms. Michelle Sims. NR 79 TC 3 Z9 3 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-4598 J9 MOL CANCER JI Mol. Cancer PD MAR 22 PY 2016 VL 15 AR 26 DI 10.1186/s12943-016-0510-x PG 19 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA DH1MK UT WOS:000372548200001 PM 27001172 ER PT J AU Hammamieh, R Muhie, S Borschel, R Gautam, A Miller, SA Chakraborty, N Jett, M AF Hammamieh, Rasha Muhie, Seid Borschel, Richard Gautam, Aarti Miller, Stacy-Ann Chakraborty, Nabarun Jett, Marti TI Temporal Progression of Pneumonic Plague in Blood of Nonhuman Primate: A Transcriptomic Analysis SO PLOS ONE LA English DT Article ID YERSINIA-PESTIS CO92; TOLL-LIKE RECEPTORS; MOUSE MODEL; KAPPA-B; BIOLOGICAL AGENTS; IMMUNE-RESPONSE; INNATE IMMUNITY; BUBONIC PLAGUE; INFECTION; EXPRESSION AB Early identification of impending illness during widespread exposure to a pathogenic agent offers a potential means to initiate treatment during a timeframe when it would be most likely to be effective and has the potential to identify novel therapeutic strategies. The latter could be critical, especially as antibiotic resistance is becoming widespread. In order to examine pre-symptomatic illness, African green monkeys were challenged intranasally with aerosolized Yersinia pestis strain CO92 and blood samples were collected in short intervals from 45 m till 42 h post-exposure. Presenting one of the first genomic investigations of a NHP model challenged by pneumonic plague, whole genome analysis was annotated in silico and validated by qPCR assay. Transcriptomic profiles of blood showed early perturbation with the number of differentially expressed genes increasing until 24 h. By then, Y. pestis had paralyzed the host defense, as suggested by the functional analyses. Early activation of the apoptotic networks possibly facilitated the pathogen to overwhelm the defense mechanisms, despite the activation of the pro-inflammatory mechanism, toll-like receptors and microtubules at the port-of-entry. The overexpressed transcripts encoding an early pro-inflammatory response particularly manifested in active lymphocytes and ubiquitin networks were a potential deviation from the rodent models, which needs further verification. In summary, the present study recognized a pattern of Y. pestis pathogenesis potentially more applicable to the human system. Independent validation using the complementary omics approach with comprehensive evaluation of the organs, such as lungs which showed early bacterial infection, is essential. C1 [Hammamieh, Rasha; Muhie, Seid; Gautam, Aarti; Miller, Stacy-Ann; Chakraborty, Nabarun; Jett, Marti] US Army Ctr Environm Hlth Res, Ft Detrick, MD 21702 USA. [Muhie, Seid] NCI, Adv Biomed Ctr, Fredrick Natl Lab Canc Res, Frederick, MD 21702 USA. [Borschel, Richard] Walter Reed Army Med Ctr, Silver Spring, MD 20910 USA. [Gautam, Aarti; Miller, Stacy-Ann; Chakraborty, Nabarun] Geneva Fdn, Ft Detrick, MD 21702 USA. RP Hammamieh, R (reprint author), US Army Ctr Environm Hlth Res, Ft Detrick, MD 21702 USA. EM Rasha.Hammamieh1.civ@mail.mil FU Defense Threat Reduction Agency [TMTI0029_09_WR_T] FX This work was supported by Defense Threat Reduction Agency, Funding #: TMTI0029_09_WR_T received by: MJ and RH. NR 59 TC 1 Z9 1 U1 3 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 22 PY 2016 VL 11 IS 3 AR e0151788 DI 10.1371/journal.pone.0151788 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH3OX UT WOS:000372697400043 PM 27003632 ER PT J AU Kugelman, JR Rossi, CA Wiley, MR Ladner, JT Nagle, ER Pfeffer, BP Garcia, K Prieto, K Wada, J Kuhn, JH Palacios, G AF Kugelman, Jeffrey R. Rossi, Cynthia A. Wiley, Michael R. Ladner, Jason T. Nagle, Elyse R. Pfeffer, Bradley P. Garcia, Karla Prieto, Karla Wada, Jiro Kuhn, Jens H. Palacios, Gustavo TI Informing the Historical Record of Experimental Nonhuman Primate Infections with Ebola Virus: Genomic Characterization of USAMRIID Ebola Virus/H.sapiens-tc/COD/1995/Kikwit-9510621 Challenge Stock "R4368" and Its Replacement "R4415" SO PLOS ONE LA English DT Article ID FILOVIRUS MEDICAL COUNTERMEASURES; SMALL GLYCOPROTEIN SGP; VARIANTS; RNA; NOMENCLATURE; GUINEA; NAMES AB The creation of licensed medical countermeasures against Select Agents such as Ebola virus (EBOV) is critically dependent on the use of standardized reagents, assays, and animal models. We performed full genome reconstruction, population genomics, contaminant analysis, and characterization of the glycoprotein gene editing site of historical United States Army Medical Research Institute of Infectious Diseases (USAMRIID) nonhuman-primate challenge stock Ebola virus Kikwit "R4368" and its 2014 replacement "R4415." We also provide characterization of the master stock used to create "R4415." The obtained data are essential to understanding the quality of the seed stock reagents used in pivotal animal studies that have been used to inform medical countermeasure development. Furthermore, these data might add to the understanding of the influence of EBOV variant populations on pathogenesis and disease outcome and inform attempts to avoid the evolution of EBOV escape mutants in response to current therapeutics. Finally, as the primary challenge stocks have changed over time, these data will provide a baseline for understanding and correlating past and future animal study results. C1 [Kugelman, Jeffrey R.; Rossi, Cynthia A.; Wiley, Michael R.; Ladner, Jason T.; Nagle, Elyse R.; Pfeffer, Bradley P.; Garcia, Karla; Prieto, Karla; Palacios, Gustavo] USAMRIID, Frederick, MD USA. [Wada, Jiro; Kuhn, Jens H.] NIAID, Integrated Res Facil Ft Detrick IRF Frederick, NIH, Frederick, MD USA. RP Palacios, G (reprint author), USAMRIID, Frederick, MD USA. EM gustavo.f.palacios.ctr@mail.mil OI Palacios, Gustavo/0000-0001-5062-1938 FU Battelle Memorial Institute; US National Institute of Allergy and Infectious Diseases (NIAID) [HHSN272200700016I] FX The content of this publication does not necessarily reflect the views or policies of the US Department of Defense, the US Department of Health and Human Services, the US Department of the Army, or the institutions and companies affiliated with the authors. This work was funded in part through Battelle Memorial Institute's prime contract with the US National Institute of Allergy and Infectious Diseases (NIAID) under Contract No. HHSN272200700016I (J.H.K.). A subcontractor to Battelle Memorial Institute who performed this work is: J.H.K, an employee of Tunnell Government Services, Inc. Tunnell Government Services provided support in the form of salaries, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. All work under contract HHSN272200700016I is performed under the agreement/understanding that it will belong to the client and will be affiliated directly to the NIH/NIAID Integrated Research Facility at Fort Detrick. The specific roles of these authors are articulated in the 'author contributions' section. NR 28 TC 1 Z9 1 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 22 PY 2016 VL 11 IS 3 AR e0150919 DI 10.1371/journal.pone.0150919 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH3OX UT WOS:000372697400022 PM 27002733 ER PT J AU Best, RB Hummer, G AF Best, Robert B. Hummer, Gerhard TI Microscopic interpretation of folding phi-values using the transition path ensemble SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE protein engineering; parallel pathways; Villin HP35; GTT WW domain; NuG2 ID MOLECULAR-DYNAMICS; FORCE-FIELDS; CHYMOTRYPSIN INHIBITOR-2; PROTEIN; STATE; SIMULATIONS; KINETICS; RATES; MICROSECONDS; NANOSECONDS AB All-atom molecular dynamics simulations now allow us to create movies of proteins folding and unfolding. However, it is difficult to assess the accuracy of the folding mechanisms observed because experiments cannot yet directly resolve events occurring along the transition paths between unfolded and folded states. Protein folding.-values provide residue-resolved information about folding mechanisms by comparing the effects of mutations on folding rates and stability, but determining.-values by separately simulating mutant proteins would be computationally demanding and prone to large statistical errors. Here we use transition path theory to develop a method for computing phi-values directly from the transition path ensemble, without the need for additional simulations. This path-based approach uses the full transition path information available from equilibrium folding and unfolding trajectories, or from transition path sampling, and does not require identification of folding transition states. Applying our approach to a set of simulations of 10 small proteins by Shaw and coworkers [Lindorff-Larsen K, Piana S, Dror RO, Shaw DE (2011) Science 334(6055): 517-520; Piana S, Lindorff-Larsen K, Shaw DE (2011) Biophys J 100(9): L47-L49; and Piana S, Lindorff-Larsen K, Shaw DE (2013) Proc Natl Acad Sci USA 110(15): 5915-5920], we find good agreement with experiments in most cases where data are available. We can further resolve the contributions to fractional.-values coming from partial contact formation versus transition path heterogeneity. Although in some cases, there is substantial heterogeneity of folding mechanism, in others, such as Ubiquitin, the mechanism is strongly conserved. C1 [Best, Robert B.] NIDDK, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. [Hummer, Gerhard] Max Planck Inst Biophys, Dept Theoret Biophys, D-60438 Frankfurt, Germany. RP Best, RB (reprint author), NIDDK, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA.; Hummer, G (reprint author), Max Planck Inst Biophys, Dept Theoret Biophys, D-60438 Frankfurt, Germany. EM robertbe@helix.nih.gov; gehummer@biophys.mpg.de RI Hummer, Gerhard/A-2546-2013; Best, Robert/H-7588-2016 OI Hummer, Gerhard/0000-0001-7768-746X; Best, Robert/0000-0002-7893-3543 FU National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health; Max Planck Society FX R.B.B. was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. G. H. was supported by the Max Planck Society. This work utilized the computational resources of the NIH High-Performance Computing Biowulf cluster (https://hpc.nih.gov). NR 62 TC 4 Z9 4 U1 7 U2 24 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 22 PY 2016 VL 113 IS 12 BP 3263 EP 3268 DI 10.1073/pnas.1520864113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH0QH UT WOS:000372488200051 PM 26957599 ER PT J AU Ma, XR Xu, LY Mueller, E AF Ma, Xinran Xu, Lingyan Mueller, Elisabetta TI Forkhead box A3 mediates glucocorticoid receptor function in adipose tissue SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Foxa3; GR signaling; dexamethasone; fat expansion; adipose tissue ID REGULATES ADIPOCYTE DIFFERENTIATION; DIET-INDUCED OBESITY; GENE-EXPRESSION; TRANSCRIPTIONAL RESPONSE; CHROMATIN ACCESSIBILITY; METABOLIC SYNDROME; FOOD-INTAKE; BODY-FAT; BINDING; MICE AB Glucocorticoids (GCs) are widely prescribed anti-inflammatory agents, but their chronic use leads to undesirable side effects such as excessive expansion of adipose tissue. We have recently shown that the forkhead box protein A3 (Foxa3) is a calorie-hoarding factor that regulates the selective enlargement of epididymal fat depots and suppresses energy expenditure in a nutritional-and age-dependent manner. It has been demonstrated that Foxa3 levels are elevated in adipose depots in response to high-fat diet regimens and during the aging process; however no studies to date have elucidated the mechanisms that control Foxa3's expression in fat. Given the established effects of GCs in increasing visceral adiposity and in reducing thermogenesis, we assessed the existence of a possible link between GCs and Foxa3. Computational prediction analysis combined with molecular studies revealed that Foxa3 is regulated by the glucocorticoid receptor (GR) in preadipocytes, adipocytes, and adipose tissues and is required to facilitate the binding of the GR to its target gene promoters in fat depots. Analysis of the long-term effects of dexamethasone treatment in mice revealed that Foxa3 ablation protects mice specifically against fat accretion but not against other pathological side effects elicited by this synthetic GC in tissues such as liver, muscle, and spleen. In conclusion our studies provide the first demonstration, to our knowledge, that Foxa3 is a direct target of GC action in adipose tissues and point to a role of Foxa3 as a mediator of the side effects induced in fat tissues by chronic treatment with synthetic steroids. C1 [Ma, Xinran; Xu, Lingyan; Mueller, Elisabetta] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Mueller, E (reprint author), NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. EM elisabettam@niddk.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health FX We thank Pasha Sarraf for discussions and comments on the manuscript. This research was supported by the Intramural Research Program of The National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. NR 50 TC 0 Z9 0 U1 4 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 22 PY 2016 VL 113 IS 12 BP 3377 EP 3382 DI 10.1073/pnas.1601281113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH0QH UT WOS:000372488200070 PM 26957608 ER PT J AU Bai, RL Stewart, CV Plenz, D Basser, PJ AF Bai, Ruiliang Stewart, Craig V. Plenz, Dietmar Basser, Peter J. TI Assessing the sensitivity of diffusion MRI to detect neuronal activity directly SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE diffusion MRI; functional; neuronal activity; organotypic culture; intracellular calcium ID CORTEX-STRIATUM COCULTURES; RAPID STRUCTURAL-CHANGES; HEALTHY RAT-BRAIN; HIGH B-VALUE; HIPPOCAMPAL SLICE; WATER DIFFUSION; IN-VITRO; NERVE-FIBERS; SENSORY STIMULATION; CEREBRAL-ISCHEMIA AB Functional MRI (fMRI) is widely used to study brain function in the neurosciences. Unfortunately, conventional fMRI only indirectly assesses neuronal activity via hemodynamic coupling. Diffusion fMRI was proposed as a more direct and accurate fMRI method to detect neuronal activity, yet confirmative findings have proven difficult to obtain. Given that the underlying relation between tissue water diffusion changes and neuronal activity remains unclear, the rationale for using diffusion MRI to monitor neuronal activity has yet to be clearly established. Here, we studied the correlation between water diffusion and neuronal activity in vitro by simultaneous calcium fluorescence imaging and diffusion MR acquisition. We used organotypic cortical cultures from rat brains as a biological model system, in which spontaneous neuronal activity robustly emerges free of hemodynamic and other artifacts. Simultaneous fluorescent calcium images of neuronal activity are then directly correlated with diffusion MR signals now free of confounds typically encountered in vivo. Although a simultaneous increase of diffusion-weighted MR signals was observed together with the prolonged depolarization of neurons induced by pharmacological manipulations (in which cell swelling was demonstrated to play an important role), no evidence was found that diffusion MR signals directly correlate with normal spontaneous neuronal activity. These results suggest that, whereas current diffusion MR methods could monitor pathological conditions such as hyperexcitability, e.g., those seen in epilepsy, they do not appear to be sensitive or specific enough to detect or follow normal neuronal activity. C1 [Bai, Ruiliang; Basser, Peter J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Quantitat Imaging & Tissue Sci, Div Imaging Behav & Genom Integr, NIH, Bethesda, MD 20892 USA. [Bai, Ruiliang] Univ Maryland, Inst Phys Sci & Technol, Biophys Program, College Pk, MD 20740 USA. [Stewart, Craig V.; Plenz, Dietmar] NIMH, Sect Crit Brain Dynam, Lab Syst Neurosci, NIH, Bethesda, MD 20892 USA. RP Basser, PJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Quantitat Imaging & Tissue Sci, Div Imaging Behav & Genom Integr, NIH, Bethesda, MD 20892 USA. EM pjbasser@helix.nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH FX We thank Prof. Robert M. Briber (University of Maryland) for lively discussions and helpful suggestions; Drs. Andreas Klaus, Timothy Bellay, and Hellmut Merkle (National Institutes of Health) and Dr. Uri Nevo (Tel-Aviv University) for help in setting up the hybrid test system; Dr. Sinisa Pajevic (Center for Information Technology, NIH) for useful discussions about time series analysis; our colleague Dr. Carlo Pierpaoli for insightful comments; and Ms. Liz Salak for editing the manuscript. This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. NR 72 TC 1 Z9 1 U1 5 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 MAR 22 PY 2016 VL 113 IS 12 BP E1728 EP E1737 DI 10.1073/pnas.1519890113 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH0QH UT WOS:000372488200019 PM 26941239 ER PT J AU Breckwoldt, MO Armoundas, AA Aon, MA Bendszus, M O'Rourke, B Schwarzlander, M Dick, TP Kurz, FT AF Breckwoldt, Michael O. Armoundas, Antonis A. Aon, Miguel A. Bendszus, Martin O'Rourke, Brian Schwarzlaender, Markus Dick, Tobias P. Kurz, Felix T. TI Mitochondrial redox and pH signaling occurs in axonal and synaptic organelle clusters SO SCIENTIFIC REPORTS LA English DT Article ID CARDIAC MYOCYTES; IN-VIVO; INDIVIDUAL MITOCHONDRIA; NEUROMUSCULAR-JUNCTIONS; SUPEROXIDE FLASHES; OSCILLATIONS; HEART; WAVES; ARABIDOPSIS; METABOLISM C1 [Breckwoldt, Michael O.; Bendszus, Martin; Kurz, Felix T.] Heidelberg Univ, Dept Neuroradiol, Neuenheimer Feld 400, D-69120 Heidelberg, Germany. [Armoundas, Antonis A.; Kurz, Felix T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. [Aon, Miguel A.; O'Rourke, Brian] Johns Hopkins Univ, Dept Med, Div Cardiol, Baltimore, MD USA. [Aon, Miguel A.] NIA, Lab Cardiovasc Sci, Baltimore, MD 21224 USA. [Schwarzlaender, Markus] Univ Bonn, Inst Crop Sci & Resource Conservat INRES, Friedrich Ebert Allee 144, D-53113 Bonn, Germany. [Dick, Tobias P.] DKFZ ZMBH Alliance, Div Redox Regulat, German Canc Res Ctr DKFZ, Neuenheimer Feld 280, D-69120 Heidelberg, Germany. RP Breckwoldt, MO; Kurz, FT (reprint author), Heidelberg Univ, Dept Neuroradiol, Neuenheimer Feld 400, D-69120 Heidelberg, Germany.; Kurz, FT (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. EM michael.breckwoldt@med.uni-heidelberg.de; felix.kurz@med.uni-heidelberg.de RI Aon, Miguel/A-6564-2008 OI Aon, Miguel/0000-0002-4355-5431 FU physician-scientist fellowship of the Medical Faculty, University of Heidelberg; Hoffmann-Klose Foundation (University of Heidelberg); DFG through the Emmy Noether-Program [SCHW1719/1-1]; DFG Priority Program "Dynamics of thiol-based redox switches in cellular physiology" [SPP1710] FX We thank T. Misgeld (TU Munich) and M. Kerschensteiner (LMU Munich) for the support of this research and the critical discussion of the manuscript. We acknowledge experimental help by F. Bareyre, P. Bradley, A. Schmalz (LMU Munich) and L. Godinho and F. Pfister (TU Munich). We thank M. Murphy (University of Cambridge) for the kind gift of MitoQ and N. Demaurex (University of Geneva) for providing the SypHer construct. M.O.B. and F.T.K. were supported by a physician-scientist fellowship of the Medical Faculty, University of Heidelberg and by the Hoffmann-Klose Foundation (University of Heidelberg). M.O.B. was supported by a Neurowind e.V. prize for experimental neurology. M.S. is grateful for funding by the DFG through the Emmy Noether-Program (SCHW1719/1-1). M.S. and T.P.D. are supported by the DFG Priority Program "Dynamics of thiol-based redox switches in cellular physiology" (SPP1710). NR 48 TC 2 Z9 2 U1 3 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAR 22 PY 2016 VL 6 AR 23251 DI 10.1038/srep23251 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH0UM UT WOS:000372499600001 PM 27000952 ER PT J AU Keswani, RK Tian, C Peryea, T Girish, G Wang, XD Rosania, GR AF Keswani, Rahul K. Tian, Chao Peryea, Tyler Girish, Gandikota Wang, Xueding Rosania, Gus R. TI Repositioning Clofazimine as a Macrophage-Targeting Photoacoustic Contrast Agent SO SCIENTIFIC REPORTS LA English DT Article ID RHEUMATOID-ARTHRITIS; INFLAMMATION; MICROSCOPY; DISEASE; ATHEROSCLEROSIS; NANOPARTICLES; PHARMACOLOGY; BIOCRYSTALS; TOMOGRAPHY; THERAPY AB Photoacoustic Tomography (PAT) is a deep-tissue imaging modality, with potential clinical applications in the diagnosis of arthritis, cancer and other disease conditions. Here, we identified Clofazimine (CFZ), a red-pigmented dye and anti-inflammatory FDA-approved drug, as a macrophage-targeting photoacoustic (PA) imaging agent. Spectroscopic experiments revealed that CFZ and its various protonated forms yielded optimal PAT signals at wavelengths -450 to 540 nm. CFZ's macrophage-targeting chemical and structural forms were detected with PA microscopy at a high contrast-to-noise ratio (CNR > 22 dB) as well as with macroscopic imaging using synthetic gelatin phantoms. In vivo, natural and synthetic CFZ formulations also demonstrated significant anti-inflammatory activity. Finally, the injection of CFZ was monitored via a real-time ultrasound-photoacoustic (US-PA) dual imaging system in a live animal and clinically relevant human hand model. These results demonstrate an anti-inflammatory drug repurposing strategy, while identifying a new PA contrast agent with potential applications in the diagnosis and treatment of arthritis. C1 [Keswani, Rahul K.; Rosania, Gus R.] Univ Michigan, Dept Pharmaceut Sci, Coll Pharm, Ann Arbor, MI 48109 USA. [Tian, Chao; Girish, Gandikota; Wang, Xueding] Univ Michigan, Dept Radiol, Ann Arbor, MI 48109 USA. [Tian, Chao; Wang, Xueding] Univ Michigan, Dept Biomed Engn, Ann Arbor, MI 48109 USA. [Peryea, Tyler] NIH, NCATS, Rockville, MD 20850 USA. RP Rosania, GR (reprint author), Univ Michigan, Dept Pharmaceut Sci, Coll Pharm, Ann Arbor, MI 48109 USA.; Wang, XD (reprint author), Univ Michigan, Dept Radiol, Ann Arbor, MI 48109 USA.; Wang, XD (reprint author), Univ Michigan, Dept Biomed Engn, Ann Arbor, MI 48109 USA. EM xdwang@umich.edu; grosania@umich.edu FU National Institute of General Medical Sciences (NIGMS) [R01GM078200]; National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [R01AR060350]; Michigan Institute for Clinical and Health Research FX We thank the Anatomical Donation Program at the University of Michigan for providing the cadaver tissue; Dr. Guan Xu, Department of Radiology and Sudha Sud, Dr. Gi Sang Yoon, Mumta Kadir, Department of Pharmaceutical Sciences at the University of Michigan for help with animal and cadaver experiments and Dr. Kathleen Stringer, Department of Clinical Pharmacy, University of Michigan for help with data analyses. This work was supported by the National Institute of General Medical Sciences (NIGMS; R01GM078200 to GRR), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS; R01AR060350 to XW) and the Michigan Institute for Clinical and Health Research (Pilot Project grant to RKK and GRR). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. NR 60 TC 3 Z9 3 U1 2 U2 13 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAR 22 PY 2016 VL 6 AR 23528 DI 10.1038/srep23528 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH1WQ UT WOS:000372576000001 PM 27000434 ER PT J AU Ribeiro, TL Ribeiro, S Copelli, M AF Ribeiro, Tiago L. Ribeiro, Sidarta Copelli, Mauro TI Repertoires of Spike Avalanches Are Modulated by Behavior and Novelty SO FRONTIERS IN NEURAL CIRCUITS LA English DT Article DE avalanches; spikes; patterns; criticality; memory; novelty; sleep ID ACTIVITY IN-VIVO; NEURONAL AVALANCHES; CORTICAL NETWORKS; ACTIVITY PATTERNS; VISUAL-CORTEX; DYNAMICS; CRITICALITY; RANGE; SLEEP; REACTIVATION AB Neuronal avalanches measured as consecutive bouts of thresholded field potentials represent a statistical signature that the brain operates near a critical point. In theory, criticality optimizes stimulus sensitivity, information transmission, computational capability and mnemonic repertoires size. Field potential avalanches recorded via multielectrode arrays from cortical slice cultures are repeatable spatiotemporal activity patterns. It remains unclear whether avalanches of action potentials observed in forebrain regions of freely-behaving rats also form recursive repertoires, and whether these have any behavioral relevance. Here, we show that spike avalanches, recorded from hippocampus (HP) and sensory neocortex of freely-behaving rats, constitute distinct families of recursive spatiotemporal patterns. A significant number of those patterns were specific to a behavioral state. Although avalanches produced during sleep were mostly similar to others that occurred during waking, the repertoire of patterns recruited during sleep differed significantly from that of waking. More importantly, exposure to novel objects increased the rate at which new patterns arose, also leading to changes in post-exposure repertoires, which were significantly different from those before the exposure. A significant number of families occurred exclusively during periods of whisker contact with objects, but few were associated with specific objects. Altogether, the results provide original evidence linking behavior and criticality at the spike level: spike avalanches form repertoires that emerge in waking, recur during sleep, are diversified by novelty and contribute to object representation. C1 [Ribeiro, Tiago L.] NIMH, Sect Crit Brain Dynam, NIH, Bethesda, MD 20892 USA. [Ribeiro, Tiago L.; Copelli, Mauro] Fed Univ Pernambuco UFPE, Dept Phys, Recife, PE, Brazil. [Ribeiro, Sidarta] Univ Fed Rio Grande Norte UFRN, Inst Brain, Natal, RN, Brazil. RP Ribeiro, TL (reprint author), NIMH, Sect Crit Brain Dynam, NIH, Bethesda, MD 20892 USA.; Ribeiro, TL (reprint author), Fed Univ Pernambuco UFPE, Dept Phys, Recife, PE, Brazil. EM tiago.linsribeiro@nih.gov RI Copelli, Mauro/C-6336-2009 OI Copelli, Mauro/0000-0001-7441-2858 FU Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES); Financiadora de Estudos e Projetos (FINEP) [01.06.1092.00]; Pro-Reitoria de Pos-Graduacao da Universidade Federal do Rio Grande do Norte (UFRN); Consclho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)/Ministrio da Tecnologia e Inovacao CNPq [481351/2011-6, 306604/2012-4, 480053/2013-8, 310712/2014-9]; Programa de Apoio a Nticleos Emergentes (PRONEM) [003/2011 FAPERN/CNPq, 12/2010 FACEPE/CNPq]; Pew Latin American Fellows Program in the Biomedical Sciences; Capes SticAmSud; FAPESP Center for Neuromathematics (Sao Paulo Research Foundation) [2013/076990]; NIMBIOS working group "Multi-scale analysis of cortical networks" FX This work was supported by Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES), Financiadora de Estudos e Projetos (FINEP) Grant 01.06.1092.00, Pro-Reitoria de Pos-Graduacao da Universidade Federal do Rio Grande do Norte (UFRN), Consclho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)/Ministrio da Tecnologia e Inovacao CNPq Grants 481351/2011-6, 306604/2012-4, 480053/2013-8 and 310712/2014-9, Programa de Apoio a Nticleos Emergentes (PRONEM) 003/2011 FAPERN/CNPq and PRONEM 12/2010 FACEPE/CNPq, Pew Latin American Fellows Program in the Biomedical Sciences, Capes SticAmSud, FAPESP Center for Neuromathematics (Grant #2013/076990, Sao Paulo Research Foundation), and NIMBIOS working group "Multi-scale analysis of cortical networks". NR 57 TC 0 Z9 0 U1 2 U2 4 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5110 J9 FRONT NEURAL CIRCUIT JI Front. Neural Circuits PD MAR 22 PY 2016 VL 10 AR 16 DI 10.3389/fncir.2016.00016 PG 11 WC Neurosciences SC Neurosciences & Neurology GA DH0PH UT WOS:000372485600002 PM 27047341 ER PT J AU Villarino, A Laurence, A Robinson, GW Bonelli, M Dema, B Afzali, B Shih, HY Sun, HW Brooks, SR Hennighausen, L Kanno, Y O'Shea, JJ AF Villarino, Alejandro Laurence, Arian Robinson, Gertraud W. Bonelli, Michael Dema, Barbara Afzali, Behdad Shih, Han-Yu Sun, Hong-Wei Brooks, Stephane R. Hennighausen, Lothar Kanno, Yuka O'Shea, John J. TI Signal transducer and activator of transcription 5 (STAT5) paralog dose governs T cell effector and regulatory functions SO ELIFE LA English DT Article ID MOUSE MAMMARY EPITHELIUM; GENE-EXPRESSION; LYMPHOID DEVELOPMENT; RNA-SEQ; DIFFERENTIATION; BINDING; PROTEINS; GENOME; MECHANISMS; APOPTOSIS AB The transcription factor STAT5 is fundamental to the mammalian immune system. However, the relationship between its two paralogs, STAT5A and STAT5B, and the extent to which they are functionally distinct, remain uncertain. Using mouse models of paralog deficiency, we demonstrate that they are not equivalent for CD4(+) 'helper' T cells, the principal orchestrators of adaptive immunity. Instead, we find that STAT5B is dominant for both effector and regulatory (Treg) responses and, therefore, uniquely necessary for immunological tolerance. Comparative analysis of genomic distribution and transcriptomic output confirm that STAT5B has fargreater impact but, surprisingly, the data point towards asymmetric expression (i.e. paralog dose), rather than distinct functional properties, as the key distinguishing feature. Thus, we propose a quantitative model of STAT5 paralog activity whereby relative abundance imposes functional specificity (or dominance) in the face of widespread structural homology. C1 [Villarino, Alejandro; Laurence, Arian; Bonelli, Michael; Dema, Barbara; Afzali, Behdad; Shih, Han-Yu; Sun, Hong-Wei; Brooks, Stephane R.; Kanno, Yuka; O'Shea, John J.] NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD USA. [Robinson, Gertraud W.; Hennighausen, Lothar] NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. RP Villarino, A (reprint author), NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD USA. EM alejandro.villarino@nih.gov OI Villarino, Alejandro/0000-0001-8068-2176 FU National Institutes of Health FX National Institutes of Health Alejandro Villarino Arian Laurence Gertraud W Robinson Michael Bonelli Barbara Dema Behdad Afzali Han-Yu Shih Hong-Wei Sun Stephen R Brooks Lothar Hennighausen Yuka Kanno John J O'Shea NR 79 TC 3 Z9 3 U1 0 U2 0 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD MAR 21 PY 2016 VL 5 AR e08384 DI 10.7554/eLife.08384 PG 26 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DM0IG UT WOS:000376026900001 ER PT J AU Kong, LJ Tang, JY Cui, M AF Kong, Lingjie Tang, Jianyong Cui, Meng TI Multicolor multiphoton in vivo imaging flow cytometry SO OPTICS EXPRESS LA English DT Article ID ADAPTIVE COMPENSATION TECHNIQUE; NEUTROPHIL-LYMPHOCYTE RATIO; CIRCULATING TUMOR-CELLS; NEURONAL-ACTIVITY; MICROSCOPY; FLUORESCENCE; CANCER; TISSUE; METASTASIS; TRACKING AB In vivo flow cytometry provides a non-invasive way of probing the biology of circulating cells during disease progression and studying cellular response to therapy. However, current methods provide little morphological information which potentially could be new biological marker for early disease diagnosis, and fail to reveal intercellular interactions. Here we report a multi-color, multiphoton in vivo imaging flow cytometry, to image circulating cells within the vasculature of scattering tissues at high spatiotemporal resolution. We apply it in imaging of cellular dynamics in bone marrow through the intact mouse skull, in situ deformability cytometry, distinguishing cellular clusters, and simultaneously monitoring multiple types of trafficking cells based on their morphologies and fluorescence emission colors. (C) 2016 Optical Society of America C1 [Kong, Lingjie; Cui, Meng] Purdue Univ, Sch Elect & Comp Engn, W Lafayette, IN 47907 USA. [Tang, Jianyong] NIAID, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Cui, Meng] Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA. [Cui, Meng] Purdue Univ, Integrated Imaging Cluster, W Lafayette, IN 47907 USA. [Cui, Meng] Purdue Univ, Bindley Biosci Ctr, W Lafayette, IN 47907 USA. RP Kong, LJ; Cui, M (reprint author), Purdue Univ, Sch Elect & Comp Engn, W Lafayette, IN 47907 USA.; Cui, M (reprint author), Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA.; Cui, M (reprint author), Purdue Univ, Integrated Imaging Cluster, W Lafayette, IN 47907 USA.; Cui, M (reprint author), Purdue Univ, Bindley Biosci Ctr, W Lafayette, IN 47907 USA. EM kong52@purdue.edu; mengcui@purdue.edu RI kong, lingjie/G-5822-2012 OI kong, lingjie/0000-0003-1974-3245 FU NIH [1U01NS094341-01]; Purdue University; Howard Hughes Medical Institute; Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX The authors thank Charles P. Lin at Harvard Medical School for the initial idea of blood flow imaging. L.K. and M.C. thank the support from NIH (1U01NS094341-01), Purdue University, and Howard Hughes Medical Institute. This research was also supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 45 TC 3 Z9 3 U1 8 U2 17 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1094-4087 J9 OPT EXPRESS JI Opt. Express PD MAR 21 PY 2016 VL 24 IS 6 BP 6126 EP 6135 DI 10.1364/OE.24.006126 PG 10 WC Optics SC Optics GA DI3JU UT WOS:000373395700068 PM 27136806 ER PT J AU Norby, FL Eryd, SA Niemeijer, MN Rose, LM Smith, AV Yin, XY Agarwal, SK Arking, DE Chasman, DL Chen, LY Eijgelsheim, M Engstrom, G Franco, OH Heeringa, J Hindy, G Hofman, A Lutsey, PL Magnani, JW McManus, DD Orho-Melander, M Pankow, JS Rukh, G Schulz, CA Uitterlinden, AG Albert, CM Benjamin, EJ Gudnason, V Smith, JG Stricker, BHC Alonso, A AF Norby, Faye L. Eryd, Samuel Adamsson Niemeijer, Maartje N. Rose, Lynda M. Smith, Albert V. Yin, Xiaoyan Agarwal, Sunil K. Arking, Dan E. Chasman, Daniel L. Chen, Lin Y. Eijgelsheim, Mark Engstrom, Gunnar Franco, Oscar H. Heeringa, Jan Hindy, George Hofman, Albert Lutsey, Pamela L. Magnani, Jared W. McManus, David D. Orho-Melander, Marju Pankow, James S. Rukh, Gull Schulz, Christina-Alexandra Uitterlinden, Andre G. Albert, Christine M. Benjamin, Emelia J. Gudnason, Vilmundur Smith, J. Gustav Stricker, Bruno H. C. Alonso, Alvaro TI Association of Lipid-Related Genetic Variants with the Incidence of Atrial Fibrillation: The AFGen Consortium SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; CORONARY-HEART-DISEASE; ATHEROSCLEROSIS RISK; MENDELIAN RANDOMIZATION; COMMUNITIES; POPULATION; DESIGN; LOCI; PREVALENCE; OBJECTIVES AB Background Several studies have shown associations between blood lipid levels and the risk of atrial fibrillation (AF). To test the potential effect of blood lipids with AF risk, we assessed whether previously developed lipid gene scores, used as instrumental variables, are associated with the incidence of AF in 7 large cohorts. Methods We analyzed 64,901 individuals of European ancestry without previous AF at baseline and with lipid gene scores. Lipid-specific gene scores, based on loci significantly associated with lipid levels, were calculated. Additionally, non-pleiotropic gene scores for high-density lipoprotein cholesterol (HDLc) and low-density lipoprotein cholesterol (LDLc) were calculated using SNPs that were only associated with the specific lipid fraction. Cox models were used to estimate the hazard ratio (HR) and 95% confidence intervals (CI) of AF per 1-standard deviation (SD) increase of each lipid gene score. Results During a mean follow-up of 12.0 years, 5434 (8.4%) incident AF cases were identified. After meta-analysis, the HDLc, LDLc, total cholesterol, and triglyceride gene scores were not associated with incidence of AF. Multivariable-adjusted HR (95% CI) were 1.01 (0.981.03); 0.98 (0.96-1.01); 0.98 (0.95-1.02); 0.99 (0.97-1.02), respectively. Similarly, non-pleiotropic HDLc and LDLc gene scores showed no association with incident AF: HR (95% CI) = 1.00 (0.97-1.03); 1.01 (0.99-1.04). Conclusions In this large cohort study of individuals of European ancestry, gene scores for lipid fractions were not associated with incident AF. C1 [Norby, Faye L.; Lutsey, Pamela L.; Pankow, James S.; Alonso, Alvaro] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Eryd, Samuel Adamsson; Engstrom, Gunnar; Hindy, George; Orho-Melander, Marju; Rukh, Gull; Schulz, Christina-Alexandra; Smith, J. Gustav] Lund Univ, Dept Clin Sci, Malmo, Sweden. [Niemeijer, Maartje N.; Eijgelsheim, Mark; Franco, Oscar H.; Heeringa, Jan; Hofman, Albert; Uitterlinden, Andre G.; Stricker, Bruno H. C.] Univ Med Ctr, Erasmus Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Rose, Lynda M.; Chasman, Daniel L.; Albert, Christine M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Prevent Med,Dept Med, Boston, MA 02115 USA. [Smith, Albert V.; Gudnason, Vilmundur] Iceland Heart Assoc, Res Inst, Kopavogur, Iceland. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Yin, Xiaoyan] Boston Univ, Sch Med, Dept Biostat, Cardiol Sect, Boston, MA 02118 USA. [Yin, Xiaoyan] Boston Univ, Sch Med, Dept Biostat, Prevent Med Sect, Boston, MA 02118 USA. [Agarwal, Sunil K.] Mt Sinai Heart Ctr, Icahn Sch Med, New York, NY USA. [Arking, Dan E.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Chen, Lin Y.] Univ Minnesota, Sch Med, Cardiac Arrhythmia Ctr, Cardiovasc Div,Dept Med, Minneapolis, MN 55455 USA. [Eijgelsheim, Mark; Uitterlinden, Andre G.; Stricker, Bruno H. C.] Univ Med Ctr, Erasmus Med Ctr, Dept Internal Med, Rotterdam, Netherlands. [Magnani, Jared W.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02118 USA. [Magnani, Jared W.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Prevent Med Sect, Boston, MA 02118 USA. [Magnani, Jared W.; Benjamin, Emelia J.] NHLBI, Framingham, MA USA. [Magnani, Jared W.; Benjamin, Emelia J.] Boston Univ, Framingham Heart Study, 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. [Albert, Christine M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc Med,Dept Med, Boston, MA 02115 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Smith, J. Gustav] Lund Univ, Dept Cardiol, Lund, Sweden. [Stricker, Bruno H. C.] Inspectorate Hlth Care, Utrecht, Netherlands. RP Norby, FL (reprint author), Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. EM flopez@umn.edu RI Alonso, Alvaro/A-4917-2010; Hindy, George/H-1864-2016; Smith, Albert Vernon/K-5150-2015 OI Alonso, Alvaro/0000-0002-2225-8323; Hindy, George/0000-0002-7257-9299; Smith, Albert Vernon/0000-0003-1942-5845 FU National Institutes of Health [N01-AG-12100]; NIA Intramural Research Program; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); National Heart, Lung, and Blood Institute [HHSN268201 100005C, HHSN268201100006C, HSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN2682 01100010C, HHSN268201100011C, HHSN26820110 0012C, RC1HL 099452, RC1HL101056, HL 043851, HL 69757, HL099355]; American Heart Association [09SDG2280087]; National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195]; Affymetrix, Inc [N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine; Boston Medical Center; Malmo city council; Swedish Cancer Society; Swedish Medical Research Council; Swedish Dairy association; Albert Pahlsson foundation; Gunnar Nilsson foundation; Swedish Heart-Lung foundation; Swedish Research Council; Crafoord foundation; Swedish National Health Service; Skane University Hospital; Netherlands Organisation of Scientific Research NWO Investments [175.010.2005.011, 911-03-012]; Research Institute for Diseases in the Elderly [014-93-015, RIDE2]; Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) [050-060-810]; Erasmus MC; Erasmus University Rotterdam; Netherlands Organisation for Scientific Research (NWO); Netherlands Organisation for Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Netherlands Genomics Initiative (NGI); Ministry of Education, Culture and Science; Ministry of Health Welfare and Sport; European Commission (DG XII); Municipality of Rotterdam; National Cancer Institute [CA 047988]; Donald W. Reynolds Foundation; Amgen; Harris Family Foundation; Watkin's Foundation; [2R01 HL092577]; [1RO1 HL076784]; [1R01 AG028321]; [6R01-NS 17950]; [KL2RR031981]; [HL-093613] FX AGES: The Age, Gene/Environment Susceptibility Reykjavik Study has been funded by National Institutes of Health contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). ARIC: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201 100005C, HHSN268201100006C, HSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN2682 01100010C, HHSN268201100011C, and HHSN26820110 0012C). This work was additionally funded by grants RC1HL 099452 and RC1HL101056 from National Heart, Lung, and Blood Institute and 09SDG2280087 from the American Heart Association. FHS: Framingham Heart Study research was conducted using data and resources from the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine based on analyses by Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Other support came from 2R01 HL092577, 1RO1 HL076784, 1R01 AG028321 (Benjamin), 6R01-NS 17950, And KL2RR031981 (McManus). MDCS: The Malmo Diet and Cancer study was made possible by grants from the Malmo city council, the Swedish Cancer Society, the Swedish Medical Research Council, the Swedish Dairy association, and the Albert Pahlsson and Gunnar Nilsson foundations. J. Gustav Smith was supported by the Swedish Heart-Lung foundation, the Swedish Research Council, the Crafoord foundation, governmental funding of clinical research within the Swedish National Health Service, and Skane University Hospital. RS: The generation and management of GWAS genotype data for the Rotterdam Study is supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project nr. 050-060-810. The Rotterdam Study is supported by the Erasmus MC and Erasmus University Rotterdam; the Netherlands Organisation for Scientific Research (NWO); the Netherlands Organisation for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); the Netherlands Genomics Initiative (NGI); the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sport; the European Commission (DG XII); and the Municipality of Rotterdam. WGHS: The Women's Genome Health Study is supported by HL 043851, HL 69757, HL099355 from the National Heart, Lung, and Blood Institute and CA 047988 from the National Cancer Institute, the Donald W. Reynolds Foundation with collaborative scientific support and funding for genotyping provided by Amgen. AF endpoint confirmation was supported by HL-093613 and a grant from the Harris Family Foundation and Watkin's Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 0 Z9 0 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 21 PY 2016 VL 11 IS 3 AR e0151932 DI 10.1371/journal.pone.0151932 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH3NW UT WOS:000372694700087 PM 26999784 ER PT J AU Ribeiro, JMC Martin-Martin, I Arca, B Calvo, E AF Ribeiro, Jose M. C. Martin-Martin, Ines Arca, Bruno Calvo, Eric TI A Deep Insight into the Sialome of Male and Female Aedes aegypti Mosquitoes SO PLOS ONE LA English DT Article ID YELLOW-FEVER MOSQUITO; SALIVARY-GLAND TRANSCRIPTS; ANOPHELES-GAMBIAE; CULEX-QUINQUEFASCIATUS; TRANSPOSABLE ELEMENTS; XANTHURENIC ACID; MALARIA VECTOR; SIALOKININ-I; VIRUS; GENE AB Only adult female mosquitoes feed on blood, while both genders take sugar meals. Accordingly, several compounds associated with blood feeding (i.e. vasodilators, anti-clotting, anti-platelets) are found only in female glands, while enzymes associated with sugar feeding or antimicrobials (such as lysozyme) are found in the glands of both sexes. We performed de novo assembly of reads from adult Aedes aegypti female and male salivary gland libraries (285 and 90 million reads, respectively). By mapping back the reads to the assembled contigs, plus mapping the reads from a publicly available Ae. aegypti library from adult whole bodies, we identified 360 transcripts (including splice variants and alleles) overexpressed tenfold or more in the glands when compared to whole bodies. Moreover, among these, 207 were overexpressed fivefold or more in female vs. male salivary glands, 85 were near equally expressed and 68 were overexpressed in male glands. We call in particular the attention to C-type lectins, angiopoietins, female-specific Antigen 5, the 9.7 kDa, 12-14 kDa, 23.5 kDa, 62/34 kDa, 4.2 kDa, proline-rich peptide, SG8, 8.7 kDa family and SGS fragments: these polypeptides are all of unknown function, but due to their overexpression in female salivary glands and putative secretory nature they are expected to affect host physiology. We have also found many transposons (some of which novel) and several endogenous viral transcripts (probably acquired by horizontal transfer) which are overexpressed in the salivary glands and may play some role in tissue-specific gene regulation or represent a mechanism of virus interference. This work contributes to a near definitive catalog of male and female salivary gland transcripts from Ae. aegypti, which will help to direct further studies aiming at the functional characterization of the many transcripts with unknown function and the understanding of their role in vector-host interaction and pathogen transmission. C1 [Ribeiro, Jose M. C.; Martin-Martin, Ines; Calvo, Eric] NIAID, Lab Malaria & Vector Res, Sect Vector Biol, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Arca, Bruno] Univ Roma La Sapienza, Dept Publ Hlth & Infect Dis, Parasitol Sect, Piazzale Aldo Moro 5, I-00185 Rome, Italy. RP Ribeiro, JMC (reprint author), NIAID, Lab Malaria & Vector Res, Sect Vector Biol, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jribeiro@nih.gov OI Calvo, Eric/0000-0001-7880-2730; Ribeiro, Jose/0000-0002-9107-0818 FU EU [228421]; MIUR (PRIN) [2010C2LKKJ_004]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA FX BA was supported by funds from the EU grant INFRAVEC (228421) and from MIUR (PRIN 2010-2011, SKINFLAM, 2010C2LKKJ_004); EC, IMM and JMCR by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA. NR 67 TC 2 Z9 2 U1 3 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 21 PY 2016 VL 11 IS 3 AR e0151400 DI 10.1371/journal.pone.0151400 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH3NW UT WOS:000372694700039 PM 26999592 ER PT J AU Rosenberg, AZ Armani, MD Fetsch, PA Xi, LQ Pham, TT Raffeld, M Chen, Y O'Flaherty, N Stussman, R Blackler, AR Du, Q Hanson, JC Roth, MJ Filie, AC Roh, MH Emmert-Buck, MR Hipp, JD Tangrea, MA AF Rosenberg, Avi Z. Armani, Michael D. Fetsch, Patricia A. Xi, Liqiang Tina Thu Pham Raffeld, Mark Chen, Yun O'Flaherty, Neil Stussman, Rebecca Blackler, Adele R. Du, Qiang Hanson, Jeffrey C. Roth, Mark J. Filie, Armando C. Roh, Michael H. Emmert-Buck, Michael R. Hipp, Jason D. Tangrea, Michael A. TI High-Throughput Microdissection for Next-Generation Sequencing SO PLOS ONE LA English DT Article ID EXPRESSION MICRODISSECTION; PROMOTER METHYLATION; MUTATION ANALYSIS; CANCER; CELLS; RETRIEVAL; VARIANT; SAMPLES; GENES AB Precision medicine promises to enhance patient treatment through the use of emerging molecular technologies, including genomics, transcriptomics, and proteomics. However, current tools in surgical pathology lack the capability to efficiently isolate specific cell populations in complex tissues/tumors, which can confound molecular results. Expression microdissection (xMD) is an immuno-based cell/subcellular isolation tool that procures targets of interest from a cytological or histological specimen. In this study, we demonstrate the accuracy and precision of xMD by rapidly isolating immunostained targets, including cytokeratin AE1/AE3, p53, and estrogen receptor (ER) positive cells and nuclei from tissue sections. Other targets procured included green fluorescent protein (GFP) expressing fibroblasts, in situ hybridization positive Epstein-Barr virus nuclei, and silver stained fungi. In order to assess the effect on molecular data, xMD was utilized to isolate specific targets from a mixed population of cells where the targets constituted only 5% of the sample. Target enrichment from this admixed cell population prior to next-generation sequencing (NGS) produced a minimum 13-fold increase in mutation allele frequency detection. These data suggest a role for xMD in a wide range of molecular pathology studies, as well as in the clinical workflow for samples where tumor cell enrichment is needed, or for those with a relative paucity of target cells. C1 [Rosenberg, Avi Z.; Hanson, Jeffrey C.; Hipp, Jason D.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Armani, Michael D.; Chen, Yun; O'Flaherty, Neil; Stussman, Rebecca; Blackler, Adele R.; Du, Qiang; Emmert-Buck, Michael R.; Tangrea, Michael A.] NCI, Pathogenet Unit, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Fetsch, Patricia A.; Roth, Mark J.; Filie, Armando C.] NCI, Cytopathol Sect, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Xi, Liqiang; Tina Thu Pham; Raffeld, Mark] NCI, Mol Diagnost Unit, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Chen, Yun] Johns Hopkins Univ, Dept Mech Engn, Baltimore, MD 21218 USA. [Roh, Michael H.] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Emmert-Buck, Michael R.] Avoneaux Med Inst, Oxford, MD USA. [Tangrea, Michael A.] Sinai Hosp, Alvin & Lois Lapidus Canc Inst, 2401 W Belvedere Ave, Baltimore, MD 21215 USA. RP Emmert-Buck, MR; Tangrea, MA (reprint author), NCI, Pathogenet Unit, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA.; Emmert-Buck, MR (reprint author), Avoneaux Med Inst, Oxford, MD USA.; Tangrea, MA (reprint author), Sinai Hosp, Alvin & Lois Lapidus Canc Inst, 2401 W Belvedere Ave, Baltimore, MD 21215 USA. EM mikeeb@atlanticbb.net; mtangrea@lifebridgehealth.org OI Chen, Yun/0000-0001-6917-7814 FU NIH National Cancer Institute, Center for Cancer Research; Center for Cancer Research at the National Cancer Institute, NIH, Bethesda, MD FX This research was supported by the intramural program of the NIH National Cancer Institute, Center for Cancer Research.; This work was supported by the intramural program of the Center for Cancer Research at the National Cancer Institute, NIH, Bethesda, MD. We would like to thank Theresa Davies-Hill and Dana Erickson for their help with sample preparation, Kris Ylaya and Stephen Hewitt for their contribution with histology processing, and Rob Robey for donation of cell lines. Michael R. Emmert-Buck and Michael A. Tangrea are inventors on NIH-held patents covering expression microdissection and are eligible to receive royalty-based payments through the NIH Technology Transfer Program. Michael A. Tangrea and Michael R. Emmert-Buck are consultants for xMD Diagnostics, LLC. NR 17 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 MAR 21 PY 2016 VL 11 IS 3 AR e0151775 DI 10.1371/journal.pone.0151775 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH3NW UT WOS:000372694700064 PM 26999048 ER PT J AU Lei, JT Qi, RX Wei, GH Nussinov, R Ma, BY AF Lei, Jiangtao Qi, Ruxi Wei, Guanghong Nussinov, Ruth Ma, Buyong TI Self-aggregation and coaggregation of the p53 core fragment with its aggregation gatekeeper variant SO PHYSICAL CHEMISTRY CHEMICAL PHYSICS LA English DT Article ID ISLET AMYLOID POLYPEPTIDE; MOLECULAR-DYNAMICS METHOD; MUTANT P53; EXPLICIT SOLVENT; ENERGY LANDSCAPE; CELL BIOLOGY; WILD-TYPE; PROTEIN; BETA; CANCER AB Recent studies suggested that p53 aggregation can lead to loss-of-function (LoF), dominant-negative (DN) and gain-of-function (GoF) effects, with adverse cancer consequences. The p53 aggregation-nucleating (ILTIITL257)-I-251 fragment is a key segment in wild-type p53 aggregation; however, an I254R mutation can prevent it. It was suggested that self-assembly of wild-type p53 and its cross-interaction with mutants differ from the classical amyloid nucleation-growth mechanism. Here, using replica exchange molecular dynamics (REMD) simulations, we studied the cross-interactions of this p53 core fragment and its aggregation rescue I254R mutant. We found that the core fragment displays strong aggregation propensity, whereas the gatekeeper I254R mutant tends to be disordered, consistent with experiments. Our cross-interaction results reveal that the wild-type p53 fragment promotes beta-sheet formation of the I254R mutant by shifting the disordered mutant peptides into aggregating states. As a result, the system has similar oligomeric structures, inter-peptide interactions and free energy landscape as the wild type fragment does, revealing a prion-like process. We also found that in the cross-interaction system, the wild-type species has higher tendency to interact with the mutant than with itself. This phenomenon illustrates synergistic effects between the p53 (ILTIITL257)-I-251 fragment and the mutant resembling prion cross-species propagation, cautioning against exploiting it in drug discovery. C1 [Lei, Jiangtao; Qi, Ruxi; Wei, Guanghong] Fudan Univ, State Key Lab Surface Phys, Key Lab Computat Phys Sci MOE, Shanghai 200433, Peoples R China. [Lei, Jiangtao; Qi, Ruxi; Wei, Guanghong] Fudan Univ, Dept Phys, Shanghai 200433, Peoples R China. [Nussinov, Ruth; Ma, Buyong] NCI, Basic Sci Program, Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Wei, GH (reprint author), Fudan Univ, State Key Lab Surface Phys, Key Lab Computat Phys Sci MOE, Shanghai 200433, Peoples R China.; Wei, GH (reprint author), Fudan Univ, Dept Phys, Shanghai 200433, Peoples R China.; Ma, BY (reprint author), NCI, Basic Sci Program, Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick, MD 21702 USA. EM ghwei@fudan.edu.cn; mabuyong@mail.nih.gov RI Ma, Buyong/F-9491-2011 OI Ma, Buyong/0000-0002-7383-719X FU NSF of China [91227102, 11274075]; NCI, NIH [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX G. W. acknowledges the financial support from the NSF of China (Grant No. 91227102 and 11274075). R. N. and B. M. thank the financial support from NCI, NIH, under contract number HHSN261200800001E. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. Simulations were performed at the NIH Biowulf supercomputer cluster and the National High Performance Computing Center of Fudan University. NR 71 TC 6 Z9 6 U1 1 U2 13 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1463-9076 EI 1463-9084 J9 PHYS CHEM CHEM PHYS JI Phys. Chem. Chem. Phys. PD MAR 21 PY 2016 VL 18 IS 11 BP 8098 EP 8107 DI 10.1039/c5cp06538k PG 10 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA DG6XP UT WOS:000372229700055 PM 26923710 ER PT J AU Park, JH Anderson, WF Gail, MH AF Park, Ju-Hyun Anderson, William F. Gail, Mitchell H. TI Parsing the Etiology of Breast Cancer Disparities Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter C1 [Park, Ju-Hyun] Dongguk Univ, Seoul, South Korea. [Anderson, William F.; Gail, Mitchell H.] NCI, Rockville, MD USA. RP Park, JH (reprint author), Dongguk Univ, Seoul, South Korea. NR 5 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 20 PY 2016 VL 34 IS 9 BP 1014 EP + DI 10.1200/JCO.2015.65.3790 PG 3 WC Oncology SC Oncology GA DJ6OZ UT WOS:000374334100021 PM 26786932 ER PT J AU Shuch, B Agochukwu, N Ricketts, CJ Vocke, CD Gautam, R Merino, M Linehan, WM Srinivasan, R AF Shuch, Brian Agochukwu, Nnenaya Ricketts, Christopher J. Vocke, Cathy D. Gautam, Rabindra Merino, Maria Linehan, W. Marston Srinivasan, Ramaparasad TI Vascular Endothelial Growth Factor Receptor-Targeted Therapy in Succinate Dehydrogenase C Kidney Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID RENAL-CELL CARCINOMA; PARAGANGLIOMA; GENE; MUTATIONS; PHEOCHROMOCYTOMA; EXPRESSION; TYPE-3; TUMORS C1 [Shuch, Brian; Agochukwu, Nnenaya; Ricketts, Christopher J.; Vocke, Cathy D.; Gautam, Rabindra; Merino, Maria; Linehan, W. Marston; Srinivasan, Ramaparasad] NCI, Bethesda, MD 20892 USA. RP Shuch, B (reprint author), NCI, Bethesda, MD 20892 USA. FU Intramural NIH HHS NR 17 TC 1 Z9 1 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 20 PY 2016 VL 34 IS 9 BP E76 EP E79 DI 10.1200/JCO.2013.51.0214 PG 4 WC Oncology SC Oncology GA DJ6OZ UT WOS:000374334100002 PM 25024072 ER PT J AU Godfrey, C Andersen, J Mngqibisa, R Scott, LE Conradie, F AF Godfrey, Catherine Andersen, Janet Mngqibisa, Rosie Scott, Lesley E. Conradie, Francesca TI Tuberculosis control SO LANCET LA English DT Letter ID HEALTH-CARE WORKERS; INFECTION C1 [Godfrey, Catherine] NIH, Bldg 10, Bethesda, MD 20892 USA. [Andersen, Janet] Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Mngqibisa, Rosie] Enhancing Care Fdn, HIV Management, Durban, South Africa. [Scott, Lesley E.] Univ Witwatersrand, Fac Hlth Sci, Sch Pathol, Dept Mol Med & Haematol, Johannesburg, South Africa. [Conradie, Francesca] Sizwe Trop Dis Hosp, HIV Management Epidemiol, Johannesburg, South Africa. RP Godfrey, C (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM Cgodfrey@niaid.nih.gov NR 6 TC 0 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD MAR 19 PY 2016 VL 387 IS 10024 BP 1157 EP 1158 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DG9OB UT WOS:000372412000017 PM 27025326 ER PT J AU Hosseinipour, MC Bisson, GP Miyahara, S Sun, X Moses, A Riviere, C Kirui, FK Badal-Faesen, S Lagat, D Nyirenda, M Naidoo, K Hakim, J Mugyenyi, P Henostroza, G Leger, PD Lama, JR Mohapi, L Alave, J Mave, V Veloso, VG Pillay, S Kumarasamy, N Bao, J Hogg, E Jones, L Zolopa, A Kumwenda, J Gupta, A AF Hosseinipour, Mina C. Bisson, Gregory P. Miyahara, Sachiko Sun, Xin Moses, Agnes Riviere, Cynthia Kirui, Fredrick K. Badal-Faesen, Sharlaa Lagat, David Nyirenda, Mulinda Naidoo, Kogieleum Hakim, James Mugyenyi, Peter Henostroza, German Leger, Paul D. Lama, Javier R. Mohapi, Lerato Alave, Jorge Mave, Vidya Veloso, Valdilea G. Pillay, Sandy Kumarasamy, Nagalingeswaran Bao, Jing Hogg, Evelyn Jones, Lynne Zolopa, Andrew Kumwenda, Johnstone Gupta, Amita CA AIDS Clinical Trials Grp A5274 TI Empirical tuberculosis therapy versus isoniazid in adult outpatients with advanced HIV initiating antiretroviral therapy (REMEMBER): a multicountry open-label randomised controlled trial SO LANCET LA English DT Article ID PLACEBO-CONTROLLED TRIAL; PREVENTIVE THERAPY; INFECTED ADULTS; XPERT MTB/RIF; DOUBLE-BLIND; SETTINGS; AFRICA; ACCURACY; COHORT; HAART AB Background Mortality within the first 6 months after initiating antiretroviral therapy is common in resource-limited settings and is often due to tuberculosis in patients with advanced HIV disease. Isoniazid preventive therapy is recommended in HIV-positive adults, but subclinical tuberculosis can be difficult to diagnose. We aimed to assess whether empirical tuberculosis treatment would reduce early mortality compared with isoniazid preventive therapy in high-burden settings. Methods We did a multicountry open-label randomised clinical trial comparing empirical tuberculosis therapy with isoniazid preventive therapy in HIV-positive outpatients initiating antiretroviral therapy with CD4 cell counts of less than 50 cells per mu L. Participants were recruited from 18 outpatient research clinics in ten countries (Malawi, South Africa, Haiti, Kenya, Zambia, India, Brazil, Zimbabwe, Peru, and Uganda). Individuals were screened for tuberculosis using a symptom screen, locally available diagnostics, and the GeneXpert MTB/RIF assay when available before inclusion. Study candidates with confirmed or suspected tuberculosis were excluded. Inclusion criteria were liver function tests 2.5 times the upper limit of normal or less, a creatinine clearance of at least 30 mL/min, and a Karnofsky score of at least 30. Participants were randomly assigned (1:1) to either the empirical group (antiretroviral therapy and empirical tuberculosis therapy) or the isoniazid preventive therapy group (antiretroviral therapy and isoniazid preventive therapy). The primary endpoint was survival (death or unknown status) at 24 weeks after randomisation assessed in the intention-to-treat population. Kaplan-Meier estimates of the primary endpoint across groups were compared by the z-test. All participants were included in the safety analysis of antiretroviral therapy and tuberculosis treatment. This trial is registered with ClinicalTrials.gov, number NCT01380080. Findings Between Oct 31, 2011, and June 9, 2014, we enrolled 850 participants. Of these, we randomly assigned 424 to receive empirical tuberculosis therapy and 426 to the isoniazid preventive therapy group. The median CD4 cell count at baseline was 18 cells per mu L (IQR 9-32). At week 24, 22 (5%) participants from each group died or were of unknown status (95% CI 3.5-7.8) for empirical group and for isoniazid preventive therapy (95% CI 3.4-7.8); absolute risk difference of -0.06% (95% CI -3.05 to 2.94). Grade 3 or 4 signs or symptoms occurred in 50 (12%) participants in the empirical group and 46 (11%) participants in the isoniazid preventive therapy group. Grade 3 or 4 laboratory abnormalities occurred in 99 (23%) participants in the empirical group and 97 (23%) participants in the isoniazid preventive therapy group. Interpretation Empirical tuberculosis therapy did not reduce mortality at 24 weeks compared with isoniazid preventive therapy in outpatient adults with advanced HIV disease initiating antiretroviral therapy. The low mortality rate of the trial supports implementation of systematic tuberculosis screening and isoniazid preventive therapy in outpatients with advanced HIV disease. C1 [Hosseinipour, Mina C.; Moses, Agnes] UNC Project, Lilongwe, Malawi. [Hosseinipour, Mina C.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Bisson, Gregory P.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Miyahara, Sachiko; Sun, Xin] Harvard Univ, Boston, MA 02115 USA. [Riviere, Cynthia; Leger, Paul D.] GHESKIO, Port Av Prince, Haiti. [Kirui, Fredrick K.] Kenya Govt Med Res Ctr, Kisumu, Kenya. [Badal-Faesen, Sharlaa] Univ Witwatersrand, Dept Med, Clin HIV Res Unit, ZA-2001 Johannesburg, South Africa. [Mohapi, Lerato] Univ Witwatersrand, Perinatal HIV Res Unit, Johannesburg, South Africa. [Lagat, David] Moi Univ, Sch Med, Eldoret, Kenya. [Nyirenda, Mulinda; Kumwenda, Johnstone] Johns Hopkins Project, Blantyre, Malawi. [Naidoo, Kogieleum] Ctr AIDS Programme Res South Africa, Durban, South Africa. [Hakim, James] Univ Zimbabwe, Harare, Zimbabwe. [Mugyenyi, Peter] Joint Clin Res Ctr, Kampala, Uganda. [Henostroza, German] Ctr Infect Dis Res Zambia, Lusaka, Zambia. [Lama, Javier R.; Alave, Jorge] Asociac Civil Impacta Salud & Educ, Lima, Peru. [Mave, Vidya] BJ Med Coll, Johns Hopkins Clin Trials Unit, Pune, Maharashtra, India. [Veloso, Valdilea G.] Fiocruz MS, Evandro Chagas Natl Inst Infect Dis, BR-21045900 Rio De Janeiro, Brazil. [Pillay, Sandy] Durban Univ Technol, Durban Int CRS, Durban, South Africa. [Kumarasamy, Nagalingeswaran] VHS, YRGCARE Med Ctr, Madras, Tamil Nadu, India. [Bao, Jing] NIAID, HJF DAIDS, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Hogg, Evelyn] Social & Sci Syst, Silver Spring, MD USA. [Jones, Lynne] Frontier Sci, Buffalo, NY USA. [Zolopa, Andrew] Stanford Univ, Palo Alto, CA 94304 USA. [Gupta, Amita] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. RP Hosseinipour, MC (reprint author), Tidziwe Ctr, UNC Project, Lilongwe, Malawi. EM mina_hosseinipour@med.unc.edu FU National Institute of Allergy and Infectious Diseases of the National Institutes of Health [UM1 AI068634, UM1 AI068636, UM1 AI106701]; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HH-SN272200800014C] FX Presented in part at the 8th IAS on HIV Pathogenesis Treatment and Prevention Conference, Vancouver Canada, July 18-22, 2015. Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award numbers UM1 AI068634, UM1 AI068636, and UM1 AI106701. JB was funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services (contract number HH-SN272200800014C). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Pharmaceutical support was provided by Gilead Sciences, but Gilead had no influence in the study design or the analysis of the data. NR 30 TC 6 Z9 6 U1 2 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD MAR 19 PY 2016 VL 387 IS 10024 BP 1198 EP 1209 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA DG9OB UT WOS:000372412000031 PM 27025337 ER PT J AU Dheda, K Barry, CE Maartens, G AF Dheda, Keertan Barry, Clifton E., III Maartens, Gary TI Tuberculosis SO LANCET LA English DT Article ID EXTENSIVELY DRUG-RESISTANT; GAMMA RELEASE ASSAYS; RECONSTITUTION INFLAMMATORY SYNDROME; RANDOMIZED CONTROLLED-TRIAL; XPERT MTB/RIF ASSAY; PLACEBO-CONTROLLED TRIAL; HEALTH-CARE WORKERS; DOSE-RANGING TRIAL; PULMONARY TUBERCULOSIS; MYCOBACTERIUM-TUBERCULOSIS AB Although the worldwide incidence of tuberculosis has been slowly decreasing, the global disease burden remains substantial (similar to 9 million cases and similar to 1.5 million deaths in 2013), and tuberculosis incidence and drug resistance are rising in some parts of the world such as Africa. The modest gains achieved thus far are threatened by high prevalence of HIV, persisting global poverty, and emergence of highly drug-resistant forms of tuberculosis. Tuberculosis is also a major problem in health-care workers in both low-burden and high-burden settings. Although the ideal preventive agent, an effective vaccine, is still some time away, several new diagnostic technologies have emerged, and two new tuberculosis drugs have been licensed after almost 50 years of no tuberculosis drugs being registered. Efforts towards an effective vaccine have been thwarted by poor understanding of what constitutes protective immunity. Although new interventions and investment in control programmes will enable control, eradication will only be possible through substantial reductions in poverty and overcrowding, political will and stability, and containing co-drivers of tuberculosis, such as HIV, smoking, and diabetes. C1 [Dheda, Keertan] Univ Cape Town, Div Pulmonol, Lung Infect & Immun Unit, ZA-7925 Cape Town, South Africa. [Dheda, Keertan] Univ Cape Town, UCT Lung Inst, ZA-7925 Cape Town, South Africa. [Maartens, Gary] Univ Cape Town, Div Clin Pharmacol, ZA-7925 Cape Town, South Africa. [Barry, Clifton E., III] Univ Cape Town, Fac Hlth Sci, Dept Med, ZA-7925 Cape Town, South Africa. [Barry, Clifton E., III] Univ Cape Town, Fac Hlth Sci, Inst Infect Dis & Mol Med, ZA-7925 Cape Town, South Africa. [Dheda, Keertan; Barry, Clifton E., III; Maartens, Gary] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Dheda, K (reprint author), Univ Cape Town, Div Pulmonol, Lung Infect & Immun Unit, ZA-7925 Cape Town, South Africa.; Dheda, K (reprint author), Univ Cape Town, Dept Med, UCT Lung Inst, ZA-7925 Cape Town, South Africa. EM keertan.dheda@uct.ac.za RI Maartens, Gary/F-3836-2014 OI Maartens, Gary/0000-0003-3080-6606 FU Foundation of Innovative New Diagnostics (FIND); eNose Company; Statens Serum Institut; bioMeriux; ALERE; Oxford Immunotec; Qiagen; Cepheid; Antrum Biotec; Hain Lifescience; Hain Life science; YD Daignostics; FIND FX KD reports grants from Foundation of Innovative New Diagnostics (FIND), eNose Company, Statens Serum Institut, and bioMeriux, and grants and personal fees from ALERE, Oxford Immunotec, Cellestis (now Qiagen), Cepheid, Antrum Biotec, and Hain Lifescience. Additionally, KD has a patent "Characterisation of novel tuberculosis-specific urinary biomarkers" pending, a patent "A smart mask for monitoring cough-related infectious diseases" pending, and a patent "Device for diagnosing EPTB" issued. CEB reports grants from Cepheid, Hain Life science, YD Daignostics, and FIND. GM served on the data safety and monitoring board for Janssen for the TMC207 C208 and C207 phase 2 trials in patients with multidrug-resistant MDR tuberculosis, 2007-12. NR 157 TC 45 Z9 45 U1 13 U2 34 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD MAR 19 PY 2016 VL 387 IS 10024 BP 1211 EP 1226 DI 10.1016/S0140-6736(15)00151-8 PG 16 WC Medicine, General & Internal SC General & Internal Medicine GA DG9OB UT WOS:000372412000033 PM 26377143 ER PT J AU Mendoza, O Bourdoncle, A Boule, JB Brosh, RM Mergny, JL AF Mendoza, Oscar Bourdoncle, Anne Boule, Jean-Baptiste Brosh, Robert M., Jr. Mergny, Jean-Louis TI G-quadruplexes and helicases SO NUCLEIC ACIDS RESEARCH LA English DT Article ID WARSAW BREAKAGE SYNDROME; RECQ FAMILY HELICASES; SINGLE-STRANDED-DNA; SACCHAROMYCES-CEREVISIAE PIF1; SUBSTRATE-SPECIFIC INHIBITION; BLOOM-SYNDROME PROTEIN; IRON-SULFUR CLUSTERS; HYBRID G-QUADRUPLEX; RNA G-QUADRUPLEX; MITOCHONDRIAL-DNA AB Guanine-rich DNA strands can fold in vitro into non-canonical DNA structures called G-quadruplexes. These structures may be very stable under physiological conditions. Evidence suggests that G-quadruplex structures may act as 'knots' within genomic DNA, and it has been hypothesized that proteins may have evolved to remove these structures. The first indication of how G-quadruplex structures could be unfolded enzymatically came in the late 1990s with reports that some well-known duplex DNA helicases resolved these structures in vitro. Since then, the number of studies reporting G-quadruplex DNA unfolding by helicase enzymes has rapidly increased. The present review aims to present a general overview of the helicase/G-quadruplex field. C1 [Mendoza, Oscar; Bourdoncle, Anne; Mergny, Jean-Louis] Univ Bordeaux, ARNA Lab, F-33000 Bordeaux, France. [Mendoza, Oscar; Bourdoncle, Anne; Mergny, Jean-Louis] CNRS, UMR 5320, IECB, INSERM,U1212, F-33600 Pessac, France. [Boule, Jean-Baptiste] CNRS, UMR 7196, INSERM, U1154,MNHN, F-75005 Paris, France. [Boule, Jean-Baptiste] Univ Paris 04, F-75005 Paris, France. [Brosh, Robert M., Jr.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Mergny, JL (reprint author), Univ Bordeaux, ARNA Lab, F-33000 Bordeaux, France.; Mergny, JL (reprint author), CNRS, UMR 5320, IECB, INSERM,U1212, F-33600 Pessac, France.; Boule, JB (reprint author), CNRS, UMR 7196, INSERM, U1154,MNHN, F-75005 Paris, France.; Boule, JB (reprint author), Univ Paris 04, F-75005 Paris, France.; Brosh, RM (reprint author), NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. EM jean-baptiste.boule@mnhn.fr; broshr@grc.nia.nih.gov; jean-louis.mergny@inserm.fr RI Mergny, Jean-Louis/E-2860-2013 OI Mergny, Jean-Louis/0000-0003-3043-8401 FU Intramural Research program of the National Institutes of Health, NIA; Agence Nationale de la Recherche (ANR) [ANR-12-IS07-0001, ANR-12-BSV8-0008-01, ANR-10-NANO-04-03]; Inserm; Conseil Regional d'Aquitaine FX Intramural Research program of the National Institutes of Health, NIA (in part, to R.M.B.); Conseil Regional d'Aquitaine and Agence Nationale de la Recherche (ANR grants 'OligoSwitch' [ANR-12-IS07-0001]; 'Quarpdiem' [ANR-12-BSV8-0008-01]; 'VIBBnano' [ANR-10-NANO-04-03 to J.L.M]. Funding for open access charge: Inserm. NR 166 TC 12 Z9 12 U1 20 U2 46 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD MAR 18 PY 2016 VL 44 IS 5 BP 1989 EP 2006 DI 10.1093/nar/gkw079 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DI8AM UT WOS:000373723100012 PM 26883636 ER PT J AU Kim, J Abdelmohsen, K Yang, XL De, S Grammatikakis, I Noh, JH Gorospe, M AF Kim, Jiyoung Abdelmohsen, Kotb Yang, Xiaoling De, Supriyo Grammatikakis, Ioannis Noh, Ji Heon Gorospe, Myriam TI LncRNA OIP5-AS1/cyrano sponges RNA-binding protein HuR SO NUCLEIC ACIDS RESEARCH LA English DT Article ID LONG NONCODING RNAS; COMPETING ENDOGENOUS RNA; MESSENGER-RNA; POSTTRANSCRIPTIONAL REGULATION; POSTTRANSLATIONAL MODIFICATION; STABILITY FACTOR; MAMMALIAN-CELLS; GENE-REGULATION; NUCLEAR-RNA; EXPRESSION AB The function of the vast majority of mammalian long noncoding (lnc) RNAs remains unknown. Here, analysis of a highly abundant mammalian lncRNA, OIP5-AS1, known as cyrano in zebrafish, revealed that OIP5-AS1 reduces cell proliferation. In human cervical carcinoma HeLa cells, the RNA-binding protein HuR, which enhances cell proliferation, associated with OIP5-AS1 and stabilized it. Tagging OIP5-AS1 with MS2 hairpins to identify associated microRNAs revealed that miR-424 interacted with OIP5-AS1 and competed with HuR for binding to OIP5-AS1. We further identified a 'sponge' function for OIP5-AS1, as high levels of OIP5-AS1 increased HuR-OIP5-AS1 complexes and prevented HuR interaction with target mRNAs, including those that encoded proliferative proteins, while conversely, lowering OIP5-AS1 increased the abundance of HuR complexes with target mRNAs. We propose that OIP5-AS1 serves as a sponge or a competing endogenous (ce)RNA for HuR, restricting its availability to HuR target mRNAs and thereby repressing HuR-elicited proliferative phenotypes. C1 [Kim, Jiyoung; Abdelmohsen, Kotb; Yang, Xiaoling; De, Supriyo; Grammatikakis, Ioannis; Noh, Ji Heon; Gorospe, Myriam] NIA, Genet Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Gorospe, M (reprint author), NIA, Genet Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM gorospem@grc.nia.nih.gov OI De, Supriyo/0000-0002-2075-7655 FU NIA Intramural Research Program, NIH FX Funding for open access charge: NIA Intramural Research Program, NIH. NR 73 TC 2 Z9 2 U1 7 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD MAR 18 PY 2016 VL 44 IS 5 BP 2378 EP 2392 DI 10.1093/nar/gkw017 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DI8AM UT WOS:000373723100043 PM 26819413 ER PT J AU Panda, AC Abdelmohsen, K Martindale, JL Di Germanio, C Yang, XL Grammatikakis, I Noh, JH Zhang, YQ Lehrmann, E Dudekula, DB De, S Becker, KG White, EJ Wilson, GM de Cabo, R Gorospe, M AF Panda, Amaresh C. Abdelmohsen, Kotb Martindale, Jennifer L. Di Germanio, Clara Yang, Xiaoling Grammatikakis, Ioannis Noh, Ji Heon Zhang, Yongqing Lehrmann, Elin Dudekula, Dawood B. De, Supriyo Becker, Kevin G. White, Elizabeth J. Wilson, Gerald M. de Cabo, Rafael Gorospe, Myriam TI Novel RNA-binding activity of MYF5 enhances Ccnd1/Cyclin D1 mRNA translation during myogenesis SO NUCLEIC ACIDS RESEARCH LA English DT Article ID POSTTRANSCRIPTIONAL GENE-REGULATION; SKELETAL-MUSCLE REGENERATION; STEM-CELL FUNCTION; REGULATORY FACTORS; SATELLITE CELLS; PRECURSOR CELLS; UP-REGULATION; MYOD; EXPRESSION; PROTEIN AB Skeletal muscle contains long multinucleated and contractile structures known as muscle fibers, which arise from the fusion of myoblasts into multinucleated myotubes during myogenesis. The myogenic regulatory factor (MRF) MYF5 is the earliest to be expressed during myogenesis and functions as a transcription factor in muscle progenitor cells (satellite cells) and myocytes. In mouse C2C12 myocytes, MYF5 is implicated in the initial steps of myoblast differentiation into myotubes. Here, using ribonucleoprotein immunoprecipitation (RIP) analysis, we discovered a novel function for MYF5 as an RNA-binding protein which associated with a subset of myoblast mRNAs. One prominent MYF5 target was Ccnd1 mRNA, which encodes the key cell cycle regulator CCND1 (Cyclin D1). Biotin-RNA pulldown, UV-crosslinking and gel shift experiments indicated that MYF5 was capable of binding the 3' untranslated region (UTR) and the coding region (CR) of Ccnd1 mRNA. Silencing MYF5 expression in proliferating myoblasts revealed that MYF5 promoted CCND1 translation and modestly increased transcription of Ccnd1 mRNA. Accordingly, overexpressing MYF5 in C2C12 cells upregulated CCND1 expression while silencing MYF5 reduced myoblast proliferation as well as differentiation of myoblasts into myotubes. Moreover, MYF5 silencing reduced myogenesis, while ectopically restoring CCND1 abundance partially rescued the decrease inmyogenesis seen after MYF5 silencing. We propose that MYF5 enhances early myogenesis in part by coordinately elevating Ccnd1 transcription and Ccnd1 mRNA translation. C1 [Panda, Amaresh C.; Abdelmohsen, Kotb; Martindale, Jennifer L.; Yang, Xiaoling; Grammatikakis, Ioannis; Noh, Ji Heon; Zhang, Yongqing; Lehrmann, Elin; Dudekula, Dawood B.; De, Supriyo; Becker, Kevin G.; Gorospe, Myriam] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. [Di Germanio, Clara; de Cabo, Rafael] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [White, Elizabeth J.; Wilson, Gerald M.] Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA. [White, Elizabeth J.; Wilson, Gerald M.] Univ Maryland, Sch Med, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Di Germanio, Clara] Univ Teramo, Fac Vet Med, Teramo, Italy. RP Panda, AC (reprint author), NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. EM amaresh.panda@nih.gov RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; PANDA, AMARESH/0000-0003-3189-8995; De, Supriyo/0000-0002-2075-7655; , rafael/0000-0003-2830-5693 FU National Institute on Aging Intramural Research Program, National Institutes of Health FX Funding for open access charge: The National Institute on Aging Intramural Research Program, National Institutes of Health. NR 59 TC 3 Z9 3 U1 1 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD MAR 18 PY 2016 VL 44 IS 5 BP 2393 EP 2408 DI 10.1093/nar/gkw023 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DI8AM UT WOS:000373723100044 PM 26819411 ER PT J AU Sviridov, DO Drake, SK Freeman, LA Remaley, AT AF Sviridov, D. O. Drake, S. K. Freeman, L. A. Remaley, A. T. TI Amphipathic polyproline peptides stimulate cholesterol efflux by the ABCA1 transporter SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Cholesterol; ABCA1; Peptides; Polypro; Cardiovascular disease ID HIGH-DENSITY-LIPOPROTEIN; LIPID EFFLUX; PROTEINS; HELIX; SPECIFICITY; STRATEGIES; RECEPTOR; MICE; HDL AB ApoA-I mimetics are short synthetic peptides that contain an amphipathic alpha-helix and stimulate cholesterol efflux by the ABCA1 transporter in a detergent-like extraction mechanism. We investigated the use of amphipathic peptides with a polypro helix for stimulating cholesterol efflux by ABCA1. Polypro peptides were synthesized with modified prolines, containing either a hydrophobic phenyl group (Pro(p)) or a polar N-acetylgalactosamine (Pro(g)) attached to the pyrrolidine ring and were designated as either PP-2, 3, 4, or 5, depending on the number of 3 amino acid repeat units (Pro(p)-Pro(g)-Pro(p)). Based on molecular modeling, these peptides were predicted to be relatively rigid and to bind to a phospholipid bilayer. By CD spectroscopy, PP peptides formed a Type-II polypro helix in an aqueous solution. PP-2 was inactive in promoting cholesterol efflux, but peptides with more than 2 repeat units were active. PP-4 showed a similar V-max, as a much longer amphipathic alpha-helical peptide, containing 37 amino acids, but had a K-m that was approximately 20-fold lower. PP peptides were specific in that they did not stimulate cholesterol efflux from cells not expressing ABCA1 and were also non-cytotoxic. Addition of PP 3, 4 and 5 to serum promoted the formation of smaller size HDL species (7 nM) and increased its capacity for ABCA1-dependent cholesterol efflux by approximately 20-35% (p < 0.05). Because of their relatively small size and increased potency, amphipathic peptides with a polypro helix may represent an alternative structural motif for the development of apoA-I mimetic peptides. (C) 2016 The Authors. Published by Elsevier Inc. C1 [Sviridov, D. O.; Freeman, L. A.; Remaley, A. T.] NHLBI, Lipoprot Metab Sect, Cardiopulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Drake, S. K.] NIH, Dept Crit Care Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. RP Sviridov, DO (reprint author), NIH, Bldg 10,Room 8N-218,10 Ctr Dr, Bethesda, MD 20892 USA. EM sviridovd@mail.nih.gov FU Intramural Research Program, National Heart, Lung, and Blood Institute, National Institutes of Health FX This work was supported by the Intramural Research Program, National Heart, Lung, and Blood Institute, National Institutes of Health. NR 30 TC 1 Z9 1 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 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAR 18 PY 2016 VL 471 IS 4 BP 560 EP 565 DI 10.1016/j.bbrc.2016.02.032 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA DI1FS UT WOS:000373242600028 PM 26879139 ER PT J AU Das, A Fischer, RS Pan, DJ Waterman, CM AF Das, Arupratan Fischer, Robert S. Pan, Duojia Waterman, Clare M. TI YAP Nuclear Localization in the Absence of Cell-Cell Contact Is Mediated by a Filamentous Actin-dependent, Myosin II- and Phospho-YAP-independent Pathway during Extracellular Matrix Mechanosensing SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE cell adhesion; cytoskeleton; Hippo pathway; mechanotransduction; myosin; F-actin; YAP; contact inhibition; contractility ID HIPPO SIGNALING PATHWAY; TUMOR-SUPPRESSOR; F-ACTIN; PROMOTES APOPTOSIS; TISSUE-GROWTH; STEM-CELL; PROLIFERATION; DROSOPHILA; PROTEIN; INHIBITION AB Cell-cell contact inhibition and the mechanical environment of cells have both been shown to regulate YAP nuclear localization to modulate cell proliferation. Changes in cellular contractility by genetic, pharmacological, and matrix stiffness perturbations regulate YAP nuclear localization. However, because contractility and F-actin organization are interconnected cytoskeletal properties, it remains unclear which of these distinctly regulates YAP localization. Here we show that in the absence of cell-cell contact, actomyosin contractility suppresses YAP phosphorylation at Ser(112), however, neither loss of contractility nor increase in YAP phosphorylation is sufficient for its nuclear exclusion. We find that actin cytoskeletal integrity is essential for YAP nuclear localization, and can override phosphoregulation or contractility-mediated regulation of YAP nuclear localization. This actin-mediated regulation is conserved during mechanotransduction, as substrate compliance increased YAP phosphorylation and reduced cytoskeletal integrity leading to nuclear exclusion of both YAP and Ser(P)(112)-YAP. These data provide evidence for two actin-mediated pathways for YAP regulation; one in which actomyosin contractility regulates YAP phosphorylation, and a second that involves cytoskeletal integrity-mediated regulation of YAP nuclear localization independent of contractility. We suggest that in non-contact inhibited cells, this latter mechanism may be important in low stiffness regimes, such as may be encountered in physiological environments. C1 [Das, Arupratan; Fischer, Robert S.; Waterman, Clare M.] NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. [Das, Arupratan; Pan, Duojia] Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. RP Waterman, CM (reprint author), NHLBI, Lab Cell & Tissue Morphodynam, NIH, Bldg 50,South Dr.,Rm 4537, Bethesda, MD 20892 USA. EM watermancm@nhlbi.nih.gov FU NHLBI Division of Intramural Research; NEI through the National Institutes of Health [EY015708] FX This work was supported by the NHLBI Division of Intramural Research (to C. M. W., R. S. F., and A. D.) and Grant EY015708 from the NEI through the National Institutes of Health. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health. NR 48 TC 10 Z9 10 U1 3 U2 9 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 18 PY 2016 VL 291 IS 12 BP 6096 EP 6110 DI 10.1074/jbc.M115.708313 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DH6IM UT WOS:000372894200005 PM 26757814 ER PT J AU Sweadner, KJ Toro, C Whitlow, CT Snively, BM Cook, JF Ozelius, LJ Markello, TC Brashear, A AF Sweadner, Kathleen J. Toro, Camilo Whitlow, Christopher T. Snively, Beverly M. Cook, Jared F. Ozelius, Laurie J. Markello, Thomas C. Brashear, Allison TI ATP1A3 Mutation in Adult Rapid-Onset Ataxia SO PLOS ONE LA English DT Article ID ALTERNATING HEMIPLEGIA; DYSTONIA-PARKINSONISM; CEREBELLAR-ATAXIA; CRYSTAL-STRUCTURE; CAPOS SYNDROME; CHILDHOOD; PROTEIN; DISORDERS; CHILDREN; SPECTRUM AB A 21-year old male presented with ataxia and dysarthria that had appeared over a period of months. Exome sequencing identified a de novo missense variant in ATP1A3, the gene encoding the alpha 3 subunit of Na,K-ATPase. Several lines of evidence suggest that the variant is causative. ATP1A3 mutations can cause rapid-onset dystonia-parkinsonism (RDP) with a similar age and speed of onset, as well as severe diseases of infancy. The patient's ATP1A3 p.Gly316Ser mutation was validated in the laboratory by the impaired ability of the expressed protein to support the growth of cultured cells. In a crystal structure of Na,K-ATPase, the mutated amino acid was directly apposed to a different amino acid mutated in RDP. Clinical evaluation showed that the patient had many characteristics of RDP, however he had minimal fixed dystonia, a defining symptom of RDP. Successive magnetic resonance imaging (MRI) revealed progressive cerebellar atrophy, explaining the ataxia. The absence of dystonia in the presence of other RDP symptoms corroborates other evidence that the cerebellum contributes importantly to dystonia pathophysiology. We discuss the possibility that a second de novo variant, in ubiquilin 4 (UBQLN4), a ubiquitin pathway component, contributed to the cerebellar neurodegenerative phenotype and differentiated the disease from other manifestations of ATP1A3 mutations. We also show that a homozygous variant in GPRIN1 (G protein-regulated inducer of neurite outgrowth 1) deletes a motif with multiple copies and is unlikely to be causative. C1 [Sweadner, Kathleen J.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Sweadner, Kathleen J.] Harvard Univ, Sch Med, Boston, MA USA. [Toro, Camilo] NHGRI, NIH Undiagnosed Dis Program Common Fund, Off Director, NIH, Bethesda, MD 20892 USA. [Toro, Camilo] NHGRI, Off Clin Director, Bethesda, MD 20892 USA. [Whitlow, Christopher T.] Wake Forest Sch Med, Dept Radiol, Winston Salem, NC USA. [Whitlow, Christopher T.] Wake Forest Sch Med, Dept Biomed Engn, Winston Salem, NC USA. [Snively, Beverly M.] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Cook, Jared F.; Brashear, Allison] Wake Forest Sch Med, Dept Neurol, Winston Salem, NC USA. [Ozelius, Laurie J.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Markello, Thomas C.] NHGRI, NIH Undiagnosed Dis Program, Common Fund, Off Director,NIH, Bethesda, MD 20892 USA. [Markello, Thomas C.] NHGRI, Human Biochem Genet Sect, Med Genet Branch, Bethesda, MD 20892 USA. RP Sweadner, KJ (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA.; Sweadner, KJ (reprint author), Harvard Univ, Sch Med, Boston, MA USA. EM sweadner@helix.mgh.harvard.edu FU Common Fund of the National Institutes of Health; National Institutes of Health (NIH) [5R01 NS058949]; National Institutes of Health (NIH) Undiagnosed Diseases Program [HSSN30221300096P, HSSN268201300238P] FX The Undiagnosed Diseases Program is funded by the Common Fund of the National Institutes of Health. This study was supported by National Institutes of Health (NIH) grant 5R01 NS058949 to AB, and by the National Institutes of Health (NIH) Undiagnosed Diseases Program HSSN30221300096P to AB and HSSN268201300238P to KJS. NR 49 TC 5 Z9 5 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 18 PY 2016 VL 11 IS 3 AR e0151429 DI 10.1371/journal.pone.0151429 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH1ZE UT WOS:000372582800063 PM 26990090 ER PT J AU Kumari, S Deng, WP Gunasekara, C Chiang, V Chen, HS Ma, H Davis, X Wei, HR AF Kumari, Sapna Deng, Wenping Gunasekara, Chathura Chiang, Vincent Chen, Huann-sheng Ma, Hao Davis, Xin Wei, Hairong TI Bottom-up GGM algorithm for constructing multilayered hierarchical gene regulatory networks that govern biological pathways or processes SO BMC BIOINFORMATICS LA English DT Article DE Multilayered gene regulatory network; Pathway; Microarray or RNA-seq data ID NAC TRANSCRIPTION FACTORS; SECONDARY WALL SYNTHESIS; EXPRESSION DATA; ARABIDOPSIS-THALIANA; ESCHERICHIA-COLI; POPULUS-TRICHOCARPA; BAYESIAN NETWORKS; MICROARRAY DATA; WOOD FORMATION; FACTORS NST1 AB Background: Multilayered hierarchical gene regulatory networks (ML-hGRNs) are very important for understanding genetics regulation of biological pathways. However, there are currently no computational algorithms available for directly building ML-hGRNs that regulate biological pathways. Results: A bottom-up graphic Gaussian model (GGM) algorithm was developed for constructing ML-hGRN operating above a biological pathway using small-to medium-sized microarray or RNA-seq data sets. The algorithm first placed genes of a pathway at the bottom layer and began to construct a ML-hGRN by evaluating all combined triple genes: two pathway genes and one regulatory gene. The algorithm retained all triple genes where a regulatory gene significantly interfered two paired pathway genes. The regulatory genes with highest interference frequency were kept as the second layer and the number kept is based on an optimization function. Thereafter, the algorithm was used recursively to build a ML-hGRN in layer-by-layer fashion until the defined number of layers was obtained or terminated automatically. Conclusions: We validated the algorithm and demonstrated its high efficiency in constructing ML-hGRNs governing biological pathways. The algorithm is instrumental for biologists to learn the hierarchical regulators associated with a given biological pathway from even small-sized microarray or RNA-seq data sets. C1 [Kumari, Sapna; Deng, Wenping; Gunasekara, Chathura; Wei, Hairong] Michigan Technol Univ, Sch Forest Resources & Environm Sci, Houghton, MI 49931 USA. [Chiang, Vincent; Davis, Xin] N Carolina State Univ, Dept Forestry & Environm Resources, Raleigh, NC 27695 USA. [Chen, Huann-sheng] NCI, Stat Methodol & Applicat Branch, Div Canc Control & Populat Sci, NIH, Rockville, MD 20850 USA. [Ma, Hao] ARS, NCCWA, USDA, Kearneysville, WV 25430 USA. RP Wei, HR (reprint author), Michigan Technol Univ, Sch Forest Resources & Environm Sci, Houghton, MI 49931 USA. EM hairong@mtu.edu NR 70 TC 1 Z9 1 U1 2 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD MAR 18 PY 2016 VL 17 AR 132 DI 10.1186/s12859-016-0981-1 PG 12 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA DH0PQ UT WOS:000372486500005 PM 26993098 ER PT J AU Lagerlof, O Slocomb, JE Hong, I Aponte, Y Blackshaw, S Hart, GW Huganir, RL AF Lagerloef, Olof Slocomb, Julia E. Hong, Ingie Aponte, Yeka Blackshaw, Seth Hart, Gerald W. Huganir, Richard L. TI The nutrient sensor OGT in PVN neurons regulates feeding SO SCIENCE LA English DT Article ID O-GLCNAC TRANSFERASE; BODY-MASS INDEX; N-ACETYLGLUCOSAMINE; X-CHROMOSOME; GLUCOSE; PHOSPHORYLATION; GLCNACYLATION; RATS; ASSOCIATION; EXPRESSION AB Maintaining energy homeostasis is crucial for the survival and health of organisms. The brain regulates feeding by responding to dietary factors and metabolic signals from peripheral organs. It is unclear how the brain interprets these signals. O-GlcNAc transferase (OGT) catalyzes the posttranslational modification of proteins by O-GlcNAc and is regulated by nutrient access. Here, we show that acute deletion of OGT from alpha CaMKII-positive neurons in adult mice caused obesity from overeating. The hyperphagia derived from the paraventricular nucleus (PVN) of the hypothalamus, where loss of OGT was associated with impaired satiety. These results identify O-GlcNAcylation in alpha CaMKII neurons of the PVN as an important molecular mechanism that regulates feeding behavior. C1 [Lagerloef, Olof; Hong, Ingie; Aponte, Yeka; Blackshaw, Seth; Huganir, Richard L.] Johns Hopkins Univ, Sch Med, Kavli Neurosci Discovery Inst, Solomon H Snyder Dept Neurosci, Baltimore, MD 21205 USA. [Lagerloef, Olof; Hart, Gerald W.] Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD 21205 USA. [Slocomb, Julia E.] Natl Inst Drug Abuse Natl Inst Hlth Johns Hopkins, Baltimore, MD 21224 USA. [Aponte, Yeka] NIDA, Intramural Res Program, Neuronal Circuits & Behav Unit, Baltimore, MD 21224 USA. RP Huganir, RL (reprint author), Johns Hopkins Univ, Sch Med, Kavli Neurosci Discovery Inst, Solomon H Snyder Dept Neurosci, Baltimore, MD 21205 USA. EM rhuganir@jhmi.edu FU NIH [R01NS036715, R01DK6167, N01-HV-00240, P01HL107153]; National Institute on Drug Abuse Intramural Research Program FX O.L., G.W.H., and R.L.H. designed all experiments; the optogenetics experiments were also designed by Y.A. and J.E.S., and the elecotrophysiological experiments were also designed by I.H. O.L. performed all experiments and analyzed all data but the electrophysiology (I.H.) and the optogenetics (J.E.S.). The optogenetics data were analyzed by J.E.S., Y.A., and O.L. O.L., G.W.H., and R.L.H. wrote the manuscript. We thank G. Schutz for providing the alpha CaMKII-CreERT2 mice, J. L. Bedont for help with in situ hybridization experiments, and R. H. White for assistance with mating and genotyping. All data necessary to understand and assess the conclusions of the manuscript are in the body of the paper and in the supplementary materials. All primary data are archived on a secure server located in the Department of Neuroscience at Johns Hopkins University (JHU). All data will be made available upon request. G.W.H. receives a share of royalty received by the university on sales of the CTD 110.6 antibody, which are managed by JHU. The research was supported by NIH (grant R01NS036715 to R.L.H. and grants R01DK6167, N01-HV-00240, and P01HL107153 to G.W.H.) and the National Institute on Drug Abuse Intramural Research Program (Y.A.). NR 23 TC 10 Z9 11 U1 14 U2 30 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 MAR 18 PY 2016 VL 351 IS 6279 BP 1293 EP 1296 DI 10.1126/science.aad5494 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG9JD UT WOS:000372397700036 PM 26989246 ER PT J AU Corti, D Misasi, J Mulangu, S Stanley, DA Kanekiyo, M Wollen, S Ploquin, A Doria-Rose, NA Staupe, RP Bailey, M Shi, W Choe, M Marcus, H Thompson, EA Cagigi, A Silacci, C Fernandez-Rodriguez, B Perez, L Sallusto, F Vanzetta, F Agatic, G Cameroni, E Kisalu, N Gordon, I Ledgerwood, JE Mascola, JR Graham, BS Muyembe-Tamfun, JJ Trefry, JC Lanzavecchia, A Sullivan, NJ AF Corti, Davide Misasi, John Mulangu, Sabue Stanley, Daphne A. Kanekiyo, Masaru Wollen, Suzanne Ploquin, Aurelie Doria-Rose, Nicole A. Staupe, Ryan P. Bailey, Michael Shi, Wei Choe, Misook Marcus, Hadar Thompson, Emily A. Cagigi, Alberto Silacci, Chiara Fernandez-Rodriguez, Blanca Perez, Laurent Sallusto, Federica Vanzetta, Fabrizia Agatic, Gloria Cameroni, Elisabetta Kisalu, Neville Gordon, Ingelise Ledgerwood, Julie E. Mascola, John R. Graham, Barney S. Muyembe-Tamfun, Jean-Jacques Trefry, John C. Lanzavecchia, Antonio Sullivan, Nancy J. TI Protective monotherapy against lethal Ebola virus infection by a potently neutralizing antibody SO SCIENCE LA English DT Article ID MONOCLONAL-ANTIBODIES; OUTBREAK; MONKEYS; DISEASE; ZAIRE AB Ebola virus disease in humans is highly lethal, with case fatality rates ranging from 25 to 90%. There is no licensed treatment or vaccine against the virus, underscoring the need for efficacious countermeasures. We ascertained that a human survivor of the 1995 Kikwit Ebola virus disease outbreak maintained circulating antibodies against the Ebola virus surface glycoprotein for more than a decade after infection. From this survivor we isolated monoclonal antibodies (mAbs) that neutralize recent and previous outbreak variants of Ebola virus and mediate antibody-dependent cell-mediated cytotoxicity in vitro. Strikingly, monotherapy with mAb114 protected macaques when given as late as 5 days after challenge. Treatment with a single human mAb suggests that a simplified therapeutic strategy for human Ebola infection may be possible. C1 [Corti, Davide; Silacci, Chiara; Fernandez-Rodriguez, Blanca; Perez, Laurent; Sallusto, Federica; Lanzavecchia, Antonio] Univ Svizzera Italiana, Inst Res Biomed, CH-6500 Bellinzona, Switzerland. [Corti, Davide; Vanzetta, Fabrizia; Agatic, Gloria; Cameroni, Elisabetta] Humabs BioMed SA, CH-6500 Bellinzona, Switzerland. [Misasi, John; Mulangu, Sabue; Stanley, Daphne A.; Kanekiyo, Masaru; Ploquin, Aurelie; Doria-Rose, Nicole A.; Staupe, Ryan P.; Bailey, Michael; Shi, Wei; Choe, Misook; Marcus, Hadar; Thompson, Emily A.; Cagigi, Alberto; Kisalu, Neville; Gordon, Ingelise; Ledgerwood, Julie E.; Mascola, John R.; Graham, Barney S.; Sullivan, Nancy J.] NIAID, Vaccine Res Ctr, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Wollen, Suzanne; Trefry, John C.] US Army, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. [Kisalu, Neville; Muyembe-Tamfun, Jean-Jacques] Natl Lab Publ Hlth, Natl Inst Biomed Res, BP 1197, Kinshasa, DEM REP CONGO. [Lanzavecchia, Antonio] ETH, Inst Microbiol, CH-8093 Zurich, Switzerland. RP Sullivan, NJ (reprint author), NIAID, Vaccine Res Ctr, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM njsull@mail.nih.gov RI Cagigi, Alberto/K-4824-2016 OI Cagigi, Alberto/0000-0002-3567-9514 FU Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases FX We thank M. Cichanowski for graphics, B. Hartman for manuscript preparation, A. Tislerics and J. McLellan for critical reading of the manuscript, A. R. Townsend for providing EBOV-GP expressing MDCK-SIAT cells, and the study volunteers for the donation of blood for these investigations. The data reported in this manuscript are tabulated in the main paper and in the supplementary materials. Antibody sequences have been deposited in GenBank with accession numbers KU594601, KU594602, KU594603, and KU594604. Supported by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases. N.J.S., S.M., B.S.G., J.E.L, D.A.S., J.-J.M.-T J.C.T., D.C., and A.L. are listed as inventors on patent applications related to anti-Ebola virus antibodies and their use. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the U.S. Department of Defense or the U.S. Department of the Army. NR 19 TC 23 Z9 23 U1 11 U2 30 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 MAR 18 PY 2016 VL 351 IS 6279 BP 1339 EP 1342 DI 10.1126/science.aad5224 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG9JD UT WOS:000372397700047 PM 26917593 ER PT J AU Misasi, J Gilman, MSA Kanekiyo, M Gui, M Cagigi, A Mulangu, S Corti, D Ledgerwood, JE Lanzavecchia, A Cunningham, J Muyembe-Tamfun, JJ Baxa, U Graham, BS Xiang, Y Sullivan, NJ McLellan, JS AF Misasi, John Gilman, Morgan S. A. Kanekiyo, Masaru Gui, Miao Cagigi, Alberto Mulangu, Sabue Corti, Davide Ledgerwood, Julie E. Lanzavecchia, Antonio Cunningham, James Muyembe-Tamfun, Jean Jacques Baxa, Ulrich Graham, Barney S. Xiang, Ye Sullivan, Nancy J. McLellan, Jason S. TI Structural and molecular basis for Ebola virus neutralization by protective human antibodies SO SCIENCE LA English DT Article ID NIEMANN-PICK C1; MEDIATED NEUTRALIZATION; CONFORMATIONAL EPITOPE; ENTRY REQUIRES; MARBURG VIRUS; VIRAL ENTRY; GLYCOPROTEIN; INFECTION; RESIDUES; DISEASE AB Ebola virus causes hemorrhagic fever with a high case fatality rate for which there is no approved therapy. Two human monoclonal antibodies, mAb100 and mAb114, in combination, protect nonhuman primates against all signs of Ebola virus disease, including viremia. Here, we demonstrate that mAb100 recognizes the base of the Ebola virus glycoprotein (GP) trimer, occludes access to the cathepsin-cleavage loop, and prevents the proteolytic cleavage of GP that is required for virus entry. We show that mAb114 interacts with the glycan cap and inner chalice of GP, remains associated after proteolytic removal of the glycan cap, and inhibits binding of cleaved GP to its receptor. These results define the basis of neutralization for two protective antibodies and may facilitate development of therapies and vaccines. C1 [Misasi, John; Kanekiyo, Masaru; Cagigi, Alberto; Mulangu, Sabue; Ledgerwood, Julie E.; Graham, Barney S.; Sullivan, Nancy J.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Gilman, Morgan S. A.; McLellan, Jason S.] Geisel Sch Med Dartmouth, Dept Biochem, Hanover, NH 03755 USA. [Baxa, Ulrich] Leidos Biomed Res Inc, Electron Microscopy Lab, Canc Res Technol Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Gui, Miao; Xiang, Ye] Tsinghua Univ, Collaborat Innovat Ctr Diag & Treatment Infect Di, Beijing Adv Innovat Ctr Struct Biol, Ctr Infect Dis Res,Dept Basic Med Sci,Sch Med, Beijing 100084, Peoples R China. [Misasi, John; Cunningham, James] Harvard Univ, Sch Med, Dept Med, Brigham & Womens Hosp, Boston, MA 02115 USA. [Corti, Davide; Lanzavecchia, Antonio] Univ Svizzera Italiana, Inst Res Biomed, CH-6500 Bellinzona, Switzerland. [Muyembe-Tamfun, Jean Jacques] Natl Lab Publ Hlth, Natl Inst Biomed Res, BP 1197, Kinshasa, DEM REP CONGO. [Misasi, John] Boston Childrens Hosp, Div Infect Dis, Boston, MA 02215 USA. [Lanzavecchia, Antonio] Swiss Fed Inst Technol, Inst Microbiol, CH-8093 Zurich, Switzerland. RP Sullivan, NJ (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.; Xiang, Y (reprint author), Tsinghua Univ, Collaborat Innovat Ctr Diag & Treatment Infect Di, Beijing Adv Innovat Ctr Struct Biol, Ctr Infect Dis Res,Dept Basic Med Sci,Sch Med, Beijing 100084, Peoples R China. EM yxiang@mail.tsinghua.edu.cn; njsull@mail.nih.gov RI Cagigi, Alberto/K-4824-2016 OI Cagigi, Alberto/0000-0002-3567-9514 FU Boston Children's Hospital Faculty Development award; National Institute of General Medical Sciences of the National Institutes of Health [T32GM008704]; 973 program [2015CB14010102]; National Natural Science Foundation of China [81550001, 31470721]; Junior Thousand Talents Program of China [20131770418]; Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E]; UChicago Argonne, LLC, for the US. Department of Energy, Office of Biological and Environmental Research [DE-AC02-06CH11357]; [NIH-5K08AI079381] FX We thank the 19-ID beamline staff at the Structural Biology Center at the Advanced Photon Source Argonne National Laboratory. We thank W. Shi and M. Choe for preparation of antibodies, J. Mascot and K Leigh for critical reading, M. Cichanowski for graphics, and B. Hartman for manuscript preparation,. The data presented in this manuscript am tabulated in the main paper and in the supplementaiy materials. Atomic coordinates and structure factors for the crystal structures of Fab114, Fab100 and the ternary complex of these Fabs bound to Ebola virus GP have been deposited in the Protein Data Bank under accession codes 5FHA, 5FHB, and 5FHC, respectively. Cryo-EM maps and related materials have been deposited to the EM Data Bank under accession codes EMD-3310 and EMD-3311. This work was supported by the Intramural Research Program of the Vaccine Research Center, the National Institute of Allergy and Infectious Diseases, and the National Institutes of Health. J.M. received grant support from NIH-5K08AI079381 and a Boston Children's Hospital Faculty Development award. M.S.A.G. was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award T32GM008704. TA. received grant support from the 973 program (2015CB14010102), the National Natural Science Foundation of China (81550001 and 31470721), and the Junior Thousand Talents Program of China (20131770418). This work was funded in part with federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E. We thank the Tsinghua University Branch of China. National Center for Protein Sciences (Beijing) for providing the EM facility support. Argonne is operated by UChicago Argonne, LLC, for the US. Department of Energy, Office of Biological and Environmental Research, under contract DE-AC02-06CH11357. N.S., S.M., B.G., J.L., J.J.M.T., D.C., and A.L. are listed as inventors on patent applications related to antibodies to Ebola virus and their use. The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 35 TC 15 Z9 15 U1 11 U2 28 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 MAR 18 PY 2016 VL 351 IS 6279 BP 1343 EP 1346 DI 10.1126/science.aad6117 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG9JD UT WOS:000372397700048 PM 26917592 ER EF