FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Chang, IS Jiang, SS Yang, JCH Su, WC Chien, LH Hsiao, CF Lee, JH Chen, CY Chen, CH Chang, GC Wang, ZM Lo, FY Chen, KY Wang, WC Chen, YM Huang, MS Tsai, YH Su, YC Hsieh, WS Shih, WC Shieh, SH Yang, TY Lan, Q Rothman, N Chen, CJ Chanock, SJ Yang, PC Hsiung, CA AF Chang, I-Shou Jiang, Shih Sheng Yang, James Chih-Hsin Su, Wu-Chou Chien, Li-Hsin Hsiao, Chin-Fu Lee, Jih-Hsiang Chen, Chih-Yi Chen, Chung-Hsing Chang, Gee-Chen Wang, Zhaoming Lo, Fang-Yi Chen, Kuan-Yu Wang, Wen-Chang Chen, Yuh-Min Huang, Ming-Shyan Tsai, Ying-Huang Su, Yu-Chun Hsieh, Wan-Shan Shih, Wen-Chi Shieh, Shwn-Huey Yang, Tsung-Ying Lan, Qing Rothman, Nathaniel Chen, Chien-Jen Chanock, Stephen J. Yang, Pan-Chyr Hsiung, Chao A. TI Genetic Modifiers of Progression-Free Survival in Never-Smoking Lung Adenocarcinoma Patients Treated with First-Line Tyrosine Kinase Inhibitors SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE lung neoplasms; molecular targeted therapy; never-smokers; genome-wide association study; single-nucleotide polymorphism ID RANDOMIZED PHASE-3 TRIAL; GENOME-WIDE ASSOCIATION; EGFR MUTATIONS; OPEN-LABEL; CANCER; GEFITINIB; CHEMOTHERAPY; ERLOTINIB; THERAPY; MULTICENTER AB Rationale: Patients with non-small cell lung cancer (NSCLC) with mutated epidermal growth factor receptor (EGFR) are relatively sensitive to EGFR-tyrosine kinase inhibitor (TKI) treatment and have longer progression-free survival (PFS) when treated with EGFR-TKI compared with platinum-based chemotherapy. However, many patients with advanced NSCLC who have mutated EGFR do not respond to first-line EGFR-TKI treatment and still have shorter PFS. Objectives: The aim of this study was to identify genetic variants associated with PFS among patients with lung adenocarcinoma who were treated with first-line EGFR-TKIs. Methods: A genome-wide association study on PFS was performed in never-smoking women diagnosed with lung adenocarcinoma and who were treated with first-line EGFR-TKIs (n = 128). Significant single-nucleotide polymorphisms (SNPs) were selected for follow-up association analysis (n = 198) and for replication assay in another independent cohort (n = 153). Measurements and Main Results: We identified SNPs at 4q12 associated with PFS at genome-wide significance (P < 10(-8)) and with an estimated hazard ratio of more than 4. This association was also replicated in a larger but similar cohort and in an independent NSCLC cohort. Follow-up functional analyses showed that these SNPs were associated with the expression of EGFR, which encodes the TKI target, and with a nearby gene neuromedin-U, which encodes a G protein-coupled receptor ligand known to be involved in the progression of NSCLC. Considering these as possible prognostic biomarkers for the treatment of patients with late-stage lung cancer, we found that these SNPs were not associated with EGFR mutation status or with polymorphism of the Bcl2-interacting mediator of cell death gene. Conclusions: Genetic variants in 4q12 merit further investigation to assess their potential as pharmacogenomic predictors for and to understand the biology underlying its influence on PFS in patients treated with TKI therapy. C1 [Chang, I-Shou; Jiang, Shih Sheng; Chen, Chung-Hsing] Natl Inst Canc Res, Zhunan, Taiwan. [Chien, Li-Hsin; Hsiao, Chin-Fu; Lo, Fang-Yi; Wang, Wen-Chang; Su, Yu-Chun; Hsieh, Wan-Shan; Shih, Wen-Chi; Hsiung, Chao A.] Natl Hlth Res Inst, Inst Populat Hlth Sci, 35 Keyan Rd, Zuhan 35053, Taiwan. [Hsiao, Chin-Fu] Natl Hlth Res Inst, Taiwan Lung Canc Tissue Specimen Informat Resourc, Zhunan, Taiwan. [Yang, James Chih-Hsin; Lee, Jih-Hsiang] Natl Taiwan Univ, Natl Taiwan Univ Hosp, Dept Oncol, Taipei, Taiwan. [Yang, Pan-Chyr] Natl Taiwan Univ, Natl Taiwan Univ Hosp, Dept Internal Med, Taipei, Taiwan. [Yang, James Chih-Hsin; Chen, Kuan-Yu; Yang, Pan-Chyr] Natl Taiwan Univ, Coll Med, Taipei, Taiwan. [Yang, James Chih-Hsin] Natl Taiwan Univ, Natl Cheng Kung Univ Hosp, Grant Inst Oncol, Taipei, Taiwan. [Yang, James Chih-Hsin] Natl Taiwan Univ, Natl Cheng Kung Univ Hosp, Canc Res Ctr, Coll Med, Taipei, Taiwan. [Chen, Kuan-Yu] Natl Taiwan Univ, Natl Cheng Kung Univ Hosp, Dept Internal Med, Div Pulm Med, Taipei, Taiwan. [Su, Wu-Chou] Natl Cheng Kung Univ, Natl Cheng Kung Univ Hosp, Coll Med, Dept Internal Med, Tainan, Taiwan. [Chen, Chih-Yi] Chung Shan Med Univ Hosp, Inst Med, Taichung, Taiwan. [Hsiao, Chin-Fu] Chung Shan Med Univ Hosp, Dept Surg, Div Thorac Surg, Taichung, Taiwan. [Chang, Gee-Chen] Natl Yang Ming Univ, Fac Med, Sch Med, Taipei, Taiwan. [Chang, Gee-Chen; Yang, Tsung-Ying] Taichung Vet Gen Hosp, Dept Internal Med, Div Chest Med, Taichung, Taiwan. [Wang, Zhaoming] NCI, Canc Genom Res Lab, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Lan, Qing; Rothman, Nathaniel; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Wang, Wen-Chang] Taipei Med Univ, Coll Med Sci & Technol, Ph D Program Translat Med, Taipei, Taiwan. [Chen, Yuh-Min] Taipei Med Univ, Coll Med Sci & Technol, Taipei, Taiwan. [Chen, Yuh-Min] Taipei Vet Gen Hosp, Dept Chest Med, Taipei, Taiwan. [Huang, Ming-Shyan] Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Sch Med, Dept Internal Med, Kaohsiung, Taiwan. [Tsai, Ying-Huang] Chiayi Chang Gung Mem Hosp, Div Pulm & Crit Care Med, Chiayi, Taiwan. [Shieh, Shwn-Huey] China Med Univ, Dept Hlth Serv Adm, Taichung, Taiwan. [Shieh, Shwn-Huey] China Med Univ, Dept Nursing, Taichung, Taiwan. [Chen, Chien-Jen] Acad Sinica, Gen Res Ctr, Taipei, Taiwan. RP Hsiung, CA (reprint author), Natl Hlth Res Inst, Inst Populat Hlth Sci, 35 Keyan Rd, Zuhan 35053, Taiwan. EM hsiung@nhri.org.tw NR 31 TC 0 Z9 0 U1 1 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD MAR 1 PY 2017 VL 195 IS 5 BP 663 EP 673 DI 10.1164/rccm.201602-0300OC PG 11 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA EM5ND UT WOS:000395357400016 PM 27669169 ER PT J AU Taubert, J Weldon, KB Parr, LA AF Taubert, Jessica Weldon, Kimberly B. Parr, Lisa A. TI Robust representations of individual faces in chimpanzees (Pan troglodytes) but not monkeys (Macaca mulatta) SO ANIMAL COGNITION LA English DT Article DE Face recognition; Face perception; Chimpanzees; Rhesus monkeys; Familiarity; Image averaging ID SPLIT-BRAIN MONKEYS; UNFAMILIAR FACES; HEMISPHERIC-SPECIALIZATION; NONHUMAN-PRIMATES; SELECTIVE REGIONS; MATCHING TASK; RECOGNITION; FAMILIAR; PERCEPTION; VIEWPOINT AB Being able to recognize the faces of our friends and family members no matter where we see them represents a substantial challenge for the visual system because the retinal image of a face can be degraded by both changes in the person (age, expression, pose, hairstyle, etc.) and changes in the viewing conditions (direction and degree of illumination). Yet most of us are able to recognize familiar people effortlessly. A popular theory for how face recognition is achieved has argued that the brain stabilizes facial appearance by building average representations that enhance diagnostic features that reliably vary between people while diluting features that vary between instances of the same person. This explains why people find it easier to recognize average images of people, created by averaging multiple images of the same person together, than single instances (i.e. photographs). Although this theory is gathering momentum in the psychological and computer sciences, there is no evidence of whether this mechanism represents a unique specialization for individual recognition in humans. Here we tested two species, chimpanzees (Pan troglodytes) and rhesus monkeys (Macaca mulatta), to determine whether average images of different familiar individuals were easier to discriminate than photographs of familiar individuals. Using a two-alternative forced-choice, match-to-sample procedure, we report a behaviour response profile that suggests chimpanzees encode the faces of conspecifics differently than rhesus monkeys and in a manner similar to humans. C1 [Taubert, Jessica; Weldon, Kimberly B.; Parr, Lisa A.] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30329 USA. [Taubert, Jessica] NIMH, Bethesda, MD 20814 USA. [Parr, Lisa A.] Emory Univ, Div Psychiat & Behav Sci, Atlanta, GA 30322 USA. RP Taubert, J (reprint author), Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30329 USA.; Taubert, J (reprint author), NIMH, Bethesda, MD 20814 USA. EM jesstaubert@gmail.com FU NIH/NCRR [RR-00165, R01-MH068791] FX This investigation was supported by RR-00165 from the NIH/NCRR to the Yerkes National Primate Research Center and R01-MH068791 to L.A. Parr. NR 68 TC 0 Z9 0 U1 5 U2 5 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1435-9448 EI 1435-9456 J9 ANIM COGN JI Anim. Cogn. PD MAR PY 2017 VL 20 IS 2 BP 321 EP 329 DI 10.1007/s10071-016-1054-6 PG 9 WC Behavioral Sciences; Zoology SC Behavioral Sciences; Zoology GA EL0LH UT WOS:000394313400018 PM 27864643 ER PT J AU Parsons, C Lee, S Jayeola, V Kathariou, S AF Parsons, Cameron Lee, Sangmi Jayeola, Victor Kathariou, Sophia TI Novel Cadmium Resistance Determinant in Listeria monocytogenes SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article DE Listeria monocytogenes; cadmium resistance; cadA; biofilm; virulence ID ESCHERICHIA-COLI O157-H7; PLASMID-BORNE CADMIUM; SEROTYPE 4B; GENETIC-CHARACTERIZATION; BENZALKONIUM CHLORIDE; UNITED-STATES; STRAINS; GENOME; OUTBREAK; SUSCEPTIBILITY AB Listeria monocytogenes is a foodborne pathogen that can cause severe disease (listeriosis) in susceptible individuals. It is ubiquitous in the environment and often exhibits resistance to heavy metals. One of the determinants that enables Listeria to tolerate exposure to cadmium is the cadAC efflux system, with CadA being a P-type ATPase. Three different cadA genes (designated cadA1 to cadA3) were previously characterized in L. monocytogenes. A novel putative cadmium resistance gene (cadA4) was recently identified through whole-genome sequencing, but experimental confirmation for its involvement in cadmium resistance is lacking. In this study, we characterized cadA4 in L. monocytogenes strain F8027, a cadmium-resistant strain of serotype 4b. By screening a mariner-based transposon library of this strain, we identified a mutant with reduced tolerance to cadmium and that harbored a single transposon insertion in cadA4. The tolerance to cadmium was restored by genetic complementation with the cadmium resistance cassette (cadA4C), and enhanced cadmium tolerance was conferred to two unrelated cadmium-sensitive strains via heterologous complementation with cadA4C. Cadmium exposure induced cadA4 expression, even at noninhibitory levels. Virulence assessments in the Galleria mellonella model suggested that a functional cadA4 suppressed virulence, potentially promoting commensal colonization of the insect larvae. Biofilm assays suggested that cadA4 inactivation reduced biofilm formation. These data not only confirm cadA4 as a novel cadmium resistance determinant in L. monocytogenes but also provide evidence for roles in virulence and biofilm formation. IMPORTANCE Listeria monocytogenes is an intracellular foodborne pathogen causing the disease listeriosis, which is responsible for numerous hospitalizations and deaths every year. Among the adaptations that enable the survival of Listeria in the environment are the abilities to persist in biofilms, grow in the cold, and tolerate toxic compounds, such as heavy metals. Here, we characterized a novel determinant that was recently identified on a larger mobile genetic island through whole-genome sequencing. This gene (cadA4) was found to be responsible for cadmium detoxification and to be a divergent member of the Cad family of cadmium efflux pumps. Virulence assessments in a Galleria mellonella model suggested that cadA4 may suppress virulence. Additionally, cadA4 may be involved in the ability of Listeria to form biofilms. Beyond the role in cadmium detoxification, the involvement of cadA4 in other cellular functions potentially explains its retention and wide distribution in L. monocytogenes. C1 [Parsons, Cameron; Lee, Sangmi; Jayeola, Victor; Kathariou, Sophia] North Carolina State Univ, Dept Food Bioproc & Nutr Sci, Raleigh, NC 27695 USA. [Lee, Sangmi] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Kathariou, S (reprint author), North Carolina State Univ, Dept Food Bioproc & Nutr Sci, Raleigh, NC 27695 USA. EM sophia_kathariou@ncsu.edu FU USDA [2011-2012-67017-30218] FX This study was partially funded by a USDA grant (no. 2011-2012-67017-30218). NR 45 TC 0 Z9 0 U1 0 U2 0 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 MAR PY 2017 VL 85 IS 4 AR UNSP e02580 DI 10.1128/AEM.02580-16 PG 16 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA EK5JK UT WOS:000393962500005 ER PT J AU Withisuphakorn, P Jiraporn, P AF Withisuphakorn, Pradit Jiraporn, Pornsit TI Co-opted directors and powerful CEOs: evidence from the CEO pay slice (CPS) SO APPLIED ECONOMICS LETTERS LA English DT Article DE Co-opted directors; co-option; CEO power; powerful CEOs; corporate governance; G30; G34 AB We explore the effect of co-opted directors on chief executive officer (CEO) power. Co-opted directors are those appointed after the incumbent CEO assumes office and are found by prior research to represent a weakened governance mechanism. Our evidence reveals that co-opted directors lead to less powerful CEOs, consistent with the substitution effect. Because co-opted directors impose less stringent oversight, the CEO is able to exercise a great deal of latitude in running the firm. Therefore, it is less necessary for the CEO to command so much power where more directors are co-opted, hence leading to less powerful CEOs. In other words, co-opted directors substitute for strong CEO power. Crucially, we find that board co-option exhibits much more explanatory power than does board independence, which has been the primary measure of board effectiveness in the literature. C1 [Withisuphakorn, Pradit] NIDA, Bangkok, Thailand. [Jiraporn, Pornsit] Penn State Univ, SGPS, Malvern, PA USA. RP Jiraporn, P (reprint author), Penn State Univ, SGPS, Malvern, PA USA. EM pxj11@psu.edu NR 6 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1350-4851 EI 1466-4291 J9 APPL ECON LETT JI Appl. Econ. Lett. PD MAR PY 2017 VL 24 IS 6 BP 381 EP 386 DI 10.1080/13504851.2016.1194960 PG 6 WC Economics SC Business & Economics GA EK1QC UT WOS:000393699600006 ER PT J AU You, L Xie, RQ Hu, HJ Gu, GQ Zheng, HM Zhang, JD Yang, XH He, XM Cui, W AF You, Ling Xie, Ruiqin Hu, Haijuan Gu, Guoqiang Zheng, Hongmei Zhang, Jidong Yang, Xiaohong He, Ximiao Cui, Wei TI High levels of serum beta 2-microglobulin predict severity of coronary artery disease SO BMC CARDIOVASCULAR DISORDERS LA English DT Article DE beta 2-Microglobulin; Severity; Coronary artery disease ID C-REACTIVE PROTEIN; ACUTE MYOCARDIAL-INFARCTION; GLOMERULAR-FILTRATION-RATE; CHRONIC STABLE ANGINA; CYSTATIN-C; PROGNOSTIC VALUE; HEART-DISEASE; NATRIURETIC PEPTIDE; GENERAL-POPULATION; MULTIPLE-MYELOMA AB Background: The identification of new risk factors for coronary artery disease (CAD) is increasingly sought in an effort to tackle this threatening disease. beta 2-microglobulin (B2M) is reported to associate with peripheral arterial disease and adverse cardiovascular outcomes. However, the association between B2M and cardiovascular disease remains under-researched. This study evaluated the effects of B2M on CAD without renal dysfunction. Methods: One thousand seven hundred sixty-two subjects (403 non-CAD subjects and 1,359 CAD subjects) were investigated. Fasting samples were collected to determine B2M level. The Gensini and SYNTAX scores were used to assess the severity of CAD. Results: CAD subjects were significantly higher in serum B2M level comparing with non-CAD subjects (1.25 +/- 0.46 vs 1.14 +/- 0.28 mg/L, p < 0.001). Serum B2M level was a risk factor of CAD after adjusting potential confounders (Odds Ratio (OR) = 2.363, 95% confidence interval (CI): 1.467-3.906, p = 0.001). Receiver operating characteristics (ROC) showed B2M level moderately predicted diagnosis of CAD (the area under the ROC curve (AUC) = 0.608, 95% CI: 0.577-0.639, p < 0.001). Furthermore, serum B2M level was positively associated with Gensini score system, SYNTAX score system and the number of disease vessels (NDV >= 2). Conclusions: The significant association between serum B2M and CAD suggests that B2M could be a biomarker for CAD. C1 [He, Ximiao] NCI, Lab Metab, NIH, 37 Convent Dr, Bethesda, MD 20892 USA. [You, Ling; Xie, Ruiqin; Hu, Haijuan; Gu, Guoqiang; Zheng, Hongmei; Zhang, Jidong; Yang, Xiaohong; Cui, Wei] Hebei Med Univ, Hosp 2, Div Cardiol, 215 Heping West Rd, Shijiazhuang 050000, Hebei, Peoples R China. RP He, XM (reprint author), NCI, Lab Metab, NIH, 37 Convent Dr, Bethesda, MD 20892 USA.; Cui, W (reprint author), Hebei Med Univ, Hosp 2, Div Cardiol, 215 Heping West Rd, Shijiazhuang 050000, Hebei, Peoples R China. EM Ximiao.He@gmail.com; cuiwei@medmail.com.cn FU Science and technology project of Hebei Province [15277715D]; key project of medical science research in Hebei Province [20150208] FX This work was generously supported by grants from the Science and technology project of Hebei Province (Grant No. 15277715D to Ling You) and grants from the key project of medical science research in Hebei Province in 2015 (Grant No. 20150208 to Ling You). NR 44 TC 0 Z9 0 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2261 J9 BMC CARDIOVASC DISOR JI BMC Cardiovasc. Disord. PD MAR 1 PY 2017 VL 17 AR 71 DI 10.1186/s12872-017-0502-9 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EM7DH UT WOS:000395471200001 PM 28249620 ER PT J AU Remaley, AT AF Remaley, Alan T. TI Undetectable HDL Cholesterol in a Patient with Flu-Like Illness SO CLINICAL CHEMISTRY LA English DT Editorial Material C1 [Remaley, Alan T.] NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. RP Remaley, AT (reprint author), NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM aremaley1@nhlbi.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 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 MAR PY 2017 VL 63 IS 3 BP 645 EP 645 DI 10.1373/clinchem.2016.263541 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA EL6LU UT WOS:000394734900005 PM 28242832 ER PT J AU Newmeyer, MN Swortwood, MJ Andersson, M Abulseoud, OA Scheidweiler, KB Huestis, MA AF Newmeyer, Matthew N. Swortwood, Madeleine J. Andersson, Maria Abulseoud, Osama A. Scheidweiler, Karl B. Huestis, Marilyn A. TI Cannabis Edibles: Blood and Oral Fluid Cannabinoid Pharmacokinetics and Evaluation of Oral Fluid Screening Devices for Predicting Delta(9)-Tetrahydrocannabinol in Blood and Oral Fluid following Cannabis Brownie Administration SO CLINICAL CHEMISTRY LA English DT Article ID CONTROLLED SMOKED CANNABIS; TANDEM MASS-SPECTROMETRY; WHOLE-BLOOD; DELTA-9-TETRAHYDROCANNABINOL CONCENTRATIONS; TESTING DEVICES; PLASMA; DRUGS; DISPOSITION; DRIVERS; THC AB BACKGROUND: Roadside oral fluid (OF) Delta(9)-tetrahycirocannabinol (THC) detection indicates recent cannabis intake. OF and blood THC pharmacokinetic data are limited and there are no on-site OF screening performance evaluations after controlled edible cannabis. CONTENT: We reviewed OF and blood cannabinoid pharmacokinetics and performance evaluations of theDraeger DrugTest (R) 5000 (DT5000) and Alere (TM) DDS (R) 2 (DDS2) on -site OF screening devices. We also present data from a controlled oral cannabis administration session. SUMMARY: OF THC maximum concentrations (C-max) were similar in freqUent as compared to occasional smokers, while blood THC C-max were higher in frequent [mean (range) 17.7 (8.0-36.1) mu g/L] smokers compared to occasional [8.2 (3.2-14.3) mu g/L] smokers. Minor cannabinoids Delta(9)-tetrahydrocannabivarin "and cannabigerol were never detected in blood, and not in OF by 5 or 8 h, respectively, with 0.3 mu g/L cutoffs. Recommended performance (analytical sensitivity, specificity, and efficiency) criteria for screening devices of >= 80% are difficult to meet when maximizing true positive (TP) results with confirmation cutoffs below the screening cutoff. TPs were greatest with OF confirmation cutoffs of THC >= 1 and >= 2 mu g/L, but analytical sensitivities were <80% due to false negative tests arising from confirmation cutoffs below the DT5000 and DDS2 screening cutoffs; all criteria were >80% with an OF THC >= mu g/L cutoff. Per- formance criteria also were >80% with a blood THC >= 5 mu g/L confirmation cutoff; however, positive OF screening results might not confirm due to the time required to collect blood after a crash or police stop. OF confirmation is recommended for roadside OF screening. (C) 2016 American Association for Clinical Chemistry C1 [Newmeyer, Matthew N.; Swortwood, Madeleine J.; Andersson, Maria; Abulseoud, Osama A.; Scheidweiler, Karl B.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab Sect, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Newmeyer, Matthew N.] Univ Maryland, Toxicol Program, Baltimore, MD 21201 USA. [Swortwood, Madeleine J.] Sam Houston State Univ, Dept Forens Sci, Coll Criminal Justice, Huntsville, TX 77340 USA. [Andersson, Maria] Karolinska Inst, Div Clin Pharmacol, Dept Lab Med, Stockholm, Sweden. [Andersson, Maria] Univ Hosp, Stockholm, Sweden. [Huestis, Marilyn A.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. RP Huestis, MA (reprint author), Univ Maryland, Sch Med, 683 Shore Rd, Severna Pk, MD 21146 USA. EM marilyn.huestis@gmail.com FU Intramural Research Program, National Institute on Drug Abuse, NIH; Graduate Partnership Program, NIH FX M.N. Newmeyer, Intramural Research Program, National Institute on Drug Abuse, NIH (to the institution); and Graduate Partnership Program, NIH; M.A. Huestis, Quantisal, DT5000, and DDS2 devices provided by the manufacturer to NIH through a Materials Transfer Agreement; and Intramural Research Program, National Institute on Drug Abuse, NIH (to the institution). NR 59 TC 1 Z9 1 U1 5 U2 5 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 MAR PY 2017 VL 63 IS 3 BP 647 EP 662 DI 10.1373/clinchem.2016.265371 PG 16 WC Medical Laboratory Technology SC Medical Laboratory Technology GA EL6LU UT WOS:000394734900007 PM 28188235 ER PT J AU Illuzzi, JL McNeill, DR Bastian, P Brenerman, B Wersto, R Russell, HR Bunz, F McKinnon, PJ Becker, KG Wilson, DM AF Illuzzi, Jennifer L. McNeill, Daniel R. Bastian, Paul Brenerman, Boris Wersto, Robert Russell, Helen R. Bunz, Fred McKinnon, Peter J. Becker, Kevin G. Wilson, David M., III TI Tumor-Associated APE1 Variant Exhibits Reduced Complementation Efficiency But Does Not Promote Cancer Cell Phenotypes SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Article DE APE1/APEX1; haploinsufficiency; base excision repair; transformation; cancer susceptibility ID APURINIC/APYRIMIDINIC ENDONUCLEASE; ABASIC ENDONUCLEASE; OXIDATIVE STRESS; REPAIR; DNA; PROTEIN; MOUSE; DAMAGE; REF-1; MICE AB Base excision repair (BER) is the major pathway for coping with most forms of endogenous DNA damage, and defects in the process have been associated with carcinogenesis. Apurinic/apyrimidinic endonuclease 1 (APE1) is a central participant in BER, functioning as a critical endonuclease in the processing of noncoding abasic sites in DNA. Evidence has suggested that APE1 missense mutants, as well as altered expression or localization of the protein, can contribute to disease manifestation. We report herein that the tumor-associated APE1 variant, R237C, shows reduced complementation efficiency of the methyl methanesulfonate hypersensitivity and impaired cell growth exhibited by APE1-deficient mouse embryonic fibroblasts. Overexpression of wild-type APE1 or the R237C variant in the nontransformed C127I mouse cell line had no effect on proliferation, cell cycle status, steady-state DNA damage levels, mitochondrial function, or cellular transformation. A human cell line heterozygous for an APE1 knockout allele had lower levels of endogenous APE1, increased cellular sensitivity to DNA-damaging agents, impaired proliferation with time, and a distinct global gene expression pattern consistent with a stress phenotype. Our results indicate that: (i) the tumor-associated R237C variant is a possible susceptibility factor, but not likely a driver of cancer cell phenotypes, (ii) overexpression of APE1 does not readily promote cellular transformation, and (iii) haploinsufficiency at the APE1 locus can have profound cellular consequences, consistent with BER playing a critical role in proliferating cells. (C) 2017 Wiley Periodicals, Inc. C1 [Illuzzi, Jennifer L.; McNeill, Daniel R.; Brenerman, Boris; Wilson, David M., III] NIA, Lab Mol Gerontol, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Bastian, Paul; Becker, Kevin G.] NIA, Lab Genet, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Wersto, Robert] NIA, Flow Cytometry Unit, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Russell, Helen R.; McKinnon, Peter J.] St Jude Childrens Res Hosp, Genet Dept, 332 N Lauderdale St, Memphis, TN 38105 USA. [Bunz, Fred] Johns Hopkins Univ, Sch Med, Dept Radiat Oncol & Mol Radiat Sci, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. RP Wilson, DM (reprint author), NIA, Lab Mol Gerontol, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM wilsonda@mail.nih.gov FU Intramural Research Program at the NIH, National Institute on Aging; NIH [NS-37956, CA-21765, CA-157535, CA-158428]; American Lebanese and Syrian Associated Charities of St. Jude Children's Research Hospital FX Grant sponsor: Intramural Research Program at the NIH, National Institute on Aging.; Grant sponsor: NIH; Grant numbers: NS-37956 and CA-21765 (to P.J.M.), and CA-157535 and CA-158428 (to F.B.).; Grant sponsor: American Lebanese and Syrian Associated Charities of St. Jude Children's Research Hospital (to P.J.M.). NR 40 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 EI 1098-2280 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD MAR PY 2017 VL 58 IS 2 BP 84 EP 98 DI 10.1002/em.22074 PG 15 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA EL5SR UT WOS:000394681700003 PM 28181292 ER PT J AU Schisterman, EF Swanson, CW Lu, YL Mumford, SL AF Schisterman, Enrique F. Swanson, Chandra W. Lu, Ya-Ling Mumford, Sunni L. TI The Changing Face of Epidemiology Gender Disparities in Citations? SO EPIDEMIOLOGY LA English DT Article ID MEDICAL SUBJECT-HEADINGS; RESEARCH PERFORMANCE; ACADEMIC POSITION; LIFE SCIENCES; TEXT-WORD; IMPACT; PRODUCTIVITY; SUCCESS; INDIVIDUALS; JOURNALS AB Background: Female biomedical scientists tend to publish fewer articles as last author than their male colleagues and accrue fewer citations per publication. We seek to understand whether epidemiology follows this pattern. Methods: We gathered aggregate information on the current gender distribution of epidemiology departments (n = 29 of 71 surveyed), societies (n = 4 of 8), and journal editorial boards (n = 6 of 6) using two online surveys and publicly available online information. Bibliometric data from 4,149 articles published between 2008 and 2012 in six high-impact epidemiology journals were drawn from Web of Science and PubMed. Results: We observed a higher prevalence of female than male doctoral students and epidemiology faculty, particularly at lower faculty ranks. A total of 54% of society members were female. Among editorial boards, all current and emeritus editors-in-chief were male and board membership was largely male (64%). Females were more likely to be first authors, but less likely to be last authors. There were no differences in accrued citations at the 50th percentile by first or last author gender. However, articles with male first and last authors tend to accrue more citations (5.7 citations, 95% CI: 2.1, 9.4), mostly driven by the most highly cited articles. This disparity is not fully explained by potential confounders, including seniority. Conclusions: We found a greater number of female epidemiologists in early-career positions and further evidence of potential gender disparity in publication metrics in epidemiology. If epidemiology continues to be practiced by a majority of women, it remains to be seen if these patterns will change over time. C1 [Schisterman, Enrique F.; Swanson, Chandra W.; Lu, Ya-Ling; Mumford, Sunni L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, 6710B Rockledge Dr MSC 7004, Bethesda, MD 20892 USA. [Lu, Ya-Ling] NIH, NIH Lib, Bldg 10, Bethesda, MD 20892 USA. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, 6710B Rockledge Dr MSC 7004, Bethesda, MD 20892 USA. EM schistee@mail.nih.gov OI Schisterman, Enrique/0000-0003-3757-641X FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health 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. NR 36 TC 0 Z9 0 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1044-3983 EI 1531-5487 J9 EPIDEMIOLOGY JI Epidemiology PD MAR PY 2017 VL 28 IS 2 BP 159 EP 168 DI 10.1097/EDE.0000000000000593 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EK5IB UT WOS:000393959000011 PM 27930394 ER PT J AU Olsson, AC Vermeulen, R Schuz, J Kromhout, H Pesch, B Peters, S Behrens, T Portengen, L Mirabelli, D Gustavsson, P Kendzia, B Almansa, J Luzon, V Vlaanderen, J Stucker, I Guida, F Consonni, D Caporaso, N Landi, MT Field, J Bruske, I Wichmann, HE Siemiatycki, J Parent, ME Richiardi, L Merletti, F Jockel, KH Ahrens, W Pohlabeln, H Plato, N Tardon, A Zaridze, D McLaughlin, J Demers, P Szeszenia-Dabrowska, N Lissowska, J Rudnai, P Fabianova, E Dumitru, RS Bencko, V Foretova, L Janout, V Boffetta, P Bueno-De-Mesquita, B Forastiere, F Bruning, T Straif, K AF Olsson, Ann C. Vermeulen, Roel Schuz, Joachim Kromhout, Hans Pesch, Beate Peters, Susan Behrens, Thomas Portengen, Lutzen Mirabelli, Dario Gustavsson, Per Kendzia, Benjamin Almansa, Josue Luzon, Veronique Vlaanderen, Jelle Stucker, Isabelle Guida, Florence Consonni, Dario Caporaso, Neil Landi, Maria Teresa Field, John Brueske, Irene Wichmann, Heinz-Erich Siemiatycki, Jack Parent, Marie-Elise Richiardi, Lorenzo Merletti, Franco Joeckel, Karl-Heinz Ahrens, Wolfgang Pohlabeln, Hermann Plato, Nils Tardon, Adonina Zaridze, David McLaughlin, John Demers, Paul Szeszenia-Dabrowska, Neonila Lissowska, Jolanta Rudnai, Peter Fabianova, Eleonora Dumitru, Rodica Stanescu Bencko, Vladimir Foretova, Lenka Janout, Vladimir Boffetta, Paolo Bueno-de-Mesquita, Bas Forastiere, Francesco Bruening, Thomas Straif, Kurt TI Exposure-Response Analyses of Asbestos and Lung Cancer Subtypes in a Pooled Analysis of Case-Control Studies SO EPIDEMIOLOGY LA English DT Article ID MADE VITREOUS FIBERS; OCCUPATIONAL-EXPOSURE; CASE-REFERENT; SYN-JEM; RISK; SMOKING; EUROPE; METAANALYSIS; CARCINOGENS; MATRIX AB Background: Evidence is limited regarding risk and the shape of the exposure-response curve at low asbestos exposure levels. We estimated the exposure-response for occupational asbestos exposure and assessed the joint effect of asbestos exposure and smoking by sex and lung cancer subtype in general population studies. Methods: We pooled 14 case-control studies conducted in 19852010 in Europe and Canada, including 17,705 lung cancer cases and 21,813 controls with detailed information on tobacco habits and lifetime occupations. We developed a quantitative job-exposure-matrix to estimate job-, time period-, and region-specific exposure levels. Fiber-years (ff/ml-years) were calculated for each subject by linking the matrix with individual occupational histories. We fit unconditional logistic regression models to estimate odds ratios (ORs), 95% confidence intervals (CIs), and trends. Results: The fully adjusted OR for ever-exposure to asbestos was 1.24 (95% CI, 1.18, 1.31) in men and 1.12 (95% CI, 0.95, 1.31) in women. In men, increasing lung cancer risk was observed with increasing exposure in all smoking categories and for all three major lung cancer subtypes. In women, lung cancer risk for all subtypes was increased in current smokers (ORs similar to two-fold). The joint effect of asbestos exposure and smoking did not deviate from multiplicativity among men, and was more than additive among women. Conclusions: Our results in men showed an excess risk of lung cancer and its subtypes at low cumulative exposure levels, with a steeper exposure-response slope in this exposure range than at higher, previously studied levels. (See video abstract at, http://links.lww.com/EDE/B161.) C1 [Olsson, Ann C.; Schuz, Joachim; Luzon, Veronique; Vlaanderen, Jelle; Straif, Kurt] Int Agcy Res Canc, Lyon, France. [Olsson, Ann C.; Gustavsson, Per; Plato, Nils] Karolinska Inst, Inst Environm Med, Stockholm, Sweden. [Vermeulen, Roel; Kromhout, Hans; Peters, Susan; Portengen, Lutzen; Almansa, Josue; Vlaanderen, Jelle] Inst Risk Assessment Sci, Utrecht, Netherlands. [Pesch, Beate; Behrens, Thomas; Kendzia, Benjamin; Bruening, Thomas] Ruhr Univ Bochum IPA, Inst Prevent & Occupat Med, German Social Accid Insurance Inst, Bochum, Germany. [Peters, Susan] Univ Western Australia, Sch Populat Hlth, Occupat Resp Epidemiol, Perth, WA, Australia. [Richiardi, Lorenzo; Merletti, Franco] Univ Turin, Dept Med Sci, Canc Epidemiol Unit, Turin, Italy. [Richiardi, Lorenzo; Merletti, Franco] CPO Piemonte, Turin, Italy. [Stucker, Isabelle; Guida, Florence] INSERM, Ctr Res Epidemiol & Populat Hlth CESP, Environm Epidemiol Canc Team, U1018, Villejuif, France. [Stucker, Isabelle; Guida, Florence] Univ Paris Sud, UMRS 1018, Villejuif, France. [Consonni, Dario] Osped Maggiore Policlin, Fdn IRCS Ca Granda, Epidemiol Unit, Milan, Italy. [Caporaso, Neil; Landi, Maria Teresa] NCI, Bethesda, MD 20892 USA. [Field, John] Univ Liverpool, Inst Translat Med, Dept Mol & Clin Canc Med, Roy Castle Lung Canc Res Programme,Canc Res Ctr, Liverpool, Merseyside, England. [Brueske, Irene; Wichmann, Heinz-Erich] Deutsch Forschungszentrum Gesundheit & Umwelt, Inst Epidemiol, Neuherberg, Germany. [Siemiatycki, Jack] Univ Montreal, Hosp Res Ctr CRCHUM, Montreal, PQ, Canada. [Parent, Marie-Elise] Univ Quebec, Inst Armand Frappier, INRS, Laval, PQ, Canada. [Joeckel, Karl-Heinz] Univ Duisburg Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany. [Ahrens, Wolfgang; Pohlabeln, Hermann] BIPS, Leibniz Inst Prevent Res & Epidemiol, Bremen, Germany. [Tardon, Adonina] Univ Oviedo, Biomed Res Ctr, Network Epidemiol & Publ Hlth CIBERESP, Oviedo, Spain. [Zaridze, David] Russian Canc Res Ctr, Moscow, Russia. [McLaughlin, John] Publ Hlth Ontario, Toronto, ON, Canada. [Demers, Paul] Canc Care Ontario, Occupat Canc Res Ctr, Toronto, ON, Canada. [Szeszenia-Dabrowska, Neonila] Nofer Inst Occupat Med, Lodz, Poland. [Lissowska, Jolanta] M Sklodowska Curie Canc Ctr, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Rudnai, Peter] Natl Ctr Publ Hlth, Budapest, Hungary. [Fabianova, Eleonora] Reg Author Publ Hlth, Banska Bystrica, Slovakia. [Dumitru, Rodica Stanescu] Inst Publ Hlth, Bucharest, Romania. [Bencko, Vladimir] Charles Univ Prague, Fac Med 1, Inst Hyg & Epidemiol, Prague, Czech Republic. [Foretova, Lenka] Masaryk Univ, Dept Canc Epidemiol & Genet, Masaryk Mem Canc Inst, Brno, Czech Republic. [Foretova, Lenka] Masaryk Univ, Dept Canc Epidemiol & Genet, Fac Med, Brno, Czech Republic. [Janout, Vladimir] Palacky Univ, Fac Med, Olomouc, Czech Republic. [Boffetta, Paolo] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA. [Boffetta, Paolo] Icahn Sch Med Mt Sinai, Inst Translat Epidemiol, New York, NY 10029 USA. [Bueno-de-Mesquita, Bas] Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands. [Forastiere, Francesco] ASL RomaE, Dept Epidemiol, Rome, Italy. RP Olsson, AC (reprint author), IARC, ENV, 150 Cours Albert Thomas, F-69372 Lyon 08, France. EM olssona@iarc.fr RI Bruning, Thomas/G-8120-2015 OI Bruning, Thomas/0000-0001-9560-5464 FU German Social Accident Insurance (DGUV) [FP 271]; Canada by Canadian Institutes for Health Research and Guzzo-SRC Chair in Environment and Cancer; National Cancer Institute of Canada; Canadian Cancer Society; Occupational Cancer Research Centre; Workplace Safety and Insurance Board; Cancer Care Ontario; Germany by Federal Ministry of Education, Science, Research, and Technology [01 HK 173/0]; Federal Ministry of Science [01 HK 546/8]; Ministry of Labour and Social Affairs [IIb7-27/13]; Poland by Polish State Committee for Scientific Research [SPUB-M-COPERNICUS/P-05/DZ-30/99/2000]; European Commission [IC15-CT96-0313] FX Joachim Schuz and Kurt Straif are part of a collaborative study with the State Russian Institute of Occupational Health (SRIOH) on asbestos and cancer risk, which includes financial support from SRIOH to IARC. Paolo Boffetta acted as expert witness for Edison SpA in asbestos-related litigation, outside the submitted work. Beate Pesch, Thomas Behrens, Benjamin Kendzia, and Thomas Bruning, as staff of the Institute for Prevention and Occupational Medicine (IPA), are employed at the "Berufsgenossenschaft Rohstoffe und chemische Industrie" (BG RCI), a public body, which is a member of the study's main sponsor, the German Social Accident Insurance (DGUV). IPA is an independent research institute of the Ruhr-Universitat Bochum. The authors are independent from the German Social Accident Insurance in study design, access to the collected data, responsibility for data analysis and interpretation, and the right to publish. The views expressed in this article are those of the authors and not necessarily those of the sponsor. The other authors report no conflicts of interest. The SYNERGY project is funded by the German Social Accident Insurance (DGUV), Grant FP 271. The original studies were funded as follows: in Canada by Canadian Institutes for Health Research and Guzzo-SRC Chair in Environment and Cancer, National Cancer Institute of Canada, Canadian Cancer Society, Occupational Cancer Research Centre, Workplace Safety and Insurance Board, Canadian Cancer Society, and Cancer Care Ontario; in France by the French Agency of Health Security (ANSES), Fondation de France, French National Research Agency (ANR), National Institute of Cancer (INCA), Fondation pour la Recherche Medicale, French Institute for Public Health Surveillance (InVS), Health Ministry (DGS), Organization for the Research on Cancer (ARC), and French Ministry of work, solidarity, and public function (DGT); in Germany by Federal Ministry of Education, Science, Research, and Technology (Grant 01 HK 173/0), Federal Ministry of Science (Grant 01 HK 546/8), and the Ministry of Labour and Social Affairs (Grant IIb7-27/13); in Italy by Environmental Epidemiology Program of the Lombardy Region, INAIL, Italian Association for Cancer Research, Region Piedmont, Compagnia di San Paolo, and Lazio Region; in Poland by Polish State Committee for Scientific Research (Grant SPUB-M-COPERNICUS/P-05/DZ-30/99/2000); in Czech Republic by MH CZ - DRO (MMCI, 00209805); in Spain by Instituto Universitario de Oncologia, Universidad de Oviedo, Asturias, Fondo de Investigacion Sanitaria (FIS) and Ciber de Epidemiologia y Salud Publica (CIBERESP); in Sweden by Swedish Council for Work Life Research and Swedish Environmental Protection Agency; in the Netherlands by Dutch Ministry of Health, Welfare and Sports, National Institute of Public Health and the Environment, and Europe Against Cancer Program; in the UK by Roy Castle Foundation; in the USA by Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Bethesda, MD; the IARC multicenter study in Central and Eastern Europe was funded by the European Commission's INCO Copernicus program (Contract IC15-CT96-0313). NR 37 TC 0 Z9 0 U1 4 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1044-3983 EI 1531-5487 J9 EPIDEMIOLOGY JI Epidemiology PD MAR PY 2017 VL 28 IS 2 BP 288 EP 299 DI 10.1097/EDE.0000000000000604 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EK5IB UT WOS:000393959000027 PM 28141674 ER PT J AU Imamachi, N Salam, KA Suzuki, Y Akimitsu, N AF Imamachi, Naoto Salam, Kazi Abdus Suzuki, Yutaka Akimitsu, Nobuyoshi TI A GC-rich sequence feature in the 3 ' UTR directs UPF1-dependent mRNA decay in mammalian cells SO GENOME RESEARCH LA English DT Article ID EXON JUNCTION COMPLEX; UPF1 PHOSPHORYLATION; STABILITY; REVEALS; SURVEILLANCE; EVOLUTION; BINDING; DEGRADATION; TRANSCRIPTS; ABUNDANCE AB Up-frameshift protein 1 (UPF1) is an ATP-dependent RNA helicase that has essential roles in RNA surveillance and in post-transcriptional gene regulation by promoting the degradation of mRNAs. Previous studies revealed that UPF1 is associated with the 3' untranslated region (UTR) of target mRNAs via as-yet-unknown sequence features. Herein, we aimed to identify characteristic sequence features of UPF1 targets. We identified 246 UPF1 targets by measuring RNA stabilization upon UPF1 depletion and by identifying mRNAs that associate with UPF1. By analyzing RNA footprint data of phosphorylated UPF1 and two CLIP-seq data of UPF1, we found that 3' UTR but not 5' UTRs or open reading frames of UPF1 targets have GC-rich motifs embedded in high GC-content regions. Reporter gene experiments revealed that GC-rich motifs in UPF1 targets were indispensable for UPF1-mediated mRNA decay. These findings highlight the important features of UPF1 target 3' UTRs. C1 [Imamachi, Naoto; Salam, Kazi Abdus; Akimitsu, Nobuyoshi] Univ Tokyo, Isotope Sci Ctr, Bunkyo Ku, Tokyo 1130032, Japan. [Suzuki, Yutaka] Univ Tokyo, Grad Sch Frontier Sci, Dept Computat Biol & Med Sci, Kashiwa, Chiba 2778562, Japan. [Salam, Kazi Abdus] NIH, Infect Dis & Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Akimitsu, N (reprint author), Univ Tokyo, Isotope Sci Ctr, Bunkyo Ku, Tokyo 1130032, Japan. EM akimitsu@ric.u-tokyo.ac.jp OI Imamachi, Naoto/0000-0002-3503-7589 FU MEXT KAKENHI [221S0002, 21115001]; Funding Program for World-Leading Innovative R&D on Science and Technology of the Japan Society for the Promotion of Science; Japan Society for the Promotion of Science FX This work was financially supported by MEXT KAKENHI (Grant Numbers 221S0002 and 21115001), the Funding Program for World-Leading Innovative R&D on Science and Technology of the Japan Society for the Promotion of Science and Research Fellowship of the Japan Society for the Promotion of Science. NR 47 TC 0 Z9 0 U1 1 U2 1 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 EI 1549-5469 J9 GENOME RES JI Genome Res. PD MAR PY 2017 VL 27 IS 3 BP 407 EP 418 DI 10.1101/gr.206060.116 PG 12 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA EN0IR UT WOS:000395694000007 PM 27940950 ER PT J AU Goldstein, I Baek, S Presman, DM Paakinaho, V Swinstead, EE Hager, GL AF Goldstein, Ido Baek, Songjoon Presman, Diego M. Paakinaho, Ville Swinstead, Erin E. Hager, Gordon L. TI Transcription factor assisted loading and enhancer dynamics dictate the hepatic fasting response SO GENOME RESEARCH LA English DT Article ID ACTIVATED RECEPTOR-ALPHA; GLUCOCORTICOID-RECEPTOR; CHROMATIN ACCESSIBILITY; REGULATORY ELEMENTS; IN-VIVO; CELLS; BINDING; GENOME; GENE; EXCHANGE AB Fasting elicits transcriptional programs in hepatocytes leading to glucose and ketone production. This transcriptional program is regulated by many transcription factors (TFs). To understand how this complex network regulates the metabolic response to fasting, we aimed at isolating the enhancers and TFs dictating it. Measuring chromatin accessibility revealed that fasting massively reorganizes liver chromatin, exposing numerous fasting-induced enhancers. By utilizing computational methods in combination with dissecting enhancer features and TF cistromes, we implicated four key TFs regulating the fasting response: glucocorticoid receptor (GR), cAMP responsive element binding protein 1 (CREB1), peroxisome proliferator activated receptor alpha (PPARA), and CCAAT/enhancer binding protein beta (CEBPB). These TFs regulate fuel production by two distinctly operating modules, each controlling a separate metabolic pathway. The gluconeogenic module operates through assisted loading, whereby GR doubles the number of sites occupied by CREB1 as well as enhances CREB1 binding intensity and increases accessibility of CREB1 binding sites. Importantly, this GR-assisted CREB1 binding was enhancer-selective and did not affect all CREB1-bound enhancers. Single-molecule tracking revealed that GR increases the number and DNA residence time of a portion of chromatin-bound CREB1 molecules. These events collectively result in rapid synergistic gene expression and higher hepatic glucose production. Conversely, the ketogenic module operates via a GR-induced TF cascade, whereby PPARA levels are increased following GR activation, facilitating gradual enhancer maturation next to PPARA target genes and delayed ketogenic gene expression. Our findings reveal a complex network of enhancers and TFs that dynamically cooperate to restore homeostasis upon fasting. C1 [Goldstein, Ido; Baek, Songjoon; Presman, Diego M.; Paakinaho, Ville; Swinstead, Erin E.; Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP Goldstein, I; Hager, GL (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. EM goldstein.ido@gmail.com; hagerg@dce41.nci.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH); National Cancer Institute (NCI); Center for Cancer Research (CCR); Sigrid Juselius Foundation FX We thank Lars Grontved, Tom Johnson, Lyuba Varticovski, Tom Misteli, and Irwin Arias for their comments and help. This work was supported by the Intramural Research Program of the National Institutes of Health (NIH), the National Cancer Institute (NCI), and the Center for Cancer Research (CCR). V.P. was supported, in part, by the Sigrid Juselius Foundation. NR 49 TC 0 Z9 0 U1 1 U2 1 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 EI 1549-5469 J9 GENOME RES JI Genome Res. PD MAR PY 2017 VL 27 IS 3 BP 427 EP 439 DI 10.1101/gr.212175.116 PG 13 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA EN0IR UT WOS:000395694000009 PM 28031249 ER PT J AU Gupta, S Jacobs, ET Baron, JA Lieberman, DA Murphy, G Ladabaum, U Cross, AJ Jover, R Liu, L Martinez, ME AF Gupta, Samir Jacobs, Elizabeth T. Baron, John A. Lieberman, David A. Murphy, Gwen Ladabaum, Uri Cross, Amanda J. Jover, Rodrigo Liu, Lin Martinez, Maria Elena TI Risk stratification of individuals with low-risk colorectal adenomas using clinical characteristics: a pooled analysis SO GUT LA English DT Article ID CANCER INCIDENCE; COLONOSCOPY SURVEILLANCE; TASK-FORCE; MORTALITY; TRIAL; POLYPECTOMY; RECURRENCE; REMOVAL; SIGMOIDOSCOPY; GUIDELINES AB Objective For individuals with 1- 2 small (<1 cm) low-risk colorectal adenomas, international guidelines range from no surveillance to offering surveillance colonoscopy in 5-10 years. We hypothesised that the risks for metachronous advanced neoplasia (AN) among patients with low-risk adenomas differ based on clinical factors distinct from those currently used. Design We pooled data from seven prospective studies to assess the risk of metachronous AN. Two groups with 1- 2 small adenomas were defined based on guidelines from the UK (n=4516) or the European Union (EU)/US (n=2477). Results Absolute risk of metachronous AN ranged from a low of 2.9% to a high of 12.2%, depending on specific risk factor and guideline used. For the UK group, the highest absolute risks for metachronous AN were found among individuals with a history of prior polyp (12.2%), villous histology (12.2%), age >= 70 years (10.9%), high- grade dysplasia (10.9%), any proximal adenoma (10.2%), distal and proximal adenoma (10.8%) or two adenomas (10.1%). For the EU/US group, the highest absolute risks for metachronous AN were among individuals with a history of prior polyp (11.5%) or the presence of both proximal and distal adenomas (11.0%). In multivariate analyses, strong associations for increasing age and history of prior polyps and odds of metachronous AN were observed, whereas more modest associations were shown for baseline proximal adenomas and those with villous features. Conclusions Risks of metachronous AN among individuals with 1- 2 small adenomas vary according to readily available clinical characteristics. These characteristics may be considered for recommending colonoscopy surveillance and require further investigation. C1 [Gupta, Samir] Veteran Affairs San Diego Healthcare Syst, Gastroenterol Sect, Dept Med, San Diego, CA USA. [Gupta, Samir] Univ Calif San Diego, Div Gastroenterol, Dept Internal Med, La Jolla, CA 92093 USA. [Gupta, Samir; Liu, Lin; Martinez, Maria Elena] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. [Jacobs, Elizabeth T.] Univ Arizona, Arizona Canc Ctr, Dept Epidemiol & Biostat, Arizona Coll Publ Hlth, Tucson, AZ USA. [Baron, John A.] Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC USA. [Lieberman, David A.] Portland Vet Affairs Med Cente, Div Gastroenterol & Hepatol, Portland, OR USA. [Lieberman, David A.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Murphy, Gwen] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Ladabaum, Uri] Stanford Univ, Dept Med, Sch Med, Div Gastroenterol Hepatol, Stanford, CA 94305 USA. [Cross, Amanda J.] NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Rockville, MD USA. [Jover, Rodrigo] Hosp Gen Univ Alicante, Inst Invest Sanitaria ISABIAL, Unidad Gastroenterol, Alicante, Spain. [Liu, Lin; Martinez, Maria Elena] Univ Calif San Diego, Dept Family Med & Publ Hlth, La Jolla, CA 92093 USA. RP Martinez, ME (reprint author), Univ Calif San Diego, Moores Canc Ctr, Dept Family Med & Publ Hlth, 3855 Hlth Sci Dr,0901, La Jolla, CA 92093 USA. EM e8martinez@ucsd.edu FU Public Health Service from the National Cancer Institute [CA-41108, CA-23074, CA95060, CA37287, CA104869, CA23108, CA59005, CA26852]; Cooperative Studies Program, Department of Veterans Affairs; USA Department of Veterans Affairs Health Services Research & Development Service of the VA Office of Research and Development [1 I01 HX001574-01A1]; Instituto de Salud Carlos III; Fondos FEDER [PI11/2630, INT-13-078, INT-14-196, UGP-13-221, PI14/01386] FX This work was supported by Public Health Service grants CA-41108, CA-23074, CA95060, CA37287, CA104869, CA23108, CA59005 and CA26852 from the National Cancer Institute. Funding for the Veteran's Affairs Study was supported by the Cooperative Studies Program, Department of Veterans Affairs. Support was also provided in part by Merit Review Award number 1 I01 HX001574-01A1 (Gupta, PI) from the USA Department of Veterans Affairs Health Services Research & Development Service of the VA Office of Research and Development. The views expressed in this article are those of the author(s) and do not necessarily represent the views of the Department of Veterans Affairs. Additional support was provide by Instituto de Salud Carlos III and Fondos FEDER (PI11/2630, INT-13-078, INT-14-196, UGP-13-221, PI14/01386).. NR 25 TC 1 Z9 1 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 EI 1468-3288 J9 GUT JI Gut PD MAR PY 2017 VL 66 IS 3 SU 1 BP 446 EP 453 DI 10.1136/gutjnl-2015-310196 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EL3BY UT WOS:000394495800010 PM 26658145 ER PT J AU Hussein, S Green, A Watane, A Reiter, D Chen, XJ Papadakis, GZ Wood, B Cypess, A Osman, M Bagci, U AF Hussein, Sarfaraz Green, Aileen Watane, Arjun Reiter, David Chen, Xinjian Papadakis, Georgios Z. Wood, Bradford Cypess, Aaron Osman, Medhat Bagci, Ulas TI Automatic Segmentation and Quantification of White and Brown Adipose Tissues from PET/CT Scans SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Article DE Visceral Fat Segmentation; Central Obesity Quantification; Segmentation of Brown Fat; Brown Adipose Tissue; Abdominal Fat Quantification; Co-Segmentation ID VISCERAL FAT ACCUMULATION; ALL-CAUSE MORTALITY; IMAGE SEGMENTATION; CARDIOVASCULAR-DISEASE; CT IMAGES; CANCER; ALGORITHM; TOMOGRAPHY; OBESITY; HUMANS AB In this paper, we investigate the automatic detection of white and brown adipose tissues using Positron Emission Tomography/Computed Tomography (PET/CT) scans, and develop methods for the quantification of these tissues at the whole-body and body-region levels. We propose a patient-specific automatic adiposity analysis system with two modules. In the first module, we detect white adipose tissue (WAT) and its two sub-types from CT scans: Visceral Adipose Tissue (VAT) and Subcutaneous Adipose Tissue (SAT). This process relies conventionally on manual or semi-automated segmentation, leading to inefficient solutions. Our novel framework addresses this challenge by proposing an unsupervised learning method to separate VAT from SAT in the abdominal region for the clinical quantification of central obesity. This step is followed by a context driven label fusion algorithm through sparse 3D Conditional Random Fields (CRF) for volumetric adiposity analysis. In the second module, we automatically detect, segment, and quantify brown adipose tissue (BAT) using PET scans because unlike WAT, BAT is metabolically active. After identifying BAT regions using PET, we perform a co-segmentation procedure utilizing asymmetric complementary information from PET and CT. Finally, we present a new probabilistic distance metric for differentiating BAT from non-BAT regions. Both modules are integrated via an automatic body-region detection unit based on one-shot learning. Experimental evaluations conducted on 151 PET/CT scans achieve state-of-the-art performances in both central obesity as well as brown adiposity quantification. C1 [Hussein, Sarfaraz; Watane, Arjun; Bagci, Ulas] Univ Cent Florida, Ctr Res Comp Vis, Orlando, FL 32826 USA. [Green, Aileen] Cardiol Clin Muskogee, Muskogee, OK 74401 USA. [Reiter, David; Papadakis, Georgios Z.; Wood, Bradford; Cypess, Aaron] NIH, Bldg 10, Bethesda, MD 20892 USA. [Chen, Xinjian] Soochow Univ, Suzhou 215006, Peoples R China. [Osman, Medhat] St Louis Univ, Dept Nucl Med, St Louis, MO 63103 USA. RP Bagci, U (reprint author), Univ Cent Florida, Ctr Res Comp Vis, Orlando, FL 32826 USA. EM ulasbagci@gmail.com OI Bagci, Ulas/0000-0001-7379-6829 NR 52 TC 0 Z9 0 U1 4 U2 4 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0278-0062 EI 1558-254X J9 IEEE T MED IMAGING JI IEEE Trans. Med. Imaging PD MAR PY 2017 VL 36 IS 3 BP 734 EP 744 DI 10.1109/TMI.2016.2636188 PG 11 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA EN6ME UT WOS:000396117300005 PM 28114010 ER PT J AU Mao, L Deng, WW Yu, GT Bu, LL Liu, JF Ma, SR Wu, L Kulkarni, AB Zhang, WF Sun, ZJ AF Mao, Liang Deng, Wei-Wei Yu, Guang-Tao Bu, Lin-Lin Liu, Jian-Feng Ma, Si-Rui Wu, Lei Kulkarni, Ashok B. Zhang, Wen-Feng Sun, Zhi-Jun TI Inhibition of SRC family kinases reduces myeloid-derived suppressor cells in head and neck cancer SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE head and neck cancer; LYN kinase; myeloid-derived suppressor cell; SRC family kinase ID HPV-NEGATIVE HEAD; NUDE-MOUSE MODEL; BREAST-CANCER; MESENCHYMAL TRANSITION; TUMOR MICROENVIRONMENT; IMMUNE SUPPRESSION; PROSTATE-CANCER; DOWN-REGULATION; T-CELL; CARCINOMA AB SRC family kinases (SFKs), a group of nonreceptor tyrosine kinases, modulate multiple cellular functions, such as cell proliferation, differentiation and metabolism. SFKs display aberrant activity in progressive stages of human cancers. However, the precise role of SFKs in the head and neck squamous cell carcinoma (HNSCC) signaling network is far from clear. In this study, we found that the inhibition of SFKs activity by dasatinib effectively reduced the tumor size and population of MDSCs in the HNSCC mouse model. Molecular analysis indicates that phosphorylation of LYN, rather than SRC, was inhibited by dasatinib treatment. Next, we analyzed LYN expression by immunostaining and found that it was overexpressed in the human HNSCC specimens. Moreover, LYN expression in stromal cells positively correlated with myeloid-derived suppressor cells (MDSCs) makers CD11b and CD33 in human HNSCC. The dual positive expression of LYN in epithelial and stromal cells (EPI+ SRT+) was associated with unfavorable overall survival of HNSCC patients. These findings indicate that SFKs may be a potential target for an effective immunotherapy of HNSCC by decreasing MDSCs and moreover, LYN will have an impact on such therapeutic strategy. C1 [Mao, Liang; Deng, Wei-Wei; Yu, Guang-Tao; Bu, Lin-Lin; Liu, Jian-Feng; Ma, Si-Rui; Wu, Lei; Sun, Zhi-Jun] Wuhan Univ, State Key Lab Breeding Base Basic Sci Stomatol, Wuhan, Peoples R China. [Mao, Liang; Deng, Wei-Wei; Yu, Guang-Tao; Bu, Lin-Lin; Liu, Jian-Feng; Ma, Si-Rui; Wu, Lei; Sun, Zhi-Jun] Wuhan Univ, Key Lab Oral Biomed, Minist Educ, Sch & Hosp Stomatol, Wuhan, Peoples R China. [Bu, Lin-Lin; Zhang, Wen-Feng; Sun, Zhi-Jun] Wuhan Univ, Sch & Hosp Stomatol, Dept Oral Maxillofacial Head Neck Oncol, Wuhan, Peoples R China. [Kulkarni, Ashok B.] Natl Inst Dent & Craniofacial Res, Funct Genom Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD USA. RP Sun, ZJ (reprint author), Wuhan Univ, Sch & Hosp Stomatol, Wuhan 430079, Peoples R China. EM sunzj@whu.edu.cn FU National Natural Science Foundation of China [81272963, 81472528, 81672668, 81272964, 81472529, 81672667]; program for new century excellent talents in university, Ministry of Education of China [NCET-13-0439] FX This work was supported by National Natural Science Foundation of China 81272963, 81472528, 81672668 (Z.J S.), 81272964, 81472529, 81672667 (W.F.Z). Z.J.S. was supported by program for new century excellent talents in university (NCET-13-0439), Ministry of Education of China. NR 53 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD MAR 1 PY 2017 VL 140 IS 5 BP 1173 EP 1185 DI 10.1002/ijc.30493 PG 13 WC Oncology SC Oncology GA EK5OQ UT WOS:000393976100019 PM 27798955 ER PT J AU Alvidrez, J Perez-Stable, J AF Alvidrez, Jennifer Perez-Stable, J. TI Diabetes Care in Latinos With Limited English Proficiency What Do Language Concordant Clinicians Add? SO JAMA INTERNAL MEDICINE LA English DT Editorial Material C1 [Alvidrez, Jennifer; Perez-Stable, J.] Natl Inst Minor Hlth & Hlth Dispar, NIH, 6707 Democracy Blvd,Ste 800, Bethesda, MD 20892 USA. [Perez-Stable, J.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. RP Perez-Stable, J (reprint author), Natl Inst Minor Hlth & Hlth Dispar, NIH, 6707 Democracy Blvd,Ste 800, Bethesda, MD 20892 USA. EM eliseo.perez-stable@nih.gov NR 11 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 MAR 1 PY 2017 VL 177 IS 3 BP 313 EP 315 DI 10.1001/jamainternmed.2016.8661 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA EN7RX UT WOS:000396201000007 PM 28114669 ER PT J AU Jefferson, AA Pearson, SD AF Jefferson, Akilah A. Pearson, Steven D. TI Conflict of Interest in Seminal Hepatitis C Virus and Cholesterol Management Guidelines SO JAMA INTERNAL MEDICINE LA English DT Article ID CLINICAL-PRACTICE GUIDELINES; AMERICAN-COLLEGE; DYSLIPIDEMIA AB IMPORTANCE Little is known regarding whether Institute of Medicine (IOM) standards for managing conflicts of interest (COI) have been met in the development of recent important clinical guidelines. OBJECTIVE To evaluate adherence to the IOM standards for limits on commercial COI, guideline development, and evaluation of evidence by the 2013 American College of Cardiology and American Heart Association cholesterol management guideline and the 2014 American Association for the Study of Liver Diseases and Infectious Diseases Society of America hepatitis C virus management guideline. DESIGN, SETTING, AND PARTICIPANTS This study was a retrospective document review of the June 2014 print version of the cholesterol guideline and the final September 2015 print version of the hepatitis C virus guideline. Each guideline was assessed for adherence to the IOM standards for commercial COI published in the 2011 special report Clinical Practice Guidelines We Can Trust. MAIN OUTCOMES AND MEASURES The IOM standards call for no commercial COI among guideline committee chairs and cochairs and for less than 50% of committee members to have commercial COI. Guideline and contemporaneous article disclosure statements were used to evaluate adherence to these standards. Each guideline was also reviewed for adherence to other IOM standards for guideline development and evidence review. RESULTS Among the 16 cholesterol guideline committee members, 7 (44%) disclosed commercial COI, all 7 reported industry-sponsored research, and 6 (38%) also reported consultancy. Of 3 guideline chairs and cochairs, 1 (33%) disclosed commercial COI. Review of contemporaneous articles identified additional commercial COI. Among the 29 hepatitis C virus guideline committee members, 21 (72%) reported commercial COI. Eighteen (62%) disclosed industry-sponsored research, 10 (34%) served on advisory boards, 5 (17%) served on data safety monitoring boards, 3 (10%) were consultants, and 3 (10%) reported other honoraria. Of 6 guideline cochairs, 4 (67%) disclosed commercial COI. All 4 disclosed additional COI in other publications that were not listed in their guideline disclosures. Contemporaneous literature review revealed an additional cochair with commercial COI. Of the 9 IOM guideline development and evidence standards, the cholesterol guideline met 5 (56%), and the hepatitis C virus guideline met them all. CONCLUSIONS AND RELEVANCE Neither the cholesterol guideline nor the hepatitis C virus guideline fully met the IOM standards for commercial COI management, and discordance between committee leader guideline disclosures and those in contemporaneous articles was common. Adherence to additional IOM standards for guideline development and evidence review was mixed. Adoption of consistent COI frameworks across specialty societies may help ensure that clinical guidelines are developed in a transparent and trustworthy manner. C1 [Jefferson, Akilah A.; Pearson, Steven D.] NIH, Ctr Clin, Dept Bioeth, 10 Ctr Dr,Room 1C118, Bethesda, MD 20892 USA. [Pearson, Steven D.] Inst Clin & Econ Review, Boston, MA USA. RP Pearson, SD (reprint author), NIH, Ctr Clin, Dept Bioeth, 10 Ctr Dr,Room 1C118, Bethesda, MD 20892 USA. EM pearsonsd@cc.nih.gov FU National Institutes of Health FX This study was supported by an intramural research grant from the National Institutes of Health. NR 24 TC 1 Z9 1 U1 1 U2 1 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 MAR 1 PY 2017 VL 177 IS 3 BP 352 EP 357 DI 10.1001/jamainternmed.2016.8439 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA EN7RX UT WOS:000396201000017 PM 28114439 ER PT J AU Olfson, M Blanco, C Marcus, SC AF Olfson, Mark Blanco, Carlos Marcus, Steven C. TI Screening for Depression Through a Glass Darkly Reply SO JAMA INTERNAL MEDICINE LA English DT Editorial Material ID MAJOR DEPRESSION C1 [Olfson, Mark] Columbia Univ, Dept Psychiat, Coll Phys & Surg, New York, NY USA. [Olfson, Mark] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Blanco, Carlos] NIDA, Bethesda, MD 20892 USA. [Marcus, Steven C.] Univ Penn, Sch Social Practice & Policy, Philadelphia, PA 19104 USA. RP Olfson, M (reprint author), Columbia Univ, New York State Psychiat Inst, Dept Psychiat, Coll Phys & Surg, 1051 Riverside Dr, New York, NY 10032 USA. EM mo49@cumc.columbia.edu FU Agency for Healthcare Quality and Research [U19 HS02112]; National Institute on Drug Abuse FX This work was supported by the Agency for Healthcare Quality and Research (grant No. U19 HS02112). Work by Dr Blanco was supported by the National Institute on Drug Abuse; Dr Blanco had no role in the grant from the Agency for Healthcare Quality and Research. NR 6 TC 0 Z9 0 U1 1 U2 1 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 MAR 1 PY 2017 VL 177 IS 3 BP 447 EP 448 DI 10.1001/jamainternmed.2016.9287 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA EN7RX UT WOS:000396201000048 PM 28264123 ER PT J AU Xue, YX Deng, JH Chen, YY Zhang, LB Wu, P Huang, GD Luo, YX Bao, YP Wang, YM Shaham, Y Shi, J Lu, L AF Xue, Yan-Xue Deng, Jia-Hui Chen, Ya-Yun Zhang, Li-Bo Wu, Ping Huang, Geng-Di Luo, Yi-Xiao Bao, Yan-Ping Wang, Yu-Mei Shaham, Yavin Shi, Jie Lu, Lin TI Effect of Selective Inhibition of Reactivated Nicotine-Associated Memories With Propranolol on Nicotine Craving SO JAMA PSYCHIATRY LA English DT Article ID RETRIEVAL-EXTINCTION PROCEDURE; ADRENERGIC-RECEPTOR BLOCKADE; DRIVEN TRAUMATIC IMAGERY; BASOLATERAL AMYGDALA; REINSTATEMENT MODEL; DEPENDENT HUMANS; PLACE PREFERENCE; SMOKING RELAPSE; CUE REACTIVITY; DRUG RELAPSE AB IMPORTANCE A relapse into nicotine addiction during abstinence often occurs after the reactivation of nicotine reward memories, either by acute exposure to nicotine (a smoking episode) or by smoking-associated conditioned stimuli (CS). Preclinical studies suggest that drug reward memories can undergo memory reconsolidation after being reactivated, during which they can be weakened or erased by pharmacological or behavioral manipulations. However, translational clinical studies using CS-induced memory retrieval-reconsolidation procedures to decrease drug craving reported inconsistent results. OBJECTIVE To develop and test an unconditioned stimulus (UCS)-induced retrieval-reconsolidation procedure to decrease nicotine craving among people who smoke. DESIGN, SETTING, AND PARTICIPANTS A translational rat study and human study in an academic outpatient medical center among 96 male smokers (aged 18-45 years) to determine the association of propranolol administration within the time window of memory reconsolidation (after retrieval of the nicotine-associated memories by nicotine UCS exposure) with relapse to nicotine-conditioned place preference (CPP) and operant nicotine seeking in rats, and measures of preference to nicotine-associated CS and nicotine craving among people who smoke. INTERVENTION The study rats were injected noncontingently with the UCS (nicotine 0.15mg/kg, subcutaneous) in their home cage, and the human study participants administered a dose of propranolol (40mg, per os; Zhongnuo Pharma). MAIN OUTCOMES AND MEASURES Nicotine CPP and operant nicotine seeking in rats, and preference and craving ratings for newly learned and preexisting real-life nicotine-associated CS among people who smoke. RESULTS Sixty-nine male smokers completed the experiment and were included for statistical analysis: 24 in the group that received placebo plus 1 hour plus UCS, 23 who received propranolol plus 1 hour plus UCS, and 22 who received UCS plus 6 hours plus propranolol. In rat relapse models, propranolol injections administered immediately after nicotine UCS-induced memory retrieval inhibited subsequent nicotine CPP and operant nicotine seeking after short (CPP, d=1.72, 95% CI, 0.63-2.77; operant seeking, d=1.61, 95% CI, 0.59-2.60) or prolonged abstinence (CPP, d=1.46, 95% CI, 0.42-2.47; operant seeking: d=1.69, 95% CI, 0.66-2.69), as well as nicotine priming-induced reinstatement of nicotine CPP (d=1.28, 95% CI, 0.27-2.26) and operant nicotine seeking (d=1.61, 95% CI, 0.59-2.60) after extinction. Among the smokers, oral propranolol administered prior to nicotine UCS-induced memory retrieval decreased subsequent nicotine preference induced by newly learned nicotine CS (CS1, Cohen d=0.61, 95% CI, 0.02-1.19 and CS2, d=0.69, 95% CI, 0.10-1.28, respectively), preexisting nicotine CS (d=0.57, 95% CI, -0.02 to 1.15), and nicotine priming (CS1, d=0.82, 95% CI, 0.22-1.41 and CS2, d=0.78, 95% CI, 0.18-1.37, respectively; preexisting nicotine CS, d=0.92, 95% CI, 0.31-1.52), as well as nicotine craving induced by the preexisting nicotine CS (d=0.64, 95% CI, 0.05-1.22), and nicotine priming (d=1.15, 95% CI, 0.52-1.76). CONCLUSIONS AND RELEVANCE In rat-to-human translational study, a novel UCS-induced memory retrieval-reconsolidation interference procedure inhibited nicotine craving induced by exposure to diverse nicotine-associated CS and nicotine itself. This procedure should be studied further in clinical trials. Copyright 2017 American Medical Association. All rights reserved. C1 [Deng, Jia-Hui; Chen, Ya-Yun; Luo, Yi-Xiao; Wang, Yu-Mei; Lu, Lin] Peking Univ, Hosp 6, Inst Mental Hlth, 51 Huayuan Rd, Beijing 100191, Peoples R China. [Xue, Yan-Xue; Deng, Jia-Hui; Chen, Ya-Yun; Zhang, Li-Bo; Wu, Ping; Huang, Geng-Di; Luo, Yi-Xiao; Bao, Yan-Ping; Shi, Jie; Lu, Lin] Peking Univ, Beijing Key Lab Drug Dependence, Natl Inst Drug Dependence, Beijing, Peoples R China. [Lu, Lin] Peking Univ, Natl Clin Res Ctr Mental Disorders, Beijing, Peoples R China. [Lu, Lin] Peking Univ, Key Lab Mental Hlth, Minist Hlth, Beijing, Peoples R China. [Shaham, Yavin] NIDA, Intramural Res Program, NIH, Baltimore, MD USA. [Lu, Lin] Peking Univ, Peking Tsinghua Ctr Life Sci, Beijing, Peoples R China. [Lu, Lin] Peking Univ, PKU IDG McGovern Inst Brain Res, Beijing, Peoples R China. RP Lu, L (reprint author), Peking Univ, Hosp 6, Inst Mental Hlth, 51 Huayuan Rd, Beijing 100191, Peoples R China. EM linlu@bjmu.edu.cn FU National Basic Research Program of China [2015CB856400, 2015CB559200, 2015CB553503]; Natural Science Foundation of China [31230033, 91432303, 31300930, 81221002, 81201032]; Ten Thousand Youth Talents; Intramural Research Program of the National Insitutue on Drug Abuse FX This research was conducted with support from grants 2015CB856400, 2015CB559200, and 2015CB553503 from the National Basic Research Program of China and grants 31230033, 91432303, 31300930, 81221002, and 81201032 from the Natural Science Foundation of China. This research also received support from Ten Thousand Youth Talents and the Intramural Research Program of the National Insitutue on Drug Abuse. NR 72 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 2168-622X EI 2168-6238 J9 JAMA PSYCHIAT JI JAMA Psychiatry PD MAR 1 PY 2017 VL 74 IS 3 BP 224 EP 232 DI 10.1001/jamapsychiatry.2016.3907 PG 9 WC Psychiatry SC Psychiatry GA EN5LP UT WOS:000396047300005 PM 28146250 ER PT J AU Levine, AG Hemmers, S Baptista, AP Schizas, M Faire, MB Moltedo, B Konopacki, C Schmidt-Supprian, M Germain, RN Treuting, PM Rudensky, AY AF Levine, Andrew G. Hemmers, Saskia Baptista, Antonio P. Schizas, Michail Faire, Mehlika B. Moltedo, Bruno Konopacki, Catherine Schmidt-Supprian, Marc Germain, Ronald N. Treuting, Piper M. Rudensky, Alexander Y. TI Suppression of lethal autoimmunity by regulatory T cells with a single TCR specificity SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID SELF-TOLERANCE; IN-VIVO; THYMUS; HOMEOSTASIS; GENERATION; DISEASE; LINEAGE; LIMITS AB The regulatory T cell (T reg cell) T cell receptor (TCR) repertoire is highly diverse and skewed toward recognition of self-antigens. TCR expression by T reg cells is continuously required for maintenance of immune tolerance and for a major part of their characteristic gene expression signature; however, it remains unknown to what degree diverse TCR -mediated interactions with cognate self-antigens are required for these processes. In this study, by experimentally switching the T reg cell TCR repertoire to a single T reg cell TCR, we demonstrate that T reg cell function and gene expression can be partially uncoupled from TCR diversity. An induced switch of the T reg cell TCR repertoire to a random repertoire also preserved, albeit to a limited degree, the ability to suppress lymphadenopathy and T helper cell type 2 activation. At the same time, these perturbations of the T reg cell TCR repertoire led to marked immune cell activation, tissue inflammation, and an ultimately severe autoimmunity, indicating the importance of diversity and specificity for optimal T reg cell function. C1 [Levine, Andrew G.; Hemmers, Saskia; Schizas, Michail; Faire, Mehlika B.; Moltedo, Bruno; Konopacki, Catherine; Rudensky, Alexander Y.] Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, Program Immunol, Ludwig Ctr, New York, NY 10065 USA. [Baptista, Antonio P.; Germain, Ronald N.] NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Schmidt-Supprian, Marc] Tech Univ Munich, Klinikum Rechts Isar, Hematol & Oncol, D-80333 Munich, Germany. [Treuting, Piper M.] Univ Washington, Sch Med, Dept Comparat Med, Seattle, WA 98195 USA. RP Rudensky, AY (reprint author), Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, Program Immunol, Ludwig Ctr, New York, NY 10065 USA. EM rudenska@mskcc.org RI Schmidt-Supprian, Marc/F-5893-2011 OI Schmidt-Supprian, Marc/0000-0002-8543-6166 FU National Institutes of Health (NIH) Medical Scientist Training Program grant [T32GM07739]; Frank Lappin Horsfall Jr. Student Fellowship; NIH grant [R37AI034206]; Ludwig Center at Memorial Sloan-Kettering Cancer Center; Hilton-Ludwig Cancer Prevention Initiative of the Conrad N. Hilton Foundation; Ludwig Cancer Research; NIH/National Cancer Institute Cancer Center Support [P30 CA008748]; Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH FX This work was supported by a National Institutes of Health (NIH) Medical Scientist Training Program grant (T32GM07739) to the Weill Cornell/Rockefeller/SloanKettering Tri-Institutional MD-PhD Program (A.G. Levine), the Frank Lappin Horsfall Jr. Student Fellowship (A.G. Levine), an NIH grant (R37AI034206 to A.Y. Rudensky), the Ludwig Center at Memorial Sloan-Kettering Cancer Center, the Hilton-Ludwig Cancer Prevention Initiative of the Conrad N. Hilton Foundation and Ludwig Cancer Research (A.Y. Rudensky), and the NIH/National Cancer Institute Cancer Center Support Grant (P30 CA008748). This research was also supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH (R.N. Germain and A.P. Baptista). A.Y. Rudensky is an investigator with the Howard Hughes Medical Institute. NR 30 TC 0 Z9 0 U1 1 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD MAR PY 2017 VL 214 IS 3 BP 609 EP 622 DI 10.1084/jem.20161318 PG 14 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA EN2GS UT WOS:000395828600004 PM 28130403 ER PT J AU Volpi, S Yamazaki, Y Brauer, PM van Rooijen, E Hayashida, A Slavotinek, A Kuehn, HS Di Rocco, M Rivolta, C Bortolomai, I Du, LK Felgentreff, K de Bruin, LO Hayashida, K Freedman, G Marcovecchio, GE Capuder, K Rath, P Luche, N Hagedorn, EJ Buoncompagni, A Royer-Bertrand, B Giliani, S Poliani, PL Imberti, L Dobbs, K Poulain, FE Martini, A Manis, J Linhardt, RJ Bosticardo, M Rosenzweig, SD Lee, H Puck, JM Zuniga-Pflucker, JC Zon, L Park, PW Superti-Furga, A Notarangelo, LD AF Volpi, Stefano Yamazaki, Yasuhiro Brauer, Patrick M. van Rooijen, Ellen Hayashida, Atsuko Slavotinek, Anne Kuehn, Hye Sun Di Rocco, Maja Rivolta, Carlo Bortolomai, Ileana Du, Likun Felgentreff, Kerstin de Bruin, Lisa Ott Hayashida, Kazutaka Freedman, George Marcovecchio, Genni Enza Capuder, Kelly Rath, Prisni Luche, Nicole Hagedorn, Elliott J. Buoncompagni, Antonella Royer-Bertrand, Beryl Giliani, Silvia Poliani, Pietro Luigi Imberti, Luisa Dobbs, Kerry Poulain, Fabienne E. Martini, Alberto Manis, John Linhardt, Robert J. Bosticardo, Marita Rosenzweig, Sergio Damian Lee, Hane Puck, Jennifer M. Zuniga-Pflucker, Juan Carlos Zon, Leonard Park, Pyong Woo Superti-Furga, Andrea Notarangelo, Luigi D. TI EXTL3 mutations cause skeletal dysplasia, immune deficiency, and developmental delay SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID SEVERE COMBINED IMMUNODEFICIENCY; EMBRYONIC STEM-CELLS; SHORT-LIMBED DWARFISM; HEPARAN-SULFATE; HEMATOPOIETIC STEM; TUMOR SUPPRESSORS; B-LYMPHOPOIESIS; HSPG SYNTHESIS; IN-VITRO; DIFFERENTIATION AB We studied three patients with severe skeletal dysplasia, T cell immunodeficiency, and developmental delay. Whole-exome sequencing revealed homozygous missense mutations affecting exostosin-like 3 (EXTL3), a glycosyltransferase involved in heparan sulfate (HS) biosynthesis. Patient-derived fibroblasts showed abnormal HS composition and altered fibroblast growth factor 2 signaling, which was rescued by overexpression of wild-type EXTL3 cDNA. Interleukin-2-mediated STAT5 phosphorylation in patients' lymphocytes was markedly reduced. Interbreeding of the extl3-mutant zebrafish (box) with Tg(rag2 : green fluorescent protein) transgenic zebrafish revealed defective thymopoiesis, which was rescued by injection of wild-type human EXTL3 RNA. Targeted differentiation of patient-derived induced pluripotent stem cells showed a reduced expansion of lymphohematopoietic progenitor cells and defects of thymic epithelial progenitor cell differentiation. These data identify EXTL3 mutations as a novel cause of severe immune deficiency with skeletal dysplasia and developmental delay and underline a crucial role of HS in thymopoiesis and skeletal and brain development. C1 [Volpi, Stefano; Buoncompagni, Antonella; Martini, Alberto] Ist Giannina Gaslini, Dept Pediat, Unita Operat Pediat 2, I-16148 Genoa, Italy. [Di Rocco, Maja] Ist Giannina Gaslini, Dept Pediat, Unit Rare Dis, I-16148 Genoa, Italy. [Yamazaki, Yasuhiro; Dobbs, Kerry; Notarangelo, Luigi D.] NIAID, Lab Host Def, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Kuehn, Hye Sun; Rosenzweig, Sergio Damian] NIH, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Brauer, Patrick M.; Zuniga-Pflucker, Juan Carlos] Univ Toronto, Dept Immunol, Sunnybrook Res Inst, Toronto, ON M5S, Canada. [van Rooijen, Ellen; Hagedorn, Elliott J.; Zon, Leonard] Harvard Med Sch, Stem Cell Program, Boston Childrens Hosp, Boston, MA 02115 USA. [Hayashida, Atsuko; Hayashida, Kazutaka; Park, Pyong Woo] Harvard Med Sch, Div Resp Dis, Boston Childrens Hosp, Boston, MA 02115 USA. [Du, Likun; Felgentreff, Kerstin; de Bruin, Lisa Ott; Capuder, Kelly; Luche, Nicole] Harvard Med Sch, Div Immunol, Boston Childrens Hosp, Boston, MA 02115 USA. [Manis, John] Harvard Med Sch, Dept Lab Med, Boston Childrens Hosp, Boston, MA 02115 USA. [Slavotinek, Anne] Univ Calif San Francisco, Dept Pediat, Div Genet, San Francisco, CA 94143 USA. [Freedman, George; Puck, Jennifer M.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. [Rivolta, Carlo; Royer-Bertrand, Beryl] Univ Lausanne, Univ Lausanne Hosp, Dept Computat Biol, Unit Med Genet, CH-1015 Lausanne, Switzerland. [Royer-Bertrand, Beryl; Superti-Furga, Andrea] Univ Lausanne, Univ Lausanne Hosp, Div Genet Med, CH-1015 Lausanne, Switzerland. [Bortolomai, Ileana; Marcovecchio, Genni Enza; Bosticardo, Marita] Ist Sci San Raffaele, San Raffaele Telethon Inst Gene Therapy, Ist Ric & Cura Carattere Sci, I-20132 Milan, Italy. [Rath, Prisni] Tata Consultancy Serv Innovat Labs, Hyderabad, Telangana, India. [Giliani, Silvia] Univ Brescia, A Nocivelli Inst Mol Med, I-25123 Brescia, Italy. [Poliani, Pietro Luigi] Univ Brescia, Dept Mol & Translat Med, I-25123 Brescia, Italy. [Imberti, Luisa] Spedali Civil Brescia, Ctr Ric Ematooncol AIL, I-25123 Brescia, Italy. [Poulain, Fabienne E.] Univ South Carolina, Dept Biol Sci, Columbia, SC 29208 USA. [Linhardt, Robert J.] Rensselaer Polytech Inst, Dept Chem & Chem Biol, Troy, NY 12180 USA. [Lee, Hane] Univ Calif Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. [Bortolomai, Ileana] CNR, Ist Ric Genet & Biomed, Milan Unit, I-20138 Milan, Italy. RP Notarangelo, LD (reprint author), NIAID, Lab Host Def, 9000 Rockville Pike, Bethesda, MD 20892 USA.; Superti-Furga, A (reprint author), Univ Lausanne, Univ Lausanne Hosp, Div Genet Med, CH-1015 Lausanne, Switzerland. EM asuperti@unil.ch; luigi.notarangelo2@nih.gov OI Rivolta, Carlo/0000-0002-0733-9950 FU Telethon Network of Genetic Biobanks [GTB12001]; Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH); NIAID, NIH [5R21AI113459]; Italian Ministry of Health [PE-2011-02347329]; Swiss National Science Foundation [156260]; National Institute of Neurological Disorders and Stroke, NIH [R00NS083714]; Faculte de Biologie et Medecine of the University of Lausanne; Krembil Foundation; Canada Research Chair in Developmental Immunology FX We thank Drs. Steven E. Brenner, Rajgopal Srinivasan, Uma Sunderam, and the UCLA Clinical Genomics Center Genomic Data Board for reviewing and interpreting WES data and Maurizio Fazio, Julie Perlin, and Anne Robertson for assistance with zebrafish experiments. The Cell Line and DNA Biobank from Patients Affected by Genetic Diseases (Istituto G. Gaslini; Telethon Network of Genetic Biobanks; project no. GTB12001) provided specimens.; This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) and by a grant from NIAID, NIH (5R21AI113459 to L. D. Notarangelo), a grant from the Italian Ministry of Health (PE-2011-02347329 to S. Giliani and L. D. Notarangelo), a grant from the Swiss National Science Foundation (156260 to C. Rivolta), and a grant from the National Institute of Neurological Disorders and Stroke, NIH (R00NS083714 to F. E. Poulain). A. Superti-Furga is supported by the Faculte de Biologie et Medecine of the University of Lausanne. J.C.Zuniga-Pflucker is supported by the Krembil Foundation and by a Canada Research Chair in Developmental Immunology. NR 55 TC 0 Z9 0 U1 4 U2 4 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD MAR PY 2017 VL 214 IS 3 BP 623 EP 637 DI 10.1084/jem.20161525 PG 15 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA EN2GS UT WOS:000395828600005 PM 28148688 ER PT J AU Lyons, JJ Liu, Y Ma, CA Yu, X O'Connell, MP Lawrence, MG Zhang, Y Karpe, K Zhao, M Siegel, AM Stone, KD Nelson, C Jones, N DiMaggio, T Darnell, DN Mendoza-Caamal, E Orozco, L Hughes, JD McElwee, J Hohman, RJ Frischmeyer-Guerrerio, PA Rothenberg, ME Freeman, AF Holland, SM Milner, JD AF Lyons, J. J. Liu, Y. Ma, C. A. Yu, X. O'Connell, M. P. Lawrence, M. G. Zhang, Y. Karpe, K. Zhao, M. Siegel, A. M. Stone, K. D. Nelson, C. Jones, N. DiMaggio, T. Darnell, D. N. Mendoza-Caamal, E. Orozco, L. Hughes, J. D. McElwee, J. Hohman, R. J. Frischmeyer-Guerrerio, P. A. Rothenberg, M. E. Freeman, A. F. Holland, S. M. Milner, J. D. TI ERBIN deficiency links STAT3 and TGF-beta pathway defects with atopy in humans SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID GROWTH-FACTOR-BETA; REGULATORY T-CELLS; EOSINOPHILIC ESOPHAGITIS; NEGATIVE REGULATION; CONNECTIVE-TISSUE; IN-VIVO; MUTATIONS; RECEPTOR; GATA-3; EXPRESSION AB Nonimmunological connective tissue phenotypes in humans are common among some congenital and acquired allergic diseases. Several of these congenital disorders have been associated with either increased TGF-beta activity or impaired STAT3 activation, suggesting that these pathways might intersect and that their disruption may contribute to atopy. In this study, we show that STAT3 negatively regulates TGF-beta signaling via ERBB2-interacting protein (ERBIN), a SMAD anchor for receptor activation and SMAD2/3 binding protein. Individuals with dominant-negative STAT3 mutations (STAT3(mut)) or a loss-of-function mutation in ERBB2IP (ERBB2IP(mut)) have evidence of deregulated TGF-beta signaling with increased regulatory T cells and total FOXP3 expression. These naturally occurring mutations, recapitulated in vitro, impair STAT3-ERBIN-SMAD2/3 complex formation and fail to constrain nuclear pSMAD2/3 in response to TGF-beta. In turn, cell-intrinsic deregulation of TGF-beta signaling is associated with increased functional IL-4R alpha expression on naive lymphocytes and can induce expression and activation of the IL-4/IL-4R alpha/GATA3 axis in vitro. These findings link increased TGF-beta pathway activation in ERBB2IP(mut) and STAT3(mut) patient lymphocytes with increased T helper type 2 cytokine expression and elevated IgE. C1 [Lyons, J. J.; Liu, Y.; Ma, C. A.; Yu, X.; O'Connell, M. P.; Zhang, Y.; Karpe, K.; Siegel, A. M.; Stone, K. D.; Nelson, C.; DiMaggio, T.; Milner, J. D.] NIAID, Genet & Pathogenesis Allergy Sect, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Zhao, M.; Hohman, R. J.] NIAID, Res Technol Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Darnell, D. N.; Freeman, A. F.; Holland, S. M.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Frischmeyer-Guerrerio, P. A.] NIAID, Food Allergy Res Unit, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Lawrence, M. G.] Univ Virginia, Dept Med, Div Asthma Allergy & Immunol, Charlottesville, VA 22903 USA. [Jones, N.] Leidos Biomed Res Inc, Clin Res Directorate CRMP, NCI Campus Frederick, Frederick, MD 21702 USA. [Mendoza-Caamal, E.; Orozco, L.] Natl Inst Genom Med, Mexico City 14610, DF, Mexico. [Hughes, J. D.; McElwee, J.] Merck & Co Inc, Merck Res Labs, Boston, MA 02115 USA. [Rothenberg, M. E.] Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Div Allergy & Immunol, Cincinnati, OH 45229 USA. RP Milner, JD (reprint author), NIAID, Genet & Pathogenesis Allergy Sect, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jdmilner@niaid.nih.gov FU Intramural Research Programs of the National Institutes of Health (NIH), National Cancer Institute (NCI), Center for Cancer Research; NIAID; NCI, NIH [HHSN261200800001E] FX This research was supported in part by the Intramural Research Programs of the National Institutes of Health (NIH), National Cancer Institute (NCI), Center for Cancer Research, and of the NIAID. This project has been funded in whole or in part with federal funds from the NCI, NIH under contract 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 45 TC 1 Z9 1 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD MAR PY 2017 VL 214 IS 3 BP 669 EP 680 DI 10.1084/jem.20161435 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA EN2GS UT WOS:000395828600008 PM 28126831 ER PT J AU Gansler, DA Huey, ED Pan, JJ Wasserman, E Grafman, JH AF Gansler, David A. Huey, Edward D. Pan, Jessica J. Wasserman, Eric Grafman, Jordan H. TI Assessing the dysexecutive syndrome in dementia SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Article ID CONFIRMATORY FACTOR-ANALYSIS; HUMAN CEREBRAL-CORTEX; FRONTOTEMPORAL DEMENTIA; EXECUTIVE FUNCTION; DIAGNOSTIC-CRITERIA; ALZHEIMERS-DISEASE; PROGRESSIVE APHASIA; BEHAVIOR; SCALE; DEGENERATION AB Objective We compared performance on tests of dysexecutive behaviour (DB) and executive function (EF) in patients with behavioural variant frontotemporal dementia (bvFTD), primary progressive aphasia (PPA) and corticobasal syndrome (CBS). Methods Patients diagnosed with bvFTD (n=124), PPA (n=34) and CBS (n=85) were recruited. EF was measured with the Delis-Kaplan Executive Function System (DKEFS: performance based), and DB was measured with the Frontal Systems Behavior Scale (FrSBe: caregiver-report based). Confirmatory factor analysis characterised the relationship between EF and DB, binary logistic regression evaluated the incremental diagnostic utility of the measures and neuroimaging data from 110 patients identified neural correlates. Results EF was lowest and DB was highest in bvFTD participants. EF and DB were distinct but related (r=-0.48). Measures correctly classified 89% of bvFTD from CBS patients and 93% of bvFTD from PPA patients -30% and 13% above base rates (59%, 80%), respectively. All modalities were useful in identifying CBS and PPA, whereas DB alone was useful for identifying bvFTD. EF was uniquely associated with caudal left dorsolateral prefrontal and lateral temporo-parietal cortices. DB was uniquely associated with the cingulate (R>L), right subcallosal and right anterior frontal cortex. EF and DB were associated with the rostral dorsolateral prefrontal cortex bilaterally. Conclusions EF and DB measures displayed criterion and construct validity, had incremental utility at low DB levels (CBS and PPA) and were associated with overlapping and distinct neural correlates. EF and DB procedures can conjointly provide useful diagnostic and descriptive information in identifying and ruling out the dysexecutive syndrome. C1 [Gansler, David A.; Pan, Jessica J.] Suffolk Univ, Dept Psychol, 41 Temple St, Boston, MA 02114 USA. [Huey, Edward D.] Columbia Univ, Dept Psychiat, New York, NY USA. [Huey, Edward D.] Columbia Univ, Dept Neurol, New York, NY USA. [Wasserman, Eric] NINDS, Behav Neurol Unit, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Grafman, Jordan H.] Northwestern Univ, Sch Med, Dept Phys Med & Rehabil, Chicago, IL USA. [Grafman, Jordan H.] Northwestern Univ, Sch Med, Dept Psychiat & Behav Sci, Cognit Neurol, Chicago, IL 60611 USA. [Grafman, Jordan H.] Rehabil Inst Chicago, Cognit Neurosci Lab, Chicago, IL 60611 USA. RP Gansler, DA (reprint author), Suffolk Univ, Dept Psychol, 41 Temple St, Boston, MA 02114 USA. EM dgansler@suffolk.edu FU NINDS FX This study was supported by NINDS intramural funding to JHG. NR 42 TC 0 Z9 0 U1 3 U2 3 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-3050 EI 1468-330X J9 J NEUROL NEUROSUR PS JI J. Neurol. Neurosurg. Psychiatry PD MAR PY 2017 VL 88 IS 3 BP 254 EP 261 DI 10.1136/jnnp-2016-313576 PG 8 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA EL3ED UT WOS:000394501500012 PM 27466358 ER PT J AU Kahin, SA Wright, DS Pejavara, A Kim, SA AF Kahin, Sahra A. Wright, Demia S. Pejavara, Anu Kim, Sonia A. TI State-Level Farmers Market Activities: A Review of CDC-Funded State Public Health Actions That Support Farmers Markets SO JOURNAL OF PUBLIC HEALTH MANAGEMENT AND PRACTICE LA English DT Review DE Centers for Disease Control and Prevention; farmers markets; fruits and vegetables; state health departments; state-level ID FOOD DESERTS; FRUIT; COMMUNITIES; PROGRAM AB Context: Introducing farmers markets to underserved areas, or supporting existing farmers markets, can increase access and availability of fruits and vegetables and encourage healthy eating. Since 2003, the Centers for Disease Control and Prevention (CDC)'s Division of Nutrition, Physical Activity, and Obesity (DNPAO) has provided guidance and funding to state health departments (SHDs) to support the implementation of interventions, including activities around farmers markets, to address healthy eating, and improve the access to and availability of fruits and vegetables at state and community levels. Objective: For this project, we identified state-level farmers market activities completed with CDC's DNPAO funding from 2003 to 2013. State-level was defined as actions taken by the state health department that influence or support farmers market work across the state. Design and Participants: We completed an analysis of SHD farmers market activities of 3 DNPAO cooperative agreements from 2003 to 2013: State Nutrition and Physical Activity Programs to Prevent Obesity and Other Chronic Diseases; Nutrition, Physical Activity and Obesity Program; and Communities Putting Prevention to Work. To identify state farmers market activities, data sources for each cooperative agreement were searched using the key words "farm," "market," " produce market," and "produce stand." State data with at least one state-level farmers market action present were then coded for the presence of itemized activities. Results: Across all cooperative agreements, the most common activities identified through analysis included the following: working on existing markets and nutrition assistance benefit programs, supporting community action, and providing training and technical assistance. Common partners were nutrition assistance benefit program offices and state or regional Department of Agriculture or agricultural extension offices. Implications for Policy & Practice: Common farmers market practices and evidence-based activities, such as nutrition assistance benefits programs and land-use policies, can be adopted as methods for farmers market policy and practice work. Conclusion: The activities identified in this study can inform future planning at the state and federal levels on environment, policy, and systems approaches that improve the food environment through farmers markets. C1 [Kahin, Sahra A.; Pejavara, Anu; Kim, Sonia A.] Ctr Dis Control & Prevent, Div Nutr Phys Act & Obes, 4770 Buford Hwy,NE,MS F-77, Atlanta, GA 30341 USA. [Wright, Demia S.] NIEHS, Worker Training Program, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RP Kahin, SA (reprint author), Ctr Dis Control & Prevent, Div Nutr Phys Act & Obes, 4770 Buford Hwy,NE,MS F-77, Atlanta, GA 30341 USA. EM xfz9@cdc.gov FU CDC FX All authors were full-time CDC staff during the writing of this article. The CDC funds authors' salaries to do this work. NR 22 TC 0 Z9 0 U1 4 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1078-4659 EI 1550-5022 J9 J PUBLIC HEALTH MAN JI J. Public Health Manag. Pract. PD MAR-APR PY 2017 VL 23 IS 2 BP 96 EP 103 DI 10.1097/PHH.0000000000000412 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EK1WM UT WOS:000393716500007 PM 27798521 ER PT J AU Ashley, PJ Freemer, M Garbe, P Rowson, D AF Ashley, Peter J. Freemer, Michelle Garbe, Paul Rowson, David TI Coordinated Federal Actions Are Needed to Reduce Racial and Ethnic Disparities in Childhood Asthma SO JOURNAL OF PUBLIC HEALTH MANAGEMENT AND PRACTICE LA English DT Editorial Material C1 [Ashley, Peter J.] US Dept Housing & Urban Dev, 451 7th St,SW,Room 8236, Washington, DC 20410 USA. [Freemer, Michelle] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Garbe, Paul] Ctr Dis Control & Prevent, Atlanta, GA USA. [Rowson, David] US EPA, Washington, DC 20460 USA. RP Ashley, PJ (reprint author), US Dept Housing & Urban Dev, 451 7th St,SW,Room 8236, Washington, DC 20410 USA. EM Peter.J.Ashley@hud.gov NR 4 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 1078-4659 EI 1550-5022 J9 J PUBLIC HEALTH MAN JI J. Public Health Manag. Pract. PD MAR-APR PY 2017 VL 23 IS 2 BP 207 EP 209 DI 10.1097/PHH.0000000000000541 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EK1WM UT WOS:000393716500025 PM 28121772 ER PT J AU Bennett, PH Magliano, DJ Alberti, KG Zimmet, P AF Bennett, Peter H. Magliano, Dianna J. Alberti, K. George Zimmet, Paul TI Challenges of monitoring global diabetes prevalence Reply SO LANCET DIABETES & ENDOCRINOLOGY LA English DT Editorial Material ID MELLITUS C1 [Bennett, Peter H.] NIH, Phoenix, AZ 85014 USA. [Magliano, Dianna J.] Baker IDI Heart & Diabet Inst, Melbourne, Vic, Australia. [Alberti, K. George] Imperial Coll, St Marys Campus, London, England. [Zimmet, Paul] Monash Univ, Dept Med, Melbourne, Vic, Australia. RP Bennett, PH (reprint author), NIH, Phoenix, AZ 85014 USA. EM pbennett@nih.gov NR 5 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 2213-8587 J9 LANCET DIABETES ENDO JI Lancet Diabetes Endocrinol. PD MAR PY 2017 VL 5 IS 3 BP 162 EP 162 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EN9RZ UT WOS:000396338600008 PM 28235491 ER PT J AU Chowell, G Viboud, C AF Chowell, Gerardo Viboud, Cecile TI Quantifying the fitness of antiviral-resistant influenza strains SO LANCET INFECTIOUS DISEASES LA English DT Editorial Material ID NEURAMINIDASE INHIBITORS; SURVEILLANCE C1 [Chowell, Gerardo] Georgia State Univ, Sch Publ Hlth, Atlanta, GA 30303 USA. [Chowell, Gerardo; Viboud, Cecile] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. RP Chowell, G (reprint author), Georgia State Univ, Sch Publ Hlth, Atlanta, GA 30303 USA.; Chowell, G (reprint author), NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM gchowell@gsu.edu NR 12 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 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD MAR PY 2017 VL 17 IS 3 BP 250 EP 251 DI 10.1016/S1473-3099(16)30522-9 PG 2 WC Infectious Diseases SC Infectious Diseases GA EL6KX UT WOS:000394732600009 PM 27914854 ER PT J AU Quaglio, G Corbetta, M Karapiperis, T Amunts, K Koroshetz, W Yamamori, T Draghia-Akli, R AF Quaglio, Gianluca Corbetta, Maurizio Karapiperis, Theodoros Amunts, Katrin Koroshetz, Walter Yamamori, Tetsuo Draghia-Akli, Ruxandra TI Understanding the brain through large, multidisciplinary research initiatives SO LANCET NEUROLOGY LA English DT Letter ID NEUROSCIENCE C1 [Quaglio, Gianluca; Karapiperis, Theodoros] European Parliament, European Parliamentary Res Serv, Sci Foresight Unit Sci & Technol Opt Assessment, Brussels, Belgium. [Corbetta, Maurizio] Univ Padua, Padua, Italy. [Corbetta, Maurizio] Washington Univ, Sch Med, St Louis, MO USA. [Amunts, Katrin] Inst Neurosci & Med, INM 1, Julich Res Ctr, Julich, Germany. [Amunts, Katrin] Univ Hosp Dusseldorf, Cecile & Oskar Vogt Brain Res, Dusseldorf, Germany. Human Brain Project, Sci & Infrastruct Board, Vienna, Austria. [Koroshetz, Walter] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Koroshetz, Walter] Natl Inst Hlth Brain Initiat, Bethesda, MD USA. [Yamamori, Tetsuo] Riken Brain Sci Inst, Wako, Saitama, Japan. [Yamamori, Tetsuo] Brain MINDS Project, Wako, Saitama, Japan. [Draghia-Akli, Ruxandra] European Commiss, Directorate General Res & Innovat, Brussels, Belgium. RP Quaglio, G (reprint author), European Parliament, European Parliamentary Res Serv, Sci Foresight Unit Sci & Technol Opt Assessment, Brussels, Belgium. EM gianluca.quaglio@europarl.europa.eu FU European Commission FX KA reports grants from the European Commission. All other authors declare no competing interests. The views expressed in this letter are the sole responsibility of the authors and do not necessarily reflect the views of their affiliated organisations. NR 7 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 EI 1474-4465 J9 LANCET NEUROL JI Lancet Neurol. PD MAR PY 2017 VL 16 IS 3 BP 183 EP 184 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA EK4ZC UT WOS:000393935700014 PM 28229889 ER PT J AU Seymour, L Bogaerts, J Perrone, A Ford, R Schwartz, LH Mandrekar, S Lin, NU Litiere, S Dancey, J Chen, A Hodi, FS Therasse, P Hoekstra, OS Shankar, LK Wolchok, JD Ballinger, M Caramella, C de Vries, EGE AF Seymour, Lesley Bogaerts, Jan Perrone, Andrea Ford, Robert Schwartz, Lawrence H. Mandrekar, Sumithra Lin, Nancy U. Litiere, Saskia Dancey, Janet Chen, Alice Hodi, F. Stephen Therasse, Patrick Hoekstra, Otto S. Shankar, Lalitha K. Wolchok, Jedd D. Ballinger, Marcus Caramella, Caroline de Vries, Elisabeth G. E. CA RECIST Working Grp TI iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics SO LANCET ONCOLOGY LA English DT Review ID CELL LUNG-CANCER; IMMUNE-RELATED RESPONSE; SOLID TUMORS; UNTREATED MELANOMA; DOUBLE-BLIND; NIVOLUMAB; IPILIMUMAB; PEMBROLIZUMAB; CARBOPLATIN; COMBINATION AB Tumours respond differently to immunotherapies compared with chemotherapeutic drugs, raising questions about the assessment of changes in tumour burden-a mainstay of evaluation of cancer therapeutics that provides key information about objective response and disease progression. A consensus guideline-iRECIST-was developed by the RECIST working group for the use of modified Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) in cancer immunotherapy trials, to ensure consistent design and data collection, facilitate the ongoing collection of trial data, and ultimate validation of the guideline. This guideline describes a standard approach to solid tumour measurements and definitions for objective change in tumour size for use in trials in which an immunotherapy is used. Additionally, it defines the minimum datapoints required from future trials and those currently in development to facilitate the compilation of a data warehouse to use to later validate iRECIST. An unprecedented number of trials have been done, initiated, or are planned to test new immune modulators for cancer therapy using a variety of modified response criteria. This guideline will allow consistent conduct, interpretation, and analysis of trials of immunotherapies. C1 [Seymour, Lesley; Dancey, Janet] Queens Univ, Canadian Canc Trials Grp, Kingston, ON K7L 3N6, Canada. [Bogaerts, Jan; Litiere, Saskia] EORTC Headquarters, Brussels, Belgium. [Perrone, Andrea] Merck & Co Inc, Translat Med, Kenilworth, NJ USA. [Ford, Robert] Clin Trials Imaging Consulting LLC, Belle Mead, NJ USA. [Schwartz, Lawrence H.] Columbia Univ, Med Ctr, Dept Radiol, New York, NY USA. [Schwartz, Lawrence H.] New York Presbyterian Hosp, New York, NY USA. [Mandrekar, Sumithra] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA. [Lin, Nancy U.; Hodi, F. Stephen] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA. [Chen, Alice] NCI, Early Clin Trials Dev Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Therasse, Patrick] Inst Rech Int Servier, Paris, France. [Hoekstra, Otto S.] Vrije Univ Amsterdam, Dept Radiol & Nucl Med, Med Ctr, Amsterdam, Netherlands. [Shankar, Lalitha K.] NCI, Diagnost Imaging Branch, Bethesda, MD 20892 USA. [Wolchok, Jedd D.] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. [Ballinger, Marcus] Weill Cornell Med & Grad Coll, New York, NY USA. [Ballinger, Marcus] Ludwig Inst Canc Res, New York, NY USA. [Ballinger, Marcus] Genentech Inc, 460 Point San Bruno Blvd, San Francisco, CA 94080 USA. [Caramella, Caroline] Gustav Roussy Canc Campus, Dept Radiol, Villejuif, France. [de Vries, Elisabeth G. E.] Univ Med Ctr Groningen, Dept Med Oncol, Groningen, Netherlands. RP Seymour, L (reprint author), Queens Univ, Canadian Canc Trials Grp, Kingston, ON K7L 3N6, Canada. EM lseymour@ctg.queensu.ca FU Canadian Cancer Society Research Institute [021039]; EORTC Cancer Research Fund; National Cancer Institute [5U10-CA11488-45] FX AC and LKS are employees of the National Institutes of Health/National Cancer Institute. This publication was supported by the Canadian Cancer Society Research Institute (grant #021039), the EORTC Cancer Research Fund, and the National Cancer Institute (grant number 5U10-CA11488-45). The contents of this paper were presented in part at the EORTC-NCI-AACR 2016 Meeting (Munich, Germany; Nov 29-Dec 2, 2016). We gratefully acknowledge the thoughtful participation of the following in this initiative: Patricia Keegan (US Food and Drug Administration, Silver Spring, MD, USA); Francesco Pignatti (European Medicine Agency, London, UK); Wendy Hayes (Bristol-Myers Squibb, Princeton, NJ, USA); Eric Rubin (Merck & Co, Kenilworth, NJ, USA). We also received written comments from Darragh Halpenny, Jean-Yves Blay, Florian Lordick, Silke Gillessen, Hirokazu Watanabe, Jose Pablo Maroto Rey, Pietro Quaglino, Howard Kaufman, Denis Lacombe, Corneel Coens, Catherine Fortpied, Jessica Menis, Francisco Vera-Badillo, Jean Powers, Michail Ignatiadis, Eric Gauthier, Michael O'Neal, Caroline Malhaire, Laure Fournier, and Glen Laird. We thank Anouk Funke for her assistance with this manuscript. NR 35 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD MAR PY 2017 VL 18 IS 3 BP E143 EP E152 PG 10 WC Oncology SC Oncology GA EN9UH UT WOS:000396344600018 PM 28271869 ER PT J AU Ng, C Goodenow, M Greenshaw, A Upshall, P Lam, R AF Ng, Chee Goodenow, Maureen Greenshaw, Andrew Upshall, Phil Lam, Raymond TI APEC digital hub for mental health SO LANCET PSYCHIATRY LA English DT Editorial Material C1 [Ng, Chee] Univ Melbourne, Dept Psychiat, Richmond, Vic 3121, Australia. [Ng, Chee] Univ Melbourne, Asia Australia Mental Hlth, Richmond, Vic 3121, Australia. [Goodenow, Maureen] NIH, Off AIDS Res, Bldg 10, Bethesda, MD 20892 USA. Univ Alberta, Dept Psychiat, Edmonton, AB, Canada. [Upshall, Phil] Mood Disorders Soc Canada, Guelph, ON, Canada. [Lam, Raymond] Univ British Columbia, Dept Psychiat, Vancouver, BC, Canada. RP Ng, C (reprint author), Univ Melbourne, Dept Psychiat, Richmond, Vic 3121, Australia.; Ng, C (reprint author), Univ Melbourne, Asia Australia Mental Hlth, Richmond, Vic 3121, Australia. NR 1 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 2215-0374 J9 LANCET PSYCHIAT JI Lancet Psychiatry PD MAR PY 2017 VL 4 IS 3 BP E3 EP E4 PG 3 WC Psychiatry SC Psychiatry GA EN9VD UT WOS:000396346800003 PM 28236959 ER PT J AU Goldberg, RB Temprosa, M Mele, L Orchard, T Mather, K Bray, G Horton, E Kitabchi, A Krakoff, J Marcovina, S Perreault, L White, N AF Goldberg, Ronald B. Temprosa, Marinella Mele, Lisa Orchard, Trevor Mather, Kieren Bray, George Horton, Edward Kitabchi, Abbas Krakoff, Jonathan Marcovina, Santica Perreault, Leigh White, Neil CA Diabet Prevention Program Res Grp TI Change in adiponectin explains most of the change in HDL particles induced by lifestyle intervention but not metformin treatment in the diabetes prevention program (Vol 65, pg 764, 2016) SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Correction C1 [Goldberg, Ronald B.] Univ Miami, Diabet Res Inst, 1450 NW 10th Ave,Suite 2054, Miami, FL 33136 USA. [Temprosa, Marinella; Mele, Lisa] George Washington Univ, Biostat Ctr, 6110 Execut Blvd,Suite 750, Rockville, MD 20852 USA. [Orchard, Trevor] Univ Pittsburgh, 3512 Fifth Ave, Pittsburgh, PA 15213 USA. [Mather, Kieren] Indiana Univ, Dept Med, 541 Clin Dr CL 365, Indianapolis, IN 46202 USA. [Bray, George] Louisiana State Univ, Pennington Biomed Res Ctr, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. [Horton, Edward] Joslin Diabet Ctr, Sect Clin Behav & Outcomes Res, One Joslin Pl, Boston, MA 02215 USA. [Horton, Edward] Harvard Med Sch, Dept Med, 25 Shattuck St, Boston, MA 02115 USA. [Kitabchi, Abbas] Univ Tennessee, Div Endocrinol, Hlth Sci Ctr, 920 Madison Ave Suite 300A, Memphis, TN 38163 USA. [Krakoff, Jonathan] NIDDK, 1550 E Indian Sch Rd, Phoenix, AZ 85014 USA. [Marcovina, Santica] Univ Washington, Northwest Lipid Res Labs, 401 Queen Anne Ave, North Seattle, WA 98109 USA. [Perreault, Leigh] Univ Colorado, Div Endocrinol Metab & Diabet, Dept Med, Anschutz Med Campus,12801 E 17th Ave, Aurora, CO 80045 USA. [White, Neil] Washington Univ, Sch Med, 660 South Euclid Ave, St Louis, MO 63110 USA. RP Goldberg, RB (reprint author), George Washington Univ, Biostat Ctr, Diabet Prevent Program Coordinating Ctr, 6110 Execut Blvd,Suite 750, Rockville, MD 20852 USA. EM dppmail@bsc.gwu.edu NR 1 TC 0 Z9 0 U1 1 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0026-0495 EI 1532-8600 J9 METABOLISM JI Metab.-Clin. Exp. PD MAR PY 2017 VL 68 BP 184 EP 186 DI 10.1016/j.metabol.2016.11.007 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EK4WF UT WOS:000393927600018 PM 28065437 ER PT J AU Zarate, CA Machado-Vieira, R AF Zarate, C. A., Jr. Machado-Vieira, R. TI Ketamine: translating mechanistic discoveries into the next generation of glutamate modulators for mood disorders SO MOLECULAR PSYCHIATRY LA English DT Editorial Material ID RAPID-ACTING ANTIDEPRESSANTS; RESISTANT BIPOLAR DEPRESSION; GLYCOGEN-SYNTHASE KINASE-3; D-ASPARTATE ANTAGONIST; AMPA RECEPTOR; NMDA ANTAGONISTS; DOUBLE-BLIND; INHIBITION; TRIAL; METABOLITES C1 [Zarate, C. A., Jr.; Machado-Vieira, R.] NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Zarate, CA (reprint author), NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. EM zaratec@mail.nih.gov FU Intramural Research Program at the National Institute of Mental Health; National Institutes of Health (IRP-NIMH-NIH) [ZIA MH002857]; NARSAD Independent Investigator Award; Brain and Behavior Mood Disorders Research Award FX Funding for this work was supported by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH; ZIA MH002857), by a NARSAD Independent Investigator Award to Dr Zarate Jr, and by a Brain and Behavior Mood Disorders Research Award to Dr Zarate Jr. We thank the 7SE research unit and staff for their support. NR 38 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD MAR PY 2017 VL 22 IS 3 BP 324 EP 327 DI 10.1038/mp.2016.249 PG 4 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA EL3RQ UT WOS:000394537100001 PM 28070122 ER PT J AU Trampush, JW Yang, MLZ Yu, J Knowles, E Davies, G Liewald, DC Starr, JM Djurovic, S Melle, I Sundet, K Christoforou, A Reinvang, I DeRosse, P Lundervold, AJ Steen, VM Espeseth, T Raikkonen, K Widen, E Palotie, A Eriksson, JG Giegling, I Konte, B Roussos, P Giakoumaki, S Burdick, KE Payton, A Ollier, W Horan, M Chiba-Falek, O Attix, DK Need, AC Cirulli, ET Voineskos, AN Stefanis, NC Avramopoulos, D Hatzimanolis, A Arking, DE Smyrnis, N Bilder, RM Freimer, NA Cannon, TD London, E Poldrack, RA Sabb, FW Congdon, E Conley, ED Scult, MA Dickinson, D Straub, RE Donohoe, G Morris, D Corvin, A Gill, M Hariri, AR Weinberger, DR Pendleton, N Bitsios, P Rujescu, D Lahti, J Le Hellard, S Keller, MC Andreassen, OA Deary, IJ Glahn, DC Malhotra, AK Lencz, T AF Trampush, J. W. Yang, M. L. Z. Yu, J. Knowles, E. Davies, G. Liewald, D. C. Starr, J. M. Djurovic, S. Melle, I. Sundet, K. Christoforou, A. Reinvang, I. DeRosse, P. Lundervold, A. J. Steen, V. M. Espeseth, T. Raikkonen, K. Widen, E. Palotie, A. Eriksson, J. G. Giegling, I. Konte, B. Roussos, P. Giakoumaki, S. Burdick, K. E. Payton, A. Ollier, W. Horan, M. Chiba-Falek, O. Attix, D. K. Need, A. C. Cirulli, E. T. Voineskos, A. N. Stefanis, N. C. Avramopoulos, D. Hatzimanolis, A. Arking, D. E. Smyrnis, N. Bilder, R. M. Freimer, N. A. Cannon, T. D. London, E. Poldrack, R. A. Sabb, F. W. Congdon, E. Conley, E. D. Scult, M. A. Dickinson, D. Straub, R. E. Donohoe, G. Morris, D. Corvin, A. Gill, M. Hariri, A. R. Weinberger, D. R. Pendleton, N. Bitsios, P. Rujescu, D. Lahti, J. Le Hellard, S. Keller, M. C. Andreassen, O. A. Deary, I. J. Glahn, D. C. Malhotra, A. K. Lencz, T. TI GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium SO MOLECULAR PSYCHIATRY LA English DT Article ID GENOME-WIDE ASSOCIATION; SCOTTISH MENTAL SURVEY; UK BIOBANK N=112151; EDUCATIONAL-ATTAINMENT; INTELLECTUAL DISABILITY; DEVELOPMENTAL DELAY; EXECUTIVE FUNCTION; HUMAN INTELLIGENCE; PROVIDES INSIGHTS; ABILITY AB The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (similar to 8M single-nucleotide polymorphisms (SNP) with minor allele frequency >= 1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome-wide significance level (P<5x10(-8)). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1 and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e. = 0.01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness. C1 [Trampush, J. W.; Yu, J.; DeRosse, P.; Lencz, T.] Zucker Hillside Hosp, Div Psychiat Res, 75-59 263rd St, Glen Oaks, NY 11004 USA. [Yang, M. L. Z.] Inst Mental Hlth, Singapore, Singapore. [Yu, J.; DeRosse, P.; Malhotra, A. K.; Lencz, T.] Feinstein Inst Med Res, Ctr Psychiat Neurosci, Manhasset, NY USA. [Knowles, E.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Davies, G.; Starr, J. M.; Deary, I. J.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland. [Davies, G.; Liewald, D. C.; Deary, I. J.] Univ Edinburgh, Dept Psychol, Edinburgh, Midlothian, Scotland. [Starr, J. M.] Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh, Midlothian, Scotland. [Djurovic, S.] Univ Bergen, Oslo Univ Hosp, Dept Med Genet, Oslo, Norway. [Djurovic, S.; Melle, I.; Christoforou, A.; Le Hellard, S.] Univ Bergen, KG Jebsen Ctr Psychosis Res, NORMENT, Bergen, Norway. [Melle, I.; Sundet, K.; Espeseth, T.] Oslo Univ Hosp, Div Mental Hlth & Addict, Oslo, Norway. [Sundet, K.; Espeseth, T.] Univ Oslo, Dept Psychol, Oslo, Norway. [Christoforou, A.] Haukeland Hosp, Ctr Med Genet & Mol Med, Dr Einar Martens Res Grp Biol Psychiat, Bergen, Norway. [Lundervold, A. J.] Univ Bergen, Dept Biol & Med Psychol, Bergen, Norway. [Raikkonen, K.] Univ Helsinki, Inst Behav Sci, Helsinki, Finland. [Widen, E.; Palotie, A.] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland. [Palotie, A.] Wellcome Trust Genome Campus, Wellcome Trust Sanger Inst, Cambridge, England. [Palotie, A.] Univ Helsinki, Dept Med Genet, Helsinki, Finland. [Palotie, A.] Univ Cent Hosp, Helsinki, Finland. [Eriksson, J. G.] Natl Inst Hlth & Welf, Helsinki, Finland. [Eriksson, J. G.] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland. [Eriksson, J. G.] Univ Helsinki, Unit Gen Practice, Cent Hosp, Helsinki, Finland. [Eriksson, J. G.] Folkhalsan Res Ctr, Helsinki, Finland. [Giegling, I.; Konte, B.; Rujescu, D.] Martin Luther Univ Halle Wittenberg, Dept Psychiat, Halle, Germany. [Roussos, P.; Burdick, K. E.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Roussos, P.; Burdick, K. E.] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Roussos, P.; Burdick, K. E.] Icahn Sch Med Mt Sinai, Inst Multiscale Biol, New York, NY 10029 USA. [Roussos, P.] James J Peters VA Med Ctr, Mental Illness Res Educ & Clin Ctr VISN 3, Bronx, NY USA. [Giakoumaki, S.] Univ Crete, Dept Psychol, Rethimnon, Greece. [Payton, A.] Univ Manchester, Manchester Acad Hlth Sci Ctr, Manchester Ctr Audiol & Deafness, Manchester, Lancs, England. [Payton, A.] Univ Manchester, Sch Biol Sci, Div Evolut & Genom Sci, Manchester, Lancs, England. [Ollier, W.] Univ Manchester, Inst Populat Hlth, Ctr Integrated Genom Med Res, Manchester, Lancs, England. [Horan, M.] Univ Manchester, Inst Brain Behav & Mental Hlth, Manchester Med Sch, Manchester, Lancs, England. [Chiba-Falek, O.; Attix, D. K.] Duke Univ, Med Ctr, Div Neurol, Bryan Alzheimers Dis Res Ctr, Durham, NC 27710 USA. [Chiba-Falek, O.; Attix, D. K.] Duke Univ, Med Ctr, Ctr Genom & Computat Biol, Durham, NC USA. [Attix, D. K.] Duke Univ, Med Ctr, Dept Neurol Psychiat & Behav Sci, Div Med Psychol, Durham, NC USA. [Need, A. C.] Imperial Coll, Dept Med, Div Brain Sci, London, England. [Cirulli, E. T.] Duke Univ, Sch Med, Ctr Appl Genom & Precis Med, Durham, NC USA. [Voineskos, A. N.] Univ Toronto, Ctr Addict & Mental Hlth, Campbell Family Mental Hlth Inst, Toronto, ON, Canada. [Stefanis, N. C.; Hatzimanolis, A.] Univ Athens, Sch Med, Eginit Hosp, Dept Psychiat, Athens, Greece. [Stefanis, N. C.; Hatzimanolis, A.] Univ Mental Hlth Res Inst, Athens, Greece. [Stefanis, N. C.; Hatzimanolis, A.] Theodor Theohari Cozzika Fdn, Neurobiol Res Inst, Athens, Greece. [Avramopoulos, D.] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. [Avramopoulos, D.; Arking, D. E.] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. [Avramopoulos, D.; Arking, D. E.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Bilder, R. M.; Freimer, N. A.; London, E.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA USA. [Cannon, T. D.] Yale Univ, Dept Psychol, New Haven, CT USA. [Poldrack, R. A.] Stanford Univ, Dept Psychol, Palo Alto, CA 94304 USA. [Sabb, F. W.] Univ Oregon, Robert & Beverly Lewis Ctr Neuroimaging, Eugene, OR 97403 USA. [Conley, E. D.] 23andMe Inc, Mountain View, CA USA. [Scult, M. A.; Hariri, A. R.] Duke Univ, Neurogenet Lab, Dept Psychol & Neurosci, Durham, NC USA. [Congdon, E.; Dickinson, D.] NIMH, Clin & Translat Neurosci Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Straub, R. E.; Weinberger, D. R.] Johns Hopkins Univ, Lieber Inst Brain Dev, Med Campus, Baltimore, MD USA. [Donohoe, G.] Natl Univ Ireland, Dept Psychol, Galway, Ireland. [Morris, D.; Corvin, A.; Gill, M.] Trinity Coll Dublin, Trinity Coll Inst Neurosci, Neuropsychiat Genet Res Grp, Dept Psychiat, Dublin, Ireland. [Bitsios, P.] Univ Crete, Fac Med, Dept Psychiat & Behav Sci, Iraklion, Greece. [Rujescu, D.; Lahti, J.] Univ Helsinki, Helsinki Collegium Adv Studies, Helsinki, Finland. [Keller, M. C.] Univ Colorado, Inst Behav Genet, Boulder, CO 80309 USA. [Andreassen, O. A.] Univ Oslo, Inst Clin Med, Oslo, Norway. [Malhotra, A. K.; Lencz, T.] Hofstra Northwell Sch Med, Dept Psychiat, Hempstead, NY USA. RP Lencz, T (reprint author), Zucker Hillside Hosp, Div Psychiat Res, 75-59 263rd St, Glen Oaks, NY 11004 USA. EM tlencz@northwell.edu OI Sundet, Kjetil/0000-0003-2850-3673; Payton, Antony/0000-0003-0335-152X FU National Institutes of Health [R01MH079800, P50 MH080173, R01 MH080912, K23 MH077807, K01 MH085812, R01 DA033369, R01 AG049789]; Research Council of Norway; South-East Norway Health Authority; KG Jebsen Foundation; Research Council of Norway [154313/V50, 177458/V50]; Bergen Research Foundation; University of Bergen; Research Council of Norway (FUGE, Psykisk Helse); Helse Vest RHF and Dr Einar Martens Fund; Academy of Finland; Finnish Diabetes Research Society; Folkhalsan Research Foundation; Novo Nordisk Foundation; Finska Lakaresallskapet; Signe and Ane Gyllenberg Foundation; University of Helsinki; Ministry of Education; Ahokas Foundation; Emil Aaltonen Foundation; Disconnected Mind project; UK Biotechnology and Biological Sciences Research Council (BBSRC) [BB/F019394/1]; Medical Research Council; Biotechnology and Biological Sciences Research Council [MR/K026992/1]; CAMH Foundation; Canadian Institutes of Health Research; National Institute of Mental Health of the National Institutes of Health [K01MH098126]; Ellison Medical Foundation New Scholar award [AG-NS-0441-08]; NIH [UL1DE019580, PL1MH083271, RL1MH083269, RL1DA024853, PL1NS062410]; National Institute of Mental Health research [R01MH085018, R01MH092515]; National Science Foundation Graduate Research Fellowship; Science Foundation Ireland [12/IP/1670, 12/IP/1359, 08/IN. 1/B1916] FX This work has been supported by grants from the National Institutes of Health (R01MH079800 and P50 MH080173 to AKM; R01 MH080912 to DCG; K23 MH077807 to KEB; K01 MH085812 to MCK). Data collection for the TOP cohort was supported by the Research Council of Norway, South-East Norway Health Authority and KG Jebsen Foundation. The NCNG study was supported by Research Council of Norway Grants 154313/V50 and 177458/V50. The NCNG GWAS was financed by grants from the Bergen Research Foundation, the University of Bergen, the Research Council of Norway (FUGE, Psykisk Helse), Helse Vest RHF and Dr Einar Martens Fund. The Helsinki Birth Cohort Study has been supported by grants from the Academy of Finland, the Finnish Diabetes Research Society, Folkhalsan Research Foundation, Novo Nordisk Foundation, Finska Lakaresallskapet, Signe and Ane Gyllenberg Foundation, University of Helsinki, Ministry of Education, Ahokas Foundation, Emil Aaltonen Foundation. For the LBC1936 cohort, phenotype collection was supported by The Disconnected Mind project. Genotyping was funded by the UK Biotechnology and Biological Sciences Research Council (BBSRC grant no. BB/F019394/1). The work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative, which is funded by the Medical Research Council and the Biotechnology and Biological Sciences Research Council (MR/K026992/1). The CAMH work was supported by the CAMH Foundation and the Canadian Institutes of Health Research. The Duke Cognition Cohort (DCC) acknowledges K Linney, JM McEvoy, P Hunt, V Dixon, T Pennuto, K Cornett, D Swilling, L Phillips, M Silver, J Covington, N Walley, J Dawson, H Onabanjo, P Nicoletti, A Wagoner, J Elmore, L Bevan, J Hunkin and R Wilson for recruitment and testing of subjects. DCC also acknowledges the Ellison Medical Foundation New Scholar award AG-NS-0441-08 for partial funding of this study as well as the National Institute of Mental Health of the National Institutes of Health under award number K01MH098126. The UCLA Consortium for Neuropsychiatric Phenomics (CNP) study acknowledges the following sources of funding from the NIH: Grants UL1DE019580 and PL1MH083271 (RMB), RL1MH083269 (TDC), RL1DA024853 (EL) and PL1NS062410. The ASPIS study was supported by National Institute of Mental Health research grants R01MH085018 and R01MH092515 to Dr Dimitrios Avramopoulos. Support for the Duke Neurogenetics Study was provided the National Institutes of Health (R01 DA033369 and R01 AG049789 to ARH) and by a National Science Foundation Graduate Research Fellowship to MAS. Recruitment, genotyping and analysis of the TCD healthy control samples were supported by Science Foundation Ireland (grants 12/IP/1670, 12/IP/1359 and 08/IN. 1/B1916). NR 73 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD MAR PY 2017 VL 22 IS 3 BP 336 EP 345 DI 10.1038/mp.2016.244 PG 10 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA EL3RQ UT WOS:000394537100003 PM 28093568 ER PT J AU Haidar, G Zerbe, CS Cheng, M Zelazny, AM Holland, SM Sheridan, KR AF Haidar, Ghady Zerbe, Christa S. Cheng, Michelle Zelazny, Adrian M. Holland, Steven M. Sheridan, Kathleen R. TI Phellinus species: An emerging cause of refractory fungal infections in patients with X-linked chronic granulomatous disease SO MYCOSES LA English DT Review DE basidiomycota; chronic granulomatous disease; internal transcribed spacer; Phellinus ID INVASIVE ASPERGILLOSIS; TROPICALIS; IDENTIFICATION; OSTEOMYELITIS AB Aspergillus spp. are a leading cause of mortality in chronic granulomatous disease (CGD), but other fungi have emerged in the era of mould prophylaxis. Of these, Phellinus spp. are an under-recognised cause of invasive fungal infections (IFIs) in CGD, and data on their presentation and management are scarce. We present a patient with CGD who developed disseminated IFI involving the lungs and brain. Surgical specimens grew a basidiomycete which was disregarded as a contaminant. After three months of progressive disease despite antifungals, he was diagnosed with Phellinus tropicalis by internal transcribed spacer (ITS) sequencing. He improved with amphotericin B and isavuconazole but required haematopoietic stem cell transplantation (HSCT). We review the literature on Phellinus infections in CGD and conclude that: (i) these infections emerge on mould-active prophylaxis and are indolent; (ii) they typically cause locally destructive disease but can disseminate; (iii) diagnosis is delayed and requires molecular methods; (iv) amphotericin B is most active in vitro; and (v) treatment is protracted and requires surgery and possibly HSCT. In conclusion, Phellinus spp. are emerging pathogens in CGD. Every effort should be made to establish the diagnosis of non-Aspergillus IFIs in patients with CGD by sending tissue specimens for molecular diagnostics. C1 [Haidar, Ghady; Sheridan, Kathleen R.] Univ Pittsburgh, Dept Med, Div Infect Dis, Med Ctr, Pittsburgh, PA USA. [Zerbe, Christa S.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Cheng, Michelle] Univ Pittsburgh, Med Ctr, Dept Med, Pittsburgh, PA USA. [Zelazny, Adrian M.] NIH, Dept Lab Med, Microbiol Serv, Bldg 10, Bethesda, MD 20892 USA. [Cheng, Michelle] Univ Calif Davis, Dept Dermatol, Davis, CA 95616 USA. RP Sheridan, KR (reprint author), Univ Pittsburgh, Med Ctr, Div Infect Dis, Pittsburgh, PA 15260 USA. EM sheridank@upmc.edu NR 19 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0933-7407 EI 1439-0507 J9 MYCOSES JI Mycoses PD MAR PY 2017 VL 60 IS 3 BP 155 EP 160 DI 10.1111/myc.12573 PG 6 WC Dermatology; Mycology SC Dermatology; Mycology GA EK5DM UT WOS:000393947100002 PM 27781311 ER PT J AU Lerch, JP van der Kouwe, AJW Raznahan, A Pans, T Johansen-Berg, H Miller, KL Smith, SM Fischl, B Sotiropoulos, SN AF Lerch, Jason P. van der Kouwe, Andre J. W. Raznahan, Armin Pans, Tomas Johansen-Berg, Heidi Miller, Karla L. Smith, Stephen M. Fischl, Bruce Sotiropoulos, Stamatios N. TI Studying neuroanatomy using MRI SO NATURE NEUROSCIENCE LA English DT Review ID VOXEL-BASED MORPHOMETRY; HUMAN CONNECTOME PROJECT; BRAIN WHITE-MATTER; NEURITE ORIENTATION DISPERSION; AXON DIAMETER DISTRIBUTION; HUMAN CORTICAL DEVELOPMENT; DIFFUSION-WEIGHTED MRI; PULSED-FIELD GRADIENT; HUMAN CEREBRAL-CORTEX; IN-VIVO AB The study of neuroanatomy using imaging enables key insights into how our brains function, are shaped by genes and environment, and change with development, aging and disease. Developments in MRI acquisition, image processing and data modeling have been key to these advances. However, MRI provides an indirect measurement of the biological signals we aim to investigate. Thus, artifacts and key questions of correct interpretation can confound the readouts provided by anatomical MRI. In this review we provide an overview of the methods for measuring macro- and mesoscopic structure and for inferring microstructural properties; we also describe key artifacts and confounds that can lead to incorrect conclusions. Ultimately, we believe that, although methods need to improve and caution is required in interpretation, structural MRI continues to have great promise in furthering our understanding of how the brain works. C1 [Lerch, Jason P.] Hosp Sick Children, Program Neurosci & Mental Hlth, Toronto, ON, Canada. [Lerch, Jason P.] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. [van der Kouwe, Andre J. W.; Fischl, Bruce] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Res, Charlestown, MA USA. [van der Kouwe, Andre J. W.; Fischl, Bruce] Harvard Med Sch, Charlestown, MA USA. [van der Kouwe, Andre J. W.; Fischl, Bruce] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [van der Kouwe, Andre J. W.; Fischl, Bruce] Harvard Med Sch, Boston, MA USA. [Raznahan, Armin] NIMH, Dev Neurogen Unit, Child Psychiat Branch, Bethesda, MD 20892 USA. [Pans, Tomas] Rotman Res Inst, Toronto, ON, Canada. [Pans, Tomas] Univ Toronto, Dept Psychol, Toronto, ON, Canada. [Pans, Tomas] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. [Pans, Tomas] Child Mind Inst, Ctr Developing Brain, New York, NY USA. [Johansen-Berg, Heidi; Miller, Karla L.; Smith, Stephen M.; Sotiropoulos, Stamatios N.] Univ Oxford, Oxford Ctr Funct MRI Brain FMRIB, Oxford, MS USA. [Fischl, Bruce] MIT, Comp Sci & Artificial Intelligence Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Sotiropoulos, Stamatios N.] Univ Nottingham, Sch Med, Sir Peter Mansfield Imaging Ctr, Nottingham NG7 2RD, England. RP Lerch, JP (reprint author), Hosp Sick Children, Program Neurosci & Mental Hlth, Toronto, ON, Canada.; Lerch, JP (reprint author), Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. EM jason.lerch@utoronto.ca FU Ontario Brain Institutes' POND grant FX We thank C. Hammill for his assistance in the preparation of Figures 2 and 3, which contain data from The Ontario Brain Institutes' POND grant (to J.P.L.), and we thank L. Wald (Massachusetts General Hospital) for providing the images in Figure 6. Figure 1 contains data from R0IMH085772-01A1 (to T.P.). NR 176 TC 0 Z9 0 U1 8 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 EI 1546-1726 J9 NAT NEUROSCI JI Nat. Neurosci. PD MAR PY 2017 VL 20 IS 3 BP 314 EP 326 DI 10.1038/nn.4501 PG 13 WC Neurosciences SC Neurosciences & Neurology GA EL9DU UT WOS:000394920400005 PM 28230838 ER PT J AU Edwards, NJ Tejeda, HA Pignatelli, M Zhang, SL McDevitt, RA Wu, J Bass, CE Bettler, B Morales, M Bonci, A AF Edwards, Nicholas J. Tejeda, Hugo A. Pignatelli, Marco Zhang, Shiliang McDevitt, Ross A. Wu, Jocelyn Bass, Caroline E. Bettler, Bernhard Morales, Marisela Bonci, Antonello TI Circuit specificity in the inhibitory architecture of the VTA regulates cocaine-induced behavior SO NATURE NEUROSCIENCE LA English DT Article ID VENTRAL TEGMENTAL AREA; MIDBRAIN DOPAMINE NEURONS; RAT SUBSTANTIA-NIGRA; GABA(B) RECEPTORS; SYNAPTIC INPUTS; REWARD; LOCALIZATION; ACTIVATION; NUCLEUS; TRANSMISSION AB Afferent inputs to the ventral tegmental area (VTA) control reward-related behaviors through regulation of dopamine neuron activity. The nucleus accumbens (NAc) provides one of the most prominent projections to the VTA; however, recent studies have provided conflicting evidence regarding the function of these inhibitory inputs. Using optogenetics, cell-specific ablation, whole cell patch clamp and immuno-electron microscopy, we found that NAc inputs synapsed directly onto dopamine neurons, preferentially activating GABA(B) receptors. GABAergic inputs from the NAc and local VTA GABA neurons were differentially modulated and activated separate receptor populations in dopamine neurons. Genetic deletion of GABA(B) receptors from dopamine neurons in adult mice did not affect general or morphine-induced locomotor activity, but markedly increased cocaine-induced locomotion. Collectively, our findings demonstrate notable selectivity in the inhibitory architecture of the VTA and suggest that long-range GABAergic inputs to dopamine neurons fundamentally regulate behavioral responses to cocaine. C1 [Edwards, Nicholas J.; Tejeda, Hugo A.; Pignatelli, Marco; Zhang, Shiliang; McDevitt, Ross A.; Wu, Jocelyn; Morales, Marisela; Bonci, Antonello] NIDA, Intramural Res Program, US Natl Inst Hlth, Baltimore, MD 21224 USA. [Bass, Caroline E.] Univ Buffalo, Dept Pharmacol & Toxicol, Buffalo, NY USA. [Bettler, Bernhard] Univ Basel, Pharmazentrum, Dept Biomed, Basel, Switzerland. [Bonci, Antonello] Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21218 USA. [Bonci, Antonello] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. RP Bonci, A (reprint author), NIDA, Intramural Res Program, US Natl Inst Hlth, Baltimore, MD 21224 USA.; Bonci, A (reprint author), Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21218 USA.; Bonci, A (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. EM antonello.bonci@nih.gov FU Intramural Research Program at the National Institute on Drug Abuse FX We thank members of the Bonci lab for insightful discussions and careful reading of the manuscript. We thank the NIDA Histology Core for help with in situ hybridization experiments, B. Sadacca for help with statistical analysis, K. Deisseroth (Stanford University) for the generation of optogenetic constructs, and B. Lowell (Beth Israel Deaconess Medical Center) for Dyn-Cre and VGAT-Cre transgenic mice. This work was supported by the Intramural Research Program at the National Institute on Drug Abuse. NR 50 TC 1 Z9 1 U1 5 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 EI 1546-1726 J9 NAT NEUROSCI JI Nat. Neurosci. PD MAR PY 2017 VL 20 IS 3 BP 438 EP 448 DI 10.1038/nn.4482 PG 11 WC Neurosciences SC Neurosciences & Neurology GA EL9DU UT WOS:000394920400021 PM 28114294 ER PT J AU Duffy, AG Greten, TF AF Duffy, Austin G. Greten, Tim F. TI Regorafenib as second-line therapy in hepatocellular carcinoma SO NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY LA English DT Editorial Material ID SORAFENIB AB Drug development in hepatocellular carcinoma had essentially stalled since 2008 when sorafenib was established as the modest standard of care. Now, a positive result in a phase III study evaluating regorafenib challenges us to weigh its clinical significance as well as its real-world benefits and potential harms. C1 [Duffy, Austin G.; Greten, Tim F.] NCI, Gastrointestinal Malignancy Sect, Thorac & Gastrointestinal Oncol Branch, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. RP Greten, TF (reprint author), NCI, Gastrointestinal Malignancy Sect, Thorac & Gastrointestinal Oncol Branch, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. EM tim.greten@nih.gov NR 9 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 1759-5045 EI 1759-5053 J9 NAT REV GASTRO HEPAT JI Nat. Rev. Gastroenterol. Hepatol. PD MAR PY 2017 VL 14 IS 3 BP 141 EP 142 DI 10.1038/nrgastro.2017.7 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EN1YA UT WOS:000395805200003 PM 28174418 ER PT J AU Prescott, JB Marzi, A Safronetz, D Robertson, SJ Feldmann, H Best, SM AF Prescott, Joseph B. Marzi, Andrea Safronetz, David Robertson, Shelly J. Feldmann, Heinz Best, Sonja M. TI Immunobiology of Ebola and Lassa virus infections SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID HUMAN DENDRITIC CELLS; DOUBLE-STRANDED-RNA; HEMORRHAGIC-FEVER; VP35 PROTEIN; WEST-AFRICA; NONHUMAN-PRIMATES; IMMUNE-RESPONSES; SIERRA-LEONE; INTERFERON ANTAGONISM; NEUTRALIZING ANTIBODY AB Two of the most important contemporary emerging viruses that affect human health in Africa are Ebola virus (EBOV) and Lassa virus (LASV). The 2013-2016 West African outbreak of EBOV was responsible for more than 11,000 deaths, primarily in Guinea, Sierra Leone and Liberia. LASV is constantly emerging in these and surrounding West African countries, with an estimate of more than 500,000 cases of Lassa fever, and approximately 5,000 deaths, annually. Both EBOV and LASV are zoonotic, and human infection often results in a severe haemorrhagic fever in both cases. However, the contribution of specific immune responses to disease differs between EBOV and LASV. This Review examines innate and adaptive immune responses to these viruses with the goal of delineating responses that are associated with protective versus pathogenic outcomes. C1 [Prescott, Joseph B.; Marzi, Andrea; Robertson, Shelly J.; Feldmann, Heinz; Best, Sonja M.] NIAID, Virol Lab, Rocky Mt Labs, NIH, 903 S Fourth St, Hamilton, MT 59840 USA. [Safronetz, David] Publ Hlth Agcy Canada, Zoonot Dis & Special Pathogens, 1015 Arlington St, Winnipeg, MB R3E 3R2, Canada. [Safronetz, David; Feldmann, Heinz] Univ Manitoba, Dept Med Microbiol, 745 Bannatyne Ave, Winnipeg, MB R3E 0J9, Canada. RP Feldmann, H; Best, SM (reprint author), NIAID, Virol Lab, Rocky Mt Labs, NIH, 903 S Fourth St, Hamilton, MT 59840 USA.; Feldmann, H (reprint author), Univ Manitoba, Dept Med Microbiol, 745 Bannatyne Ave, Winnipeg, MB R3E 0J9, Canada. EM feldmannh@niaid.nih.gov; sbest@niaid.nih.gov FU Division of Intramural Research, National Institutes of Allergy and Infectious Diseases, US National Institutes of Health FX This work was supported by the Division of Intramural Research, National Institutes of Allergy and Infectious Diseases, US National Institutes of Health. NR 140 TC 0 Z9 0 U1 5 U2 5 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 MAR PY 2017 VL 17 IS 3 BP 195 EP 207 DI 10.1038/nri.2016.138 PG 13 WC Immunology SC Immunology GA EN2GI UT WOS:000395827600004 PM 28111475 ER PT J AU Chirenje, ZM Gundacker, HM Richardson, B Rabe, L Gaffoor, Z Nair, G Mirembe, BG Piper, JM Hillier, S Marrazzo, J AF Chirenje, Zvavahera Mike Gundacker, Holly M. Richardson, Barbra Rabe, Lorna Gaffoor, Zakir Nair, Gonasagrie (Lulu) Mirembe, Brenda Gati Piper, Jeanna M. Hillier, Sharon Marrazzo, Jeanne TI Risk Factors for Incidence of Sexually Transmitted Infections Among Women in a Human Immunodeficiency Virus Chemoprevention Trial: VOICE (MTN-003) SO SEXUALLY TRANSMITTED DISEASES LA English DT Article ID PELVIC-INFLAMMATORY-DISEASE; CHLAMYDIA-TRACHOMATIS; HIV-INFECTION; SOUTH-AFRICA; SERVICES; HEALTH; TRANSMISSION; GONORRHEA AB Background: In sub-Saharan Africa, there are limited data on the incidence of sexually transmitted infections (STIs) among women, largely because routine screening for asymptomatic infection is not performed. We conducted a secondary analysis to measure STI incidence rates and determine risk factors for new STI acquisition among women enrolled in the VOICE trial. Methods: We analyzed data from 4843 women screened for chlamydia, gonorrhoea, syphilis, and trichomonas infection at baseline, annually, at interim visits when clinically indicated and at their study termination visit. Risk reduction counseling and condoms were provided throughout the trial. Results: Twenty percent of evaluable participants had one or more curable STIs at baseline. Over 5660 person-years at risk (PYAR) of observation, incidence rates were 13.8%(95% confidence interval [CI], 12.7-14.8) PYAR for chlamydia, 3.5% (95% CI, 3.0-4.1) PYAR gonorrhea, 0.1% (95% CI, 0.6-1.1) PYAR syphilis, and 6.6% (95% CI, 5.8-7.2) PYAR trichomoniasis. South African sites had the highest incidence of chlamydia. The Uganda site had the highest incidence of gonorrhoea and syphilis, and Zimbabwe the lowest incidence overall. The majority of these cases were diagnosed at a routine scheduled testing visit. In multivariate analysis, positive baseline STI, younger than 25 years, being unmarried, and some alcohol consumption were associated with acquiring a new STI. Conclusions: We observed high rates of STIs during follow up among women in the VOICE study. Women living in human immunodeficiency virus endemic countries should be screened for common STIs. C1 [Chirenje, Zvavahera Mike] Univ Zimbabwe Univ Calif San Francisco Res Progra, Harare, Zimbabwe. [Gundacker, Holly M.] Fred Hutchinson Canc Res Ctr, SCHARP, 1124 Columbia St, Seattle, WA 98104 USA. [Richardson, Barbra] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Rabe, Lorna; Hillier, Sharon] Magee Womens Res Inst, Pittsburgh, PA USA. [Gaffoor, Zakir] MRC, HIV Prevent Res Unit, Durban, South Africa. [Nair, Gonasagrie (Lulu)] Univ KwaZulu Natal, CAPRISA, Durban, South Africa. [Mirembe, Brenda Gati] MU JHU Res Collaborat, Kampala, Uganda. [Piper, Jeanna M.] NIAID, Div Aids, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Hillier, Sharon] Univ Pittsburgh, Pittsburgh, PA USA. [Marrazzo, Jeanne] Univ Alabama Birmingham, Birmingham, AL USA. RP Chirenje, ZM (reprint author), UZ UCSF Collaborat Res Programme, 15 Philips Rd, Harare, Zimbabwe. EM chirenje@uz-ucsf.co.zw FU National Institute of Allergy and Infectious Diseases [UM1AI068633, UM1AI068615, UM1AI106707]; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Mental Health of the U.S. National Institutes of Health FX The VOICE study (VOICE ClinicalTrials.gov number, NCT00705679) was supported by MTN. MTN is funded by the National Institute of Allergy and Infectious Diseases (UM1AI068633, UM1AI068615, UM1AI106707), with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, all components of the U.S. National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 21 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 0148-5717 EI 1537-4521 J9 SEX TRANSM DIS JI Sex. Transm. Dis. PD MAR PY 2017 VL 44 IS 3 BP 135 EP 140 DI 10.1097/OLQ.0000000000000568 PG 6 WC Infectious Diseases SC Infectious Diseases GA EL1CX UT WOS:000394359200001 PM 28178109 ER PT J AU Altan-Bonnett, N AF Altan-Bonnett, Nihal TI Lipid Tales of Viral Replication and Transmission SO TRENDS IN CELL BIOLOGY LA English DT Review ID RNA VIRUS-REPLICATION; HOST RETICULON PROTEINS; 4-KINASE III-BETA; PHOSPHATIDYLINOSITOL 4-PHOSPHATE; PLASMA-MEMBRANE; IN-VITRO; EXTRACELLULAR VESICLES; CELLULAR MEMBRANES; PHOSPHATIDYLSERINE; AUTOPHAGY AB Positive-strand RNA viruses are the largest group of RNA viruses on Earth and cellular membranes are critical for all aspects of their life cycle, from entry and replication to exit. In particular, membranes serve as platforms for replication and as carriers to transmit these viruses to other cells, the latter either as an envelope surrounding a single virus or as the vesicle containing a population of viruses. Notably, many animal and human viruses appear to induce and exploit phosphatidylinositol 4-phosphate/cholesterol-enriched membranes for replication, whereas many plant and insect-vectored animal viruses utilize phosphatidylethanolamine/cholesterol-enriched membranes for the same purpose; and phosphatidylserine-enriched membrane carriers are widely used by both single and populations of viruses for transmission. Here I discuss the implications for viral pathogenesis and therapeutic development of this remarkable convergence on specific membrane lipid blueprints for replication and transmission. C1 [Altan-Bonnett, Nihal] NHLBI, Lab Host Pathogen Dynam, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Altan-Bonnett, N (reprint author), NHLBI, Lab Host Pathogen Dynam, NIH, Bldg 10, Bethesda, MD 20892 USA. EM nihal.altan-bonnet@nih.gov FU Intramural NIH HHS [Z99 HL999999] NR 99 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0962-8924 J9 TRENDS CELL BIOL JI Trends Cell Biol. PD MAR PY 2017 VL 27 IS 3 SI SI BP 201 EP 213 DI 10.1016/j.tcb.2016.09.011 PG 13 WC Cell Biology SC Cell Biology GA EN2NR UT WOS:000395847700004 PM 27838086 ER PT J AU Belenko, S Knight, D Wasserman, GA Dennis, ML Wiley, T Taxman, FS Oser, C Dembo, R Robertson, AA Sales, J AF Belenko, Steven Knight, Danica Wasserman, Gail A. Dennis, Michael L. Wiley, Tisha Taxman, Faye S. Oser, Carrie Dembo, Richard Robertson, Angela A. Sales, Jessica TI The Juvenile Justice Behavioral Health Services Cascade: A new framework for measuring unmet substance use treatment services needs among adolescent offenders SO JOURNAL OF SUBSTANCE ABUSE TREATMENT LA English DT Article DE Substance abuse treatment; Juvenile justice; Delinquent youth; Barriers to treatment access; Continuum of services; Evidence-based practices ID ALCOHOL-USE DISORDERS; ABUSE TREATMENT; ADDICTION TREATMENT; CRIMINAL-JUSTICE; DRUG COURT; HIV CARE; COMORBIDITY; YOUTH; RISK; ENGAGEMENT AB Overview: Substance use and substance use disorders are highly prevalent among youth under juvenile justice (JJ) supervision, and related to delinquency, psychopathology, social problems, risky sex and sexually transmitted infections, and health problems. However, numerous gaps exist in the identification of behavioral health (BH) problems and in the subsequent referral, initiation and retention in treatment for youth in community justice settings. This reflects both organizational and systems factors, including coordination between justice and BH agencies. Methods and results: This paper presents a new framework, the Juvenile Justice Behavioral Health Services Cascade ("Cascade"), for measuring unmet substance use treatment needs to illustrate how the cascade approach can be useful in understanding service delivery issues and identifying strategies to improve treatment engagement and outcomes for youth under community JJ supervision. We discuss the organizational and systems barriers for linking delinquent youth to BH services, and explain how the Cascade can help understand and address these barriers. We provide a detailed description of the sequential steps and measures of the Cascade, and then offer an example of its application from the Juvenile Justice Translational Research on Interventions for Adolescents in the Legal System project (JJ-TRIALS), a multi-site research cooperative funded by the National Institute on Drug Abuse. Conclusion: As illustrated with substance abuse treatment, the Cascade has potential for informing and guiding efforts to improve behavioral health service linkages for adolescent offenders, developing and testing interventions and policies to improve interagency and cross-systems coordination, and informing the development of measures and interventions for improving the implementation of treatment in complex multisystem service settings. (C) 2017 Elsevier Inc. All rights reserved. C1 [Belenko, Steven] Temple Univ, 1115 Polett Walk, Philadelphia, PA 19122 USA. [Knight, Danica] Texas Christian Univ, 3034 Sandage Ave, Ft Worth, TX 76129 USA. [Wasserman, Gail A.] Columbia Univ, 1051 Riverside Dr,Unit 78, New York, NY 10032 USA. [Dennis, Michael L.] Chestnut Hlth Syst, 448 Wylie Dr, Normal, IL 61701 USA. [Wiley, Tisha] NIDA, 6001 Execut Blvd,Room 5191, Bethesda, MD 20892 USA. [Taxman, Faye S.] George Mason Univ, 4087 Univ Dr,4100,MSN 6D3, Fairfax, VA 22030 USA. [Oser, Carrie] Univ Kentucky, 1531 Patterson Off Tower, Lexington, KY 40506 USA. [Dembo, Richard] Univ S Florida, 4202 E Fowler Ave, Tampa, FL 33620 USA. [Robertson, Angela A.] Mississippi State Univ, 1 Res Blvd,Suite 103, Starkville, MS 39759 USA. [Sales, Jessica] Emory Univ, Rollins Sch Publ Hlth, 1518 Clifton Rd,Room 570, Atlanta, GA 30322 USA. RP Belenko, S (reprint author), Temple Univ, 1115 Polett Walk, Philadelphia, PA 19122 USA. EM sbelenko@temple.edu; d.knight@tcu.edu; wassermg@nyspi.columbia.edu; mdennis@chestnut.org; wileytr@nida.nih.gov; ftaxman@gmu.edu; Carrie.oser@uky.edu; rdembo@usf.edu; Angela.robertson@ssrc.msstate.edu; jmcderm@emory.edu OI Dennis, Michael/0000-0002-2580-5345 FU Juvenile Justice Translational Research on Interventions for Adolescents in the Legal System project (JJ-TRIALS); National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH); Chestnut Health Systems [U01DA036221]; Columbia University [U01DA036226]; Emory University [U01DA036233]; Mississippi State University [U01DA036176]; Temple University [U01DA036225]; Texas Christian University [U01DA036224]; University of Kentucky [U01DA036158] FX This study was funded under the Juvenile Justice Translational Research on Interventions for Adolescents in the Legal System project (JJ-TRIALS) cooperative agreement, funded by the National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH). The authors gratefully acknowledge the collaborative contributions of NIDA and support from the following grant awards: Chestnut Health Systems (U01DA036221); Columbia University (U01DA036226); Emory University (U01DA036233); Mississippi State University (U01DA036176); Temple University (U01DA036225); Texas Christian University (U01DA036224); and University of Kentucky (U01DA036158). The NIDA Science Officer on this project is Tisha Wiley. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIDA, NIH, or the participating universities or juvenile justice systems. NR 84 TC 0 Z9 0 U1 5 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0740-5472 J9 J SUBST ABUSE TREAT JI J. Subst. Abus. Treat. PD MAR PY 2017 VL 74 BP 80 EP 91 DI 10.1016/j.jsat.2016.12.012 PG 12 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA EK2CG UT WOS:000393734400012 PM 28132705 ER PT J AU de Sousa, RT Loch, AA Carvalho, AF Brunoni, AR Haddad, MR Henter, ID Zarate, CA Machado-Vieira, R AF de Sousa, Rafael T. Loch, Alexandre A. Carvalho, Andre F. Brunoni, Andre R. Haddad, Marie Reine Henter, Ioline D. Zarate, Carlos A., Jr. Machado-Vieira, Rodrigo TI Genetic Studies on the Tripartite Glutamate Synapse in the Pathophysiology and Therapeutics of Mood Disorders SO NEUROPSYCHOPHARMACOLOGY LA English DT Review ID MAJOR DEPRESSIVE DISORDER; BIPOLAR AFFECTIVE-DISORDER; GENOME-WIDE ASSOCIATION; STAR-ASTERISK-D; CHINESE HAN POPULATION; 3 GRIN2B POLYMORPHISMS; RECEPTOR GENE; ANTIDEPRESSANT TREATMENT; FUNCTIONAL POLYMORPHISM; FLUVOXAMINE RESPONSE AB Both bipolar disorder (BD) and major depressive disorder (MDD) have high morbidity and share a genetic background. Treatment options for these mood disorders are currently suboptimal for many patients; however, specific genetic variables may be involved in both pathophysiology and response to treatment. Agents such as the glutamatergic modulator ketamine are effective in treatment-resistant mood disorders, underscoring the potential importance of the glutamatergic system as a target for improved therapeutics. Here we review genetic studies linking the glutamatergic system to the pathophysiology and therapeutics of mood disorders. We screened 763 original genetic studies of BD or MDD that investigated genes encoding targets of the pathway/mediators related to the so-called tripartite glutamate synapse, including pre- and post-synaptic neurons and glial cells; 60 papers were included in this review. The findings suggest the involvement of glutamate-related genes in risk for mood disorders, treatment response, and phenotypic characteristics, although there was no consistent evidence for a specific gene. Target genes of high interest included GRIA3 and GRIK2 (which likely play a role in emergent suicidal ideation after antidepressant treatment), GRIK4 (which may influence treatment response), and GRM7 (which potentially affects risk for mood disorders). There was stronger evidence that glutamate-related genes influence risk for BD compared with MDD. Taken together, the studies show a preliminary relationship between glutamate-related genes and risk for mood disorders, suicide, and treatment response, particularly with regard to targets on metabotropic and ionotropic receptors. C1 [de Sousa, Rafael T.; Henter, Ioline D.; Zarate, Carlos A., Jr.; Machado-Vieira, Rodrigo] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Ctr Clin, 10 Ctr Dr,Room 2-D39C, Bethesda, MD 20892 USA. [de Sousa, Rafael T.; Loch, Alexandre A.; Brunoni, Andre R.; Machado-Vieira, Rodrigo] Univ Sao Paulo, Inst & Dept Psychiat, Neurosci Lab, LIM 27, Sao Paulo, Brazil. [Carvalho, Andre F.] Univ Fed Ceara, Translat Psychiat Res Grp, Fac Med, Fortaleza, Ceara, Brazil. [Carvalho, Andre F.] Univ Fed Ceara, Dept Clin Med, Fac Med, Fortaleza, Ceara, Brazil. [Haddad, Marie Reine] NICHHD, Sect Translat Neurosci, NIH, Bethesda, MD 20892 USA. [Machado-Vieira, Rodrigo] Univ Sao Paulo, Ctr Interdisciplinary Res Appl Neurosci NAPN, Sao Paulo, Brazil. RP de Sousa, RT (reprint author), NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Ctr Clin, 10 Ctr Dr,Room 2-D39C, Bethesda, MD 20892 USA. EM rafael.desousa@nih.gov RI Loch, Alexandre/C-8526-2011; OI Loch, Alexandre/0000-0002-0006-8107; Russowsky Brunoni, Andre/0000-0002-6310-3571; MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190 FU Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) [ZIA MH002857]; NARSAD Independent Investigator; Brain & Behavior Mood Disorders Research Award FX Funding for this work was supported by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH; ZIA MH002857), by a NARSAD Independent Investigator to Dr Zarate, and by a Brain & Behavior Mood Disorders Research Award to Dr Zarate. Dr Zarate is listed as a co-inventor on a patent for the use of, ketamine and its metabolites in major depression. He has assigned his rights in the patent to the US government but will share a percentage of any royalties that may be received by the government. The remaining authors declare no conflict of interest. NR 95 TC 1 Z9 1 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD MAR PY 2017 VL 42 IS 4 BP 787 EP 800 DI 10.1038/npp.2016.149 PG 14 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA EK1ZC UT WOS:000393725600002 PM 27510426 ER PT J AU Hui, WF Betoko, A Savant, JD Abraham, AG Greenbaum, LA Warady, B Moxey-Mims, MM Furth, SL AF Hui, Wun Fung Betoko, Aisha Savant, Jonathan D. Abraham, Alison G. Greenbaum, Larry A. Warady, Bradley Moxey-Mims, Marva M. Furth, Susan L. TI Assessment of dietary intake of children with chronic kidney disease SO PEDIATRIC NEPHROLOGY LA English DT Article DE Dietary assessment; Nutrient intake; Children; Chronic kidney disease ID FOOD FREQUENCY QUESTIONNAIRE; PRESCHOOL-CHILDREN; SALT INTAKE; GROWTH; REPRODUCIBILITY; ADOLESCENTS; PHOSPHORUS; OBESITY; WEIGHT; ENERGY AB Our aim was to characterize the nutrient intake of children with chronic kidney disease (CKD) relative to recommended intake levels. We conducted a cross-sectional study of dietary intake assessed by Food Frequency Questionnaire (FFQ) in The North American Chronic Kidney Disease in Children (CKiD) prospective cohort study. Nutrient intake was analyzed to estimate the daily consumption levels of various nutrients and compared with national guidelines for intake. There were 658 FFQs available for analysis; 69.9 % of respondents were boys, with a median age [Interquartile range (IQR)] of 11 years (8-15). Median daily sodium, potassium, and phosphorus intake was 3089 mg (2294-4243), 2384 mg (1804-3076), and 1206 mg (894-1612) respectively. Sodium and phosphorus consumptions were higher than recommended in all age groups. Caloric intake decreased with dropping glomerular filtration rate (GFR) (p = 0.003). The median daily caloric intakes were 1307 kcal in male children 2-3 years old, 1875 kcal in children 4-8 years old, 1923 kcal in those 9-13 years old, and 2427 kcal in those 14-18 years old. Respective levels for girls were 1467 kcal, 1736 kcal, 1803 kcal, and 2281 kcal. Median protein intake exceeded recommended levels in all age groups, particularly among younger participants. Younger children were more likely than older children to exceed the recommended intakes for phosphorus (p < 0.001) and the age-specific recommended caloric intake (p < 0.001). Macronutrient distribution (carbohydrate:fat:protein) was consistent with recommendation. Children in the CKiD cohort consumed more sodium, phosphorus, protein, and calories than recommended. The gap between actual consumption and recommendations indicates a need for improved nutritional counseling and monitoring. C1 [Hui, Wun Fung; Savant, Jonathan D.; Furth, Susan L.] Childrens Hosp Philadelphia, Dept Pediat, 34th St & Civ Ctr Blvd, Philadelphia, PA 19104 USA. [Betoko, Aisha; Abraham, Alison G.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Greenbaum, Larry A.] Emory Univ, Atlanta, GA 30322 USA. [Greenbaum, Larry A.] Childrens Healthcare Atlanta, Atlanta, GA USA. [Warady, Bradley] Childrens Mercy Hosp, Div Pediat Nephrol, Kansas City, MO 64108 USA. [Moxey-Mims, Marva M.] Natl Inst Diabet & Digest & Kidney Dis, NIH, Bethesda, MD USA. RP Furth, SL (reprint author), Childrens Hosp Philadelphia, Dept Pediat, 34th St & Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM furths@email.chop.edu OI Betoko, Aisha/0000-0003-1245-8257 FU National Institute of Diabetes and Digestive and Kidney Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Heart, Lung and Blood Institute [U01-DK-66143, U01-DK-66174, U01DK-082194, U01-DK-66116] FX National Institute of Diabetes and Digestive and Kidney Diseases, with additional funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung and Blood Institute (grants U01-DK-66143, U01-DK-66174, U01DK-082194, and U01-DK-66116). NR 39 TC 0 Z9 0 U1 3 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0931-041X EI 1432-198X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD MAR PY 2017 VL 32 IS 3 BP 485 EP 494 DI 10.1007/s00467-016-3491-5 PG 10 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA EK2MC UT WOS:000393760400015 PM 27687620 ER PT J AU Thanos, PK Kim, R Delis, F Rocco, MJ Cho, J Volkow, ND AF Thanos, Panayotis K. Kim, Ronald Delis, Foteini Rocco, Mark J. Cho, Jacob Volkow, Nora D. TI Effects of chronic methamphetamine on psychomotor and cognitive functions and dopamine signaling in the brain SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Chronic; Methamphetamine; Dopamine; Behavior; Brain; Reward deficiency syndrome; Positron emission tomography ID TRANSPORTER COMPLEX-FORMATION; IMPAIRS RECOGNITION MEMORY; PLACEBO-CONTROLLED TRIAL; OBJECT RECOGNITION; RAT-BRAIN; NUCLEUS-ACCUMBENS; D2 RECEPTORS; ABSTINENT METHAMPHETAMINE; NEUROTRANSMITTER RELEASE; BEHAVIORAL-RESPONSES AB Methamphetamine (MA) studies in animals usually involve acute, binge, or short-term exposure to the drug. However, addicts take substantial amounts of MA for extended periods of time. Here we wished to study the effects of MA exposure on brain and behavior, using an animal model analogous to this pattern of MA intake. MA doses, 4 and 8 mg/kg/day, were based on previously reported average daily freely available MA self-administration levels. We examined the effects of 16 week MA treatment on psychomotor and cognitive function in the rat using open field and novel object recognition tests and we studied the adaptations of the dopaminergic system, using in vitro and in vivo receptor imaging. We show that chronic MA treatment, at doses that correspond to the average daily freely available self-administration levels in the rat, disorganizes open field activity, impairs alert exploratory behavior and anxiety-like state, and downregulates dopamine transporter in the striatum. Under these treatment conditions, dopamine terminal functional integrity in the nucleus accumbens is also affected. In addition, lower dopamine D1 receptor binding density, and, to a smaller degree, lower dopamine D2 receptor binding density were observed. Potential mechanisms related to these alterations are discussed. (C) 2016 Published by Elsevier B.V. C1 [Thanos, Panayotis K.; Kim, Ronald; Rocco, Mark J.; Cho, Jacob] Univ Buffalo, Res Inst Addict, Behav Neuropharmacol & Neuroimaging Lab Addict, Buffalo, NY 14203 USA. [Delis, Foteini; Volkow, Nora D.] Univ Ioannina, Sch Med, Dept Pharmacol, Ioannina 45100, Greece. [Volkow, Nora D.] NIAAA, Lab Neuroimaging, Intramural Program, Bethesda, MD 20892 USA. RP Thanos, PK (reprint author), 1021 Main St, Buffalo, NY 14203 USA. EM pthanos@ria.buffalo.edu FU Research Foundation of New York FX This work was supported by the Research Foundation of New York. The authors have no competing financial interests to declare. NR 94 TC 0 Z9 0 U1 8 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 EI 1872-7549 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD MAR 1 PY 2017 VL 320 BP 282 EP 290 DI 10.1016/j.bbr.2016.12.010 PG 9 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA EJ5FV UT WOS:000393244100032 PM 27993694 ER PT J AU Halladay, LR Blair, HT AF Halladay, Lindsay R. Blair, Hugh T. TI Prefrontal infralimbic cortex mediates competition between excitation and inhibition of body movements during pavlovian fear conditioning SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE fear conditioning; freezing; flight; fear expression; defensive; RGD ID:2308852 ID DORSOLATERAL PERIAQUEDUCTAL GRAY; BEHAVIORAL FLEXIBILITY; LATERAL AMYGDALA; NUCLEUS-ACCUMBENS; DISSOCIABLE ROLES; DEFENSE REACTIONS; PRELIMBIC CORTEX; AVERSIVE STIMULI; EXTINCTION; RAT AB The infralimbic subregion of the prefrontal cortex (IL) is broadly involved in behavioral flexibility, risk assessment, and outcome reinforcement. In aversive conditioning tasks, the IL has been implicated in fear extinction and in mediating transitions between Pavlovian and instrumental responses. Here we examine the role of the IL in mediating transitions between two competing Pavlovian fear responses, conditioned motor inhibition (CMI) and conditioned motor excitation (CME). Rats were trained to fear an auditory conditioned stimulus (CS) by pairing it with periorbital shock to one eyelid (the unconditioned stimulus [US]). Trained animals exhibited CMI responses (movement suppression) to the CS when they had not recently encountered the US (>24 hr), but, after recent encounters with the US (<5 min), the CS evoked CME responses (turning in circles away from anticipated shock). Animals then received bilateral infusions of muscimol or picrotoxin to inactivate or hyperactivate the IL, respectively. Neither drug reliably affected CMI responses, but there was a bidirectional effect on CME responses; inactivation of the IL attenuated CME responses, whereas hyperactivation potentiated CME responses. These results provide evidence that activation of the IL may promote behavioral strategies that involve mobilizing the body and suppress strategies that involve immobilizing the body. (c) 2016 Wiley Periodicals, Inc. C1 [Halladay, Lindsay R.; Blair, Hugh T.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA USA. [Halladay, Lindsay R.] NIAAA, NIH, Bethesda, MD USA. RP Halladay, LR (reprint author), 5625 Fishers Lane,Room 2N09, Rockville, MD 20852 USA. EM lindsay.halladay@nih.gov FU National Institutes of Health [R01 MH073700, 5 T32 NS058280-03] FX Contract grant sponsor: National Institutes of Health; Contract grant numbers: R01 MH073700 (to H.T.B.); Contract grant number: 5 T32 NS058280-03 (to L.R.H.) NR 57 TC 1 Z9 1 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0360-4012 EI 1097-4547 J9 J NEUROSCI RES JI J. Neurosci. Res. PD MAR PY 2017 VL 95 IS 3 BP 853 EP 862 DI 10.1002/jnr.23736 PG 10 WC Neurosciences SC Neurosciences & Neurology GA EJ8DC UT WOS:000393453800005 PM 26997207 ER PT J AU Carlin, JL Jain, S Gizewski, E Wan, TC Tosh, DK Xiao, CY Auchampach, JA Jacobson, KA Gavrilova, O Reitman, ML AF Carlin, Jesse Lea Jain, Shalini Gizewski, Elizabeth Wan, Tina C. Tosh, Dilip K. Xiao, Cuiying Auchampach, John A. Jacobson, Kenneth A. Gavrilova, Oksana Reitman, Marc L. TI Hypothermia in mouse is caused by adenosine A(1) and A(3) receptor agonists and AMP via three distinct mechanisms SO NEUROPHARMACOLOGY LA English DT Article DE Hypothermia; Adenosine; A(1)AR; A(3)AR; AMP; Torpor ID ADIPOSE-TISSUE THERMOGENESIS; BODY-TEMPERATURE; SPECIES-DIFFERENCES; DAILY TORPOR; ISCHEMIA/REPERFUSION INJURY; NEUROPATHIC PAIN; A(2A) RECEPTORS; SYRIAN-HAMSTERS; MAMMALIAN BRAIN; METABOLIC-RATE AB Small mammals have the ability to enter torpor, a hypothermic, hypometabolic state, allowing impressive energy conservation. Administration of adenosine or adenosine 5'-monophosphate (AMP) can trigger a hypothermic, torpor-like state. We investigated the mechanisms for hypothermia using telemetric monitoring of body temperature in wild type and receptor knock out (Adoral(-/-), Adora3(-/-)) mice. Confirming prior data, stimulation of the A(3) adenosine receptor (AR) induced hypothermia via peripheral mast cell degranulation, histamine release, and activation of central histamine H-1 receptors. In contrast, A(1)AR agonists and AMP both acted centrally to cause hypothermia. Commonly used, selective A1AR agonists, including N-6-cyclopentyladenosine (CPA), N-6-cyclohexyladenosine (CHA), and MRS5474, caused hypothermia via both A(1)AR and A(3)AR when given intraperitoneally. Intracerebroventricular dosing, low peripheral doses of CI-ENBA [(+/-)-5'-chloro-5'-deoxy-N-6-endo-norbornyladenosine], or using Adora3(-/-) mice allowed selective stimulation of A(1)AR. AMP-stimulated hypothermia can occur independently of A(1)AR, A(3)AR, and mast cells. A(1)AR and A(3)AR agonists and AMP cause regulated hypothermia that was characterized by a drop in total energy expenditure, physical inactivity, and preference for cooler environmental temperatures, indicating a reduced body temperature set point. Neither A(1)AR nor A(3)AR was required for fasting-induced torpor. A(1)AR and A(3)AR agonists and AMP trigger regulated hypothermia via three distinct mechanisms. Published by Elsevier Ltd. C1 [Carlin, Jesse Lea; Xiao, Cuiying; Reitman, Marc L.] Natl Inst Diabet & Digest & Kidney Dis, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Jain, Shalini; Gavrilova, Oksana] Natl Inst Diabet & Digest & Kidney Dis, Mouse Metab Core, NIH, Bethesda, MD 20892 USA. [Tosh, Dilip K.; Jacobson, Kenneth A.] Natl Inst Diabet & Digest & Kidney Dis, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Gizewski, Elizabeth; Wan, Tina C.; Auchampach, John A.] Med Coll Wisconsin, Dept Pharmacol, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. RP Reitman, ML (reprint author), Natl Inst Diabet & Digest & Kidney Dis, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. EM marc.reitman@nih.gov OI Reitman, Marc/0000-0002-0426-9475 FU Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases [ZIA DK075063, ZIA DK031117]; National Heart, Lung, and Blood Institute [R01H1077707] FX We thank Jurgen Schnermann for discussions. This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases [ZIA DK075063; ZIA DK031117] and by the National Heart, Lung, and Blood Institute [R01H1077707]. NR 81 TC 0 Z9 0 U1 5 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 EI 1873-7064 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD MAR 1 PY 2017 VL 114 BP 101 EP 113 DI 10.1016/j.neuropharm.2016.11.026 PG 13 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA EI8SW UT WOS:000392779300010 PM 27914963 ER PT J AU Cocola, C Molgora, S Piscitelli, E Veronesi, MC Greco, M Bragato, C Moro, M Crosti, M Gray, B Milanesi, L Grieco, V Luvoni, GC Kehler, J Bellipanni, G Reinbold, R Zucchi, I Giordano, A AF Cocola, Cinzia Molgora, Stefano Piscitelli, Eleonora Veronesi, Maria Cristina Greco, Marianna Bragato, Cinzia Moro, Monica Crosti, Mariacristina Gray, Brian Milanesi, Luciano Grieco, Valeria Luvoni, Gaia Cecilia Kehler, James Bellipanni, Gianfranco Reinbold, Rolland Zucchi, Ileana Giordano, Antonio TI FGF2 and EGF Are Required for Self-Renewal and Organoid Formation of Canine Normal and Tumor Breast Stem Cells SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE CANINES; CANCER; STEM; ORGANOIDS; MAMMOSPHERE; ACINI; FGF2; MAMMARY; BREAST ID MAMMARY-GLAND; INITIATING CELLS; IN-VITRO; CANCER; CULTURE; SYSTEM; MODEL AB Recent studies suggest that human tumors are generated from cancer cells with stem cell (SC) properties. Spontaneously occurring cancers in dogs contain a diversity of cells that like for human tumors suggest that certain canine tumors are also generated from cancer stem cells (CSCs). CSCs, like normal SCs, have the capacity for self-renewal as mammospheres in suspension cultures. To understand how cells with SC properties contribute to canine mammary gland tumor development and progression, comparative analysis between normal SCs and CSCs, obtained from the same individual, is essential. We have utilized the property of sphere formation to develop culture conditions for propagating stem/progenitor cells from canine normal and tumor tissue. We show that cells from dissociated mammospheres retain sphere reformation capacity for several serial passages and have the capacity to generate organoid structures ex situ. Utilizing various culture conditions for passaging SCs and CSCs, fibroblast growth factor 2 (FGF2) and epidermal growth factor (EGF) were found to positively or negatively regulate mammosphere regeneration, organoid formation, and multi-lineage differentiation potential. The response of FGF2 and EGF on SCs and CSCs was different, with increased FGF2 and EGF self-renewal promoted in SCs and repressed in CSCs. Our protocol for propagating SCs from normal and tumor canine breast tissue will provide new opportunities in comparative mammary gland stem cell analysis between species and anticancer treatment and therapies for dogs. J. Cell. Biochem. 118: 570-584, 2017. (c) 2016 Wiley Periodicals, Inc. C1 [Cocola, Cinzia; Molgora, Stefano; Piscitelli, Eleonora; Greco, Marianna; Milanesi, Luciano; Reinbold, Rolland; Zucchi, Ileana] CNR, Ist Tecnol Biomed, Via Flli Cervi 93, I-20090 Milan, Italy. [Veronesi, Maria Cristina; Grieco, Valeria] Univ Milan, Dept Vet Med, Via Celoria 10, I-20133 Milan, Italy. [Bragato, Cinzia] Fdn IRCCS Ist Neurol C Besta, Neuromuscular Dis & Neuroimmunol Unit, Muscle Cell Biol Lab, Via Temolo 4, Milan, Italy. [Moro, Monica; Crosti, Mariacristina] Fdn Ist Nazl Genet Mol Romeo & Enrica Invernizzi, Via Francesco Sforza 35, I-20122 Milan, Italy. [Gray, Brian] Mol Targeting Technol Inc, W Chester, PA USA. [Luvoni, Gaia Cecilia] Univ Milan, Dept Hlth Anim Sci & Food Safety, I-20133 Milan, Italy. [Kehler, James] NIDDK, NIH, Bethesda, MD 20814 USA. [Bellipanni, Gianfranco; Giordano, Antonio] NIDDK, NIH, Temple, TX 20814 USA. [Bellipanni, Gianfranco; Giordano, Antonio] Temple Univ, Coll Sci & Technol, Dept Biol, Temple, TX USA. [Bellipanni, Gianfranco; Giordano, Antonio] Temple Univ, Coll Sci & Technol, Sbarro Inst Canc Res & Mol Med, Philadelphia, PA 19122 USA. EM rolland.reinbold@itb.cnr.it; ileana.zucchi@itb.cnr.it OI Milanesi, Luciano/0000-0002-1201-3939 FU Cariplo Progetti-Internazionali; MIUR-FIRB [RBAP11-BYNP, RBAP11Z4Z9]; Progetto Bandiera MIUR-CNR Interomics; Progetto Bandiera MIUR-CNR Epigen FX Grant sponsor: Cariplo Progetti-Internazionali 2008-2015; Grant sponsor: MIUR-FIRB; Grant numbers: RBAP11-BYNP, RBAP11Z4Z9; Grant sponsor: Progetto Bandiera MIUR-CNR Interomics 2015; Grant sponsor: Progetto Bandiera MIUR-CNR Epigen 2016. NR 35 TC 1 Z9 1 U1 20 U2 20 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0730-2312 EI 1097-4644 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD MAR PY 2017 VL 118 IS 3 BP 570 EP 584 DI 10.1002/jcb.25737 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EI4VR UT WOS:000392492200015 PM 27632571 ER PT J AU Xu, T Zhang, H Xin, C Kim, E Long, LR Xue, ZY Antani, S Huang, XL AF Xu, Tao Zhang, Han Xin, Cheng Kim, Edward Long, L. Rodney Xue, Zhiyun Antani, Sameer Huang, Xiaolei TI Multi-feature based benchmark for cervical dysplasia classification evaluation SO PATTERN RECOGNITION LA English DT Article DE Cervical cancer screening; Computer aided diagnosis; Image classification; Pyramid histogram; Local binary patterns; Convolutional neural network ID IMAGING-SYSTEM; PATTERNS AB Cervical cancer is one of the most common types of cancer in women worldwide. Most deaths due to the disease occur in less developed areas of the world. In this work, we introduce a new image dataset along with expert annotated diagnoses for evaluating image-based cervical disease classification algorithms. A large number of Cervigram (R) images are selected from a database provided by the US National Cancer Institute. For each image, we extract three complementary pyramid features: Pyramid histogram in L*A*B* color space (PLAB), Pyramid Histogram of Oriented Gradients (PHOG), and Pyramid histogram of Local Binary Patterns (PLBP). Other than hand-crafted pyramid features, we investigate the performance of convolutional neural network (CNN) features for cervical disease classification. Our experimental results demonstrate the effectiveness of both our handcrafted and our deep features. We intend to release this multi-feature dataset and our extensive evaluations using seven classic classifiers can serve as the baseline. C1 [Xu, Tao; Xin, Cheng; Huang, Xiaolei] Lehigh Univ, Dept Comp Sci & Engn, Bethlehem, PA 18015 USA. [Zhang, Han] Rutgers State Univ, Dept Comp Sci, Piscataway, NJ USA. [Kim, Edward] Villanova Univ, Dept Comp Sci, Villanova, PA 19085 USA. [Long, L. Rodney; Xue, Zhiyun; Antani, Sameer] NIH, Natl Lib Med, Bethesda, MD USA. RP Huang, XL (reprint author), Lehigh Univ, Dept Comp Sci & Engn, Bethlehem, PA 18015 USA. EM xih206@lehigh.edu FU Intramural Research Program of the National Institutes of Health (NIH), National Library of Medicine (NLM); Lister Hill National Center for Biomedical Communications (LHNCBC) [HHSN276201000693P] FX This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Library of Medicine (NLM), and Lister Hill National Center for Biomedical Communications (LHNCBC), under Contract HHSN276201000693P. We would also like to acknowledge the expert advice and support from Dr. Mark Schiffman and Dr. Nicolas Wentzensen of the National Cancer Institute (NCI) in the use and interpretation of data from the NCI Guanacaste Project. NR 31 TC 0 Z9 0 U1 30 U2 30 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0031-3203 EI 1873-5142 J9 PATTERN RECOGN JI Pattern Recognit. PD MAR PY 2017 VL 63 BP 468 EP 475 DI 10.1016/j.patcog.2016.09.027 PG 8 WC Computer Science, Artificial Intelligence; Engineering, Electrical & Electronic SC Computer Science; Engineering GA EE7HG UT WOS:000389785900038 ER PT J AU Rajbhandari, N Lin, WC Wehde, BL Triplett, AA Wagner, KU AF Rajbhandari, Nirakar Lin, Wan-chi Wehde, Barbara L. Triplett, Aleata A. Wagner, Kay-Uwe TI Autocrine IGF1 Signaling Mediates Pancreatic Tumor Cell Dormancy in the Absence of Oncogenic Drivers SO CELL REPORTS LA English DT Article ID EPITHELIAL-CELLS; CANCER; MOUSE; KRAS; PROGRESSION; EXPRESSION; RESISTANCE; RECEPTOR; MODELS; INITIATION AB Mutant KRAS and c-MYC are oncogenic drivers and rational therapeutic targets for the treatment of pancreatic cancer. Although tumor growth and homeostasis are largely dependent on these oncogenes, a few residual cancer cells are able to survive the ablation of mutant KRAS and c-MYC. By performing a genome-wide gene expression analysis of in vivo-derived bulk tumor cells and residual cancer cells lacking the expression of mutant KRAS or c-MYC, we have identified an increase in autocrine IGF1/AKT signaling as a common survival mechanism in dormant cancer cells. The pharmacological inhibition of IGF-1R reduces residual disease burden and cancer recurrence, suggesting that this molecular pathway is crucial for the survival of cancer cells in the absence of the primary oncogenic drivers. C1 [Rajbhandari, Nirakar; Lin, Wan-chi; Wehde, Barbara L.; Triplett, Aleata A.; Wagner, Kay-Uwe] Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, 985950 Nebraska Med Ctr, Omaha, NE 68198 USA. [Rajbhandari, Nirakar; Wagner, Kay-Uwe] Univ Nebraska Med Ctr, Dept Biochem & Mol Biol, 985950 Nebraska Med Ctr, Omaha, NE 68198 USA. [Wagner, Kay-Uwe] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, 985950 Nebraska Med Ctr, Omaha, NE 68198 USA. [Lin, Wan-chi] NIEHS, Immun Inflammat & Dis Lab, NIH, 111 TW Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. RP Wagner, KU (reprint author), Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, 985950 Nebraska Med Ctr, Omaha, NE 68198 USA.; Wagner, KU (reprint author), Univ Nebraska Med Ctr, Dept Biochem & Mol Biol, 985950 Nebraska Med Ctr, Omaha, NE 68198 USA.; Wagner, KU (reprint author), Univ Nebraska Med Ctr, Dept Pathol & Microbiol, 985950 Nebraska Med Ctr, Omaha, NE 68198 USA. EM kuwagner@unmc.edu FU Nebraska Cancer and Smoking Disease Research Program (NE DHHS) [LB506 2011-36, LB506 2016-54]; Public Health Service Grant [R21 CA155175, CA202917]; UNMC Graduate Studies Office FX The authors thank the UNMC Genomics Core Facility for assistance in nextgeneration sequencing (NGS) service and the UNMC Cell Analysis Core facility for flow cytometry. We are grateful to Karen K. Dulany for the preparation of histological sections. Financial support provided to K.-U.W. by the Nebraska Cancer and Smoking Disease Research Program (NE DHHS LB506 2011-36 and LB506 2016-54) was imperative to finance the maintenance of mutant mice and the collection of tumor tissues for transcriptome analysis. Additional funding was provided by Public Health Service Grant CA202917 (K.-U.W.). The work on the c-MYC-associated pancreatic cancer model was supported by Public Health Service Grant R21 CA155175 (K.-U.W.). N.R. and W.-c. L. were supported through a research assistantship from the UNMC Graduate Studies Office. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD FEB 28 PY 2017 VL 18 IS 9 BP 2243 EP 2255 DI 10.1016/j.celrep.2017.02.013 PG 13 WC Cell Biology SC Cell Biology GA EP4CO UT WOS:000397328400016 PM 28249168 ER PT J AU Wu, ZH Plotnikov, SV Moalim, AY Waterman, CM Liu, J AF Wu, Zhanghan Plotnikov, Sergey V. Moalim, Abdiwahab Y. Waterman, Clare M. Liu, Jian TI Two Distinct Actin Networks Mediate Traction Oscillations to Confer Focal Adhesion Mechanosensing SO BIOPHYSICAL JOURNAL LA English DT Article ID FLUORESCENT SPECKLE MICROSCOPY; CELL-MATRIX ADHESIONS; MIGRATING CELLS; NASCENT ADHESIONS; MECHANICAL FORCE; RETROGRADE FLOW; STRESS FIBERS; ALPHA-ACTININ; MOTILE CELLS; DYNAMICS AB Focal adhesions (FAs) are integrin-based transmembrane assemblies that connect a cell to its extracellular matrix (ECM). They are mechanosensors through which cells exert actin cytoskeleton-mediated traction forces to sense the ECM stiffness. Interestingly, FAs themselves are dynamic structures that adapt their growth in response to mechanical force. It is unclear how the cell manages the plasticity of the FA structure and the associated traction force to accurately sense ECM stiffness. Strikingly, FA traction forces oscillate in time and space, and govern the cell mechanosensing of ECM stiffness. However, precisely how and why the FA traction oscillates is unknown. We developed a model of FA growth that integrates the contributions of the branched actin network and stress fibers (SFs). Using the model in combination with experimental tests, we show that the retrograde flux of the branched actin network promotes the proximal growth of the FA and contributes to a traction peak near the FA's distal tip. The resulting traction gradient within the growing FA favors SF formation near the FA's proximal end. The SF-mediated actomyosin contractility further stabilizes the FA and generates a second traction peak near the center of the FA. Forminmediated SF elongation negatively feeds back with actomyosin contractility, resulting in central traction peak oscillation. This underpins the observed FA traction oscillation and, importantly, broadens the ECM stiffness range over which FAs can accurately adapt to traction force generation. Actin cytoskeleton-mediated FA growth and maturation thus culminate with FA traction oscillation to drive efficient FA mechanosensing. C1 [Wu, Zhanghan; Liu, Jian] NHLBI, Theoret Cellular Phys Sect, Biochem & Biophys Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. [Plotnikov, Sergey V.; Moalim, Abdiwahab Y.] Univ Toronto, Dept Cell & Syst Biol, Toronto, ON, Canada. [Waterman, Clare M.] NHLBI, Lab Cell & Tissue Morphodynam, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Liu, J (reprint author), NHLBI, Theoret Cellular Phys Sect, Biochem & Biophys Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM jian.liu@nih.gov FU Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health; Connaught Fund New Investigator Award; Canada Foundation for Innovation [34473]; Natural Sciences and Engineering Research Council of Canada [RGPIN-2015-05114] FX This work was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health. This work was partially supported by a Connaught Fund New Investigator Award to S.V.P. and by grants from the Canada Foundation for Innovation (#34473) and the Discovery Grant Program of the Natural Sciences and Engineering Research Council of Canada (RGPIN-2015-05114) to S.V.P. NR 65 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD FEB 28 PY 2017 VL 112 IS 4 BP 780 EP 794 DI 10.1016/j.bpj.2016.12.035 PG 15 WC Biophysics SC Biophysics GA EM9FU UT WOS:000395617800022 PM 28256237 ER PT J AU Nash, RA Hutton, GJ Racke, MK Popat, U Devine, SM Steinmiller, KC Griffith, LM Muraro, PA Openshaw, H Sayre, PH Stuve, O Arnold, DL Wener, MH Georges, GE Wundes, A Kraft, GH Bowen, JD AF Nash, Richard A. Hutton, George J. Racke, Michael K. Popat, Uday Devine, Steven M. Steinmiller, Kaitlyn C. Griffith, Linda M. Muraro, Paolo A. Openshaw, Harry Sayre, Peter H. Stuve, Olaf Arnold, Douglas L. Wener, Mark H. Georges, George E. Wundes, Annette Kraft, George H. Bowen, James D. TI High-dose immunosuppressive therapy and autologous HCT for relapsing-remitting MS SO NEUROLOGY LA English DT Article ID STEM-CELL TRANSPLANTATION; AGGRESSIVE MULTIPLE-SCLEROSIS; DISEASE-ACTIVITY; NO EVIDENCE; MARROW-TRANSPLANTATION; CLINICAL-TRIAL; MRI LESIONS; FOLLOW-UP; DISABILITY; EXPERIENCE AB Objective: To evaluate the safety, efficacy, and durability of multiple sclerosis (MS) disease stabilization after high-dose immunosuppressive therapy (HDIT) and autologous hematopoietic cell transplantation (HCT). Methods: High-Dose Immunosuppression and Autologous Transplantation for Multiple Sclerosis (HALT-MS) is a phase II clinical trial of HDIT/HCT for patients with relapsing-remitting (RR) MS who experienced relapses with disability progression (Expanded Disability Status Scale [EDSS] 3.0-5.5) while on MS disease-modifying therapy. The primary endpoint was event-free survival (EFS), defined as survival without death or disease activity from any one of: disability progression, relapse, or new lesions on MRI. Participants were evaluated through 5 years posttransplant. Toxicities were reported using the National Cancer Institute Common Terminology Criteria for Adverse Events (AE). Results: Twenty-five participants were evaluated for transplant and 24 participants underwent HDIT/HCT. Median follow-up was 62 months (range 12-72). EFS was 69.2% (90% confidence interval [CI] 50.2-82.1). Progression-free survival, clinical relapse-free survival, and MRI activity-free survival were 91.3% (90% CI 74.7%-97.2%), 86.9% (90% CI 69.5%-94.7%), and 86.3% (90% CI 68.1%-94.5%), respectively. AE due to HDIT/HCT were consistent with expected toxicities and there were no significant late neurologic adverse effects noted. Improvements were noted in neurologic disability with a median change in EDSS of 20.5 (interquartile range -1.5 to 0.0; p = 0.001) among participants who survived and completed the study. Conclusion: HDIT/HCT without maintenance therapy was effective for inducing long-term sustained remissions of active RRMS at 5 years. C1 [Nash, Richard A.] Colorado Blood Canc Inst, Denver, CO 80218 USA. [Hutton, George J.] Baylor Coll Med, Houston, TX 77030 USA. [Racke, Michael K.; Devine, Steven M.] Ohio State Univ, Columbus, OH 43210 USA. [Popat, Uday] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Steinmiller, Kaitlyn C.] Rho Inc, Chapel Hill, NC USA. [Griffith, Linda M.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Muraro, Paolo A.] Imperial Coll London, Div Brain Sci, London, England. [Openshaw, Harry] City Hope Natl Med Ctr, 1500 E Duarte Rd, Duarte, CA 91010 USA. [Sayre, Peter H.] Univ Calif San Francisco, Immune Tolerance Network, San Francisco, CA 94143 USA. [Stuve, Olaf] Univ Texas Southwestern, Dallas, TX USA. [Arnold, Douglas L.] McGill Univ, NeuroRx, Montreal, PQ, Canada. [Georges, George E.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Wener, Mark H.; Wundes, Annette; Kraft, George H.] Univ Washington, Seattle, WA 98195 USA. [Bowen, James D.] Swedish Med Ctr, Med Ctr, Seattle, WA USA. RP Nash, RA (reprint author), Colorado Blood Canc Inst, Denver, CO 80218 USA. EM richard.nash@healthonecares.com FU Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases (DAIT-NIAID), NIH,; DAIT; NIAID; NIH FX This work was sponsored by the Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases (DAIT-NIAID), NIH, and conducted by the Immune Tolerance Network (ITN) (UM1 AI 109565) and DAIT-NIAID-funded statistical and clinical coordinating centers (UM2 AI 117870). The funding organization and sponsor, DAIT, NIAID, NIH, participated in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and the decision to submit the manuscript for publication. Baxter Healthcare Corporation, Deerfield, IL, supplied the Isolex 300i Magnetic Cell Selection System machines, Disposable Sets, and CD34 Reagent Kits used for the HALT-MS clinical trial to DAIT, NIAID, without charge. The opinions expressed are those of the authors and do not represent the position of the National Institute of Allergy and Infectious Diseases, the NIH, or the US Government. NR 38 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 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 28 PY 2017 VL 88 IS 9 BP 842 EP 852 DI 10.1212/WNL.0000000000003660 PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA EP4HH UT WOS:000397341100014 PM 28148635 ER PT J AU Dimitriades, VR Devlin, V Pittaluga, S Su, HC Holland, SM Wilson, W Dunleavy, K Shah, NN Freeman, AF AF Dimitriades, Victoria R. Devlin, Vincent Pittaluga, Stefania Su, Helen C. Holland, Steven M. Wilson, Wyndham Dunleavy, Kieron Shah, Nirali N. Freeman, Alexandra F. TI DOCK 8 Deficiency, EBV+ Lymphomatoid Granulomatosis, and Intrafamilial Variation in Presentation SO FRONTIERS IN PEDIATRICS LA English DT Article DE DOCK8; lymphomatoid granulomatosis; lymphomatous granulomatosis; eBV lymphoproliferation; bone marrow transplantation ID STEM-CELL TRANSPLANTATION; DEDICATOR; PHENOTYPE; MUTATIONS AB Dedicator of cytokinesis 8 ( DOCK8) deficiency is an autosomal recessive, combined immunodeficiency within the spectrum of hyper-IgE syndromes. Epstein-Barr virus-positive lymphomatoid granulomatosis ( LYG) ( EBV+LYG) is a rare diagnosis and a previously unreported presentation of DOCK8 deficiency. A 10-year-old girl was initially evaluated for mild eczema and recurrent sinopulmonary infections. She had normal immunoglobulins with elevated IgE, poor polysaccharide response with low switched memory B cells, low CD4 count, and normal mitogen and antigen responses. Despite clinical improvement following immunoglobulin replacement, a prolonged cough prompted a CT scan, which showed nodules. Biopsy identified a Grade 2 EBV+LYG. Due to an inadequate response with chemotherapy, further workup for primary immunodeficiency was performed. With her symptoms of eczema and IgE elevation, along with her brother's history of recurrent sinopulmonary infections and warts, targeted sequencing of DOCK8 was performed revealing compound heterozygous mutations for the two siblings. Both patients were successfully transplanted with resolution of the LYG and warts, respectively. This is the first reported case of LYG in DOCK8 deficiency. The EBV-driven lymphoproliferative disease along with the infection history in the brother led to the diagnosis of DOCK8 deficiency and curative hematopoietic stem cell transplants. C1 [Dimitriades, Victoria R.] Univ Calif Davis, Med Ctr, Dept Pediat, Div Infect Dis Immunol & Allergy, Sacramento, CA 95817 USA. [Devlin, Vincent] Louisiana State Univ, Med Ctr, Dept Pediat, New Orleans, LA 70112 USA. [Pittaluga, Stefania] NCI, Dept Pathol, NIH, Bethesda, MD 20892 USA. [Su, Helen C.; Holland, Steven M.; Freeman, Alexandra F.] NIAID, NIH, Bethesda, MD 20892 USA. [Wilson, Wyndham; Dunleavy, Kieron; Shah, Nirali N.] NCI, NIH, Bethesda, MD 20892 USA. RP Freeman, AF (reprint author), NIAID, NIH, Bethesda, MD 20892 USA. EM freemaal@mail.nih.gov NR 12 TC 0 Z9 0 U1 2 U2 2 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 2296-2360 J9 FRONT PEDIATR JI Front. Pediatr. PD FEB 28 PY 2017 VL 5 AR 38 DI 10.3389/fped.2017.00038 PG 4 WC Pediatrics SC Pediatrics GA EL8UB UT WOS:000394894500001 PM 28293550 ER PT J AU Dabelea, D Stafford, JM Mayer-Davis, EJ D'Agostino, R Dolan, L Imperatore, G Linder, B Lawrence, JM Marcovina, SM Mottl, AK Black, MH Pop-Busui, R Saydah, S Hamman, RF Pihoker, C AF Dabelea, Dana Stafford, Jeanette M. Mayer-Davis, Elizabeth J. D'Agostino, Ralph Dolan, Lawrence Imperatore, Giuseppina Linder, Barbara Lawrence, Jean M. Marcovina, Santica M. Mottl, Amy K. Black, Mary Helen Pop-Busui, Rodica Saydah, Sharon Hamman, Richard F. Pihoker, Catherine CA SEARCH Diabet Youth Res Grp TI Association of Type 1 Diabetes vs Type 2 Diabetes Diagnosed During Childhood and Adolescence With Complications During Teenage Years and Young Adulthood SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID PERIPHERAL NEUROPATHY; FUTURE-DIRECTIONS; ONSET TYPE-1; RISK-FACTORS; YOUTH; SEARCH; PREVALENCE; COHORT; RETINOPATHY; MORTALITY AB IMPORTANCE The burden and determinants of complications and comorbidities in contemporary youth-onset diabetes are unknown. OBJECTIVE To determine the prevalence of and risk factors for complications related to type 1 diabetes vs type 2 diabetes among teenagers and young adults who had been diagnosed with diabetes during childhood and adolescence. DESIGN, SETTING, AND PARTICIPANTS Observational study from 2002 to 2015 in 5 US locations, including 2018 participants with type 1 and type 2 diabetes diagnosed at younger than 20 years, with single outcome measures between 2011 and 2015. EXPOSURES Type 1 and type 2 diabetes and established risk factors (hemoglobin A(1c) level, body mass index, waist-height ratio, and mean arterial blood pressure). MAIN OUTCOMES AND MEASURES Diabetic kidney disease, retinopathy, peripheral neuropathy, cardiovascular autonomic neuropathy, arterial stiffness, and hypertension. RESULTS Of 2018 participants, 1746 had type 1 diabetes (mean age, 17.9 years [SD 4.1]; 1327 non-Hispanic white [76.0%]; 867 female patients [49.7%]), and 272 had type 2 (mean age, 22.1 years [SD 3.5]; 72 non-Hispanic white [26.5%]; 181 female patients [66.5%]). Mean diabetes duration was 7.9 years (both groups). Patients with type 2 diabetes vs those with type 1 had higher age-adjusted prevalence of all measured complications except cardiovascular autonomic neuropathy. After adjustment for established risk factors measured over time, participants with type 2 diabetes vs those with type 1 had significantly higher odds of diabetic kidney disease, retinopathy, and peripheral neuropathy but no significant difference in the odds of arterial stiffness and hypertension. [GRAPHICS] CONCLUSIONS AND RELEVANCE Among teenagers and young adults who had been diagnosed with diabetes during childhood or adolescence, the prevalence of complications and comorbidities was higher among those with type 2 diabetes compared with type 1, but frequent in both groups. These findings support early monitoring of youth with diabetes for development of complications. C1 [Dabelea, Dana; Hamman, Richard F.] Colorado Sch Publ Hlth, Dept Epidemiol, B-119, Aurora, CO 80045 USA. [Stafford, Jeanette M.; D'Agostino, Ralph] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Mayer-Davis, Elizabeth J.] Univ N Carolina, Dept Nutr, Chapel Hill, NC 27599 USA. [Mayer-Davis, Elizabeth J.] Univ N Carolina, Dept Med, Chapel Hill, NC 27599 USA. [Dolan, Lawrence] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Imperatore, Giuseppina; Saydah, Sharon] Ctr Dis Control & Prevent, Div Diabet Translat, Atlanta, GA USA. [Linder, Barbara] Natl Inst Diabet & Digest & Kidney Dis, Div Diabet Endocrinol & Metab Dis, Bethesda, MD USA. [Lawrence, Jean M.; Black, Mary Helen] Kaiser Permanente Southern Calif, Dept Res & Evaluat, Pasadena, CA 91101 USA. [Marcovina, Santica M.] Univ Washington, Northwest Lipid Res Lab, Seattle, WA USA. [Mottl, Amy K.] Univ N Carolina, Sch Med, Div Nephrol & Hypertens, Chapel Hill, NC USA. [Pop-Busui, Rodica] Univ Michigan, Div Metab Endocrinol & Diabet, Ann Arbor, MI 48109 USA. [Pihoker, Catherine] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. RP Dabelea, D (reprint author), Colorado Sch Publ Hlth, Dept Epidemiol, B-119, Aurora, CO 80045 USA. EM dana.dabelea@ucdenver.edu FU National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases; Centers for Disease Control and Prevention (CDC); CDC [RFP DP15-002]; NIH, National Institute of Diabetes and Digestive and Kidney Diseases; Kaiser Permanente Southern California [U18DP006133, U48/CCU919219, U01 DP000246, U18DP002714]; University of Colorado-Denver [U18DP006139, U48/CCU819241-3, U01 DP000247, U18DP000247-06A1]; Cincinnati's Children's Hospital Medical Center [U18DP006134, U48/CCU519239, U01 DP000248, 1U18DP002709]; University of North Carolina at Chapel Hill [U18DP006138, U48/CCU419249, U01 DP000254, U18DP002708]; Seattle Children's Hospital [U18DP006136, U58/CCU019235-4, U01 DP000244, U18DP002710-01]; Wake Forest University School of Medicine [U18DP006131, U48/CC U919219, U01 DP000250, 200-2010-35171] FX The SEARCH for Diabetes in Youth Cohort Study (1UC4DK108173-01) is funded by the National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases and supported by the Centers for Disease Control and Prevention (CDC). The Population Based Registry of Diabetes in Youth Study (RFP DP15-002) is funded by the CDC and supported by the NIH, National Institute of Diabetes and Digestive and Kidney Diseases. Sites: Kaiser Permanente Southern California (U18DP006133, U48/CCU919219, U01 DP000246, and U18DP002714), University of Colorado-Denver (U18DP006139, U48/CCU819241-3, U01 DP000247, and U18DP000247-06A1), Cincinnati's Children's Hospital Medical Center (U18DP006134, U48/CCU519239, U01 DP000248, and 1U18DP002709), University of North Carolina at Chapel Hill (U18DP006138, U48/CCU419249, U01 DP000254, and U18DP002708), Seattle Children's Hospital (U18DP006136, U58/CCU019235-4, U01 DP000244, and U18DP002710-01), and Wake Forest University School of Medicine (U18DP006131, U48/CC U919219, U01 DP000250, and 200-2010-35171). NR 39 TC 1 Z9 1 U1 4 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 28 PY 2017 VL 317 IS 8 BP 825 EP 835 DI 10.1001/jama.2017.0686 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA EM7PW UT WOS:000395505600020 PM 28245334 ER PT J AU Varshney, A Scott, LJ Welch, RP Erdos, MR Chines, PS Narisu, N Albanus, RD Orchard, P Wolford, BN Kursawe, R Vadlamudi, S Cannon, ME Didion, JP Hensley, J Kirilusha, A Bonnycastle, LL Taylor, DL Watanabe, R Mohlke, KL Boehnke, M Collins, FS Parker, SCJ Stitzel, ML AF Varshney, Arushi Scott, Laura J. Welch, Ryan P. Erdos, Michael R. Chines, Peter S. Narisu, Narisu Albanus, Ricardo D'O. Orchard, Peter Wolford, Brooke N. Kursawe, Romy Vadlamudi, Swarooparani Cannon, Maren E. Didion, John P. Hensley, John Kirilusha, Anthony Bonnycastle, Lori L. Taylor, D. Leland Watanabe, Richard Mohlke, Karen L. Boehnke, Michael Collins, Francis S. Parker, Stephen C. J. Stitzel, Michael L. CA NISC Comparative Sequencing Progra TI Genetic regulatory signatures underlying islet gene expression and type 2 diabetes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE chromatin; diabetes; eQTL; epigenome; footprint ID GENOME-WIDE ASSOCIATION; PANCREATIC BETA-CELL; INSULIN-SECRETION; GENOTYPE IMPUTATION; VARIANTS; CHROMATIN; DISEASE; RFX6; DISCOVERY; IDENTIFICATION AB Genome-wide association studies (GWAS) have identified > 100 independent SNPs that modulate the risk of type 2 diabetes (T2D) and related traits. However, the pathogenic mechanisms of most of these SNPs remain elusive. Here, we examined genomic, epigenomic, and transcriptomic profiles in human pancreatic islets to understand the links between genetic variation, chromatin landscape, and gene expression in the context of T2D. We first integrated genome and transcriptome variation across 112 islet samples to produce dense cis-expression quantitative trait loci (cis-eQTL) maps. Additional integration with chromatin-state maps for islets and other diverse tissue types revealed that cis-eQTLs for islet-specific genes are specifically and significantly enriched in islet stretch enhancers. High-resolution chromatin accessibility profiling using assay for transposase-accessible chromatin sequencing (ATACseq) in two islet samples enabled us to identify specific transcription factor (TF) footprints embedded in active regulatory elements, which are highly enriched for islet cis-eQTL. Aggregate allelic bias signatures in TF footprints enabled us de novo to reconstruct TF binding affinities genetically, which support the high-quality nature of the TF footprint predictions. Interestingly, we found that T2D GWAS loci were strikingly and specifically enriched in islet Regulatory Factor X (RFX) footprints. Remarkably, within and across independent loci, T2D risk alleles that overlap with RFX footprints uniformly disrupt the RFX motifs at high-information content positions. Together, these results suggest that common regulatory variations have shaped islet TF footprints and the transcriptome and that a confluent RFX regulatory grammar plays a significant role in the genetic component of T2D predisposition. C1 [Varshney, Arushi; Parker, Stephen C. J.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Scott, Laura J.; Welch, Ryan P.; Boehnke, Michael] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Scott, Laura J.; Welch, Ryan P.; Boehnke, Michael] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Erdos, Michael R.; Chines, Peter S.; Narisu, Narisu; Didion, John P.; Kirilusha, Anthony; Bonnycastle, Lori L.; Taylor, D. Leland; Collins, Francis S.] NHGRI, NIH, Bethesda, MD 20892 USA. [Albanus, Ricardo D'O.; Orchard, Peter; Wolford, Brooke N.; Hensley, John; Parker, Stephen C. J.] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Kursawe, Romy; Stitzel, Michael L.] Jackson Lab Genom Med, Farmington, CT 06032 USA. [Vadlamudi, Swarooparani; Cannon, Maren E.; Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [NISC Comparative Sequencing Progra] NHGRI, NIH, Intramural Sequencing Ctr, Bethesda, MD 20892 USA. [Taylor, D. Leland] European Bioinformat Inst, Wellcome Trust Genome Campus, European Mol Biol Lab, Hinxton CB10 1SD, Cambs, England. [Watanabe, Richard] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA. [Watanabe, Richard] Univ Southern Calif, Keck Sch Med, Dept Physiol & Biophys, Los Angeles, CA 90089 USA. RP Parker, SCJ (reprint author), Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA.; Collins, FS (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA.; Parker, SCJ (reprint author), Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. EM collinsf@od.nih.gov; scjp@umich.edu OI Taylor, Leland/0000-0001-6498-6970 FU National Institute of Diabetes and Digestive and Kidney Diseases Grants [F31HL127984, U01DK062370, ZIAHG000024, R00DK099240, 5R00DK092251, R01DK093757, U01DK105561, R01DK072193]; American Diabetes Association Pathway to Stop Diabetes Grant [1-14-INI-07]; Intramural Research Program of the National Human Genome Research Institute, NIH FX We thank additional members of our laboratories and Finland-United States Investigation of NIDDM Genetics (FUSION) Study investigators for helpful comments on and critiques of the study and manuscript. This study was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants F31HL127984 (to M.E.C.), U01DK062370 (to M.B.), ZIAHG000024 (to F.S.C.), R00DK099240 (to S.C.J.P.), 5R00DK092251 (to M.L.S.), and R01DK093757, U01DK105561, and R01DK072193 (to K.L.M.) and American Diabetes Association Pathway to Stop Diabetes Grant 1-14-INI-07 (to S.C.J.P.). This research was supported, in part, by the Intramural Research Program of the National Human Genome Research Institute, NIH. NR 56 TC 0 Z9 0 U1 2 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 28 PY 2017 VL 114 IS 9 BP 2301 EP 2306 DI 10.1073/pnas.1621192114 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EM1TZ UT WOS:000395101200062 PM 28193859 ER PT J AU Lau, MSY Dalziel, BD Funk, S McClelland, A Tiffany, A Riley, S Metcalf, CJE Grenfell, BT AF Lau, Max S. Y. Dalziel, Benjamin Douglas Funk, Sebastian McClelland, Amanda Tiffany, Amanda Riley, Steven Metcalf, C. Jessica E. Grenfell, Bryan T. TI Spatial and temporal dynamics of superspreading events in the 2014-2015 West Africa Ebola epidemic SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Ebola; superspreading; offspring distribution; Bayesian inference ID VIRUS DISEASE; TRANSMISSION; OUTBREAK AB The unprecedented scale of the Ebola outbreak in Western Africa (2014-2015) has prompted an explosion of efforts to understand the transmission dynamics of the virus and to analyze the performance of possible containment strategies. Models have focused primarily on the reproductive numbers of the disease that represent the average number of secondary infections produced by a random infectious individual. However, these population-level estimates may conflate important systematic variation in the number of cases generated by infected individuals, particularly found in spatially localized transmission and superspreading events. Although superspreading features prominently in first-hand narratives of Ebola transmission, its dynamics have not been systematically characterized, hindering refinements of future epidemic predictions and explorations of targeted interventions. We used Bayesian model inference to integrate individual-level spatial information with other epidemiological data of community-based (undetected within clinical-care systems) cases and to explicitly infer distribution of the cases generated by each infected individual. Our results show that super-spreaders play a key role in sustaining onward transmission of the epidemic, and they are responsible for a significant proportion (similar to 61%) of the infections. Our results also suggest age as a key demographic predictor for superspreading. We also show that community-based cases may have progressed more rapidly than those notified within clinical-care systems, and most transmission events occurred in a relatively short distance (with median value of 2.51 km). Our results stress the importance of characterizing superspreading of Ebola, enhance our current understanding of its spatiotemporal dynamics, and highlight the potential importance of targeted control measures. C1 [Lau, Max S. Y.; Metcalf, C. Jessica E.; Grenfell, Bryan T.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Dalziel, Benjamin Douglas] Oregon State Univ, Dept Integrat Biol, Corvallis, OR 97331 USA. [Dalziel, Benjamin Douglas] Oregon State Univ, Dept Math, Corvallis, OR 97331 USA. [Funk, Sebastian] London Sch Hyg & Trop Med, Ctr Math Modelling Infect Dis, London WC1E 7HT, England. [McClelland, Amanda] Int Federat Red Cross & Red Crescent Societies, CH-1211 Geneva 19, Switzerland. [Tiffany, Amanda] Epicentre, CH-1211 Geneva 6, Switzerland. [Riley, Steven] Imperial Coll London, Dept Infect Dis Epidemiol, Ctr Outbreak Anal & Modelling, MRC, London SW7 2AZ, England. [Grenfell, Bryan T.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Lau, MSY (reprint author), Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. EM msylau@princeton.edu FU Bill & Melinda Gates Foundation [OPP1091919]; RAPIDD program of the Science and Technology Directorate Department of Homeland Security; UK Medical Research Council (MRC); MRC Career Award in Biostatistics [MR/K021680/1]; Fogarty International Center, National Institutes of Health FX This work was supported by Bill & Melinda Gates Foundation Grant OPP1091919; the RAPIDD program of the Science and Technology Directorate Department of Homeland Security and the Fogarty International Center, National Institutes of Health; and the UK Medical Research Council (MRC). S.F. was also supported by MRC Career Award in Biostatistics MR/K021680/1. NR 34 TC 0 Z9 0 U1 2 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 28 PY 2017 VL 114 IS 9 BP 2337 EP 2342 DI 10.1073/pnas.1614595114 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EM1TZ UT WOS:000395101200068 PM 28193880 ER PT J AU Feeley, EM Pilla-Moffett, DM Zwack, EE Piro, AS Finethy, R Kolb, JP Martinez, J Brodsky, IE Coers, J AF Feeley, Eric M. Pilla-Moffett, Danielle M. Zwack, Erin E. Piro, Anthony S. Finethy, Ryan Kolb, Joseph P. Martinez, Jennifer Brodsky, Igor E. Coers, Joern TI Galectin-3 directs antimicrobial guanylate binding proteins to vacuoles furnished with bacterial secretion systems SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE interferon; guanylate binding proteins; immunity-related GTPase; galectin; ubiquitin ID LEGIONELLA-PNEUMOPHILA; TOXOPLASMA-GONDII; HOST-DEFENSE; YERSINIA-PSEUDOTUBERCULOSIS; PARASITOPHOROUS VACUOLE; AUTOPHAGY PROTEINS; SALMONELLA; RESISTANCE; PATHOGENS; IMMUNITY AB Many invasive bacteria establish pathogen-containing vacuoles (PVs) as intracellular niches for microbial growth. Immunity to these infections is dependent on the ability of host cells to recognize PVs as targets for host defense. The delivery of several host defense proteins to PVs is controlled by IFN-inducible guanylate binding proteins (GBPs), which themselves dock to PVs through poorly characterized mechanisms. Here, we demonstrate that GBPs detect the presence of bacterial protein secretion systems as "patterns of pathogenesis" associated with PVs. We report that the delivery of GBP2 to Legionella-containing vacuoles is dependent on the bacterial Dot/Icm secretion system, whereas the delivery of GBP2 to Yersiniacontaining vacuoles (YCVs) requires hypersecretion of Yersinia translocon proteins. We show that the presence of bacterial secretion systems directs cytosolic carbohydrate-binding protein Galectin-3 to PVs and that the delivery of GBP1 and GBP2 to Legionella-containing vacuoles or YCVs is substantially diminished in Galectin-3-deficient cells. Our results illustrate that insertion of bacterial secretion systems into PV membranes stimulates Galectin-3-dependent recruitment of antimicrobial GBPs to PVs as part of a coordinated host defense program. C1 [Feeley, Eric M.; Pilla-Moffett, Danielle M.; Piro, Anthony S.; Finethy, Ryan; Coers, Joern] Duke Univ Med Ctr, Dept Mol Genet & Microbiol, Durham, NC 27710 USA. [Zwack, Erin E.; Brodsky, Igor E.] Univ Penn, Sch Vet Med, Dept Pathobiol, Philadelphia, PA 19104 USA. [Kolb, Joseph P.; Martinez, Jennifer] NIEHS, Natl Inst Hlth, Res Triangle Pk, NC 27709 USA. [Coers, Joern] Duke Univ Med Ctr, Dept Immunol, Durham, NC 27710 USA. RP Coers, J (reprint author), Duke Univ Med Ctr, Dept Mol Genet & Microbiol, Durham, NC 27710 USA.; Coers, J (reprint author), Duke Univ Med Ctr, Dept Immunol, Durham, NC 27710 USA. EM jorn.coers@duke.edu FU National Institutes of Health [R21AI122048, R01AI103197, R01AI103062]; Investigators in the Pathogenesis of Infectious Disease Awards from the Burroughs Wellcome Fund FX We thank Dr. Gregory Taylor for sharing Irgm1-/Irgm3-/- mouse bone marrow cells, Dr. Felix Randow for sharing YFP-Galectin expression constructs, Dr. Sunny Shin for sharing the mCherry expression plasmid, and Sarah Luoma for technical assistance. This work was supported by National Institutes of Health Grants R21AI122048 (to J.C.), R01AI103197 (to J.C.), and R01AI103062 (to I. E. B.), and Investigators in the Pathogenesis of Infectious Disease Awards from the Burroughs Wellcome Fund (to J.C. and I.E.B.). NR 57 TC 0 Z9 0 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 28 PY 2017 VL 114 IS 9 BP E1698 EP E1706 DI 10.1073/pnas.1615771114 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EM1TZ UT WOS:000395101200016 PM 28193861 ER PT J AU Knudson, KM Pritzl, CJ Saxena, V Altman, A Daniels, MA Teixeiro, E AF Knudson, Karin M. Pritzl, Curtis J. Saxena, Vikas Altman, Amnon Daniels, Mark A. Teixeiro, Emma TI NF kappa B-Pim-1-Eomesodermin axis is critical for maintaining CD8 T-cell memory quality SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE CD8 T-cell memory; NFkB; Pim1; Eomesodermin ID NF-KAPPA-B; KINASE C-THETA; TRANSCRIPTIONAL CONTROL; TERMINAL KINASE; CUTTING EDGE; IKK COMPLEX; RECEPTOR; EFFECTOR; DIFFERENTIATION; SURVIVAL AB T-cell memory is critical for long-term immunity. However, the factors involved in maintaining the persistence, function, and phenotype of the memory pool are undefined. Eomesodermin (Eomes) is required for the establishment of the memory pool. Here, we show that in T cells transitioning to memory, the expression of high levels of Eomes is not constitutive but rather requires a continuum of cell-intrinsic NF kappa B signaling. Failure to maintain NF kappa B signals after the peak of the response led to impaired Eomes expression and a defect in the maintenance of CD8 T-cell memory. Strikingly, we found that antigen receptor [T-cell receptor (TCR)] signaling regulates this process through expression of the NF(kappa)Bdependent kinase proviral integration site for Moloney murine leukemia virus-1 (PIM-1), which in turn regulates NF kappa B and Eomes. T cells defective in TCR-dependent NF kappa B signaling were impaired in late expression of Pim-1, Eomes, and CD8 memory. These defects were rescued when TCR-dependent NF kappa B signaling was restored. We also found that NF kappa B-Pim-1 signals were required at memory to maintain memory CD8 T-cell longevity, effector function, and Eomes expression. Hence, an NF kappa B-Pim-1Eomes axis regulates Eomes levels to maintain memory fitness. C1 [Knudson, Karin M.; Pritzl, Curtis J.; Saxena, Vikas; Daniels, Mark A.; Teixeiro, Emma] Univ Missouri, Sch Med, Dept Mol Microbiol & Immunol, Columbia, MO 65212 USA. [Knudson, Karin M.] Natl Canc Inst, Natl Inst Hlth, Ctr Canc Res, Lab Tumor Immunol & Biol, Bethesda, MD 20814 USA. [Altman, Amnon] Jolla Inst Allergy & Immunol, Divis Cell Biol, San Diego, CA 92121 USA. RP Teixeiro, E (reprint author), Univ Missouri, Sch Med, Dept Mol Microbiol & Immunol, Columbia, MO 65212 USA. EM teixeiropernase@missouri.edu FU University of Missouri Mission Enhancement Fund; University of Missouri Life Sciences Fellowship; National Institutes of Health [R01 AI110420, R01 CA35299] FX We thank S. Guerder, M. Croft, S. Reiner, and N. Kim for providing retroviral constructs; S. S. Way, M. Bevan, and D. Zehn for providing Listeria monocytogenes strains; B. Osborne, S. Jameson, and Sara Hamilton for critical discussion; R. Kedl for performing experiments with CD70-deficient mice; B. Hahm and M. Vijayan for providing the NF.B reporter construct; and M. Johnson, D. Burke, and M. Lange for providing the VSV-G construct. This work was supported by the University of Missouri Mission Enhancement Fund, the University of Missouri Life Sciences Fellowship (to K.M.K.), and the National Institutes of Health Grants R01 AI110420 (to E.T.) and R01 CA35299 (to A.A.). NR 56 TC 0 Z9 0 U1 2 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 28 PY 2017 VL 114 IS 9 BP E1659 EP E1667 DI 10.1073/pnas.1608448114 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EM1TZ UT WOS:000395101200012 PM 28193872 ER PT J AU Cubenas-Potts, C Rowley, MJ Lyu, XW Li, G Lei, EP Corces, VG AF Cubenas-Potts, Caelin Rowley, M. Jordan Lyu, Xiaowen Li, Ge Lei, Elissa P. Corces, Victor G. TI Different enhancer classes in Drosophila bind distinct architectural proteins and mediate unique chromatin interactions and 3D architecture SO NUCLEIC ACIDS RESEARCH LA English DT Article ID INTEGRATIVE GENOMICS VIEWER; LONG-RANGE INTERACTIONS; GENE-EXPRESSION; RNA-POLYMERASE; HI-C; INSULATOR FUNCTION; ACTIVE CHROMATIN; HUMAN-CELLS; PROMOTER; ORGANIZATION AB Eukaryotic gene expression is regulated by enhancer-promoter interactions but the molecular mechanisms that govern specificity have remained elusive. Genome-wide studies utilizing STARR-seq identified two enhancer classes in Drosophila that interact with different core promoters: housekeeping enhancers (hkCP) and developmental enhancers (dCP). We hypothesized that the two enhancer classes are occupied by distinct architectural proteins, affecting their enhancer-promoter contacts. By evaluating ChIP-seq occupancy of architectural proteins, typical enhancer-associated proteins, and histone modifications, we determine that both enhancer classes are enriched for RNA Polymerase II, CBP, and architectural proteins but there are also distinctions. hkCP enhancers contain H3K4me3 and exclusively bind Cap-H2, Chromator, DREF and Z4, whereas dCP enhancers contain H3K4me1 and are more enriched for Rad21 and Fs(1) h-L. Additionally, we map the interactions of each enhancer class utilizing a Hi-C dataset with <1 kb resolution. Results suggest that hkCP enhancers are more likely to form multi-TSS interaction networks and be associated with topologically associating domain (TAD) borders, while dCP enhancers are more often bound to one or two TSSs and are enriched at chromatin loop anchors. The data support a model suggesting that the unique architectural protein occupancy within en-hancers is one contributor to enhancer-promoter interaction specificity. C1 [Cubenas-Potts, Caelin; Rowley, M. Jordan; Lyu, Xiaowen; Li, Ge; Corces, Victor G.] Emory Univ, Dept Biol, 1510 Clifton Rd NE, Atlanta, GA 30322 USA. [Lei, Elissa P.] NIDDK, Nucl Org & Gene Express Sect, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. [Li, Ge] Emory Univ, Div Digest Dis, 1670 Clairmont Rd, Decatur, GA 30033 USA. [Cubenas-Potts, Caelin] Ctr Dis Control & Prevent, Meningitis & Vaccine Preventable Dis Branch, Div Bacterial Dis, Natl Ctr Immunizat & Resp Dis, 1600 Clifton Rd, Atlanta, GA 30333 USA. RP Corces, VG (reprint author), Emory Univ, Dept Biol, 1510 Clifton Rd NE, Atlanta, GA 30322 USA. EM vgcorces@gmail.com FU U.S. Public Health Service Award [R01 GM035463]; National Institutes of Health; National Research Service Award [F32 GM113570] FX U.S. Public Health Service Award R01 GM035463 (to V.G.C.); Intramural Research Program of the NIDDK (to E.L.) from the National Institutes of Health and Ruth L. Kirschstein National Research Service Award F32 GM113570 (to M.J.R.). Funding for open access charge: U.S. Public Health Service Award [R01 GM035463]. Conflict of interest statement. None declared. NR 71 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD FEB 28 PY 2017 VL 45 IS 4 BP 1714 EP 1730 DI 10.1093/nar/gkw1114 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EN5OO UT WOS:000396055400022 ER PT J AU Hamilton, WL Claessens, A Otto, TD Kekre, M Fairhurst, RM Rayner, JC Kwiatkowski, D AF Hamilton, William L. Claessens, Antoine Otto, Thomas D. Kekre, Mihir Fairhurst, Rick M. Rayner, Julian C. Kwiatkowski, Dominic TI Extreme mutation bias and high AT content in plasmodium falciparum SO NUCLEIC ACIDS RESEARCH LA English DT Article ID LOW-COMPLEXITY REGIONS; COPY NUMBER VARIATION; GENOME-WIDE VIEW; MALARIA PARASITE; NUCLEOTIDE SUBSTITUTION; ESCHERICHIA-COLI; DNA-SEQUENCES; VAR GENES; INFECTED ERYTHROCYTES; MOLECULAR-SPECTRUM AB For reasons that remain unknown, the Plasmodium falciparum genome has an exceptionally high AT content compared to other Plasmodium species and eukaryotes in general - nearly 80% in coding regions and approaching 90% in non-coding regions. Here, we examine how this phenomenon relates to genome-wide patterns of de novo mutation. Mutation accumulation experiments were performed by sequential cloning of six P. falciparum isolates growing in human erythrocytes in vitro for 4 years, with 279 clones sampled for whole genome sequencing at different time points. Genome sequence analysis of these samples revealed a significant excess of G:C to A:T transitions compared to other types of nucleotide substitution, which would naturally cause AT content to equilibrate close to the level seen across the P. fal-ciparum reference genome (80.6% AT). These data also uncover an extremely high rate of small indel mutation relative to other species, primarily associated with repetitive AT-rich sequences, in addition to larger-scale structural rearrangements focused in antigen-coding var genes. In conclusion, high AT content in P. falciparum is driven by a systematic mutational bias and ultimately leads to an unusual level of microstructural plasticity, raising the question of whether this contributes to adaptive evolution. C1 [Hamilton, William L.; Claessens, Antoine; Otto, Thomas D.; Kekre, Mihir; Rayner, Julian C.; Kwiatkowski, Dominic] Wellcome Trust Sanger Inst, Malaria Programme, Hinxton CB10 1SA, England. [Hamilton, William L.] Univ Cambridge, Sch Clin Med, Cambridge Biomed Campus,Hills Rd, Cambridge CB2 0SP, England. [Claessens, Antoine] Med Res Council Unit Gambia, Atlantic Rd,POB 273, Banjul, Gambia. [Claessens, Antoine] London Sch Hyg & Trop Med, Dept Pathogen Mol Biol, London WC1E 7HT, England. [Fairhurst, Rick M.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Kwiatkowski, Dominic] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. RP Hamilton, WL (reprint author), Wellcome Trust Sanger Inst, Malaria Programme, Hinxton CB10 1SA, England.; Hamilton, WL (reprint author), Univ Cambridge, Sch Clin Med, Cambridge Biomed Campus,Hills Rd, Cambridge CB2 0SP, England. EM will.l.hamilton@gmail.com FU Wellcome Trust [098051]; Medical Research Council [G0600718] FX Wellcome Trust [098051]; Medical Research Council [G0600718]. Funding for open access charge: Wellcome Trust. NR 100 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD FEB 28 PY 2017 VL 45 IS 4 BP 1889 EP 1901 DI 10.1093/nar/gkw1259 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EN5OO UT WOS:000396055400035 ER PT J AU Kirby, TW Gassman, NR Smith, CE Zhao, ML Horton, JK Wilson, SH London, RE AF Kirby, Thomas W. Gassman, Natalie R. Smith, Cassandra E. Zhao, Ming-Lang Horton, Julie K. Wilson, Samuel H. London, Robert E. TI DNA polymerase beta contains a functional nuclear localization signal at its N-terminus SO NUCLEIC ACIDS RESEARCH LA English DT Article ID BASE-EXCISION-REPAIR; IMPORTIN-ALPHA ISOFORMS; TRIPLE-A-SYNDROME; OXIDATIVE-STRESS; IN-VITRO; MOUSE FIBROBLASTS; OVER-EXPRESSION; BREAST-CANCER; CELL-CYCLE; LIGASE I AB DNA polymerase beta (pol beta) requires nuclear localization to fulfil its DNA repair function. Although its small size has been interpreted to imply the absence of a need for active nuclear import, sequence and structural analysis suggests that a monopartite nuclear localization signal (NLS) may reside in the Nterminal lyase domain. Binding of this domain to Importin alpha 1 (Imp alpha 1) was confirmed by gel filtration and NMR studies. Affinity was quantified by fluorescence polarization analysis of a fluorescein-tagged peptide corresponding to pol beta residues 2-13. These studies indicate high affinity binding, characterized by a low micromolar K-d, that is selective for the murine Importin alpha 1 (mImp alpha 1) minor site, with the Kd strengthening to similar to 140 nM for the full lyase domain (residues 2-87). A further reduction in Kd obtains in binding studies with human Importin alpha 5 (hImp alpha 5), which in some cases has been demonstrated to bind small domains connected to the NLS. The role of this NLS was confirmed by fluorescent imaging of wild-type and NLS-mutated pol beta (R4S, K5S) in mouse embryonic fibroblasts lacking endogenous pol beta. Together these data demonstrate that pol beta contains a specific NLS sequence in the N-terminal lyase domain that promotes transport of the protein independent of its interaction partners. Active nuclear uptake allows development of a nuclear/cytosolic concentration gradient against a background of passive diffusion. C1 [Kirby, Thomas W.; Gassman, Natalie R.; Smith, Cassandra E.; Zhao, Ming-Lang; Horton, Julie K.; Wilson, Samuel H.; London, Robert E.] NIEHS, Genome Integr & Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Gassman, Natalie R.] Univ S Alabama, Mitchell Canc Inst, Mol & Metab Oncol, 1660 Springhill Ave, Mobile, AL 36604 USA. [Smith, Cassandra E.] Univ Colorado, Sch Med, Anschutz Med Campus,Campus Box C296 AMC, Aurora, CO 80045 USA. RP London, RE (reprint author), NIEHS, Genome Integr & Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM london@niehs.nih.gov FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [ZIA ES050111, Z01 ES050158, ES050159, R00ES023813] FX Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [project number ZIA ES050111 to R.E.L. and project numbers Z01 ES050158 and ES050159 to S.H.W., R00ES023813 to N.R.G., in part]. Funding for open access charge: Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [project number ZIA ES050111]. NR 94 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD FEB 28 PY 2017 VL 45 IS 4 BP 1958 EP 1970 DI 10.1093/nar/gkw1257 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EN5OO UT WOS:000396055400040 ER PT J AU Halman, JR Satterwhite, E Roark, B Chandler, M Viard, M Ivanina, A Bindewald, E Kasprzak, WK Panigaj, M Bui, MN Lu, JS Miller, J Khisamutdinov, EF Shapiro, BA Dobrovolskaia, MA Afonin, KA AF Halman, Justin R. Satterwhite, Emily Roark, Brandon Chandler, Morgan Viard, Mathias Ivanina, Anna Bindewald, Eckart Kasprzak, Wojciech K. Panigaj, Martin Bui, My N. Lu, Jacob S. Miller, Johann Khisamutdinov, Emil F. Shapiro, Bruce A. Dobrovolskaia, Marina A. Afonin, Kirill A. TI Functionally-interdependent shape-switching nanoparticles with controllable properties SO NUCLEIC ACIDS RESEARCH LA English DT Article ID RNA-DNA HYBRIDS; SPLIT FUNCTIONALITIES; MAMMALIAN-CELLS; PH CHANGES; PROTEIN; CYTOKINES; NANOTECHNOLOGY; INTERFERENCE; NANOMACHINE; ACTIVATION AB We introduce a new concept that utilizes cognate nucleic acid nanoparticles which are fully complementary and functionally-interdependent to each other. In the described approach, the physical interaction between sets of designed nanoparticles initiates a rapid isothermal shape change which triggers the activation of multiple functionalities and biological pathways including transcription, energy transfer, functional aptamers and RNA interference. The individual nanoparticles are not active and have controllable kinetics of re-association and fine-tunable chemical and thermodynamic stabilities. Computational algorithms were developed to accurately predict melting temperatures of nanoparticles of various compositions and trace the process of their re-association in silico. Additionally, tunable immunostimulatory properties of described nanoparticles suggest that the particles that do not induce pro-inflammatory cytokines and high levels of interferons can be used as scaffolds to carry therapeutic oligonucleotides, while particles with strong interferon and mild proinflammatory cytokine induction may qualify as vaccine adjuvants. The presented concept provides a simple, cost-effective and straightforward model for the development of combinatorial regulation of biological processes in nucleic acid nanotechnology. C1 [Halman, Justin R.; Satterwhite, Emily; Roark, Brandon; Chandler, Morgan; Ivanina, Anna; Afonin, Kirill A.] Univ North Carolina Charlotte, Dept Chem, Nanoscale Sci Program, Charlotte, NC 28223 USA. [Viard, Mathias; Lu, Jacob S.; Miller, Johann; Shapiro, Bruce A.] NCI, RNA Biol Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Viard, Mathias; Bindewald, Eckart; Kasprzak, Wojciech K.] Frederick Natl Lab Canc Res, Basic Sci Program, Leidos Biomed Res Inc, RNA Biol Lab, Frederick, MD 21702 USA. [Panigaj, Martin] Pavol Jozef Safarik Univ Kosice, Inst Biol & Ecol, Fac Sci, Kosice 04154, Slovakia. [Bui, My N.; Khisamutdinov, Emil F.] Ball State Univ, Dept Chem, Muncie, IN 47306 USA. [Dobrovolskaia, Marina A.] Frederick Natl Lab Canc Res, Nanotechnol Characterizat Lab, Canc Res Technol Program, Leidos Biomed Res Inc, Frederick, MD 21702 USA. [Afonin, Kirill A.] Univ North Carolina Charlotte, Ctr Biomed Engn & Sci, Charlotte, NC 28223 USA. RP Afonin, KA (reprint author), Univ North Carolina Charlotte, Dept Chem, Nanoscale Sci Program, Charlotte, NC 28223 USA.; Afonin, KA (reprint author), Univ North Carolina Charlotte, Ctr Biomed Engn & Sci, Charlotte, NC 28223 USA. EM kafonin@uncc.edu RI Nanotechnology Characterization Lab, NCL/K-8454-2012 FU Department of Chemistry UNCC start-up funds; UNCC Faculty Research Grant; Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN26120080001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; Slovak Academic Information Agency (SAIA) FX The research was supported by Department of Chemistry UNCC start-up funds and UNCC Faculty Research Grant to KAA. MAD, MV, EB, WKK disclose that this project has been funded in whole or in part with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN26120080001E. This Research was supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. Government. MP participation on the project was supported [in part] by Slovak Academic Information Agency (SAIA). NR 55 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD FEB 28 PY 2017 VL 45 IS 4 BP 2210 EP 2220 DI 10.1093/nar/gkx008 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EN5OO UT WOS:000396055400060 ER PT J AU Chan, WV Pearson, TA Bennett, GC Cushman, WC Gaziano, TA Gorman, PN Handler, J Krumholz, HM Kushner, RF MacKenzie, TD Sacco, RL Smith, SC Stevens, VJ Wells, BL AF Chan, Wiley V. Pearson, Thomas A. Bennett, Glen C. Cushman, William C. Gaziano, Thomas A. Gorman, Paul N. Handler, Joel Krumholz, Harlan M. Kushner, Robert F. MacKenzie, Thomas D. Sacco, Ralph L. Smith, Sidney C., Jr. Stevens, Victor J. Wells, Barbara L. TI ACC/AHA Special Report: Clinical Practice Guideline Implementation Strategies: A Summary of Systematic Reviews by the NHLBI Implementation Science Work Group: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines SO CIRCULATION LA English DT Review DE AHA Scientific Statements; cost; detailing; effectiveness; evidence-based; incentives; interventions; reminders; systematic review ID DECISION-SUPPORT-SYSTEMS; HEALTH-CARE; VENOUS THROMBOEMBOLISM; IMPROVE PROPHYLAXIS; DISEASE MANAGEMENT; PATIENT OUTCOMES; MEDICATION USE; INTERVENTIONS; METAANALYSIS; QUALITY AB Background: In 2008, the National Heart, Lung, and Blood Institute convened an Implementation Science Work Group to assess evidence-based strategies for effectively implementing clinical practice guidelines. This was part of a larger effort to update existing clinical practice guidelines on cholesterol, blood pressure, and overweight/obesity. Objectives: Review evidence from the published implementation science literature and identify effective or promising strategies to enhance the adoption and implementation of clinical practice guidelines. Methods: This systematic review was conducted on 4 critical questions, each focusing on the adoption and effectiveness of 4 intervention strategies: (1) reminders, (2) educational outreach visits, (3) audit and feedback, and (4) provider incentives. A scoping review of the Rx for Change database of systematic reviews was used to identify promising guideline implementation interventions aimed at providers. Inclusion and exclusion criteria were developed a priori for each question, and the published literature was initially searched up to 2012, and then updated with a supplemental search to 2015. Two independent reviewers screened the returned citations to identify relevant reviews and rated the quality of each included review. Results: Audit and feedback and educational outreach visits were generally effective in improving both process of care (15 of 21 reviews and 12 of 13 reviews, respectively) and clinical outcomes (7 of 12 reviews and 3 of 5 reviews, respectively). Provider incentives showed mixed effectiveness for improving both process of care (3 of 4 reviews) and clinical outcomes (3 reviews equally distributed between generally effective, mixed, and generally ineffective). Reminders showed mixed effectiveness for improving process of care outcomes (27 reviews with 11 mixed and 3 generally ineffective results) and were generally ineffective for clinical outcomes (18 reviews with 6 mixed and 9 generally ineffective results). Educational outreach visits (2 of 2 reviews), reminders (3 of 4 reviews), and provider incentives (1 of 1 review) were generally effective for cost reduction. Educational outreach visits (1 of 1 review) and provider incentives (1 of 1 review) were also generally effective for cost-effectiveness outcomes. Barriers to clinician adoption or adherence to guidelines included time constraints (8 reviews/overviews); limited staffing resources (2 overviews); timing (5 reviews/overviews); clinician skepticism (5 reviews/overviews); clinician knowledge of guidelines (4 reviews/overviews); and higher age of the clinician (1 overview). Facilitating factors included guideline characteristics such as format, resources, and end-user involvement (6 reviews/overviews); involving stakeholders (5 reviews/overviews); leadership support (5 reviews/overviews); scope of implementation (5 reviews/overviews); organizational culture such as multidisciplinary teams and low-baseline adherence (9 reviews/overviews); and electronic guidelines systems (3 reviews). Conclusion: The strategies of audit and feedback and educational outreach visits were generally effective in improving both process of care and clinical outcomes. Reminders and provider incentives showed mixed effectiveness, or were generally ineffective. No general conclusion could be reached about cost effectiveness, because of limitations in the evidence. Important gaps exist in the evidence on effectiveness of implementation interventions, especially regarding clinical outcomes, cost effectiveness and contextual issues affecting successful implementation. C1 [Chan, Wiley V.] Kaiser Permanente Northwest, Guidelines & Evidence Based Med, Portland, OR 97210 USA. [Pearson, Thomas A.] Univ Rochester, Med Ctr, Res & Educ, Rochester, NY 14627 USA. [Bennett, Glen C.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Cushman, William C.] Univ Tennessee, Hlth Sci Ctr, Preventat Med, Knoxville, TN 37996 USA. [Gaziano, Thomas A.] Harvard Med Sch, Boston, MA USA. [Gaziano, Thomas A.] Brigham & Womens Hosp, Cardiovasc Med, Boston, MA 02115 USA. [Gorman, Paul N.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Handler, Joel] Southern Calif Permanente Med Grp, Portland, OR USA. [Krumholz, Harlan M.] Yale New Haven Med Ctr, 20 York St, New Haven, CT 06504 USA. [Kushner, Robert F.] Northwestern Univ, Med, Evanston, IL 60208 USA. [MacKenzie, Thomas D.] Denver Hlth Fdn, Denver, CO USA. [Sacco, Ralph L.] Univ Miami, Hlth Syst, Dept Neurol, Coral Gables, FL 33124 USA. [Smith, Sidney C., Jr.] Univ North Carolina Chapel Hill, Med, Chapel Hill, NC USA. [Stevens, Victor J.] Kaiser Permanente, Ctr Hlth Res, Portland, OR USA. [Wells, Barbara L.] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Chan, WV (reprint author), Kaiser Permanente Northwest, Guidelines & Evidence Based Med, Portland, OR 97210 USA. FU federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services, under GSA [GS-10F-0112J, HHSN2268201100098U] FX This project was funded in whole or in part with federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services, under GSA contract No. GS-10F-0112J, Order No. HHSN2268201100098U. NR 54 TC 0 Z9 0 U1 3 U2 3 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 FEB 28 PY 2017 VL 135 IS 9 BP E122 EP E137 DI 10.1161/CIR.0000000000000481 PG 16 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EM8GO UT WOS:000395549700002 PM 28126839 ER PT J AU Larson, CL Heinzen, RA AF Larson, Charles L. Heinzen, Robert A. TI High-Content Imaging Reveals Expansion of the Endosomal Compartment during Coxiella burnetii Parasitophorous Vacuole Maturation SO FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY LA English DT Article DE endosome; lysosome; intracellular pathogen; endocytic trafficking; fluorescence microscopy; Chlamydia trachomatis; Coxiella burnetii ID CHLAMYDIAL INCLUSION; LYSOSOMAL BIOGENESIS; HOST-CELL; PATHWAY; TRAFFICKING; TRANSFERRIN; REPLICATE; INFECTION; AUTOPHAGY; PROTEINS AB Coxiella burnetii is an obligate intracellular pathogen and the causative agent of human Q fever. Replication of the bacteriumwithin a large parasitophorous vacuole (PV) resembling a host phagolysosome is required for pathogenesis. PV biogenesis is a pathogen driven process that requires engagement of several host cell vesicular trafficking pathways to acquire vacuole components. The goal of this study was to determine if infection by C. burnetii modulates endolysosomal flux to potentially benefit PV formation. HeLa cells, infected with C. burnetii or left uninfected, were incubated with fluorescent transferrin (Tf) for 0-30 min, and the amount of Tf internalized by cells quantitated by high-content imaging. At 3 and 5 days, but not 1 day post-infection, the maximal amounts of fluorescent Tf internalized by infected cells were significantly greater than uninfected cells. The rates of Tf uptake and recycling were the same for infected and uninfected cells; however, residual Tf persisted in EEA. 1 positive compartments adjacent to large PV after 30 min of recycling in the absence of labeled Tf. On average, C. burnetii-infected cells contained significantlymore CD63-positive endosomes than uninfected cells. In contrast, cells containing large vacuoles generated by Chlamydia trachomatis exhibited increased rates of Tf internalization without increased CD63 expression. Our results suggest that C. burnetii infection expands the endosomal system to increase capacity for endocytic material. Furthermore, this study demonstrates the power of high-content imaging for measurement of cellular responses to infection by intracellular pathogens. C1 [Larson, Charles L.; Heinzen, Robert A.] NIAID, Coxiella Pathogenesis Sect, Bacteriol Lab, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. RP Heinzen, RA (reprint author), NIAID, Coxiella Pathogenesis Sect, Bacteriol Lab, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. EM rheinzen@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health [ZAI AI000931] FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health #ZAI AI000931 to RH. NR 39 TC 0 Z9 0 U1 1 U2 1 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 2235-2988 J9 FRONT CELL INFECT MI JI Front. Cell. Infect. Microbiol. PD FEB 28 PY 2017 VL 7 AR 48 DI 10.3389/fcimb.2017.00048 PG 10 WC Immunology; Microbiology SC Immunology; Microbiology GA EL8UX UT WOS:000394896900001 PM 28293541 ER PT J AU Truzzi, A Bornstein, MH Senese, VP Shinohara, K Setoh, P Esposito, G AF Truzzi, Anna Bornstein, Marc H. Senese, Vincenzo P. Shinohara, Kazuyuki Setoh, Peipei Esposito, Gianluca TI Serotonin Transporter Gene Polymorphisms and Early Parent-Infant Interactions Are Related to Adult Male Heart Rate Response to Female Crying SO FRONTIERS IN PHYSIOLOGY LA English DT Article DE parent-infant interaction; serotonin transporter gene; opposite-sex conspecific interaction; gene* environment; physiological responses; social distress ID ENVIRONMENT INTERACTION; ROMANTIC RELATIONSHIPS; ATTACHMENT STYLES; SOCIAL-SKILLS; LIFE EVENTS; 5-HTTLPR; DEPRESSION AB Adults' adaptive interactions with intimate partners enhance well-being. Here we hypothesized that adult males' physiological responses to opposite-sex conspecifics' distress result from an interaction between an environmental factor (early social interaction with caregivers) and a genetic factor (a polymorphism within the promoter region of the serotonin transporter gene, 5-HTTLPR). We assessed heart rate changes in 42 non-married male adults to distress vocalizations (female, infant, and bonobo cries). Males' early interaction with parents was assessed using the Parental Bonding Instrument. Buccal mucosa cell samples were collected to assess their 5-HTTLPR genotype. A significant interaction emerged between early experience and genetic predisposition. Males with a genetic predisposition for higher sensitivity to environmental factors showed atypical physiological responses to adult female cries according to their experienced early maternal parenting. Environmental experiences and genetic characteristics are associated with adult males' physiological responses to socially meaningfully stimuli. Understanding the mechanisms that modulate responses to opposite-sex conspecifics may improve personal well-being and social adaptiveness. C1 [Truzzi, Anna; Esposito, Gianluca] Univ Trento, Dept Psychol & Cognit Sci, Rovereto, Italy. [Truzzi, Anna] RIKEN, Brain Sci Inst, Lab Affiliat Social Behav, Saitama, Japan. [Bornstein, Marc H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Child & Family Res, Bethesda, MD USA. [Senese, Vincenzo P.] Univ Naples 2, Dept Psychol, Psychometr Lab, Naples, Italy. [Shinohara, Kazuyuki] Nagasaki Univ, Dept Neurobiol & Behav, Unit Basic Med Sci, Nagasaki, Japan. [Setoh, Peipei; Esposito, Gianluca] Nanyang Technol Univ, Sch Humanities & Social Sci, Div Psychol, Singapore, Singapore. RP Esposito, G (reprint author), Univ Trento, Dept Psychol & Cognit Sci, Rovereto, Italy.; Esposito, G (reprint author), Nanyang Technol Univ, Sch Humanities & Social Sci, Div Psychol, Singapore, Singapore. EM gianluca.esposito@unitn.it FU Intramural Research Program of the NIH; NICHD; NAP-SUG program of the Nanyang Technological University FX All participants in this study are gratefully acknowledged. This research was partially supported by the Intramural Research Program of the NIH, NICHD as well as the NAP-SUG program of the Nanyang Technological University. NR 29 TC 0 Z9 0 U1 0 U2 0 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-042X J9 FRONT PHYSIOL JI Front. Physiol. PD FEB 28 PY 2017 VL 8 AR 111 DI 10.3389/fphys.2017.00111 PG 6 WC Physiology SC Physiology GA EL7PH UT WOS:000394812500001 PM 28293197 ER PT J AU Chan, WV Pearson, TA Bennett, GC Cushman, WC Gaziano, TA Gorman, PN Handler, J Krumholz, HM Kushner, RF MacKenzie, TD Sacco, RL Smith, SC Stevens, VJ Wells, BL AF Chan, Wiley V. Pearson, Thomas A. Bennett, Glen C. Cushman, William C. Gaziano, Thomas A. Gorman, Paul N. Handler, Joel Krumholz, Harlan M. Kushner, Robert F. MacKenzie, Thomas D. Sacco, Ralph L. Smith, Sidney C., Jr. Stevens, Victor J. Wells, Barbara L. TI ACC/AHA Special Report: Clinical Practice Guideline Implementation Strategies: A Summary of Systematic Reviews by the NHLBI Implementation Science Work Group SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE ACC/AHA Clinical Practice Guideline; evidence-based; effectiveness; interventions; detailing; incentives; reminders; cost; systematic review ID DECISION-SUPPORT-SYSTEMS; HEALTH-CARE; VENOUS THROMBOEMBOLISM; IMPROVE PROPHYLAXIS; DISEASE MANAGEMENT; PATIENT OUTCOMES; MEDICATION USE; INTERVENTIONS; METAANALYSIS; QUALITY AB BACKGROUND In 2008, the National Heart, Lung, and Blood Institute convened an Implementation Science Work Group to assess evidence-based strategies for effectively implementing clinical practice guidelines. This was part of a larger effort to update existing clinical practice guidelines on cholesterol, blood pressure, and overweight/obesity. OBJECTIVES Review evidence from the published implementation science literature and identify effective or promising strategies to enhance the adoption and implementation of clinical practice guidelines. METHODS This systematic review was conducted on 4 critical questions, each focusing on the adoption and effectiveness of 4 intervention strategies: (1) reminders, (2) educational outreach visits, (3) audit and feedback, and (4) provider incentives. A scoping review of the Rx for Change database of systematic reviews was used to identify promising guideline implementation interventions aimed at providers. Inclusion and exclusion criteria were developed a priori for each question, and the published literature was initially searched up to 2012, and then updated with a supplemental search to 2015. Two independent reviewers screened the returned citations to identify relevant reviews and rated the quality of each included review. RESULTS Audit and feedback and educational outreach visits were generally effective in improving both process of care (15 of 21 reviews and 12 of 13 reviews, respectively) and clinical outcomes (7 of 12 reviews and 3 of 5 reviews, respectively). Provider incentives showed mixed effectiveness for improving both process of care (3 of 4 reviews) and clinical outcomes (3 reviews equally distributed between generally effective, mixed, and generally ineffective). Reminders showed mixed effectiveness for improving process of care outcomes (27 reviews with 11 mixed and 3 generally ineffective results) and were generally ineffective for clinical outcomes (18 reviews with 6 mixed and 9 generally ineffective results). Educational outreach visits (2 of 2 reviews), reminders (3 of 4 reviews), and provider incentives (1 of 1 review) were generally effective for cost reduction. Educational outreach visits (1 of 1 review) and provider incentives (1 of 1 review) were also generally effective for cost-effectiveness outcomes. Barriers to clinician adoption or adherence to guidelines included time constraints (8 reviews/overviews); limited staffing resources (2 overviews); timing (5 reviews/overviews); clinician skepticism (5 reviews/overviews); clinician knowledge of guidelines (4 reviews/overviews); and higher age of the clinician (1 overview). Facilitating factors included guideline characteristics such as format, resources, and end-user involvement (6 reviews/overviews); involving stakeholders (5 reviews/overviews); leadership support (5 reviews/overviews); scope of implementation (5 reviews/overviews); organizational culture such as multidisciplinary teams and low-baseline adherence (9 reviews/overviews); and electronic guidelines systems (3 reviews). CONCLUSION The strategies of audit and feedback and educational outreach visits were generally effective in improving both process of care and clinical outcomes. Reminders and provider incentives showed mixed effectiveness, or were generally ineffective. No general conclusion could be reached about cost effectiveness, because of limitations in the evidence. Important gaps exist in the evidence on effectiveness of implementation interventions, especially regarding clinical outcomes, cost effectiveness and contextual issues affecting successful implementation. C1 [Chan, Wiley V.; Cushman, William C.; Gaziano, Thomas A.; Gorman, Paul N.; Handler, Joel; Krumholz, Harlan M.; Kushner, Robert F.; MacKenzie, Thomas D.; Sacco, Ralph L.; Smith, Sidney C., Jr.; Stevens, Victor J.; Wells, Barbara L.] NHLBI, Implementat Sci Work Grp, Bldg 10, Bethesda, MD 20892 USA. [Bennett, Glen C.] NHLBI, Ctr Translat Res & Implementat Sci, Bldg 10, Bethesda, MD 20892 USA. [Cushman, William C.] Vet Affairs Med Ctr, Memphis, TN USA. [Wells, Barbara L.] NHLBI, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA. RP Chan, WV (reprint author), NHLBI, Implementat Sci Work Grp, Bldg 10, Bethesda, MD 20892 USA. FU National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services under GSA [GS-10F-0112J, HHSN2268201100098U] FX This project was funded in whole or in part with federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services, under GSA contract No. GS-10F-0112J, Order No. HHSN2268201100098U. NR 54 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB 28 PY 2017 VL 69 IS 8 BP 1076 EP 1092 DI 10.1016/j.jacc.2016.11.004 PG 17 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EN9YY UT WOS:000396356700013 PM 28132746 ER PT J AU Schneller, JL Lee, CM Bao, G Venditti, CP AF Schneller, Jessica L. Lee, Ciaran M. Bao, Gang Venditti, Charles P. TI Genome editing for inborn errors of metabolism: advancing towards the clinic SO BMC MEDICINE LA English DT Review DE Inborn errors of metabolism; Genome editing; CRISPR/Cas9; Zinc-finger nucleases; Liver metabolic disorders ID ADENOASSOCIATED VIRUS VECTORS; STAPHYLOCOCCUS-AUREUS CAS9; ZINC-FINGER NUCLEASES; UREA CYCLE DISORDERS; IN-VIVO; MOUSE MODEL; GENE-THERAPY; MUSCULAR-DYSTROPHY; MESSENGER-RNA; OFF-TARGET AB Inborn errors of metabolism (IEM) include many disorders for which current treatments aim to ameliorate disease manifestations, but are not curative. Advances in the field of genome editing have recently resulted in the in vivo correction of murine models of IEM. Site-specific endonucleases, such as zinc-finger nucleases and the CRISPR/Cas9 system, in combination with delivery vectors engineered to target disease tissue, have enabled correction of mutations in disease models of hemophilia B, hereditary tyrosinemia type I, ornithine transcarbamylase deficiency, and lysosomal storage disorders. These in vivo gene correction studies, as well as an overview of genome editing and future directions for the field, are reviewed and discussed herein. C1 [Schneller, Jessica L.] SUNY Stony Brook, Dept Biomed Engn, Stony Brook, NY USA. [Schneller, Jessica L.; Venditti, Charles P.] NHGRI, Med Genom & Metab Genet Branch, NIH, Bldg 10,Room,7N248A, Bethesda, MD 20892 USA. [Lee, Ciaran M.; Bao, Gang] Rice Univ, Dept Bioengn, 6500 Main St, Houston, TX 77030 USA. RP Venditti, CP (reprint author), NHGRI, Med Genom & Metab Genet Branch, NIH, Bldg 10,Room,7N248A, Bethesda, MD 20892 USA. EM venditti@mail.nih.gov OI Lee, Ciaran/0000-0002-0789-9149 FU National Institutes of Health; Cancer Prevention and Research Institute of Texas [RR140081] FX JLS and CPV were supported by the intramural research program of the National Human Genome Research Institute in the National Institutes of Health. This work was supported in part by the Cancer Prevention and Research Institute of Texas (RR140081 to GB). NR 81 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7015 J9 BMC MED JI BMC Med. PD FEB 27 PY 2017 VL 15 AR 43 DI 10.1186/s12916-017-0798-4 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA EN5UD UT WOS:000396070300001 PM 28238287 ER PT J AU Jackson, LH Vlachodimitropoulou, E Shangaris, P Roberts, TA Ryan, TM Campbell-Washburn, AE David, AL Porter, JB Lythgoe, MF Stuckey, DJ AF Jackson, Laurence H. Vlachodimitropoulou, Evangelia Shangaris, Panicos Roberts, Thomas A. Ryan, Thomas M. Campbell-Washburn, Adrienne E. David, Anna L. Porter, John B. Lythgoe, Mark F. Stuckey, Daniel J. TI Non-invasive MRI biomarkers for the early assessment of iron overload in a humanized mouse model of beta-thalassemia SO SCIENTIFIC REPORTS LA English DT Article ID SICKLE-CELL-DISEASE; MAGNETIC-RESONANCE; GLOBIN GENE; T2 MEASUREMENT; MYOCARDIAL T2; CARDIAC IRON; STEM-CELLS; SURVIVAL; BETA(0)-THALASSEMIA; CARDIOMYOPATHY AB beta-thalassemia (beta T) is a genetic blood disorder causing profound and life threatening anemia. Current clinical management of beta T is a lifelong dependence on regular blood transfusions, a consequence of which is systemic iron overload leading to acute heart failure. Recent developments in gene and chelation therapy give hope of better prognosis for patients, but successful translation to clinical practice is hindered by the lack of thorough preclinical testing using representative animal models and clinically relevant quantitative biomarkers. Here we demonstrate a quantitative and non-invasive preclinical Magnetic Resonance Imaging (MRI) platform for the assessment of beta T in the.gamma beta(0)/gamma beta(A) humanized mouse model of beta T. Changes in the quantitative MRI relaxation times as well as severe splenomegaly were observed in the heart, liver and spleen in beta T. These data showed high sensitivity to iron overload and a strong relationship between quantitative MRI relaxation times and hepatic iron content. Importantly these changes preceded the onset of iron overload cardiomyopathy, providing an early biomarker of disease progression. This work demonstrates that multiparametric MRI is a powerful tool for the assessment of preclinical beta T, providing sensitive and quantitative monitoring of tissue iron sequestration and cardiac dysfunction-parameters essential for the preclinical development of new therapeutics. C1 [Jackson, Laurence H.; Roberts, Thomas A.; Lythgoe, Mark F.; Stuckey, Daniel J.] UCL, Div Med, Ctr Adv Biomed Imaging, London, England. [Vlachodimitropoulou, Evangelia; Porter, John B.] UCL, Dept Haematol, London, England. [Shangaris, Panicos; David, Anna L.] UCL, Inst Womens Hlth, London, England. [Ryan, Thomas M.] Univ Alabama Birmingham, Dept Biochem & Mol Genet, Birmingham, AL USA. [Campbell-Washburn, Adrienne E.] NHLBI, Lab Imaging Technol, Biochem & Biophys Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Stuckey, DJ (reprint author), UCL, Div Med, Ctr Adv Biomed Imaging, London, England. EM d.stuckey@ucl.ac.uk FU Medical Research Council, UK [MR/K50077X/1]; Medical Research Council [MR/J013110/1]; King's College London; UCL Comprehensive Cancer Imaging Centre CR-UK; EPSRC; MRC (England); DoH (England); National Centre for the Replacement, Reduction and Refinement of Animal in Research (NC3Rs); UK Regenerative Medicine Platform Safety Hub [MRC: MR/K026739/1]; Eli Lilly and Company; Wellcome Trust Sparks Research Training Fellowship FX DJS is a BHF Intermediate Basic Science Research Fellow (FS/15/33/31608). LHJ is supported by the Medical Research Council, UK (MR/K50077X/1). ML receives funding from Medical Research Council (MR/J013110/1); the King's College London and UCL Comprehensive Cancer Imaging Centre CR-UK & EPSRC, in association with the MRC and DoH (England); the National Centre for the Replacement, Reduction and Refinement of Animal in Research (NC3Rs); UK Regenerative Medicine Platform Safety Hub (MRC: MR/K026739/1); Eli Lilly and Company. EVK is an Onassis Scholar (Athens, Greece). This study was supported by researchers at the National Institute for Health Research University College London Hospitals Biomedical Research Centre (ALD). PS is funded by a Wellcome Trust Sparks Research Training Fellowship. NR 47 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD FEB 27 PY 2017 VL 7 AR 43439 DI 10.1038/srep43439 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EL8NZ UT WOS:000394878300001 PM 28240317 ER PT J AU Sowrirajan, B Saito, Y Poudyal, D Chen, Q Sui, HY DeRavin, SS Imamichi, H Sato, T Kuhns, DB Noguchi, N Malech, HL Lane, HC Imamichi, T AF Sowrirajan, Bharatwaj Saito, Yoshiro Poudyal, Deepak Chen, Qian Sui, Hongyan DeRavin, Suk See Imamichi, Hiromi Sato, Toyotaka Kuhns, Douglas B. Noguchi, Noriko Malech, Harry L. Lane, H. Clifford Imamichi, Tomozumi TI Interleukin-27 Enhances the Potential of Reactive Oxygen Species Generation from Monocyte-derived Macrophages and Dendritic cells by Induction of p47(phox) SO SCIENTIFIC REPORTS LA English DT Article ID EXTRACELLULAR-SUPEROXIDE DISMUTASE; FAMILY NADPH OXIDASES; CD4(+) T-CELLS; HIV-1 INFECTION; COMPLETE REGRESSION; IL-27; EXPRESSION; ACTIVATION; CARCINOMA; ANTITUMOR AB Interleukin (IL)-27, a member of the IL-12 cytokine family, plays an important and diverse role in the function of the immune system. We have previously demonstrated that IL-27 is an anti-viral cytokine which inhibits HIV-1, HIV-2, Influenza virus and herpes simplex virus infection, and enhances the potential of reactive oxygen species (ROS) generating activity during differentiation of monocytes to macrophages. In this study, we further investigated the mechanism of the enhanced potential for ROS generation by IL-27. Real time PCR, western blot and knock down assays demonstrate that IL-27 is able to enhance the potential of superoxide production not only during differentiation but also in terminally differentiated-macrophages and immature dendritic cells (iDC) in association with the induction of p47(phox), a cytosolic component of the ROS producing enzyme, NADPH oxidase, and the increase in amounts of phosphorylated p47phox upon stimulation. We also demonstrate that IL-27 is able to induce extracellular superoxide dismutase during differentiation of monocytes but not in terminal differentiated macrophages. Since ROS plays an important role in a variety of inflammation, our data demonstrate that IL-27 is a potent regulator of ROS induction and may be a novel therapeutic target. C1 [Sowrirajan, Bharatwaj; Poudyal, Deepak; Chen, Qian; Sui, Hongyan; Sato, Toyotaka; Imamichi, Tomozumi] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Lab Human Retrovirol & Immunoinformat, Frederick, MD 21702 USA. [Saito, Yoshiro; Noguchi, Noriko] Doshisha Univ, Fac Life & Med Sci, Dept Med Life Syst, Syst Life Sci Lab, Kyoto 6100394, Japan. [DeRavin, Suk See; Malech, Harry L.] NIAID, Lab Host Defenses, NIH, Bethesda, MD 20802 USA. [Imamichi, Hiromi; Lane, H. Clifford] NIAID, Lab Immunoregulat, NIH, Bethesda, MD 20892 USA. [Kuhns, Douglas B.] Leidos Biomed Res Inc, Neutrophil Monitoring Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Imamichi, T (reprint author), Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Lab Human Retrovirol & Immunoinformat, Frederick, MD 21702 USA. EM timamichi@mail.nih.gov OI Saito, Yoshiro/0000-0002-0559-5889 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; National Institute of Allergy and Infectious Diseases FX Authors thank Dr. T. Kamata for discussion and B. Sherman for critical reading. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported [in part] by the National Institute of Allergy and Infectious Diseases. NR 53 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD FEB 27 PY 2017 VL 7 AR 43441 DI 10.1038/srep43441 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EL8OI UT WOS:000394879200001 PM 28240310 ER PT J AU Chan, M Elias, C Fauci, A Lake, A Berkley, S AF Chan, Margaret Elias, Chris Fauci, Anthony Lake, Anthony Berkley, Seth TI Reaching everyone, everywhere with life-saving vaccines SO LANCET LA English DT Editorial Material C1 [Chan, Margaret] WHO, Geneva, Switzerland. [Elias, Chris] Bill & Melinda Gates Fdn, Seattle, WA 98109 USA. [Fauci, Anthony] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Lake, Anthony] United Nations Childrens Fund, New York, NY USA. [Berkley, Seth] Gavi, Geneva, Switzerland. RP Elias, C (reprint author), Bill & Melinda Gates Fdn, Seattle, WA 98109 USA. NR 8 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 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD FEB 25 PY 2017 VL 389 IS 10071 BP 777 EP 779 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA EL9UU UT WOS:000394966400011 PM 28248159 ER PT J AU Ginsburg, O Badwe, R Boyle, P Derricks, G Dare, A Evans, T Eniu, A Jimenez, J Kutluk, T Lopes, G Mohammed, SI Qiao, YL Rashid, SF Summers, D Sarfati, D Temmerman, M Trimble, EL Padela, AI Aggarwal, A Sullivan, R AF Ginsburg, Ophira Badwe, Rajan Boyle, Peter Derricks, Gemma Dare, Anna Evans, Tim Eniu, Alexandru Jimenez, Jorge Kutluk, Tezer Lopes, Gilberto Mohammed, Sulma I. Qiao, You-Lin Rashid, Sabina Faiz Summers, Diane Sarfati, Diana Temmerman, Marleen Trimble, Edward L. Padela, Aasim I. Aggarwal, Ajay Sullivan, Richard TI Changing global policy to deliver safe, equitable, and affordable care for women's cancers SO LANCET LA English DT Article ID UNIVERSAL HEALTH COVERAGE; HIGH-INCOME COUNTRIES; BREAST-CANCER; SCREENING PRACTICES; AMERICAN MUSLIMS; DISEASE BURDEN; MORTALITY; MIDDLE; INDIA; AFRICA AB Breast and cervical cancer are major threats to the health of women globally, particularly in low-income and middle-income countries. Radical progress to close the global cancer divide for women requires not only evidence-based policy making, but also broad multisectoral collaboration that capitalises on recent progress in the associated domains of women's health and innovative public health approaches to cancer care and control. Such multisectoral collaboration can serve to build health systems for cancer, and more broadly for primary care, surgery, and pathology. This Series paper explores the global health and public policy landscapes that intersect with women's health and global cancer control, with new approaches to bringing policy to action. Cancer is a major global social and political priority, and women's cancers are not only a tractable socioeconomic policy target in themselves, but also an important Trojan horse to drive improved cancer control and care. C1 [Ginsburg, Ophira] Univ Toronto, Dalla Lana Sch Publ Hlth, Fac Med, Womens Coll Res Inst, Toronto, ON, Canada. [Ginsburg, Ophira; Temmerman, Marleen] WHO, Geneva, Switzerland. [Badwe, Rajan] Tata Mem Hosp, Bombay, Maharashtra, India. [Boyle, Peter] Int Prevent Res Inst, Lyon, France. [Boyle, Peter] Univ Strathclyde, Inst Global Publ Hlth iPRI, Glasgow, Lanark, Scotland. [Derricks, Gemma] Brunel Univ, London, England. [Dare, Anna] Univ Toronto, Ctr Global Hlth Res, Toronto, ON, Canada. [Dare, Anna] Univ Toronto, Dept Surg, Toronto, ON, Canada. [Evans, Tim] World Bank Grp, Hlth Nutr & Populat Global Practice, Washington, DC USA. [Eniu, Alexandru] Canc Inst Ion Chiricuta, Cluj Napoca, Romania. [Jimenez, Jorge] Pontificia Univ Catolica Chile, Santiago, Chile. [Kutluk, Tezer] Hacettepe Univ, Dept Pediat Oncol, Ankara, Turkey. [Lopes, Gilberto] Oncoclin Grp, Sao Paulo, Brazil. [Lopes, Gilberto] Univ Miami, Miller Sch Med, Coral Gables, FL 33124 USA. [Mohammed, Sulma I.] Purdue Univ, Purdue Ctr Canc Res, W Lafayette, IN 47907 USA. [Mohammed, Sulma I.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Qiao, You-Lin] Chinese Acad Med Sci, Natl Canc Ctr, Dept Canc Epidemiol, Beijing, Peoples R China. [Qiao, You-Lin] Peking Union Med Coll, Beijing, Peoples R China. [Rashid, Sabina Faiz] BRAC Univ, James P Grant Sch Publ Hlth, Dhaka, Bangladesh. [Summers, Diane] UNICEF, South Asia Reg Off, Kathmandu, Nepal. [Sarfati, Diana] Univ Otago, Dept Publ Hlth, Wellington, New Zealand. [Temmerman, Marleen] Univ Ghent, Ghent, Belgium. [Temmerman, Marleen] Aga Khan Univ, Nairobi, Kenya. [Trimble, Edward L.] NCI, Ctr Global Hlth, Bethesda, MD 20892 USA. [Padela, Aasim I.] Univ Chicago, Initiat Islam & Med, Chicago, IL 60637 USA. [Padela, Aasim I.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Aggarwal, Ajay] London Sch Hyg & Trop, London, England. [Aggarwal, Ajay; Sullivan, Richard] Kings Hlth Partners, Kings Ctr Global Hlth, Kings Hlth Partners Comprehens Canc Ctr, Inst Canc Policy, London, England. [Aggarwal, Ajay; Sullivan, Richard] Kings Coll London, London, England. Univ Toronto, Womens Coll Hosp, Toronto, ON M5S 1B2, Canada. RP Ginsburg, O (reprint author), Univ Toronto, Womens Coll Hosp, 75 Grenville St, Toronto, ON M5S 1B2, Canada. EM ophira.ginsburg@wchospital.ca OI Sullivan, Richard/0000-0002-6435-1825 FU Canadian Institutes for Health Research; Dalla Lana School of Public Health, University of Toronto; EU Commission [602536]; American Cancer Society [MRSG-14-032-01-CPPB] FX This work was part funded by Canadian Institutes for Health Research and the Dalla Lana School of Public Health, University of Toronto, and the EU Commission Grant Mapping NCD (no: 602536). OG thanks Ms Sabiha Merchant (Women's College Research Institute, Toronto, ON, Canada) for administrative support. RS thanks the NCI Centre for Global Health for their core support and Dr G Lewison and Miss M Begum for research analysis (Institue of Cancer Policy, King's College London, London, UK). AIP was supported by a Mentored Research Scholar Grant in Applied and Clinical Research (MRSG-14-032-01-CPPB), from the American Cancer Society. The opinions expressed here are those of the authors and do not necessarily represent an official position of the organisations with which they are affiliated. NR 71 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD FEB 25 PY 2017 VL 389 IS 10071 BP 871 EP 880 DI 10.1016/S0140-6736(16)31393-9 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA EL9UU UT WOS:000394966400039 PM 27814964 ER PT J AU Chawla, B Hedman, AC Sayedyahossein, S Erdemir, HH Li, ZG Sacks, DB AF Chawla, Bhavna Hedman, Andrew C. Sayedyahossein, Samar Erdemir, Huseyin H. Li, Zhigang Sacks, David B. TI Absence of IQGAP1 Protein Leads to Insulin Resistance SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Akt PKB; insulin; insulin receptor; insulin receptor substrate 1 (IRS-1); insulin resistance; mitogen-activated protein kinase (MAPK); phosphatidylinositide 3-kinase (PI 3-kinase); IQGAP1 ID PLECKSTRIN-HOMOLOGY DOMAIN; HEPATOCELLULAR-CARCINOMA; MICE LACKING; PTB DOMAIN; IQ MOTIFS; RECEPTOR; IRS-1; SCAFFOLD; BINDING; ACTIVATION AB Insulin binds to the insulin receptor (IR) and induces tyrosine phosphorylation of the receptor and insulin receptor substrate-1 (IRS-1), leading to activation of the PKB/Akt and MAPK/ERK pathways. IQGAP1 is a scaffold protein that interacts with multiple binding partners and integrates diverse signaling cascades. Here we show that IQGAP1 associates with both IR and IRS-1 and influences insulin action. In vitro analysis with pure proteins revealed that the IQ region of IQGAP1 binds directly to the intracellular domain of IR. Similarly, the phosphotyrosine-binding domain of IRS-1 mediates a direct interaction with the C-terminal tail of IQGAP1. Consistent with these observations, both IR and IRS-1 co-immunoprecipitated with IQGAP1 from cells. Investigation of the functional effects of the interactions revealed that in the absence of IQGAP1, insulin-stimulated phosphorylation of Akt and ERK, as well as the association of phosphatidylinositol 3-kinase with IRS-1, were significantly decreased. Importantly, loss of IQGAP1 results in impaired insulin signaling and glucose homeostasis in vivo. Collectively, these data reveal that IQGAP1 is a scaffold for IR and IRS-1 and implicate IQGAP1 as a participant in insulin signaling. C1 [Chawla, Bhavna; Hedman, Andrew C.; Sayedyahossein, Samar; Erdemir, Huseyin H.; Li, Zhigang; Sacks, David B.] NIH, Dept Lab Med, 10 Ctr Dr,10-2C306, Bethesda, MD 20892 USA. [Chawla, Bhavna] US FDA, Ctr Biol Evaluat & Res, Div Emerging & Transfus Transmitted Dis, Silver Spring, MD 20993 USA. [Erdemir, Huseyin H.] Cleveland Clin, Dept Pediat Hematol Oncol, Cleveland, OH 44195 USA. [Erdemir, Huseyin H.] Cleveland Clin, BMT, Cleveland, OH 44195 USA. RP Sacks, DB (reprint author), NIH, Dept Lab Med, 10 Ctr Dr,10-2C306, Bethesda, MD 20892 USA. EM david.sacks2@nih.gov OI Sacks, David/0000-0003-3100-0735 FU National Institutes of Health Intramural Research Program FX This work was supported by the National Institutes of Health Intramural Research Program. 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 53 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 24 PY 2017 VL 292 IS 8 BP 3273 EP 3289 DI 10.1074/jbc.M116.752642 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EM8CM UT WOS:000395538800019 PM 28082684 ER PT J AU Carrer, A Parris, JLD Trefely, S Henry, RA Montgomery, DC Torres, A Viola, JM Kuo, YM Blair, IA Meier, JL Andrews, AJ Snyder, NW Wellen, KE AF Carrer, Alessandro Parris, Joshua L. D. Trefely, Sophie Henry, Ryan A. Montgomery, David C. Torres, AnnMarie Viola, John M. Kuo, Yin-Ming Blair, Ian A. Meier, Jordan L. Andrews, Andrew J. Snyder, Nathaniel W. Wellen, Kathryn E. TI Impact of a High-fat Diet on Tissue Acyl-CoA and Histone Acetylation Levels SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Acetyl-CoA; adipose tissue; diet; histone acetylation; liver ID ATP-CITRATE-LYASE; ONE-CARBON METABOLISM; CELLULAR-METABOLISM; DNA METHYLATION; DYNAMICS; TRANSCRIPTION; EPIGENETICS; MECHANISMS; COENZYME; CANCER AB Cellular metabolism dynamically regulates the epigenome via availability of the metabolite substrates of chromatin-modifying enzymes. The impact of diet on the metabolism-epigenome axis is poorly understood but could alter gene expression and influence metabolic health. ATP citrate-lyase produces acetyl-CoA in the nucleus and cytosol and regulates histone acetylation levels in many cell types. Consumption of a high-fat diet (HFD) results in suppression of ATP citrate-lyase levels in tissues such as adipose and liver, but the impact of diet on acetyl-CoA and histone acetylation in these tissues remains unknown. Here we examined the effects of HFD on levels of acyl-CoAs and histone acetylation in mouse white adipose tissue (WAT), liver, and pancreas. We report that mice consuming a HFD have reduced levels of acetyl-CoA and/or acetyl-CoA:CoA ratio in these tissues. In WAT and the pancreas, HFD also impacted the levels of histone acetylation; in particular, histone H3 lysine 23 acetylation was lower in HFD-fed mice. Genetic deletion of Acly in cultured adipocytes also suppressed acetyl-CoA and histone acetylation levels. In the liver, no significant effects on histone acetylation were observed with a HFD despite lower acetyl-CoA levels. Intriguingly, acetylation of several histone lysines correlated with the acetyl-CoA: (iso)butyryl-CoA ratio in liver. Butyryl-CoA and isobutyryl-CoA interacted with the acetyltransferase P300/CBP-associated factor (PCAF) in liver lysates and inhibited its activity in vitro. This study thus provides evidence that diet can impact tissue acyl-CoA and histone acetylation levels and that acetyl-CoA abundance correlates with acetylation of specific histone lysines in WAT but not in the liver. C1 [Carrer, Alessandro; Parris, Joshua L. D.; Trefely, Sophie; Torres, AnnMarie; Viola, John M.; Wellen, Kathryn E.] Univ Penn, Perelman Sch Med, Abramson Family Canc Res Inst, Dept Canc Biol, Philadelphia, PA 19104 USA. [Blair, Ian A.] Univ Penn, Perelman Sch Med, Dept Syst Pharmacol & Translat Therapeut, Philadelphia, PA 19104 USA. [Trefely, Sophie; Snyder, Nathaniel W.] Drexel Univ, AJ Drexel Autism Inst, Philadelphia, PA 19104 USA. [Henry, Ryan A.; Kuo, Yin-Ming; Andrews, Andrew J.] Fox Chase Canc Ctr, Dept Canc Biol, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Montgomery, David C.; Meier, Jordan L.] NCI, Biol Chem Lab, Ctr Canc Res, NIH, Ft Detrick, MD 21702 USA. RP Wellen, KE (reprint author), Univ Penn, Perelman Sch Med, Dept Canc Biol, 421 Curie Blvd,BRB 2-2 Rm 653, Philadelphia, PA 19104 USA. EM wellenk@exchange.upenn.edu OI Carrer, Alessandro/0000-0002-9300-6879 FU American Diabetes Association [7-12-JF-59]; Pancreatic Cancer Action Network-American Association; Abramson Cancer Center Basic Science Center; NCI, National Institutes of Health [R01CA174761, ZIABC011488]; National Institutes of Health [R21HD087866, K22ES26235]; Penn-PREP post-baccalaureate program; Penn-PORT IRACDA postdoctoral fellowship [K12 GM081259] FX This work was supported by American Diabetes Association Grant 7-12-JF-59, NCI, National Institutes of Health Grant R01CA174761, by a Pancreatic Cancer Action Network-American Association for Cancer Research career development award (to K. E. W.), by the Abramson Cancer Center Basic Science Center for Excellence in Cancer Metabolism (to K. E. W. and I. A. B.), by National Institutes of Health Grants R21HD087866 and K22ES26235 (to N. W. S.), and by NCI, National Institutes of Health Grant ZIABC011488-04 (to J. L. M.). 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.; Supported by the Penn-PREP post-baccalaureate program.; Supported by Penn-PORT IRACDA postdoctoral fellowship K12 GM081259. NR 43 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 24 PY 2017 VL 292 IS 8 BP 3312 EP 3322 DI 10.1074/jbc.M116.750620 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EM8CM UT WOS:000395538800022 PM 28077572 ER PT J AU Yadav, H Devalaraja, S Chung, ST Rane, SG AF Yadav, Hariom Devalaraja, Samir Chung, Stephanie T. Rane, Sushil G. TI TGF-1/Smad3 Pathway Targets PP2A-AMPK-FoxO1 Signaling to Regulate Hepatic Gluconeogenesis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE AMP-activated kinase (AMPK); diabetes; FOXO; gluconeogenesis; liver; obesity; phosphoprotein phosphatase; SMAD transcription factor; transforming growth factor (TGF-) ID ACTIVATED PROTEIN-KINASE; TGF-BETA; GENE-EXPRESSION; C-ELEGANS; PHOSPHOENOLPYRUVATE CARBOXYKINASE; INSULIN SENSITIVITY; DIETARY RESTRICTION; TRANSGENIC MICE; DB/DB MICE; GROWTH AB Maintenance of glucose homeostasis is essential for normal physiology. Deviation from normal glucose levels, in either direction, increases susceptibility to serious medical complications such as hypoglycemia and diabetes. Maintenance of glucose homeostasis is achieved via functional interactions among various organs: liver, skeletal muscle, adipose tissue, brain, and the endocrine pancreas. The liver is the primary site of endogenous glucose production, especially during states of prolonged fasting. However, enhanced gluconeogenesis is also a signature feature of type 2 diabetes (T2D). Thus, elucidating the signaling pathways that regulate hepatic gluconeogenesis would allow better insight into the process of normal endogenous glucose production as well as how this process is impaired in T2D. Here we demonstrate that the TGF-1/Smad3 signaling pathway promotes hepatic gluconeogenesis, both upon prolonged fasting and during T2D. In contrast, genetic and pharmacological inhibition of TGF-1/Smad3 signals suppressed endogenous glucose production. TGF-1 and Smad3 signals achieved this effect via the targeting of key regulators of hepatic gluconeogenesis, protein phosphatase 2A (PP2A), AMP-activated protein kinase (AMPK), and FoxO1 proteins. Specifically, TGF-1 signaling suppressed the LKB1-AMPK axis, thereby facilitating the nuclear translocation of FoxO1 and activation of key gluconeogenic genes, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. These findings underscore an important role of TGF-1/Smad3 signaling in hepatic gluconeogenesis, both in normal physiology and in the pathophysiology of metabolic diseases such as diabetes, and are thus of significant medical relevance. C1 [Yadav, Hariom; Devalaraja, Samir; Chung, Stephanie T.; Rane, Sushil G.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20854 USA. RP Rane, SG (reprint author), NIDDK, Clin Res Ctr, Diabet Endocrinol & Obes Branch, NIH, Bldg 10,9000 Rockville Pike, Bethesda, MD 20814 USA. EM ranes@mail.nih.gov FU National Institutes of Health Intramural Research Program FX This work was supported by a grant from the National Institutes of Health Intramural Research Program. 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 43 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 24 PY 2017 VL 292 IS 8 BP 3420 EP 3432 DI 10.1074/jbc.M116.764910 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EM8CM UT WOS:000395538800031 PM 28069811 ER PT J AU Gonzalez, M DeVico, AL Spouge, JL AF Gonzalez, Mileidy DeVico, Anthony L. Spouge, John L. TI Conserved signatures indicate HIV-1 transmission is under strong selection and thus is not a "stochastic" process SO RETROVIROLOGY LA English DT Letter DE Transmitted/founder virus; T/F; Transmission signatures; Selection during HIV transmission; Phenotypic versus genotypic selection ID RHESUS MACAQUES; INFECTION; TRIAL; BREAKTHROUGH; VACCINATION; SEQUENCES; SIVSME660; TYPE-1; GP120; STEP AB Recently, Oberle et al. published a paper in Retrovirology evaluating the question of whether selection plays a role in HIV transmission. The Oberle study found no obvious genotypic or phenotypic differences between donors and recipients of epidemiologically linked pairs from the Swiss cohort. Thus, Oberle et al. characterized HIV-1 B transmission as largely "stochastic", an imprecise and potentially misleading term. Here, we re-analyzed their data and placed them in the context of transmission data for over 20 other human and animal trials. The present study finds that the transmitted/founder (T/F) viruses from the Swiss cohort show the same non-random genetic signatures conserved in 118 HIV-1, 40 SHIV, and 12 SIV T/F viruses previously published by two independent groups. We provide alternative interpretations of the Swiss cohort data and conclude that the sequences of their donor viruses lacked variability at the specific sites where other studies were able to demonstrate genotypic selection. Oberle et al. observed no phenotypic selection in vitro, so the problem of determining the in vivo phenotypic mechanisms that cause genotypic selection in HIV remains open. C1 [Gonzalez, Mileidy; Spouge, John L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Stat Computat Biol Grp, Bethesda, MD USA. [DeVico, Anthony L.] Univ Maryland Sch Med, Inst Human Virol, Div Basic Sci & Vaccine Res, Baltimore, MD USA. RP Gonzalez, M (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Stat Computat Biol Grp, Bethesda, MD USA. EM mileidy.gonzalez@nih.gov FU Intramural Research Program of the NIH; National Library of Medicine; The Bill and Melinda Gates Foundation; NIAID; NIH FX MG and JLS were supported by the Intramural Research Program of the NIH, National Library of Medicine. ALD was funded by grants from The Bill and Melinda Gates Foundation and NIAID,NIH. NR 17 TC 2 Z9 2 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD FEB 24 PY 2017 VL 14 AR 13 DI 10.1186/s12977-016-0326-1 PG 4 WC Virology SC Virology GA EN5QY UT WOS:000396061800001 PM 28231858 ER PT J AU Cherry, JL AF Cherry, Joshua L. TI A practical exact maximum compatibility algorithm for reconstruction of recent evolutionary history SO BMC BIOINFORMATICS LA English DT Article DE Phylogeny; Maximum compatibility; Homoplasy; Bacterial genomes ID CHARACTERS; PARSIMONY AB Background: Maximum compatibility is a method of phylogenetic reconstruction that is seldom applied to molecular sequences. It may be ideal for certain applications, such as reconstructing phylogenies of closely-related bacteria on the basis of whole-genome sequencing. Results: Here I present an algorithm that rapidly computes phylogenies according to a compatibility criterion. Although based on solutions to the maximum clique problem, this algorithm deals properly with ambiguities in the data. The algorithm is applied to bacterial data sets containing up to nearly 2000 genomes with several thousand variable nucleotide sites. Run times are several seconds or less. Computational experiments show that maximum compatibility is less sensitive than maximum parsimony to the inclusion of nucleotide data that, though derived from actual sequence reads, has been identified as likely to be misleading. Conclusions: Maximum compatibility is a useful tool for certain phylogenetic problems, such as inferring the relationships among closely-related bacteria from whole-genome sequence data. The algorithm presented here rapidly solves fairly large problems of this type, and provides robustness against misleading characters than can pollute large-scale sequencing data. C1 [Cherry, Joshua L.] Natl Ctr Biotechnol Informat, Natl Inst Hlth, Natl Lib Med, Bethesda, MD 20894 USA. RP Cherry, JL (reprint author), Natl Ctr Biotechnol Informat, Natl Inst Hlth, Natl Lib Med, Bethesda, MD 20894 USA. EM jcherry@ncbi.nlm.nih.gov FU Intramural Research Program of the NIH,; National Library of Medicine FX This research was supported by the Intramural Research Program of the NIH, National Library of Medicine. NR 18 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD FEB 23 PY 2017 VL 18 AR 127 DI 10.1186/s12859-017-1520-4 PG 12 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA EP6RM UT WOS:000397506600004 PM 28231758 ER PT J AU DiNapoli, SR Ortiz, AM Wu, F Matsuda, K Twigg, HL Hirsch, VM Knox, K Brenchley, JM AF DiNapoli, Sarah R. Ortiz, Alexandra M. Wu, Fan Matsuda, Kenta Twigg, Homer L., III Hirsch, Vanessa M. Knox, Kenneth Brenchley, Jason M. TI Tissue-resident macrophages can contain replication-competent virus in antiretroviral-naive, SIV-infected Asian macaques SO JCI INSIGHT LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; CD4(+) T-CELLS; CENTRAL-NERVOUS-SYSTEM; LINKED GLYCOSYLATION SITE; NEUROCOGNITIVE DISORDERS; RHESUS MACAQUES; PERIVASCULAR MACROPHAGES; BRONCHOALVEOLAR LAVAGE; LATENT RESERVOIR; HIV-1 INFECTION AB SIV DNA can be detected in lymphoid tissue-resident macrophages of chronically SIV-infected Asian macaques. These macrophages also contain evidence of recently phagocytosed SIV-infected CD4(+) T cells. Here, we examine whether these macrophages contain replication-competent virus, whether viral DNA can be detected in tissue-resident macrophages from antiretroviral (ARV) therapy-treated animals and humans, and how the viral sequences amplified from macrophages and contemporaneous CD4(+) T cells compare. In ARV-naive animals, we find that lymphoid tissue-resident macrophages contain replication-competent virus if they also contain viral DNA in ARV-naive Asian macaques. The genetic sequence of the virus within these macrophages is similar to those within CD4(+) T cells from the same anatomic sites. In ARV-treated animals, we find that viral DNA can be amplified from lymphoid tissue-resident macrophages of SIV-infected Asian macaques that were treated with ARVs for at least 5 months, but we could not detect replicationcompetent virus from macrophages of animals treated with ARVs. Finally, we could not detect viral DNA in alveolar macrophages from HIV-infected individuals who received ARVs for 3 years and had undetectable viral loads. These data demonstrate that macrophages can contain replicationcompetent virus, but may not represent a significant reservoir for HIV in vivo. C1 [DiNapoli, Sarah R.; Ortiz, Alexandra M.; Brenchley, Jason M.] NIAID, Lab Parasit Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Wu, Fan; Matsuda, Kenta; Hirsch, Vanessa M.] NIAID, Lab Mol Microbiol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Twigg, Homer L., III] Indiana Univ, Dept Med, Indianapolis, IN USA. [Knox, Kenneth] Univ Arizona, Dept Med, Tucson, AZ USA. RP Brenchley, JM (reprint author), 4 Ctr Dr Room 201,9000 Rockville Pike, Bethesda, MD 20892 USA. EM jbrenchl@mail.nih.gov FU Division of Intramural Research/NIAID/NIH FX We would like to acknowledge Heather Cronise, JoAnne Swerczek, Richard Herbert, and all the veterinary staff at the NIH animal center. We would like to thank CLIC/BBC for advice and helpful discussions. We would like to thank Brandon Keele and Bernard Lafont for assistance in analyzing SIV Env sequencing data. Funding for this study was provided in part by the Division of Intramural Research/NIAID/NIH. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 71 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD FEB 23 PY 2017 VL 2 IS 4 AR e91214 DI 10.1172/jci.insight.91214 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EN5ET UT WOS:000396029100014 PM 28239657 ER PT J AU Li, QX Bu, W Gabriel, E Aguilar, F Hoshino, Y Miyadera, H Hess, C Hornung, RL Roy, A Cohen, JI AF Li, Qingxue Bu, Wei Gabriel, Erin Aguilar, Fiona Hoshino, Yo Miyadera, Hiroko Hess, Christoph Hornung, Ronald L. Roy, Amitava Cohen, Jeffrey I. TI HLA-DQ beta 1 alleles associated with Epstein-Barr virus (EBV) infectivity and EBV gp42 binding to cells SO JCI INSIGHT LA English DT Article ID AGE-SPECIFIC PREVALENCE; CLASS-II; B-LYMPHOCYTES; SOLUBLE GP42; RECEPTOR; ACQUISITION; CORECEPTOR; ANTIGENS; REVEALS; HLA-DR1 AB Epstein-Barr virus (EBV) infects B cells and similar to 95% of adults are infected. EBV glycoprotein gp42 is essential for entry of virus into B cells. EBV gp42 binds to the beta 1 chain of HLA-DQ, -DR, and -DP on B cells, and uses these molecules for infection. To investigate if certain HLA-DQ alleles are associated with EBV seronegativity, we recruited similar to 3,300 healthy adult blood donors, identified 106 EBV-seronegative individuals, and randomly selected a control group of EBV-seropositive donors from the donor pool. A larger than expected proportion of EBV-seronegative subjects were HLA-DQ beta 1 *04/*05 and *06/*06, and to a lesser extent, *02/*03, compared with the control group, while a larger than expected portion of EBV-seropositive persons were HLA-DQ beta 1 *02/*02. We examined the ability of EBV gp42 to bind to different HLA-DQ molecules using human and mouse cells stably expressing these alleles. EBV gp42 bound less effectively to cells expressing HLA-DQ beta 1 *04/*05, *06/*06, or *03/*03 than to cells expressing HLA-DQ beta 1 *02/*02. These data are consistent with our observations of increased EBV seronegativity with DQ beta 1 *04/*05 or *06/*06 alleles. These findings emphasize the importance of a single genetic locus (HLA-DQ beta 1) to influence infectivity with EBV. C1 [Li, Qingxue; Bu, Wei; Aguilar, Fiona; Hoshino, Yo; Cohen, Jeffrey I.] NIAID, Med Virol Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Gabriel, Erin] NIAID, Div Clin Res, Biostat Res Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Miyadera, Hiroko] Univ Tokyo, Grad Sch Med, Dept Human Genet, Tokyo, Japan. [Miyadera, Hiroko] Natl Ctr Global Hlth & Med, Res Ctr Hepatitis & Immunol, Chiba, Japan. [Hess, Christoph] Univ Basel Hosp, Dept Biomed & Med Outpatient Div, Immunobiol Lab, Basel, Switzerland. [Hornung, Ronald L.] Leidos Biomed Res Inc, Clin Serv Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Roy, Amitava] NIH, Bioinformat & Computat Biosci Branch, Rocky Mt Labs, Hamilton, MT USA. RP Cohen, JI (reprint author), NIH, Bldg 50,Room 6134,50 South Dr,MSC8007, Bethesda, MD 20892 USA. EM jcohen@niaid.nih.gov FU intramural research program of the National Institute of Allergy and Infectious Diseases; National Cancer Institute, NIH [HHSN261200800001E] FX We thank Melanie Spriggs for plasmid pDC409-BZLF2 and Sharon Adams for assistance with HLA typing. We thank Toshio Kitamura for providing pMXs plasmids and Henri-Jacques Delecluse and Bill Sugden for the cell line expressing 293-EBV. This work was supported by the intramural research program of the National Institute of Allergy and Infectious Diseases. This project has been funded in whole or in part with federal funds from the National Cancer Institute, NIH, under contract 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 46 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD FEB 23 PY 2017 VL 2 IS 4 AR e85687 DI 10.1172/jci.insight.85687 PG 17 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EN5ET UT WOS:000396029100001 PM 28239644 ER PT J AU Musich, T Jones, JC Keele, BF Jenkins, LMM Demberg, T Uldrick, TS Yarchoan, R Robert-Guroff, M AF Musich, Thomas Jones, Jennifer C. Keele, Brandon F. Jenkins, Lisa M. Miller Demberg, Thorsten Uldrick, Thomas S. Yarchoan, Robert Robert-Guroff, Marjorie TI Flow virometric sorting and analysis of HIV quasispecies from plasma SO JCI INSIGHT LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; SIMIAN IMMUNODEFICIENCY; PARTICLES; CYTOMETRY; INFECTION; PROTEINS; GP120; ANTIBODIES; RESPONSES; KINETICS AB Flow cytometry is utilized extensively for cellular analysis, but technical limitations have prevented its routine application for characterizing virus. The recent introduction of nanoscale fluorescence-activated cytometric cell sorting now allows analysis of individual virions. Here, we demonstrate staining and sorting of infectious HIV. Fluorescent antibodies specific for cellular molecules found on budding virions were used to label CCR5-tropic Bal HIV and CXCR4-tropic NL4.3 HIV Env-expressing pseudovirions made in THP-1 cells (monocyte/macrophage) and H9 cells (T cells), respectively. Using a flow cytometer, we resolved the stained virus beyond isotype staining and demonstrated purity and infectivity of sorted virus populations on cells with the appropriate coreceptors. We subsequently sorted infectious simian/human immunodeficiency virus from archived plasma. Recovery was approximately 0.5%, but virus present in plasma was already bound to viral-specific IgG generated in vivo, likely contributing to the low yield. Importantly, using two broadly neutralizing HIV antibodies, PG9 and VRC01, we also sorted virus from archived human plasma and analyzed the sorted populations genetically and by proteomics, identifying the quasispecies present. The ability to sort infectious HIV from clinically relevant samples provides material for detailed molecular, genetic, and proteomic analyses applicable to future design of vaccine antigens and potential development of personalized treatment regimens. C1 [Musich, Thomas; Demberg, Thorsten; Robert-Guroff, Marjorie] NCI, Immune Biol Retroviral Infect Sect, Bethesda, MD USA. [Jones, Jennifer C.] NCI, Mol Immunogenet & Vaccine Res Sect, Vaccine Branch, Bethesda, MD 20892 USA. [Keele, Brandon F.] Leidos Biomed Res Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Jenkins, Lisa M. Miller] NCI, Collaborat Prot Technol Resource, Cell Biol Lab, Bethesda, MD 20892 USA. [Uldrick, Thomas S.; Yarchoan, Robert] NCI, Retroviral Dis Sect, HIV & AIDS Malignancy Branch, Bethesda, MD 20892 USA. [Demberg, Thorsten] Immat US Inc, Houston, TX USA. RP Robert-Guroff, M (reprint author), NCI, NIH, Vaccine Branch, 41 Medlars Dr,Bldg 41,Room D804, Bethesda, MD 20892 USA. EM guroffm@mail.nih.gov RI Jones, Jennifer/C-8691-2015 OI Jones, Jennifer/0000-0002-9488-7719 FU Intramural Research Program of the NIH, National Cancer Institute [HHSN261200800001E] FX We would like to thank Karen Aleman for her help with the clinical samples used in this study and Stefanie Musich for her graphical help in preparing this manuscript. The following reagents were obtained through the NIH AIDS Research and Reference Reagent Program, Division of AIDS, National Institute of Allergy and Infectious Diseases: anti-HIV-1 gp120 monoclonal PG9; anti-HIV-1 gp120 monoclonal VRC01 from John Mascola; HIV-1 gp120 mAb 7B2-AAA from Barton F. Haynes and HuaXin Liao; and U373-MAGI-CCR5E and U373-MAGI-CXCR4 CEM cells from Michael Emerman. This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, and contract 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 US government. NR 33 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD FEB 23 PY 2017 VL 2 IS 4 AR e90626 DI 10.1172/jci.insight.90626 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EN5ET UT WOS:000396029100011 PM 28239654 ER PT J AU Lack, J Gillard, M Cam, M Paner, GP VanderWeele, DJ AF Lack, Justin Gillard, Marc Cam, Maggie Paner, Gladell P. VanderWeele, David J. TI Circulating tumor cells capture disease evolution in advanced prostate cancer SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article DE Circulating tumor cells; Castrate resistant prostate cancer; Tumor evolution; Neuroendocrine prostate cancer ID SEQUENCING DATA; SAMPLES; EXPRESSION; MUTATIONS; FRAMEWORK; GENOMICS; TISSUE; AR-V7 AB Background: Genetic analysis of advanced cancer is limited by availability of representative tissue. Biopsies of prostate cancer metastasized to bone are invasive with low quantity of tumor tissue. The prostate cancer genome is dynamic, however, with temporal heterogeneity requiring repeated evaluation as the disease evolves. Circulating tumor cells (CTCs) offer an alternative, "liquid biopsy", though single CTC sequencing efforts are laborious with high failure rates. Methods: We performed exome sequencing of matched treatment-naive tumor tissue, castrate resistant tumor tissue, and pooled CTC samples, and compared mutations identified in each. Results: Thirty-seven percent of CTC mutations were private to CTCs, one mutation was shared with treatment-naive disease alone, and 62% of mutations were shared with castrate-resistant disease, either alone or with treatment-naive disease. An acquired nonsense mutation in the Retinoblastoma gene, which is associated with progression to small cell cancer, was identified in castrate resistant and CTC samples, but not treatment-naive disease. This timecourse correlated with the tumor acquiring neuroendocrine features and a change to neuroendocrine-specific therapy. Conclusions: These data support the use of pooled CTCs to facilitate the genetic analysis of late stage prostate cancer. C1 [Lack, Justin; Cam, Maggie] NCI, Ctr Canc Res Collaborat Bioinformat Resource, Ctr Canc Res, Bethesda, MD 20892 USA. [Gillard, Marc] Univ Chicago, Dept Surg, Chicago, IL 60615 USA. [Paner, Gladell P.] Univ Chicago, Dept Pathol, Chicago, IL 60615 USA. [VanderWeele, David J.] NCI, Lab Genitourinary Pathogenesis, Ctr Canc Res, 37 Convent Dr,Rm 1066A, Bethesda, MD 20892 USA. [VanderWeele, David J.] Univ Chicago, Dept Med, Chicago, IL 60615 USA. RP VanderWeele, DJ (reprint author), NCI, Lab Genitourinary Pathogenesis, Ctr Canc Res, 37 Convent Dr,Rm 1066A, Bethesda, MD 20892 USA. EM david.vanderweele@nih.gov FU Office of the Assistant Secretary of Defense for Health Affairs, through the Prostate Cancer Research Program [W81XWH-13-1-0451]; University of Chicago Cancer Center Support Grant [P30 CA014599]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs, through the Prostate Cancer Research Program under Award No. W81XWH-13-1-0451 (DVW). Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. The U.S. Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick MD 21702-5014 is the awarding and administering acquisition office. This work was also supported by the University of Chicago Cancer Center Support Grant P30 CA014599 (DVW), and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (DVW). This work utilized the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov). NR 28 TC 0 Z9 0 U1 3 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD FEB 23 PY 2017 VL 15 AR 44 DI 10.1186/s12967-017-1138-3 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EM8MT UT WOS:000395566200001 PM 28228136 ER PT J AU White, SH McDermott, MM Sufit, RL Kosmac, K Bugg, AW Gonzalez-Freire, M Ferrucci, L Tian, L Zhao, LH Gao, Y Kibbe, MR Criqui, MH Leeuwenburgh, C Peterson, CA AF White, Sarah H. McDermott, Mary M. Sufit, Robert L. Kosmac, Kate Bugg, Alex W. Gonzalez-Freire, Marta Ferrucci, Luigi Tian, Lu Zhao, Lihui Gao, Ying Kibbe, Melina R. Criqui, Michael H. Leeuwenburgh, Christiaan Peterson, Charlotte A. TI Walking performance is positively correlated to calf muscle fiber size in peripheral artery disease subjects, but fibers show aberrant mitophagy: an observational study (vol 14, 284, 2016) SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Correction C1 [White, Sarah H.; Kosmac, Kate; Bugg, Alex W.; Peterson, Charlotte A.] Univ Kentucky, Coll Hlth Sci, 900 S Limestone CTW105, Lexington, KY 40536 USA. [White, Sarah H.; Kosmac, Kate; Bugg, Alex W.; Peterson, Charlotte A.] Univ Kentucky, Ctr Muscle Biol, 900 S Limestone CTW105, Lexington, KY 40536 USA. [McDermott, Mary M.] Northwestern Univ, Div Gen Internal Med, Dept Med, Feinberg Sch Med, 750 North Lake Shore Dr,10th Floor, Chicago, IL 60611 USA. [McDermott, Mary M.; Zhao, Lihui; Gao, Ying] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Sufit, Robert L.] Northwestern Univ, Dept Neurol, Feinberg Sch Med, Chicago, IL 60611 USA. [Gonzalez-Freire, Marta; Ferrucci, Luigi] NIA, Baltimore, MD 21224 USA. [Tian, Lu] Stanford Univ, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Kibbe, Melina R.] Northwestern Univ, Dept Surg, Feinberg Sch Med, 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 Med & Publ Hlth, La Jolla, CA 92093 USA. [Leeuwenburgh, Christiaan] Univ Florida, Dept Aging & Geriatr Res, Inst Aging, Gainesville, FL USA. RP Peterson, CA (reprint author), Univ Kentucky, Coll Hlth Sci, 900 S Limestone CTW105, Lexington, KY 40536 USA.; Peterson, CA (reprint author), Univ Kentucky, Ctr Muscle Biol, 900 S Limestone CTW105, Lexington, KY 40536 USA.; McDermott, MM (reprint author), Northwestern Univ, Div Gen Internal Med, Dept Med, Feinberg Sch Med, 750 North Lake Shore Dr,10th Floor, Chicago, IL 60611 USA. EM mdm608@northwestern.edu; cpete4@uky.edu NR 1 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD FEB 23 PY 2017 VL 15 AR 45 DI 10.1186/s12967-017-1127-6 PG 1 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EM8MT UT WOS:000395566200002 PM 28241774 ER PT J AU Lewandowski, LB Watt, MH Schanberg, LE Thielman, NM Scott, C AF Lewandowski, Laura B. Watt, Melissa H. Schanberg, Laura E. Thielman, Nathan M. Scott, Christiaan TI Missed opportunities for timely diagnosis of pediatric lupus in South Africa: a qualitative study SO PEDIATRIC RHEUMATOLOGY LA English DT Article DE Lupus; Pediatric SLE; Africa; Access to care; Chronic illness; Qualitative ID HEALTH-CARE; ERYTHEMATOSUS; MORTALITY; RHEUMATOLOGY; ACCESS; CHALLENGES; NEPHRITIS; CHILDREN; SLE; DISPARITIES AB Background: Systemic Lupus Erythematosus (SLE) is a serious multisystem autoimmune disease, which is more aggressive in children and people of African descent. In South Africa, pediatric SLE (pSLE) patients are at high risk for severe disease. Similar to pSLE worldwide, South African children and adolescents with SLE require subspecialized medical care. The aim of this study is to describe the care-seeking experiences of families and examine factors that contribute to delays in the diagnosis of pSLE. Specifically, we sought to identify factors to inform interventions that support the timely referral and diagnosis of pediatric SLE patients in South Africa. Methods: In-depth, semi-structured interviews were conducted with 22 caregivers of pSLE patients recruited from two government hospitals in Cape Town, South Africa in 2014. Interviews were audio-recorded, transcribed, and analyzed for themes related to barriers to diagnosis. Results: Six themes were identified and classified as either caregiver or health system barriers to diagnosis. Caregiver barriers included lack of knowledge regarding SLE, financial difficulties, and the social stigma of SLE. Health system barriers were lack of trained staff, a complex medical system, and misdiagnosis. Conclusion: Caregivers reported missed opportunities for diagnosing pSLE in their children. Raising public awareness may improve caregiver awareness and reduce stigma of pSLE. Improving family education at diagnosis holds potential to increase patient-physician trust and mitigate fear. Education modules for primary care providers at initial point of contact with the health care system may improve recognition of early pSLE and facilitate expedited referral to a specialist. C1 [Lewandowski, Laura B.] NIH DHHS, Natl Inst Arthritis Musculoskeletal & Skin Dis, 9000 Rockville Pike,Bldg 10,12 N248 Room 28, Bethesda, MD USA. [Lewandowski, Laura B.; Watt, Melissa H.; Thielman, Nathan M.] Duke Univ, Duke Global Hlth Inst, 310 Trent Dr, Durham, NC 27710 USA. [Schanberg, Laura E.] Duke Univ Med Ctr, Pediat Rheumatol, 2301 Erwin Rd, Durham, NC USA. [Scott, Christiaan] Univ Cape Town, Red Cross War Mem Childrens Hosp, Klipfontein Rd,Rondebosch, Cape Town, South Africa. RP Lewandowski, LB (reprint author), NIH DHHS, Natl Inst Arthritis Musculoskeletal & Skin Dis, 9000 Rockville Pike,Bldg 10,12 N248 Room 28, Bethesda, MD USA.; Lewandowski, LB (reprint author), Duke Univ, Duke Global Hlth Inst, 310 Trent Dr, Durham, NC 27710 USA. EM laura.lewandowski@nih.gov FU Lupus Foundation of America Early Career Award; training grant at Duke University [T32 AI0007217]; Duke Global Health Institute Fieldwork; Fogarty International Center (NIH) [R25TW009337] FX LBL was funded by the Lupus Foundation of America Early Career Award, a training grant at Duke University (T32 AI0007217), a Duke Global Health Institute Fieldwork grant, and the Fogarty International Center (NIH R25TW009337). NR 55 TC 0 Z9 0 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1546-0096 J9 PEDIATR RHEUMATOL JI Pediatr. Rheumatol. PD FEB 23 PY 2017 VL 15 AR 14 DI 10.1186/s12969-017-0144-6 PG 9 WC Pediatrics; Rheumatology SC Pediatrics; Rheumatology GA EP4AF UT WOS:000397322100001 PM 28231857 ER PT J AU Mork, J Aronson, A Demner-Fushman, D AF Mork, James Aronson, Alan Demner-Fushman, Dina TI 12 years on - Is the NLM medical text indexer still useful and relevant? SO JOURNAL OF BIOMEDICAL SEMANTICS LA English DT Article DE Indexing methods; Text categorization; MeSH; MEDLINE; Machine learning; BioASQ AB Background: Facing a growing workload and dwindling resources, the US National Library of Medicine (NLM) created the Indexing Initiative project in 1996. This cross-library team's mission is to explore indexing methodologies for ensuring quality and currency of NLM document collections. The NLM Medical Text Indexer (MTI) is the main product of this project and has been providing automated indexing recommendations since 2002. After all of this time, the questions arise whether MTI is still useful and relevant. Methods: To answer the question about MTI usefulness, we track a wide variety of statistics related to how frequently MEDLINE indexers refer to MTI recommendations, how well MTI performs against human indexing, and how often MTI is used. To answer the question of MTI relevancy compared to other available tools, we have participated in the 2013 and 2014 BioASQ Challenges. The BioASQ Challenges have provided us with an unbiased comparison between the MTI system and other systems performing the same task. Results: Indexers have continually increased their use of MTI recommendations over the years from 15.75% of the articles they index in 2002 to 62.44% in 2014 showing that the indexers find MTI to be increasingly useful. The MTI performance statistics show significant improvement in Precision (+0.2992) and F-1 (+0.1997) with modest gains in Recall (+0.0454) over the years. MTI consistency is comparable to the available indexer consistency studies. MTI performed well in both of the BioASQ Challenges ranking within the top tier teams. Conclusions: Based on our findings, yes, MTI is still relevant and useful, and needs to be improved and expanded. The BioASQ Challenge results have shown that we need to incorporate more machine learning into MTI while still retaining the indexing rules that have earned MTI the indexers' trust over the years. We also need to expand MTI through the use of full text, when and where it is available, to provide coverage of indexing terms that are typically only found in the full text. The role of MTI at NLM is also expanding into new areas, further reinforcing the idea that MTI is increasingly useful and relevant. C1 [Mork, James; Aronson, Alan; Demner-Fushman, Dina] US Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. RP Mork, J (reprint author), US Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM jmork@mail.nlm.nih.gov FU Intramural Research Program of the National Institutes of Health; National Library of Medicine FX This work was supported by the Intramural Research Program of the National Institutes of Health and the National Library of Medicine. We would like to thank our colleagues Francois Lang and Willie Rogers for providing direct and indirect support of MTI. We would also like to extend special acknowledgment to Hua Florence Chang who was the original creator of MTI. Florence's foresight has provided us with a robust and tunable program. We would also like to take this opportunity to thank George Paliouras and the entire BioASQ Team for organizing the BioASQ Challenges and providing the opportunity to evaluate MTI. Finally, we would like to thank the NLM indexers and Indexing staff for their continued support and collaboration they have provided over the last twelve years teaching the MTI team how they index and ensuring that MTI succeeds. NR 24 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2041-1480 J9 J BIOMED SEMANT JI J. Biomed. Semant. PD FEB 23 PY 2017 VL 8 AR 8 DI 10.1186/s13326-017-0113-5 PG 10 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA EP5NJ UT WOS:000397425300001 PM 28231809 ER PT J AU Makarova, KS Zhang, F Koonin, EV AF Makarova, Kira S. Zhang, Feng Koonin, Eugene V. TI SnapShot: Class 1 CRISPR-Cas Systems SO CELL LA English DT Editorial Material ID IMMUNITY C1 [Makarova, Kira S.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Zhang, Feng] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Zhang, Feng] MIT, McGovern Inst Brain Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Makarova, KS (reprint author), NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. NR 9 TC 0 Z9 0 U1 7 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD FEB 23 PY 2017 VL 168 IS 5 BP 946 EP + PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EN8YB UT WOS:000396284800023 PM 28235204 ER PT J AU Kidder, BL Hu, GQ Cui, KR Zhao, KJ AF Kidder, Benjamin L. Hu, Gangqing Cui, Kairong Zhao, Keji TI SMYD5 regulates H4K20me3-marked heterochromatin to safeguard ES cell self-renewal and prevent spurious differentiation SO EPIGENETICS & CHROMATIN LA English DT Article DE Embryonic stem cells; SMYD5; H4K20me3; Repetitive DNA; LTR; LINE; Pluripotent; Epigenetics; Chromatin; Heterochromatin; Genomics; RNA-Seq; ChIP-Seq; Self-renewal; Gene expression; Embryoid body; Differentiation; Histone methyltransferase ID EMBRYONIC STEM-CELLS; CORE TRANSCRIPTIONAL NETWORK; GENE-EXPRESSION; MOUSE DEVELOPMENT; METHYLTRANSFERASE ESET; LYSINE-9 METHYLATION; LTR RETROTRANSPOSONS; ENRICHMENT ANALYSIS; GENOME INTEGRITY; STRUCTURAL BASIS AB Background: Epigenetic regulation of chromatin states is thought to control the self-renewal and differentiation of embryonic stem (ES) cells. However, the roles of repressive histone modifications such as trimethylated histone 4 lysine 20 (H4K20me3) in pluripotency and development are largely unknown. Results: Here, we show that the histone lysine methyltransferase SMYD5 mediates H4K20me3 at heterochromatin regions. Depletion of SMYD5 leads to compromised self-renewal, including dysregulated expression of OCT4 targets, and perturbed differentiation. SMYD5-bound regions are enriched with repetitive DNA elements. Knockdown of SMYD5 results in a global decrease of H4K20me3 levels, a redistribution of heterochromatin constituents including H3K9me3/2, G9a, and HP1a, and de-repression of endogenous retroelements. A loss of SMYD5-dependent silencing of heterochromatin nearby genic regions leads to upregulated expression of lineage-specific genes, thus contributing to the decreased self-renewal and perturbed differentiation of SMYD5-depleted ES cells. Conclusions: Altogether, these findings implicate a role for SMYD5 in regulating ES cell self-renewal and H4K20me3-marked heterochromatin. C1 [Kidder, Benjamin L.] Wayne State Univ, Sch Med, Dept Oncol, Detroit, MI 48202 USA. [Kidder, Benjamin L.] Wayne State Univ, Sch Med, Karmanos Canc Inst, Detroit, MI 48202 USA. [Kidder, Benjamin L.; Hu, Gangqing; Cui, Kairong; Zhao, Keji] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. RP Kidder, BL (reprint author), Wayne State Univ, Sch Med, Dept Oncol, Detroit, MI 48202 USA.; Kidder, BL (reprint author), Wayne State Univ, Sch Med, Karmanos Canc Inst, Detroit, MI 48202 USA.; Kidder, BL; Zhao, KJ (reprint author), NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. EM Benjamin.kidder@wayne.edu; keji.zhao@nih.gov FU Division of Intramural Research of the National Heart, Lung and Blood Institute; Karmanos Cancer Institute, Wayne State University; National Heart, Lung and Blood Institute [1K22HL126842-01A1] FX This work was supported by the Division of Intramural Research of the National Heart, Lung and Blood Institute, Karmanos Cancer Institute, Wayne State University, and a grant from the National Heart, Lung and Blood Institute (1K22HL126842-01A1) awarded to BLK. NR 69 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-8935 J9 EPIGENET CHROMATIN JI Epigenetics Chromatin PD FEB 23 PY 2017 VL 10 AR 8 DI 10.1186/s13072-017-0115-7 PG 20 WC Genetics & Heredity SC Genetics & Heredity GA EM7IP UT WOS:000395485000001 PM 28250819 ER PT J AU Kumar, V Moritz, AE Keck, TM Bonifazi, A Ellenberger, MP Sibley, CD Free, RB Shi, L Lane, JR Sibley, DR Newman, AH AF Kumar, Vivek Moritz, Amy E. Keck, Thomas M. Bonifazi, Alessandro Ellenberger, Michael P. Sibley, Christopher D. Free, R. Benjamin Shi, Lei Lane, J. Robert Sibley, David R. Newman, Amy Hauck TI Synthesis and Pharmacological Characterization of Novel trans-Cyclopropylmethyl-Linked Bivalent Ligands That Exhibit Selectivity and Allosteric Pharmacology at the Dopamine D-3 Receptor (D3R) SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; MEDICINAL CHEMISTRY PERSPECTIVE; ANTIPSYCHOTIC-DRUGS; BITOPIC LIGAND; ANTAGONISTS; DISCOVERY; ANALOGS; DESIGN; POTENT; HYPOTHESIS AB The development of bitopic ligands directed toward D-2-like receptors has proven to be of particular interest to improve the selectivity and/or affinity of these ligands and as an approach to modulate and bias their efficacies. The structural similarities between dopamine D-3 receptor (D3R)-selective molecules that display bitopic or allosteric pharmacology and those that are simply competitive antagonists are subtle and intriguing. Herein we synthesized a series of molecules in which the primary and secondary pharmaco-phores were derived from the D3R-selective antagonists SB269,652 (1) and SB277011A (2) whose structural similarity and pharmacological disparity provided the perfect templates for SAR investigation. Incorporating a trans-cyclopropylmethyl linker between pharmacophores and manipulating linker length resulted in the identification of two bivalent noncompetitive D3R-selective antagonists, 18a and 25a, which further delineates SAR associated with allosterism at D3R and provides leads toward novel drug development. C1 [Kumar, Vivek; Keck, Thomas M.; Bonifazi, Alessandro; Ellenberger, Michael P.; Sibley, Christopher D.; Newman, Amy Hauck] NIDA, Med Chem Sect, Mol Targets & Medicat Discovery Branch, Intramural Res Program,NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. [Shi, Lei] NINDS, Computat Chem & Mol Biophys Unit, Mol Targets & Medicat Discovery Branch, NIH, 35 Convent Dr, Baltimore, MD 21224 USA. [Moritz, Amy E.; Free, R. Benjamin; Sibley, David R.] NINDS, Mol Neuropharmacol Sect, NIH, 35 Convent Dr,MSC-3723, Bethesda, MD 20892 USA. [Lane, J. Robert] Monash Univ, Monash Inst Pharmaceut Sci, Drug Discovery Biol, 399 Royal Parade, Parkville, Vic 3052, Australia. [Keck, Thomas M.] Rowan Univ, Coll Sci & Math, Dept Biomed & Translat Sci, Dept Chem & Biochem, 201 Mullica Hill Rd, Glassboro, NJ 08028 USA. RP Newman, AH (reprint author), NIDA, Med Chem Sect, Mol Targets & Medicat Discovery Branch, Intramural Res Program,NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. EM anewman@intra.nida.nih.gov FU Intramural Research Programs of the National Institute on Drug Abuse; National Institute of Neurological Disorders and Stroke FX Support for this research was provided by the Intramural Research Programs of the National Institute on Drug Abuse (V.K, T.M.K, A.B., M.P.E., and A.H.N.) and the National Institute of Neurological Disorders and Stroke (A.E.M., C.D.S., R.B.F., and D.R.S.). J.R.L. is a RD Wright Biomedical Career Development Fellow (NHMRC). NR 54 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD FEB 23 PY 2017 VL 60 IS 4 BP 1478 EP 1494 DI 10.1021/acs.jmedchem.6b01688 PG 17 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA EL9FH UT WOS:000394924900017 PM 28186762 ER PT J AU Mordmuller, B Surat, G Lagler, H Chakravarty, S Ishizuka, AS Lalremruata, A Gmeiner, M Campo, JJ Esen, M Ruben, AJ Held, J Calle, CL Mengue, JB Gebru, T Ibanez, J Sulyok, M James, ER Billingsley, PF Kc, N Manoj, A Murshedkar, T Gunasekera, A Appen, AGE Li, T Stafford, RE Li, ML Felgner, PL Seder, RA Richie, TL Sim, BKL Hoffman, SL Kremsner, PG AF Mordmueller, Benjamin Surat, Guezin Lagler, Heimo Chakravarty, Sumana Ishizuka, Andrew S. Lalremruata, Albert Gmeiner, Markus Campo, Joseph J. Esen, Meral Ruben, Adam J. Held, Jana Calle, Carlos Lamsfus Mengue, Juliana B. Gebru, Tamirat Ibanez, Javier Sulyok, Mihaly James, Eric R. Billingsley, Peter F. Kc, Natasha Manoj, Anita Murshedkar, Tooba Gunasekera, Anusha Appen, Abraham G. E. Li, Tao Stafford, Richard E. Li, Minglin Felgner, Phil L. Seder, Robert A. Richie, Thomas L. Sim, B. Kim Lee Hoffman, Stephen L. Kremsner, Peter G. TI Sterile protection against human malaria by chemoattenuated PfSPZ vaccine SO NATURE LA English DT Article ID PLASMODIUM-FALCIPARUM SPOROZOITES; DIRECT VENOUS INOCULATION; T-CELL IMMUNITY; LIVER-STAGE; CHLOROQUINE PROPHYLAXIS; HUMAN VOLUNTEERS; IMMUNIZATION; INFECTION; ANTIGEN; ANTIBODIES AB A highly protective malaria vaccine would greatly facilitate the prevention and elimination of malaria and containment of drug-resistant parasites(1). A high level (more than 90%) of protection against malaria in humans has previously been achieved only by immunization with radiation-attenuated Plasmodium falciparum (Pf) sporozoites (PfSPZ) inoculated by mosquitoes(2-4); by intravenous injection of aseptic, purified, radiation-attenuated, cryopreserved PfSPZ ('PfSPZ Vaccine')(5,6); or by infectious PfSPZ inoculated by mosquitoes to volunteers taking chloroquine(7-10) or mefloquine(11) (chemoprophylaxis with sporozoites). We assessed immunization by direct venous inoculation of aseptic, purified, cryopreserved, non-irradiated PfSPZ ('PfSPZ Challenge'(12,13)) to malaria-naive, healthy adult volunteers taking chloroquine for antimalarial chemoprophylaxis (vaccine approach denoted as PfSPZ-CVac)(14). Three doses of 5.12 x 10(4) PfSPZ of PfSPZ Challenge(12,13) at 28-day intervals were well tolerated and safe, and prevented infection in 9 out of 9 (100%) volunteers who underwent controlled human malaria infection ten weeks after the last dose (group III). Protective efficacy was dependent on dose and regimen. Immunization with 3.2 x 10(3) (group I) or 1.28 x 10(4) (group II) PfSPZ protected 3 out of 9 (33%) or 6 out of 9 (67%) volunteers, respectively. Three doses of 5.12 x 10(4) PfSPZ at five-day intervals protected 5 out of 8 (63%) volunteers. The frequency of Pf-specific polyfunctional CD4 memory T cells was associated with protection. On a 7,455 peptide Pf proteome array, immune sera from at least 5 out of 9 group III vaccinees recognized each of 22 proteins. PfSPZ-CVac is a highly efficacious vaccine candidate; when we are able to optimize the immunization regimen (dose, interval between doses, and drug partner), this vaccine could be used for combination mass drug administration and a mass vaccination program approach to eliminate malaria from geographically defined areas. C1 [Mordmueller, Benjamin; Surat, Guezin; Lagler, Heimo; Lalremruata, Albert] Univ Tubingen, Inst Trop Med, Partner Site, D-72074 Tubingen, Germany. [Gmeiner, Markus; Held, Jana; Gebru, Tamirat; James, Eric R.] German Ctr Infect Res, Partner Site, D-72074 Tubingen, Germany. [Chakravarty, Sumana; Billingsley, Peter F.; Murshedkar, Tooba; Hoffman, Stephen L.] Med Univ Vienna, Div Infect Dis & Trop Med, Dept Med, A-1090 Vienna, Austria. [Seder, Robert A.] Sanaria Inc, Rockville, MD 20850 USA. [Gmeiner, Markus; Ibanez, Javier; James, Eric R.; Kc, Natasha] NIAID, NIH, Vaccine Res Ctr VRC, Bethesda, MD 20892 USA. [Billingsley, Peter F.; Kc, Natasha] Antigen Discovery Inc, Irvine, CA 92618 USA. [Campo, Joseph J.; Mengue, Juliana B.; James, Eric R.; Manoj, Anita] Protein Potential LLC, Rockville, MD 20850 USA. [Ishizuka, Andrew S.; Calle, Carlos Lamsfus; Appen, Abraham G. E.; Li, Tao] Univ Calif Irvine, Dept Med, Irvine, CA 92697 USA. RP Hoffman, SL (reprint author), Med Univ Vienna, Div Infect Dis & Trop Med, Dept Med, A-1090 Vienna, Austria. EM slhoffman@sanaria.com OI Sulyok, Mihaly/0000-0002-6960-5126; Lagler, Heimo/0000-0003-3240-7385 FU German Federal Ministry of Education and Research (BMBF) through the German Center for Infection Research (DZIF); National Institute of Allergy and Infectious Diseases of the National Institutes of Health under SBIR [5R44AI058375, 5R44AI055229]; intramural research program of the VRC, NIAID, NIH; NIAID SBIR [5R44AI066791]; Bill & Melinda Gates Foundation FX The authors thank the vaccine trial participants for their contribution and commitment to vaccine research. We thank F. Adomat, S. Adukpo, M. Aldejohann, S. Bolte, S. Borrmann, A. Bouyoukou Hounkpatin, S. Bruckner, E. Bruske, J. Fernandes, P. Granados Bayon, J. Hass, S. Jeyaraj, J. Keim, A. Knoblich, R. Kollner, A. Kreidenweiss, D. N. Ndungu, R. Ritter, J. A. Selvaraj, Z. Sulyok, S. Theil, N. Theurer, and I. Westermann for support in conducting the trial, and P. Darrah and M. Roederer for assistance with the interpretation of the T-cell data. We thank the Sanaria and Protein Potential teams for manufacture and shipping of investigational products, PfSPZ Challenge and diluents, regulatory, quality, and clinical site activities, and legal and administrative support, including especially D. Cheney (nee Padilla), Y. Abebe, E. Saverino, Y. Wu, E. Fomumbod, A. Awe, M. King, M. Orozco, A. Patil, Y. Wen, K. Nelson, J. Overby, S. Matheny, V. Pitch, B. Jiang, L. Gao, R. Xu, T. T. Wai, S. Monsheimer, P. De La Vega, M. Laskowski, H. Huang, M. Marquette, J. Jackson, F. Beams, R. Douglas, R. C. Thompson, D. Dolberg and A. Hoffman. We thank J. Inglese and P. Dranchak of the National Center for Advancing Translational Sciences (NCATS), NIH for support with the automated immunofluorescence assay and inhibition of sporozoite invasion assays. We appreciate the expert reviews of the Safety Monitoring Committee (W. Chen, P. Coyne and P. Zanger). The clinical trial was funded by the German Federal Ministry of Education and Research (BMBF) through the German Center for Infection Research (DZIF). Manufacture of investigational product by Sanaria was supported in part by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under SBIR award numbers 5R44AI058375 and 5R44AI055229. T cell studies were supported by the intramural research program of the VRC, NIAID, NIH. Proteome microarray studies were supported by NIAID SBIR grant 5R44AI066791 and funding from the Bill & Melinda Gates Foundation. NR 45 TC 0 Z9 0 U1 5 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD FEB 23 PY 2017 VL 542 IS 7642 BP 445 EP + DI 10.1038/nature21060 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EM1RG UT WOS:000395094100029 PM 28199305 ER PT J AU Thomou, T Mori, MA Dreyfuss, JM Konishi, M Sakaguchi, M Wolfrum, C Rao, TN Winnay, JN Garcia-Martin, R Grinspoon, SK Gorden, P Kahn, CR AF Thomou, Thomas Mori, Marcelo A. Dreyfuss, Jonathan M. Konishi, Masahiro Sakaguchi, Masaji Wolfrum, Christian Rao, Tata Nageswara Winnay, Jonathon N. Garcia-Martin, Ruben Grinspoon, Steven K. Gorden, Phillip Kahn, C. Ronald TI Adipose-derived circulating miRNAs regulate gene expression in other tissues SO NATURE LA English DT Article ID EXTRACELLULAR VESICLES; MICRORNA BIOGENESIS; MEMBRANE-VESICLES; HUMAN OBESITY; EXOSOMES; CELLS; RNA; DIFFERENTIATION; MICROVESICLES; METABOLISM AB Adipose tissue is a major site of energy storage and has a role in the regulation of metabolism through the release of adipokines. Here we show that mice with an adipose-tissue-specific knockout of the microRNA (miRNA)-processing enzyme Dicer (ADicerKO), as well as humans with lipodystrophy, exhibit a substantial decrease in levels of circulating exosomal miRNAs. Transplantation of both white and brown adipose tissue-brown especially-into ADicerKO mice restores the level of numerous circulating miRNAs that are associated with an improvement in glucose tolerance and a reduction in hepatic Fgf21 mRNA and circulating FGF21. This gene regulation can be mimicked by the administration of normal, but not ADicerKO, serum exosomes. Expression of a human-specific miRNA in the brown adipose tissue of one mouse in vivo can also regulate its 3'UTR reporter in the liver of another mouse through serum exosomal transfer. Thus, adipose tissue constitutes an important source of circulating exosomal miRNAs, which can regulate gene expression in distant tissues and thereby serve as a previously undescribed form of adipokine. C1 [Thomou, Thomas; Konishi, Masahiro; Sakaguchi, Masaji; Rao, Tata Nageswara; Winnay, Jonathon N.; Garcia-Martin, Ruben; Kahn, C. Ronald] Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02215 USA. [Thomou, Thomas; Dreyfuss, Jonathan M.; Konishi, Masahiro; Sakaguchi, Masaji; Rao, Tata Nageswara; Winnay, Jonathon N.; Garcia-Martin, Ruben; Grinspoon, Steven K.; Kahn, C. Ronald] Harvard Med Sch, Boston, MA 02115 USA. [Mori, Marcelo A.] Univ Estadual Campinas, Dept Biochem & Tissue Biol, Campinas, SP, Brazil. [Dreyfuss, Jonathan M.] Joslin Diabet Ctr, Bioinformat Core, Boston, MA 02215 USA. [Dreyfuss, Jonathan M.] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [Wolfrum, Christian] ETHZ, Dept Hlth Sci & Metab, Zurich, Switzerland. [Rao, Tata Nageswara] Univ Basel Hosp, Dept Biomed, Expt Hematol, Basel, Switzerland. [Grinspoon, Steven K.] Massachusetts Gen Hosp, MGH Program Nutr Metab, Boston, MA 02114 USA. [Gorden, Phillip] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. RP Kahn, CR (reprint author), Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02215 USA.; Kahn, CR (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM c.ronald.kahn@joslin.harvard.edu OI Dreyfuss, Jonathan/0000-0001-7242-3991 FU NIH [R01 DK082659, R01 DK033201, P30 DK040561]; Mary K. Iacocca Professorship; Joslin Diabetes Center DRC [P30DK036836]; FAPESP [2010/52557-0, 2015/01316-7] FX We thank M. Torriani and K. V. Fitch for assistance with HIV lipodystrophy samples; M. Lynnes, S. Kasif, and A. M. Cypess for help with reagents and discussions; and the Joslin Histology, Media and Physiology Core Facilities for help with experiments. This study was supported by grants from the NIH R01 DK082659 and R01 DK033201, the Mary K. Iacocca Professorship, and the Joslin Diabetes Center DRC Grant P30DK036836. S.K.G. was funded by grants from the NIH (P30 DK040561). M.A.M. was funded by grants from FAPESP (2010/52557-0 and 2015/01316-7). NR 50 TC 1 Z9 1 U1 14 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD FEB 23 PY 2017 VL 542 IS 7642 BP 450 EP + DI 10.1038/nature21365 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EM1RG UT WOS:000395094100030 PM 28199304 ER PT J AU Compagno, M Wang, Q Pighi, C Cheong, TC Meng, FL Poggio, T Yeap, LS Karaca, E Blasco, RB Langellotto, F Ambrogio, C Voena, C Wiestner, A Kasar, SN Brown, JR Sun, J Wu, CJ Gostissa, M Alt, FW Chiarle, R AF Compagno, Mara Wang, Qi Pighi, Chiara Cheong, Taek-Chin Meng, Fei-Long Poggio, Teresa Yeap, Leng-Siew Karaca, Elif Blasco, Rafael B. Langellotto, Fernanda Ambrogio, Chiara Voena, Claudia Wiestner, Adrian Kasar, Siddha N. Brown, Jennifer R. . Sun, Jing Wu, Catherine J. Gostissa, Monica Alt, Frederick W. Chiarle, Roberto TI Phosphatidylinositol 3-kinase delta blockade increases genomic instability in B cells SO NATURE LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; INDUCED CYTIDINE DEAMINASE; CLASS-SWITCH RECOMBINATION; SEQUENCING REVEALS; CHROMOSOMAL TRANSLOCATIONS; SUPER-ENHANCERS; TARGETING BTK; AID; DNA; HYPERMUTATION AB Activation-induced cytidine deaminase (AID) is a B-cell-specific enzyme that targets immunoglobulin genes to initiate class switch recombination and somatic hypermutation(1). In addition, through off-target activity, AID has a much broader effect on genomic instability by initiating oncogenic chromosomal translocations and mutations involved in the development and progression of lymphoma(2). AID expression is tightly regulated in B cells and its overexpression leads to enhanced genomic instability and lymphoma formation3. The phosphatidylinositol 3-kinase delta (PI3K delta) pathway regulates AID by suppressing its expression in B cells4. Drugs for leukaemia or lymphoma therapy such as idelalisib, duvelisib and ibrutinib block PI3K delta activity directly or indirectly(5-8), potentially affecting AID expression and, consequently, genomic stability in B cells. Here we show that treatment of primary mouse B cells with idelalisib or duvelisib, and to a lesser extent ibrutinib, enhanced the expression of AID and increased somatic hypermutation and chromosomal translocation frequency to the Igh locus and to several AID off-target sites. Both of these effects were completely abrogated in AID-deficient B cells. PI3K delta inhibitors or ibrutinib increased the formation of AID-dependent tumours in pristane-treated mice. Consistently, PI3K delta inhibitors enhanced AID expression and translocation frequency to IGH and AID off-target sites in human chronic lymphocytic leukaemia and mantle cell lymphoma cell lines, and patients treated with idelalisib, but not ibrutinib, showed increased somatic hypermutation in AID off-targets. In summary, we show that PI3K delta or Bruton's tyrosine kinase inhibitors increase genomic instability in normal and neoplastic B cells by an AID-dependent mechanism. This effect should be carefully considered, as such inhibitors can be administered to patients for years. C1 [Compagno, Mara; Wang, Qi; Pighi, Chiara; Cheong, Taek-Chin; Karaca, Elif; Blasco, Rafael B.; Langellotto, Fernanda; Voena, Claudia; Chiarle, Roberto] Childrens Hosp Boston, Dept Pathol, Boston, MA 02115 USA. [Compagno, Mara; Wang, Qi; Pighi, Chiara; Cheong, Taek-Chin; Karaca, Elif; Blasco, Rafael B.; Langellotto, Fernanda; Voena, Claudia; Chiarle, Roberto] Harvard Med Sch, Boston, MA 02115 USA. [Meng, Fei-Long; Yeap, Leng-Siew; Gostissa, Monica; Alt, Frederick W.] Boston Childrens Hosp, Howard Hughes Med Inst, Program Cellular & Mol Med, Boston, MA 02115 USA. [Meng, Fei-Long; Yeap, Leng-Siew; Gostissa, Monica; Alt, Frederick W.] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Poggio, Teresa; Voena, Claudia; Chiarle, Roberto] Univ Torino, Dept Mol Biotechnol & Hlth Sci, I-10126 Turin, Italy. [Kasar, Siddha N.; Brown, Jennifer R. .; Sun, Jing] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Wiestner, Adrian] Natl Heart Lung & Blood Inst, Hematol Branch, Bethesda, MD USA. [Meng, Fei-Long] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Shanghai 200031, Peoples R China. [Yeap, Leng-Siew] Shanghai Jiao Tong Univ, Sch Med, Shanghai Inst Immunol, Shanghai 200025, Peoples R China. [Langellotto, Fernanda; Gostissa, Monica] Agenus Inc, 3 Forbes Rd, Lexington, MA 02421 USA. RP Chiarle, R (reprint author), Childrens Hosp Boston, Dept Pathol, Boston, MA 02115 USA.; Chiarle, R (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Chiarle, R (reprint author), Univ Torino, Dept Mol Biotechnol & Hlth Sci, I-10126 Turin, Italy. EM roberto.chiarle@childrens.harvard.edu FU NIH [R01 CA196703-01, 1U10CA180861-01, R01AI077595]; Associazione Italiana per la Ricerca sul Cancro [IG-12023, MFAG 10708]; Worldwide Cancer Research grant [12-0216]; Compagnia di San Paolo-Comitato Gigi Ghirotti; American Cancer Society [RSG-13-002-01-CCE]; National Research Foundation of Korea(NRF); PhRMA Foundation; NHLBI, NIH FX We thank K. Okkenhaug and F. Garcon for providing wild-type and mutated PI3K delta constructs, F. Zhang for providing CRISPR/Cas9 plasmids. We thank M. Fleming and M. M. Awad for critically reading the manuscript. This work was supported by NIH grants R01 CA196703-01 to R.C.; 1U10CA180861-01 to C.J.W., R01AI077595 to F.W.A; Associazione Italiana per la Ricerca sul Cancro grant IG-12023 to R.C. and MFAG 10708 to M.C.; Worldwide Cancer Research grant 12-0216 to R.C.; Compagnia di San Paolo-Comitato Gigi Ghirotti to M.C.; American Cancer Society Grant RSG-13-002-01-CCE to J.R.B.; T.C.C. is supported by a National Research Foundation of Korea(NRF) fellowship; L.S.Y. was a Cancer Research Institute postdoctoral fellow; F.M. was a Lymphoma Research Foundation postdoctoral fellow; J.S. is a recipient of a PhRMA Foundation Research Fellowship; C.J.W. is Scholar of the Leukemia and Lymphoma Society; F.W.A. is an investigator of the Howard Hughes Medical Institute. A.W. is supported by the intramural program of NHLBI, NIH. NR 43 TC 1 Z9 1 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD FEB 23 PY 2017 VL 542 IS 7642 BP 489 EP + DI 10.1038/nature21406 PG 22 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EM1RG UT WOS:000395094100039 PM 28199309 ER PT J AU Schlusser, KE Pilcher, C Kallas, EG Santos, BR Deeks, SG Facente, S Keating, SM Busch, MP Murphy, G Welte, A Quinn, T Eshleman, SH Laeyendecker, O AF Schlusser, Katherine E. Pilcher, Christopher Kallas, Esper G. Santos, Breno R. Deeks, Steven G. Facente, Shelley Keating, Sheila M. Busch, Michael P. Murphy, Gary Welte, Alex Quinn, Thomas Eshleman, Susan H. Laeyendecker, Oliver TI Comparison of cross-sectional HIV incidence assay results from dried blood spots and plasma SO PLOS ONE LA English DT Article ID BED-ENZYME-IMMUNOASSAY; TYPE-1 SEROCONVERSION; CHALLENGES AB Background Assays have been developed for cross-sectional HIV incidence estimation using plasma samples. Large scale surveillance programs are planned using dried blood spot (DBS) specimens for incidence assessment. However, limited information exists on the performance of HIV cross-sectional incidence assays using DBS. Methods The assays evaluated were: Maxim HIV-1 Limiting Antigen Avidity EIA (LAg-Avidity), Sedia HIV-1 BED-Capture EIA (BED-CEIA), and CDC modified BioRad HIV-1/2 Plus O Aviditybased Assay (CDC-BioRad Avidity) using pre-determined cutoff values. 100 matched HIV-1 positive plasma and DBS samples, with known duration of infection, from the Consortium for the Evaluation and Performance of HIV Incidence Assays repository were tested. All assays were run in duplicate. To examine the degree of variability within and between results for each sample type, both categorical and continuous results were analyzed. Associations were assessed with Bland Altman, R-2 values and Cohen's kappa coefficient (kappa). Results Intra-assay variability using the same sample type was similar for all assays (R-2 0.96 to 1.00). The R-2 values comparing DBS and plasma results for LAg-Avidity, BED-CEIA, and CDC-BioRad Avidity were 0.96, 0.94, and 0.84, respectively. The concordance and. values between DBS and plasma for all three assays were > 87% and > 0.64, respectively. The Bland-Altman analysis showed significant differences between plasma and DBS samples. For all three assays, a higher number of samples were classified as recent infections using DBS samples. Conclusions DBS and plasma sample results were highly correlated. However, when compared to plasma, each assay performed somewhat differently in DBS at the lower and higher ends of the dynamic range. DBS samples were more likely to be classified as recently infected by all three assays, which may lead to overestimation of incidence in surveys using performance criteria derived for plasma samples. C1 [Schlusser, Katherine E.; Quinn, Thomas; Laeyendecker, Oliver] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Pilcher, Christopher; Deeks, Steven G.; Facente, Shelley; Keating, Sheila M.; Busch, Michael P.] Univ Calif San Francisco, Sch Med, Dept Med, San Francisco, CA USA. [Kallas, Esper G.] Univ Sao Paulo, Sao Paulo, Brazil. [Kallas, Esper G.] Grp Hosp Conceicao, Porto Alegre, RS, Brazil. [Keating, Sheila M.; Busch, Michael P.] Blood Syst Res Inst, San Francisco, CA USA. [Murphy, Gary] Publ Hlth England, London, England. [Welte, Alex] Univ Stellenbosch, South African DST NRF Ctr Excellence Epidemiol Mo, Stellenbosch, South Africa. [Quinn, Thomas; Laeyendecker, Oliver] NIAID, Immunoregulat Lab, Div Intramural Res, NIH, Baltimore, MD USA. [Eshleman, Susan H.] Johns Hopkins Univ Sch Med, Dept Pathol, Baltimore, MD USA. RP Laeyendecker, O (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA.; Laeyendecker, O (reprint author), NIAID, Immunoregulat Lab, Div Intramural Res, NIH, Baltimore, MD USA. EM olaeyen1@jhmi.edu FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), NIH; HIV Prevention Trials Network (HPTN) - NIAID, National Institutes of Child Health and Human Development (NICH/HD), National Institute on Drug Abuse, National Institute of Mental Health; Office of AIDS Research; Office of NIH, DHHS [UM1 AI1068613, R01 AI095068, R34MH096606]; Bill and Melinda Gates Foundation [OPP1017716]; NIH [P01 AI071713, R01 HD074511, P30 AI027763, R24 AI067039]; Brazilian Ministry of Health, Brazilian Program [914/BRA/3014-UNESCO]; Sao Paulo City Health Department [2004-0.168.922-7] FX This study was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), NIH. Other support was provided by the HIV Prevention Trials Network (HPTN) sponsored by the NIAID, National Institutes of Child Health and Human Development (NICH/HD), National Institute on Drug Abuse, National Institute of Mental Health, and Office of AIDS Research, of the NIH, DHHS, UM1 AI1068613 (Eshleman), R01 AI095068 (Eshleman) and R34MH096606 (Pilcher). Funding for this project was also provided by the Bill and Melinda Gates Foundation (grant OPP1017716). The AM PLIAR and Options Cohorts received funding from the NIH (grants P01 AI071713 and R01 HD074511). The SCOPE study also received funding from the NIH (grants P30 AI027763 and R24 AI067039). The Sao Paulo Cohort acknowledges funding by the Brazilian Ministry of Health, Brazilian Program for STD and AIDS (grant 914/BRA/3014-UNESCO) and the Sao Paulo City Health Department (grant 2004-0.168.922-7). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 19 TC 0 Z9 0 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 FEB 23 PY 2017 VL 12 IS 2 AR e0172283 DI 10.1371/journal.pone.0172283 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EL5SX UT WOS:000394682400033 ER PT J AU Jorissen, W Wouters, E Bogie, JF Vanmierlo, T Noben, JP Sviridov, D Hellings, N Somers, V Valcke, R Vanwijmeersch, B Stinissen, P Mulder, MT Remaley, AT Hendriks, JJA AF Jorissen, Winde Wouters, Elien Bogie, Jeroen F. Vanmierlo, Tim Noben, Jean-Paul Sviridov, Denis Hellings, Niels Somers, Veerle Valcke, Roland Vanwijmeersch, Bart Stinissen, Piet Mulder, Monique T. Remaley, Alan T. Hendriks, Jerome J. A. TI Relapsing-remitting multiple sclerosis patients display an altered lipoprotein profile with dysfunctional HDL SO SCIENTIFIC REPORTS LA English DT Article ID HIGH-DENSITY-LIPOPROTEIN; APOLIPOPROTEIN-A-I; TUMOR-NECROSIS-FACTOR; ACUTE-PHASE RESPONSE; REVERSE CHOLESTEROL TRANSPORT; CORONARY-ARTERY-DISEASE; CENTRAL-NERVOUS-SYSTEM; INSULIN-RESISTANCE; FACTOR-ALPHA; CARDIOVASCULAR-DISEASE AB Lipoproteins modulate innate and adaptive immune responses. In the chronic inflammatory disease multiple sclerosis (MS), reports on lipoprotein level alterations are inconsistent and it is unclear whether lipoprotein function is affected. Using nuclear magnetic resonance (NMR) spectroscopy, we analysed the lipoprotein profile of relapsing-remitting (RR) MS patients, progressive MS patients and healthy controls (HC). We observed smaller LDL in RRMS patients compared to healthy controls and to progressive MS patients. Furthermore, low-BMI (BMI <= 23 kg/m(2)) RRMS patients show increased levels of small HDL (sHDL), accompanied by larger, triglyceride (TG)-rich VLDL, and a higher lipoprotein insulin resistance (LP-IR) index. These alterations coincide with a reduced serum capacity to accept cholesterol via ATP-binding cassette (ABC) transporter G1, an impaired ability of HDL3 to suppress inflammatory activity of human monocytes, and modifications of HDL3's main protein component ApoA-I. In summary, lipoprotein levels and function are altered in RRMS patients, especially in low-BMI patients, which may contribute to disease progression in these patients. C1 [Jorissen, Winde; Wouters, Elien; Bogie, Jeroen F.; Vanmierlo, Tim; Noben, Jean-Paul; Hellings, Niels; Somers, Veerle; Stinissen, Piet; Hendriks, Jerome J. A.] Hasselt Univ, Dept Immunol & Biochem, Biomed, Diepenbeek, Belgium. [Sviridov, Denis; Remaley, Alan T.] NIH, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Valcke, Roland] Hasselt Univ, Fac Sci Mol & Phys Plant Physiol, Diepenbeek, Belgium. [Vanwijmeersch, Bart] Revalidat & MS Ctr, Overpelt, Belgium. [Mulder, Monique T.] Erasmus MC, Dept Vasc & Met Dis, Rotterdam, Netherlands. RP Hendriks, JJA (reprint author), Hasselt Univ, Dept Immunol & Biochem, Biomed, Diepenbeek, Belgium. EM jerome.hendriks@uhasselt.be RI Vanmierlo, Tim/C-7773-2013; OI Vanmierlo, Tim/0000-0003-2912-0578; Noben, Jean-Paul/0000-0003-3368-5686 FU European Molecular Biology Organization (EMBO); Agentschap Innovatie door Wetenschap en Technologie (IWT); Fonds Wetenschappelijk Onderzoek (FWO); NHLBI; Hercules Foundation FX The authors thank Dr. Maureen Sampson, Dr. Francesca Solmi and Dr. Michele Ampe for the statistical support, Erik Royackers for the excellent technical assistance, and Dr. Anatol Kontush and Virginie Bito for critically reading the manuscript. This work was supported by grants from the European Molecular Biology Organization (EMBO), the Agentschap Innovatie door Wetenschap en Technologie (IWT), and the Fonds Wetenschappelijk Onderzoek (FWO). Research by ATR was supported by intramural DIR research funds from NHLBI. Funding of the LTQ-Orbitrap mass spectrometer was obtained through Hercules Foundation. NR 108 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD FEB 23 PY 2017 VL 7 AR 43410 DI 10.1038/srep43410 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EL6TG UT WOS:000394754500001 PM 28230201 ER PT J AU Amar, MJA Kaler, M Courville, AB Shamburek, R Sampson, M Wolska, A Remaley, AT AF Amar, Marcelo J. A. Kaler, Maryann Courville, Amber B. Shamburek, Robert Sampson, Maureen Wolska, Anna Remaley, Alan T. TI Randomized double blind clinical trial on the effect of oral alpha-cyclodextrin on serum lipids (vol 15, pg 115, 2016) SO LIPIDS IN HEALTH AND DISEASE LA English DT Correction C1 [Amar, Marcelo J. A.; Kaler, Maryann; Courville, Amber B.; Shamburek, Robert; Sampson, Maureen; Wolska, Anna; Remaley, Alan T.] NHLBI, Lipoprot Metab Sect, NIH, Bldg 10,Room 8 N-228,10 Ctr Dr,MSC 1666, Bethesda, MD 20892 USA. RP Amar, MJA (reprint author), NHLBI, Lipoprot Metab Sect, NIH, Bldg 10,Room 8 N-228,10 Ctr Dr,MSC 1666, Bethesda, MD 20892 USA. EM ma90x@nih.gov NR 1 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-511X J9 LIPIDS HEALTH DIS JI Lipids Health Dis. PD FEB 22 PY 2017 VL 16 DI 10.1186/s12944-017-0435-4 PG 1 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA EO6EU UT WOS:000396785500002 PM 28228137 ER PT J AU Wang, RH Bai, J Deng, J Fang, CJ Chen, XY AF Wang, Rui-Hui Bai, Jie Deng, Jun Fang, Chen-Jie Chen, Xiaoyuan TI TAT-Modified Gold Nanoparticle Carrier with Enhanced Anticancer Activity and Size Effect on Overcoming Multidrug Resistance SO ACS APPLIED MATERIALS & INTERFACES LA English DT Article DE AuNPs; TAT; anthracene derivatives; antiproliferation; size effect on MDR ID P-GLYCOPROTEIN; CELLULAR UPTAKE; CANCER-CELLS; DRUG-DELIVERY; BINDING; COMPLEXES; TRANSACTIVATOR; TRANSCRIPTION; ENDOCYTOSIS; DOXORUBICIN AB Highly efficient targeted delivery is crucial for successful anticancer chemotherapy. In this study, we developed a drug delivery system ANS-TAT-AuNP that loads anticancer molecule 2-(9-anthracenylmethylene)-hydrazinecarbothioamide (ANS) via conjugation with cell penetrating peptide TAT modified AuNPs. The in vitro study showed that the IC50 value of ANS-TAT-AuNPs(3.8 nm), reduced by 11.28- (24 h) and 12.64-fold (48 h) after incubation with liver hepatocellular carcinoma HepG(2) cells compared to that of free ANS, suggesting that TAT modified AuNPs could enhance the antiproliferative activity of ANS. Also, ANS-TAT-AuNPs showed a size effect on overcoming multidrug resistance (MDR). The potential of ANS-TAT-AuNPs in overcoming MDR was assessed with MCF-7/ADR drug-resistant cell line, the drug resistance index (DRI) of which was extremely high (>190). The DRI of ANS-TAT-AuNPs(22.1 nm) decreased dramatically to 1.48 (24 h) and 2.20 (48 h), while that of ANS-TAT-AuNPs3.8. decreased to 7.64 (24 h) and 7.77 (48 h), indicating that ANS-TAT-AuNPs(22.2 nm) could treat extremely resistant MCF-7/ADR cancer cells as drug sensitive ones. The data suggest that the larger AuNPs had more profound effect on overcoming MDR, which could effectively prevent drug efflux due to their size being much larger than that of the p-glycoprotein channel (9-25 angstrom). C1 [Wang, Rui-Hui; Bai, Jie; Fang, Chen-Jie] Capital Med Univ, Sch Pharmaceut Sci, Beijing 100069, Peoples R China. [Deng, Jun] Capital Med Univ, Core Facil Ctr, Beijing 100069, Peoples R China. [Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Natl Inst Hlth, Lab Mol Imaging & Nanomed, Bethesda, MD 20892 USA. RP Fang, CJ (reprint author), Capital Med Univ, Sch Pharmaceut Sci, Beijing 100069, Peoples R China.; Chen, XY (reprint author), Natl Inst Biomed Imaging & Bioengn, Natl Inst Hlth, Lab Mol Imaging & Nanomed, Bethesda, MD 20892 USA. EM cjfang@ccmu.edu.cn; shawn.chen@nih.gov FU NSFC [21571133, 21171120]; Natural Science Foundation of Beijing Municipality [7132020]; Intramural Research Program, National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH) FX The authors thank the NSFC (21571133, 21171120), Natural Science Foundation of Beijing Municipality (7132020), and the Intramural Research Program, National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH) for financial support. The authors also thank Dr. Yilin Lu for his nice support in the Raman spectroscopy. NR 53 TC 0 Z9 0 U1 3 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1944-8244 J9 ACS APPL MATER INTER JI ACS Appl. Mater. Interfaces PD FEB 22 PY 2017 VL 9 IS 7 BP 5828 EP 5837 DI 10.1021/acsami.6b15200 PG 10 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Science & Technology - Other Topics; Materials Science GA EL7VQ UT WOS:000394829800019 PM 28124900 ER PT J AU Rudebeck, PH Ripple, JA Mitz, AR Averbeck, BB Murray, EA AF Rudebeck, Peter H. Ripple, Joshua A. Mitz, Andrew R. Averbeck, Bruno B. Murray, Elisabeth A. TI Amygdala Contributions to Stimulus-Reward Encoding in the Macaque Medial and Orbital Frontal Cortex during Learning SO JOURNAL OF NEUROSCIENCE LA English DT Article DE amygdala; learning; macaque; prefrontal; reward ID PRIMATE ORBITOFRONTAL CORTEX; ANTERIOR CINGULATE CORTEX; PREFRONTAL CORTEX; BASOLATERAL AMYGDALA; RHESUS-MONKEYS; NEURONAL-ACTIVITY; DECISION-MAKING; LESIONS; MECHANISMS; CHOICES AB Orbitofrontal cortex (OFC), medial frontal cortex (MFC), and amygdala mediate stimulus-reward learning, but the mechanisms through which they interact are unclear. Here, we investigated how neurons in macaque OFC and MFC signaled rewards and the stimuli that predicted them during learning with and without amygdala input. Macaques performed a task that required them to evaluate two stimuli and then choose one to receive the reward associated with that option. Four main findings emerged. First, amygdala lesions slowed the acquisition and use of stimulus-reward associations. Further analyses indicated that this impairment was due, at least in part, to ineffective use of negative feedback to guide subsequent decisions. Second, the activity of neurons in OFC and MFC rapidly evolved to encode the amount of reward associated with each stimulus. Third, amygdalectomy reduced encoding of stimulus-reward associations during the evaluation of different stimuli. Reward encoding of anticipated and received reward after choices were made was not altered. Fourth, amygdala lesions led to an increase in the proportion of neurons in MFC, but not OFC, that encoded the instrumental response that monkeys made on each trial. These correlated changes in behavior and neural activity after amygdala lesions strongly suggest that the amygdala contributes to the ability to learn stimulus-reward associations rapidly by shaping encoding within OFC and MFC. C1 [Rudebeck, Peter H.] Friedman Brain Inst, Icahn Sch Med, New York, NY 10029 USA. [Rudebeck, Peter H.; Ripple, Joshua A.; Mitz, Andrew R.; Averbeck, Bruno B.; Murray, Elisabeth A.] Natl Inst Hlth, Sect Neurobiol Learning & Memory, Neuropsychol Lab, Bethesda, MD 20892 USA. RP Rudebeck, PH (reprint author), Friedman Brain Inst, Icahn Sch Med, New York, NY 10029 USA.; Rudebeck, PH (reprint author), Natl Inst Hlth, Sect Neurobiol Learning & Memory, Neuropsychol Lab, Bethesda, MD 20892 USA. EM peter.rudebeck@mssm.edu FU National Institute of Mental Health [ZI-AMH002886, R01MH110822]; NARSAD FX This work was supported by the National Institute of Mental Health (Intramural Research Program Grant ZI-AMH002886 to E.A.M.; BRAINS Award R01MH110822 to P.H.R.) and NARSAD (Young Investigator Award to P.H.R.). Wethank Kevin Blomstrom, Kevin Fomalont and Ravi Chacko for assistance with data collection; James Fellows, Ping Yu Chen, and David Yu for help with surgery and histology; and Steven Wise for discussion and comments. NR 48 TC 0 Z9 0 U1 0 U2 0 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 22 PY 2017 VL 37 IS 8 BP 2186 EP 2202 DI 10.1523/JNEUROSCI.0933-16.2017 PG 17 WC Neurosciences SC Neurosciences & Neurology GA EP2BV UT WOS:000397188900020 PM 28123082 ER PT J AU Aflaki, E Westbroek, W Sidransky, E AF Aflaki, Elma Westbroek, Wendy Sidransky, Ellen TI The Complicated Relationship between Gaucher Disease and Parkinsonism: Insights from a Rare Disease SO NEURON LA English DT Review ID ALPHA-SYNUCLEIN CLEARANCE; CHAPERONE-MEDIATED AUTOPHAGY; GLUCOCEREBROSIDASE MUTATIONS; DOPAMINE NEURONS; ASHKENAZI JEWS; PHARMACOLOGICAL CHAPERONE; LYSOSOMAL BIOGENESIS; SUBSTRATE REDUCTION; BETA-GLUCOSIDASE; GBA MUTATIONS AB The discovery of a link between mutations in GBA1, encoding the lysosomal enzyme glucocerebrosidase, and the synucleinopathies directly resulted from the clinical recognition of patients with Gaucher disease with parkinsonism. Mutations in GBA1 are now the most common known genetic risk factor for several Lewy body disorders, and an inverse relationship exists between levels of glucocerebrosidase and oligomeric alpha-synuclein. While the underlying mechanisms are still debated, this complicated association is shedding light on the role of lysosomes in neurodegenerative disorders, demonstrating how insights from a rare disorder can direct research into the pathogenesis and therapy of seemingly unrelated common diseases. C1 [Aflaki, Elma; Westbroek, Wendy; Sidransky, Ellen] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Sidransky, E (reprint author), NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. EM sidranse@mail.nih.gov FU Intramural NIH HHS [Z99 HG999999] NR 97 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD FEB 22 PY 2017 VL 93 IS 4 BP 737 EP 746 DI 10.1016/j.neuron.2017.01.018 PG 10 WC Neurosciences SC Neurosciences & Neurology GA EO1AE UT WOS:000396429100007 PM 28231462 ER PT J AU Cho, YE Im, EJ Moon, PG Mezey, E Song, BJ Baek, MC AF Cho, Young-Eun Im, Eun-Ju Moon, Pyong-Gon Mezey, Esteban Song, Byoung-Joon Baek, Moon-Chang TI Increased liver-specific proteins in circulating extracellular vesicles as potential biomarkers for drug- and alcohol-induced liver injury SO PLOS ONE LA English DT Article ID ACETAMINOPHEN HEPATOTOXICITY; NONALCOHOLIC STEATOHEPATITIS; MESSENGER-RNAS; TOXICITY; EXOSOMES; IDENTIFICATION; DISEASES; MOUSE; HEPATOCYTES; MICRORNAS AB Drug- and alcohol-induced liver injury are a leading cause of liver failure and transplantation. Emerging evidence suggests that extracellular vesicles (EVs) are a source of biomarkers because they contain unique proteins reflecting the identity and tissue-specific origin of the EV proteins. This study aimed to determine whether potentially hepatotoxic agents, such as acetaminophen (APAP) and binge alcohol, can increase the amounts of circulating EVs and evaluate liver-specific EV proteins as potential biomarkers for liver injury. The circulating EVs, isolated from plasma of APAP-exposed, ethanol-fed mice, or alcoholic hepatitis patients versus normal control counterparts, were characterized by proteomics and biochemical methods. Liver specific EV proteins were analyzed by immunoblots and ELISA. The amounts of total and liver-specific proteins in circulating EVs from APAP-treated mice significantly increased in a dose-and time-dependent manner. Proteomic analysis of EVs from APAP-exposed mice revealed that the amounts of liver-specific and/or hepatotoxic proteins were increased compared to those of controls. Additionally, the increased protein amounts in EVs following APAP exposure returned to basal levels when mice were treated with N-acetylcysteine or glutathione. Similar results of increased amounts and liver-specific proteins in circulating EVs were also observed in mice exposed to hepatotoxic doses of thioacetamide or D-galactosamine but not by non-hepatotoxic penicillin or myotoxic bupivacaine. Additionally, binge ethanol exposure significantly elevated liver-specific proteins in circulating EVs from mice and alcoholics with alcoholic hepatitis, compared to control counterparts. These results indicate that circulating EVs in drug-and alcohol-mediated hepatic injury contain liver-specific proteins that could serve as specific biomarkers for hepatotoxicity. C1 [Cho, Young-Eun; Im, Eun-Ju; Moon, Pyong-Gon; Baek, Moon-Chang] Kyungpook Natl Univ, Cell & Matrix Res Inst, Sch Med, Dept Mol Med, Daegu, South Korea. [Cho, Young-Eun; Song, Byoung-Joon] NIAAA, Sect Mol Pharmacol & Toxicol, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD USA. [Mezey, Esteban] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. RP Baek, MC (reprint author), Kyungpook Natl Univ, Cell & Matrix Res Inst, Sch Med, Dept Mol Med, Daegu, South Korea. EM mcbaek@knu.ac.kr FU National Research Foundation of Korea (NRF) - Korea government [2014R1A5A2009242]; Intramural Fund of the National Institute on Alcoholism and Alcohol Abuse, NIH, U.S.A; Korean Research Institute of Bioscience and Biotechnology FX This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korea government (2014R1A5A2009242) and by the Intramural Fund of the National Institute on Alcoholism and Alcohol Abuse, NIH, U.S.A. In addition, this research was partially supported by the Korean Biomedical Scientist Fellowship Program Award (to YEC) by the Korean Research Institute of Bioscience and Biotechnology. NR 55 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 FEB 22 PY 2017 VL 12 IS 2 AR e0172463 DI 10.1371/journal.pone.0172463 PG 23 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EL5SK UT WOS:000394680900044 PM 28225807 ER PT J AU Nasser, HM Calu, DJ Schoenbaum, G Sharpe, MJ AF Nasser, Helen M. Calu, Donna J. Schoenbaum, Geoffrey Sharpe, Melissa J. TI The Dopamine Prediction Error: Contributions to Associative Models of Reward Learning SO FRONTIERS IN PSYCHOLOGY LA English DT Review DE prediction error; attention; associative learning; dopamine; model-based learning ID VENTRAL TEGMENTAL AREA; RAT PREFRONTAL CORTEX; VISUAL-ATTENTION; NUCLEUS-ACCUMBENS; BASOLATERAL AMYGDALA; AVERSIVE STIMULI; NEURONS ENCODE; CONDITIONED INHIBITION; ORBITOFRONTAL CORTEX; COMPLEX ENVIRONMENTS AB Phasic activity of midbrain dopamine neurons is currently thought to encapsulate the prediction-error signal described in Sutton and Barto's (1981) model-free reinforcement learning algorithm. This phasic signal is thought to contain information about the quantitative value of reward, which transfers to the reward-predictive cue after learning. This is argued to endow the reward-predictive cue with the value inherent in the reward, motivating behavior toward cues signaling the presence of reward. Yet theoretical and empirical research has implicated prediction-error signaling in learning that extends far beyond a transfer of quantitative value to a reward-predictive cue. Here, we review the research which demonstrates the complexity of how dopaminergic prediction errors facilitate learning. After briefly discussing the literature demonstrating that phasic dopaminergic signals can act in the manner described by Sutton and Barto (1981), we consider how these signals may also influence attentional processing across multiple attentional systems in distinct brain circuits. Then, we discuss how prediction errors encode and promote the development of context-specific associations between cues and rewards. Finally, we consider recent evidence that shows dopaminergic activity contains information about causal relationships between cues and rewards that reflect information garnered from rich associative models of the world that can be adapted in the absence of direct experience. In discussing this research we hope to support the expansion of how dopaminergic prediction errors are thought to contribute to the learning process beyond the traditional concept of transferring quantitative value. C1 [Nasser, Helen M.; Calu, Donna J.; Schoenbaum, Geoffrey] Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. [Schoenbaum, Geoffrey; Sharpe, Melissa J.] NIDA, Cellular Neurobiol Res Branch, Intramural Res Program, Baltimore, MD 21224 USA. [Schoenbaum, Geoffrey] Johns Hopkins Univ, Solomon H Snyder Dept Neurosci, Baltimore, MD USA. [Sharpe, Melissa J.] Princeton Univ, Princeton Neurosci Inst, Princeton, NJ 08544 USA. RP Nasser, HM (reprint author), Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA.; Sharpe, MJ (reprint author), NIDA, Cellular Neurobiol Res Branch, Intramural Res Program, Baltimore, MD 21224 USA.; Sharpe, MJ (reprint author), Princeton Univ, Princeton Neurosci Inst, Princeton, NJ 08544 USA. EM helennasser2200@gmail.com; melissa.sharpe@nih.gov OI Calu, Donna/0000-0003-2377-9494 FU Intramural Research Program of the National Institute on Drug Abuse FX The work was supported by the Intramural Research Program of the National Institute on Drug Abuse. NR 140 TC 0 Z9 0 U1 7 U2 7 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-1078 J9 FRONT PSYCHOL JI Front. Psychol. PD FEB 22 PY 2017 VL 8 AR 244 DI 10.3389/fpsyg.2017.00244 PG 17 WC Psychology, Multidisciplinary SC Psychology GA EL3WP UT WOS:000394550300001 PM 28275359 ER PT J AU Qiu, ZJ Zhang, ZH Roschke, A Varga, T Aplan, PD AF Qiu, Zhijun Zhang, Zhenhua Roschke, Anna Varga, Tamas Aplan, Peter D. TI Generation of Gross Chromosomal Rearrangements by a Single Engineered DNA Double Strand Break SO SCIENTIFIC REPORTS LA English DT Article ID CHRONIC MYELOID-LEUKEMIA; END-JOINING PATHWAY; HOMOLOGOUS RECOMBINATION; GENOMIC INSTABILITY; SEQUENCING REVEALS; TOPOISOMERASE-II; HISTONE H2AX; STEM-CELLS; REPAIR; TRANSLOCATIONS AB Gross chromosomal rearrangements (GCRs), including translocations, inversions amplifications, and deletions, can be causal events leading to malignant transformation. GCRs are thought to be triggered by DNA double strand breaks (DSBs), which in turn can be spontaneous or induced by external agents (eg. cytotoxic chemotherapy, ionizing radiation). It has been shown that induction of DNA DSBs at two defined loci can produce stable balanced chromosomal translocations, however, a single engineered DNA DSB could not. Herein, we report that although a single engineered DNA DSB in H2AX "knockdown" cells did not generate GCRs, repair of a single engineered DNA DSB in fibroblasts that had ablated H2ax did produce clonal, stable GCRs, including balanced translocations and megabase-pair inversions. Upon correction of the H2ax deficiency, cells no longer generated GCRs following a single engineered DNA DSB. These findings demonstrate that clonal, stable GCRs can be produced by a single engineered DNA DSB in H2ax knockout cells, and that the production of these GCRs is ameliorated by H2ax expression. C1 [Qiu, Zhijun; Zhang, Zhenhua; Roschke, Anna; Varga, Tamas; Aplan, Peter D.] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. RP Aplan, PD (reprint author), NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. EM aplanp@mail.nih.gov FU National Cancer Institute, NIH FX This work was supported by the intramural program of the National Cancer Institute, NIH. The authors would like to thank Andre Nussenzweig and Hua Tang Chen for the kind gift of H2ax knockout fibroblasts. NR 48 TC 0 Z9 0 U1 3 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 FEB 22 PY 2017 VL 7 AR 43156 DI 10.1038/srep43156 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EL3QP UT WOS:000394534200001 PM 28225067 ER PT J AU Hu, LS Hu, SQ Guo, LY Shen, CC Yang, MH Rasooly, A AF Hu, Lanshuang Hu, Shengqiang Guo, Linyan Shen, Congcong Yang, Minghui Rasooly, Avraham TI DNA Generated Electric Current Biosensor SO ANALYTICAL CHEMISTRY LA English DT Article ID BREAST-CANCER PATIENTS; ELECTROCHEMICAL DETECTION; ENZYME-IMMUNOASSAY; GOLD NANOPARTICLES; SERUM; HER2; AMPLIFICATION; HER-2/NEU; CELLS AB In addition to its primary function as a genetic material, deoxyribonucleic acid (DNA) is also a potential biologic energy source for molecular electronics. For the first time, we demonstrate that DNA can generate a redox electric current. As an example of this new functionality, DNA generated redox current was used for electrochemical detection of human epidermal growth factor receptor 2 (HER2), a clinically important breast cancer biomarker. To induce redox current, the phosphate of the single stranded DNA aptamer backbone was reacted with molybdate to form redox molybdophosphate precipitate and generate an electrochemical current of similar to 16.8 mu A/ mu M cm(2). This detection of HER2 was performed using a sandwich detection assay. A HER2 specific peptide was immobilized onto a gold electrode surface for capturing HER2 in buffer and serum. The HER2 specific aptamer was used as both ligand to bind the captured HER2 and to generate a redox current signal. When tested for HER2 detection, the electrochemical current generated by the aptasensor was proportional to HER2 concentration in the range of 0.01 to 5 ng/mL, with a current generated in the range of similar to 6.37 to 31.8 mu A/cm(2) in both buffer and serum. This detection level is within the clinically relevant range of HER2 concentrations. This method of electrochemical signal amplification greatly simplifies the signal transduction of aptasensors, broadening their use for HER2 analysis. This novel approach of using the same aptamer as biosensor ligand and as transducer can be universally extended to other aptasensors for a wide array of biodetection applications. Moreover, electric currents generated by DNA or other nucleic acids can be used in molecular electronics or implanted devices for both power generation and measurement of output. C1 [Hu, Lanshuang; Hu, Shengqiang; Guo, Linyan; Shen, Congcong; Yang, Minghui] Cent S Univ, Coll Chem & Chem Engn, Changsha 410083, Hunan, Peoples R China. [Rasooly, Avraham] NCI, NIH, Rockville, MD 20850 USA. RP Yang, MH (reprint author), Cent S Univ, Coll Chem & Chem Engn, Changsha 410083, Hunan, Peoples R China.; Rasooly, A (reprint author), NCI, NIH, Rockville, MD 20850 USA. EM yangminghui@csu.edu.cn; rasoolya@mail.nih.gov FU National Key Basic Research Program of China [2014CB744502]; National Natural Science Foundation of China [21575165]; Natural Science Foundation of Hunan Province [2015JJ1019] FX The authors thank the support of this work by the National Key Basic Research Program of China (Grant 2014CB744502), the National Natural Science Foundation of China (Grant No. 21575165), and the Natural Science Foundation of Hunan Province (Grant No. 2015JJ1019). NR 44 TC 0 Z9 0 U1 10 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 EI 1520-6882 J9 ANAL CHEM JI Anal. Chem. PD FEB 21 PY 2017 VL 89 IS 4 BP 2547 EP 2552 DI 10.1021/acs.analchem.6b04756 PG 6 WC Chemistry, Analytical SC Chemistry GA EL6IG UT WOS:000394724700052 PM 28219246 ER PT J AU Libich, DS Tugarinov, V Ghirlando, R Clore, GM AF Libich, David S. Tugarinov, Vitali Ghirlando, Rodolfo Clore, G. Marius TI Confinement and Stabilization of Fyn SH3 Folding Intermediate Mimetics within the Cavity of the Chaperonin GroEL Demonstrated by Relaxation-Based NMR SO BIOCHEMISTRY LA English DT Article ID MOLECULAR CHAPERONES; CONFORMATIONAL STATES; PROTEINS; EXCHANGE; SECB AB The interaction of two folding intermediate mimetics of the model protein substrate Fyn SH3 with the chaperonin GroEL, a supramolecular foldase/unfoldase machine, has been investigated by N-15 relaxation-based nuclear magnetic resonance spectroscopy (lifetime line broadening, dark state exchange saturation transfer, and relaxation dispersion). The two mimetics comprise C-terminal truncations of wild-type and triple-mutant (A39V/N53P/V55L) Fyn SH3 in which the C-terminal strand of the SH3 domain is unfolded, while preserving the remaining domain structure. Quantitative analysis of the data reveals that a mobile state of the SH3 domain confined and tethered within the cavity of GroEL, possibly through interactions with the disordered, methionine-rich C-terminal tail(s), can be detected, and that the native state of the folding intermediate mimetics is stabilized by both confinement within and binding to apo GroEL. These data provide a basis for understanding the passive activity of GroEL as a foldase/unfoldase: the unfolded state, in the absence of hydrophobic GroEL-binding consensus sequences, is destabilized within the cavity because of its larger radius of gyration compared to that of the folding intermediate, while the folding intermediate is stabilized relative to the native state because of exposure of a hydrophobic patch that favors GroEL binding. C1 [Libich, David S.; Tugarinov, Vitali; Clore, G. Marius] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Ghirlando, Rodolfo] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM mariusc@mail.nih.gov FU Intramural Program of NIDDK, NIH; AIDS Targeted Antiviral program of the Office of the Director of the NIH FX This work was supported by the Intramural Program of NIDDK, NIH, and by the AIDS Targeted Antiviral program of the Office of the Director of the NIH (to G.M.C.). NR 23 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 21 PY 2017 VL 56 IS 7 BP 903 EP 906 DI 10.1021/acs.biochem.6b01237 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EL6IL UT WOS:000394725300001 PM 28156097 ER PT J AU Donahue, RN Lepone, LM Grenga, I Jochems, C Fantini, M Madan, RA Heery, CR Gulley, JL Schlom, J AF Donahue, Renee N. Lepone, Lauren M. Grenga, Italia Jochems, Caroline Fantini, Massimo Madan, Ravi A. Heery, Christopher R. Gulley, James L. Schlom, Jeffrey TI Analyses of the peripheral immunome following multiple administrations of avelumab, a human IgG1 anti-PD-L1 monoclonal antibody SO JOURNAL FOR IMMUNOTHERAPY OF CANCER LA English DT Article DE Avelumab; Anti-PD-L1; Checkpoint inhibitor; Immunotherapy; Peripheral immunome; Immune subsets; ADCC; Antibody-dependent cell-mediated cytotoxicity ID DEPENDENT CELLULAR CYTOTOXICITY; NATURAL-KILLER-CELLS; T-CELLS; TUMOR-CELLS; OPEN-LABEL; CANCER; RECEPTORS; THERAPY; TRIAL; NK AB Background: Multiple anti-PD-L1/PD-1 checkpoint monoclonal antibodies (MAb) have shown clear evidence of clinical benefit. All except one have been designed or engineered to omit the possibility to mediate antibody-dependent cell-mediated cytotoxicity (ADCC) as a second potential mode of anti-tumor activity; the reason for this is the concern of lysis of PD-L1 positive immune cells. Avelumab is a fully human IgG1 MAb which has been shown in prior in vitro studies to mediate ADCC versus a range of human tumor cells, and clinical studies have demonstrated anti-tumor activity versus a range of human cancers. This study was designed to investigate the effect on immune cell subsets in the peripheral blood of cancer patients prior to and following multiple administrations of avelumab. Methods: One hundred twenty-three distinct immune cell subsets in the peripheral blood of cancer patients (n = 28) in a phase I trial were analyzed by flow cytometry prior to and following one, three, and nine cycles of avelumab. Changes in soluble (s) CD27 and sCD40L in plasma were also evaluated. In vitro studies were also performed to determine if avelumab would mediate ADCC of PBMC. Results: No statistically significant changes in any of the 123 immune cell subsets analyzed were observed at any dose level, or number of doses, of avelumab. Increases in the ratio of sCD27: sCD40L were observed, suggesting potential immune activation. Controlled in vitro studies also showed lysis of tumor cells by avelumab versus no lysis of PBMC from five donors. Conclusions: These studies demonstrate the lack of any significant effect on multiple immune cell subsets, even those expressing PD-L1, following multiple cycles of avelumab. These results complement prior studies showing anti-tumor effects of avelumab and comparable levels of adverse events with avelumab versus other anti-PD-1/PD-L1 MAbs. These studies provide the rationale to further exploit the potential ADCC mechanismof action of avelumab as well as other human IgG1 checkpoint inhibitors. C1 [Donahue, Renee N.; Lepone, Lauren M.; Grenga, Italia; Jochems, Caroline; Fantini, Massimo; Heery, Christopher R.; Schlom, Jeffrey] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, 10 Ctr Dr,Room 8B09, Bethesda, MD 20892 USA. [Madan, Ravi A.; Gulley, James L.] NCI, Genitourinary Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Schlom, J (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, 10 Ctr Dr,Room 8B09, Bethesda, MD 20892 USA. EM js141c@nih.gov FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health; EMD Serono; NCI FX This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health, and via a Cooperative Research and Development Agreement (CRADA) between EMD Serono and the NCI. NR 35 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2051-1426 J9 J IMMUNOTHER CANCER JI J. Immunother. Cancer PD FEB 21 PY 2017 VL 5 AR 20 DI 10.1186/s40425-017-0220-y PG 16 WC Oncology SC Oncology GA EO8CH UT WOS:000396916000001 PM 28239472 ER PT J AU Ito, D Schureck, MA Desai, SA AF Ito, Daisuke Schureck, Marc A. Desai, Sanjay A. TI An essential dual-function complex mediates erythrocyte invasion and channel-mediated nutrient uptake in malaria parasites SO ELIFE LA English DT Article ID SURFACE ANION CHANNEL; FALCIPARUM-INFECTED ERYTHROCYTES; CLAG MULTIGENE FAMILY; RED-BLOOD-CELLS; PLASMODIUM-FALCIPARUM; RHOPTRY PROTEIN; PTEX COMPONENT; RESISTANCE; REVEALS; TRAFFICKING AB Malaria parasites evade immune detection by growth and replication within erythrocytes. After erythrocyte invasion, the intracellular pathogen must increase host cell uptake of nutrients from plasma. Here, we report that the parasite-encoded RhopH complex contributes to both invasion and channel-mediated nutrient uptake. As rhoph2 and rhoph3 gene knockouts were not viable in the human P. falciparum pathogen, we used conditional knockdowns to determine that the encoded proteins are essential and to identify their stage-specific functions. We exclude presumed roles for RhopH2 and CLAG3 in erythrocyte invasion but implicate a RhopH3 contribution either through ligand-receptor interactions or subsequent parasite internalization. These proteins then traffic via an export translocon to the host membrane, where they form a nutrient channel. Knockdown of either RhopH2 or RhopH3 disrupts the entire complex, interfering with organellar targeting and subsequent trafficking. Therapies targeting this complex should attack the pathogen at two critical points in its cycle. C1 [Ito, Daisuke; Schureck, Marc A.; Desai, Sanjay A.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20892 USA. RP Desai, SA (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20892 USA. EM sdesai@niaid.nih.gov FU Intramural Research Program of the National Institutes of Health; National Institute of Allergy and Infectious Diseases FX We thank Josh Beck, Daniel Goldberg, Thomas Wellems, Jose-Juan Lopez-Rubio, Philip Shaw, and Takafumi Tsuboi for providing plasmids, antibodies, and/or parasite clones; Josh Beck and Daniel Goldberg for helpful discussions and sharing their unpublished results on PTEX activity; Nicole Potchen and Meera Garriga for critical reading of the manuscript; and Ryan Kissinger and Anita Mora for artwork. DSM1 (MRA-1161) was obtained through MR4 as part of the BEI Resources Repository, NIAID, NIH. SAD is a named inventor on US and international patent applications and on an issued US patent on the drug targets presented in this manuscript ('INHIBITORS OF THE PLASMODIAL SURFACE ANION CHANNEL AS ANTIMALARIALS', International Patent Application Publication WO/2010/011537; Chinese Patent Application 200980137435; European Patent Application EP2313100A1; Indian Patent Application 470/CHENP/2011; US Patent Application Publication US2014/0088082A1; and issued US Patent U58,618,090). The other authors have no conflicts of interest. This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 54 TC 2 Z9 2 U1 1 U2 1 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD FEB 21 PY 2017 VL 6 DI 10.7554/eLife.23485 PG 24 WC Biology SC Life Sciences & Biomedicine - Other Topics GA EP8KC UT WOS:000397623300001 ER PT J AU Dumitrescu, L Ritchie, MD Denny, JC El Rouby, NM McDonough, CW Bradford, Y Ramirez, AH Bielinski, SJ Basford, MA Chai, HS Peissig, P Carrell, D Pathak, J Rasmussen, LV Wang, XM Pacheco, JA Kho, AN Hayes, MG Matsumoto, M Smith, ME Li, RL Cooper-DeHoff, RM Kullo, IJ Chute, CG Chisholm, RL Jarvik, GP Larson, EB Carey, D McCarty, CA Williams, MS Roden, DM Bottinger, E Johnson, JA de Andrade, M Crawford, DC AF Dumitrescu, Logan Ritchie, Marylyn D. Denny, Joshua C. El Rouby, Nihal M. McDonough, Caitrin W. Bradford, Yuki Ramirez, Andrea H. Bielinski, Suzette J. Basford, Melissa A. Chai, High Seng Peissig, Peggy Carrell, David Pathak, Jyotishman Rasmussen, Luke V. Wang, Xiaoming Pacheco, Jennifer A. Kho, Abel N. Hayes, M. Geoffrey Matsumoto, Martha Smith, Maureen E. Li, Rongling Cooper-DeHoff, Rhonda M. Kullo, Iftikhar J. Chute, Christopher G. Chisholm, Rex L. Jarvik, Gail P. Larson, Eric B. Carey, David McCarty, Catherine A. Williams, Marc S. Roden, Dan M. Bottinger, Erwin Johnson, Julie A. de Andrade, Mariza Crawford, Dana C. TI Genome-wide study of resistant hypertension identified from electronic health records SO PLOS ONE LA English DT Article ID GENETIC EPIDEMIOLOGY RESEARCH; AMERICAN-HEART-ASSOCIATION; CORONARY-ARTERY-DISEASE; BLOOD-PRESSURE RESPONSE; AGING GERA COHORT; MEDICAL-RECORDS; EMERGE NETWORK; CONTROL RATES; QUALITY-CONTROL; PULSE PRESSURE AB Resistant hypertension is defined as high blood pressure that remains above treatment goals in spite of the concurrent use of three antihypertensive agents from different classes. Despite the important health consequences of resistant hypertension, few studies of resistant hypertension have been conducted. To perform a genome-wide association study for resistant hypertension, we defined and identified cases of resistant hypertension and hypertensives with treated, controlled hypertension among > 47,500 adults residing in the US linked to electronic health records (EHRs) and genotyped as part of the electronic MEdical Records & GEnomics (eMERGE) Network. Electronic selection logic using billing codes, laboratory values, text queries, and medication records was used to identify resistant hypertension cases and controls at each site, and a total of 3,006 cases of resistant hypertension and 876 controlled hypertensives were identified among eMERGE Phase I and II sites. After imputation and quality control, a total of 2,530,150 SNPs were tested for an association among 2,830 multi-ethnic cases of resistant hypertension and 876 controlled hypertensives. No test of association was genome-wide significant in the full dataset or in the dataset limited to European American cases (n = 1,719) and controls (n = 708). The most significant finding was CLNK rs13144136 at p = 1.00x10(-6) (odds ratio = 0.68; 95% CI = 0.58-0.80) in the full dataset with similar results in the European American only dataset. We also examined whether SNPs known to influence blood pressure or hypertension also influenced resistant hypertension. None was significant after correction for multiple testing. These data highlight both the difficulties and the potential utility of EHR-linked genomic data to study clinically-relevant traits such as resistant hypertension. C1 [Dumitrescu, Logan] Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37212 USA. [Ritchie, Marylyn D.; Bradford, Yuki] Geisinger Hlth Syst, Biomed & Translat Informat, Danville, PA USA. [Denny, Joshua C.; Wang, Xiaoming] Vanderbilt Univ, Dept Biomed Informat, 221 Kirkland Hall, Nashville, TN 37235 USA. [Denny, Joshua C.; Ramirez, Andrea H.; Roden, Dan M.] Vanderbilt Univ, Dept Med, Nashville, TN USA. [El Rouby, Nihal M.; McDonough, Caitrin W.; Cooper-DeHoff, Rhonda M.; Johnson, Julie A.] Univ Florida, Coll Pharm, Dept Pharmacotherapy & Translat Res, Gainesville, FL USA. [El Rouby, Nihal M.; McDonough, Caitrin W.; Cooper-DeHoff, Rhonda M.; Johnson, Julie A.] Univ Florida, Coll Pharm, Ctr Pharmacogen, Gainesville, FL USA. [Bielinski, Suzette J.] Mayo Clin, Div Epidemiol, Rochester, MN USA. [Basford, Melissa A.] Vanderbilt Univ, Res Off, 221 Kirkland Hall, Nashville, TN 37235 USA. [Chai, High Seng; Pathak, Jyotishman; Matsumoto, Martha; de Andrade, Mariza] Mayo Clin, Div Biomed Stat & Informat, Dept Hlth Sci Res, Rochester, MN USA. [Peissig, Peggy] Marshfield Clin Res Fdn, Biomed Informat Res Ctr, Marshfield, WI USA. [Carrell, David; Larson, Eric B.] Grp Hlth Res Inst, Seattle, WA USA. [Rasmussen, Luke V.] Northwestern Univ, Dept Prevent Med, Div Hlth & Biomed Informat, Chicago, IL 60611 USA. [Pacheco, Jennifer A.; Smith, Maureen E.; Chisholm, Rex L.] Northwestern Univ, Ctr Genet Med, Chicago, IL 60611 USA. [Kho, Abel N.; Hayes, M. Geoffrey] Northwestern Univ, Dept Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Li, Rongling] NHGRI, Div Genom Med, Bethesda, MD 20892 USA. [Cooper-DeHoff, Rhonda M.; Crawford, Dana C.] Case Western Reserve Univ, Inst Computat Biol, Epidemiol & Biostat, Cleveland, OH 44106 USA. [Kullo, Iftikhar J.] Mayo Clin, Dept Cardiovasc Dis, Rochester, MN USA. [Chute, Christopher G.] Johns Hopkins Univ, Div Gen Internal Med, Baltimore, MD USA. [Jarvik, Gail P.] Univ Washington, Med Ctr, Dept Med, Seattle, WA 98195 USA. [Carey, David] Geisinger Hlth Syst, Weis Ctr Res, Danville, PA USA. [McCarty, Catherine A.] Essentia Inst Rural Hlth, Duluth, MN USA. [Williams, Marc S.] Geisinger Hlth Syst, Genom Med Inst, Danville, PA USA. [Roden, Dan M.] Vanderbilt Univ, Dept Pharmacol, Nashville, TN USA. [Bottinger, Erwin] Mt Sinai, Charles R Bronfman Inst Personalized Med, New York, NY USA. [Johnson, Julie A.] Univ Florida, Coll Med, Div Cardiovasc Med, Gainesville, FL USA. RP Crawford, DC (reprint author), Case Western Reserve Univ, Inst Computat Biol, Epidemiol & Biostat, Cleveland, OH 44106 USA. EM dana.crawford@case.edu FU NHGRI; NIGMS [U01HG04599, U01HG006379, U01HG004610, U01HG006375, U01HG004608, U01HG004609, U01HG006388, U01HG04603, U01HG006378, U01HG006385, U01HG006382, U01HG006380, U01HG006830, U01HG006828]; Vanderbilt CTSA grant from NCATS/NIH [UL1 TR000445]; Mayo Clinic Biobank - Mayo Clinic Center for Individualized Medicine; NIH [R01 HL074730, U01 GM074492, U01 NS038529, R01 NS073346]; [KL2 TR001429] FX The eMERGE Network is funded by NHGRI, with additional funding from NIGMS through the following grants: U01HG04599 and U01HG006379 to Mayo Clinic; U01HG004610 and U01HG006375 to Group Health Cooperative and University of Washington, Seattle; U01HG004608 to Marshfield Clinic; U01HG006389 to Essentia Institute of Rural Health; U01HG004609 and U01HG006388 to Northwestern University; U01HG04603 and U01HG006378 to Vanderbilt University; U01HG006385 to the Coordinating Center; U01HG006382 to Geisinger Clinic; U01HG006380 to Mount Sinai School of Medicine; U01HG006830 to The Children's Hospital of Philadelphia; and U01HG006828 to Cincinnati Children's Hospital and Boston Children's Hospital. A portion of the dataset(s) used for the analyses described were obtained from Vanderbilt University Medical Centers BioVU, supported by institutional funding and by the Vanderbilt CTSA grant UL1 TR000445 from NCATS/NIH, and the Mayo Clinic Biobank supported by the Mayo Clinic Center for Individualized Medicine. INVEST-GENES was funded by NIH grants R01 HL074730 and U01 GM074492. SPS3 and SPS3-GENES were funded by NIH grants U01 NS038529, U01 GM074492, and R01 NS073346. CWM was also supported by KL2 TR001429. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 93 TC 0 Z9 0 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 FEB 21 PY 2017 VL 12 IS 2 AR e0171745 DI 10.1371/journal.pone.0171745 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EL5QV UT WOS:000394676800017 PM 28222112 ER PT J AU Ulmer, B Tingler, M Kurz, S Maerker, M Andre, P Monch, D Campione, M Deissler, K Lewandoski, M Thumberger, T Schweickert, A Fainsod, A Steinbeisser, H Blum, M AF Ulmer, Baerbel Tingler, Melanie Kurz, Sabrina Maerker, Markus Andre, Philipp Moench, Dina Campione, Marina Deissler, Kirsten Lewandoski, Mark Thumberger, Thomas Schweickert, Axel Fainsod, Abraham Steinbeisser, Herbert Blum, Martin TI A novel role of the organizer gene Goosecoid as an inhibitor of Wnt/PCP-mediated convergent extension in Xenopus and mouse SO SCIENTIFIC REPORTS LA English DT Article ID PLANAR-CELL-POLARITY; NEURAL-TUBE CLOSURE; HOMEOBOX GENE; SIGNALING PATHWAYS; MARGINAL ZONE; SUBCELLULAR-LOCALIZATION; VERTEBRATE EMBRYOS; SPEMANNS ORGANIZER; AMPHIOXUS GENOME; GASTRULATION AB Goosecoid (Gsc) expression marks the primary embryonic organizer in vertebrates and beyond. While functions have been assigned during later embryogenesis, the role of Gsc in the organizer has remained enigmatic. Using conditional gain-of-function approaches in Xenopus and mouse to maintain Gsc expression in the organizer and along the axial midline, neural tube closure defects (NTDs) arose and dorsal extension was compromised. Both phenotypes represent convergent extension (CE) defects, arising from impaired Wnt/planar cell polarity (PCP) signaling. Dvl2 recruitment to the cell membrane was inhibited by Gsc in Xenopus animal cap assays and key Wnt/PCP factors (RhoA, Vangl2, Prickle, Wnt11) rescued Gsc-mediated NTDs. Re-evaluation of endogenous Gsc functions in MO-mediated gene knockdown frog and knockout mouse embryos unearthed PCP/CE-related phenotypes as well, including cartilage defects in Xenopus and misalignment of inner ear hair cells in mouse. Our results assign a novel function to Gsc as an inhibitor of Wnt/PCP-mediated CE. We propose that in the organizer Gsc represses CE as well: Gsc-expressing prechordal cells, which leave the organizer first, migrate and do not undergo CE like the Gsc-negative notochordal cells, which subsequently emerge from the organizer. In this model, Gsc provides a switch between cell migration and CE, i.e. cell intercalation. C1 [Ulmer, Baerbel; Tingler, Melanie; Kurz, Sabrina; Maerker, Markus; Andre, Philipp; Moench, Dina; Campione, Marina; Deissler, Kirsten; Thumberger, Thomas; Schweickert, Axel; Blum, Martin] Univ Hohenheim, Garbenstr 30, D-70599 Stuttgart, Germany. [Lewandoski, Mark] NCI, Canc & Dev Biol Lab, Genet Vertebrate Dev Sect, NIH, Frederick, MD 21702 USA. [Fainsod, Abraham] Hebrew Univ Jerusalem, Inst Med Res Israel Canada, Dept Dev Biol & Canc Res, IL-9112102 Jerusalem, Israel. [Steinbeisser, Herbert] Univ Heidelberg Hosp, Inst Human Genet, Neuenheimer Feld 366, D-69120 Heidelberg, Germany. [Ulmer, Baerbel] Univ Med Ctr Hamburg Eppendorf, Cardiovasc Res Ctr, Dept Expt Pharmacol & Toxicol, D-20246 Hamburg, Germany. [Campione, Marina] Univ Padua, CNR, Inst Neurosci, Dept Biomed Sci, I-35100 Padua, Italy. [Thumberger, Thomas] Heidelberg Univ, Ctr Organismal Studies COS Heidelberg, Neuenheimer Feld 230, D-69120 Heidelberg, Germany. RP Blum, M (reprint author), Univ Hohenheim, Garbenstr 30, D-70599 Stuttgart, Germany. EM martin.blum@uni-hohenheim.de FU Volkswagen Foundation; Landesgraduiertenforderung Baden-Wurttemberg FX This paper is dedicated to the memory of the late Herbert Steinbeiber, who passed away in 2014. He was involved in this project from its beginning in the 1990 s; the Dvl2 membrane recruitment experiments in animal caps were performed in his laboratory. We thank all members of the Blum lab for continuous support and suggestions. Verena Andre, Andreas Faissler, Simone Kienle, Anna Schafer and Susanne Seitz helped with some of the experiments. This work was supported by a grant from the Volkswagen Foundation to MB and a fellowship from the Landesgraduiertenforderung Baden-Wurttemberg to BU. NR 92 TC 0 Z9 0 U1 3 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 FEB 21 PY 2017 VL 7 AR 43010 DI 10.1038/srep43010 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EL5ZA UT WOS:000394699000001 PM 28220837 ER PT J AU Kwon, EM Connelly, JP Hansen, NF Donovan, FX Winkler, T Davis, BW Alkadi, H Chandrasekharappa, SC Dunbar, CE Mullikin, JC Liu, P AF Kwon, Erika M. Connelly, John P. Hansen, Nancy F. Donovan, Frank X. Winkler, Thomas Davis, Brian W. Alkadi, Halah Chandrasekharappa, Settara C. Dunbar, Cynthia E. Mullikin, James C. Liu, Paul TI iPSCs and fibroblast subclones from the same fibroblast population contain comparable levels of sequence variations SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE iPSCs; fibroblasts; reprogramming; genomic variation; exome sequencing ID PLURIPOTENT STEM-CELLS; COPY NUMBER VARIATION; HUMAN GENOME; SOMATIC MOSAICISM; CODING MUTATIONS; EXPRESSION AB Genome integrity of induced pluripotent stem cells (iPSCs) has been extensively studied in recent years, but it is still unclear whether iPSCs contain more genomic variations than cultured somatic cells. One important question is the origin of genomic variations detected in iPSCs-whether iPSC reprogramming induces such variations. Here, we undertook a unique approach by deriving fibroblast subclones and clonal iPSC lines from the same fibroblast population and applied next-generation sequencing to compare genomic variations in these lines. Targeted deep sequencing of parental fibroblasts revealed that most variants detected in clonal iPSCs and fibroblast subclones were rare variants inherited from the parental fibroblasts. Only a small number of variants remained undetectable in the parental fibroblasts, which were thus likely to be de novo. Importantly, the clonal iPSCs and fibroblast subclones contained comparable numbers of de novo variants. Collectively, our data suggest that iPSC reprogramming is not mutagenic. C1 [Kwon, Erika M.; Connelly, John P.; Alkadi, Halah; Liu, Paul] NHGRI, Oncogenesis & Dev Sect, NIH, Bethesda, MD 20892 USA. [Hansen, Nancy F.; Mullikin, James C.] NHGRI, Comparat Genom Unit, NIH Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. [Donovan, Frank X.; Chandrasekharappa, Settara C.] NHGRI, Genom Core, NIH, Bethesda, MD 20892 USA. [Winkler, Thomas; Dunbar, Cynthia E.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Davis, Brian W.] NHGRI, Canc Genet & Comparat Genom Branch, Bethesda, MD 20892 USA. [Connelly, John P.] Washington Univ, Genome Engn & iPSC Ctr, St Louis, MO 63110 USA. RP Liu, P (reprint author), NHGRI, Oncogenesis & Dev Sect, NIH, Bethesda, MD 20892 USA. EM pliu@mail.nih.gov FU Intramural Research Programs of National Human Genome Research Institute; National Heart, Lung, and Blood Institute, NIH FX We thank Dionyssia Clagett (Georgetown University) for establishing fibroblast lines from patients with FPD, Ms. Ursula Harper for performing short tandem repeat mapping for sample identify confirmation, members of the NIH Intramural Sequencing Center for their support on WES and targeted sequencing, and Julia Fekecs for expert design of Fig. 1. The research was supported by the Intramural Research Programs of National Human Genome Research Institute and National Heart, Lung, and Blood Institute, NIH. NR 32 TC 0 Z9 0 U1 2 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 21 PY 2017 VL 114 IS 8 BP 1964 EP 1969 DI 10.1073/pnas.1616035114 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EM1TI UT WOS:000395099500075 PM 28167771 ER PT J AU Kurth, EG Peremyslov, VV Turner, HL Makarova, KS Iranzo, J Mekhedov, SL Koonin, EV Dolja, VV AF Kurth, Elizabeth G. Peremyslov, Valera V. Turner, Hannah L. Makarova, Kira S. Iranzo, Jaime Mekhedov, Sergei L. Koonin, Eugene V. Dolja, Valerian V. TI Myosin-driven transport network in plants SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE myosins; receptors; adaptors; cytoplasmic streaming; nuclear transport ID CLASS-XI MYOSINS; F-ACTIN ORGANIZATION; ROOT HAIR; CELL EXPANSION; ARABIDOPSIS; PROTEIN; TRAFFICKING; MEMBRANE; MOTILITY; DOMAIN AB We investigate the myosin XI-driven transport network in Arabidopsis using protein-protein interaction, subcellular localization, gene knockout, and bioinformatics analyses. The two major groups of nodes in this network are myosins XI and their membrane-anchored receptors (MyoB) that, together, drive endomembrane trafficking and cytoplasmic streaming in the plant cells. The network shows high node connectivity and is dominated by generalists, with a smaller fraction of more specialized myosins and receptors. We show that interaction with myosins and association with motile vesicles are common properties of the MyoB family receptors. We identify previously uncharacterized myosin-binding proteins, putative myosin adaptors that belong to two unrelated families, with four members each (MadA and MadB). Surprisingly, MadA1 localizes to the nucleus and is rapidly transported to the cytoplasm, suggesting the existence of myosin XI-driven nucleocytoplasmic trafficking. In contrast, MadA2 and MadA3, as well as MadB1, partition between the cytosolic pools of motile endomembrane vesicles that colocalize with myosin XI-K and diffuse material that does not. Gene knockout analysis shows that MadB1-4 contribute to polarized root hair growth, phenocopying myosins, whereas MadA1-4 are redundant for this process. Phylogenetic analysis reveals congruent evolutionary histories of the myosin XI, MyoB, MadA, and MadB families. All these gene families emerged in green algae and show concurrent expansions via serial duplication in flowering plants. Thus, the myosin XI transport network increased in complexity and robustness concomitantly with the land colonization by flowering plants and, by inference, could have been a major contributor to this process. C1 [Kurth, Elizabeth G.; Peremyslov, Valera V.; Turner, Hannah L.; Dolja, Valerian V.] Oregon State Univ, Dept Bot & Plant Pathol, Corvallis, OR 97331 USA. [Makarova, Kira S.; Iranzo, Jaime; Mekhedov, Sergei L.; Koonin, Eugene V.; Dolja, Valerian V.] Natl Inst Hlth, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Dolja, Valerian V.] Oregon State Univ, Ctr Genome Res & Biocomp, Corvallis, OR 97331 USA. RP Koonin, EV; Dolja, VV (reprint author), Natl Inst Hlth, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA.; Dolja, VV (reprint author), Oregon State Univ, Ctr Genome Res & Biocomp, Corvallis, OR 97331 USA. EM koonin@ncbi.nlm.nih.gov; doljav@oregonstate.edu FU US-Israel Binational Science Foundation [2013084]; US Department of Health and Human Services FX We thank Prof. Viktor Zarsky for critical reading of the manuscript and helpful suggestions. V.V.D. is a Fellow, Scientific Visitors Program, National Center for Biotechnology Information, NIH. The work in the V.V.D. laboratory was supported, in part, by US-Israel Binational Science Foundation Award 2013084. The research in group of E.V.K. is supported by intramural funds of the US Department of Health and Human Services (to the National Library of Medicine). NR 53 TC 1 Z9 1 U1 2 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 21 PY 2017 VL 114 IS 8 BP E1385 EP E1394 DI 10.1073/pnas.1620577114 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EM1TI UT WOS:000395099500011 PM 28096376 ER PT J AU DeFilippis, AP Young, R McEvoy, JW Michos, ED Sandfort, V Kronmal, RA McClelland, RL Blaha, MJ AF DeFilippis, Andrew Paul Young, Rebekah McEvoy, John W. Michos, Erin D. Sandfort, Veit Kronmal, Richard A. McClelland, Robyn L. Blaha, Michael J. TI Risk score overestimation: the impact of individual cardiovascular risk factors and preventive therapies on the performance of the American Heart Association-American College of Cardiology-Atherosclerotic Cardiovascular Disease risk score in a modern multi-ethnic cohort SO EUROPEAN HEART JOURNAL LA English DT Article DE Cardiovascular risk prediction; Prevention; Risk factors ID POPULATION; VALIDATION; GUIDELINES; STATINS; DESIGN AB Aims To evaluate the 2013 American Heart Association (AHA)-American College of Cardiology (ACC)-Atherosclerotic Cardiovascular Disease (ASCVD) risk score among four different race/ethnic groups and to ascertain which factors are most associated with risk overestimation by the AHA-ACC-ASCVD score. Methods and results The Multi-Ethnic Study of Atherosclerosis (MESA), a prospective community-based cohort, was used to examine calibration and discrimination of the AHA-ACC-ASCVD risk score in 6441 White, Black, Chinese, and Hispanic Americans (aged 45-79 years and free of known ASCVD at baseline). Using univariable and multivariable absolute risk regression, we modelled the impact of individual risk factors on the discordance between observed and predicted 10-year ASCVD risk. Overestimation was observed in all race/ethnic groups in MESA and was highest among Chinese (252% for women and 314% for men) and lowest in White women (72%) and Hispanic men (67%). Higher age, Chinese race/ethnicity (when compared with White), systolic blood pressure (treated and untreated), diabetes, alcohol use, exercise, lipid-lowering medication, and aspirin use were all associated with more risk overestimation, whereas family history was associated with less risk overestimation in a multivariable model (all P< 0.05). Conclusion The AHA-ACC-ASCVD risk score overestimates ASCVD risk among men, women, and all four race/ethnic groups evaluated in a modern American primary prevention cohort. Clinicians treating patients similar to those in MESA, particularly older individuals and those with factors associated with more risk overestimation, may consider interpreting absolute ASCVD risk estimates with caution. C1 [DeFilippis, Andrew Paul] Jewish Hosp, Louisville, KY 40202 USA. [DeFilippis, Andrew Paul; McEvoy, John W.; Michos, Erin D.; Blaha, Michael J.] Johns Hopkins Ciccarone Ctr Prevent Heart Dis, Baltimore, MD 21287 USA. [DeFilippis, Andrew Paul] Univ Louisville, Div Cardiovasc Med, 550 South Jackson St, Louisville, KY 40202 USA. [Young, Rebekah; Kronmal, Richard A.; McClelland, Robyn L.] Univ Washington, Seattle, WA 98195 USA. [Sandfort, Veit] NIH, Bldg 10, Bethesda, MD 20892 USA. RP DeFilippis, AP (reprint author), Jewish Hosp, Louisville, KY 40202 USA.; DeFilippis, AP (reprint author), Johns Hopkins Ciccarone Ctr Prevent Heart Dis, Baltimore, MD 21287 USA.; DeFilippis, AP (reprint author), Univ Louisville, Div Cardiovasc Med, 550 South Jackson St, Louisville, KY 40202 USA. EM apdefi01@louisville.edu FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169]; NCRR [UL1-TR-000040, UL1-TR-001079] FX This research was supported by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 from the National Heart, Lung, and Blood Institute and by grants UL1-TR-000040 and UL1-TR-001079 from NCRR. NR 22 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD FEB 21 PY 2017 VL 38 IS 8 BP 598 EP 608 DI 10.1093/eurheartj/ehw301 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EO6EL UT WOS:000396784600007 PM 27436865 ER PT J AU Fradkin, JE Rodgers, GP AF Fradkin, Judith E. Rodgers, Griffin P. TI Glycemic Therapy for Type 2 Diabetes: Choices Expand, Data Lag Behind SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID DRUGS C1 [Fradkin, Judith E.; Rodgers, Griffin P.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Fradkin, Judith E.] MSC 2560,6707 Democracy Blvd, Bethesda, MD 20892 USA. [Rodgers, Griffin P.] 31 Ctr Dr,Room 9A52, Bethesda, MD 20892 USA. RP Fradkin, JE (reprint author), MSC 2560,6707 Democracy Blvd, Bethesda, MD 20892 USA. EM judith.fradkin@nih.gov NR 9 TC 0 Z9 0 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD FEB 21 PY 2017 VL 166 IS 4 BP 309 EP + DI 10.7326/M16-2883 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA EL7FO UT WOS:000394786700026 PM 28055042 ER PT J AU McCullough, LE Chen, J Cho, YH Khankari, NK Bradshaw, PT White, AJ Teitelbaum, SL Terry, MB Neugut, AI Hibshoosh, H Santella, RM Gammon, MD AF McCullough, Lauren E. Chen, Jia Cho, Yoon Hee Khankari, Nikhil K. Bradshaw, Patrick T. White, Alexandra J. Teitelbaum, Susan L. Terry, Mary Beth Neugut, Alfred I. Hibshoosh, Hanina Santella, Regina M. Gammon, Marilie D. TI Modification of the association between recreational physical activity and survival after breast cancer by promoter methylation in breast cancer-related genes SO BREAST CANCER RESEARCH LA English DT Article DE Physical activity; Epigenetics; Methylation; Breast cancer; Survival ID CPG ISLAND HYPERMETHYLATION; DNA METHYLATION; LONG-ISLAND; CELL; TUMOR; TIME; EXPRESSION; SUBTYPES; CARCINOGENESIS; EPIGENETICS AB Background: Mechanisms underlying the inverse association between physical activity and survival after breast cancer are unresolved, but DNA methylation may play a role. We hypothesized that promoter methylation of breast cancer-related genes, as well as global methylation, may modify the association between prediagnostic recreational physical activity (RPA) and breast cancer mortality. Methods: Using a population-based sample of 1254 women diagnosed with first primary breast cancer, we examined modification of the RPA-mortality association by gene-specific promoter methylation and global methylation. Average lifetime RPA was assessed from menarche to diagnosis through structured in-home interviews. Promoter methylation of 13 breast cancer-related genes was evaluated in archived tumor by methylation-specific polymerase chain reaction and MethyLight assay. Global methylation in white blood cell DNA was determined at long interspersed nucleotide element 1 and by the luminometric methylation assay. After approximately 15 years of follow-up, 486 patients had died, and 186 of the deaths were breast cancer-related. We used Cox proportional hazards regression to estimate HRs and 95% CIs as well as likelihood ratio tests to assess multiplicative interactions. Results: All-cause mortality was lower only among physically active women with methylated promoter of APC (HR 0.60, 95% CI 0.40-0.80), CCND2 (HR 0.56, 95% CI 0.32-0.99), HIN (HR 0.55, 95% CI 0.38-0.80), and TWIST1 (HR 0.28, 95% CI 0.14-0.56) in tumors, but not among those with unmethylated tumors (significant interaction p < 0.05). We found no interaction between RPA and global methylation. Conclusions: The improved survival after breast cancer that is associated with RPA may be more pronounced in women with promoter tumor methylation in biologically plausible genes. C1 [McCullough, Lauren E.] Emory Univ, Dept Epidemiol, Atlanta, GA 30322 USA. [Chen, Jia; Teitelbaum, Susan L.] Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY 10029 USA. [Chen, Jia] Icahn Sch Med Mt Sinai, Dept Pediat, New York, NY 10029 USA. [Chen, Jia] Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA. [Cho, Yoon Hee] Univ Montana, Dept Biomed & Pharmaceut Sci, Missoula, MT 59812 USA. [Khankari, Nikhil K.] Vanderbilt Univ, Med Ctr, Div Epidemiol, Nashville, TN 37203 USA. [Bradshaw, Patrick T.] Univ Calif Berkeley, Div Epidemiol, Berkeley, CA 94720 USA. [White, Alexandra J.] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Terry, Mary Beth; Neugut, Alfred I.] Columbia Univ, Dept Epidemiol, New York, NY 10032 USA. [Neugut, Alfred I.] Columbia Univ, Dept Med, New York, NY 10032 USA. [Hibshoosh, Hanina] Columbia Univ, Dept Pathol, New York, NY 10032 USA. [Santella, Regina M.] Columbia Univ, Dept Environm Hlth Sci, New York, NY 10032 USA. [Gammon, Marilie D.] Univ North Carolina Chapel Hill, Dept Epidemiol, Chapel Hill, NC 27599 USA. RP McCullough, LE (reprint author), Emory Univ, Dept Epidemiol, Atlanta, GA 30322 USA. EM lauren.mccullough@emory.edu FU National Institutes of Health [R25CA057726, U01CA/ES66572, R01CA66572, R01CA109753, 3R01CA109753-04S1, P30ES009089, P30ES10126]; U.S. Department of Defense [BC972772]; Intramural Research Program of the National Institutes of Health through the National Institute of Environmental Health Sciences FX This work was supported in part by grants from the National Institutes of Health (R25CA057726, U01CA/ES66572, R01CA66572, R01CA109753, 3R01CA109753-04S1, P30ES009089, P30ES10126) and the U.S. Department of Defense (BC972772). This research was also supported in part by the Intramural Research Program of the National Institutes of Health through the National Institute of Environmental Health Sciences. NR 56 TC 0 Z9 0 U1 4 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-542X EI 1465-5411 J9 BREAST CANCER RES JI Breast Cancer Res. PD FEB 21 PY 2017 VL 19 AR 19 DI 10.1186/s13058-017-0811-z PG 11 WC Oncology SC Oncology GA EL7UB UT WOS:000394825000001 PM 28222775 ER PT J AU Mattapallil, MJ Caspi, RR AF Mattapallil, Mary J. Caspi, Rachel R. TI Compliments of Factor H: What's in it for AMD? SO IMMUNITY LA English DT Editorial Material ID MACULAR DEGENERATION AB Genetic variations in complement factor H (CFH) confer greater risk for age-related macular degeneration (AMD). In this issue of Immunity, Calippe et al. (2017) uncover a non-canonical role for CFH in the inhibition of mononuclear phagocyte elimination from sub-retinal lesions, providing insight into the pathophysiology of AMD associated with CFH variants. C1 [Mattapallil, Mary J.; Caspi, Rachel R.] NEI, Bethesda, MD 20892 USA. RP Caspi, RR (reprint author), NEI, Bethesda, MD 20892 USA. EM caspir@nei.nih.gov FU NIH/NEI Intramural grant [ZIA EY000184-34] FX NIH/NEI Intramural grant ZIA EY000184-34 (R.R.C.) provided funding for this research. NR 9 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD FEB 21 PY 2017 VL 46 IS 2 BP 167 EP 169 DI 10.1016/j.immuni.2017.02.008 PG 4 WC Immunology SC Immunology GA EO0TM UT WOS:000396410900003 PM 28228273 ER PT J AU Brewitz, A Eickhoff, S Dahling, S Quast, T Bedoui, S Kroczek, RA Kurts, C Garbi, N Barchet, W Iannacone, M Klauschen, F Kolanus, W Kaisho, T Colonna, M Germain, RN Kastenmuller, W AF Brewitz, Anna Eickhoff, Sarah Daehling, Sabrina Quast, Thomas Bedoui, Sammy Kroczek, Richard A. Kurts, Christian Garbi, Natalio Barchet, Winfried Iannacone, Matteo Klauschen, Frederick Kolanus, Waldemar Kaisho, Tsuneyasu Colonna, Marco Germain, Ronald N. Kastenmueller, Wolfgang TI CD8(+) T Cells Orchestrate pDC-XCR1(+) Dendritic Cell Spatial and Functional Cooperativity to Optimize Priming SO IMMUNITY LA English DT Article ID LYMPH-NODES; ANTIVIRAL IMMUNITY; CROSS-PRESENTATION; VIRAL-INFECTION; VIRUS-INFECTION; IFN-GAMMA; IN-VIVO; ACTIVATION; ANTIGEN; CD4(+) AB Adaptive cellular immunity is initiated by antigenspecific interactions between T lymphocytes and dendritic cells (DCs). Plasmacytoid DCs (pDCs) support antiviral immunity by linking innate and adaptive immune responses. Here we examined pDC spatiotemporal dynamics during viral infection to uncover when, where, and how they exert their functions. We found that pDCs accumulated at sites of CD8(+) T cell antigen-driven activation in a CCR5-dependent fashion. Furthermore, activated CD8(+) T cells orchestrated the local recruitment of lymph node-resident XCR1 chemokine receptor-expressing DCs via secretion of the XCL1 chemokine. Functionally, this CD8+ T cell-mediated reorganization of the local DC network allowed for the interaction and cooperation of pDCs and XCR1(+) DCs, thereby optimizing XCR1(+) DC maturation and cross-presentation. These data support a model in which CD8(+) T cells upon activation create their own optimal priming microenvironment by recruiting additional DC subsets to the site of initial antigen recognition. C1 [Brewitz, Anna; Eickhoff, Sarah; Daehling, Sabrina; Kurts, Christian; Garbi, Natalio; Kastenmueller, Wolfgang] Univ Bonn, Inst Expt Immunol, D-53127 Bonn, Germany. [Quast, Thomas; Kolanus, Waldemar] Univ Bonn, Mol Immunol & Cell Biol Life & Med Sci Inst, D-53115 Bonn, Germany. [Bedoui, Sammy] Univ Melbourne, Peter Doherty Inst Infect & Immun, Dept Microbiol & Immunol, Parkville, Vic 3010, Australia. [Kroczek, Richard A.] Robert Koch Inst, Mol Immunol, D-13353 Berlin, Germany. [Barchet, Winfried] Univ Bonn, Inst Clin Chem & Clin Pharmacol, D-53127 Bonn, Germany. [Iannacone, Matteo] Univ Vita Salute San Raffaele, Div Immunol Transplantat & Infect Dis, Via Olgettina 58, I-20132 Milan, Italy. [Iannacone, Matteo] Univ Vita Salute San Raffaele, Expt Imaging Ctr, IRCCS San Raffaele Sci Inst, Via Olgettina 58, I-20132 Milan, Italy. [Klauschen, Frederick] Charite, Inst Pathol, CharitePlatz 1, D-10117 Berlin, Germany. [Klauschen, Frederick] Einstein Fdn Berlin, D-10117 Berlin, Germany. [Kaisho, Tsuneyasu] Wakayama Med Univ, Inst Adv Med, Dept Immunol, Wakayama 6418509, Japan. [Kaisho, Tsuneyasu] RIKEN Ctr Integrat Med Sci IMS RCAI, Lab Inflammatory Regulat, Yokohama, Kanagawa 2300045, Japan. [Kaisho, Tsuneyasu] Osaka Univ, World Premier Int Res Ctr Initiat, Immunol Frontier Res Ctr, Lab Immune Regulat, Suita, Osaka 5650871, Japan. [Colonna, Marco] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63108 USA. [Germain, Ronald N.] Natl Inst Allergy & Infect Dis, Lab Syst Biol, Lymphocyte Biol Sect, NIH, Bethesda, MD 20892 USA. [Brewitz, Anna; Eickhoff, Sarah; Daehling, Sabrina; Kurts, Christian; Garbi, Natalio; Kastenmueller, Wolfgang] Univ Hosp, Inst Expt Immunol, D-53127 Bonn, Germany. [Barchet, Winfried; Kastenmueller, Wolfgang] Univ Hosp, Inst Clin Chem & Clin Pharmacol, D-53127 Bonn, Germany. RP Kastenmuller, W (reprint author), Univ Bonn, Inst Expt Immunol, D-53127 Bonn, Germany.; Kastenmuller, W (reprint author), Univ Hosp, Inst Expt Immunol, D-53127 Bonn, Germany.; Kastenmuller, W (reprint author), Univ Hosp, Inst Clin Chem & Clin Pharmacol, D-53127 Bonn, Germany. EM wkastenm@uni-bonn.de FU NRW-Ruckkehrerprogramm of the German state of Northrhine-Westfalia; Kishimoto Foundation; Japan Society for the Promotion of Science (JSPS) [26293106]; Einstein Foundation Berlin; Intramural Research Program, NIAID, NIH; DFG Graduate program [2168/1]; [SFB704] FX We would like to thank S. Ebbinghaus and S. Rathmann for technical assistance and D.H. Busch for kindly providing MHCI multimers. This research was supported by the Intramural Research Program, NIAID, NIH. W. Kastenmuller, N.G., C.K., and W. Kolanus are members of the DFG Excellence Cluster ImmunoSensation in Bonn, Germany, and are supported by grant SFB704. S.D., S.B., and W. Kastenmuller are supported by the DFG Graduate program 2168/1 (Bo&MeRang). W. Kastenmuller is supported by NRW-Ruckkehrerprogramm of the German state of Northrhine-Westfalia. T.K. was supported by the Kishimoto Foundation and a Grant-in-Aid for Scientific Research (B) from Japan Society for the Promotion of Science (JSPS, 26293106). F.K. is supported by the Einstein Foundation Berlin (JF-Klauschen-2014). NR 47 TC 1 Z9 1 U1 4 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD FEB 21 PY 2017 VL 46 IS 2 BP 205 EP 219 DI 10.1016/j.immuni.2017.01.003 PG 15 WC Immunology SC Immunology GA EO0TM UT WOS:000396410900010 PM 28190711 ER PT J AU Paules, CI Fauci, AS AF Paules, Catharine I. Fauci, Anthony S. TI Emerging and Reemerging Infectious Diseases The Dichotomy Between Acute Outbreaks and Chronic Endemicity SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID ZIKA VIRUS-INFECTION; WEST NILE VIRUS C1 [Paules, Catharine I.; Fauci, Anthony S.] NIAID, Off Director, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Fauci, AS (reprint author), NIAID, 31 Ctr Dr,MSC 2520,Bldg 31,Room 7A-03, Bethesda, MD 20892 USA. EM afauci@niaid.nih.gov NR 7 TC 0 Z9 0 U1 3 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 21 PY 2017 VL 317 IS 7 BP 691 EP 692 DI 10.1001/jama.2016.21079 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA EL8WR UT WOS:000394901600011 PM 28097318 ER PT J AU Resnick, SM Matsumoto, AM Stephens-Shields, AJ Ellenberg, SS Gill, TM Shumaker, SA Pleasants, DD Barrett-Connor, E Bhasin, S Cauley, JA Cella, D Crandall, JP Cunningham, GR Ensrud, KE Farrar, JT Lewis, CE Molitch, ME Pahor, M Swerdloff, RS Cifelli, D Anton, S Basaria, S Diem, SJ Wang, C Hou, XL Snyder, PJ AF Resnick, Susan M. Matsumoto, Alvin M. Stephens-Shields, Alisa J. Ellenberg, Susan S. Gill, Thomas M. Shumaker, Sally A. Pleasants, Debbie D. Barrett-Connor, Elizabeth Bhasin, Shalender Cauley, Jane A. Cella, David Crandall, Jill P. Cunningham, Glenn R. Ensrud, Kristine E. Farrar, John T. Lewis, Cora E. Molitch, Mark E. Pahor, Marco Swerdloff, Ronald S. Cifelli, Denise Anton, Stephen Basaria, Shehzad Diem, Susan J. Wang, Christina Hou, Xiaoling Snyder, Peter J. TI Testosterone Treatment and Cognitive Function in Older Men With Low Testosterone and Age-Associated Memory Impairment SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID SERUM TESTOSTERONE; SEX-HORMONES; ALZHEIMER-DISEASE; VERBAL MEMORY; ELDERLY-MEN; SUPPLEMENTATION; TRIAL; PERFORMANCE; DEPRESSION AB IMPORTANCE Most cognitive functions decline with age. Prior studies suggest that testosterone treatment may improve these functions. OBJECTIVE To determine if testosterone treatment compared with placebo is associated with improved verbal memory and other cognitive functions in older men with low testosterone and age-associated memory impairment (AAMI). DESIGN, SETTING, AND PARTICIPANTS The Testosterone Trials (TTrials) were 7 trials to assess the efficacy of testosterone treatment in older men with low testosterone levels. The Cognitive Function Trial evaluated cognitive function in all TTrials participants. In 12 US academic medical centers, 788 men who were 65 years or older with a serum testosterone level less than 275 ng/mL and impaired sexual function, physical function, or vitality were allocated to testosterone treatment (n = 394) or placebo (n = 394). A subgroup of 493 men met criteria for AAMI based on baseline subjective memory complaints and objective memory performance. Enrollment in the TTrials began June 24, 2010; the final participant completed treatment and assessment in June 2014. INTERVENTIONS Testosterone gel (adjusted to maintain the testosterone level within the normal range for young men) or placebo gel for 1 year. MAIN OUTCOMES AND MEASURES The primary outcome was the mean change from baseline to 6 months and 12 months for delayed paragraph recall (score range, 0 to 50) among men with AAMI. Secondary outcomes were mean changes in visual memory (Benton Visual Retention Test; score range, 0 to -26), executive function (Trail-Making Test B minus A; range, -290 to 290), and spatial ability (Card Rotation Test; score range, -80 to 80) among men with AAMI. Tests were administered at baseline, 6 months, and 12 months. RESULTS Among the 493 men with AAMI (mean age, 72.3 years [SD, 5.8]; mean baseline testosterone, 234 ng/dL [SD, 65.1]), 247were assigned to receive testosterone and 246 to receive placebo. Of these groups, 247 men in the testosterone group and 245 men in the placebo completed the memory study. There was no significant mean change from baseline to 6 and 12 months in delayed paragraph recall score among men with AAMI in the testosterone and placebo groups (adjusted estimated difference, -0.07 [95% CI, -0.92 to 0.79]; P = .88). Mean scores for delayed paragraph recall were 14.0 at baseline, 16.0 at 6 months, and 16.2 at 12 months in the testosterone group and 14.4 at baseline, 16.0 at 6 months, and 16.5 at 12 months in the placebo group. Testosterone was also not associated with significant differences in visual memory (-0.28 [95% CI, -0.76 to 0.19]; P = .24), executive function (-5.51 [95% CI, -12.91 to 1.88]; P = .14), or spatial ability (-0.12 [95% CI, -1.89 to 1.65]; P = .89). CONCLUSIONS AND RELEVANCE Among older men with low testosterone and age-associated memory impairment, treatment with testosterone for 1 year compared with placebo was not associated with improved memory or other cognitive functions. C1 [Snyder, Peter J.] Univ Penn, Div Endocrinol Diabet & Metab, Perelman Sch Med, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA. [Resnick, Susan M.] NIA, Lab Behav Neurosci, NIH, Baltimore, MD 21224 USA. [Matsumoto, Alvin M.] Dept Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA USA. [Matsumoto, Alvin M.] Univ Washington, Sch Med, Dept Internal Med, Div Gerontol & Geriatr Med, Seattle, WA USA. [Stephens-Shields, Alisa J.; Ellenberg, Susan S.; Hou, Xiaoling] Univ Penn, Dept Biostat & Epidemiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Gill, Thomas M.] Yale Sch Med, Div Geriatr Med, New Haven, CT USA. [Shumaker, Sally A.; Pleasants, Debbie D.; Basaria, Shehzad] Wake Forest Sch Med, Winston Salem, NC USA. [Barrett-Connor, Elizabeth] Univ Calif San Diego, Sch Med, Dept Internal Med, La Jolla, CA 92093 USA. [Barrett-Connor, Elizabeth] Univ Calif San Diego, Sch Med, Div Epidemiol, Dept Family Med & Publ Hlth, La Jolla, CA 92093 USA. [Bhasin, Shalender] Harvard Med Sch, Brigham & Womens Hosp, Res Program Mens Hlth Aging & Metab, Boston, MA USA. [Cauley, Jane A.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Cella, David] Northwestern Univ, Dept Med Social Sci, Feinberg Sch Med, Chicago, IL 60611 USA. [Crandall, Jill P.] Albert Einstein Coll Med, Div Endocrinol, Bronx, NY 10467 USA. [Crandall, Jill P.] Albert Einstein Coll Med, Div Geriatr, Bronx, NY 10467 USA. [Cunningham, Glenn R.] Baylor Coll Med, Dept Med, Div Diabet Endocrinol & Metab, Houston, TX 77030 USA. [Cunningham, Glenn R.] Baylor Coll Med, Dept Mol & Cellular Biol, Div Diabet Endocrinol & Metab, Houston, TX 77030 USA. [Cunningham, Glenn R.] Baylor St Lukes Med Ctr, Houston, TX USA. [Cunningham, Glenn R.; Ensrud, Kristine E.; Diem, Susan J.] Univ Minnesota, Dept Med, Div Epidemiol & Community Hlth, Box 736 UMHC, Minneapolis, MN 55455 USA. [Ensrud, Kristine E.] Minneapolis Vet Affairs Hlth Care Syst, Minneapolis, MN USA. [Farrar, John T.; Cifelli, Denise] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Lewis, Cora E.] Univ Alabama Birmingham, Div Prevent Med, Birmingham, AL USA. [Molitch, Mark E.] Northwestern Univ, Div Endocrinol Metab & Mol Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Pahor, Marco; Anton, Stephen] Univ Florida, Dept Aging & Geriatr Res, Gainesville, FL USA. [Swerdloff, Ronald S.; Wang, Christina] Harbor Univ Calif Los Angeles Med Ctr, Div Endocrinol, Torrance, CA USA. [Swerdloff, Ronald S.; Wang, Christina] Los Angeles Biomed Res Inst, Torrance, CA USA. RP Snyder, PJ (reprint author), Univ Penn, Div Endocrinol Diabet & Metab, Perelman Sch Med, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM pjs@mail.med.upenn.edu FU NIA/NIH [U01 AG030644, R01 AG37679]; National Heart, Lung, and Blood Institute; National Institute of Neurological Disorders and Stroke; National Institute of Child Health and Human Development; AndroGel; placebo gel; Claude D. Pepper Older Americans Independence Center (OAIC) [P30-AG013679]; Claude D. Pepper OAIC [P30AG021342]; Yale Clinical and Translational Science Award [UL1TR000142]; Department of Veterans Affairs Puget Sound Health Care System; NIA [K07AG043587]; Intramural Research Program of NIA/NIH; National Institute for Diabetes and Digestive and Kidney Diseases of NIH [DK079626]; Boston Claude D. Pepper OAIC [5P30AG031679] FX The Testosterone Trials were supported by grant U01 AG030644 from the NIA/NIH, supplemented by funds from the National Heart, Lung, and Blood Institute; National Institute of Neurological Disorders and Stroke; and National Institute of Child Health and Human Development. AbbVie provided funding, AndroGel, and placebo gel. The Boston site was partially supported by grant P30-AG013679 from the Claude D. Pepper Older Americans Independence Center (OAIC). The Yale Field Center was partially supported by grant P30AG021342 from the Claude D. Pepper OAIC and grant UL1TR000142 from the Yale Clinical and Translational Science Award. Additional support was from the Department of Veterans Affairs Puget Sound Health Care System (Dr Matsumoto); the Academic Leadership Award (K07AG043587) from the NIA (Dr Gill); the Intramural Research Program of NIA/NIH (Dr Resnick); grant DK079626 from the National Institute for Diabetes and Digestive and Kidney Diseases of NIH to the University of Alabama at Birmingham Diabetes Research and Training Center (Dr Lewis); grant R01 AG37679 from NIA/NIH (Dr Cauley); and grant 5P30AG031679 from the Boston Claude D. Pepper OAIC (Dr Bhasin). NR 37 TC 1 Z9 1 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 21 PY 2017 VL 317 IS 7 BP 717 EP 727 DI 10.1001/jama.2016.21044 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA EL8WR UT WOS:000394901600019 PM 28241356 ER PT J AU Deedwania, P Acharya, T AF Deedwania, Prakash Acharya, Tushar TI Anticoagulation in Atrial Fibrillation Is the Paradigm Really Shifting? SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE atrial fibrillation; novel oral anticoagulant agents; registry data; stroke prevention ID ANTITHROMBOTIC THERAPY; ORAL ANTICOAGULANTS; AF; MANAGEMENT; REGISTRY C1 [Deedwania, Prakash] Univ Calif San Francisco, Dept Internal Med, Div Cardiol, Fresno, CA USA. [Acharya, Tushar] NHLBI, Adv Cardiovasc Imaging Lab, Cardiovasc & Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Deedwania, P (reprint author), Univ Calif San Francisco, Dept Internal Med, Div Cardiol, Acad Off, 2335 East Kashian Lane,Suite 460, Fresno, CA 93701 USA. EM pdeedwania@fresno.ucsf.edu NR 12 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 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB 21 PY 2017 VL 69 IS 7 BP 786 EP 788 DI 10.1016/j.jacc.2016.11.062 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EN9SR UT WOS:000396340400004 PM 28209219 ER PT J AU Webb, TR Erdmann, J Stirrups, KE Stitziel, NO Masca, NGD Jansen, H Kanoni, S Nelson, CP Ferrario, PG Konig, IR Eicher, JD Johnson, AD Hamby, SE Betsholtz, C Ruusalepp, A Franzen, O Schadt, EE Bjorkegren, JLM Weeke, PE Auer, PL Schick, UM Lu, YC Zhang, H Dube, MP Goel, A Farrall, M Peloso, GM Won, HH Do, R van Iperen, E 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, C El-Mokhtari, NE Franke, A 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 Virtamo, J Nikpay, M Olivieri, O Provost, S AlQarawi, A Robertson, NR Akinsansya, KO Reilly, DF Vogt, TF Yin, W Asselbergs, FW Kooperberg, C Jackson, RD Stahl, E Muller-Nurasyid, M Strauch, K Varga, TV Waldenberger, M Zeng, LY Chowdhury, R Salomaa, V Ford, I Jukema, JW Amouyel, P Kontto, J Nordestgaard, BG Ferrieres, J Saleheen, D Sattar, N Surendran, P Wagner, A 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 Samani, NJ Schunkert, H Deloukas, P Kathiresan, S AF Webb, Thomas R. Erdmann, Jeanette Stirrups, Kathleen E. Stitziel, Nathan O. Masca, Nicholas G. D. Jansen, Henning Kanoni, Stavroula Nelson, Christopher P. Ferrario, Paola G. Koenig, Inke R. Eicher, John D. Johnson, Andrew D. Hamby, Stephen E. Betsholtz, Christer Ruusalepp, Arno Franzen, Oscar Schadt, Eric E. Bjoerkegren, Johan L. M. Weeke, Peter E. 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 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, Pier A. Duga, Stefano Marziliano, Nicola Denny, Josh C. Shaffer, Christian El-Mokhtari, Nour Eddine Franke, Andre 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. Virtamo, Jarma Nikpay, Majid Olivieri, Oliviero Provost, Sylvie AlQarawi, Alaa Robertson, Neil R. Akinsansya, Karen O. Reilly, Dermot F. Vogt, Thomas F. Yin, Wu Asselbergs, Folkert W. Kooperberg, Charles Jackson, Rebecca D. Stahl, Eli Mueller-Nurasyid, Martina Strauch, Konstantin Varga, Tibor V. Waldenberger, Melanie Zeng, Lingyao Chowdhury, Rajiv Salomaa, Veikko Ford, Ian Jukema, J. Wouter Amouyel, Philippe Kontto, Jukka Nordestgaard, Borge G. Ferrieres, Jean Saleheen, Danish Sattar, Naveed Surendran, Praveen Wagner, Aline 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. Samani, Nilesh J. Schunkert, Heribert Deloukas, Panos Kathiresan, Sekar CA Wellcome Trust Case Control MORGAM Investigators Myocardial Infarction Genetics TI Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE cholesteryl ester transfer protein; expression quantitative trait loci; genetics; genome-wide association; single nucleotide polymorphism ID GENOME-WIDE ASSOCIATION; DENSITY-LIPOPROTEIN RECEPTOR; ABDOMINAL AORTIC-ANEURYSM; HEART-DISEASE; SCAVENGER RECEPTOR; PHOSPHOLIPASE A(2); COMMON VARIANTS; CETP MASS; SR-BI; RISK AB BACKGROUND Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits. OBJECTIVES This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. METHODS In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs. RESULTS We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 x 10(-4) with a range of other diseases/traits. CONCLUSIONS We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk. (C) 2017 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. C1 [Webb, Thomas R.; Masca, Nicholas G. D.; Nelson, Christopher P.; Hamby, Stephen E.; Braund, Peter S.; Samani, Nilesh J.] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England. [Webb, Thomas R.; Masca, Nicholas G. D.; Nelson, Christopher P.; Hamby, Stephen E.; Braund, Peter S.; Thompson, John R.; Samani, Nilesh J.] Glenfield Hosp, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England. [Erdmann, Jeanette; Willenborg, Christina] Univ Lubeck, Inst Cardiogenet, Lubeck, Germany. [Erdmann, Jeanette; Ferrario, Paola G.; Koenig, Inke R.] DZHK German Res Ctr Cardiovasc Res, Lubeck, Germany. [Erdmann, Jeanette] Univ Heart Ctr Luebeck, Lubeck, Germany. 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[Akinsansya, Karen O.; Reilly, Dermot F.; Vogt, Thomas F.; Yin, Wu] Merck Sharp & Dohme Ltd, Rahway, NJ USA. [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. [Asselbergs, Folkert W.] UCL, Fac Populat Hlth Sci, Inst Cardiovasc Sci, London, England. [Jackson, Rebecca D.] Ohio State Univ, Dept Med, Div Endocrinol Diabet & Metab, Columbus, OH 43210 USA. [Stahl, Eli] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Mueller-Nurasyid, Martina; Strauch, Konstantin] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Genet Epidemiol, Neuherberg, Germany. [Mueller-Nurasyid, Martina] Ludwig Maximilians Univ Munchen, Dept Med 1, Univ Hosp Grosshadern, Munich, Germany. [Strauch, Konstantin; Surendran, Praveen] Ludwig Maximilians Univ Munchen, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Chowdhury, Rajiv; Young, Robin; Howson, Joanna M. M.; Butterworth, Adam S.; Danesh, John] Univ Cambridge, Dept Publ Hlth & Primary Care, MRC BHF Cardiovasc Epidemiol Unit, Cambridge, England. [Ford, Ian] Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland. [Jukema, J. Wouter] Leiden Univ, Med Ctr, Leiden & Interuniv Cardiol Inst Netherlands, Dept Cardiol, Utrecht, Netherlands. [Amouyel, Philippe] Univ Lille, INSERM, CHU Lille, Inst Pasteur Lille,RID AGE U1167, Lille, France. [Nordestgaard, Borge G.] Copenhagen Univ Hosp & Med Sci, Copenhagen, Denmark. [Nordestgaard, Borge G.] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark. [Ferrieres, Jean] Toulouse Univ, Sch Med, Toulouse, France. [Saleheen, Danish] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Saleheen, Danish] Ctr Noncommunicable Dis, Karachi, Pakistan. [Sattar, Naveed] Univ Glasgow, Glasgow Cardiovasc Res Ctr, British Heart Fdn, Glasgow, Lanark, Scotland. 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[Kraus, William E.; Shah, Svati H.] Duke Univ, Dept Med, Div Cardiol, Durham, NC USA. [Orho-Melander, Marju] Lund Univ, Clin Res Ctr, Dept Clin Sci Malmo, Malmo, Sweden. [Melander, Olle] Lund Univ, Malmo Univ Hosp, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden. [Rader, Daniel J.] Univ Penn, Dept Genet, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Rader, Daniel J.] Univ Penn, Inst Translat Med & Therapeut, Perelman Sch Med, Philadelphia, PA 19104 USA. [Reilly, Muredach P.] Columbia Univ, Dept Med, Div Cardiol, New York, NY USA. [Reilly, Muredach P.] Columbia Univ, Irving Inst Clin & Translat Res, New York, NY USA. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. [Reiner, Alex P.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Roden, Dan M.] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA. [Thompson, John R.] Univ Leicester, Dept Hlth Sci, Leicester, Leics, England. [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. [Kathiresan, Sekar] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP 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.; Deloukas, P (reprint author), King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence R, Jeddah, Saudi Arabia. EM njs@le.ac.uk; p.deloukas@qmul.ac.uk RI Webb, Tom/C-6237-2011; OI Dube, Marie-Pierre/0000-0001-8442-4393; Kontto, Jukka/0000-0003-3899-9852; Peters, Annette/0000-0001-6645-0985 FU Merck Sharp Dohme; Pfizer; Novo Nordisk; Eli Lilly; Servier; Sanofi-Aventis; Janssen; Roche; Boehringer-Ingelheim; Takeda; Merck; AstraZeneca; Amgen; Sanofi; Amarin; DalCor FX Dr. Vogt was an employee of Merck when aspects of this research was conducted, but is now retired from Merck. A cholesteryl ester transfer protein inhibitor, Anacetrapib ( MK-0859), is currently undergoing clinical investigation in the REVEAL outcome trial sponsored by Merck Sharp & Dohme. Dr. Schick is an employee of Recombine. Dr. Dube has equity in DalCor Pharmaceuticals. Dr. McCarthy is a member of advisory boards for Pfizer and Novo Nordisk; has received honoraria from Pfizer, Novo Nordisk, and Eli Lilly; and has received research funding provided by Pfizer, Novo Nordisk, Eli Lilly, Servier, Sanofi-Aventis, Janssen, Roche, Boehringer-Ingelheim, Takeda, Merck, and AstraZeneca. Dr. Ferrieres has received grants from Merck Sharp & Dohme, Amgen, and Sanofi. Dr. Sattar has served as a consultant for Amgen and Sanofi. Dr. Butterworth has received grants from Pfizer and Merck. Dr. Danesh has served as a consultant for Takeda; has served on the Novartis Cardiovascular & Metabolic Advisory Board and International Cardiovascular and Metabolism Research and Development Portfolio Committee of Novartis; has served on the UK Atherosclerosis Advisory Board of Merck Sharp & Dohme; has served on the advisory board of Sanofi; has served on the Pfizer Population Research Advisory Panel; and has financial relationships with the British Heart Foundation, BUPA Foundation, diaDexus, European Research Council, European Union, Evelyn Trust, Fogarty International Centre, GlaxoSmithKline, Merck, National Heart, Lung, and Blood Institute, National Health Service Blood and Transplant, National Institute for Health Research, National Institute of Neurological Disorders and Stroke, Novartis, Pfizer, Roche, Sanofi, Takeda, The Wellcome Trust, UK Biobank, University of British Columbia, and UK Medical Research Council. Dr. Tardif has received research grants from Amarin, AstraZeneca, Merck, Pfizer, Eli Lilly, Sanofi, Servier, and DalCor; has received honoraria from Pfizer (to his institution), Servier, DalCor, and Sanofi (to his institution); and has received modest equity interest from DalCor. Dr. Kathiresan has financial/ other relationships with Regeneron, Bayer, Catabasis, Merck, Celera, Genomics PLC, San Therapeutics, Novartis, Sanofi, AstraZeneca, Alnylam, Eli Lilly, Leerink Partners, and Noble Insights. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. A full list of acknowledgments and funding sources is included in the Online Appendix. Drs. Webb, Erdmann, Strirrups, Stitziel, Samani, Schunkert, Deloukas, and Kathiresan contributed equally to this work. NR 44 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 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB 21 PY 2017 VL 69 IS 7 BP 823 EP 836 DI 10.1016/j.jacc.2016.11.056 PG 14 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EN9SR UT WOS:000396340400009 PM 28209224 ER PT J AU Lucanic, M Plummer, WT Chen, E Harke, J Foulger, AC Onken, B Coleman-Hulbert, AL Dumas, KJ Guo, SZ Johnson, E Bhaumik, D Xue, J Crist, AB Presley, MP Harinath, G Sedore, CA Chamoli, M Kamat, S Chen, MK Angeli, S Chang, C Willis, JH Edgar, D Royal, MA Chao, EA Patel, S Garrett, T Ibanez-Ventoso, C Hope, J Kish, JL Guo, M Lithgow, GJ Driscoll, M Phillips, PC AF Lucanic, Mark Plummer, W. Todd Chen, Esteban Harke, Jailynn Foulger, Anna C. Onken, Brian Coleman-Hulbert, Anna L. Dumas, Kathleen J. Guo, Suzhen Johnson, Erik Bhaumik, Dipa Xue, Jian Crist, Anna B. Presley, Michael P. Harinath, Girish Sedore, Christine A. Chamoli, Manish Kamat, Shaunak Chen, Michelle K. Angeli, Suzanne Chang, Christina Willis, John H. Edgar, Daniel Royal, Mary Anne Chao, Elizabeth A. Patel, Shobhna Garrett, Theo Ibanez-Ventoso, Carolina Hope, June Kish, Jason L. Guo, Max Lithgow, Gordon J. Driscoll, Monica Phillips, Patrick C. TI Impact of genetic background and experimental reproducibility on identifying chemical compounds with robust longevity effects SO NATURE COMMUNICATIONS LA English DT Article ID ADULT CAENORHABDITIS-ELEGANS; EXTENDS LIFE-SPAN; DIETARY RESTRICTION; STRESS RESISTANCE; C. ELEGANS; INCREASE; RESVERATROL; POPULATIONS; DROSOPHILA; ORGANISMS AB Limiting the debilitating consequences of ageing is a major medical challenge of our time. Robust pharmacological interventions that promote healthy ageing across diverse genetic backgrounds may engage conserved longevity pathways. Here we report results from the Caenorhabditis Intervention Testing Program in assessing longevity variation across 22 Caenorhabditis strains spanning 3 species, using multiple replicates collected across three independent laboratories. Reproducibility between test sites is high, whereas individual trial reproducibility is relatively low. Of ten pro-longevity chemicals tested, six significantly extend lifespan in at least one strain. Three reported dietary restriction mimetics are mainly effective across C. elegans strains, indicating species and strain-specific responses. In contrast, the amyloid dye ThioflavinT is both potent and robust across the strains. Our results highlight promising pharmacological leads and demonstrate the importance of assessing lifespans of discrete cohorts across repeat studies to capture biological variation in the search for reproducible ageing interventions. C1 [Lucanic, Mark; Plummer, W. Todd; Foulger, Anna C.; Dumas, Kathleen J.; Bhaumik, Dipa; Presley, Michael P.; Chamoli, Manish; Angeli, Suzanne; Edgar, Daniel; Chao, Elizabeth A.; Garrett, Theo; Hope, June; Kish, Jason L.; Lithgow, Gordon J.] Buck Inst Res Aging, 8001 Redwood Blvd, Novato, CA 94945 USA. [Chen, Esteban; Onken, Brian; Guo, Suzhen; Xue, Jian; Harinath, Girish; Kamat, Shaunak; Chang, Christina; Royal, Mary Anne; Patel, Shobhna; Ibanez-Ventoso, Carolina; Driscoll, Monica] Rutgers State Univ, Dept Mol Biol & Biochem, Nelson Biol Labs, Piscataway, NJ 08854 USA. [Harke, Jailynn; Coleman-Hulbert, Anna L.; Johnson, Erik; Crist, Anna B.; Sedore, Christine A.; Chen, Michelle K.; Willis, John H.; Phillips, Patrick C.] Univ Oregon, Inst Ecol & Evolut, Eugene, OR 97403 USA. [Guo, Max] NIA, Div Aging Biol, 7201 Wisconsin Ave, Bethesda, MD 20892 USA. [Harke, Jailynn] NCI, Mol Biol Lab, Bldg 37, Bethesda, MD 20892 USA. RP Lithgow, GJ (reprint author), Buck Inst Res Aging, 8001 Redwood Blvd, Novato, CA 94945 USA.; Driscoll, M (reprint author), Rutgers State Univ, Dept Mol Biol & Biochem, Nelson Biol Labs, Piscataway, NJ 08854 USA.; Phillips, PC (reprint author), Univ Oregon, Inst Ecol & Evolut, Eugene, OR 97403 USA. EM glithgow@buckinstitute.org; driscoll@dls.rutgers.edu; pphil@uoregon.edu FU NIH Office of Research Infrastructure Programs [P40 OD010440]; Larry L. Hillblom Foundation; Glenn Foundation for Medical Research; NIH grants [UL1024917, 1R01AG029631, R21AG048528, UO1AG045844, U01AG045864] FX We acknowledge all the members of the Lithgow, Driscoll and Phillips labs for helpful discussions particularly focused on detailed protocols. We also thank the CITP Advisory Committee and Ronald Kohanski (National Institute on Aging). We thank Asher Cutter, Marie-Anne Felix and Christian Braendle for providing strains that they had directly collected. Additional strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). This work was supported by funding from the Larry L. Hillblom Foundation, the Glenn Foundation for Medical Research and NIH grants (UL1024917, supporting the Interdisciplinary Research Consortium on Geroscience, 1R01AG029631, R21AG048528, UO1AG045844 and U01AG045864). NR 60 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD FEB 21 PY 2017 VL 8 AR 14256 DI 10.1038/ncomms14256 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EL3CY UT WOS:000394498400001 PM 28220799 ER PT J AU Ren, NSX Ji, M Tokar, EJ Busch, EL Xu, XJ Lewis, D Li, XC Jin, AW Zhang, YP Wu, WKK Huang, WC Li, LP Fargo, DC Keku, TO Sandler, RS Li, XL AF Ren, Natalie S. X. Ji, Ming Tokar, Erik J. Busch, Evan L. Xu, Xiaojiang Lewis, DeAsia Li, Xiangchun Jin, Aiwen Zhang, Yanping Wu, William K. K. Huang, Weichun Li, Leping Fargo, David C. Keku, Temitope O. Sandler, Robert S. Li, Xiaoling TI Haploinsufficiency of SIRT1 Enhances Glutamine Metabolism and Promotes Cancer Development SO CURRENT BIOLOGY LA English DT Article ID CARE OUTCOMES RESEARCH; COLORECTAL-CANCER; CELL-SURVIVAL; P53; TUMORIGENESIS; MICE; DAMAGE; HOMEOSTASIS; ACTIVATION; EXPRESSION AB SIRT1, the most conserved mammalian NAID(+)-dependent protein deacetylase, plays a vital role in the regulation of metabolism, stress responses, and genome stability. However, the role of SIRT1 in the multi-step process leading to transformation and/or tumorigenesis, as either a tumor suppressor or tumor promoter, is complex and may be dependent upon the context in which SIRT1 activity is altered, and the role of SIRT1 in tumor metabolism is unknown. Here, we demonstrate that SIRT1 dose-dependently regulates cellular glutamine metabolism and apoptosis, which in turn differentially impact cell proliferation and cancer development. Heterozygous deletion of Sirt1 induces c-Myc expression, enhancing glutamine metabolism and subsequent proliferation, autophagy, stress resistance, and cancer formation. In contrast, homozygous deletion of Sirt1 triggers cellular apoptotic pathways, increases cell death, diminishes autophagy, and reduces cancer formation. Consistent with the observed dose dependence in cells, intestine-specific Sirt1 heterozygous mice have enhanced intestinal tumor formation, whereas intestine-specific Sirt1 homozygous knockout mice have reduced development of colon cancer. Furthermore, SIRT1 reduction, but not deletion, is associated with human colorectal tumors, and colorectal cancer patients with low protein expression of SIRT1 have a poor prognosis. Taken together, our findings indicate that the dose-dependent regulation of tumor metabolism and possibly apoptosis by SIRT1 mechanistically contribute to the observed dual roles of SIRT1 in tumorigenesis. Our study highlights the importance of maintenance of a suitable SIRT1 dosage for metabolic and tissue homeostasis, which will have important implications in SIRT1-small-molecule-activator/inhibitor-based therapeutic strategies for cancers. C1 [Ren, Natalie S. X.; Ji, Ming; Lewis, DeAsia; Li, Xiaoling] NIEHS, Signal Transduct Lab, POB 12233, Res Triangle Pk, NC 27709 USA. [Tokar, Erik J.] Natl Toxicol Program, Stem Cell Toxicol Grp, Res Triangle Pk, NC 27709 USA. [Busch, Evan L.] Univ North Carolina Chapel Hill, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Xu, Xiaojiang; Fargo, David C.] NIEHS, Integrat Bioinformat Branch, POB 12233, Res Triangle Pk, NC 27709 USA. [Huang, Weichun; Li, Leping] NIEHS, Biostat & Computat Biol Branch, POB 12233, Res Triangle Pk, NC 27709 USA. [Li, Xiangchun; Wu, William K. K.] Chinese Univ Hong Kong, Inst Digest Dis, Dept Anaesthesia & Intens Care, Hong Kong, Hong Kong, Peoples R China. [Li, Xiangchun; Wu, William K. K.] Chinese Univ Hong Kong, State Key Lab Digest Dis, Hong Kong, Hong Kong, Peoples R China. [Jin, Aiwen; Zhang, Yanping] Univ North Carolina Chapel Hill, Dept Radiat Oncol, Chapel Hill, NC 27599 USA. [Jin, Aiwen; Zhang, Yanping] Univ North Carolina Chapel Hill, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Keku, Temitope O.; Sandler, Robert S.] Univ North Carolina Chapel Hill, Dept Med, Chapel Hill, NC 27599 USA. [Busch, Evan L.] Harvard Med Sch, Channing Div Network Med, Dept Med, Boston, MA 02115 USA. [Busch, Evan L.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Busch, Evan L.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Li, XL (reprint author), NIEHS, Signal Transduct Lab, POB 12233, Res Triangle Pk, NC 27709 USA. EM lix3@niehs.nih.gov FU Intramural Research Program of National Institute of Environmental Health Sciences [Z01 ES102205]; NIH [P30DK034987, U01CA93326]; National Cancer Institute [5T32CA009001, 3P30CA016086] FX We thank Drs. Anton Jetten and Dmitry Gordenin and members of the Xiaoling Li laboratory for critical reading of the manuscript. We also thank Dr. Yi Fang and Ms. Qing Xu for technical support, Dr. E. Terence Adams from Integrated Laboratory Systems for histopathologic evaluation of colon tumors developed in mice, and Stephanie Cohen (image analysis) and Yongjuan Xia and Gabriela De la Cruz (staining) in the UNC Translational Pathology Laboratory (TPL) for expert technical assistance. This research was supported by the Intramural Research Program of National Institute of Environmental Health Sciences to Xiaoling Li (Z01 ES102205) and was also supported, in part, by extramural grants from the NIH (P30DK034987 and U01CA93326). E.L.B. was supported in part by a grant from the National Cancer Institute (5T32CA009001). The UNC TPL is supported in part by grants from the National Cancer Institute (3P30CA016086). NR 45 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 EI 1879-0445 J9 CURR BIOL JI Curr. Biol. PD FEB 20 PY 2017 VL 27 IS 4 BP 483 EP 494 DI 10.1016/j.cub.2016.12.047 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EL6IF UT WOS:000394724600018 PM 28162896 ER PT J AU Ferreira, MP Coghill, AE Chaves, CB Bergmann, A Thuler, LC Soares, EA Pfeiffer, RM Engels, EA Soares, MA AF Ferreira, Mariana P. Coghill, Anna E. Chaves, Claudia B. Bergmann, Anke Thuler, Luiz C. Soares, Esmeralda A. Pfeiffer, Ruth M. Engels, Eric A. Soares, Marcelo A. TI Outcomes of cervical cancer among HIV-infected and HIV-uninfected women treated at the Brazilian National Institute of Cancer SO AIDS LA English DT Article DE AIDS; cervical cancer; HIV infection; relapse; survival; treatment response ID HUMAN-IMMUNODEFICIENCY-VIRUS; UNITED-STATES; TRANSPLANT RECIPIENTS; MORTALITY; RISK; AIDS; PEOPLE AB Objective: We assessed mortality, treatment response, and relapse among HIV-infected and HIV-uninfected women with cervical cancer in Rio de Janeiro, Brazil. Design: Cohort study of 87 HIV-infected and 336 HIV-uninfected women with cervical cancer. Methods: Patients at the Brazilian National Institute of Cancer (2001-2013) were matched on age, calendar year of diagnosis, clinical stage, and tumor histology. Staging and treatment with surgery, radiotherapy, and/or chemotherapy followed international guidelines. We used a Markov model to assess responses to initial therapy, and Cox models for mortality and relapse after complete response (CR). Results: Among 234 deaths, most were from cancer (82% in HIV-infected vs. 93% in HIV-uninfected women); only 9% of HIV-infected women died from AIDS. HIV was not associated withmortality during initial follow-up but was associated more than 1-2 years after diagnosis [ overall mortality: stage-adjusted hazard ratio 2.02, 95% confidence interval (CI) 1.27-3.22; cancer-specific mortality: 4.35, 1.86-10.2]. Among 222 patients treated with radiotherapy, HIV-infected had similar response rates to initial cancer therapy as HIV-uninfected women (hazard ratio 0.98, 95% CI 0.58-1.66). However, among women who were treated and had a CR, HIV was associated with elevated risk of subsequent relapse (hazard ratio 3.60, 95% CI 1.86-6.98, adjusted for clinical stage). Conclusion: Among women with cervical cancer, HIV infection was not associated with initial treatment response or early mortality, but relapse after attaining a CR and late mortality were increased in those with HIV. These results point to a role for an intact immune system in control of residual tumor burden among treated cervical cancer patients. (C) 2017 Wolters Kluwer Health, Inc. All rights reserved. C1 [Ferreira, Mariana P.; Soares, Esmeralda A.; Soares, Marcelo A.] Inst Nacl Canc, Programa Oncovirol, Rua Andre Cavalcanti 37-40, BR-20231050 Rio De Janeiro, RJ, Brazil. [Coghill, Anna E.; Pfeiffer, Ruth M.; Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Chaves, Claudia B.] Inst Nacl Canc, Secao Ginecol Oncol, Rio De Janeiro, RJ, Brazil. [Chaves, Claudia B.; Bergmann, Anke] Inst Nacl Canc, Programa Carcinogenese Mol, Rio De Janeiro, RJ, Brazil. [Bergmann, Anke; Thuler, Luiz C.] Inst Nacl Canc, Programa Pesquisa Clin, Rio De Janeiro, RJ, Brazil. RP Soares, MA (reprint author), Inst Nacl Canc, Programa Oncovirol, Rua Andre Cavalcanti 37-40, BR-20231050 Rio De Janeiro, RJ, Brazil. EM masoares@inca.gov.br FU US-Brazil Collaborative Research Program of the US National Institutes of Health; Brazilian Ministry of Health [467874/2014-0]; Brazilian Ministry of Science and Technology [467874/2014-0]; Intramural Research Program of the US National Cancer Institute FX The study was supported by a grant under the US-Brazil Collaborative Research Program of the US National Institutes of Health and the Brazilian Ministries of Health and of Science and Technology (no. 467874/2014-0). MPF was supported through an MSc fellowship by the Brazilian Ministry of Health. C.B.C., A.B., L.C.T., E.A.S., and M.A.S. were supported by intramural resources of the Brazilian Ministry of Health. A.E.C., R.M.P., and E.A.E. were supported by the Intramural Research Program of the US National Cancer Institute. NR 23 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 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD FEB 20 PY 2017 VL 31 IS 4 BP 523 EP 531 DI 10.1097/QAD.0000000000001367 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA EK2JW UT WOS:000393754600011 PM 28060014 ER PT J AU Moukambi, F Rodrigues, V Fortier, Y Rabezanahary, H Borde, C Krust, B Andreani, G Silvestre, R Petrovas, C Laforge, M Estaquier, J AF Moukambi, Felicien Rodrigues, Vasco Fortier, Yasmina Rabezanahary, Henintsoa Borde, Chloe Krust, Bernard Andreani, Guadalupe Silvestre, Ricardo Petrovas, Constantinos Laforge, Mireille Estaquier, Jerome TI CD4 T Follicular Helper Cells and HIV Infection: Friends or Enemies? SO FRONTIERS IN IMMUNOLOGY LA English DT Review DE AIDS; Tfh; CD4; B cell; vaccine; pathogen; SIV; reservoir ID SIMIAN IMMUNODEFICIENCY VIRUS; CHRONIC VIRAL-INFECTION; CENTER B-CELL; AFRICAN-GREEN MONKEYS; TRANSCRIPTION FACTOR; SIV INFECTION; LYMPH-NODES; TFH CELLS; LENTIVIRAL INFECTIONS; DISEASE PROGRESSION AB Follicular T helper (Tfh) cells, a subset of CD4 T lymphocytes, are essential for memory B cell activation, survival, and differentiation and assist B cells in the production of antigen-specific antibodies. Work performed in recent years pointed out the importance of Tfh cells in the context of HIV and SIV infections. The importance of tissue distribution of Tfh is also an important point since their frequency differs between peripheral blood and lymph nodes compared to the spleen, the primary organ for B cell activation, and differentiation. Our recent observations indicated an early and profound loss of splenic Tfh cells. The role of transcriptional activator and repressor factors that control Tfh differentiation is also discussed in the context of HIV/SIV infection. Because Tfh cells are important for B cell differentiation and antibody production, accelerating the Tfh responses early during HIV/SIV infection could be promising as novel immunotherapeutic approach or alternative vaccine strategies. However, because Tfh cells are infected during the HIV/SIV infection and represent a reservoir, this may interfere with HIV vaccine strategy. Thus, Tfh represent the good and bad guys during HIV infection. C1 [Moukambi, Felicien; Rabezanahary, Henintsoa; Andreani, Guadalupe; Estaquier, Jerome] Univ Laval, Fac Med, Res Ctr, Ctr Hosp Univ CHU Quebec, Quebec City, PQ, Canada. [Rodrigues, Vasco; Fortier, Yasmina; Borde, Chloe; Krust, Bernard; Laforge, Mireille; Estaquier, Jerome] Paris Descartes Univ, Fac Med St Peres, CNRS, FR3636, Paris, France. [Silvestre, Ricardo] Univ Minho, Sch Hlth Sci, Life & Hlth Sci Res Inst ICVS, Braga, Portugal. [Silvestre, Ricardo] ICVS 3Bs PT Govt Associate Lab, Braga, Portugal. [Petrovas, Constantinos] NIAID, Tissue Anal Core, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Estaquier, J (reprint author), Univ Laval, Fac Med, Res Ctr, Ctr Hosp Univ CHU Quebec, Quebec City, PQ, Canada.; Estaquier, J (reprint author), Paris Descartes Univ, Fac Med St Peres, CNRS, FR3636, Paris, France. EM estaquier@yahoo.fr FU Agence Nationale de Recherches sur le Sida et les Hepatites Virales (ANRS); Canadian HIV Cure Enterprise Team Grant from the Canadian Institutes of Health Research (CIHR) [HIG-13305]; CANFAR; IAS; Fondation du CHU de Quebec; ANRS; Canada Research Chair; FCT-Fundacao para a Ciencia e a Tecnologia/MEC-Ministerio da Educacao e Ciencia atraves de fundos nacionais; Fundacao para a Ciencia e a Tecnologia (FCT) [IF/00021/2014]; FEDER [4293] FX This work was supported by grants to JE from the Agence Nationale de Recherches sur le Sida et les Hepatites Virales (ANRS) and from The Canadian HIV Cure Enterprise Team Grant HIG-13305 from the Canadian Institutes of Health Research (CIHR) in partnership with CANFAR and IAS. FM is supported by a fellowship from Fondation du CHU de Quebec. CB and YF are supported by fellowships from ANRS. JE acknowledges the support of the Canada Research Chair program. RS is supported by FCT-Fundacao para a Ciencia e a Tecnologia/MEC-Ministerio da Educacao e Ciencia atraves de fundos nacionais e quando aplicavel cofinanciado pelo FEDER, no ambito do Acordo de Parceria PT2020 referente a unidade de investigacao no 4293. RS is supported by the Fundacao para a Ciencia e a Tecnologia (FCT) (IF/00021/2014). NR 108 TC 0 Z9 0 U1 3 U2 3 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 FEB 20 PY 2017 VL 8 AR 135 DI 10.3389/fimmu.2017.00135 PG 8 WC Immunology SC Immunology GA EL0HN UT WOS:000394303600001 PM 28265271 ER PT J AU Nair, SG Patel, DP Sanyal, M Singhal, P Shrivastav, PS AF Nair, Sneha G. Patel, Daxesh P. Sanyal, Mallika Singhal, Puran Shrivastav, Pranav S. TI Simultaneous analysis of glucocorticosteroid fluticasone propionate and its metabolite fluticasone propionate 17 beta-carboxylic acid in human plasma by UPLC-MS/MS at sub pg/mL level SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE Fluticasone propionate; Fluticasone propionate 17/beta-carboxylic acid; UPLC-MS/MS; Sub pg/mL; Human plasma; Nasal spray ID TANDEM MASS-SPECTROMETRY; NASAL SPRAY FORMULATIONS; LC-MS/MS; SAMPLES AB A highly sensitive and rapid ultra performance liquid chromatography-tandem mass spectrometry method has been developed for the simultaneous determination of fluticasone propionate (FP) and its major metabolite, fluticasone propionate-17beta-carboxylic acid (FP 17 beta-CA) in human plasma. The analytes and their deuterated internal standards, FP-d3 and FP 17 beta-CA-d3 were extracted from 500 mu L plasma samples by solid phase extraction on Oasis MAX cartridges. The chromatographic analysis was performed on ACQUITY UPLC BEH C18 (50mm x 2.1 mm, 1.7 mu m) column using methanol-acetonitrile (50:50, v/v) and 2.0 mM ammonium trifluroacetate (ATFA) (85:15, v/v) as the mobile phase. Following separation of the analytes, protonated precursor production transitions (FP: m/z 501.1 -> 293.2, FP17 beta-CA: m/z 453.3 -> 293.2, FP-d3: m/z 504.2 -> 293.2, FP 17 beta-CA-d3: m/z 456.3 -> 293.2) were monitored on FP 17 beta-CA a triple quadrupole mass spectrometer, operating in multiple reaction monitoring (MRM) and positive ionization mode. The calibration curves were established in the range of 0.5-100pg/mL with a correlation coefficient (r(2))>= 0.9992 for both the analytes. The intra-batch and inter-batch accuracy and precision varied from 95.5-103.4% and 0.74-5.06% across quality controls for both the analytes. The mean assay recoveries for FP and FP 17 beta-CA were 84.2% and 93.5% respectively. The validated method was successfully applied to support a bioequivalence study of 200 mu g FP, administered using nasal spray formulation in 18 healthy Indian subjects. Reproducibility of the method was assessed by reanalysis of 98 incurred study samples. (C) 2016 Elsevier B.V. All rights reserved. C1 [Nair, Sneha G.; Shrivastav, Pranav S.] Gujarat Univ, Sch Sci, Dept Chem, Ahmadabad 380009, Gujarat, India. [Patel, Daxesh P.] NCI, Lab Metab, Ctr Canc Res, Bethesda, MD 20892 USA. [Sanyal, Mallika] St Xaviers Coll, Dept Chem, Ahmadabad 380009, Gujarat, India. [Singhal, Puran] Alkem Labs Ltd, Bioanalyt Dept, Mumbai 400013, Maharashtra, India. RP Shrivastav, PS (reprint author), Gujarat Univ, Sch Sci, Dept Chem, Ahmadabad 380009, Gujarat, India. EM pranav_shrivastav@yahoo.com NR 21 TC 0 Z9 0 U1 8 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0731-7085 EI 1873-264X J9 J PHARMACEUT BIOMED JI J. Pharm. Biomed. Anal. PD FEB 20 PY 2017 VL 135 BP 1 EP 7 DI 10.1016/j.jpba.2016.12.008 PG 7 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA EJ0NB UT WOS:000392905200001 PM 27987390 ER PT J AU Groen, IIA Silson, EH Baker, CI AF Groen, Iris I. A. Silson, Edward H. Baker, Chris I. TI Contributions of low- and high-level properties to neural processing of visual scenes in the human brain SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE natural scenes; functional magnetic resonance imaging; electro-encephalography; category-selectivity; retinotopy; image statistics ID PARAHIPPOCAMPAL PLACE AREA; HUMAN OCCIPITOTEMPORAL CORTEX; SELECTIVE CORTICAL REGIONS; LATERAL OCCIPITAL CORTEX; REAL-WORLD SCENES; OBJECT RECOGNITION; TIME-COURSE; IMAGE STATISTICS; DECISION-MAKING; NATURAL SCENES AB Visual scene analysis in humans has been characterized by the presence of regions in extrastriate cortex that are selectively responsive to scenes compared with objects or faces. While these regions have often been interpreted as representing high-level properties of scenes (e.g. category), they also exhibit substantial sensitivity to low-level (e.g. spatial frequency) and mid-level (e.g. spatial layout) properties, and it is unclear how these disparate findings can be united in a single framework. In this opinion piece, we suggest that this problem can be resolved by questioning the utility of the classical low- to high-level framework of visual perception for scene processing, and discuss why low-and mid-level properties may be particularly diagnostic for the behavioural goals specific to scene perception as compared to object recognition. In particular, we highlight the contributions of low-level vision to scene representation by reviewing (i) retinotopic biases and receptive field properties of scene-selective regions and (ii) the temporal dynamics of scene perception that demonstrate overlap of low-and mid-level feature representations with those of scene category. We discuss the relevance of these findings for scene perception and suggest a more expansive framework for visual scene analysis. This article is part of the themed issue 'Auditory and visual scene analysis'. C1 [Groen, Iris I. A.; Silson, Edward H.; Baker, Chris I.] NIH, Lab Brain & Cognit, 10 Ctr Dr 10-3N228, Bethesda, MD 20892 USA. RP Groen, IIA (reprint author), NIH, Lab Brain & Cognit, 10 Ctr Dr 10-3N228, Bethesda, MD 20892 USA. EM iris.groen@nih.gov OI Groen, Iris/0000-0002-5536-6128; Baker, Chris/0000-0001-6861-8964 FU National Institutes of Health [ZIA-MH-002909]; Rubicon Fellowship from Netherlands Organization for Scientific Research (NWO) FX I.I.A.G., E.H.S. and C.I.B. are supported by the Intramural Program of the National Institutes of Health (ZIA-MH-002909). I.I.A.G. is also supported by a Rubicon Fellowship from the Netherlands Organization for Scientific Research (NWO). NR 122 TC 1 Z9 1 U1 13 U2 13 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 EI 1471-2970 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD FEB 19 PY 2017 VL 372 IS 1714 AR 20160102 DI 10.1098/rstb.2016.0102 PG 11 WC Biology SC Life Sciences & Biomedicine - Other Topics GA EI1AD UT WOS:000392206300003 ER PT J AU Gostic, KM Ambrose, M Worobey, M Lloyd-Smith, JO AF Gostic, Katelyn M. Ambrose, Monique Worobey, Michael Lloyd-Smith, James O. TI Maternal antibodies' role in immunity Response SO SCIENCE LA English DT Letter ID ORIGINAL ANTIGENIC SIN; INFLUENZA-VIRUSES C1 [Gostic, Katelyn M.; Ambrose, Monique; Lloyd-Smith, James O.] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA. [Worobey, Michael] Univ Arizona, Dept Ecol & Evolutionary Biol, Tucson, AZ 85721 USA. [Lloyd-Smith, James O.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Worobey, M; Lloyd-Smith, JO (reprint author), Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA.; Worobey, M (reprint author), Univ Arizona, Dept Ecol & Evolutionary Biol, Tucson, AZ 85721 USA.; Lloyd-Smith, JO (reprint author), NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. EM worobey@email.arizona.edu; jlloydsmith@ucla.edu NR 8 TC 0 Z9 0 U1 3 U2 3 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD FEB 17 PY 2017 VL 355 IS 6326 BP 705 EP 705 DI 10.1126/science.aam7389 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EM2AC UT WOS:000395117700031 PM 28209868 ER PT J AU Dotsey, E Ushach, I Pone, E Nakajima, R Jasinskas, A Argueta, DA Dillon, A DiPatrizio, N Davies, H Zlotnik, A Crompton, PD Felgner, PL AF Dotsey, Emmanuel Ushach, Irina Pone, Egest Nakajima, Rie Jasinskas, Algis Argueta, Donovan A. Dillon, Andrea DiPatrizio, Nicholas Davies, Huw Zlotnik, Albert Crompton, Peter D. Felgner, Philip L. TI Transient Cannabinoid Receptor 2 Blockade during Immunization Heightens Intensity and Breadth of Antigen-specific Antibody Responses in Young and Aged mice SO SCIENTIFIC REPORTS LA English DT Article ID ENDOCANNABINOID SYSTEM; T-CELLS; B-CELLS; PROTEOME MICROARRAYS; IMMUNE-RESPONSES; LYMPHOID ORGANS; DENDRITIC CELLS; MARGINAL ZONE; CB2 RECEPTOR; DIFFERENTIATION AB The hallmark of vaccines is their ability to prevent the spread of infectious pathogens and thereby serve as invaluable public health tool. Despite their medical relevance, there is a gap in our understanding of the physiological factors that mediate innate and adaptive immune response to vaccines. The endocannabinoid (eCB) system is a critical modulator of homeostasis in vertebrates. Our results indicate that macrophages and dendritic cells produce the endocannabinoid, 2-arachidonoyl-sn-glycerol (2-AG) upon antigen activation. We have also established that 2-AG levels are upregulated in the serum and in the lymph node of mice during vaccination. We hypothesized that the intrinsic release of eCBs from immune cells during activation by pathogenic antigens mitigate inflammation, but also suppress overall innate and adaptive immune response. Here we demonstrate, for the first time, that transient administration of the cannabinoid receptor 2 antagonist AM630 (10 mg/kg) or inverse agonist JTE907 (3 mg/kg) during immunization heightens the intensity and breadth of antigen-specific immune responses in young and aged mice through the upregulation of immunomodulatory genes in secondary lymphoid tissues. C1 [Dotsey, Emmanuel; Ushach, Irina; Nakajima, Rie; Jasinskas, Algis; Davies, Huw; Felgner, Philip L.] Univ Calif Irvine, Dept Med, Div Infect Dis, Irvine, CA 92717 USA. [Pone, Egest] Univ Calif Irvine, Dept Pharmaceut Sci, Irvine, CA USA. [Argueta, Donovan A.; Dillon, Andrea; DiPatrizio, Nicholas] Univ Calif Riverside, Div Biomed Sci, Sch Med, Riverside, CA 92521 USA. [Zlotnik, Albert] Univ Calif Irvine, Dept Physiol & Biophys, Irvine, CA 92717 USA. [Crompton, Peter D.] NIAID, Malaria Infect Biol & Immun Unit, Immunogenet Lab, NIH, Rockville, MD USA. RP Dotsey, E (reprint author), Univ Calif Irvine, Dept Med, Div Infect Dis, Irvine, CA 92717 USA. EM edotsey@uci.edu OI Argueta, Donovan/0000-0002-8234-141X FU NIH [R01 AI095916-01A1, R01 AI095916-02S1]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH FX This study was supported by NIH grants R01 AI095916-01A1 and R01 AI095916-02S1. PDC is supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH. NR 74 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD FEB 17 PY 2017 VL 7 AR 42584 DI 10.1038/srep42584 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EL0MU UT WOS:000394317300001 PM 28209996 ER PT J AU Ishikawa, K Medina, SH Schneider, JP Klar, AJS AF Ishikawa, Ken Medina, Scott H. Schneider, Joel P. Klar, Amar J. S. TI Glycan Alteration Imparts Cellular Resistance to a Membrane-Lytic Anticancer Peptide SO CELL CHEMICAL BIOLOGY LA English DT Article ID SCHIZOSACCHAROMYCES-POMBE; FISSION-YEAST; REVERSE-TRANSCRIPTASE; FILAMENTOUS GROWTH; DRUG-RESISTANCE; PROTEIN-KINASE; CANCER; GALACTOSE; IDENTIFICATION; FLOCCULATION AB Although resistance toward small-molecule chemotherapeutics has been well studied, the potential of tumor cells to avoid destruction by membrane-lytic compounds remains unexplored. Anticancer peptides (ACPs) are a class of such agents that disrupt tumor cell membranes through rapid and non-stereospecific mechanisms, encouraging the perception that cellular resistance toward ACPs is unlikely to occur. We demonstrate that eukaryotic cells can, indeed, develop resistance to the model oncolytic peptide SVS-1, which preferentially disrupts the membranes of cancer cells. Utilizing fission yeast as a model organism, we show that ACP resistance is largely controlled through the loss of cell-surface anionic saccharides. A similar mechanism was discovered in mammalian cancer cells where removal of negatively charged sialic acid residues directly transformed SVS-1-sensitive cell lines into resistant phenotypes. These results demonstrate that changes in cell-surface glycosylation play a major role in tumor cell resistance toward oncolytic peptides. C1 [Ishikawa, Ken; Klar, Amar J. S.] NCI, Gene Regulat & Chromosome Biol Lab, NIH, Frederick, MD 21702 USA. [Ishikawa, Ken; Medina, Scott H.; Schneider, Joel P.] NCI, Biol Chem Lab, NIH, Frederick, MD 21702 USA. RP Klar, AJS (reprint author), NCI, Gene Regulat & Chromosome Biol Lab, NIH, Frederick, MD 21702 USA.; Schneider, JP (reprint author), NCI, Biol Chem Lab, NIH, Frederick, MD 21702 USA. EM joel.schneider@nih.gov; klara@mail.nih.gov FU Intramural Research Program of the National Cancer Institute, NIH FX This work was supported by the Intramural Research Program of the National Cancer Institute, NIH. We thank Mike Bonaduce, Shuo Gu, Lisheng Dai, Kimberley Peifley, and Stephen Lockett for technical assistance and/ or for the use of their facilities, as well as Henry Levin for providing reagents for the yeast transposon mutagenesis procedure. Bulk quantities of the sialyltransferase inhibitor 3Fax- Peracetyl Neu5Ac was synthesized and provided by Gary Pauly. We thank Sherimay Ablan and Eric Freed for providing Jurkat cell line. We thank our colleagues Yuji Yamada, Stephen Hughes, and Jeffrey Strathern for valuable discussions. NR 30 TC 1 Z9 1 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2451-9448 J9 CELL CHEM BIOL JI Cell Chem. Biol. PD FEB 16 PY 2017 VL 24 IS 2 BP 149 EP 158 DI 10.1016/j.chembiol.2016.12.009 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EP5NB UT WOS:000397424400009 PM 28089756 ER PT J AU Kulkarni, RA Worth, AJ Zengeya, TT Shrimp, JH Garlick, JM Roberts, AM Montgomery, DC Sourbier, C Gibbs, BK Mesaros, C Tsai, YC Das, S Chan, KC Zhou, M Andresson, T Weissman, AM Linehan, WM Blair, IA Snyder, NW Meier, JL AF Kulkarni, Rhushikesh A. Worth, Andrew J. Zengeya, Thomas T. Shrimp, Jonathan H. Garlick, Julie M. Roberts, Allison M. Montgomery, David C. Sourbier, Carole Gibbs, Benjamin K. Mesaros, Clementina Tsai, Yien Che Das, Sudipto Chan, King C. Zhou, Ming Andresson, Thorkell Weissman, Allan M. Linehan, W. Marston Blair, Ian A. Snyder, Nathaniel W. Meier, Jordan L. TI Discovering Targets of Non-enzymatic Acylation by Thioester Reactivity Profiling SO CELL CHEMICAL BIOLOGY LA English DT Article ID ACID SYNTHASE INHIBITION; COENZYME-A; HISTONE ACETYLATION; CANCER-CELLS; PROTEIN ACETYLATION; LYSINE ACETYLTRANSFERASES; CRYSTAL-STRUCTURE; CITRATE LYASE; METABOLISM; COA AB Non-enzymatic protein modification driven by thioester reactivity is thought to play a major role in the establishment of cellular lysine acylation. However, the specific protein targets of this process are largely unknown. Here we report an experimental strategy to investigate non-enzymatic acylation in cells. Specifically, we develop a chemoproteomic method that separates thioester reactivity from enzymatic utilization, allowing selective enrichment of non-enzymatic acylation targets. Applying this method to cancer cell lines identifies numerous candidate targets of nonenzymatic acylation, including several enzymes in lower glycolysis. Functional studies highlight malonyl-CoA as a reactive thioester metabolite that can modify and inhibit glycolytic enzyme activity. Finally, we show that synthetic thioesters can be used as novel reagents to probe non-enzymatic acylation in living cells. Our studies provide new insights into the targets and drivers of non-enzymatic acylation, and demonstrate the utility of reactivity-based methods to experimentally investigate this phenomenon in biology and disease. C1 [Kulkarni, Rhushikesh A.; Zengeya, Thomas T.; Shrimp, Jonathan H.; Garlick, Julie M.; Roberts, Allison M.; Montgomery, David C.; Meier, Jordan L.] NCI, Biol Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Worth, Andrew J.; Mesaros, Clementina; Blair, Ian A.] Univ Penn, Penn SRP Ctr, Ctr Excellence Environm Toxicol, Philadelphia, PA 19104 USA. [Sourbier, Carole; Gibbs, Benjamin K.; Linehan, W. Marston] NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20817 USA. [Tsai, Yien Che; Weissman, Allan M.] NCI, Lab Prot Dynam & Signaling, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Das, Sudipto; Chan, King C.; Zhou, Ming; Andresson, Thorkell] Leidos Biomed Res Inc, Prot Characterizat Lab, Canc Res Technol Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Snyder, Nathaniel W.] Drexel Univ, AJ Drexel Autism Inst, 3020 Market St, Philadelphia, PA 19104 USA. RP Meier, JL (reprint author), NCI, Biol Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. EM jordan.meier@nih.gov OI Tsai, Yien Che/0000-0001-9624-1092 FU Pennsylvania Department of Health CURE; NIH [K22ES26235, P30ES013508, ZIA BC011488-02]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research [ZIA BC011488-02] FX The authors thank Dr. Carissa Grose (Protein Expression Laboratory) for assisting with cloning and preparation of plasmid DNA, Dr. David Evans and Lori Bowles (Developmental Therapeutics Program) for NCI-60 cell lines, and Dr. Daniel McVicar (Cancer Inflammation Program) and Dr. Martin Schnermann (Chemical Biology Laboratory) for helpful discussions. This work was supported by a Pennsylvania Department of Health CURE grant, the NIH (K22ES26235 and P30ES013508), and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (ZIA BC011488-02). NR 59 TC 1 Z9 1 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2451-9448 J9 CELL CHEM BIOL JI Cell Chem. Biol. PD FEB 16 PY 2017 VL 24 IS 2 BP 231 EP 242 DI 10.1016/j.chembiol.2017.01.002 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EP5NB UT WOS:000397424400016 PM 28163016 ER PT J AU Battistelli, C Cicchini, C Santangelo, L Tramontano, A Grassi, L Gonzalez, FJ de Nonno, V Grassi, G Amicone, L Tripodi, M AF Battistelli, C. Cicchini, C. Santangelo, L. Tramontano, A. Grassi, L. Gonzalez, F. J. de Nonno, V. Grassi, G. Amicone, L. Tripodi, M. TI The Snail repressor recruits EZH2 to specific genomic sites through the enrollment of the lncRNA HOTAIR in epithelial-to-mesenchymal transition SO ONCOGENE LA English DT Article ID LONG NONCODING RNA; NUCLEAR FACTOR 4-ALPHA; E-CADHERIN EXPRESSION; TRANSCRIPTION FACTORS; COMPLEX 2; CHROMATIN MODIFICATION; CARCINOMA PROGRESSION; MOLECULAR-MECHANISMS; EMT/MET DYNAMICS; GENE-EXPRESSION AB The transcription factor Snail is a master regulator of cellular identity and epithelial-to-mesenchymal transition (EMT) directly repressing a broad repertoire of epithelial genes. How chromatin modifiers instrumental to its activity are recruited to Snail-specific binding sites is unclear. Here we report that the long non-coding RNA (lncRNA) HOTAIR (for HOX Transcript Antisense Intergenic RNA) mediates a physical interaction between Snail and enhancer of zeste homolog 2 (EZH2), an enzymatic subunit of the polycomb-repressive complex 2 and the main writer of chromatin-repressive marks. The Snail-repressive activity, here monitored on genes with a pivotal function in epithelial and hepatic morphogenesis, differentiation and cell-type identity, depends on the formation of a tripartite Snail/HOTAIR/EZH2 complex. These results demonstrate an lncRNA-mediated mechanism by which a transcriptional factor conveys a general chromatin modifier to specific genes, thereby allowing the execution of hepatocyte transdifferentiation; moreover, they highlight HOTAIR as a crucial player in the Snail-mediated EMT. C1 [Battistelli, C.; Cicchini, C.; Santangelo, L.; de Nonno, V.; Amicone, L.; Tripodi, M.] Sapienza Univ Rome, Ist Pasteur Italia Fdn Cenci Bolognetti, Dept Cellular Biotechnol & Haematol, Sez Genet Mol, Rome, Italy. [Tramontano, A.] Sapienza Univ Rome, Ist Pasteur Italia Fdn Cenci Bolognetti, Dept Phys, Rome, Italy. [Grassi, L.] Sapienza Univ Rome, Dept Phys, Rome, Italy. [Gonzalez, F. J.] NCI, Ctr Canc Res, Lab Metab, NIH, Bethesda, MD 20892 USA. [Grassi, G.; Tripodi, M.] IRCCS, Natl Inst Infect Dis L Spallanzani, Rome, Italy. RP Cicchini, C; Tripodi, M (reprint author), Sapienza Univ Rome, Fdn Cenci Bolognetti, Ist Pasteur Italia, Dipartimento Biotecnol Cellulari & Ematol,Sez Gen, Viale Regina Elena 324, I-00161 Rome, Italy. EM cicchini@bce.uniroma1.it; tripodi@bce.uniroma1.it FU Associazione Italiana per la Ricerca sul Cancro (AIRC) [IG 14114]; Ministero della Salute; Ministero Universita e Ricerca Scientifica [PRIN 20108XYHJS]; Epigenomics Flagship Project-EPIGEN FX We thank I Bozzoni and SA Ciafre for suggestions and critical revision of the manuscript. This was supported by Associazione Italiana per la Ricerca sul Cancro (AIRC) IG 14114; Ministero della Salute; Ministero Universita e Ricerca Scientifica PRIN 20108XYHJS; Epigenomics Flagship Project-EPIGEN. NR 57 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD FEB 16 PY 2017 VL 36 IS 7 BP 942 EP 955 DI 10.1038/onc.2016.260 PG 14 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA EK8JG UT WOS:000394169100007 PM 27452518 ER PT J AU Uldrick, TS AF Uldrick, Thomas S. TI iNKT cell defects in HHV-8-associated MCD SO BLOOD LA English DT Editorial Material ID MULTICENTRIC CASTLEMAN-DISEASE; KAPOSI-SARCOMA; T-CELLS; INFECTION; AIDS AB In this issue of Blood, Sbihi et al provide the first evidence of invariant natural killer T (iNKT) cell abnormalities in patients with human herpesvirus 8 (HHV-8) -associated multicentric Castleman disease (MCD). C1 [Uldrick, Thomas S.] NCI, Bethesda, MD USA. RP Uldrick, TS (reprint author), NCI, Bethesda, MD USA. NR 9 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD FEB 16 PY 2017 VL 129 IS 7 BP 806 EP 807 DI 10.1182/blood-2016-11-751875 PG 4 WC Hematology SC Hematology GA EO9OW UT WOS:000397019000003 PM 28209751 ER PT J AU Arfelt, KN Barington, L Benned-Jensen, T Kubale, V Kovalchuk, AL Daugvilaite, V Christensen, JP Thomsen, AR Egerod, KL Bassi, MR Spiess, K Schwartz, TW Wang, HS Morse, HC Holst, PJ Rosenkilde, MM AF Arfelt, Kristine Niss Barington, Line Benned-Jensen, Tau Kubale, Valentina Kovalchuk, Alexander L. Daugvilaite, Viktorija Christensen, Jan Pravsgaard Thomsen, Allan Randrup Egerod, Kristoffer L. Bassi, Maria R. Spiess, Katja Schwartz, Thue W. Wang, Hongsheng Morse, Herbert C., III Holst, Peter J. Rosenkilde, Mette M. TI EBI2 overexpression in mice leads to B1 B-cell expansion and chronic lymphocytic leukemia-like B-cell malignancies SO BLOOD LA English DT Article ID 7-TRANSMEMBRANE RECEPTOR; CONSTITUTIVE ACTIVITY; LIGAND MODULATION; IL-10 PRODUCTION; MARGINAL ZONE; B-1 CELLS; EXPRESSION; IDENTIFICATION; MIGRATION; MOUSE AB Human and mouse chronic lymphocytic leukemia (CLL) develops from CD5(+) B cells that in mice and macaques are known to define the distinct B1a B-cell lineage. B1a cells are characterized by lack of germinal center (GC) development, and the B1a cell population is increased in mice with reduced GC formation. As a major mediator of follicular B-cell migration, the G protein-coupled receptor Epstein-Barr virus-induced gene 2 (EBI2 or GPR183) directs B-cell migration in the lymphoid follicles in response to its endogenous ligands, oxysterols. Thus, upregulation of EBI2 drives the B cells toward the extrafollicular area, whereas downregulation is essential for GC formation. We therefore speculated whether increased expression of EBI2 would lead to an expanded B1 cell subset and, ultimately, progression to CLL. Here, we demonstrate that B-cell-targeted expression of human EBI2 (hEBI2) in mice reduces GC-dependent immune responses, reduces total immunoglobulin M (igM) and igG levels, and leads to increased proliferation and upregulation of cellular oncogenes. Furthermore, hEBI2 overexpression leads to an abnormally expanded CD5(+) B1a B-cell subset (present as early as 4 days after birth), late-onset lymphoid cancer development, and premature death. These findings are highly similar to those observed in CLL patients and identify EBI2 as a promoter of B-cell malignancies. C1 [Arfelt, Kristine Niss; Barington, Line; Benned-Jensen, Tau; Kubale, Valentina; Daugvilaite, Viktorija; Egerod, Kristoffer L.; Spiess, Katja; Schwartz, Thue W.; Rosenkilde, Mette M.] Univ Copenhagen, Fac Hlth & Med Sci, Dept Neurosci & Pharmacol, Copenhagen, Denmark. [Kovalchuk, Alexander L.; Wang, Hongsheng; Morse, Herbert C., III] NIAID, Virol & Cellular Immunol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Christensen, Jan Pravsgaard; Thomsen, Allan Randrup; Bassi, Maria R.; Holst, Peter J.] Univ Copenhagen, Dept Immunol & Microbiol, Copenhagen, Denmark. [Egerod, Kristoffer L.; Schwartz, Thue W.] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark. RP Holst, PJ (reprint author), CSS, Ctr Med Parasitol, Bldg 22&23,Oster Farigmagsgade 5, DK-1014 Copenhagen, Denmark.; Rosenkilde, MM (reprint author), Univ Copenhagen, Dept Neurosci & Pharmacol, Blegdamsvej 3b,Bldg 18-5, DK-2200 Copenhagen, Denmark. EM pholst@sund.ku.dk; rosenkilde@sund.ku.dk OI Daugvilaite, Viktorija /0000-0001-8786-348X FU NovoNordisk Foundation; Danish Council for Independent Research [Medical Sciences]; Lundbeck Foundation; University of Copenhagen; Aase and Einar Danielsen Foundation; A.P. Moller Foundation for Advancement of Medical Science; National Institutes of Health; National Institute of Allergy and Infectious Diseases; Slovenian Research Agency [P4-0053] FX This work was supported in part by the NovoNordisk Foundation, the Danish Council for Independent Research [Medical Sciences], the Lundbeck Foundation, the University of Copenhagen, the Aase and Einar Danielsen Foundation, the A.P. Moller Foundation for the Advancement of Medical Science (K.N.A., L.B., T.B.-J., V.K., V.D., K.S., P.J.H., and M.M.R.), and the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases (A.L.K. and H.C.M.). V.K. was further supported by the Slovenian Research Agency (P4-0053). NR 48 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD FEB 16 PY 2017 VL 129 IS 7 BP 866 EP 878 DI 10.1182/blood-2016-02-697185 PG 13 WC Hematology SC Hematology GA EO9OW UT WOS:000397019000011 ER PT J AU Nelson, KB Sartwelle, TP Rouse, DJ AF Nelson, Karin B. Sartwelle, Thomas P. Rouse, Dwight J. TI Most cases of cerebral palsy are associated with antenatal events Reply SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Letter C1 [Nelson, Karin B.] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Sartwelle, Thomas P.] Deans & Lyons, Houston, TX USA. [Rouse, Dwight J.] Women & Infants Hosp Rhode Isl, Providence, RI 02908 USA. [Rouse, Dwight J.] Brown Univ, Providence, RI 02912 USA. RP Nelson, KB (reprint author), NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM nelsonk@ninds.nih.gov NR 6 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BMJ-BRIT MED J JI BMJ-British Medical Journal PD FEB 16 PY 2017 VL 356 AR j835 DI 10.1136/bmj.j835 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA EL4GN UT WOS:000394579800008 PM 28209563 ER PT J AU Smargon, AA Cox, DBT Pyzocha, NK Zheng, KJ Slaymaker, IM Gootenberg, JS Abudayyeh, OA Essletzbichler, P Shmakov, S Makarova, KS Koonin, EV Zhang, F AF Smargon, Aaron A. Cox, David B. T. Pyzocha, Neena K. Zheng, Kaijie Slaymaker, Ian M. Gootenberg, Jonathan S. Abudayyeh, Omar A. Essletzbichler, Patrick Shmakov, Sergey Makarova, Kira S. Koonin, Eugene V. Zhang, Feng TI Cas13b Is a Type VI-B CRISPR-Associated RNA-Guided RNase Differentially Regulated by Accessory Proteins Csx27 and Csx28 SO MOLECULAR CELL LA English DT Article ID BINDING PROTEINS; THERMUS-THERMOPHILUS; PYROCOCCUS-FURIOSUS; COMPLEX; SYSTEMS; PREDICTION; IDENTIFICATION; TRANSCRIPTOME; ALIGNMENT; IMMUNITY AB CRISPR-Cas adaptive immune systems defend microbes against foreign nucleic acids via RNA-guided endonucleases. Using a computational sequence database mining approach, we identify two class 2 CRISPR-Cas systems (subtype VI-B) that lack Cas1 and Cas2 and encompass a single large effector protein, Cas13b, along with one of two previously uncharacterized associated proteins, Csx27 and Csx28. We establish that these CRISPR-Cas systems can achieve RNA interference when heterologously expressed. Through a combination of biochemical and genetic experiments, we show that Cas13b processes its own CRISPR array with short and long direct repeats, cleaves target RNA, and exhibits collateral RNase activity. Using an E. coli essential gene screen, we demonstrate that Cas13b has a double-sided protospacer-flanking sequence and elucidate RNA secondary structure requirements for targeting. We also find that Csx27 represses, whereas Csx28 enhances, Cas13b-mediated RNA interference. Characterization of these CRISPR systems creates opportunities to develop tools to manipulate and monitor cellular transcripts. C1 [Smargon, Aaron A.; Cox, David B. T.; Pyzocha, Neena K.; Zheng, Kaijie; Slaymaker, Ian M.; Gootenberg, Jonathan S.; Abudayyeh, Omar A.; Essletzbichler, Patrick; Zhang, Feng] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Smargon, Aaron A.; Cox, David B. T.; Pyzocha, Neena K.; Zheng, Kaijie; Slaymaker, Ian M.; Gootenberg, Jonathan S.; Abudayyeh, Omar A.; Essletzbichler, Patrick; Zhang, Feng] MIT, McGovern Inst Brain Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Smargon, Aaron A.; Cox, David B. T.; Pyzocha, Neena K.; Zheng, Kaijie; Slaymaker, Ian M.; Gootenberg, Jonathan S.; Abudayyeh, Omar A.; Essletzbichler, Patrick; Zhang, Feng] MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA. [Smargon, Aaron A.; Cox, David B. T.; Pyzocha, Neena K.; Zheng, Kaijie; Slaymaker, Ian M.; Gootenberg, Jonathan S.; Abudayyeh, Omar A.; Essletzbichler, Patrick; Zhang, Feng] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Smargon, Aaron A.; Zhang, Feng] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. [Cox, David B. T.; Abudayyeh, Omar A.] Harvard Med Sch, Harvard MIT Div Hlth Sci & Technol, Boston, MA 02115 USA. [Cox, David B. T.; Pyzocha, Neena K.] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Gootenberg, Jonathan S.] Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA. [Shmakov, Sergey] Skolkovo Inst Sci & Technol, Skolkovo 143025, Russia. [Shmakov, Sergey; Makarova, Kira S.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Zhang, F (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.; Zhang, F (reprint author), MIT, McGovern Inst Brain Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Zhang, F (reprint author), MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA.; Zhang, F (reprint author), MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Zhang, F (reprint author), MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. EM zhang@broadinstitute.org OI Essletzbichler, Patrick/0000-0003-2237-0005 FU National Institute of General Medical Sciences [T32GM007753]; Simons Center for the Social Brain; D.O.E. Computational Science Graduate Fellowship; Paul and Daisy Soros Fellowship; Friends of the McGovern Institute Fellowship; Poitras Center for Affective Disorders; U.S. Department of Health and Human services; Skoltech-MIT Next Generation Program grant; NIH through NIMH [5DP1-MH100706, 1R01-MH110049]; NSF; New York Stem Cell Foundation; Allen Distinguished Investigator Program, through The Paul G. Allen Frontiers Group; Simons Foundation; Vallee Foundation; Howard Hughes Medical Institute; Skoltech-MIT Next Generation Program; James and Patricia Poitras and the Poitras Center for Affective Disorders; Robert Metcalfe FX We would like to thank R. Belliveau for overall research support, R. Macrae for critical reading of the manuscript, and the entire Zhang laboratory for support and advice. D.B.T.C. is supported by award number T32GM007753 from the National Institute of General Medical Sciences. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences or the NIH. I.M.S. is supported by the Simons Center for the Social Brain. J.S.G. is supported by a D.O.E. Computational Science Graduate Fellowship. O.A.A. is supported by a Paul and Daisy Soros Fellowship, a Friends of the McGovern Institute Fellowship, and the Poitras Center for Affective Disorders. K.S.M., E.V.K., and S.S. are supported by the intramural program of the U.S. Department of Health and Human services (to the National Library of Medicine). S.S. is also supported by a Skoltech-MIT Next Generation Program grant (to K. Severinov and F.Z.). F.Z. is supported by the NIH through NIMH (5DP1-MH100706 and 1R01-MH110049); NSF; the New York Stem Cell Foundation; the Allen Distinguished Investigator Program, through The Paul G. Allen Frontiers Group; the Simons and Vallee Foundations; the Howard Hughes Medical Institute; the Skoltech-MIT Next Generation Program; James and Patricia Poitras and the Poitras Center for Affective Disorders; Robert Metcalfe; and David Cheng. F.Z. is a New York Stem Cell Foundation-Robertson Investigator. A patent application has been filed related to this work, and the authors plan to make the reagents widely available to the academic community through Addgene and to provide protocols and software tools via the Zhang lab website (http://www.genome-engineering.org) and GitHub (https://www.github.com/fengzhanglab). NR 40 TC 1 Z9 1 U1 5 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD FEB 16 PY 2017 VL 65 IS 4 BP 618 EP + DI 10.1016/j.molcel.2016.12.023 PG 20 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EO1BB UT WOS:000396431500006 PM 28065598 ER PT J AU Younge, N Goldstein, RF Bann, CM Hintz, SR Patel, RM Smith, PB Bell, EF Rysavy, MA Duncan, AF Vohr, BR Das, A Goldberg, RN Higgins, RD Cotten, CM AF Younge, Noelle Goldstein, Ricki F. Bann, Carla M. Hintz, Susan R. Patel, Ravi M. Smith, P. Brian Bell, Edward F. Rysavy, Matthew A. Duncan, Andrea F. Vohr, Betty R. Das, Abhik Goldberg, Ronald N. Higgins, Rosemary D. Cotten, C. Michael CA Eunice Kennedy Shriver Natl Inst C Human Dev Neonatal Res Network TI Survival and Neurodevelopmental Outcomes among Periviable Infants SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID BIRTH-WEIGHT INFANTS; EXTREMELY PRETERM INFANTS; ACTIVE PERINATAL-CARE; WEEKS GESTATIONAL-AGE; BAYLEY-III; NATIONAL INSTITUTE; CHILDREN BORN; SCHOOL-AGE; MORTALITY; MORBIDITY AB BACKGROUND Data reported during the past 5 years indicate that rates of survival have increased among infants born at the borderline of viability, but less is known about how increased rates of survival among these infants relate to early childhood neurodevelopmental outcomes. METHODS We compared survival and neurodevelopmental outcomes among infants born at 22 to 24 weeks of gestation, as assessed at 18 to 22 months of corrected age, across three consecutive birth-year epochs ( 2000-2003 [ epoch 1], 2004-2007 [ epoch 2], and 20082011 [ epoch 3]). The infants were born at 11 centers that participated in the National Institute of Child Health and Human Development Neonatal Research Network. The primary outcome measure was a three-level outcome - survival without neurodevelopmental impairment, survival with neurodevelopmental impairment, or death. After accounting for differences in infant characteristics, including birth center, we used multinomial generalized logit models to compare the relative risk of survival without neurodevelopmental impairment, survival with neurodevelopmental impairment, and death. RESULTS Data on the primary outcome were available for 4274 of 4458 infants ( 96%) born at the 11 centers. The percentage of infants who survived increased from 30% ( 424 of 1391 infants) in epoch 1 to 36% ( 487 of 1348 infants) in epoch 3 ( P<0.001). The percentage of infants who survived without neurodevelopmental impairment increased from 16% ( 217 of 1391) in epoch 1 to 20% ( 276 of 1348) in epoch 3 (P = 0.001), whereas the percentage of infants who survived with neurodevelopmental impairment did not change significantly ( 15% [ 207 of 1391] in epoch 1 and 16% [ 211 of 1348] in epoch 3, P = 0.29). After adjustment for changes in the baseline characteristics of the infants over time, both the rate of survival with neurodevelopmental impairment as compared with death) and the rate of survival without neurodevelopmental impairment ( as compared with death) increased over time ( adjusted relative risks, 1.27 [95% confidence interval {CI}, 1.01 to 1.59] and 1.59 [ 95% CI, 1.28 to 1.99], respectively). CONCLUSIONS The rate of survival without neurodevelopmental impairment increased between 2000 and 2011 in this large cohort of periviable infants. ( Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT00063063 and NCT00009633.) C1 [Younge, Noelle; Goldstein, Ricki F.; Smith, P. Brian; Goldberg, Ronald N.; Cotten, C. Michael] Duke Univ, Dept Pediat, DUMC Box 2739, Durham, NC 27710 USA. [Bann, Carla M.; Das, Abhik] RTI Int, Stat & Epidemiol Unit, Res Triangle Pk, NC USA. [Hintz, Susan R.] Stanford Univ, Sch Med, Dept Pediat, Palo Alto, CA 94304 USA. [Hintz, Susan R.] Lucile Packard Childrens Hosp, Palo Alto, CA USA. [Patel, Ravi M.] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA. [Patel, Ravi M.] Childrens Healthcare Atlanta, Atlanta, GA USA. [Bell, Edward F.; Rysavy, Matthew A.] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. [Rysavy, Matthew A.] Univ Wisconsin, Dept Pediat, Madison, WI USA. [Duncan, Andrea F.] Univ Texas Houston, Sch Med, Dept Pediat, Houston, TX USA. [Vohr, Betty R.] Brown Univ, Women & Infants Hosp, Dept Pediat, Providence, RI 02908 USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Younge, N (reprint author), Duke Univ, Dept Pediat, DUMC Box 2739, Durham, NC 27710 USA. EM noelle.younge@duke.edu FU National Institutes of Health [5T32HD043728-10, HD060558-05, 4K12HD043494-14]; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Center for Research Resources; National Center for Advancing Translational Sciences for the Neonatal Research Network's Generic Database and Follow-up Studies [U10 HD27904, U10 HD21364, M01 RR80, U10 HD68284, U10 HD27853, M01 RR8084, U10 HD40492, M01 RR30, U10 HD27851, M01 RR39, U10 HD27856, M01 RR750, U10 HD68278, U10 HD36790, U10 HD27880, M01 RR70, UL1 TR93, U10 HD53119, M01 RR54]; [U10 HD68244]; [U10 HD68263]; [U10 HD40521]; [UL1 RR24160]; [M01 RR44]; [UL1 TR42]; [U10 HD21415]; [U10 HD21373]; [U10 HD40689]; [M01 RR633]; [U10 HD53124]; [M01 RR64]; [UL1 TR105]; [U10 HD40498]; [M01 RR7122]; [U10 HD21385]; [U10 HD27871]; [UL1 RR24139]; [M01 RR125]; [UL1 TR142]; [M01 RR59]; [U10 HD21397]; [M01 RR16587]; [U10 HD27881]; [U10 HD53089]; [M01 RR997]; [U10 HD34216]; [M01 RR32]; [U10 HD68270]; [U10 HD40461]; [U10 HD53109] FX Supported by grants from the National Institutes of Health ( including grants 5T32HD043728-10, HD060558-05, and 4K12HD043494-14 to Dr. Younge) and from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, grants from the National Center for Research Resources, and cooperative agreements from the National Center for Advancing Translational Sciences for the Neonatal Research Network's Generic Database and Follow-up Studies (U10 HD27904, U10 HD21364, M01 RR80, U10 HD68284, U10 HD27853, M01 RR8084, U10 HD40492, M01 RR30, U10 HD27851, M01 RR39, U10 HD27856, M01 RR750, U10 HD68278, U10 HD36790, U10 HD27880, M01 RR70, UL1 TR93, U10 HD53119, M01 RR54, U10 HD34216, M01 RR32, U10 HD68270, U10 HD40461, U10 HD53109, M01 RR59, U10 HD21397, M01 RR16587, U10 HD27881, U10 HD53089, M01 RR997, U10 HD68244, U10 HD68263, U10 HD40521, UL1 RR24160, M01 RR44, UL1 TR42, U10 HD21415, U10 HD21373, U10 HD40689, M01 RR633, U10 HD53124, M01 RR64, UL1 TR105, U10 HD40498, M01 RR7122, U10 HD21385, U10 HD27871, UL1 RR24139, M01 RR125, and UL1 TR142). NR 39 TC 1 Z9 1 U1 3 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 16 PY 2017 VL 376 IS 7 BP 617 EP 628 DI 10.1056/NEJMoa1605566 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA EO0QJ UT WOS:000396402700013 PM 28199816 ER PT J AU Davey, RT Nordwall, J Proschan, MA AF Davey, Richard T., Jr. Nordwall, Jacquie Proschan, Michael A. CA Prevail II Study Team TI Trial of ZMapp for Ebola Virus Infection REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Davey, Richard T., Jr.; Proschan, Michael A.] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Nordwall, Jacquie] Univ Minnesota, Minneapolis, MN USA. RP Davey, RT (reprint author), NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM rdavey@niaid.nih.gov NR 3 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 16 PY 2017 VL 376 IS 7 BP 700 EP 701 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA EO0QJ UT WOS:000396402700026 PM 28199801 ER PT J AU Rosenberg, SA Tran, E Robbins, PF AF Rosenberg, Steven A. Tran, Eric Robbins, Paul F. TI T-Cell Transfer Therapy Targeting Mutant KRAS REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Rosenberg, Steven A.; Tran, Eric; Robbins, Paul F.] NCI, Bethesda, MD 20892 USA. RP Rosenberg, SA (reprint author), NCI, Bethesda, MD 20892 USA. EM sar@nih.gov NR 5 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 16 PY 2017 VL 376 IS 7 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA EO0QJ UT WOS:000396402700004 ER PT J AU Gaksch, M Jorde, R Grimnes, G Joakimsen, R Schirmer, H Wilsgaard, T Mathiesen, EB Njolstad, I Lochen, ML Marz, W Kleber, ME Tomaschitz, A Grubler, M Eiriksdottir, G Gudmundsson, EF Harris, TB Cotch, MF Aspelund, T Gudnason, V Rutters, F Beulens, JWJ van't Riet, E Nijpels, G Dekker, JM Grove-Laugesen, D Rejnmark, L Busch, MA Mensink, GBM Scheidt-Nave, C Thamm, M Swart, KMA Brouwer, IA Lips, P van Schoor, NM Sempos, CT Durazo-Arvizu, RA Skrabakova, Z Dowling, KG Cashman, KD Kiely, M Pilz, S AF Gaksch, Martin Jorde, Rolf Grimnes, Guri Joakimsen, Ragnar Schirmer, Henrik Wilsgaard, Tom Mathiesen, Ellisiv B. Njolstad, Inger Lochen, Maja-Lisa Maerz, Winfried Kleber, Marcus E. Tomaschitz, Andreas Gruebler, Martin Eiriksdottir, Gudny Gudmundsson, Elias F. Harris, Tamara B. Cotch, Mary F. Aspelund, Thor Gudnason, Vilmundur Rutters, Femke Beulens, Joline W. J. van't Riet, Esther Nijpels, Giel Dekker, Jacqueline M. Grove-Laugesen, Diana Rejnmark, Lars Busch, Markus A. Mensink, Gert B. M. Scheidt-Nave, Christa Thamm, Michael Swart, Karin M. A. Brouwer, Ingeborg A. Lips, Paul van Schoor, Natasja M. Sempos, Christopher T. Durazo-Arvizu, Ramon A. Skrabakova, Zuzana Dowling, Kirsten G. Cashman, Kevin D. Kiely, Mairead Pilz, Stefan TI Vitamin D and mortality: Individual participant data meta-analysis of standardized 25-hydroxyvitamin D in 26916 individuals from a European consortium SO PLOS ONE LA English DT Article ID ALL-CAUSE MORTALITY; DOSE-RESPONSE DATA; D DEFICIENCY; D TRIALS; HEALTH; OUTCOMES; CANCER; PREVENTION; DISEASE; COHORT AB Background Vitamin D deficiency may be a risk factor for mortality but previous meta-analyses lacked standardization of laboratory methods for 25-hydroxyvitamin D (25[OH]D) concentrations and used aggregate data instead of individual participant data (IPD). We therefore performed an IPD meta-analysis on the association between standardized serum 25(OH)D and mortality. Methods In a European consortium of eight prospective studies, including seven general population cohorts, we used the Vitamin D Standardization Program (VDSP) protocols to standardize 25(OH)D data. Meta-analyses using a one step procedure on IPD were performed to study associations of 25(OH)D with all-cause mortality as the primary outcome, and with cardiovascular and cancer mortality as secondary outcomes. This meta-analysis is registered at ClinicalTrials.gov, number NCT02438488. Findings We analysed 26916 study participants (median age 61.6 years, 58% females) with a median 25(OH) D concentration of 53.8 nmol/L. During a median follow-up time of 10.5 years, 6802 persons died. Compared to participants with 25(OH)D concentrations of 75 to 99.99 nmol/L, the adjusted hazard ratios (with 95% confidence interval) for mortality in the 25(OH)D groups with 40 to 49.99, 30 to 39.99, and <30 nmol/L were 1.15 (1.00 +/- 1.29), 1.33 (1.16 +/- 1.51), and 1.67 (1.44 +/- 1.89), respectively. We observed similar results for cardiovascular mortality, but there was no significant linear association between 25(OH)D and cancer mortality. There was also no significantly increased mortality risk at high 25(OH)D levels up to 125 nmol/L. Interpretation In the first IPD meta-analysis using standardized measurements of 25(OH)D we observed an association between low 25(OH)D and increased risk of all-cause mortality. It is of public health interest to evaluate whether treatment of vitamin D deficiency prevents premature deaths. C1 [Gaksch, Martin; Gruebler, Martin; Pilz, Stefan] Med Univ Graz, Div Endocrinol & Diabetol, Dept Internal Med, Graz, Austria. [Jorde, Rolf; Grimnes, Guri; Joakimsen, Ragnar; Mathiesen, Ellisiv B.] Univ Tromso, Dept Clin Med, Tromso Endocrine Res Grp, Tromso, Norway. [Schirmer, Henrik] UiT Arctic Univ Norway, Dept Clin Med, Tromso Cardiovasc Res Grp UNN, Tromso, Norway. [Wilsgaard, Tom; Njolstad, Inger; Lochen, Maja-Lisa] UiT Arctic Univ Norway, Dept Community Med, Tromso, Norway. [Maerz, Winfried; Kleber, Marcus E.] Heidelberg Univ, Mannheim Inst Publ Hlth Social & Prevent Med, Mannheim Med Fac, Mannheim, Germany. [Maerz, Winfried] Synlab Acad, Mannheim, Germany. [Maerz, Winfried] Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria. [Kleber, Marcus E.] Univ Ulm, Med Ctr, Dept Internal Med Cardiol 2, Ulm, Germany. [Tomaschitz, Andreas; Gruebler, Martin] Med Univ Graz, Dept Cardiol, Graz, Austria. [Tomaschitz, Andreas] Specialist Clin Rehabil Bad Aussee, Bad Aussee, Austria. [Tomaschitz, Andreas] Charite, Campus Virchow Klinikum, Dept Internal Med Cardiol, Berlin, Germany. [Gruebler, Martin] Univ Hosp Bern, Dept Cardiol, Swiss Cardiovasc Ctr Bern, Bern, Switzerland. [Eiriksdottir, Gudny; Gudmundsson, Elias F.; Aspelund, Thor; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Harris, Tamara B.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. [Cotch, Mary F.] NEI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. [Aspelund, Thor; Gudnason, Vilmundur] Univ Iceland, Fac Med, Sch Hlth Sci, Reykjavik, Iceland. [Rutters, Femke; Beulens, Joline W. J.; van't Riet, Esther; Nijpels, Giel; Dekker, Jacqueline M.; Swart, Karin M. A.; van Schoor, Natasja M.; Pilz, Stefan] Vrije Univ Amsterdam Med Ctr, Dept Epidemiol & Biostat, Amsterdam, Netherlands. [Rutters, Femke; Beulens, Joline W. J.; van't Riet, Esther; Nijpels, Giel; Dekker, Jacqueline M.; Swart, Karin M. A.; van Schoor, Natasja M.; Pilz, Stefan] Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. [Beulens, Joline W. J.; Pilz, Stefan] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Grove-Laugesen, Diana; Rejnmark, Lars] Aarhus Univ Hosp, Dept Endocrinol & Internal Med, Aarhus, Denmark. [Busch, Markus A.; Mensink, Gert B. M.; Scheidt-Nave, Christa; Thamm, Michael] Robert Koch Inst, Dept Epidemiol & Hlth Monitoring, Berlin, Germany. [Brouwer, Ingeborg A.] Vrije Univ Amsterdam, Dept Hlth Sci, Amsterdam, Netherlands. [Brouwer, Ingeborg A.] Vrije Univ Amsterdam, EMGO Inst Hlth & Care Res, Fac Earth & Life Sci, Amsterdam, Netherlands. [Lips, Paul] Vrije Univ Amsterdam Med Ctr, Dept Internal Med, Endocrine Sect, Amsterdam, Netherlands. [Sempos, Christopher T.] NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA. [Durazo-Arvizu, Ramon A.] Loyola Univ, Med Ctr, Dept Prevent Med & Epidemiol, 2160 S 1st Ave, Maywood, IL 60153 USA. [Skrabakova, Zuzana; Dowling, Kirsten G.; Cashman, Kevin D.; Kiely, Mairead] Univ Coll Cork, Cork Ctr Vitamin D & Nutr Res, Sch Food & Nutr Sci, Cork, Ireland. [Cashman, Kevin D.] Univ Coll Cork, Dept Med, Cork, Ireland. [Kiely, Mairead] Univ Coll Cork, Irish Ctr Fetal & Neonatal Translat Res INFANT, Cork, Ireland. RP Pilz, S (reprint author), Med Univ Graz, Div Endocrinol & Diabetol, Dept Internal Med, Graz, Austria.; Pilz, S (reprint author), Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands.; Pilz, S (reprint author), Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. EM stefan.pilz@chello.at FU European Community [613977] FX This project has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under Grant Agreement 613977 for the ODIN Integrated Project [Food-based solutions for optimal vitamin D nutrition and health through the life cycle http://www.odin-vitd.eu/]. Funding for the individual studies contributing data to this effort can be found in Appendix (S1File), section 11. NR 40 TC 0 Z9 0 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 16 PY 2017 VL 12 IS 2 AR e0170791 DI 10.1371/journal.pone.0170791 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EL2BG UT WOS:000394424500013 PM 28207791 ER PT J AU Luo, ZP Dauter, Z AF Luo, Zhipu Dauter, Zbigniew TI Embarras de richesses - It is not good to be too anomalous: Accurate structure of selenourea, a chiral crystal of planar molecules SO PLOS ONE LA English DT Article ID DIFFRACTION AB Selenourea, SeC(NH2)(2), recently found an application as a derivatization reagent providing a significant anomalous diffraction signal used for phasing macromolecular crystal structures. The crystal structure of selenourea itself was solved about 50 years ago, from data recorded on films and evaluated by eye and refined to R= 0.15 with errors of bond lengths and angles about 0.1 angstrom and 6 degrees. In the current work this structure is re-evaluated on the basis of synchrotron data and refined to R1 = 0.021 with bond and angle errors about 0.007 angstrom and 0.5. The nine planar molecules of selenourea pack either in the P3(1) or in the P3(2) unit cell. All unique molecules are connected by a complex network of Se center dot center dot center dot H-N hydrogen bonds and Se center dot center dot center dot Se contacts. The packing of selenourea molecules is highly pseudosymmetric, approximating either of the P3(1(2))12, R3, and R32 space groups. Because the overwhelming majority of diffracted X-ray intensity originates form the anomalously scattering selenium atoms, the measurable anomalous Bijvoet differences are diminished and it was not possible to solve this crystal structure based on the anomalous signal alone. C1 [Luo, Zhipu; Dauter, Zbigniew] NCI, Synchrotron Radiat Res Sect, Argonne Natl Lab, Argonne, IL 60439 USA. RP Dauter, Z (reprint author), NCI, Synchrotron Radiat Res Sect, Argonne Natl Lab, Argonne, IL 60439 USA. EM dauter@anl.gov FU Intramural Research Program of the National Cancer Institute FX This work was supported by the Intramural Research Program of the National Cancer Institute. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 18 TC 0 Z9 0 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 FEB 16 PY 2017 VL 12 IS 2 AR e0171740 DI 10.1371/journal.pone.0171740 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EL2BG UT WOS:000394424500049 PM 28207770 ER PT J AU Deziel, NC Nuckols, JR Jones, RR Graubard, BI De Roos, AJ Pronk, A Gourley, C Colt, JS Ward, MH AF Deziel, Nicole C. Nuckols, John R. Jones, Rena R. Graubard, Barry I. De Roos, Anneclaire J. Pronk, Anjoeka Gourley, Chris Colt, Joanne S. Ward, Mary H. TI Comparison of industrial emissions and carpet dust concentrations of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans in a multi-center US study SO SCIENCE OF THE TOTAL ENVIRONMENT LA English DT Article DE Dioxins; Furans; Geographic information systems; Dust; Air pollution; Environmental exposure; Non-Hodgkin lymphoma (NHL) ID SOLID-WASTE INCINERATOR; IN-HOUSE DUST; NON-HODGKINS-LYMPHOMA; PERSISTENT ORGANIC POLLUTANTS; HUMAN EXPOSURE; ATTIC DUST; UNITED-STATES; TREATMENT-PLANT; SERUM-LEVELS; PCBS AB Proximity to facilities emitting polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/F) has been associated with increased risk of non-Hodgkin lymphoma (NHL). There is limited information about whether proximity to industrial sources leads to indoor PCDD/F contamination of homes. We measured carpet dust concentrations (pg/g) of 17 toxic PCDD/F congeners and calculated their toxic equivalence (TEQ) in 100 homes in a population-based case-control study of NHL in Detroit, Los Angeles, Seattle, and Iowa (1998-2000). We took global positioning system readings at residences and obtained coordinates and PCDD/F emissions (ng TEQ/yr) from an Environmental Protection Agency database for 6 facility types: coal-fired electricity generating plants, cement kilns burning non-hazardous waste, hazardous waste incinerators, medical waste incinerators, municipal solid waste incinerators, and sewage sludge incinerators. For each residence, we computed an inverse distance-squared weighted average emission index (AEI [pg TEQ/km(2)/yr]) for all facilities within 5 km from 1983 to 2000. We also computed AEIs for each of the 6 facility types. We evaluated relationships between PCDD/F dust concentrations and the all-facility AEI or categories of facility-type AEIs using multivariable linear regression, adjusting for study center, demographics, and home characteristics. A doubling of the all-facility AEI was associated with a 4-8% increase in PCDD/F dust concentrations of 7 of 17 PCDD/F congeners and the TEQ (p-value < 0.1). We also observed positive associations between PCDD/F dust concentrations and facility-type AEIs (highest vs. lowest exposure category) for municipal solid Waste incinerators (9 PCDD/F, TEQ), and medical waste incinerators (7 PCDD/F, TEQ) (p < 0.1). Our results from diverse geographical areas suggest that industrial PCDD/F emission sources contribute to residential PCDD/F dust concentrations. Our emissions index could be improved by incorporating local meteorological data and terrain characteristics. Future research is needed to better understand the links between nearby emission sources, human exposure pathways, and health risks. (C) 2016 Elsevier B.V. All rights reserved. C1 [Deziel, Nicole C.] Yale Sch Publ Hlth, Dept Environm Hlth Sci, 60 Coll St, New Haven, CT 06510 USA. [Deziel, Nicole C.; Jones, Rena R.; Graubard, Barry I.; Colt, Joanne S.; Ward, Mary H.] NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, 9609 Med Ctr Dr, Rockville, MD 20850 USA. [Nuckols, John R.] Colorado State Univ, Dept Environm Hlth Sci, 1681 Campus Delivery, Ft Collins, CO 80523 USA. [Nuckols, John R.] JRN Environm Hlth Sci Ltd, 10916 Wickshire Way, North Bethesda, MD 20852 USA. [De Roos, Anneclaire J.] Drexel Univ, Dornsife Sch Publ Hlth, Dept Environm & Occupat Hlth, 3215 Market S1, Philadelphia, PA 19104 USA. [Pronk, Anjoeka] TNO, Zeist, Netherlands. [Gourley, Chris] Southwest Res Inst, 6220 Culebra Rd, San Antonio, TX 78238 USA. RP Deziel, NC (reprint author), Yale Sch Publ Hlth, Dept Environm Hlth Sci, 60 Coll St, New Haven, CT 06510 USA. EM nicole.deziel@yale.edu FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), National Institutes of Health; NCI-Iowa SEER [N01-CN-67008]; NCI-Los Angeles County SEER [N01-CN-67010]; NCI-Seattle SEER [N01-PC-67009]; NCI-Detroit SEER [N01-PC-65064]; Colorado State University FX This study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), National Institutes of Health; NCI-Iowa SEER contract N01-CN-67008; NCI-Los Angeles County SEER contract N01-CN-67010; NCI-Seattle SEER contract N01-PC-67009; and NCI-Detroit SEER contract N01-PC-65064. John Nuckols was supported, in part, through an intergovernmental personnel and Colorado State University. NR 76 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0048-9697 EI 1879-1026 J9 SCI TOTAL ENVIRON JI Sci. Total Environ. PD FEB 15 PY 2017 VL 580 BP 1276 EP 1286 DI 10.1016/j.scitotenv.2016.12.090 PG 11 WC Environmental Sciences SC Environmental Sciences & Ecology GA EM5LS UT WOS:000395353600125 PM 28017415 ER PT J AU Shiels, MS Althoff, KN Pfeiffer, RM Achenbach, CJ Abraham, AG Castilho, J Cescon, A D'Souza, G Dubrow, R Eron, JJ Gebo, K Gill, MJ Goedert, JJ Grover, S Hessol, NA Justice, A Kitahata, M Mayor, A Moore, RD Napravnik, S Novak, RM Thorne, JE Silverberg, MJ Engels, EA AF Shiels, Meredith S. Althoff, Keri N. Pfeiffer, Ruth M. Achenbach, Chad J. Abraham, Alison G. Castilho, Jessica Cescon, Angela D'Souza, Gypsyamber Dubrow, Robert Eron, Joseph J. Gebo, Kelly Gill, M. John Goedert, James J. Grover, Surbhi Hessol, Nancy A. Justice, Amy Kitahata, Mari Mayor, Angel Moore, Richard D. Napravnik, Sonia Novak, Richard M. Thorne, Jennifer E. Silverberg, Michael J. Engels, Eric A. CA North American AIDS Cohort Collabo TI HIV Infection, Immunosuppression, and Age at Diagnosis of Non-AIDS-Defining Cancers SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE HIV; cancer; immunosuppression; AIDS; aging ID HUMAN-IMMUNODEFICIENCY-VIRUS; TRANSPLANT RECIPIENTS; UNITED-STATES; LUNG-CANCER; RISK-FACTORS; INDIVIDUALS; CARCINOMA; COHORT; METAANALYSIS; POPULATION AB Background. It is unclear whether immunosuppression leads to younger ages at cancer diagnosis among people living with human immunodeficiency virus (PLWH). A previous study found that most cancers are not diagnosed at a younger age in people with AIDS, with the exception of anal and lung cancers. This study extends prior work to include all PLWH and examines associations between AIDS, CD4 count, and age at cancer diagnosis. Methods. We compared the median age at cancer diagnosis between PLWH in the North American AIDS Cohort Collaboration on Research and Design and the general population using data from the Surveillance, Epidemiology and End Results Program. We used statistical weights to adjust for population differences. We also compared median age at cancer diagnosis by AIDS status and CD4 count. Results. After adjusting for population differences, younger ages at diagnosis (P <.05) were observed for PLWH compared with the general population for lung (difference in medians = 4 years), anal (difference = 4), oral cavity/ pharynx (difference = 2), and kidney cancers (difference = 2) and myeloma (difference = 4). Among PLWH, having an AIDS- defining event was associated with a younger age at myeloma diagnosis (difference = 4; P =.01), and CD4 count < 200 cells/mu L (vs >= 500) was associated with a younger age at lung cancer diagnosis (difference = 4; P =.006). Conclusions. Among PLWH, most cancers are not diagnosed at younger ages. However, this study strengthens evidence that lung cancer, anal cancer, and myeloma are diagnosed at modestly younger ages, and also shows younger ages at diagnosis of oral cavity/ pharynx and kidney cancers, possibly reflecting accelerated cancer progression, etiologic heterogeneity, or risk factor exposure in PLWH. C1 [Shiels, Meredith S.; Pfeiffer, Ruth M.] Natl Canc Inst, Div Canc Epidemiol & Genet, Rockville, MD USA. [Althoff, Keri N.; Abraham, Alison G.; D'Souza, Gypsyamber] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Achenbach, Chad J.] Northwestern Univ, Feinberg Sch Med, Ctr Global hlth, Dept Med Div Infectious Dis, Chicago, IL 60208 USA. [Abraham, Alison G.] Johns Hopkins Sch Med, Dept Ophthalmol, Baltimore, MD USA. [Castilho, Jessica] Vanderbilt Univ Sch Med, Div Infectious Dis, Nashville, TN USA. [Cescon, Angela] Northern Ontario Sch Med, Sudbury, ON, Canada. [Dubrow, Robert] Yale Sch Publ Hlth, Dept Epidemiol, New Haven, CT USA. [Eron, Joseph J.] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Gebo, Kelly] Johns Hopkins Sch Med, Dept Med, Baltimore, MD USA. [Gill, M. John] Univ Calgary, Dept Med, Calgary, AB T2N 1N4, Canada. [Grover, Surbhi] Univ Penn, Dept Radiat Oncol, Philadelphia, PA 19104 USA. [Hessol, Nancy A.] Univ Calif San Francisco, Sch Pharm, San Francisco, CA 94143 USA. [Justice, Amy] Yale Sch Med, Dept Med, New Haven, CT USA. [Kitahata, Mari] Univ Washington, Ctr AIDS Res, Seattle, WA 98195 USA. [Mayor, Angel] Univ Cent Caribe, Sch Med, Bayamon, PR USA. [Novak, Richard M.] Univ Illinois, Coll Med, Div Infectious Dis, Chicago, IL 60680 USA. [Silverberg, Michael J.] Kaiser Permanente Northern California, Div Res, Oakland, CA USA. RP Shiels, MS (reprint author), NCI, NIH, 9609 Med Ctr Dr,Rm 6F-218 MSC 9767, Bethesda, MD 20892 USA. EM shielsms@mail.nih.gov FU ICMJE FX All authors certify no potential conflicts of interest. The authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. NR 31 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD FEB 15 PY 2017 VL 64 IS 4 BP 468 EP 475 DI 10.1093/cid/ciw764 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EP3SB UT WOS:000397300900019 ER PT J AU Kadri, SS O'Grady, NP AF Kadri, Sameer S. O'Grady, Naomi P. TI How Will We Pay for the New Infectious Diseases/Critical Care Medicine Subspecialty? Reply SO CLINICAL INFECTIOUS DISEASES LA English DT Letter C1 [Kadri, Sameer S.; O'Grady, Naomi P.] NIH, Dept Crit Care Med, Ctr Clin, 10 Ctr Dr,Bldg 10,2C-145, Bethesda, MD 20892 USA. RP Kadri, SS (reprint author), NIH, Dept Crit Care Med, Ctr Clin, 10 Ctr Dr,Bldg 10,2C-145, Bethesda, MD 20892 USA. EM sameer.kadri@nih.gov NR 2 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD FEB 15 PY 2017 VL 64 IS 4 BP 531 EP 531 DI 10.1093/cid/ciw790 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EP3SB UT WOS:000397300900035 ER PT J AU Holt, MP Punkosdy, GA Glass, DD Shevach, EM AF Holt, Michael P. Punkosdy, George A. Glass, Deborah D. Shevach, Ethan M. TI TCR Signaling and CD28/CTLA-4 Signaling Cooperatively Modulate T Regulatory Cell Homeostasis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MULTIORGAN TISSUE DESTRUCTION; IN-VIVO; STEADY-STATE; CTLA-4; ACTIVATION; SELF; MICE; CD28; IL-2; CD4 AB Foxp3(+) T regulatory cells (Tregs), conventional CD4(+)Foxp3(-) T cells, and CD8(+) T cells represent heterogeneous populations composed of naive phenotype (NP, CD44(low)) and memory phenotype (MP, CD44(high)) subpopulations. NP and MP subsets differ in their activation state, contribution to immune function, and capacity to proliferate in vivo. To further understand the factors that contribute to the differential homeostasis of NP/MP subsets, we examined the differential effects of CD28 and CTLA-4 interaction with CD80/CD86, as well as MHC class II-TCR interaction within mouse Treg pools and CD4(+) and CD8(+) T cell pools. Blockade of CD80/CD86 with CTLA-4-Ig markedly reduced the cycling and absolute numbers of MP Tregs and MP CD4(+) T cells, with minimal effect on the NP T cell subpopulations. Blockade of MHC class II-TCR interaction led to selective expansion of MP Tregs and MP CD4(+) and CD8(+) T cells that was reversed upon cotreatment with CTLA-4-Ig. Treatment with anti-CTLA-4 mAb altered MP Treg and MP CD4(+) and CD8(+) T cell homeostasis in a manner similar to that observed with anti-MHC class II. We postulate a complex pathway in which CD28 is the primary driver of Treg proliferation and CTLA-4 functions as the main brake but is likely dependent on TCR signals and CD80/CD86. These findings have important implications for the use of biologic agents targeting such pathways to modulate autoimmune and neoplastic disease. C1 [Holt, Michael P.; Glass, Deborah D.; Shevach, Ethan M.] NIAID, Immunol Lab, NIH, Bldg 10,Room 11N315,10 Ctr Dr,MSC 1892, Bethesda, MD 20892 USA. [Punkosdy, George A.] Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA. [Punkosdy, George A.] Emory Univ, Sch Med, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. RP Shevach, EM (reprint author), NIAID, Immunol Lab, NIH, Bldg 10,Room 11N315,10 Ctr Dr,MSC 1892, Bethesda, MD 20892 USA. EM eshevach@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by funds from the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 53 TC 1 Z9 1 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD FEB 15 PY 2017 VL 198 IS 4 BP 1503 EP 1511 DI 10.4049/jimmunol.1601670 PG 9 WC Immunology SC Immunology GA EN3HC UT WOS:000395898600014 PM 28053234 ER PT J AU Del Brutto, OH Nash, TE White, AC Rajshekhar, V Wilkins, PP Singh, G Vasquez, CM Salgado, P Gilman, RH Garcia, HH AF Del Brutto, O. H. Nash, T. E. White, A. C., Jr. Rajshekhar, V. Wilkins, P. P. Singh, G. Vasquez, C. M. Salgado, P. Gilman, R. H. Garcia, H. H. TI Revised set of diagnostic criteria for neurocysticercosis (in reply to Garg and Malhotra) SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Letter DE Cysticercosis; Neurocysticercosis; Diagnostic criteria C1 [Del Brutto, O. H.] Univ Espiritu Santo Ecuador, Sch Med, Guayaquil, Ecuador. [Nash, T. E.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [White, A. C., Jr.] Univ Texas Med Branch, Dept Internal Med, Div Infect Dis, Galveston, TX 77555 USA. [Rajshekhar, V.] Christian Med Coll & Hosp, Dept Neurol Sci, Vellore, Tamil Nadu, India. [Wilkins, P. P.] Parasitol Serv, Marathon, FL USA. [Singh, G.] Dayanand Med Coll, Dept Neurol, Ludhiana, Punjab, India. [Vasquez, C. M.] Inst Nacl Ciencias Neurol, Dept Neurosurg, Lima, Peru. [Salgado, P.] Natl Inst Neurol & Neurosurg, Neuroimaging Unit, Mexico City, DF, Mexico. [Gilman, R. H.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA. [Garcia, H. H.] Univ Peruana Cayetano Heredia, Sch Sci, Ctr Global Hlth Tumbes, Lima, Peru. [Garcia, H. H.] Univ Peruana Cayetano Heredia, Sch Sci, Dept Microbiol, Lima, Peru. RP Del Brutto, OH (reprint author), Air Ctr 3542,POB 522970, Miami, FL 33152 USA. EM oscardelbrutto@hotmail.com NR 9 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X EI 1878-5883 J9 J NEUROL SCI JI J. Neurol. Sci. PD FEB 15 PY 2017 VL 373 BP 350 EP 351 DI 10.1016/j.jns.2016.12.018 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EK8US UT WOS:000394200700081 PM 28011076 ER PT J AU Ha, S Mendola, P AF Ha, Sandie Mendola, Pauline TI Invited Commentary: Ambient Environment and the Risk of Preterm Birth SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material DE air pollution; meteorology; preterm birth; temperature ID AIR-POLLUTION; RESIDENTIAL-MOBILITY; PREGNANCY OUTCOMES; EVENTS AB Preterm birth is a common adverse birth outcome known to be associated with increased infant mortality, and it often results in a higher burden of offspring morbidity in both the short and long terms. The potential for environmental factors, particularly air pollution and meteorological parameters, to increase preterm birth risk has received significant attention worldwide, but the findings are generally inconsistent, with variations in study designs and methods across populations and geographic locations. In the current issue of the Journal, GiorgisAllemand et al. (Am J Epidemiol. 2017; 185(4):247-258) take the field a step further than most prior investigations of the ambient environment. They examined the associations of ambient air pollution and meteorological factors with preterm risk among 13 cohorts across 11 European countries. No association with air pollution was observed, but associations with increased preterm birth risk were found for both increased atmospheric pressure and ambient temperature exposures during the first trimester. The study is notable in attempting to address several important issues that challenge the field, including exposure misclassification and defining critical windows of exposure. Their comprehensive evaluation of ambient exposures is to be commended. C1 [Ha, Sandie; Mendola, Pauline] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, 6710B Rockledge Dr Room 3119, Bethesda, MD 20817 USA. RP Mendola, P (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, 6710B Rockledge Dr Room 3119, Bethesda, MD 20817 USA. EM pauline.mendola@nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This work was supported in part by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 16 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD FEB 15 PY 2017 VL 185 IS 4 BP 259 EP 261 DI 10.1093/aje/kww138 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EP2WU UT WOS:000397245100002 ER PT J AU Power, RA Tansey, KE Buttenschon, HN Cohen-Woods, S Bigdeli, T Hall, LS Kutalik, Z Lee, SH Ripke, S Steinberg, S Teumer, A Viktorin, A Wray, NR Arolt, V Baune, BT Boomsma, DI Borglum, AD Byrne, EM Castelao, E Craddock, N Craig, IW Dannlowski, U Deary, IJ Degenhardt, F Forstner, AJ Gordon, SD Grabe, HJ Grove, J Hamilton, SP Hayward, C Heath, AC Hocking, LJ Homuth, G Hottenga, JJ Kloiber, S Krogh, J Landen, M Lang, MR Levinson, DF Lichtenstein, P Lucae, S MacIntyre, DJ Madden, P Magnusson, PKE Martin, NG McIntosh, AM Middeldorp, CM Milaneschi, Y Montgomery, GW Mors, O Muller-Myhsok, B Nyholt, DR Oskarsson, H Owen, MJ Padmanabhan, S Penninx, BWJH Pergadia, ML Porteous, DJ Potash, JB Preisig, M Rivera, M Shi, JX Shyn, SI Sigurdsson, E Smit, JH Smith, BH Stefansson, H Stefansson, K Strohmaier, J Sullivan, PF Thomson, P Thorgeirsson, TE Van der Auwera, S Weissman, MM Breen, G Lewis, CM AF Power, Robert A. Tansey, Katherine E. Buttenschon, Henriette Normolle Cohen-Woods, Sarah Bigdeli, Tim Hall, Lynsey S. Kutalik, Zoltn Lee, S. Hong Ripke, Stephan Steinberg, Stacy Teumer, Alexander Viktorin, Alexander Wray, Naomi R. Arolt, Volker Baune, Bernard T. Boomsma, Dorret I. Borglum, Anders D. Byrne, Enda M. Castelao, Enrique Craddock, Nick Craig, Ian W. Dannlowski, Udo Deary, Ian J. Degenhardt, Franziska Forstner, Andreas J. Gordon, Scott D. Grabe, Hans J. Grove, Jakob Hamilton, Steven P. Hayward, Caroline Heath, Andrew C. Hocking, Lynne J. Homuth, Georg Hottenga, Jouke J. Kloiber, Stefan Krogh, Jesper Landen, Mikael Lang, Maren Levinson, Douglas F. Lichtenstein, Paul Lucae, Susanne MacIntyre, Donald J. Madden, Pamela Magnusson, Patrik K. E. Martin, Nicholas G. McIntosh, Andrew M. Middeldorp, Christel M. Milaneschi, Yuri Montgomery, Grant W. Mors, Ole Muller-Myhsok, Bertram Nyholt, Dale R. Oskarsson, Hogni Owen, Michael J. Padmanabhan, Sandosh Penninx, Brenda W. J. H. Pergadia, Michele L. Porteous, David J. Potash, James B. Preisig, Martin Rivera, Margarita Shi, Jianxin Shyn, Stanley I. Sigurdsson, Engilbert Smit, Johannes H. Smith, Blair H. Stefansson, Hreinn Stefansson, Kari Strohmaier, Jana Sullivan, Patrick F. Thomson, Pippa Thorgeirsson, Thorgeir E. Van der Auwera, Sandra Weissman, Myrna M. Breen, Gerome Lewis, Cathryn M. CA CONVERGE Consortium CARDIoGRAM Consortium GERAD1 Consortium TI Genome-wide Association for Major Depression Through Age at Onset Stratification: Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Age at onset; GWAS; Heterogeneity; Major depressive disorder; Polygenic scoring; Stratification ID HAN CHINESE WOMEN; FAMILY-HISTORY; RECURRENT DEPRESSION; ALZHEIMERS-DISEASE; FOLLOW-UP; TWIN; METAANALYSIS; POPULATION; MORTALITY; RISK AB BACKGROUND: Major depressive disorder (MDD) is a disabling mood disorder, and despite a known heritable component, a large meta-analysis of genome-wide association studies revealed no replicable genetic risk variants. Given prior evidence of heterogeneity by age at onset in MDD, we tested whether genome-wide significant risk variants for MDD could be identified in cases subdivided by age at onset. METHODS: Discovery case-control genome-wide association studies were performed where cases were stratified using increasing/decreasing age-at-onset cutoffs; significant single nucleotide polymorphisms were tested in nine independent replication samples, giving a total sample of 22,158 cases and 133,749 control subjects for subsetting. Polygenic score analysis was used to examine whether differences in shared genetic risk exists between earlier and adult-onset MDD with commonly comorbid disorders of schizophrenia, bipolar disorder, Alzheimer's disease, and coronary artery disease. RESULTS: We identified one replicated genome-wide significant locus associated with adult-onset (>27 years) MDD (rs7647854, odds ratio: 1.16, 95% confidence interval: 1.11-1.21, p = 5.2 x 10(-11)). Using polygenic score analyses, we show that earlier-onset MDD is genetically more similar to schizophrenia and bipolar disorder than adult-onset MDD. CONCLUSIONS: We demonstrate that using additional phenotype data previously collected by genetic studies to tackle phenotypic heterogeneity in MDD can successfully lead to the discovery of genetic risk factor despite reduced sample size. Furthermore, our results suggest that the genetic susceptibility to MDD differs between adult-and earlier-onset MDD, with earlier-onset cases having a greater genetic overlap with schizophrenia and bipolar disorder. C1 [Power, Robert A.; Craig, Ian W.; Rivera, Margarita; Breen, Gerome; Lewis, Cathryn M.] Kings Coll London, Inst Psychiat Psychol & Neurosci, London, England. [Tansey, Katherine E.; Craddock, Nick; Owen, Michael J.] Cardiff Univ, Sch Med, Inst Psychol Med & Clin Neurosci, Med Res Council,Ctr Neuropsychiatr Genet & Genom, Cardiff, S Glam, Wales. [Buttenschon, Henriette Normolle; Grove, Jakob; Mors, Ole] Aarhus Univ, Dept Clin Med, Translat Neuropsychiatry Unit HNB, Initiat Integrat Psychiat Res,iPSYCH, Aarhus, Denmark. [Cohen-Woods, Sarah; Baune, Bernard T.] Univ Adelaide, Sch Med, Discipline Psychiat, Adelaide, SA, Australia. [Bigdeli, Tim] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Dept Psychiat, Richmond, VA USA. [Kutalik, Zoltn] Univ Vaudois, Ctr Hosp, Inst Social & Prevent Med, Lausanne, Switzerland. [Lee, S. Hong; Wray, Naomi R.; Byrne, Enda M.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia. [Lee, S. Hong] Univ New England, Sch Environm & Rural Sci, Armidale, NSW, Australia. [Ripke, Stephan] Massachusetts Inst Technol & Harvard, Broad Inst, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Ripke, Stephan] Massachusetts Gen Hosp, Analyt & Translational Genet Unit, Boston, MA 02114 USA. [Ripke, Stephan] Harvard Med Sch, Boston, MA 02114 USA. [Ripke, Stephan] Charite, Dept Psychiat & Psychotherapy, Berlin, Germany. [Steinberg, Stacy; Stefansson, Hreinn; Stefansson, Kari; Thorgeirsson, Thorgeir E.] deCODE Genet, Reykjavik, Iceland. [Teumer, Alexander] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Viktorin, Alexander; Landen, Mikael; Lichtenstein, Paul; Magnusson, Patrik K. E.; Sullivan, Patrick F.] Karolinska Inst, Dept Med Epidemiol & Biostatist, Stockholm, Sweden. [Arolt, Volker; Dannlowski, Udo] Univ Munster, Dept Psychiat & Psychotherapy, Munster, Germany. [Boomsma, Dorret I.; Hottenga, Jouke J.; Middeldorp, Christel M.] Vrije Univ, Inst Hlth & Care Res & Neurosci Campus Amsterdam, EMGO, Amsterdam, Netherlands. [Hottenga, Jouke J.; Middeldorp, Christel M.] Aarhus Univ, ISEQ, Dept Biomed, Aarhus, Denmark. [Grove, Jakob] Aarhus Univ, ISEQ, Ctr Integrat Sequencing, Aarhus, Denmark. [Dannlowski, Udo] Univ Lausanne Hosp, Lausanne, Switzerland. [Dannlowski, Udo] Univ Marburg, Dept Psychiat, Marburg, Germany. [Deary, Ian J.; McIntosh, Andrew M.; Thomson, Pippa] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland. [Deary, Ian J.] Univ Edinburgh, Dept Psychol, Edinburgh, Midlothian, Scotland. [Degenhardt, Franziska; Forstner, Andreas J.] Univ Bonn, Life & Brain Ctr, Dept Genom, Inst Human Genet, Bonn, Germany. [Gordon, Scott D.; Martin, Nicholas G.; Montgomery, Grant W.] QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia. [Grabe, Hans J.; Van der Auwera, Sandra] Univ Med Greifswald, Dept Psychiat & Psychotherapy, Greifswald, Germany. [Hamilton, Steven P.] Univ Edinburgh, Kaiser Permanente San Francisco Med Ctr, Dept Psychiat, San Francisco, CA USA. [Hayward, Caroline; MacIntyre, Donald J.; Thomson, Pippa] Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Med Genet Sect, Edinburgh, Midlothian, Scotland. [Heath, Andrew C.; Madden, Pamela] Washington Univ St Louis, Dept Psychiat, St Louis, MO USA. [Hocking, Lynne J.] Univ Aberdeen, Div Appl Hlth Sci, Aberdeen, Scotland. [Homuth, Georg] Ernst Moritz Arndt Univ Greifswald, Interfaculty Inst Genet & Funct Genom, Greifswald, Germany. [Kloiber, Stefan; Lucae, Susanne; Muller-Myhsok, Bertram] Max Planck Inst Psychiat, Munich, Germany. [Krogh, Jesper] Univ Copenhagen, Mental Hlth Serv Capital Reg, Mental Hlth Ctr Copenhagen, Copenhagen, Denmark. [Lang, Maren] Univ Gothenburg, Inst Neuroscience & Physiol, Gothenburg, Sweden. [Lang, Maren; Shi, Jianxin] Heidelberg Univ, Fac Med, Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, Mannheim, Germany. [Levinson, Douglas F.] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA USA. [Milaneschi, Yuri; Penninx, Brenda W. J. H.; Smit, Johannes H.] Vrije Univ Med Ctr, EMGO Inst Hlth & Care Res & Neuro Sci Campus Amst, Dept Psychiat, Amsterdam, Netherlands. [Mors, Ole] Aarhus Univ Hosp, Psychosis Res Unit, Risskov, Denmark. [Muller-Myhsok, Bertram] Munich Cluster Syst Neurol, Munich, Germany. [Muller-Myhsok, Bertram] Univ Liverpool, Inst Translat Med, Liverpool, Merseyside, England. [Nyholt, Dale R.] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Brisbane, Qld, Australia. [Oskarsson, Hogni] Therapeia, Reykjavik, Iceland. [Padmanabhan, Sandosh] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [Pergadia, Michele L.] Florida Atlant Univ, Charles E Schmidt Coll Med, Boca Raton, FL USA. [Potash, James B.] Univ Iowa, Dept Psychiat, Coll Med, Iowa City, IA USA. [Rivera, Margarita] Univ Granada, Ctr Invest Biomed Red Salud Mental, Granada, Spain. [Rivera, Margarita] Univ Granada, Hospit Univ Granada, Inst Invest Biosanitaria ibs, Granada, Spain. [Shi, Jianxin] Natl Canc Inst, Div Canc Epidemiol & Genet, NIH, Bethesda, MD USA. [Shyn, Stanley I.] Grp Hlth, Dept Psychiat, Seattle, WA USA. [Sigurdsson, Engilbert] Univ Iceland, Fac Med, Reykjavik, Iceland. [Sigurdsson, Engilbert] Landspitali Univ Hosp, Dept Psychiat, Reykjavik, Iceland. [Smith, Blair H.] Univ Dundee, Div Populat Hlth Sci, Dundee, Scotland. [Sullivan, Patrick F.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Weissman, Myrna M.] Columbia Univ, Coll Physicians & Surg, New York, NY USA. [Weissman, Myrna M.] Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. [Weissman, Myrna M.] New York State Psychiat Inst & Hosp, New York, NY USA. RP Lewis, CM (reprint author), Kings Coll London, Inst Psychiat Psychol & Neurosci, London, England. EM cathryn.lewis@kcl.ac.uk OI Thorgeirsson, Thorgeir/0000-0002-5149-7040; McIntosh, Andrew/0000-0002-0198-4588 FU National Institute of Mental Health (NIMH) [MH085520, MH080403]; SURFsara; Netherlands Scientific Organization [NWO 480-05-003]; department of Psychology; Dutch Brain Foundation; German Federal Ministry of Education and Research (BMBF) through the Integrated Genome Research Network Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia [01GS08144, 01GS08147]; National Genome Research Network plus, and through the Integrated Network Integrated Understanding of Causes and Mechanisms in Mental Disorders; e:Med Programme [01ZX1314A, 01ZX1314G]; German Research Foundation (DFG) [FOR2107, RI908/11-1, NO246/10-1]; NIMH R01 [MH061686, MH059542, MH075131, MH059552, MH059541, MH060912]; BMBF Program Molecular Diagnostics: Validation of Biomarkers for Diagnosis and Outcome in Major Depression [01ES0811]; Bavarian Ministry of Commerce; BMBF in the framework of the National Genome Research [NGFN2, NGFN-Plus, FKZ 01GS0481, 01GS08145]; Netherlands Organization for Scientific Research (MagW/ZonMW) [904-61-090, 985-10-002, 904-61-193, 480-04004, 400-05-717, 912-100-20]; Spinozapremie [56-464-14192]; Geestkracht program [10-000-1002]; Center for Medical Systems Biology (NWO Genomics); Biobanking and Biomolecular Resources Research Infrastructure; Vrije Universiteit's Institutes for Health and Care Research and Neuroscience Campus Amsterdam; BIC/BioAssist/RK [2008.024]; European Science Foundation [EU/QLRT-200101254]; European Community's Seventh Framework Program [FP7/2007-2013]; ENGAGE [HEALTH-F4-2007-201413]; European Science Council [ERC 230374]; GAIN of the Foundation for the US National Institutes of Health; GAIN; NIMH [MH081802, MH072802, N01MH90003]; Australian National Health and Medical Research Council [241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496675, 496739, 552485, 552498, 613602, 613608, 613674, 619667]; Australian Research Council [FT0991360, FT0991022]; FP-5 GenomEUtwin Project [QLG2-CT-2002-01254]; US National Institutes of Health [AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, MH66206, DA12854, DA019951, U01 DK066134]; Center for Inherited Disease Research (Baltimore, MD); UK Medical Research Council and GlaxoSmithKline [G0701420]; National Institute for Health Research Specialist Biomedical Research Centre for Mental Health at the South London; Maudsley National Health Service Foundation Trust; Institute of Psychiatry, King's College London; UK Medical Research Council [G0000647]; Marie Curie Industry-Academia Partnership and Pathways [286213]; European Commission Framework 6 grant (EC) [LSHB-CT2003- 503428]; GlaxoSmithKline; Faculty of Biology and Medicine of Lausanne; Swiss National Science Foundation [3200B0-105993, 3200B0-118308, 33CSCO-122661, 33CS30-139468, 33CS30-148401]; GlaxoSmithKline Clinical Genetics; 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; DFG [GR 1912/5-1, FOR 2107, DA1151/5-1]; Swedish Ministry for Higher Education; Swedish Research Council [M-2005-1112]; GenomEUtwin [QLG2-CT-2002-01254, EU/QLRT2001-01254]; Swedish Foundation for Strategic Research; Danish Strategic Research Council; Stanley Research Foundation; European Union [N Health-F2-2008-222963]; Innovative Medizinische Forschung of the Medical Faculty of Munster [DA120903, DA111107, DA211012]; Wellcome Trust Strategic Award "Stratifying Resilience and Depression Longitudinally" [104036/Z/14/Z]; Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6]; Scottish Funding Council [HR03006]; Broad Institute Center for Genotyping and Analysis [U54 RR020278]; NIMH; National Alliance for Research on Schizophrenia and Depression; BBSRC; MRC; German Federal Ministry of Education and Research; European Union (FP 7); Interdisciplinary Center for Clinical Research Munster; National Health and Medical Research Council Australia; MRC-BBSRC, Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative [MR/K026992/1]; German Research Foundation; Federal Ministry of Education; Research Germany and speakers honoraria from Eli Lilly and Servier; Medical Research Council (MRC); Biotechnology and Biological Sciences Research Council (BBSRC); NRS Career Fellowship - Chief Scientist Office; Scottish Funding Council Senior Clinical Fellowship; Dame Theresa and Mortimer Sackler Foundation; Netherlands Organization for Scientific Research [NOW VENI 916-76-125] FX The PGC was funded by National Institute of Mental Health (NIMH) Grant Nos. MH085520 (to PFS) and MH080403. Statistical analyses were carried out on the Genetic Cluster Computer (http://www. geneticcluster.org) hosted by SURFsara and financially supported by the Netherlands Scientific Organization Grant No. NWO 480-05-003 (to D. Posthuma) and the department of Psychology, Vrije Universiteit Amsterdam along with a supplement from the Dutch Brain Foundation. The Bonn/Mannheim GWAS was supported by the German Federal Ministry of Education and Research (BMBF) through the Integrated Genome Research Network Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia Grant Nos. 01GS08144 and 01GS08147, under the auspices of the National Genome Research Network plus, and through the Integrated Network Integrated Understanding of Causes and Mechanisms in Mental Disorders, under the auspices of the e:Med Programme Grant Nos. 01ZX1314A and 01ZX1314G. The Bonn/Mannheim GWAS was also supported by the German Research Foundation (DFG) Grant Nos. FOR2107, RI908/11-1, and NO246/10-1. The GenRED GWAS project was supported by NIMH R01 Grant Nos. MH061686 (to DFL), MH059542 (to W.H. Coryell), MH075131 (W.B. Lawson), MH059552 (JBP), MH059541 (W.A. Scheftner), and MH060912 (MMW). Max Planck Institute of Psychiatry MARS study was supported by the BMBF Program Molecular Diagnostics: Validation of Biomarkers for Diagnosis and Outcome in Major Depression by Grant No. 01ES0811. Genotyping was supported by the Bavarian Ministry of Commerce, and the BMBF in the framework of the National Genome Research Network by Grant Nos. NGFN2 and NGFN-Plus, FKZ 01GS0481 and 01GS08145. The Netherlands Study of Depression and Anxiety and the Netherlands Twin Register contributed to Genetic Association Information Network (GAIN)-MDD and to MDD2000. Funding for NTR/NESDA was from the following: the Netherlands Organization for Scientific Research (MagW/ZonMW Grant Nos. 904-61-090, 985-10-002, 904-61-193, 480-04004, 400-05-717, 912-100-20; Spinozapremie Grant No. 56-464-14192; Geestkracht program Grant No. 10-000-1002); the Center for Medical Systems Biology (NWO Genomics), Biobanking and Biomolecular Resources Research Infrastructure, Vrije Universiteit's Institutes for Health and Care Research and Neuroscience Campus Amsterdam, BIC/BioAssist/RK (Grant No. 2008.024); the European Science Foundation (Grant No. EU/QLRT-200101254); the European Community's Seventh Framework Program (Grant No. FP7/2007-2013); ENGAGE (Grant No. HEALTH-F4-2007-201413); and the European Science Council (Grant No. ERC 230374). Genotyping was funded in part by the GAIN of the Foundation for the US National Institutes of Health, and analysis was supported by grants from GAIN and the NIMH (Grant No. MH081802). Funding for the QIMR samples was provided by the Australian National Health and Medical Research Council (Grant Nos. 241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496675, 496739, 552485, 552498, 613602, 613608, 613674, 619667), the Australian Research Council (Grant Nos. FT0991360, FT0991022), the FP-5 GenomEUtwin Project (Grant No. QLG2-CT-2002-01254), and the US National Institutes of Health (Grant Nos. AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, MH66206, DA12854, DA019951), and the Center for Inherited Disease Research (Baltimore, MD). RADIANT was funded by the following: a joint grant from the UK Medical Research Council and GlaxoSmithKline (Grant No.; G0701420); the National Institute for Health Research Specialist Biomedical Research Centre for Mental Health at the South London and Maudsley National Health Service Foundation Trust and the Institute of Psychiatry, King's College London; the UK Medical Research Council (Grant No. G0000647), and the Marie Curie Industry-Academia Partnership and Pathways (Grant No. 286213). The GENDEP study was funded by a European Commission Framework 6 grant (EC Contract Ref.: LSHB-CT2003- 503428). Genotyping of STAR* D was supported by NIMH Grant No. MH072802 (to SPH). STAR* D was funded by NIMH Grant No. N01MH90003 to the University of Texas Southwestern Medical Center at Dallas (to A.J. Rush). The CoLaus/PsyCoLaus study was supported by research grants from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, and the Swiss National Science Foundation (Grant Nos. 3200B0-105993, 3200B0-118308, 33CSCO-122661, 33CS30-139468, 33CS30-148401) and two grants from GlaxoSmithKline Clinical Genetics. 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 (Grant Nos. 01ZZ9603, 01ZZ0103, 01ZZ0403), the Ministry of Cultural Affairs, and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (Grant No. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg-West Pomerania. SHIP-LEGEND is funded by the DFG (Grant No. GR 1912/5-1). The TwinGene study was supported by the Swedish Ministry for Higher Education, the Swedish Research Council (Grant No. M-2005-1112), GenomEUtwin (Grant Nos. EU/QLRT2001-01254,QLG2-CT-2002-01254), the Swedish Foundation for Strategic Research and the US National Institutes of Health (Grant No. U01 DK066134). The collection of PRISME control subjects and genotyping of the 883 Danish control subjects was supported by grants from The Danish Strategic Research Council, The Stanley Research Foundation, and H. Lundbeck A/S. The Muenster Depression cohorts were supported by the European Union (Grant No. N Health-F2-2008-222963) and by grants from the DFG (Grant Nos. FOR 2107 and DA1151/5-1 [ to UD]), Innovative Medizinische Forschung of the Medical Faculty of Munster (Grant Nos. DA120903, DA111107, and DA211012 [ all to UD]). Generation Scotland is supported by a Wellcome Trust Strategic Award "Stratifying Resilience and Depression Longitudinally" (Reference No.: 104036/Z/14/Z) and core support from the Chief Scientist Office of the Scottish Government Health Directorates (Grant No. CZD/16/6) and the Scottish Funding Council (Grant No. HR03006).; The NIMH Cell Repository at Rutgers University and the NIMH Center for Collaborative Genetic Studies on Mental Disorders made essential contributions to this project. Genotyping was carried out by the Broad Institute Center for Genotyping and Analysis with support from Grant No. U54 RR020278 (which partially subsidized the genotyping of the GenRED cases). Collection and quality control analyses of the control dataset were supported by grants from NIMH and the National Alliance for Research on Schizophrenia and Depression.; We acknowledge the contributions of Dr. George S Zubenko and Dr. Wendy N Zubenko, Department of Psychiatry, University of Pittsburgh School of Medicine, to the GenRED I project. We are grateful to Knowledge Networks (Menlo Park, CA) for assistance in collecting the control dataset. We express our profound appreciation to the families who participated in this project, and to the many clinicians who facilitated the referral of participants to the study. We thank the twins and their families registered at the Australian Twin Registry for their participation in the many studies that have contributed to this research. We thank V. Mooser, G. Weaber, and P. Vollenweider who initiated the CoLaus project. We express our gratitude to the Lausanne inhabitants who volunteered to participate in the PsyCoLaus study. We would like to acknowledge the PRISME-study group, Denmark, for collection of the PRISME samples. We thank David M. Hougaard, Section of Neonatal Screening and Hormones, Statens Serum Institute, Copenhagen, Denmark; Preben Bo Mortensen, National Centre for Register-based Research, Aarhus University, Denmark; Merete Nordentoft, Mental Health Centre, Copenhagen, Denmark; and The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark. Funding from the BBSRC and MRC is gratefully acknowledged.; Data used in the preparation of this article were obtained from the Genetic and Environmental Risk for Alzheimer's disease (GERAD1) Consortium. As such, the investigators within the GERAD1 consortia contributed to the design and implementation of GERAD1 and/or provided data but did not participate in analysis or writing of this report.; SS, HS, KS, and TET are employees of deCODE Genetics/Amgen. VA received funds from the German Federal Ministry of Education and Research, from the European Union (FP 7), and from the Interdisciplinary Center for Clinical Research Munster, and he has served on the advisory boards of, or has given presentations on behalf of the following companies: Astra-Zeneca, Janssen-Organon, Lilly, Lundbeck, Servier, Pfizer, Otsuka, and Trommsdorff. BTB has received funding from the National Health and Medical Research Council Australia and honoraria from Lundbeck, BristolMeyers Squibb, Sanofi, Servier, Astra-Zeneca, Pfizer. IJD is supported by the MRC-BBSRC, Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (Grant No. MR/K026992/1). HJG has received funding from German Research Foundation and Federal Ministry of Education and Research Germany and speakers honoraria from Eli Lilly and Servier. CH acknowledges support from the Medical Research Council (MRC) and the Biotechnology and Biological Sciences Research Council (BBSRC). DJM is supported by an , funded by the Chief Scientist Office. AMM is supported by a Scottish Funding Council Senior Clinical Fellowship and by the Dame Theresa and Mortimer Sackler Foundation and has received research support from Pfizer, Janssen, and Lilly. CMM was supported by the Netherlands Organization for Scientific Research (Grant No. NOW VENI 916-76-125). BM- M has consulted for Affectis Pharmaceuticals. MP has served on the advisory boards of Lundbeck and Eli Lilly NR 56 TC 2 Z9 2 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD FEB 15 PY 2017 VL 81 IS 4 BP 325 EP 335 DI 10.1016/j.biopsych.2016.05.010 PG 11 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA EO9MT UT WOS:000397013500012 PM 27519822 ER PT J AU Pinsky, PF Prorok, PC Yu, K Kramer, BS Black, A Gohagan, JK Crawford, ED Grubb, RL Andriole, GL AF Pinsky, Paul F. Prorok, Philip C. Yu, Kelly Kramer, Barnett S. Black, Amanda Gohagan, John K. Crawford, E. David Grubb, Robert L. Andriole, Gerald L. TI Extended Mortality Results for Prostate Cancer Screening in the PLCO Trial With Median Follow-Up of 15 Years SO CANCER LA English DT Article DE digital rectal examination (DRE); prostate cancer; prostate-specific antigen (PSA); randomized trial; screening ID SERVICES TASK-FORCE; PSA TESTING RATES AB BACKGROUND: Two large-scale prostate cancer screening trials using prostate-specific antigen (PSA) have given conflicting results in terms of the efficacy of such screening. One of those trials, the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, previously reported outcomes with 13 years of follow-up. This study presents updated findings from the PLCO trial. METHODS: The PLCO trial randomized subjects from 1993 to 2001 to an intervention or control arm. Intervention-arm men received annual PSA tests for 6 years and digital rectal examinations for 4 years. This study used a linkage with the National Death Index to extend mortality follow-up to a maximum of 19 years after randomization. RESULTS: Men were randomized to the intervention arm (n=38,340) or the control arm (n=38,343). The median follow-up time was 14.8 years (25th/75th, 12.7/16.5 years) in the intervention arm and 14.7 years (25th/75th, 12.6/16.4 years) in the control arm. There were 255 deaths from prostate cancer in the intervention arm and 244 deaths from prostate cancer in the control arm; this meant a rate ratio (RR) of 1.04 (95% confidence interval [ CI], 0.87-1.24). The RR for all-cause mortality was 0.977 (95% CI, 0.950-1.004). It was estimated that 86% of the men in the control arm and 99% of the men in the intervention arm received any PSA testing during the trial, and the estimated yearly screening-phase PSA testing rates were 46% and 84%, respectively. CONCLUSIONS: Extended follow-up of the PLCO trial over a median of 15 years continues to indicate no reduction in prostate cancer mortality for the intervention arm versus the control arm. Because of the high rate of control-arm PSA testing, this finding can be viewed as showing no benefit of organized screening versus opportunistic screening. (C) 2016 American Cancer Society. C1 [Pinsky, Paul F.; Prorok, Philip C.; Kramer, Barnett S.] NCI, Canc Prevent Div, NIH, 9609 Med Ctr Dr,Room 5E108, Bethesda, MD 20892 USA. [Yu, Kelly; Black, Amanda] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Gohagan, John K.] NIH, Off Dis Prevent, Bldg 10, Bethesda, MD 20892 USA. [Crawford, E. David] Univ Colorado, Sch Med, Dept Surg, Aurora, CO USA. [Grubb, Robert L.; Andriole, Gerald L.] Washington Univ, Sch Med, Div Urol, St Louis, MO USA. RP Pinsky, PF (reprint author), NCI, Canc Prevent Div, NIH, 9609 Med Ctr Dr,Room 5E108, Bethesda, MD 20892 USA. EM pp4f@nih.gov FU National Cancer Institute [HHSN261201100008C] FX This study was funded in part by National Cancer Institute contract HHSN261201100008C to E. David Crawford, Robert Grubb, and Gerald Andriole; the other authors are employees of the National Institutes of Health. NR 16 TC 2 Z9 2 U1 1 U2 1 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD FEB 15 PY 2017 VL 123 IS 4 BP 592 EP 599 DI 10.1002/cncr.30474 PG 8 WC Oncology SC Oncology GA EO6ZP UT WOS:000396841300010 PM 27911486 ER PT J AU Drahos, J Ricker, W Pfeiffer, RM Cook, MB AF Drahos, Jennifer Ricker, Winnie Pfeiffer, Ruth M. Cook, Michael B. TI Metabolic Syndrome and Risk of Esophageal Adenocarcinoma in Elderly Patients in the United States: An Analysis of SEER-Medicare Data SO CANCER LA English DT Article DE Barrett esophagus; esophageal cancer; gastroesophageal reflux; obesity; risk factors ID GASTROESOPHAGEAL-REFLUX DISEASE; BARRETTS-ESOPHAGUS; SYNDROME INCREASES; CANCER-RISK; OBESITY; ASSOCIATION; SEX; EPIDEMIOLOGY; METAANALYSIS; POPULATION AB BACKGROUND: Metabolic syndrome (MetS) is associated with cancer risk and increases the risk of Barrett esophagus, which is the precursor lesion of esophageal adenocarcinoma (EA), primarily in the absence of gastroesophageal reflux disease (GERD). However, to the authors' knowledge, little is known regarding whether MetS is associated with the risk of EA. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database, the authors evaluated whether MetS was associated with EA. A total of 3167 cases of EA were compared with individually matched population controls (5: 1); a subset of 575 EA cases were able to be individually matched with 575 Barrett esophagus controls. MetS was defined using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes in the period 1 to 3 years before the diagnosis of EA or control selection. Unconditional logistic regression was used to estimate adjusted odds ratios and 95% confidence intervals. Potential effect modification by GERD symptoms and sex was examined in stratified models. RESULTS: EA was found to be significantly associated with MetS (odds ratio, 1.16; 95% confidence interval, 1.06-1.26) compared with population controls. In males, the association was restricted to those individuals without prior GERD; however, in females, MetS was found to be associated with EA regardless of GERD status. Effect modification by sex was observed (P for interaction=.01). MetS was not found to be associated with EA risk when compared with Barrett esophagus controls. CONCLUSIONS: In this older population, MetS was found to be associated with an increased risk of EA in males without GERD and females regardless of GERD status. Given the lack of an association when compared with Barrett esophagus controls, MetS may impact EA risk by primarily increasing the risk of the precursor lesion, Barrett esophagus. (C) 2016 American Cancer Society. C1 [Drahos, Jennifer; Pfeiffer, Ruth M.; Cook, Michael B.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Ricker, Winnie] Informat Management Serv Inc, Rockville, MD USA. RP Drahos, J (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 9609 Med Ctr Dr,MSC 9774, Bethesda, MD 20892 USA. EM jdrahos@gmail.com FU National Cancer Institute at the National Institutes of Health; Department of Health and Human Services FX Supported by the Intramural Program of the National Cancer Institute at the National Institutes of Health and the 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 41 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD FEB 15 PY 2017 VL 123 IS 4 BP 657 EP 665 DI 10.1002/cncr.30365 PG 9 WC Oncology SC Oncology GA EO6ZP UT WOS:000396841300017 PM 27861759 ER PT J AU Adamo, M Boten, JA Coyle, LM Cronin, KA Lam, CJK Negoita, S Penberthy, L Stevens, JL Ward, KC AF Adamo, Margaret (Peggy) Boten, Jessica A. Coyle, Linda M. Cronin, Kathleen A. Lam, Clara J. K. Negoita, Serban Penberthy, Lynne Stevens, Jennifer L. Ward, Kevin C. CA Natl Canc Inst Surveillance TI Validation of Prostate-Specific Antigen Laboratory Values Recorded in Surveillance, Epidemiology, and End Results Registries SO CANCER LA English DT Article DE data quality; implied decimal; laboratory value; prostate cancer; prostate-specific antigen (PSA); staging; Surveillance; Epidemiology; and End Results (SEER) program ID BEAM RADIATION-THERAPY; RADICAL PROSTATECTOMY; CANCER; RECOMMENDATION; RECURRENCE; NOMOGRAM; PREDICT; UPDATE; MARKER; MEN AB BACKGROUND: Researchers have used prostate-specific antigen (PSA) values collected by central cancer registries to evaluate tumors for potential aggressive clinical disease. An independent study collecting PSA values suggested a high error rate (18%) related to implied decimal points. To evaluate the error rate in the Surveillance, Epidemiology, and End Results (SEER) program, a comprehensive review of PSA values recorded across all SEER registries was performed. METHODS: Consolidated PSA values for eligible prostate cancer cases in SEER registries were reviewed and compared with text documentation from abstracted records. Four types of classification errors were identified: implied decimal point errors, abstraction or coding implementation errors, nonsignificant errors, and changes related to "unknown" values. RESULTS: A total of 50,277 prostate cancer cases diagnosed in 2012 were reviewed. Approximately 94.15% of cases did not have meaningful changes (85.85% correct, 5.58% with a nonsignificant change of <1 ng/mL, and 2.80% with no clinical change). Approximately 5.70% of cases had meaningful changes (1.93% due to implied decimal point errors, 1.54% due to abstract or coding errors, and 2.23% due to errors related to unknown categories). Only 419 of the original 50,277 cases (0.83%) resulted in a change in disease stage due to a corrected PSA value. CONCLUSIONS: The implied decimal error rate was only 1.93% of all cases in the current validation study, with a meaningful error rate of 5.81%. The reasons for the lower error rate in SEER are likely due to ongoing and rigorous quality control and visual editing processes by the central registries. The SEER program currently is reviewing and correcting PSA values back to 2004 and will re-release these data in the public use research file. (C) 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. C1 [Adamo, Margaret (Peggy); Boten, Jessica A.; Cronin, Kathleen A.; Lam, Clara J. K.; Penberthy, Lynne] NCI, Surveillance Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,Rm 4E454, Rockville, MD 20850 USA. [Coyle, Linda M.; Stevens, Jennifer L.] Informat Management Serv Inc, Calverton, MD USA. [Negoita, Serban] Westat Corp, Rockville, MD USA. [Ward, Kevin C.] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. RP Cronin, KA (reprint author), NCI, Surveillance Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,Rm 4E454, Rockville, MD 20850 USA. EM Kathy.cronin@nih.gov FU Surveillance Research Program of the Division of Cancer Control and Population Sciences at the National Cancer Institute/National Institutes of Health contracts FX Supported by Surveillance Research Program of the Division of Cancer Control and Population Sciences at the National Cancer Institute/National Institutes of Health contracts with the Surveillance, Epidemiology, and End Results registries. The authors gratefully acknowledge the contributions of the state and regional cancer registry staffs for their work in collecting the data used for this study. NR 21 TC 0 Z9 0 U1 1 U2 1 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD FEB 15 PY 2017 VL 123 IS 4 BP 697 EP 703 DI 10.1002/cncr.30401 PG 7 WC Oncology SC Oncology GA EO6ZP UT WOS:000396841300022 ER PT J AU Carta, D Bortolozzi, R Sturlese, M Salmaso, V Hamel, E Basso, G Calderan, L Quintieri, L Moro, S Viola, G Ferlin, MG AF Carta, Davide Bortolozzi, Roberta Sturlese, Mattia Salmaso, Veronica Hamel, Ernest Basso, Giuseppe Calderan, Laura Quintieri, Luigi Moro, Stefano Viola, Giampietro Ferlin, Maria Grazia TI Synthesis, structure-activity relationships and biological evaluation of 7-phenyl-pyrroloquinolinone 3-amide derivatives as potent antimitotic agents SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article DE Microtubules; Phenylpyrroloquinolinone; Tubulin; Apoptosis; Molecular docking; Structure-activity relationships ID SHOW POTENT; IN-VITRO; TUBULIN; CANCER; POLYMERIZATION; GENERATION; APOPTOSIS; MITOCHONDRIA; INHIBITORS; CELLS AB A small library of 7-pyrrolo[3,2-f]quinolinones was obtained by introducing benzoyl, sulfonyl and carbamoyl side chains at the 3-N position, and their cytotoxicity against a panel of leukemic and solid tumor cell lines was evaluated. Most of them showed high antiproliferative activity with GI(50)s ranging from micro-to sub-nanomolar values, and these values correlated well with the inhibitory activities of the compounds against tubulin polymerization. Based on a recently proposed colchicine bind site inhibitors (CBSIs) pharmacophore, the interactions of the novel 7-PPyQs at the colchicine domain were rationalized. The most active compounds (4a and 4b) did not induce significant cell death in normal human lymphocytes, suggesting that the compounds may be selective against cancer cells. In particular, 4a was a potent inducer of apoptosis in both the HeLa and Jurkat cell lines. On the other hand, the sulfonyl derivative 4b exhibited a lower potency in comparison with 4a. With both compounds, induction of apoptosis was associated with dissipation of the mitochondrial transmembrane potential and production of reactive oxygen species, suggesting that cells treated with the compounds followed the intrinsic pathway of apoptosis. (C) 2016 Elsevier Masson SAS. C1 [Carta, Davide; Sturlese, Mattia; Salmaso, Veronica; Calderan, Laura; Quintieri, Luigi; Moro, Stefano; Ferlin, Maria Grazia] Univ Padua, Dept Pharmaceut & Pharmacol Sci, I-35131 Padua, Italy. [Bortolozzi, Roberta; Basso, Giuseppe; Viola, Giampietro] Univ Padua, Dept Womans & Childs Hlth, Lab Oncohematol, I-35128 Padua, Italy. [Hamel, Ernest] Natl Inst Hlth, Screening Technol Branch, Dev Therapeut Program,Div Canc Treatment & Diag, Fredrick Natl Lab Canc Res,Natl Canc Inst, Frederick, MD 21702 USA. RP Ferlin, MG (reprint author), Univ Padua, Dept Pharmaceut & Pharmacol Sci, I-35131 Padua, Italy. EM mariagrazia.ferlin@unipd.it RI Viola, Giampietro/I-4095-2012 OI Viola, Giampietro/0000-0001-9329-165X FU University of Padova, Italy; University of Padova, Italy (UNIPD, Progetto Giovani Studiosi) [79122]; European COST Action (GLISTEN) [CM1207] FX The computational work coordinated by S.M. has been supported with financial support from the University of Padova, Italy. MMS lab is also very grateful to Chemical Computing Group and OpenEye Scientific for the scientific and technical partnership. S.M. participates in the European COST Action CM1207 (GLISTEN). The work of M.S. has been supported by University of Padova, Italy (UNIPD, Progetto Giovani Studiosi 2013: Protocol number 79122). The content of this paper is solely the responsibility of the authors and does not necessarily reflect the official views of the Italian Ministry of Health. NR 30 TC 0 Z9 0 U1 6 U2 6 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0223-5234 EI 1768-3254 J9 EUR J MED CHEM JI Eur. J. Med. Chem. PD FEB 15 PY 2017 VL 127 BP 643 EP 660 DI 10.1016/j.ejmech.2016.10.026 PG 18 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA EP1VQ UT WOS:000397172800052 PM 27823884 ER PT J AU Bouhrara, M Spencer, RG AF Bouhrara, Mustapha Spencer, Richard G. TI Rapid simultaneous high-resolution mapping of myelin water fraction and relaxation times in human brain using BMC-mcDESPOT SO NEUROIMAGE LA English DT Article DE Brain; MRI; High-resolution mapping; Myelin water fraction; Relaxation times ID STATE FREE PRECESSION; MRI T-2 RELAXATION; PROGRESSIVE MULTIPLE-SCLEROSIS; STOCHASTIC REGION CONTRACTION; APPEARING WHITE-MATTER; TEMPORAL-LOBE EPILEPSY; MAGNETIC-RESONANCE; IN-VIVO; T2 RELAXATION; OFF-RESONANCE AB A number of central nervous system (CNS) diseases exhibit changes in myelin content and magnetic resonance longitudinal, T-1, and transverse, T-2, relaxation times, which therefore represent important biomarkers of CNS pathology. Among the methods applied for measurement of myelin water fraction (MWF) and relaxation times, the multicomponent driven equilibrium single pulse observation of T-1 and T-2 (mcDESPOT) approach is of particular interest. mcDESPOT permits whole brain mapping of multicomponent T-1 and T-2, with data acquisition accomplished within a clinically realistic acquisition time. Unfortunately, previous studies have indicated the limited performance of mcDESPOT in the setting of the modest signal-to-noise range of high-resolution mapping, required for the depiction of small structures and to reduce partial volume effects. Recently, we showed that a new Bayesian Monte Carlo (BMC) analysis substantially improved determination of MWF from mcDESPOT imaging data. However, our previous study was limited in that it did not discuss determination of relaxation times. Here, we extend the BMC analysis to the simultaneous determination of whole-brain MWF and relaxation times using the two-component mcDESPOT signal model. Simulation analyses and in-vivo human brain studies indicate the overall greater performance of this approach compared to the stochastic region contraction (SRC) algorithm, conventionally used to derive parameter estimates from mcDESPOT data. SRC estimates of the transverse relaxation time of the long T-2 fraction, T-2,T-l, and the longitudinal relaxation time of the short T-1 fraction, T-1,T-s , clustered towards the lower and upper parameter search space limits, respectively, indicating failure of the fitting procedure. We demonstrate that this effect is absent in the BMC analysis. Our results also showed improved parameter estimation for BMC as compared to SRC for high-resolution mapping. Overall we find that the combination of BMC analysis and mcDESPOT, BMC-mcDESPOT, shows excellent performance for accurate high-resolution whole-brain mapping of MWF and bi-component transverse and longitudinal relaxation times within a clinically realistic acquisition time. C1 [Bouhrara, Mustapha; Spencer, Richard G.] NIA, Magnet Resonance Imaging & Spect Sect, Clin Invest Lab, NIH,Intramural Res Program, BRC 04B-116,251 Bayview Blvd, Baltimore, MD 21224 USA. RP Bouhrara, M; Spencer, RG (reprint author), NIA, Magnet Resonance Imaging & Spect Sect, Clin Invest Lab, NIH,Intramural Res Program, BRC 04B-116,251 Bayview Blvd, Baltimore, MD 21224 USA. EM bouhraram@mail.nih.gov; spencer@helix.nih.gov FU Intramural Research Program of the NIH, National Institute on Aging FX This work was supported by the Intramural Research Program of the NIH, National Institute on Aging. We thank David A. Reiter and Christopher M. Bergeron for assistance with data acquisition. NR 103 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD FEB 15 PY 2017 VL 147 BP 800 EP 811 DI 10.1016/j.neuroimage.2016.09.064 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EL3ZW UT WOS:000394560600068 PM 27729276 ER PT J AU Chen, G Taylor, PA Shin, YW Reynolds, RC Cox, RW AF Chen, Gang Taylor, Paul A. Shin, Yong-Wook Reynolds, Richard C. Cox, Robert W. TI Untangling the relatedness among correlations, Part II: Inter-subject correlation group analysis through linear mixed-effects modeling SO NEUROIMAGE LA English DT Article ID FMRI GROUP-ANALYSIS; STATISTICAL-ANALYSIS; SOFTWARE; DISTANCE AB It has been argued that naturalistic conditions in FMRI studies provide a useful paradigm for investigating perception and cognition through a synchronization measure, inter-subject correlation (ISC). However, one analytical stumbling block has been the fact that the ISC values associated with each single subject are not independent, and our previous paper (Chen et al., 2016) used simulations and analyses of real data to show that the methodologies adopted in the literature do not have the proper control for false positives. In the same paper, we proposed nonparametric subject-wise bootstrapping and permutation testing techniques for one and two groups, respectively, which account for the correlation structure, and these greatly outperformed the prior methods in controlling the false positive rate (FPR); that is, subject-wise bootstrapping (SWB) worked relatively well for both cases with one and two groups, and subject-wise permutation (SWP) testing was virtually ideal for group comparisons. Here we seek to explicate and adopt a parametric approach through linear mixed-effects (LME) modeling for studying the ISC values, building on the previous correlation framework, with the benefit that the LME platform offers wider adaptability, more powerful interpretations, and quality control checking capability than nonparametric methods. We describe both theoretical and practical issues involved in the modeling and the manner in which LME with crossed random effects (CRE) modeling is applied. A data-doubling step further allows us to conveniently track the subject index, and achieve easy implementations. We pit the LME approach against the best nonparametric methods, and find that the LME framework achieves proper control for false positives. The new LME methodologies are shown to be both efficient and robust, and they will be publicly available in AFNI (http://afni.nimh.nih.gov). C1 [Chen, Gang; Taylor, Paul A.; Reynolds, Richard C.; Cox, Robert W.] NIMH, Sci & Stat Comp Core, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Shin, Yong-Wook] Univ Ulsan, Coll Med, Dept Psychiat, Asan Med Ctr, Ulsan, South Korea. RP Chen, G (reprint author), NIMH, Sci & Stat Comp Core, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM gangchen@mail.nih.gov FU NTMH; NINDS Intramural Research Programs of the NIH/HHS, USA [ZICMH002888]; Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea [2012-0230] FX Our work benefited significantly from the statistical computational language and environment R, the LME package lme4 with the capability to modeling crossed random effects, and the great support of the R community. The research and writing of the paper were supported by the NTMH and NINDS Intramural Research Programs (ZICMH002888) of the NIH/HHS, USA, and by a grant (2012-0230) from the Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea. NR 23 TC 0 Z9 0 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD FEB 15 PY 2017 VL 147 BP 825 EP 840 DI 10.1016/j.neuroimage.2016.08.029 PG 16 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EL3ZW UT WOS:000394560600070 PM 27751943 ER PT J AU Torrisi, S Nord, CL Balderston, NL Roiser, JP Grillon, C Ernst, M AF Torrisi, Salvatore Nord, Camilla L. Balderston, Nicholas L. Roiser, Jonathan P. Grillon, Christian Ernst, Monique TI Resting state connectivity of the human habenula at ultra-high field SO NEUROIMAGE LA English DT Article DE 7 T; Anxiety; Depression; Seed-based functional connectivity ID LATERAL HABENULA; HUMAN BRAIN; FUNCTIONAL CONNECTIVITY; 7 T; NUCLEI; FMRI; DEPRESSION; FLUCTUATIONS; STIMULI; SYSTEM AB The habenula, a portion of the epithalamus, is implicated in the pathophysiology of depression, anxiety and addiction disorders. Its small size and connection to other small regions prevent standard human imaging from delineating its structure and connectivity with confidence. Resting state functional connectivity is an established method for mapping connections across the brain from a seed region of interest. The present study takes advantage of 7 T fMRI to map, for the first time, the habenula resting state network with very high spatial resolution in 32 healthy human participants. Results show novel functional connections in humans, including functional connectivity with the septum and bed nucleus of the stria terminalis (BNST). Results also show many habenula connections previously described only in animal research, such as with the nucleus basalis of Meynert, dorsal raphe, ventral tegmental area (VTA), and periaqueductal grey (PAG). Connectivity with caudate, thalamus and cortical regions such as the anterior cingulate, retrosplenial cortex and auditory cortex are also reported. This work, which demonstrates the power of ultra-high field for mapping human functional connections, is a valuable step toward elucidating subcortical and cortical regions of the habenula network. C1 [Torrisi, Salvatore; Balderston, Nicholas L.; Grillon, Christian; Ernst, Monique] NIMH, Sect Neurobiol Fear & Anxiety, Bethesda, MD 20892 USA. [Nord, Camilla L.; Roiser, Jonathan P.] UCL, Neurosci & Cognit Neuropsychiat Grp, London, England. RP Torrisi, S (reprint author), NIMH, Sect Neurobiol Fear & Anxiety, Bethesda, MD 20892 USA. FU Intramural Research Program of the National Institutes of Mental Health [ZIAMH002798, 02-M-0321, NCT00047853] FX Special thanks to Rick Reynolds and Daniel Glen for analysis help, Katherine O'Connell, Andrew Davis, Gaby Alvarez and Joseph Leshin for data collection help, Bari Fuchs for generating the anatomical underlay, Erika Raven for iron deposition insight, and Okihide Hikosaka for valuable feedback. This work utilized the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov). This work was supported by the Intramural Research Program of the National Institutes of Mental Health, project number ZIAMH002798 (clinical protocol 02-M-0321, NCT00047853) to CG. JPR is a consultant for Cambridge Cognition, though this is not relevant to the current work. The authors report no competing interest. The author(s) declare that, except for income received from the primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest. NR 62 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD FEB 15 PY 2017 VL 147 BP 872 EP 879 DI 10.1016/j.neuroimage.2016.10.034 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EL3ZW UT WOS:000394560600074 PM 27780778 ER PT J AU Chen, G Taylor, PA Cox, RW AF Chen, Gang Taylor, Paul A. Cox, Robert W. TI Is the statistic value all we should care about in neuroimaging? SO NEUROIMAGE LA English DT Article ID RESTING STATE FMRI; METAANALYSIS; ACTIVATION; GUIDELINES; RESPONSES; MODEL; POWER AB Here we address an important issue that has been embedded within the neuroimaging community for a long time: the absence of effect estimates in results reporting in the literature. The statistic value itself, as a dimensionless measure, does not provide information on the biophysical interpretation of a study, and it certainly does not represent the whole picture of a study. Unfortunately, in contrast to standard practice in most scientific fields, effect (or amplitude) estimates are usually not provided in most results reporting in the current neuroimaging publications and presentations. Possible reasons underlying this general trend include (1) lack of general awareness, (2) software limitations, (3) inaccurate estimation of the BOLD response, and (4) poor modeling due to our relatively limited understanding of FMRI signal components. However, as we discuss here, such reporting damages the reliability and interpretability of the scientific findings themselves, and there is in fact no overwhelming reason for such a practice to persist. In order to promote meaningful interpretation, cross validation, reproducibility, meta and power analyses in neuroimaging, we strongly suggest that, as part of good scientific practice, effect estimates should be reported together with their corresponding statistic values. We provide several easily adaptable recommendations for facilitating this process. C1 [Chen, Gang; Taylor, Paul A.; Cox, Robert W.] NIMH, Sci & Stat Comp Core, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Chen, G (reprint author), NIMH, Sci & Stat Comp Core, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM gangchen@mail.nih.gov FU NIME; NINDS Intramural Research Programs of the NIH/HHS, USA [ZICMH002888] FX We thank Laurentius Huber for useful discussions on the physical dependence of BOLD on MR acquisition. The research and writing of the paper were supported by the NIME and NINDS Intramural Research Programs (ZICMH002888) of the NIH/HHS, USA. NR 51 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD FEB 15 PY 2017 VL 147 BP 952 EP 959 DI 10.1016/j.neuroimage.2016.09.066 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EL3ZW UT WOS:000394560600081 PM 27729277 ER PT J AU Sclafani, JA Constantin, A Ho, PS Akuthota, V Chan, L AF Sclafani, Joseph A. Constantin, Alexandra Ho, Pei-Shu Akuthota, Venu Chan, Leighton TI y Descriptive Analysis of Spinal Neuroaxial Injections, Surgical Interventions, and Physical Therapy Utilization for Degenerative Lumbar Spondylolisthesis Within Medicare Beneficiaries from 2000 to 2011 SO SPINE LA English DT Article DE degenerative spondylolisthesis; epidural steroid injection; interventional pain management; low back pain; Medicare; physical therapy; prevalence; spinal interventional techniques; treatment utilization ID LOW-BACK-PAIN; SPONDYLOLYSIS; DISPLACEMENT; ASSOCIATION; POPULATION; PREVALENCE; DIAGNOSIS; EXERCISE; WOMEN AB Study Design. A retrospective, observational study. Objective. The aim of this study was to determine the utilization of various treatment modalities in the management of degenerative spondylolisthesis within Medicare beneficiaries. Summary of Background Data. Degenerative lumbar spondylolisthesis is a condition often identified in symptomatic low back pain. A variety of treatment algorithms including physical therapy and interventional techniques can be used to manage clinically significant degenerative spondylolisthesis. Methods. This study utilized the 5% national sample of Medicare carrier claims from 2000 through 2011. A cohort of beneficiaries with a new International Classification of Diseases 9th edition (ICD-9) diagnosis code for degenerative lumbar spondylolisthesis was identified. Current procedural terminology codes were used to identify the number of procedures performed each year by specialty on this cohort. Results. A total of 95,647 individuals were included in the analysis. Average age at the time of initial diagnosis was 72.8 +/- 9.8 years. Within this study cohort, spondylolisthesis was more prevalent in females (69%) than males and in Caucasians (88%) than other racial demographics. Over 50% of beneficiaries underwent at least one injection, approximately one-third (37%) participated in physical therapy, one in five (21%) underwent spinal surgery, and one-third (36%) did not utilize any of these interventions. Greater than half of all procedures (124,280/216,088) occurred within 2 years of diagnosis. The ratio of focal interventions (transforaminal and facet interventions) to less selective (interlaminar) procedures was greater for the specialty of Physical Medicine and Rehabilitation than for the specialties of Anesthesiology, Interventional Radiology, Neurosurgery, and Orthopedic Surgery. The majority of physical therapy was dedicated to passive treatment modalities and range of motion exercises rather than active strengthening modalities within this cohort. Conclusion. Interventional techniques and physical therapy are frequently used treatment modalities for symptomatic degenerative spondylolisthesis. Understanding utilization of these techniques is important to determine relative clinical efficacies and to optimize future health care expenditures. C1 [Sclafani, Joseph A.] Medstar Georgetown Univ, Natl Rehabil Hosp, Washington, DC USA. [Akuthota, Venu] Univ Colorado, Denver, CO 80202 USA. [Sclafani, Joseph A.; Constantin, Alexandra; Ho, Pei-Shu; Chan, Leighton] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Sclafani, JA (reprint author), 102 Irving St NW, Washington, DC 20010 USA. EM sclafani@ucla.edu FU National Institutes of Health FX The Intramural Research Program of the National Institutes of Health funds were received in support of this work. NR 25 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 0362-2436 EI 1528-1159 J9 SPINE JI SPINE PD FEB 15 PY 2017 VL 42 IS 4 BP 240 EP 246 DI 10.1097/BRS.0000000000001724 PG 7 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA EM9OS UT WOS:000395641600013 PM 28207664 ER PT J AU Thomas, A Tanaka, M Trepel, J Reinhold, WC Rajapakse, VN Pommier, Y AF Thomas, Anish Tanaka, Mamoru Trepel, Jane Reinhold, William C. Rajapakse, Vinodh N. Pommier, Yves TI Temozolomide in the Era of Precision Medicine SO CANCER RESEARCH LA English DT Review ID O-6-METHYLGUANINE-DNA METHYLTRANSFERASE; PROMOTER HYPERMETHYLATION; COLORECTAL-CANCER; GLIOBLASTOMA; METHYLATION; INACTIVATION; INHIBITION AB In the January 1, 2017, issue of Cancer Research, Nagel and colleagues demonstrate the value of assays that determine the DNA repair capacity of cancers in predicting response to temozolomide. Using a fluorescence-based multiplex flow cyto-metric host cell reactivation assay that provides simultaneous readout of DNA repair capacity across multiple pathways, they show that the multivariate drug response models derived from cell line data were applicable to patient-derived xenograft models of glioblastoma. In this commentary, we first outline the mechanism of activity and current clinical application of temozolomide, which, until now, has been largely limited to glioblastoma. Given the challenges of clinical application of functional assays, we argue that functional readouts be approximated by genomic signatures. In this context, a combination of MGMT activity and mismatch repair (MMR) status of the tumor are important parameters that determine sensitivity to temozolomide. More reliable methods are needed to determine MGMT activity as DNA methylation, the current standard, does not accurately reflect the expression of MGMT. Also, genomics for MMR are warranted. Furthermore, based on patterns of MGMT expression across different solid tumors, we make a case for revisiting temozolomide use in a broader spectrum of cancers based on our current understanding of its molecular basis of activity. (C) 2017 AACR. C1 NCI, Ctr Canc Res, Dev Therapeut Branch, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Mol Pharmacol Lab, Bethesda, MD 20892 USA. RP Thomas, A (reprint author), NIH, Bldg 37,Room 5068, Bethesda, MD 20892 USA. EM anish.thomas@nih.gov; pommier@nih.gov FU Center for Cancer Research, the Intramural Program of the NCI [Z01 BC 006150] FX This work was supported by the Center for Cancer Research, the Intramural Program of the NCI (Z01 BC 006150). NR 21 TC 1 Z9 1 U1 3 U2 3 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 FEB 15 PY 2017 VL 77 IS 4 BP 823 EP 826 DI 10.1158/0008-5472.CAN-16-2983 PG 4 WC Oncology SC Oncology GA EK4HN UT WOS:000393887800003 PM 28159862 ER PT J AU Xie, GQ Chen, HQ Jia, DY Shu, ZQ Palmer, WH Huang, YC Zeng, XK Hou, SX Jiao, RJ Deng, WM AF Xie, Gengqiang Chen, Hanqing Jia, Dongyu Shu, Zhiqiang Palmer, William Hunt Huang, Yi-Chun Zeng, Xiankun Hou, Steven X. Jiao, Renjie Deng, Wu-Min TI The SWI/SNF Complex Protein Snr1 Is a Tumor Suppressor in Drosophila Imaginal Tissues SO CANCER RESEARCH LA English DT Article ID NOTCH; PROLIFERATION; MUTATIONS; GENOME; CANCER; GROWTH; GENES; CELLS; ENDOCYTOSIS; TRAFFICKING AB Components of the SWI/SNF chromatin-remodeling complex are among the most frequently mutated genes in various human cancers, yet only SMARCB1/hSNF5, a core member of the SWI/SNF complex, is mutated in malignant rhabdoid tumors (MRT). HowSMARCB1/hSNF5 functions differently from other members of the SWI/SNF complex remains unclear. Here, we use Drosophila imaginal epithelial tissues to demonstrate that Snr1, the conserved homolog of human SMARCB1/hSNF5, prevents tumorigenesis by maintaining normal endosomal trafficking-mediated signaling cascades. Removal of Snr1 resulted in neoplastic tumorigenic overgrowth in imaginal epithelial tissues, whereas deple-tion of any other members of the SWI/SNF complex did not induce similar phenotypes. Unlike other components of the SWI/SNF complex that were detected only in the nucleus, Snr1 was observed in both the nucleus and the cytoplasm. Aberrant regulation of multiple signaling pathways, including Notch, JNK, and JAK/STAT, was responsible for tumor progression upon snr1-depletion. Our results suggest that the cytoplasmic Snr1 may play a tumor suppressive role in Drosophila imaginal tissues, offering a foundation for understanding the pivotal role of SMARCB1/hSNF5 in suppressing MRT during early childhood. (C) 2017 AACR. C1 [Xie, Gengqiang; Jia, Dongyu; Shu, Zhiqiang; Palmer, William Hunt; Huang, Yi-Chun; Deng, Wu-Min] Florida State Univ, Dept Biol Sci, Tallahassee, FL 32306 USA. [Chen, Hanqing; Jiao, Renjie] Chinese Acad Sci, Inst Biophys, State Key Lab Brain & Cognit Sci, Beijing, Peoples R China. [Zeng, Xiankun; Hou, Steven X.] NCI, Basic Res Lab, NIH, Frederick, MD 21701 USA. [Jiao, Renjie] Guangzhou Med Univ, Sino French Hoffmann Inst, Guangzhou, Guangdong, Peoples R China. RP Deng, WM (reprint author), Florida State Univ, 319 Stadium Dr,King Life Sci Bldg, Tallahassee, FL 32306 USA.; Jiao, RJ (reprint author), Chinese Acad Sci, Beijing 100101, Peoples R China. EM rjiao@sun5.ibp.ac.cn; wumin@bio.fsu.edu OI Xie, Gengqiang/0000-0002-2064-4757 FU NIH [R01GM072562]; National Science Foundation [IOS-1052333]; National Natural Science Foundation of China [81470846, 31271573, 31529004]; Chinese Academy of Sciences [XDA04020413-02] FX W.-M. Deng is supported by the NIH (grant number R01GM072562) and the National Science Foundation (grant number IOS-1052333). R. Jiao is supported by grants from the National Natural Science Foundation of China (81470846, 31271573, and 31529004) and the Chinese Academy of Sciences (XDA04020413-02). NR 48 TC 0 Z9 0 U1 2 U2 2 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 FEB 15 PY 2017 VL 77 IS 4 BP 862 EP 873 DI 10.1158/0008-5472.CAN-16-0963 PG 12 WC Oncology SC Oncology GA EK4HN UT WOS:000393887800007 PM 27923836 ER PT J AU Dzinic, SH Bernardo, MM Li, XH Fernandez-Valdivia, R Ho, YS Mi, QS Bandyopadhyay, S Lonardo, F Vranic, S Oliveira, DSM Bonfil, RD Dyson, G Chen, K Omerovic, A Sheng, XJ Han, X Wu, DH Bi, XL Cabaravdic, D Jakupovic, U Wahba, M Pang, AR Harajli, D Sakr, WA Sheng, SJ AF Dzinic, Sijana H. Bernardo, M. Margarida Li, Xiaohua Fernandez-Valdivia, Rodrigo Ho, Ye-Shih Mi, Qing-Sheng Bandyopadhyay, Sudeshna Lonardo, Fulvio Vranic, Semir Oliveira, Daniel S. M. Bonfil, R. Daniel Dyson, Gregory Chen, Kang Omerovic, Almasa Sheng, Xiujie Han, Xiang Wu, Dinghong Bi, Xinling Cabaravdic, Dzenana Jakupovic, Una Wahba, Marian Pang, Aaron Harajli, Deanna Sakr, Wael A. Sheng, Shijie TI An Essential Role of Maspin in Embryogenesis and Tumor Suppression SO CANCER RESEARCH LA English DT Article ID LUNG-CANCER; PULMONARY ADENOCARCINOMA; EXPRESSION PATTERNS; CRYSTAL-STRUCTURE; STEM-CELLS; PROSTATE; GENE; PROGRESSION; MODEL; MICE AB Maspin (SerpinB5) is an epithelial-specific tumor suppressor gene product that displays context-dependent cellular functions. Maspin-deficient mouse models created to date have not definitively established maspin functions critical for cancer suppression. In this study, we generated a mouse strain in which exon 4 of the Maspin gene was deleted, confirming its essential role in development but also enabling a breeding scheme to bypass embryonic lethality. Phenotypic characterization of this viable strain established that maspin deficiency was associated with a reduction in maximum body weight and a variety of context-dependent epithelial abnor-malities. Specifically, maspin-deficient mice exhibited pulmonary adenocarcinoma, myoepithelial hyperplasia of the mammary gland, hyperplasia of luminal cells of dorsolateral and anterior prostate, and atrophy of luminal cells of ventral prostate and stratum spinosum of epidermis. These cancer phenotypes were accompanied by increased inflammatory stroma. These mice also displayed the autoimmune disorder alopecia aerate. Overall, our findings defined context-specific tumor suppressor roles for maspin in a clinically relevant model to study maspin functions in cancer and other pathologies. (C) 2017 AACR. C1 [Dzinic, Sijana H.; Bernardo, M. Margarida; Li, Xiaohua; Fernandez-Valdivia, Rodrigo; Bandyopadhyay, Sudeshna; Lonardo, Fulvio; Oliveira, Daniel S. M.; Bonfil, R. Daniel; Omerovic, Almasa; Cabaravdic, Dzenana; Jakupovic, Una; Pang, Aaron; Harajli, Deanna; Sakr, Wael A.; Sheng, Shijie] Wayne State Univ, Sch Med, Dept Pathol, 540 East Canfield St, Detroit, MI 48201 USA. [Dzinic, Sijana H.; Bernardo, M. Margarida; Li, Xiaohua; Fernandez-Valdivia, Rodrigo; Mi, Qing-Sheng; Bandyopadhyay, Sudeshna; Lonardo, Fulvio; Oliveira, Daniel S. M.; Bonfil, R. Daniel; Dyson, Gregory; Chen, Kang; Omerovic, Almasa; Cabaravdic, Dzenana; Jakupovic, Una; Pang, Aaron; Harajli, Deanna; Sakr, Wael A.; Sheng, Shijie] Barbara Ann Karmanos Canc Inst, Tumor Biol & Microenvironm Program, Detroit, MI USA. [Ho, Ye-Shih] Wayne State Univ, Sch Med, Inst Environm Hlth Sci, Detroit, MI USA. [Mi, Qing-Sheng; Chen, Kang; Wu, Dinghong; Bi, Xinling] Wayne State Univ, Sch Med, Dept Immunol & Microbiol, Detroit, MI 48201 USA. [Mi, Qing-Sheng; Wu, Dinghong; Bi, Xinling] Henry Ford Hlth Syst, Dept Dermatol, Detroit, MI USA. [Vranic, Semir] Univ Clin Ctr, Dept Pathol, Div Expt Pathol, Sarajevo, Bosnia & Herceg. [Oliveira, Daniel S. M.; Bonfil, R. Daniel; Chen, Kang] Wayne State Univ, Sch Med, Dept Urol, Detroit, MI USA. [Bonfil, R. Daniel; Dyson, Gregory; Chen, Kang; Sheng, Shijie] Wayne State Univ, Sch Med, Dept Oncol, Detroit, MI USA. [Chen, Kang] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Detroit, MI USA. [Chen, Kang] NIAID, Mucosal Immunol Studies Team, NIH, Bethesda, MD 20892 USA. [Sheng, Xiujie] Guangzhou Med Univ, Affiliated Hosp 3, Dept Obstet & Gynecol, Guangzhou, Guangdong, Peoples R China. [Han, Xiang] Peking Univ, Affiliated Hosp 3, Hlth Sci Ctr, Beijing, Peoples R China. [Wahba, Marian] Sinai Grace Hosp, Detroit Med Ctr, Dept Internal Med, Detroit, MI USA. RP Sheng, SJ (reprint author), Wayne State Univ, Sch Med, Dept Pathol, 540 East Canfield St, Detroit, MI 48201 USA. EM ssheng@med.wayne.edu OI Vranic, Semir/0000-0001-9743-7265 FU NIH [CA127735, CA084176, P30 CA022453]; Fund for Cancer Research; Ruth Sager Memorial Fund; Wayne State University Vice President Office for Research; Wayne State University; Karmanos Cancer Institute Applied Genomics Technology Center FX This work was supported by NIH grants (CA127735 and CA084176 to S. Sheng), Fund for Cancer Research (S. Sheng and E. Heath), and the Ruth Sager Memorial Fund (S. Sheng), the Wayne State University Vice President Office for Research (S. Sheng), and NIH grant P30 CA022453 (to Karmanos Cancer Institute with S. Sheng as a program leader). The NIH grant P30 CA022453 also supports the Wayne State University and Karmanos Cancer Institute Applied Genomics Technology Center. NR 55 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2017 VL 77 IS 4 BP 886 EP 896 DI 10.1158/0008-5472.CAN-16-2219 PG 11 WC Oncology SC Oncology GA EK4HN UT WOS:000393887800009 PM 27923833 ER PT J AU Sampson, JN Falk, RT Schairer, C Moore, SC Fuhrman, BJ Dallal, CM Bauer, DC Dorgan, JF Shu, XO Zheng, W Brinton, LA Gail, MH Ziegler, RG Xu, X Hoover, RN Gierach, GL AF Sampson, Joshua N. Falk, Roni T. Schairer, Catherine Moore, Steven C. Fuhrman, Barbara J. Dallal, Cher M. Bauer, Douglas C. Dorgan, Joanne F. Shu, Xiao-Ou Zheng, Wei Brinton, Louise A. Gail, Mitchell H. Ziegler, Regina G. Xu, Xia Hoover, Robert N. Gierach, Gretchen L. TI Association of Estrogen Metabolism with Breast Cancer Risk in Different Cohorts of Postmenopausal Women SO CANCER RESEARCH LA English DT Article ID CHROMATOGRAPHY-MASS SPECTROMETRY; ASSAY REPRODUCIBILITY; ENDOGENOUS ESTROGENS; URINARY ESTROGENS; SERUM ESTROGENS; RECEPTOR; ESTRADIOL; CARCINOGENESIS; MECHANISMS AB Endogenous estradiol and estrone are linked causally to increased risks of breast cancer. In this study, we evaluated multiple competing hypotheses for how metabolism of these parent estrogens may influence risk. Prediagnostic concentrations of estradiol, estrone, and 13 metabolites were measured in 1,298 postmenopausal cases of breast cancer and 1,524 matched controls in four separate patient cohorts. The median time between sample collection and diagnosis was 4.4 to 12.7 years across the cohorts. Estrogen analytes were measured in serum or urine by liquid chromatography-tandem mass spectrometry. Total estrogen levels (summing all 15 estrogens/estrogen metabolites) were associated strongly and positively with breast cancer risk. Normalizing total estrogen levels, we also found that a relative increase in levels of 2-hydroxylation pathway metabolites, or in the ratio of 2-hydroxylation: 16-hydroxylation pathway metabolites, were associated inversely with breast cancer risk. These associations varied by total estrogen levels, with the largest risk reductions occurring in women in the highest tertile. With appropriate validation, these findings suggest opportunities for breast cancer prevention by modifying individual estrogen metabolism profiles through either lifestyle alterations or chemopreventive strategies. (C)2017 AACR. C1 [Sampson, Joshua N.; Falk, Roni T.; Schairer, Catherine; Moore, Steven C.; Brinton, Louise A.; Gail, Mitchell H.; Ziegler, Regina G.; Hoover, Robert N.; Gierach, Gretchen L.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Fuhrman, Barbara J.] Univ Arkansas Med Sci, Fay W Boozman Coll Publ Hlth, Little Rock, AR 72205 USA. [Dallal, Cher M.] Univ Maryland, Sch Publ Hlth, College Pk, MD 20742 USA. [Bauer, Douglas C.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Dorgan, Joanne F.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37212 USA. [Xu, Xia] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD USA. [Sampson, Joshua N.] 9609 Med Ctr Dr,Room 7-E594, Bethesda, MD 20892 USA. RP Gierach, GL (reprint author), NCI, 9609 Med Ctr Dr,Room 7-E108, Bethesda, MD 20892 USA.; Sampson, JN (reprint author), 9609 Med Ctr Dr,Room 7-E594, Bethesda, MD 20892 USA. EM sampsonjn@mail.nih.gov; gierachg@mail.nih.gov RI Gierach, Gretchen/E-1817-2016 OI Gierach, Gretchen/0000-0002-0165-5522 FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute and National Cancer Institute federal funds [HHSN261200800001E]; [R37CA70867]; [UM1CA182910] FX This study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute and National Cancer Institute federal funds awarded under Contract No. HHSN261200800001E to SAIC-Frederick, Inc. The Shanghai Women's Health Study is supported by R37CA70867 (W. Zheng) and UM1CA182910 (W. Zheng). NR 27 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2017 VL 77 IS 4 BP 918 EP 925 DI 10.1158/0008-5472.CAN-16-1717 PG 8 WC Oncology SC Oncology GA EK4HN UT WOS:000393887800012 PM 28011624 ER PT J AU Attali, I Tobelaim, WS Persaud, A Motamedchaboki, K Simpson-Lavy, KJ Mashahreh, B Levin-Kravets, O Keren-Kaplan, T Pilzer, I Kupiec, M Wiener, R Wolf, DA Rotin, D Prag, G AF Attali, Ilan Tobelaim, William Sam Persaud, Avinash Motamedchaboki, Khatereh Simpson-Lavy, Kobi J. Mashahreh, Bayan Levin-Kravets, Olga Keren-Kaplan, Tal Pilzer, Inbar Kupiec, Martin Wiener, Reuven Wolf, Dieter A. Rotin, Daniela Prag, Gali TI Ubiquitylation-dependent oligomerization regulates activity of Nedd4 ligases SO EMBO JOURNAL LA English DT Article DE inactivation; Nedd4; oligomerization; Rsp5; ubiquitylation ID E3 UBIQUITIN LIGASES; EPITHELIAL NA+ CHANNEL; POTASSIUM CHANNEL; PROTEIN LIGASES; BINDING SITE; HECT DOMAIN; C2 DOMAIN; DEGRADATION; MONOUBIQUITINATION; FAMILY AB Ubiquitylation controls protein function and degradation. Therefore, ubiquitin ligases need to be tightly controlled. We discovered an evolutionarily conserved allosteric restraint mechanism for Nedd4 ligases and demonstrated its function with diverse substrates: the yeast soluble proteins Rpn10 and Rvs167, and the human receptor tyrosine kinase FGFR1 and cardiac I-KS potassium channel. We found that a potential trimerization interface is structurally blocked by the HECT domain alpha 1-helix, which further undergoes ubiquitylation on a conserved lysine residue. Genetic, bioinformatics, biochemical and biophysical data show that attraction between this alpha 1-conjugated ubiquitin and the HECT ubiquitin-binding patch pulls the alpha 1-helix out of the interface, thereby promoting trimerization. Strikingly, trimerization renders the ligase inactive. Arginine substitution of the ubiquitylated lysine impairs this inactivation mechanism and results in unrestrained FGFR1 ubiquitylation in cells. Similarly, electrophysiological data and TIRF microscopy show that NEDD4 unrestrained mutant constitutively downregulates the I-KS channel, thus confirming the functional importance of E3-ligase autoinhibition. C1 [Attali, Ilan; Levin-Kravets, Olga; Keren-Kaplan, Tal; Pilzer, Inbar; Prag, Gali] Tel Aviv Univ, Dept Biochem & Mol Biol, George S Wise Fac Life Sci, Tel Aviv, Israel. [Tobelaim, William Sam] Sackler Tel Aviv Univ, Dept Physiol & Pharmacol, Tel Aviv, Israel. [Persaud, Avinash; Rotin, Daniela] Univ Toronto, Hosp Sick Children, Cell Biol Program, Toronto, ON, Canada. [Persaud, Avinash; Rotin, Daniela] Univ Toronto, Dept Biochem, Toronto, ON, Canada. [Motamedchaboki, Khatereh; Wolf, Dieter A.] Sanford Burnham Prebys Med Discovery Inst, Tumor Initiat & Maintenance Program, La Jolla, CA USA. [Motamedchaboki, Khatereh; Wolf, Dieter A.] NCI, Ctr Canc, Prote Facil, Sanford Burnham Prebys Med Discovery Inst, La Jolla, CA USA. [Simpson-Lavy, Kobi J.] Tel Aviv Univ, Dept Mol Microbiol & Biotechnol, George S Wise Fac Life Sci, Tel Aviv, Israel. [Mashahreh, Bayan; Wiener, Reuven] Hebrew Univ Jerusalem, Inst Med Res Israel Canada, Dept Biochem & Mol Biol, Hadassah Med Sch, Jerusalem, Israel. [Wolf, Dieter A.] Xiamen Univ, Sch Pharmaceut Sci, Xiamen, Peoples R China. [Prag, Gali] Tel Aviv Univ, Sagol Sch Neurosci, Tel Aviv, Israel. RP Prag, G (reprint author), Tel Aviv Univ, Dept Biochem & Mol Biol, George S Wise Fac Life Sci, Tel Aviv, Israel.; Prag, G (reprint author), Tel Aviv Univ, Sagol Sch Neurosci, Tel Aviv, Israel. EM prag@post.tau.ac.il NR 69 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0261-4189 EI 1460-2075 J9 EMBO J JI Embo J. PD FEB 15 PY 2017 VL 36 IS 4 BP 425 EP 440 DI 10.15252/embj.201694314 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EL2JU UT WOS:000394446700006 PM 28069708 ER PT J AU Stolz, A Putyrski, M Kutle, I Huber, J Wang, CX Major, V Sidhu, SS Youle, RJ Rogov, VV Dotsch, V Ernst, A Dikic, I AF Stolz, Alexandra Putyrski, Mateusz Kutle, Ivana Huber, Jessica Wang, Chunxin Major, Viktoria Sidhu, Sachdev S. Youle, Richard J. Rogov, Vladimir V. Doetsch, Volker Ernst, Andreas Dikic, Ivan TI Fluorescence-based ATG8 sensors monitor localization and function of LC3/GABARAP proteins SO EMBO JOURNAL LA English DT Article DE ATG8; immunofluorescence; LC3; phage display; selective autophagy ID AUTOPHAGOSOME-LYSOSOME FUSION; UBIQUITIN-LIKE PROTEINS; SELECTIVE AUTOPHAGY; LIR MOTIF; PROTEASOMAL DEGRADATION; STRUCTURAL BASIS; PHOSPHORYLATION; RECEPTORS; MITOPHAGY; COMPLEX AB Autophagy is a cellular surveillance pathway that balances metabolic and energy resources and transports specific cargos, including damaged mitochondria, other broken organelles, or pathogens for degradation to the lysosome. Central components of autophagosomal biogenesis are six members of the LC3 and GABARAP family of ubiquitin-like proteins (mATG8s). We used phage display to isolate peptides that possess bona fide LIR (LC3-interacting region) properties and are selective for individual mATG8 isoforms. Sensitivity of the developed sensors was optimized by multiplication, charge distribution, and fusion with a membrane recruitment (FYVE) or an oligomerization (PB1) domain. We demonstrate the use of the engineered peptides as intracellular sensors that recognize specifically GABARAP, GABL1, GABL2, and LC3C, as well as a bispecific sensor for LC3A and LC3B. By using an LC3C-specific sensor, we were able to monitor recruitment of endogenous LC3C to Salmonella during xenophagy, as well as to mitochondria during mitophagy. The sensors are general tools to monitor the fate of mATG8s and will be valuable in decoding the biological functions of the individual LC3/GABARAPs. C1 [Stolz, Alexandra; Putyrski, Mateusz; Major, Viktoria; Ernst, Andreas; Dikic, Ivan] Goethe Univ, Inst Biochem 2, Frankfurt, Germany. [Putyrski, Mateusz; Ernst, Andreas] Project Grp Translat Med & Pharmacol TMP, Fraunhofer Inst Mol Biol & Appl Ecol IME, Frankfurt, Germany. [Kutle, Ivana; Dikic, Ivan] Buchmann Inst Mol Life Sci, Frankfurt, Germany. [Huber, Jessica; Rogov, Vladimir V.; Doetsch, Volker] Goethe Univ, Inst Biophys Chem, Frankfurt, Germany. [Wang, Chunxin; Youle, Richard J.] NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Sidhu, Sachdev S.] Univ Toronto, Donnelly Ctr, Banting & Best Dept Med Res, Toronto, ON, Canada. [Sidhu, Sachdev S.] Univ Toronto, Donnelly Ctr, Dept Mol Genet, Toronto, ON, Canada. RP Ernst, A; Dikic, I (reprint author), Goethe Univ, Inst Biochem 2, Frankfurt, Germany.; Ernst, A (reprint author), Project Grp Translat Med & Pharmacol TMP, Fraunhofer Inst Mol Biol & Appl Ecol IME, Frankfurt, Germany.; Dikic, I (reprint author), Buchmann Inst Mol Life Sci, Frankfurt, Germany. EM ernst@biochem2.de; dikic@biochem2.uni-frankfurt.de NR 61 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0261-4189 EI 1460-2075 J9 EMBO J JI Embo J. PD FEB 15 PY 2017 VL 36 IS 4 BP 549 EP 564 DI 10.15252/embj.201695063 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EL2JU UT WOS:000394446700014 PM 28028054 ER PT J AU Livingston, WS Gill, JM Cota, MR Olivera, A O'Keefe, JL Martin, C Latour, LL AF Livingston, Whitney S. Gill, Jessica M. Cota, Martin R. Olivera, Anlys O'Keefe, Jessica L. Martin, Christiana Latour, Lawrence L. TI Differential Gene Expression Associated with Meningeal Injury in Acute Mild Traumatic Brain Injury SO JOURNAL OF NEUROTRAUMA LA English DT Article DE brain trauma; concussion; gene expression; MRI ID GLASGOW COMA SCALE; BARRIER DISRUPTION; APACHE-II; INFLAMMATION; STROKE; MENINGITIS; PREDICTION; OUTCOMES; HUMANS; SCORES AB Injury to the meninges is not uncommon after traumatic brain injury (TBI), yet minimal research has been directed toward understanding the relevant biology. After a concussive event, the meninges are observed to abnormally enhance on post-contrast magnetic resonance imaging (MRI) in some patients, but not all. The aim of this work is to identify genes differentially expressed in patients with meningeal injury. Patients presenting to the emergency room with suspected TBI received a standard research MRI and blood draw within 48 h of injury. Two groups of patients were included: those with and without abnormal enhancement of the meninges on post-contrast MRI, both without other imaging findings. Groups were compared on microarray gene expression in peripheral blood samples using Affymetrix (Santa Clara, CA) and Partek Genomics Suite (Partek, Inc., St. Louis, MO) software (false discovery rate, <0.05). Forty patients were enrolled with a time from injury to MRI/blood draw of 16.8 h (interquartile range, 7.5-24.1). We observed 76 genes to be differentially expressed in patients with meningeal injury compared to those without, such as receptor for Fc fragment of IgA, multiple C2 domains, transmembrane 2, and G-protein-coupled receptor 27, which have been previously associated with initiating inflammatory mediators, phagocytosis, and other regulatory mechanisms. Post-contrast MRI is able to detect meningeal injury and has a unique biological signature observed through gene expression. These findings suggest that an acute inflammatory response occurs in response to injury to the meninges following a concussion. C1 [Livingston, Whitney S.; Gill, Jessica M.; Olivera, Anlys; Martin, Christiana] NINR, NIH, Bethesda, MD 20892 USA. [Gill, Jessica M.; Latour, Lawrence L.] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Cota, Martin R.; O'Keefe, Jessica L.; Latour, Lawrence L.] NINDS, NIH, 10 Ctr Dr,Bldg 10,B1D733, Bethesda, MD 20892 USA. RP Latour, LL (reprint author), NINDS, NIH, 10 Ctr Dr,Bldg 10,B1D733, Bethesda, MD 20892 USA. EM latourl@ninds.nih.gov FU Department of Defense in the Center for Neuroscience and Regenerative Medicine (CNRM); NINDS; National Institute of Nursing Research (NINR) FX The authors are grateful to the patients and their families, for without them this research would not be possible. The authors acknowledge the staff at Johns Hopkins Suburban Hospital, MedStar Washington Hospital Center, and the National Institute of Neurological Disorders and Stroke (NINDS) Acute Stroke Team for their assistance during this study. Support for this work included Department of Defense in the Center for Neuroscience and Regenerative Medicine (CNRM), the NINDS, and the National Institute of Nursing Research (NINR). NR 28 TC 0 Z9 0 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD FEB 15 PY 2017 VL 34 IS 4 BP 853 EP 860 DI 10.1089/neu.2016.4479 PG 8 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA EL0XD UT WOS:000394344200012 PM 27430610 ER PT J AU Johnson, TP Tyagi, R Lee, PR Lee, MH Johnson, KR Kowalak, J Elkahloun, A Medynets, M Hategan, A Kubofcik, J Sejvar, J Ratto, J Bunga, S Makumbi, I Aceng, JR Nutman, TB Dowell, SF Nath, A AF Johnson, Tory P. Tyagi, Richa Lee, Paul R. Lee, Myoung-Hwa Johnson, Kory R. Kowalak, Jeffrey Elkahloun, Abdel Medynets, Marie Hategan, Alina Kubofcik, Joseph Sejvar, James Ratto, Jeffrey Bunga, Sudhir Makumbi, Issa Aceng, Jane R. Nutman, Thomas B. Dowell, Scott F. Nath, Avindra TI Nodding syndrome may be an autoimmune reaction to the parasitic worm Onchocerca volvulus SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID MUSCLE-CELLS; MUNDRI COUNTY; CASE SERIES; EPILEPSY; TANZANIA; UGANDA; ENCEPHALITIS; EXPRESSION; ANTIBODIES; RECEPTOR AB Nodding syndrome is an epileptic disorder of unknown etiology that occurs in children in East Africa. There is an epidemiological association with Onchocerca volvulus, the parasitic worm that causes onchocerciasis (river blindness), but there is limited evidence that the parasite itself is neuroinvasive. We hypothesized that nodding syndrome may be an autoimmune-mediated disease. Using protein chip methodology, we detected autoantibodies to leiomodin-1 more abundantly in patients with nodding syndrome compared to unaffected controls from the same village. Leiomodin-1 autoantibodies were found in both the sera and cerebrospinal fluid of patients with nodding syndrome. Leiomodin-1 was found to be expressed in mature and developing human neurons in vitro and was localized in mouse brain to the CA3 region of the hippocampus, Purkinje cells in the cerebellum, and cortical neurons, structures that also appear to be affected in patients with nodding syndrome. Antibodies targeting leiomodin-1 were neurotoxic in vitro, and leiomodin-1 antibodies purified from patients with nodding syndrome were cross-reactive with O. volvulus antigens. This study provides initial evidence supporting the hypothesis that nodding syndrome is an autoimmune epileptic disorder caused by molecular mimicry with O. volvulus antigens and suggests that patients may benefit from immunomodulatory therapies. C1 [Johnson, Tory P.; Tyagi, Richa; Lee, Paul R.; Lee, Myoung-Hwa; Hategan, Alina; Nath, Avindra] NINDS, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. [Johnson, Kory R.] NINCDS, Bioinformat Sect, NIH, Bethesda, MD 20892 USA. [Kowalak, Jeffrey] NINCDS, Clin Prote Unit, NIH, Bethesda, MD 20892 USA. [Elkahloun, Abdel] NINCDS, Microarray Core Facil, NIH, Bethesda, MD 20892 USA. [Medynets, Marie] NINCDS, Neural Differentiat Unit, NIH, Bethesda, MD 20892 USA. [Kubofcik, Joseph; Nutman, Thomas B.] NINCDS, Helminth Immunol Sect, Lab Parasit Dis, NIH, Bethesda, MD 20892 USA. [Sejvar, James] Ctr Dis Control & Prevent, Div High Consequence Pathogens & Pathol, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA 30333 USA. [Ratto, Jeffrey; Bunga, Sudhir] Ctr Dis Control & Prevent, Div Global Hlth Protect, Ctr Global Hlth, Atlanta, GA 30333 USA. [Makumbi, Issa; Aceng, Jane R.] Minist Hlth, Kampala, Uganda. [Dowell, Scott F.] Bill & Melinda Gates Fdn, Seattle, WA 98109 USA. RP Nath, A (reprint author), NINDS, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. EM natha@ninds.nih.gov FU NIH; CDC FX This research was supported by the Intramural Research Programs of the NIH and CDC. The findings and conclusions of this report are those of the authors and do not necessarily represent the official position of the CDC. NR 35 TC 1 Z9 1 U1 1 U2 1 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD FEB 15 PY 2017 VL 9 IS 377 AR eaaf6953 DI 10.1126/scitranslmed.aaf6953 PG 10 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA EL2LL UT WOS:000394451100002 ER PT J AU Correa-De-Araujo, R Harris-Love, MO Miljkovic, I Fragala, MS Anthony, BW Manini, TM AF Correa-de-Araujo, Rosaly Harris-Love, Michael O. Miljkovic, Iva Fragala, Maren S. Anthony, Brian W. Manini, Todd M. TI The Need for Standardized Assessment of Muscle Quality in Skeletal Muscle Function Deficit and Other Aging-Related Muscle Dysfunctions: A Symposium Report SO FRONTIERS IN PHYSIOLOGY LA English DT Review DE muscle quality; sarcopenia; muscle strength; muscle power; skeletal muscle function deficit; myosteatosis; imaging ID INTERMUSCULAR ADIPOSE-TISSUE; MAGNETIC-RESONANCE-SPECTROSCOPY; CLINICALLY RELEVANT WEAKNESS; DUCHENNE MUSCULAR-DYSTROPHY; FNIH SARCOPENIA PROJECT; DIFFERENT FIBER TYPES; LOW LEAN MASS; OLDER-ADULTS; INSULIN-RESISTANCE; BODY-COMPOSITION AB A growing body of scientific literature suggests that not only changes in skeletal muscle mass, but also other factors underpinning muscle quality, play a role in the decline in skeletal muscle function and impaired mobility associated with aging. A symposium on muscle quality and the need for standardized assessment was held on April 28, 2016 at the International Conference on Frailty and Sarcopenia Research in Philadelphia, Pennsylvania. The purpose of this symposium was to provide a venue for basic science and clinical researchers and expert clinicians to discuss muscle quality in the context of skeletal muscle function deficit and other aging-related muscle dysfunctions. The present article provides an expanded introduction concerning the emerging definitions of muscle quality and a potential framework for scientific inquiry within the field. Changes in muscle tissue composition, based on excessive levels of inter-and intra-muscular adipose tissue and intramyocellular lipids, have been found to adversely impact metabolism and peak force generation. However, methods to easily and rapidly assess muscle tissue composition in multiple clinical settings and with minimal patient burden are needed. Diagnostic ultrasound and other assessment methods continue to be developed for characterizing muscle pathology, and enhanced sonography using sensors to provide user feedback and improve reliability is currently the subject of ongoing investigation and development. In addition, measures of relative muscle force such as specific force or grip strength adjusted for body size have been proposed as methods to assess changes in muscle quality. Furthermore, performance-based assessments of muscle power via timed tests of function and body size estimates, are associated with lower extremity muscle strength may be responsive to age-related changes in muscle quality. Future aims include reaching consensus on the definition and standardized assessments of muscle quality, and providing recommendations to address critical clinical and technology research gaps within the field. C1 [Correa-de-Araujo, Rosaly] NIA, Div Geriatr & Clin Gerontol, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Harris-Love, Michael O.] Vet Affairs Med Ctr, Clin Res Ctr, Muscle Morphol Mech & Performance Lab, Human Performance Res Unit, Washington, DC 20422 USA. [Harris-Love, Michael O.] Vet Affairs Med Ctr, Geriatr & Extended Care Serv Res Serv, Washington, DC 20422 USA. [Harris-Love, Michael O.] George Washington Univ, Milken Inst Sch Publ Hlth, Dept Exercise & Nutrit Sci, Washington, DC 20052 USA. [Miljkovic, Iva] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Fragala, Maren S.] Quest Diagnost, Madison, NJ USA. [Anthony, Brian W.] MIT, Lab Mfg & Prod, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Anthony, Brian W.] MIT, Med lect Device Realizat Ctr, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Manini, Todd M.] Univ Florida, Coll Med, Inst Aging, Dept Aging & Geriatr Res, Gainesville, FL USA. RP Correa-De-Araujo, R (reprint author), NIA, Div Geriatr & Clin Gerontol, NIH, US Dept HHS, Bethesda, MD 20892 USA.; Harris-Love, MO (reprint author), Vet Affairs Med Ctr, Clin Res Ctr, Muscle Morphol Mech & Performance Lab, Human Performance Res Unit, Washington, DC 20422 USA.; Harris-Love, MO (reprint author), Vet Affairs Med Ctr, Geriatr & Extended Care Serv Res Serv, Washington, DC 20422 USA.; Harris-Love, MO (reprint author), George Washington Univ, Milken Inst Sch Publ Hlth, Dept Exercise & Nutrit Sci, Washington, DC 20052 USA. EM rosaly.correa-de-araujo@nih.gov; michael.harris-love@va.gov FU VA Office of Research and Development-Rehabilitation RD Service [1IK2RX001854-01] FX This publication was partially supported by the VA Office of Research and Development-Rehabilitation R&D Service (1IK2RX001854-01). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 166 TC 0 Z9 0 U1 2 U2 2 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-042X J9 FRONT PHYSIOL JI Front. Physiol. PD FEB 15 PY 2017 VL 8 AR 87 DI 10.3389/fphys.2017.00087 PG 19 WC Physiology SC Physiology GA EK6TV UT WOS:000394057900001 PM 28261109 ER PT J AU Adler-Wailes, DC Kramer, JA DePamphilis, ML AF Adler-Wailes, Diane C. Kramer, Joshua A. DePamphilis, Melvin L. TI Geminin Is Essential for Pluripotent Cell Viability During Teratoma Formation, but Not for Differentiated Cell Viability During Teratoma Expansion SO STEM CELLS AND DEVELOPMENT LA English DT Article DE DNA rereplication; embryonal carcinoma cells; embryonic stem cells; geminin; germ cell neoplasia; teratocarcinoma ID EMBRYONIC STEM-CELLS; PRIMORDIAL GERM-CELLS; MOUSE EMBRYOS; BREAST-CANCER; TUMORS; PROLIFERATION; EXPRESSION; REPLICATION; DERIVATION; CULTURE AB Pluripotent embryonic stem cells (ESCs) are unusual in that geminin has been reported to be essential either to prevent differentiation by maintaining expression of pluripotency genes or to prevent DNA rereplication-dependent apoptosis. To distinguish between these two incompatible hypotheses, immune-compromised mice were inoculated subcutaneously with ESCs harboring conditional Gmnn alleles alone or together with a tamoxifen-dependent Cre recombinase gene. Mice were then injected with tamoxifen at various times during which the ESCs proliferated and differentiated into a teratoma. For comparison, the same ESCs were cultured in vitro in the presence of monohydroxytamoxifen. The results revealed that geminin is a haplosufficient gene that is essential for ESC viability before they differentiate into a teratoma, but once a teratoma is established, the differentiated cells can continue to proliferate in the absence of Gmnn alleles, geminin protein, and pluripotent stem cells. Thus, differentiated cells did not require geminin for efficient proliferation within the context of a solid tissue, although they did when teratoma cells were cultured in vitro. These results provide proof-of-principle that preventing geminin function could prevent malignancy in tumors derived from pluripotent cells by selectively eliminating the progenitor cells with little harm to normal cells. C1 [Adler-Wailes, Diane C.; DePamphilis, Melvin L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bldg 6A,Room 3A15,6 Ctr Dr, Bethesda, MD 20892 USA. [Kramer, Joshua A.] Leidos Biomed Res Inc, Lab Anim Sci Program, Bethesda, MD USA. RP DePamphilis, ML (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bldg 6A,Room 3A15,6 Ctr Dr, Bethesda, MD 20892 USA. EM depamphm@mail.nih.gov FU national institute for Child Health and Human Development; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX this project was supported in part by the national institute for Child Health and Human Development and, in part, by 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. The Scientific Director, NICHD/NIH, approved this research for publication (BMGR/SEDR-MD/ MD-16-07729-R). NR 67 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1547-3287 EI 1557-8534 J9 STEM CELLS DEV JI Stem Cells Dev. PD FEB 15 PY 2017 VL 26 IS 4 BP 285 EP 302 DI 10.1089/scd.2016.0260 PG 18 WC Cell & Tissue Engineering; Hematology; Medicine, Research & Experimental; Transplantation SC Cell Biology; Hematology; Research & Experimental Medicine; Transplantation GA EK0XJ UT WOS:000393650100007 PM 27821018 ER PT J AU Bodelon, C Oh, H Chatterjee, N Garcia-Closas, M Palakal, M Sherman, ME Pfeiffer, RM Geller, BM Vacek, PM Weaver, DL Chicoine, RE Papathomas, D Xiang, J Patel, DA Khodr, ZG Linville, L Clare, SE Visscher, DW Mies, C Hewitt, SM Brinton, LA Storniolo, AM He, CY Chanock, SJ Gierach, GL Figueroa, JD AF Bodelon, Clara Oh, Hannah Chatterjee, Nilanjan Garcia-Closas, Montserrat Palakal, Maya Sherman, Mark E. Pfeiffer, Ruth M. Geller, Berta M. Vacek, Pamela M. Weaver, Donald L. Chicoine, Rachael E. Papathomas, Daphne Xiang, Jackie Patel, Deesha A. Khodr, Zeina G. Linville, Laura Clare, Susan E. Visscher, Daniel W. Mies, Carolyn Hewitt, Stephen M. Brinton, Louise A. Storniolo, Anna Maria He, Chunyan Chanock, Stephen J. Gierach, Gretchen L. Figueroa, Jonine D. TI Association between breast cancer genetic susceptibility variants and terminal duct lobular unit involution of the breast SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE genetic susceptibility; terminal duct lobular unit; involution; breast cancer ID GENOME-WIDE ASSOCIATION; MAMMOGRAPHIC DENSITY; COMMON VARIANTS; CONFER SUSCEPTIBILITY; 14Q24.1 RAD51L1; RISK-FACTORS; IDENTIFIES 2; LOCI; TISSUE; MUTATION AB Terminal duct lobular units (TDLUs) are the predominant source of future breast cancers, and lack of TDLU involution (higher TDLU counts, higher acini count per TDLU and the product of the two) is a breast cancer risk factor. Numerous breast cancer susceptibility single nucleotide polymorphisms (SNPs) have been identified, but whether they are associated with TDLU involution is unknown. In a pooled analysis of 872 women from two studies, we investigated 62 established breast cancer SNPs and relationships with TDLU involution. Poisson regression models with robust variance were used to calculate adjusted perallele relative risks (with the non-breast cancer risk allele as the referent) and 95% confidence intervals between TDLU measures and each SNP. All statistical tests were two-sided; P < 0.05 was considered statistically significant. Overall, 36 SNPs (58.1%) were related to higher TDLU counts although this was not statistically significant (p = 0.25). Six of the 62 SNPs (9.7%) were nominally associated with at least one TDLU measure: rs616488 (PEX14), rs11242675 (FOXQ1) and rs6001930 (MKL1) were associated with higher TDLU count (p = 0.047, 0.045 and 0.031, respectively); rs1353747 (PDE4D) and rs6472903 (8q21.11) were associated with higher acini count per TDLU (p = 0.007 and 0.027, respectively); and rs1353747 (PDE4D) and rs204247 (RANBP9) were associated with the product of TDLU and acini counts (p = 0.024 and 0.017, respectively). Our findings suggest breast cancer SNPs may not strongly influence TDLU involution. Agnostic genome-wide association studies of TDLU involution may provide new insights on its biologic underpinnings and breast cancer susceptibility. C1 [Bodelon, Clara; Oh, Hannah; Chatterjee, Nilanjan; Garcia-Closas, Montserrat; Palakal, Maya; Sherman, Mark E.; Pfeiffer, Ruth M.; Papathomas, Daphne; Xiang, Jackie; Patel, Deesha A.; Khodr, Zeina G.; Linville, Laura; Brinton, Louise A.; Chanock, Stephen J.; Gierach, Gretchen L.; Figueroa, Jonine D.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Sherman, Mark E.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Geller, Berta M.; Vacek, Pamela M.; Weaver, Donald L.; Chicoine, Rachael E.] Univ Vermont, Coll Med, Dept Biostat, Burlington, VT USA. [Geller, Berta M.; Vacek, Pamela M.; Weaver, Donald L.; Chicoine, Rachael E.] Vermont Canc Ctr, Burlington, VT USA. [Clare, Susan E.] Northwestern Univ, Dept Surg, Feinberg Sch Med, Chicago, IL 60611 USA. [Visscher, Daniel W.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Mies, Carolyn] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA USA. [Hewitt, Stephen M.] NCI, Pathol Lab, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. [Storniolo, Anna Maria] Indiana Univ, Simon Canc Ctr, Susan G Komen Tissue Bank, Indianapolis, IN 46204 USA. [He, Chunyan] Indiana Univ, Dept Epidemiol, Richard M Fairbanks Sch Publ Hlth, Indianapolis, IN 46204 USA. [Figueroa, Jonine D.] Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh EH8 9YL, Midlothian, Scotland. [Figueroa, Jonine D.] Univ Edinburgh, Edinburgh Canc Res Ctr, Edinburgh EH8 9YL, Midlothian, Scotland. RP Bodelon, C (reprint author), Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Rm 7-E236, Bethesda, MD 20892 USA. EM clara.bodelon@nih.gov RI Gierach, Gretchen/E-1817-2016 OI Gierach, Gretchen/0000-0002-0165-5522 FU National Cancer Institute FX Grant sponsor: Intramural Research Program of the National Cancer Institute NR 44 TC 0 Z9 0 U1 8 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD FEB 15 PY 2017 VL 140 IS 4 BP 825 EP 832 DI 10.1002/ijc.30512 PG 8 WC Oncology SC Oncology GA EG0FA UT WOS:000390705400009 PM 27859137 ER PT J AU Moran, LJ Fraser, LM Sundernathan, T Deussen, AR Louise, J Yelland, LN Grivell, RM Macpherson, A Gillman, MW Robinson, JS Owens, JA Dodd, JM AF Moran, Lisa J. Fraser, Louise M. Sundernathan, Tulika Deussen, Andrea R. Louise, Jennie Yelland, Lisa N. Grivell, Rosalie M. Macpherson, Anne Gillman, Matthew W. Robinson, Jeffrey S. Owens, Julie A. Dodd, Jodie M. TI The effect of an antenatal lifestyle intervention in overweight and obese women on circulating cardiometabolic and inflammatory biomarkers: secondary analyses from the LIMIT randomised trial SO BMC MEDICINE LA English DT Article DE Pregnancy; Overweight and obesity; Dietary and lifestyle intervention; Randomised trial; Cardiometabolic markers; Inflammatory markers ID GESTATIONAL DIABETES-MELLITUS; C-REACTIVE PROTEIN; BODY-MASS INDEX; NECROSIS-FACTOR-ALPHA; WEIGHT-GAIN; PREGNANT-WOMEN; INSULIN-RESISTANCE; HEALTH OUTCOMES; CARDIOVASCULAR-DISEASE; METABOLIC SYNDROME AB Background: Maternal overweight and obesity during pregnancy is associated with insulin resistance, hyperglycaemia, hyperlipidaemia and a low-grade state of chronic inflammation. The aim of this pre-specified analysis of secondary outcome measures was to evaluate the effect of providing antenatal dietary and lifestyle advice on cardiometabolic and inflammatory biomarkers. Methods: We conducted a multicentre trial in which pregnant women who were overweight or obese were randomised to receive either Lifestyle Advice or Standard Care. We report a range of pre-specified secondary maternal and newborn cardiometabolic and inflammatory biomarker outcomes. Maternal whole venous blood was collected at trial entry (mean 14 weeks gestation; non-fasting), at 28 weeks gestation (fasting), and at 36 weeks gestation (non-fasting). Cord blood was collected after birth and prior to the delivery of the placenta. A range of cardiometabolic and inflammatory markers were analysed (total cholesterol, triglycerides, non-esterified fatty acids, high-density lipoprotein cholesterol, insulin, glucose, leptin, adiponectin, C-reactive protein, granulocyte macrophage-colony stimulating factor, interferon gamma, TNF-alpha, and interleukins 1 beta, 2, 4, 5, 6, 8, and 10). Participants were analysed in the groups to which they were randomised, and were included in the analyses if they had a measure at any time point. Results: One or more biological specimens were available from 1951 women (989 Lifestyle Advice and 962 Standard Care), with cord blood from 1174 infants (596 Lifestyle Advice and 578 Standard Care). There were no statistically significant differences in mean cardiometabolic and inflammatory marker concentrations across pregnancy and in infant cord blood between treatment groups. Estimated treatment group differences were close to zero, with 95% confidence intervals spanning a range of differences that were short of clinical relevance. There was no evidence to suggest that the intervention effect was modified by mate Conclusions: Despite our findings, it will be worth considering potential relationships between cardiometabolic and inflammatory markers and clinical outcomes, including longer-term infant health and adiposity. C1 [Moran, Lisa J.; Fraser, Louise M.; Sundernathan, Tulika; Deussen, Andrea R.; Louise, Jennie; Yelland, Lisa N.; Grivell, Rosalie M.; Macpherson, Anne; Robinson, Jeffrey S.; Owens, Julie A.; Dodd, Jodie M.] Univ Adelaide, Robinson Res Inst & Discipline Obstet & Gynaecol, Adelaide, SA 5005, Australia. [Moran, Lisa J.] Monash Univ, Monash Ctr Hlth Res Implementat, Clayton, Vic, Australia. [Louise, Jennie; Yelland, Lisa N.] Univ Adelaide, Sch Populat Hlth, Adelaide, SA, Australia. [Yelland, Lisa N.] South Australian Hlth & Med Res Inst, Adelaide, SA, Australia. [Grivell, Rosalie M.] Flinders Univ S Australia, Dept Obstet & Gynaecol, Bedford Pk, SA, Australia. [Gillman, Matthew W.] Harvard Med Sch, Harvard Pilgrim Hlth Care Inst, Dept Populat Med, Obes Prevent Program, Boston, MA USA. [Gillman, Matthew W.] NIH, Environm Influences Child Hlth Outcomes ECHO, Rockville, MD USA. [Dodd, Jodie M.] Womens & Childrens Hosp, Dept Perinatal Med, Womens & Babies Div, Adelaide, SA, Australia. RP Dodd, JM (reprint author), Univ Adelaide, Robinson Res Inst & Discipline Obstet & Gynaecol, Adelaide, SA 5005, Australia.; Dodd, JM (reprint author), Womens & Childrens Hosp, Dept Perinatal Med, Womens & Babies Div, Adelaide, SA, Australia. EM jodie.dodd@adelaide.edu.au FU National Health and Medical Research Council (NHMRC), Australia [519240]; Diabetes Australia Research Trust; US National Institute of Health (NIH) [R01 HL094235-01]; NHMRC Practitioner Fellowship [627005]; NHMRC Early Career Fellowship [1052388, 1073514]; South Australian Cardiovascular Research Development Program (SACVRDP) Fellowship [AC11S374]; National Heart Foundation of Australia; South Australian Department of Health; South Australian Health and Medical Research Institute FX This project was funded by a 4-year project grant from the National Health and Medical Research Council (NHMRC), Australia (ID 519240); Diabetes Australia Research Trust; and US National Institute of Health (NIH) (R01 HL094235-01). JM Dodd is supported through a NHMRC Practitioner Fellowship (ID 627005). LN Yelland is supported through a NHMRC Early Career Fellowship (ID 1052388). RM Grivell is supported through a NHMRC Early Career Fellowship (ID 1073514). LJ Moran is supported through a South Australian Cardiovascular Research Development Program (SACVRDP) Fellowship (AC11S374); a program collaboratively funded by the National Heart Foundation of Australia, the South Australian Department of Health, and the South Australian Health and Medical Research Institute. Infrastructure support was provided by The University of Adelaide, the Women's and Children's Hospital, Flinders Medical Centre, and the Lyell McEwin Hospital, Adelaide. NR 51 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7015 J9 BMC MED JI BMC Med. PD FEB 14 PY 2017 VL 15 AR 32 DI 10.1186/s12916-017-0790-z PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA EN3UD UT WOS:000395932500001 PM 28193219 ER PT J AU Lacuey, N Zonjy, B Londono, L Lhatoo, SD AF Lacuey, Nuria Zonjy, Bilal Londono, Luisa Lhatoo, Samden D. TI Amygdala and hippocampus are symptomatogenic zones for central apneic seizures SO NEUROLOGY LA English DT Article ID EPILEPSY; STIMULATION; ONSET; DEATH AB Objective: To identify limbic sites of respiratory control in the human brain, and by extension, the symptomatogenic zone for central apnea. Methods: We used direct stimulation of anatomically, precisely placed stereotactic EEG electrodes to analyze breathing responses. We prospectively studied 3 patients who were explored with stereotactically implanted depth electrodes. The amygdala and hippocampus, as well as extralimbic sites (orbitofrontal, temporal tip, and temporal neocortex), were investigated. Results: Individual stimulation of the amygdala and hippocampal head consistently elicited central apnea in the expiratory phase, as did exquisitely focal hippocampal seizures. Conclusions: These findings confirm that hippocampus and amygdala are limbic breathing control sites in humans, as well as the symptomatogenic zone for central apneic seizures. C1 [Lacuey, Nuria; Zonjy, Bilal; Londono, Luisa; Lhatoo, Samden D.] UH Cleveland Med Ctr, Epilepsy Ctr, Cleveland, OH 44106 USA. [Lacuey, Nuria] Vall dHebron Univ Hosp, Dept Neurol, Barcelona, Spain. [Lacuey, Nuria] Univ Autonoma Barcelona, Dept Med, E-08193 Barcelona, Spain. [Lhatoo, Samden D.] NINDS, Ctr SUDEP Res CSR, Cleveland, OH USA. RP Lacuey, N (reprint author), UH Cleveland Med Ctr, Epilepsy Ctr, Cleveland, OH 44106 USA.; Lacuey, N (reprint author), Vall dHebron Univ Hosp, Dept Neurol, Barcelona, Spain.; Lacuey, N (reprint author), Univ Autonoma Barcelona, Dept Med, E-08193 Barcelona, Spain. EM nuria.lacuey@uhhospitals.org FU Universitat Autonoma de Barcelona, Doctorate thesis in Medicine FX This work was supported in part by the Universitat Autonoma de Barcelona as part of a Doctorate thesis in Medicine. NR 10 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 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 14 PY 2017 VL 88 IS 7 BP 701 EP 705 DI 10.1212/WNL.0000000000003613 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA EP4IP UT WOS:000397344500018 PM 28087822 ER PT J AU Introne, WJ Westbroek, W Groden, CA Bhambhani, V Golas, GA Baker, EH Lehky, TJ Snow, J Ziegler, SG Malicdan, MCV Adams, DR Dorward, HM Hess, RA Huizing, M Gahl, WA Toro, C AF Introne, Wendy J. Westbroek, Wendy Groden, Catherine A. Bhambhani, Vikas Golas, Gretchen A. Baker, Eva H. Lehky, Tanya J. Snow, Joseph Ziegler, Shira G. Malicdan, May Christine V. Adams, David R. Dorward, Heidi M. Hess, Richard A. Huizing, Marjan Gahl, William A. Toro, Camilo TI Neurologic involvement in patients with atypical Chediak-Higashi disease SO NEUROLOGY LA English DT Article ID PARKINSONIAN-SYNDROME; CLINICAL PHENOTYPE; LYST; IDENTIFICATION; LYSOSOMES; MUTATIONS; GENOTYPE; DOMAIN; CELLS; BEIGE AB Objective: To delineate the developmental and progressive neurodegenerative features in 9 young adults with the atypical form of Chediak-Higashi disease (CHD) enrolled in a natural history study. Methods: Patients with atypical clinical features, but diagnostically confirmed CHD by standard evaluation of blood smears and molecular genotyping, underwent complete neurologic evaluation, MRI of the brain, electrophysiologic examination, and neuropsychological testing. Fibroblasts were collected to investigate the cellular phenotype and correlation with the clinical presentation. Results: In 9 mildly affected patients with CHD, we documented learning and behavioral difficulties along with developmental structural abnormalities of the cerebellum and posterior fossa, which are apparent early in childhood. A range of progressive neurologic problems emerge in early adulthood, including cerebellar deficits, polyneuropathies, spasticity, cognitive decline, and parkinsonism. Conclusions: Patients with undiagnosed atypical CHD manifesting some of these wide-ranging yet nonspecific neurologic complaints may reside in general and specialty neurology clinics. The absence of the typical bleeding or infectious diathesis in mildly affected patients with CHD renders them difficult to diagnose. Identification of these individuals is important not only for close surveillance of potential CHD-related systemic complications but also for a full understanding of the natural history of CHD and the potential role of the disease-causing protein, LYST, to the pathophysiology of other neurodevelopmental and neurodegenerative disorders. C1 [Introne, Wendy J.; Groden, Catherine A.; Bhambhani, Vikas; Golas, Gretchen A.; Gahl, William A.; Toro, Camilo] Childrens Hosp & Clin Minnesota, Dept Med Genet, Clin Director, Minneapolis, MN USA. [Westbroek, Wendy; Ziegler, Shira G.; Malicdan, May Christine V.; Adams, David R.; Dorward, Heidi M.; Hess, Richard A.; Huizing, Marjan; Gahl, William A.] Childrens Hosp & Clin Minnesota, Human Biochem Genet Sect, Med Genet Branch, Dept Med Genet, Minneapolis, MN USA. [Baker, Eva H.] Childrens Hosp & Clin Minnesota, Human Biochem Genet Sect, Ctr Clin, Natl Human Genome Res Inst,Dept Radiol & Imaging, Minneapolis, MN USA. [Lehky, Tanya J.] Childrens Hosp & Clin Minnesota, Human Biochem Genet Sect, Elect Sect Off Clin Director, Natl Inst Neurol Disorders & Stroke, Minneapolis, MN USA. [Snow, Joseph] Childrens Hosp & Clin Minnesota, Human Biochem Genet Sect, Clin Director, Natl Inst Mental Hlth, Minneapolis, MN USA. [Bhambhani, Vikas] Childrens Hosp & Clin Minnesota, Human Biochem Genet Sect, Natl Inst Hlth, Metab & Clin Geneticist, Minneapolis, MN USA. RP Introne, WJ (reprint author), Childrens Hosp & Clin Minnesota, Dept Med Genet, Clin Director, Minneapolis, MN USA. EM wintrone@mail.nih.gov FU Intramural Research Programs of the National Human Genome Research Institute; National Institute of Neurological Disorders and Stroke; the Hatfield Clinical Center, NIH, Bethesda, MD FX Supported by the Intramural Research Programs of the National Human Genome Research Institute, the National Institute of Neurological Disorders and Stroke, and the Hatfield Clinical Center, NIH, Bethesda, MD. NR 32 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 14 PY 2017 VL 88 IS 7 BP E57 EP E65 DI 10.1212/WNL.0000000000003622 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA EP4IP UT WOS:000397344500004 PM 28193763 ER PT J AU Dall, GV Vieusseux, JL Korach, KS Arao, Y Hewitt, SC Hamilton, KJ Dzierzak, E Boon, WC Simpson, ER Ramsay, RG Stein, T Morris, JS Anderson, RL Risbridger, GP Britt, KL AF Dall, Genevieve V. Vieusseux, Jessica L. Korach, Kenneth S. Arao, Yukitomo Hewitt, Sylvia C. Hamilton, Katherine J. Dzierzak, Elaine Boon, Wah Chin Simpson, Evan R. Ramsay, Robert G. Stein, Torsten Morris, Joanne S. Anderson, Robin L. Risbridger, Gail P. Britt, Kara L. TI SCA-1 Labels a Subset of Estrogen-Responsive Bipotential Repopulating Cells within the CD24(+) CD49f(hi) Mammary Stem Cell-Enriched Compartment SO STEM CELL REPORTS LA English DT Article ID IN-VIVO; BREAST-CANCER; SELF-RENEWAL; GLAND; MOUSE; SUSCEPTIBILITY; DIFFERENTIATION; CARCINOGENESIS; EXPRESSION; PREGNANCY AB Estrogen stimulates breast development during puberty and mammary tumors in adulthood through estrogen receptor-alpha (ER alpha). These effects are proposed to occur via ER alpha(+) luminal cells and not the mammary stem cells (MaSCs) that are ER alpha(neg). Since ER alpha(+) luminal cells express stem cell antigen-1 (SCA-1), we sought to determine if SCA-1 could define an ER alpha(+) subset of EpCAM(+)/CD24(+)/CD49f(hi) MaSCs. We show that the MaSC population has a distinct SCA-1(+) population that is abundant in pre-pubertal mammary glands. The SCA-1(+) MaSCs have less stem cell markers and less in vivo repopulating activity than their SCA-1(neg) counterparts. However, they express ERa and specifically enter the cell cycle at puberty. Using estrogen-deficient aromatase knockouts (ArKO), we showed that the SCA-1(+) MaSC could be directly modulated by estrogen supplementation. Thus, SCA-1 enriches for an ER alpha(+), estrogen-sensitive subpopulation within the CD24(+)/CD49f(hi) MaSC population that may be responsible for the hormonal sensitivity of the developing mammary gland. C1 [Dall, Genevieve V.; Vieusseux, Jessica L.; Britt, Kara L.] Peter MacCallum Canc Ctr, Canc Genet Lab, 305 Grattan St, Melbourne, Vic 3000, Australia. [Dall, Genevieve V.; Risbridger, Gail P.; Britt, Kara L.] Monash Univ, Dept Anat & Dev Biol, Clayton, Vic 3800, Australia. [Korach, Kenneth S.; Arao, Yukitomo; Hewitt, Sylvia C.; Hamilton, Katherine J.] NIEHS, Reprod & Dev Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Dzierzak, Elaine] Univ Edinburgh, MRC, Ctr Inflammat Res, Queens Med Res Inst, Edinburgh EH16 4TJ, Midlothian, Scotland. [Boon, Wah Chin] Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Parkville, Vic 3010, Australia. [Simpson, Evan R.] Hudson Inst Med Res, Clayton, Vic 3168, Australia. [Ramsay, Robert G.] Peter MacCallum Canc Ctr, Differentiat & Transcript Lab, 305 Grattan St, Melbourne, Vic 3000, Australia. [Stein, Torsten] Univ Glasgow, Inst Canc Sci, Coll MVLS, Glasgow G12 8QQ, Lanark, Scotland. [Morris, Joanne S.] Univ Glasgow, Sch Vet Med, Coll MVLS, Glasgow G61 1QH, Lanark, Scotland. [Anderson, Robin L.; Britt, Kara L.] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Parkville, Vic 3010, Australia. [Anderson, Robin L.] La Trobe Univ, Bundoora, Vic 3083, Australia. RP Britt, KL (reprint author), Peter MacCallum Canc Ctr, Canc Genet Lab, 305 Grattan St, Melbourne, Vic 3000, Australia.; Britt, KL (reprint author), Monash Univ, Dept Anat & Dev Biol, Clayton, Vic 3800, Australia.; Britt, KL (reprint author), Univ Melbourne, Sir Peter MacCallum Dept Oncol, Parkville, Vic 3010, Australia. EM kara.britt@petermac.org RI Risbridger, Gail/B-8655-2008 OI Risbridger, Gail/0000-0003-3089-4028 FU Australian Postgradutate Scholarship; NBCF ECR Fellowship [ECF 11-01]; NHMRC New Investigator grant [APP1044661]; VCA ECR fellowship [ECSG08_07]; NBCF Senior Fellowship; Division of Intramural Research/NIEHS [1ZIAESO70065]; NHMRC fellowship FX G.D., Australian Postgradutate Scholarship; K.B., NBCF ECR Fellowship (ECF 11-01), NHMRC New Investigator grant (APP1044661), and VCA ECR fellowship (ECSG08_07); R.L.A., NBCF Senior Fellowship; K.S. K., Division of Intramural Research/NIEHS [1ZIAESO70065]; G.P.R., NHMRC fellowship. We thank Dr. Carl Walkey (St Vincents Institute) and A/Prof Steve Lane (QIMR Berghofer) for their helpful discussions about cell-cycle-specific staining, the flow core facility at Monash University, and the FACS facility at Peter Mac as well as Monash Micro Imaging Facility and Peter Mac microscopy groups for provision of instrumentation, training, and general support. NR 49 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2213-6711 J9 STEM CELL REP JI Stem Cell Rep. PD FEB 14 PY 2017 VL 8 IS 2 BP 417 EP 431 DI 10.1016/j.stemcr.2016.12.022 PG 15 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA EP0TH UT WOS:000397099100021 PM 28132885 ER PT J AU Brait, M Izumchenko, E Kagohara, LT Long, S Wysocki, PT Faherty, B Fertig, EJ Khor, TO Bruckheimer, E Baia, G Ciznadija, D Sloma, I Ben-Zvi, I Paz, K Sidransky, D AF Brait, Mariana Izumchenko, Evgeny Kagohara, Luciane T. Long, Samuel Wysocki, Piotr T. Faherty, Brian Fertig, Elana J. Khor, Tin Oo Bruckheimer, Elizabeth Baia, Gilson Ciznadija, Daniel Sloma, Ido Ben-Zvi, Ido Paz, Keren Sidransky, David TI Comparative mutational landscape analysis of patient-derived tumour xenografts SO BRITISH JOURNAL OF CANCER LA English DT Article DE mutation; ddPCR; NGS; PDX; WES; mutation detection techniques; qPCR ID REAL-TIME PCR; PANCREATIC-CANCER; COLORECTAL-CANCER; SOMATIC MUTATIONS; DIAGNOSTIC-TOOL; KRAS; EGFR; BRAF; IDENTIFICATION; GENOME AB Background: Screening of patients for cancer-driving mutations is now used for cancer prognosis, remission scoring and treatment selection. Although recently emerged targeted next-generation sequencing-based approaches offer promising diagnostic capabilities, there are still limitations. There is a pressing clinical need for a well-validated, rapid, cost-effective mutation profiling system in patient specimens. Given their speed and cost-effectiveness, quantitative PCR mutation detection techniques are well suited for the clinical environment. The qBiomarker mutation PCR array has high sensitivity and shorter turnaround times compared with other methods. However, a direct comparison with existing viable alternatives are required to assess its true potential and limitations. Methods: In this study, we evaluated a panel of 117 patient-derived tumour xenografts by the qBiomarker array and compared with other methods for mutation detection, including Ion AmpliSeq sequencing, whole-exome sequencing and droplet digital PCR. Results: Our broad analysis demonstrates that the qBiomarker's performance is on par with that of other labour-intensive and expensive methods of cancer mutation detection of frequently altered cancer-associated genes, and provides a foundation for supporting its consideration as an option for molecular diagnostics. Conclusions: This large-scale direct comparison and validation of currently available mutation detection approaches is extremely relevant for the current scenario of precision medicine and will lead to informed choice of screening methodologies, especially in lower budget conditions or time frame limitations. C1 [Brait, Mariana; Izumchenko, Evgeny; Kagohara, Luciane T.; Wysocki, Piotr T.; Faherty, Brian; Sidransky, David] Johns Hopkins Univ, Dept Otolaryngol & Head & Neck Surg, Sch Med, Baltimore, MD 21231 USA. [Long, Samuel] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, Frederick, MD 21702 USA. [Fertig, Elana J.; Sidransky, David] Johns Hopkins Univ, Dept Oncol, Sch Med, Dept Oncol, Baltimore, MD 21231 USA. [Khor, Tin Oo; Bruckheimer, Elizabeth; Baia, Gilson; Ciznadija, Daniel; Sloma, Ido; Ben-Zvi, Ido; Paz, Keren] Champ Oncol, Baltimore, MD 21205 USA. RP Sidransky, D (reprint author), Johns Hopkins Univ, Dept Otolaryngol & Head & Neck Surg, Sch Med, Baltimore, MD 21231 USA.; Sidransky, D (reprint author), Johns Hopkins Univ, Dept Oncol, Sch Med, Dept Oncol, Baltimore, MD 21231 USA. EM dsidrans@jhmi.edu FU CCR NIH HHS [HHSN261200800001C]; NCI NIH HHS [HHSN261200800001E] NR 49 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD FEB 14 PY 2017 VL 116 IS 4 BP 515 EP 523 DI 10.1038/bjc.2016.450 PG 9 WC Oncology SC Oncology GA EL2JT UT WOS:000394446600013 PM 28118322 ER PT J AU Kar, SP Adler, E Tyrer, J Hazelett, D Anton-Culver, H Bandera, EV Beckmann, MW Berchuck, A Bogdanova, N Brinton, L Butzow, R Campbell, I Carty, K Chang-Claude, J Cook, LS Cramer, DW Cunningham, JM Dansonka-Mieszkowska, A Doherty, JA Dork, T Durst, M Eccles, D Fasching, PA Flanagan, J Gentry-Maharaj, A Glasspool, R Goode, EL Goodman, MT Gronwald, J Heitz, F Hildebrandt, MAT Hogdall, E Hogdall, CK Huntsman, DG Jensen, A Karlan, BY Kelemen, LE Kiemeney, LA Kjaer, SK Kupryjanczyk, J Lambrechts, D Levine, DA Li, QY Lissowska, J Lu, KRH Lubinski, J Massuger, LFAG McGuire, V McNeish, I Menon, U Modugno, F Monteiro, AN Moysich, KB Ness, RB Nevanlinna, H Paul, J Pearce, CL Pejovic, T Permuth, JB Phelan, C Pike, MC Poole, EM Ramus, SJ Risch, HA Rossing, MA Salvesen, HB Schildkraut, JM Sellers, TA Sherman, M Siddiqui, N Sieh, W Song, HL Southey, M Terry, KL Tworoger, SS Walsh, C Wentzensen, N Whittemore, AS Wu, ANH Yang, H Zheng, W Ziogas, A Freedman, ML Gayther, SA Pharoah, PDP Lawrenson, K AF Kar, Siddhartha P. Adler, Emily Tyrer, Jonathan Hazelett, Dennis Anton-Culver, Hoda Bandera, Elisa V. Beckmann, Matthias W. Berchuck, Andrew Bogdanova, Natalia Brinton, Louise Butzow, Ralf Campbell, Ian Carty, Karen Chang-Claude, Jenny Cook, Linda S. Cramer, Daniel W. Cunningham, Julie M. Dansonka-Mieszkowska, Agnieszka Doherty, Jennifer Anne Doerk, Thilo Duerst, Matthias Eccles, Diana Fasching, Peter A. Flanagan, James Gentry-Maharaj, Aleksandra Glasspool, Rosalind Goode, Ellen L. Goodman, Marc T. Gronwald, Jacek Heitz, Florian Hildebrandt, Michelle A. T. Hogdall, Estrid Hogdall, Claus K. Huntsman, David G. Jensen, Allan Karlan, Beth Y. Kelemen, Linda E. Kiemeney, Lambertus A. Kjaer, Susanne K. Kupryjanczyk, Jolanta Lambrechts, Diether Levine, Douglas A. Li, Qiyuan Lissowska, Jolanta Lu, Karen H. Lubinski, Jan Massuger, Leon F. A. G. McGuire, Valerie McNeish, Iain Menon, Usha Modugno, Francesmary Monteiro, Alvaro N. Moysich, Kirsten B. Ness, Roberta B. Nevanlinna, Heli Paul, James Pearce, Celeste L. Pejovic, Tanja Permuth, Jennifer B. Phelan, Catherine Pike, Malcolm C. Poole, Elizabeth M. Ramus, Susan J. Risch, Harvey A. Rossing, Mary Anne Salvesen, Helga B. Schildkraut, Joellen M. Sellers, Thomas A. Sherman, Mark Siddiqui, Nadeem Sieh, Weiva Song, Honglin Southey, Melissa Terry, Kathryn L. Tworoger, Shelley S. Walsh, Christine Wentzensen, Nicolas Whittemore, Alice S. Wu, Anna H. Yang, Hannah Zheng, Wei Ziogas, Argyrios Freedman, Matthew L. Gayther, Simon A. Pharoah, Paul D. P. Lawrenson, Kate TI Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci SO BRITISH JOURNAL OF CANCER LA English DT Article DE serous ovarian cancer; transcription factor; PAX8; genome-wide association study; gene set enrichment analysis ID GENOME-WIDE ASSOCIATION; FUNCTIONAL-CHARACTERIZATION; RISK LOCI; EXPRESSION; GWAS; IDENTIFICATION; PROSTATE; BREAST; CELLS; VARIANTS AB Background: Genome-wide association studies (GWAS) have identified 18 loci associated with serous ovarian cancer (SOC) susceptibility but the biological mechanisms driving these findings remain poorly characterised. Germline cancer risk loci may be enriched for target genes of transcription factors (TFs) critical to somatic tumorigenesis. Methods: All 615 TF-target sets from the Molecular Signatures Database were evaluated using gene set enrichment analysis (GSEA) and three GWAS for SOC risk: discovery (2196 cases/4396 controls), replication (7035 cases/21 693 controls; independent from discovery), and combined (9627 cases/30 845 controls; including additional individuals). Results: The PAX8-target gene set was ranked 1/615 in the discovery (P-GSEA<0.001; FDR = 0.21), 7/615 in the replication (P-GSEA = 0.004; FDR = 0.37), and 1/615 in the combined (P-GSEA<0.001; FDR = 0.21) studies. Adding other genes reported to interact with PAX8 in the literature to the PAX8-target set and applying an alternative to GSEA, interval enrichment, further confirmed this association (P = 0.006). Fifteen of the 157 genes from this expanded PAX8 pathway were near eight loci associated with SOC risk at P<10(-5) (including six with P<5 x 10(-8)). The pathway was also associated with differential gene expression after shRNA-mediated silencing of PAX8 in HeyA8 (P-GSEA = 0.025) and IGROV1 (P-GSEA = 0.004) SOC cells and several PAX8 targets near SOC risk loci demonstrated in vitro transcriptomic perturbation. Conclusions: Putative PAX8 target genes are enriched for common SOC risk variants. This finding from our agnostic evaluation is of particular interest given that PAX8 is well-established as a specific marker for the cell of origin of SOC. C1 [Kar, Siddhartha P.; Tyrer, Jonathan; Pharoah, Paul D. P.] Univ Cambridge, Dept Publ Hlth & Primary Care, Strangeways Res Lab, Cambridge CB1 8RN, England. [Adler, Emily; Pearce, Celeste L.; Pike, Malcolm C.; Wu, Anna H.] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Tyrer, Jonathan; Song, Honglin; Pharoah, Paul D. P.] Univ Cambridge, Dept Oncol, Strangeways Res Lab, Cambridge CB1 8RN, England. [Hazelett, Dennis] Cedars Sinai Med Ctr, Dept Biomed Sci, Bioinformat & Computat Biol Res Ctr, Los Angeles, CA 90048 USA. [Hazelett, Dennis; Gayther, Simon A.; Lawrenson, Kate] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. [Anton-Culver, Hoda] Univ Calif Irvine, Dept Epidemiol, UCI Ctr Canc Genet Res & Prevent, Genet Epidemiol Res Inst,Sch Med, Irvine, CA 92697 USA. [Bandera, Elisa V.] Rutgers Canc Inst New Jersey, Canc Prevent & Control Program, New Brunswick, NJ 08903 USA. [Beckmann, Matthias W.; Fasching, Peter A.] Friedrich Alexander Univ Erlangen Nuremberg, Univ Hosp Erlangen, Dept Gynecol & Obstet, Comprehens Canc Ctr Erlangen Nuremberg, Univ Str 21-23, D-91054 Erlangen, Germany. [Berchuck, Andrew] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA. [Bogdanova, Natalia] Hannover Med Sch, Radiat Oncol Res Unit, D-30625 Hannover, Germany. [Brinton, Louise; Sherman, Mark; Wentzensen, Nicolas; Yang, Hannah] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Butzow, Ralf] Univ Helsinki, Dept Pathol, Helsinki 00100, Finland. [Butzow, Ralf; Nevanlinna, Heli] Helsinki Univ Hosp, Helsinki 00100, Finland. [Campbell, Ian] Peter MacCallum Canc Ctr, Div Res, Canc Genet Lab, St Andrews Pl, East Melbourne, Vic 3002, Australia. [Campbell, Ian] Univ Melbourne, Dept Pathol, Parkville, Vic 3010, Australia. [Carty, Karen; Glasspool, Rosalind; Paul, James] Beatson West Scotland Canc Ctr, Glasgow G12 0YN, Lanark, Scotland. [Chang-Claude, Jenny] Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Germany. [Chang-Claude, Jenny] Univ Med Ctr Hamburg Eppendorf, UCCH, D-20246 Hamburg, Germany. [Cook, Linda S.] Univ New Mexico, Dept Internal Med, Div Epidemiol & Biostat, Albuquerque, NM 87131 USA. [Cramer, Daniel W.; Terry, Kathryn L.] Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, 75 Francis St, Boston, MA 02115 USA. [Cunningham, Julie M.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. [Dansonka-Mieszkowska, Agnieszka; Kupryjanczyk, Jolanta] Maria Sklodowska Curie Mem Canc Ctr & Inst Oncol, Dept Pathol, PL-02781 Warsaw, Poland. [Doherty, Jennifer Anne] Geisel Sch Med Dartmouth, Dept Pathol, Hanover, NH 03756 USA. [Doerk, Thilo] Hannover Med Sch, Gynaecol Res Unit, D-30625 Hannover, Germany. [Duerst, Matthias] Jena Univ Hosp Friedrich Schiller Univ, Dept Gynecol, D-07737 Jena, Germany. [Eccles, Diana] Univ Southampton, Fac Med, Southampton SO16 5YA, Hants, England. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Flanagan, James] Imperial Coll London, Dept Surg & Canc, London SW7 2AZ, England. [Gentry-Maharaj, Aleksandra; Menon, Usha] UCL, Inst Womens Hlth, Dept Womens Canc, London W1T 7DN, England. [Glasspool, Rosalind] Beatson West Scotland Canc Ctr, Glasgow G12 0YN, Lanark, Scotland. [Goode, Ellen L.] Mayo Clin, Div Epidemiol, Dept Hlth Sci Res, Rochester, MI 55905 USA. [Goodman, Marc T.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Canc Prevent & Control, Los Angeles, CA 90048 USA. [Goodman, Marc T.] Cedars Sinai Med Ctr, Dept Biomed Sci, Commun & Populat Hlth Res Inst, Los Angeles, CA 90048 USA. [Gronwald, Jacek; Lubinski, Jan] Pomeranian Med Univ, Dept Genet & Pathol, Int Hereditary Canc Ctr, PL-70001 Szczecin, Poland. [Heitz, Florian] Kliniken Essen Mitte Evang Huyssens Stiftung Knap, Dept Gynecol & Gynecol Oncol, D-45136 Essen, Germany. [Heitz, Florian] Dr Horst Schmidt Kliniken Wiesbaden, Dept Gynecol & Gynecol Oncol, D-65199 Wiesbaden, Germany. [Hildebrandt, Michelle A. T.] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Hogdall, Estrid; Jensen, Allan; Kjaer, Susanne K.] Danish Canc Soc Res Ctr, Dept Virus Lifestyle & Genes, DK-2100 Copenhagen, Denmark. [Hogdall, Estrid] Univ Copenhagen, Herlev Hosp, Dept Pathol, Mol Unit, DK-1165 Copenhagen, Denmark. [Hogdall, Claus K.] Univ Copenhagen, Dept Gynecol, Juliane Marie Ctr, Rigshosp, DK-2100 Copenhagen, Denmark. [Huntsman, David G.] BC Canc Agcy, Vancouver Gen Hosp BC Canc Agcy, British Columbias Ovarian Canc Res OVCARE Program, Vancouver, BC V5Z 1L3, Canada. [Huntsman, David G.] Univ British Columbia, Vancouver, BC V5Z 1L3, Canada. [Huntsman, David G.] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5Z 1L3, Canada. [Huntsman, David G.] Univ British Columbia, Dept Obstet & Gynaecol, Vancouver, BC V5Z 1L3, Canada. [Huntsman, David G.] BC Canc Agcy, Dept Mol Oncol, Res Ctr, Vancouver, BC V5Z 1L3, Canada. [Karlan, Beth Y.; Walsh, Christine] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA. [Kelemen, Linda E.] Med Univ South Carolina, Dept Publ Hlth Sci, Charleston, SC 29435 USA. [Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, NL-6500 HB Nijmegen, Netherlands. [Kjaer, Susanne K.] Univ Copenhagen, Dept Gynaecol, Rigshosp, DK-2100 Copenhagen, Denmark. [Lambrechts, Diether] VIB, Vesalius Res Ctr, B-3000 Leuven, Belgium. [Lambrechts, Diether] Univ Leuven, Dept Oncol, Lab Translat Genet, B-3000 Louvain, Belgium. [Levine, Douglas A.] Mem Sloan Kettering Canc Ctr, Dept Surg, Gynecol Serv, New York, NY 10065 USA. [Li, Qiyuan] Dana Farber Canc Inst, Dept Med Oncol, Ctr Funct Canc Epigenet, Boston, MA 02215 USA. [Li, Qiyuan] Xiamen Univ, Coll Med, Xiamen 361102, Peoples R China. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr & Inst Oncol, Dept Canc Epidemiol & Prevent, PL-02781 Warsaw, Poland. [Lu, Karen H.] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. [Massuger, Leon F. A. G.] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Mol Life Sci, Dept Gynaecol, NL-6500 HB Nijmegen, Netherlands. [McGuire, Valerie; Sieh, Weiva; Whittemore, Alice S.] Stanford Univ, Sch Med, Dept Hlth Res & Policy Epidemiol, Stanford, CA 94305 USA. [McNeish, Iain] Univ Glasgow, Inst Canc Sci, Wolfson Wohl Canc Res Ctr, Inst Canc Res, Glasgow G12 0YN, Lanark, Scotland. [Modugno, Francesmary] Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Div Gynecol Oncol, Pittsburgh, PA 15213 USA. [Modugno, Francesmary] Univ Pittsburgh, Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Modugno, Francesmary] Magee Womens Res Inst, Womens Canc Res Program, Ovarian Canc Ctr Excellence, Pittsburgh, PA 15213 USA. [Modugno, Francesmary] Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15213 USA. [Monteiro, Alvaro N.; Permuth, Jennifer B.; Phelan, Catherine; Sellers, Thomas A.] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL 33612 USA. [Moysich, Kirsten B.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Nevanlinna, Heli] Univ Helsinki, Dept Obstet & Gynecol, Helsinki 00100, Finland. [Nevanlinna, Heli] Univ Texas Houston, Sch Publ Hlth, Houston, TX 77030 USA. [Pearce, Celeste L.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Pejovic, Tanja] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97239 USA. [Pejovic, Tanja] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97239 USA. [Pike, Malcolm C.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA. [Poole, Elizabeth M.; Tworoger, Shelley S.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02215 USA. [Poole, Elizabeth M.; Tworoger, Shelley S.] Harvard Med Sch, Boston, MA 02215 USA. [Ramus, Susan J.] Univ New South Wales, Fac Med, Sydney, NSW 2052, Australia. [Risch, Harvey A.] Yale Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT 06510 USA. [Rossing, Mary Anne] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, Seattle, WA 98109 USA. [Rossing, Mary Anne] Univ Washington, Dept Epidemiol, Seattle, WA 98109 USA. [Salvesen, Helga B.] Haukeland Univ Horpital, Dept Gynecol & Obstet, N-5058 Bergen, Norway. [Salvesen, Helga B.] Univ Bergen, Dept Clin Sci, Ctr Canc Biomarkers, N-5058 Bergen, Norway. [Schildkraut, Joellen M.] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA. [Schildkraut, Joellen M.] Duke Canc Inst, Canc Control & Populat Sci, Durham, NC 27710 USA. [Siddiqui, Nadeem] Glasgow Royal Infirm, Dept Gynaecol Oncol, Glasgow G4 0SF, Lanark, Scotland. [Southey, Melissa] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Melbourne, Vic 3002, Australia. [Terry, Kathryn L.; Tworoger, Shelley S.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA. [Zheng, Wei] Vanderbilt Univ, Div Epidemiol, Vanderbilt Ingram Canc Ctr, Med Ctr Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37232 USA. [Ziogas, Argyrios] Univ Calif Irvine, Dept Epidemiol, Irvine, CA 92697 USA. [Freedman, Matthew L.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Freedman, Matthew L.] Eli & Edythe L Broad Inst, Cambridge, MA 02142 USA. [Gayther, Simon A.] Cedars Sinai Med Ctr, Dept Biomed Sci, Los Angeles, CA 90048 USA. [Lawrenson, Kate] Cedars Sinai Med Ctr, Dept Obstet & Gynecol, Div Gynecol Oncol, Los Angeles, CA 90048 USA. RP Kar, SP (reprint author), Univ Cambridge, Dept Publ Hlth & Primary Care, Strangeways Res Lab, Cambridge CB1 8RN, England. EM sk718@medschl.cam.ac.uk RI Dork, Thilo/J-8620-2012 FU Medical Research Council [G0501974]; NCI NIH HHS [R01 CA136924, K07 CA080668, K07 CA092044, K07 CA095666, K07 CA143047, K22 CA138563, N01 CN025403, N01 PC067010, N01PC35137, P01 CA017054, P01 CA087969, P30 CA014089, P30 CA015083, P30 CA016056, P50 CA105009, P50 CA136393, P50 CA159981, R00 CA184415, R01 CA049449, R01 CA050385, R01 CA054419, R01 CA058598, R01 CA058860, R01 CA063678, R01 CA063682, R01 CA064277, R01 CA067262, R01 CA074850, R01 CA076016, R01 CA080742, R01 CA083918, R01 CA087538, R01 CA087696, R01 CA095023, R01 CA106414, R01 CA112523, R01 CA114343, R01 CA122443, R01 CA126841, R01 CA149429, R03 CA113148, R03 CA115195, R37 CA070867, U01 CA069417, U19 CA148112, UM1 CA176726, UM1 CA182910, UM1 CA186107]; NCRR NIH HHS [M01 RR000056] NR 48 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD FEB 14 PY 2017 VL 116 IS 4 BP 524 EP 535 DI 10.1038/bjc.2016.426 PG 12 WC Oncology SC Oncology GA EL2JT UT WOS:000394446600014 PM 28103614 ER PT J AU Scadding, GW Calderon, MA Shamji, MH Eifan, AO Penagos, M Dumitru, F Sever, ML Bahnson, HT Lawson, K Harris, KM Plough, AG Panza, JL Qin, TL Lim, N Tchao, NK Togias, A Durham, SR AF Scadding, Guy W. Calderon, Moises A. Shamji, Mohamed H. Eifan, Aarif O. Penagos, Martin Dumitru, Florentina Sever, Michelle L. Bahnson, Henry T. Lawson, Kaitie Harris, Kristina M. Plough, Audrey G. Panza, Joy Laurienzo Qin, Tielin Lim, Noha Tchao, Nadia K. Togias, Alkis Durham, Stephen R. CA Immune Tolerance Network GRASS Stu TI Effect of 2 Years of Treatment With Sublingual Grass Pollen Immunotherapy on Nasal Response to Allergen Challenge at 3 Years Among Patients With Moderate to Severe Seasonal Allergic Rhinitis The GRASS Randomized Clinical Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID RESPIRATORY ALLERGY; EFFICACY; RHINOCONJUNCTIVITIS; CESSATION; OUTCOMES; ASTHMA; SAFETY; TABLET; SCORE AB Importance Sublingual immunotherapy and subcutaneous immunotherapy are effective in seasonal allergic rhinitis. Three years of continuous treatment with subcutaneous immunotherapy and sublingual immunotherapy has been shown to improve symptoms for at least 2 years following discontinuation of treatment. Objective To assess whether 2 years of treatment with grass pollen sublingual immunotherapy, compared with placebo, provides improved nasal response to allergen challenge at 3-year follow-up. Design, Setting, and Participants A randomized double-blind, placebo-controlled, 3-parallel-group study performed in a single academic center, Imperial College London, of adult patients with moderate to severe seasonal allergic rhinitis (interfering with usual daily activities or sleep). First enrollment was March 2011, last follow-up was February 2015. Interventions Thirty-six participants received 2 years of sublingual immunotherapy (daily tablets containing 15 mu g of major allergen Phleum p 5 and monthly placebo injections), 36 received subcutaneous immunotherapy (monthly injections containing 20 mu g of Phleum p 5 and daily placebo tablets) and 34 received matched double-placebo. Nasal allergen challenge was performed before treatment, at 1 and 2 years of treatment, and at 3 years (1 year after treatment discontinuation). Main Outcomes and Measures Total nasal symptom scores (TNSS; range; 0 [best] to 12 [worst]) were recorded between 0 and 10 hours after challenge. The minimum clinically important difference for change in TNSS within an individual is 1.08. The primary outcome was TNSS comparing sublingual immunotherapy vs placebo at year 3. Subcutaneous immunotherapy was included as a positive control. The study was not powered to compare sublingual immunotherapy with subcutaneous immunotherapy. Results Among 106 randomized participants (mean age, 33.5 years; 34 women [32.1%]), 92 completed the study at 3 years. In the intent-to-treat population, mean TNSS score for the sublingual immunotherapy group was 6.36 (95% CI, 5.76 to 6.96) at pretreatment and 4.73 (95% CI, 3.97 to 5.48) at 3 years, and for the placebo group, the score was 6.06 (95% CI, 5.23 to 6.88) at pretreatment and 4.81 (95% CI, 3.97 to 5.65) at 3 years. The between-group difference (adjusted for baseline) was -0.18 (95% CI, -1.25 to 0.90; [P = .75]). Conclusions and Relevance Among patients with moderate to severe seasonal allergic rhinitis, 2 years of sublingual grass pollen immunotherapy was not significantly different from placebo in improving the nasal response to allergen challenge at 3-year follow-up. C1 [Scadding, Guy W.; Calderon, Moises A.; Shamji, Mohamed H.; Eifan, Aarif O.; Penagos, Martin; Dumitru, Florentina; Durham, Stephen R.] Imperial Coll, London, England. [Scadding, Guy W.; Calderon, Moises A.; Shamji, Mohamed H.; Eifan, Aarif O.; Penagos, Martin; Dumitru, Florentina; Durham, Stephen R.] Royal Brompton & Harefield Hosp NHS Fdn Trust, London, England. [Sever, Michelle L.; Bahnson, Henry T.; Lawson, Kaitie] Rho Fed Syst Div, Chapel Hill, NC USA. [Bahnson, Henry T.] Benaroya Res Inst, Immune Tolerance Network, Seattle, WA USA. [Harris, Kristina M.; Qin, Tielin; Lim, Noha] Immune Tolerance Network, Bethesda, MD USA. [Plough, Audrey G.; Tchao, Nadia K.] Immune Tolerance Network, San Francisco, CA USA. [Panza, Joy Laurienzo; Togias, Alkis] NIAID, Rockville, MD USA. [Tchao, Nadia K.] Amgen Inc, Dept Early Dev Hematol Oncol, San Francisco, CA USA. RP Durham, SR (reprint author), Imperial Coll London, Natl Heart & Lung Inst, Allergy & Clin Immunol, Sect Inflammat Repair & Dev, Dovehouse St, London SW3 6LY, England. EM s.durham@imperial.ac.uk OI Eifan, Aarif/0000-0003-4098-4211 FU DAIT-NIAID, National Institutes of Health (NIH) [NO1-AI-15416, UM1AI109565, UM2AI117870]; DAIT-NIAID [UM2AI117870, HHSN272200800029C, HHSN272201200004C, HHSN272201200002C] FX The trial was conducted by the ITN with financial support from the DAIT-NIAID, National Institutes of Health (NIH) under award numbers NO1-AI-15416, UM1AI109565, and UM2AI117870; the following DAIT-NIAID-funded groups: Statistical and Clinical Coordinating Centers (contract HHSN272200800029C and grant UM2AI117870), Clinical Site Monitoring Center (contract HHSN272201200004C), and Regulatory Management Center (contract HHSN272201200002C); ALK-Abello A/S Horsholm, Denmark supplied Alutard SQ Grass Pollen, and Grazax, and matching placebos used for the GRASS clinical trial to DAIT-NIAID without charge. Dr Durham served as the sponsor of the Medicines and Healthcare Products Regulatory Agency Clinical Trial Application. NR 34 TC 1 Z9 1 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 14 PY 2017 VL 317 IS 6 BP 615 EP 625 DI 10.1001/jama.2016.21040 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA EL8LI UT WOS:000394870900016 PM 28196255 ER PT J AU Nielles-Vallespin, S Khalique, Z Ferreira, PF de Silva, R Scott, AD Kilner, P McGill, LA Giannakidis, A Gatehouse, PD Ennis, D Aliotta, E Al-Khalil, M Kellman, P Mazilu, D Balaban, RS Firmin, DN Arai, AE Pennell, DJ AF Nielles-Vallespin, Sonia Khalique, Zohya Ferreira, Pedro F. de Silva, Ranil Scott, Andrew D. Kilner, Philip McGill, Laura-Ann Giannakidis, Archontis Gatehouse, Peter D. Ennis, Daniel Aliotta, Eric Al-Khalil, Majid Kellman, Peter Mazilu, Dumitru Balaban, Robert S. Firmin, David N. Arai, Andrew E. Pennell, Dudley J. TI Assessment of Myocardial Microstructural Dynamics by In Vivo Diffusion Tensor Cardiac Magnetic Resonance SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE dilated cardiomyopathy; helical structure; hypertrophic cardiomyopathy; laminar structure; left ventricle; sheetlet structure ID HYPERTROPHIC CARDIOMYOPATHY; FIBER ORIENTATION; LEFT-VENTRICLE; HISTOLOGICAL VALIDATION; LAMINAR ARCHITECTURE; EUROPEAN-SOCIETY; WATER DIFFUSION; TASK-FORCE; MRI; STRAIN AB BACKGROUND Cardiomyocytes are organized in microstructures termed sheetlets that reorientate during left ventricular thickening. Diffusion tensor cardiac magnetic resonance (DT-CMR) may enable noninvasive interrogation of in vivo cardiac microstructural dynamics. Dilated cardiomyopathy (DCM) is a condition of abnormal myocardium with unknown sheetlet function. OBJECTIVES This study sought to validate in vivo DT-CMR measures of cardiac microstructure against histology, characterize microstructural dynamics during left ventricular wall thickening, and apply the technique in hypertrophic cardiomyopathy (HCM) and DCM. METHODS In vivo DT-CMR was acquired throughout the cardiac cycle in healthy swine, followed by in situ and ex vivo DT-CMR, then validated against histology. In vivo DT-CMR was performed in 19 control subjects, 19 DCM, and 13 HCM patients. RESULTS In swine, a DT-CMR index of sheetlet reorientation (E2A) changed substantially (E2A mobility similar to 46 degrees). E2A changes correlated with wall thickness changes (in vivo r(2) = 0.75; in situ r(2) = 0.89), were consistently observed under all experimental conditions, and accorded closely with histological analyses in both relaxed and contracted states. The potential contribution of cyclical strain effects to in vivo E2A was similar to 17%. In healthy human control subjects, E2A increased from diastole (18 degrees) to systole (65 degrees; p < 0.001; E2A mobility = 45 degrees). HCM patients showed significantly greater E2A in diastole than control subjects did (48 degrees; p < 0.001) with impaired E2A mobility (23 degrees; p < 0.001). In DCM, E2A was similar to control subjects in diastole, but systolic values were markedly lower (40 degrees; p < 0.001) with impaired E2A mobility (20 degrees; p < 0.001). CONCLUSIONS Myocardial microstructure dynamics can be characterized by in vivo DT-CMR. Sheetlet function was abnormal in DCM with altered systolic conformation and reduced mobility, contrasting with HCM, which showed reduced mobility with altered diastolic conformation. These novel insights significantly improve understanding of contractile dysfunction at a level of noninvasive interrogation not previously available in humans. C1 [Nielles-Vallespin, Sonia; Kellman, Peter; Mazilu, Dumitru; Balaban, Robert S.; Arai, Andrew E.] NHLBI, NIH, Dept Hlth & Human Serv, Bldg 10, Bethesda, MD 20892 USA. [Nielles-Vallespin, Sonia; Khalique, Zohya; Ferreira, Pedro F.; de Silva, Ranil; Scott, Andrew D.; Kilner, Philip; McGill, Laura-Ann; Giannakidis, Archontis; Gatehouse, Peter D.; Al-Khalil, Majid; Firmin, David N.; Pennell, Dudley J.] Royal Brompton & Harefield Natl Hlth Serv Fdn Tru, Cardiovasc Magnet Resonance Unit, London, England. [Nielles-Vallespin, Sonia; Khalique, Zohya; Ferreira, Pedro F.; de Silva, Ranil; Scott, Andrew D.; Kilner, Philip; McGill, Laura-Ann; Giannakidis, Archontis; Gatehouse, Peter D.; Firmin, David N.; Pennell, Dudley J.] Imperial Coll London, Natl Heart & Lung Inst, London, England. [Khalique, Zohya; Ferreira, Pedro F.; de Silva, Ranil; Scott, Andrew D.; Kilner, Philip; Firmin, David N.; Pennell, Dudley J.] Royal Brompton & Harefield Natl Hlth Serv Fdn Tru, Natl Inst Hlth Res, Cardiovasc Biomed Res Unit, London, England. [Khalique, Zohya; Ferreira, Pedro F.; de Silva, Ranil; Scott, Andrew D.; Kilner, Philip; Firmin, David N.; Pennell, Dudley J.] Imperial Coll London, London, England. [Ennis, Daniel; Aliotta, Eric] Univ Calif Los Angeles, David Geffen Sch Med, Dept Radiol Sci, Los Angeles, CA 90095 USA. RP Nielles-Vallespin, S (reprint author), NHLBI, NIH, Bldg 10,Room B1D401,10 Ctr Dr, Bethesda, MD 20892 USA. EM sonia.nielles-vallespin@nih.gov FU National Heart, Lung, and Blood Institute, National Institutes of Health, Division of Intramural Research, Department of Health and Human Services [HL004607-14CPB]; British Heart Foundation; National Institute of Health Research Cardiovascular Biomedical Research Unit at the Royal Brompton Hospital and Imperial College, London; Siemens Medical Solutions; Siemens FX This work was supported by the National Heart, Lung, and Blood Institute, National Institutes of Health, Division of Intramural Research, Department of Health and Human Services (HL004607-14CPB); the British Heart Foundation; and the National Institute of Health Research Cardiovascular Biomedical Research Unit at the Royal Brompton Hospital and Imperial College, London. Dr. Gatehouse has a departmental research agreement and collaborates on other work with Siemens. Dr. Ennis has received research support from Siemens Medical Solutions. Dr. Arai is a principal investigator on a U.S. government Cooperative Research and Development Agreement with Siemens Medical Solutions (HL-CR-05-004); and has a research agreement with Bayer. Dr. Pennell is a shareholder and Director of Cardiovascular Imaging Solutions; and has received research support from Siemens. Royal Brompton Hospital has research collaboration agreements with Siemens AG Medical Solutions. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Nielles-Vallespin, Khalique, and Ferreira contributed equally to this work and are joint first authors. Drs. Firmin, Arai, and Pennell contributed equally to this work and are joint senior authors. NR 49 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 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB 14 PY 2017 VL 69 IS 6 BP 661 EP 676 DI 10.1016/j.jacc.2016.11.051 PG 16 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EN9SC UT WOS:000396338900009 PM 28183509 ER PT J AU Lansky, AJ Messe, SR Brickman, AM Dwyer, M van der Worp, HB Lazar, RM Pietras, CG Abrams, KJ McFadden, E Petersen, NH Browndyke, J Prendergast, B Ng, VG Cutlip, DE Kapadia, S Krucoff, MW Linke, A Moy, CS Schofer, J van Es, GA Virmani, R Popma, J Parides, MK Kodali, S Bilello, M Zivadinov, R Akar, J Furie, KL Gress, D Voros, S Moses, J Greer, D Forrest, JK Holmes, D Kappetein, AP Mack, M Baumbach, A AF Lansky, Alexandra J. Messe, Steven R. Brickman, Adam M. Dwyer, Michael van der Worp, H. Bart Lazar, Ronald M. Pietras, Cody G. Abrams, Kevin J. McFadden, Eugene Petersen, Nils H. Browndyke, Jeffrey Prendergast, Bernard Ng, Vivian G. Cutlip, Donald E. Kapadia, Samir Krucoff, Mitchell W. Linke, Axel Moy, Claudia Scala Schofer, Joachim van Es, Gerrit-Anne Virmani, Renu Popma, Jeffrey Parides, Michael K. Kodali, Susheel Bilello, Michel Zivadinov, Robert Akar, Joseph Furie, Karen L. Gress, Daryl Voros, Szilard Moses, Jeffrey Greer, David Forrest, John K. Holmes, David Kappetein, Arie P. Mack, Michael Baumbach, Andreas TI Proposed Standardized Neurological Endpoints for Cardiovascular Clinical Trials An Academic Research Consortium Initiative SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Review DE cardiovascular; methodology; neurological definitions; outcomes; stroke trials ID AORTIC-VALVE IMPLANTATION; ASSOCIATION/AMERICAN STROKE ASSOCIATION; TRANSIENT ISCHEMIC ATTACK; HEALTH-CARE PROFESSIONALS; CEREBRAL-ISCHEMIA; COGNITIVE IMPAIRMENT; CONSENSUS DOCUMENT; CARDIAC-SURGERY; DIFFUSION; METAANALYSIS AB Surgical and catheter-based cardiovascular procedures and adjunctive pharmacology have an inherent risk of neurological complications. The current diversity of neurological endpoint definitions and ascertainment methods in clinical trials has led to uncertainties in the neurological risk attributable to cardiovascular procedures and inconsistent evaluation of therapies intended to prevent or mitigate neurological injury. Benefit-risk assessment of such procedures should be on the basis of an evaluation of well-defined neurological outcomes that are ascertained with consistent methods and capture the full spectrum of neurovascular injury and its clinical effect. The Neurologic Academic Research Consortium is an international collaboration intended to establish consensus on the definition, classification, and assessment of neurological endpoints applicable to clinical trials of a broad range of cardiovascular interventions. Systematic application of the proposed definitions and assessments will improve our ability to evaluate the risks of cardiovascular procedures and the safety and effectiveness of preventive therapies. (C) 2017 The Authors. Published by Elsevier Inc. on behalf of the American College of Cardiology Foundation. All rights reserved. C1 [Lansky, Alexandra J.; Pietras, Cody G.; Ng, Vivian G.; Akar, Joseph; Forrest, John K.] Yale Sch Med, Dept Internal Med, Div Cardiovasc Med, 135 Coll St,Suite 101, New Haven, CT 06510 USA. [Lansky, Alexandra J.; Pietras, Cody G.; Ng, Vivian G.] Yale Cardiovasc Res Grp, New Haven, CT USA. [Lansky, Alexandra J.; Baumbach, Andreas] St Bartholomews Hosp, William Harvey Res Inst, Dept Cardiol, London, England. [Lansky, Alexandra J.; Baumbach, Andreas] Queen Mary Univ London, London, England. [Messe, Steven R.] Hosp Univ Penn, Dept Neurol, 3400 Spruce St, Philadelphia, PA 19104 USA. [Brickman, Adam M.; Lazar, Ronald M.] Columbia Univ, Coll Phys & Surg, Dept Neurol, New York, NY USA. [Dwyer, Michael; Zivadinov, Robert] SUNY Buffalo, Buffalo Neuroimaging Anal, Buffalo, NY USA. [van der Worp, H. Bart] Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Neurol & Neurosurg, Utrecht, Netherlands. [Abrams, Kevin J.] Baptist Hosp Miami, Baptist Cardiac & Vasc Inst, Miami, FL USA. [McFadden, Eugene] Cork Univ Hosp, Dept Cardiol, Cork, Ireland. [Petersen, Nils H.; Greer, David] Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06510 USA. [Browndyke, Jeffrey] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Div Geriatr Behav Hlth, Durham, NC USA. [Prendergast, Bernard] St Thomas Hosp, Dept Cardiol, London, England. [Cutlip, Donald E.] Beth Israel Deaconess Med Ctr, Dept Med, Div Cardiovasc Med, Boston, MA 02215 USA. [Kapadia, Samir] Cleveland Clin, Dept Cardiovasc Med, Cleveland, OH 44106 USA. [Krucoff, Mitchell W.] Duke Univ, Med Ctr, Dept Cardiol, Durham, NC USA. [Linke, Axel] Univ Leipzig, Dept Internal Med Cardiol, Leipzig, Germany. [Moy, Claudia Scala] NINDS, Off Clin Res, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Schofer, Joachim] Albertine Heart Ctr, Medicare Ctr, Hamburg, Germany. [Schofer, Joachim] Albertine Heart Ctr, Dept Percutaneous Intervent Struct Heart Dis, Hamburg, Germany. [van Es, Gerrit-Anne] Cardialysis, Rotterdam, Netherlands. [Virmani, Renu] CVpath Inst, Gaithersburg, MD USA. [Popma, Jeffrey; Parides, Michael K.] Mt Sinai Grp, Icahn Sch Med, New York, NY USA. [Kodali, Susheel; Moses, Jeffrey] Columbia Univ, Med Ctr, Dept Internal Med, Div Cardiol, New York, NY USA. [Bilello, Michel] Hosp Univ Penn, Dept Radiol, 3400 Spruce St, Philadelphia, PA 19104 USA. [Furie, Karen L.] Rhode Isl Hosp, Dept Neurol, Providence, RI USA. [Gress, Daryl] Univ Nebraska Med Ctr, Dept Neurol Sci, Omaha, NE USA. [Voros, Szilard] Global Inst Res & Global Genom Grp, Richmond, VA USA. [Holmes, David] Mayo Clin, Dept Cardiovasc Dis, Rochester, MN USA. [Kappetein, Arie P.] Erasmus Univ, Med Ctr, Dept Cardiothorac Surg, Rotterdam, Netherlands. [Mack, Michael] Heart Hosp, Baylor Plano Res Ctr, Dept Cardiovasc Surg, Plano, TX USA. RP Lansky, AJ (reprint author), Yale Sch Med, Dept Internal Med, Div Cardiovasc Med, 135 Coll St,Suite 101, New Haven, CT 06510 USA. EM alexandra.lansky@yale.edu FU Boston Scientific; Edwards Lifesciences; Medtronic Corporation; St. Jude Medical; NeuroSave Inc.; Keystone Heart Ltd.; Keystone Heart; GlaxoSmithKline; Bayer; Direct Flow Medical; Novartis; Claret Medical; Dutch Heart Foundation [2010T075]; Medtronic; Abbott Vascular; 480 Biomedical; Abbott Vascular Japan; Atrium; Biosensors International; Biotronik; Cordis Johnson Johnson; Kona; Microport Medical; OrbusNeich Medical; ReCore; SINO Medical Technology; Terumo Corporation; W.L. Gore; Abbott; Teva Pharmaceuticals; Biogen Idec; EMD Serono; Genzyme-Sanofi; IMS Health; Intekrin FX Grants to support travel costs, meeting rooms, and lodging for academic attendees at the San Francisco and New York meetings were provided by Boston Scientific, Edwards Lifesciences, Medtronic Corporation, St. Jude Medical, NeuroSave Inc., and Keystone Heart Ltd. The NeuroARC meetings involved members of the U.S. Center for Devices and Radiological Health, U.S. Food and Drug Association (FDA). The opinions or assertions herein are the views of the authors, and are not to be construed as reflecting the views of the FDA. Dr. Lansky has received research grant support from Keystone Heart, NeuroSave Inc., and Boston Scientific; and has received speaker/consultant fees from Keystone Heart. Dr. Messe has received research support from GlaxoSmithKline and Bayer; and is participating on the Clinical Events Committee for the SALUS trial, sponsored by Direct Flow Medical. Dr. Brickman has served as a consultant for Keystone Heart, ERT, and ProPhase LLC. Dr. Dwyer has received research grant support and is on the advisory board for Novartis; has received research grant support and consulting fees from Claret Medical; and is on the advisory board for EMD Serono. Dr. van der Worp is supported by a grant from the Dutch Heart Foundation (2010T075). Dr. Lazar has received grant support and consulting fees from Claret Medical. Dr. Abrams has received consultant fees and equity for Keystone Heart. Dr. Prendergast has received lecture fees from Edwards Lifesciences and Boston Scientific. Dr. Cutlip has received research contract funding from Medtronic and Boston Scientific to his institution. Dr. Kapadia has served as the coprincipal investigator for the Sentinel study sponsored by Claret Medical (unpaid). Dr. Krucoff has received research grants from and served as a consultant for Abbott Vascular, Medtronic, Boston Scientific, and St. Jude Medical. Dr. Linke has received research grant support from Medtronic and Claret Medical; has served as a consultant for Medtronic, Bard, and St. Jude Medical; has received speaker honoraria from Medtronic, St. Jude Medical, Symetis, Edwards Lifesciences, and Boston Scientific; and has stock options in Claret Medical. Dr. Virmani has received research support from 480 Biomedical, Abbott Vascular Japan, Atrium, Biosensors International, Biotronik, Boston Scientific, Cordis Johnson & Johnson, GlaxoSmithKline, Kona, Medtronic, Microport Medical, OrbusNeich Medical, ReCore, SINO Medical Technology, Terumo Corporation, and W.L. Gore. Dr. Popma has received institutional grants from Medtronic, Boston Scientific, Abbott, and Direct Flow Medical; has served on the medical advisory board of Boston Scientific; and has received consultant fees from and has equity in Direct Flow Medical. Dr. Kodali has served on the Steering Committee of the PARTNER III Trial, sponsored by Edwards Lifesciences; has served as a consultant to Medtronic; is the principal investigator of the Sentinel Trial sponsored by Claret Medical; has served on the scientific advisory boards of Thubrikar Aortic Valve Inc. and Dura Biotech; has received research support and travel reimbursement from Edwards Lifesciences, Claret Medical, and Medtronic; and has equity in Thubrikar Aortic Valve (minimal) and Dura Biotech. Dr. Zivadinov has received speaker/consultant fees from Teva Pharmaceuticals, Biogen Idec, EMD Serono, Genzyme-Sanofi, Claret Medical, IMS Health, and Novartis; and has received research grants from Teva Pharmaceuticals, Genzyme-Sanofi, Novartis, Claret Medical, Intekrin, and IMS Health. Dr.; Gress has served as a consultant to Medtronic; and has served on the scientific advisory board of Ornim, Keystone Heart, and Silk Road Medical. Dr. Voros is a founder, shareholder, and executive of Global Institute for Research; and is a minority shareholder in Keystone Heart. Dr. Moses has equity in Claret. Dr. Forrest has received grant support and consulting fees from Edwards Lifesciences and Medtronic. Dr. Baumbach has received research grants and speakers fees for Keystone Heart. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 68 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 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB 14 PY 2017 VL 69 IS 6 BP 679 EP 691 DI 10.1016/j.jacc.2016.11.045 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EN9SC UT WOS:000396338900011 PM 28183511 ER PT J AU Yang, L Pratt, C Valencia, E Conover, S Fernandez, R Burrone, MS Cavalcanti, MT Lovisi, G Rojas, G Alvarado, R Galea, S Price, LN Susser, E AF Yang, L. Pratt, C. Valencia, E. Conover, S. Fernandez, R. Burrone, M. S. Cavalcanti, M. T. Lovisi, G. Rojas, G. Alvarado, R. Galea, S. Price, L. N. Susser, E. TI RedeAmericas: building research capacity in young leaders for sustainable growth in community mental health services in Latin America SO GLOBAL MENTAL HEALTH LA English DT Article DE Capacity building; career development; global mental health; Latin America; mentorship program; other ID MIDDLE-INCOME COUNTRIES; IMPLEMENTATION; ILLNESS; STIGMA AB The purpose of this paper is to describe the development and initial accomplishments of a training program of young leaders in community mental health research as part of a Latin American initiative known as RedeAmericas. RedeAmericas was one of five regional 'Hubs' funded by the National Institute of Mental Health (NIMH) to improve community mental health care and build mental health research capacity in low-and middle-income countries. It included investigators in six Latin American cities - Santiago, Chile; Medellin, Colombia; Rio de Janeiro, Brazil; and Cordoba, Neuquen, and Buenos Aires in Argentina - working together with a team affiliated with the Global Mental Health program at Columbia University in New York City. One component of RedeAmericas was a capacity-building effort that included an Awardee program for early career researchers in the mental health field. We review the aims of this component, how it developed, and what was learned that would be useful for future capacity-building efforts, and also comment on future prospects for maintaining this type of effort. C1 [Yang, L.] NYU, Coll Global Publ Hlth, New York, NY USA. [Yang, L.; Pratt, C.; Valencia, E.; Susser, E.] Columbia Univ, Mailman Sch Publ Hlth, 722 West 168th St 1030, New York, NY 10032 USA. [Valencia, E.; Alvarado, R.] Univ Chile, Sch Publ Hlth, Fac Med, Santiago, Chile. [Conover, S.] CUNY, Hunter Coll, Silberman Sch Social Work, New York, NY 10021 USA. [Fernandez, R.; Burrone, M. S.] Natl Univ Cordoba, Sch Publ Hlth, Cordoba, Argentina. [Cavalcanti, M. T.] Univ Fed Rio de Janeiro, Inst Psychiat, Rio De Janeiro, Brazil. [Lovisi, G.] Univ Fed Rio de Janeiro, Sch Publ Hlth, Rio De Janeiro, Brazil. [Rojas, G.] Univ Chile, Fac Med, Clin Hosp, Santiago, Chile. [Galea, S.] Boston Univ, Sch Publ Hlth, Boston, MA 02215 USA. [Price, L. N.] NIMH, NIH, Bethesda, MD USA. [Susser, E.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. RP Susser, E (reprint author), Columbia Univ, Mailman Sch Publ Hlth, 722 West 168th St 1030, New York, NY 10032 USA.; Susser, E (reprint author), New York State Psychiat Inst & Hosp, New York, NY 10032 USA. EM ess8@cumc.columbia.edu FU US National Institute of Mental Health of the National Institutes of Health [U19MH095718] FX The research reported in this article was supported by the US National Institute of Mental Health of the National Institutes of Health under award number U19MH095718. The views expressed are those of the authors and do not necessarily represent those of the National Institute of Mental Health, the National Institutes of Health, the Department of Health and Human Services, or the US Government. NR 21 TC 0 Z9 0 U1 1 U2 1 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 2054-4251 J9 GLOB MENT HEALTH JI Glob. Ment. Health PD FEB 14 PY 2017 VL 4 AR e3 DI 10.1017/gmh.2017.2 PG 9 WC Psychiatry SC Psychiatry GA EL0IF UT WOS:000394305400001 ER PT J AU Hoglinger, D Nadler, A Haberkant, P Kirkpatrick, J Schifferer, M Stein, F Hauke, S Porter, FD Schultz, C AF Hoeglinger, Doris Nadler, Andre Haberkant, Per Kirkpatrick, Joanna Schifferer, Martina Stein, Frank Hauke, Sebastian Porter, Forbes D. Schultz, Carsten TI Trifunctional lipid probes for comprehensive studies of single lipid species in living cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE lipid-protein interaction; sphingosine; diacylglycerol; caged lipids; Niemann-Pick disease type C ID NIEMANN-PICK-DISEASE; SACCHAROMYCES-CEREVISIAE; CORRELATED FLUORESCENCE; ELECTRON-MICROSCOPY; PHOSPHATIDIC-ACID; PLASMA-MEMBRANE; SPHINGOSINE; METABOLISM; PROTEINS; VISUALIZATION AB Lipid-mediated signaling events regulate many cellular processes. Investigations of the complex underlying mechanisms are difficult because several different methods need to be used under varying conditions. Here we introduce multifunctional lipid derivatives to study lipid metabolism, lipid-protein interactions, and intracellular lipid localization with a single tool per target lipid. The probes are equipped with two photoreactive groups to allow photoliberation (uncaging) and photo-cross-linking in a sequential manner, as well as a click-handle for subsequent functionalization. We demonstrate the versatility of the design for the signaling lipids sphingosine and diacylglycerol; uncaging of the probe for these two species triggered calcium signaling and intracellular protein translocation events, respectively. We performed proteomic screens to map the lipid-interacting proteome for both lipids. Finally, we visualized a sphingosine transport deficiency in patient-derived Niemann-Pick disease type C fibroblasts by fluorescence as well as correlative light and electron microscopy, pointing toward the diagnostic potential of such tools. We envision that this type of probe will become important for analyzing and ultimately understanding lipid signaling events in a comprehensive manner. C1 [Hoeglinger, Doris; Nadler, Andre; Haberkant, Per; Kirkpatrick, Joanna; Schifferer, Martina; Stein, Frank; Hauke, Sebastian; Schultz, Carsten] European Mol Biol Lab, Cell Biol & Biophys Unit, D-69117 Heidelberg, Germany. [Hoeglinger, Doris] Univ Oxford, Dept Pharmacol, Oxford OX1 3QT, England. [Nadler, Andre] Max Planck Inst Mol Cell Biol & Genet, D-01307 Dresden, Germany. [Kirkpatrick, Joanna] Leibniz Inst, Aging Fritz Lipmann Inst, D-07745 Jena, Germany. [Porter, Forbes D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Natl Inst Hlth, Divis Translat Med, Bethesda, MD 20892 USA. RP Schultz, C (reprint author), European Mol Biol Lab, Cell Biol & Biophys Unit, D-69117 Heidelberg, Germany. EM schultz@embl.de OI Hoeglinger, Doris/0000-0002-6862-0076 FU European Union Seventh Framework Programme [289278]; Deutsche Forschungsgemeinschaft [Transregio 83]; intramural research program of the National Institute of Child Health and Human Development; European Union FX We thank the Advanced Light Microscopy Facility and the Proteomic Core Facility of the European Molecular Biology Laboratory (EMBL). This research has received funding from the European Union Seventh Framework Programme under Grant Agreement 289278-"Sphingonet"- as well as Transregio 83 funded by the Deutsche Forschungsgemeinschaft. This work was partially supported by the intramural research program of the National Institute of Child Health and Human Development. M.S. is a fellow of the EMBL Interdisciplinary Postdoc Program, cofunded by the European Union. NR 46 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 FEB 14 PY 2017 VL 114 IS 7 BP 1566 EP 1571 DI 10.1073/pnas.1611096114 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EK5TR UT WOS:000393989300058 PM 28154130 ER PT J AU Sripathy, S Leko, V Adrianse, RL Loe, T Foss, EJ Dalrymple, E Lao, U Gatbonton-Schwager, T Carter, KT Payer, B Paddison, PJ Grady, WM Lee, JT Bartolomei, MS Bedalov, A AF Sripathy, Smitha Leko, Vid Adrianse, Robin L. Loe, Taylor Foss, Eric J. Dalrymple, Emily Lao, Uyen Gatbonton-Schwager, Tonibelle Carter, Kelly T. Payer, Bernhard Paddison, Patrick J. Grady, William M. Lee, Jeannie T. Bartolomei, Marisa S. Bedalov, Antonio TI Screen for reactivation of MeCP2 on the inactive X chromosome identifies the BMP/TGF-beta superfamily as a regulator of XIST expression SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE XIST; X inactivation; MeCP2; Rett syndrome; BMP/TGF-beta ID DE-LANGE-SYNDROME; RETT-SYNDROME; SACCHAROMYCES-CEREVISIAE; INTELLECTUAL DISABILITY; HISTONE ACETYLATION; DOSAGE COMPENSATION; DNA DEMETHYLATION; MUTATIONS; RNF12; TRANSCRIPTION AB Rett syndrome (RS) is a debilitating neurological disorder affecting mostly girls with heterozygous mutations in the gene encoding the methyl-CpG-binding protein MeCP2 on the X chromosome. Because restoration of MeCP2 expression in a mouse model reverses neurologic deficits in adult animals, reactivation of the wild-type copy of MeCP2 on the inactive X chromosome (Xi) presents a therapeutic opportunity in RS. To identify genes involved in MeCP2 silencing, we screened a library of 60,000 shRNAs using a cell line with a MeCP2 reporter on the Xi and found 30 genes clustered in seven functional groups. More than half encoded proteins with known enzymatic activity, and six were members of the bone morphogenetic protein (BMP)/TGF-beta pathway. shRNAs directed against each of these six genes down-regulated X-inactive specific transcript (XIST), a key player in X-chromosome inactivation that encodes an RNA that coats the silent X chromosome, and modulation of regulators of this pathway both in cell culture and in mice demonstrated robust regulation of XIST. Moreover, we show that Rnf12, an X-encoded ubiquitin ligase important for initiation of X-chromosome inactivation and XIST transcription in ES cells, also plays a role in maintenance of the inactive state through regulation of BMP/TGF-beta signaling. Our results identify pharmacologically suitable targets for reactivation of MeCP2 on the Xi and a genetic circuitry that maintains XIST expression and X-chromosome inactivation in differentiated cells. C1 [Sripathy, Smitha; Leko, Vid; Adrianse, Robin L.; Loe, Taylor; Foss, Eric J.; Dalrymple, Emily; Lao, Uyen; Gatbonton-Schwager, Tonibelle; Carter, Kelly T.; Grady, William M.; Bedalov, Antonio] Fred Hutchinson Canc Res Ctr, Clin Res Div, Seattle, WA 98109 USA. [Payer, Bernhard; Lee, Jeannie T.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. [Payer, Bernhard; Lee, Jeannie T.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Payer, Bernhard; Lee, Jeannie T.] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Paddison, Patrick J.] Fred Hutchinson Canc Res Ctr, Human Biol Div, Seattle, WA 98109 USA. [Grady, William M.] Univ Washington, Sch Med, Div Gastroenterol, Seattle, WA 98195 USA. [Bartolomei, Marisa S.] Univ Penn, Dept Cell & Dev Biol, Perelman Sch Med, Epigenet Program, Philadelphia, PA 19104 USA. [Bedalov, Antonio] Univ Washington, Sch Med, Dept Biochem & Med, Seattle, WA 98195 USA. [Leko, Vid] NHLBI, Hematol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Bedalov, A (reprint author), Fred Hutchinson Canc Res Ctr, Clin Res Div, Seattle, WA 98109 USA.; Lee, JT (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA.; Lee, JT (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA.; Lee, JT (reprint author), Harvard Med Sch, Dept Genet, Boston, MA 02115 USA.; Bedalov, A (reprint author), Univ Washington, Sch Med, Dept Biochem & Med, Seattle, WA 98195 USA. EM lee@molbio.mgh.harvard.edu; abedalov@fhcrc.org FU Rett Syndrome Research Trust FX We thank Kathrin Plath for providing us with CMVluciferase/.XIST mouse embryonic fibroblasts, Joost Gribnau for the Rnf12 expression plasmids, Ross Dickins for shRNA library, and Christine Disteche for Patski cells. This work was supported by grants from the Rett Syndrome Research Trust (to A.B., M.S.B., and J.T.L.). NR 52 TC 0 Z9 0 U1 1 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 14 PY 2017 VL 114 IS 7 BP 1619 EP 1624 DI 10.1073/pnas.1621356114 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EK5TR UT WOS:000393989300067 PM 28143937 ER PT J AU Taniguchi, K Moroishi, T de Jong, PR Krawczyk, M Grebbin, BM Luo, HY Xu, RH Golob-Schwarzl, N Schweiger, C Wang, KP Di Caroa, G Feng, Y Fearon, ER Raz, E Kenner, L Farin, HF Guan, KL Haybaeck, J Datz, C Zhang, K Karin, M AF Taniguchi, Koji Moroishi, Toshiro de Jong, Petrus R. Krawczyk, Michal Grebbin, Britta Moyo Luo, Huiyan Xu, Rui-hua Golob-Schwarzl, Nicole Schweiger, Caroline Wang, Kepeng Di Caroa, Giuseppe Feng, Ying Fearon, Eric R. Raz, Eyal Kenner, Lukas Farin, Henner F. Guan, Kun-Liang Haybaeck, Johannes Datz, Christian Zhang, Kang Karin, Michael TI YAP-IL-6ST autoregulatory loop activated on APC loss controls colonic tumorigenesis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE colorectal cancer; adenomatous polyposis coli; IL-6ST/gp130; YAP; STAT3 ID COLORECTAL-CANCER; IL-6 FAMILY; STEM-CELLS; IN-VITRO; INFLAMMATION; YAP/TAZ; INACTIVATION; REGENERATION; HOMEOSTASIS; METASTASIS AB Loss of tumor suppressor adenomatous polyposis coli (APC) activates beta-catenin to initiate colorectal tumorigenesis. However, beta-catenin (CTNNB1) activating mutations rarely occur in human colorectal cancer (CRC). We found that APC loss also results in up-regulation of IL-6 signal transducer (IL-6ST/gp130), thereby activating Src family kinases (SFKs), YAP, and STAT3, which are simultaneously up-regulated in the majority of human CRC. Although, initial YAP activation, which stimulates IL6ST gene transcription, may be caused by reduced serine phosphorylation, sustained YAP activation depends on tyrosine phosphorylation by SFKs, whose inhibition, along with STAT3-activating JAK kinases, causes regression of established colorectal tumors. These results explain why APC loss is a more potent initiating event than the mere activation of CTNNB1. C1 [Taniguchi, Koji; Wang, Kepeng; Di Caroa, Giuseppe; Karin, Michael] Univ Calif San Diego, Lab Gene Regulat & Signal Transduct, La Jolla, CA 92093 USA. [Taniguchi, Koji; Wang, Kepeng; Di Caroa, Giuseppe; Karin, Michael] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA. [Taniguchi, Koji; Wang, Kepeng; Di Caroa, Giuseppe; Karin, Michael] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA. [Taniguchi, Koji] Kyushu Univ, Grad Sch Med Sci, Dept Surg & Sci, Fukuoka 8128582, Japan. [Taniguchi, Koji] Keio Univ, Sch Med, Dept Microbiol & Immunol, Tokyo 1608582, Japan. [Moroishi, Toshiro; Guan, Kun-Liang] Univ Calif San Diego, Moores Canc Ctr, Dept Pharmacol, La Jolla, CA 92093 USA. [de Jong, Petrus R.; Raz, Eyal] Univ Calif San Diego, Sch Med, Dept Med, La Jolla, CA 92093 USA. [de Jong, Petrus R.] NCI, Sanford Burnham Prebys Med Discovery Inst, Designated Canc Ctr, La Jolla, CA 92037 USA. [Krawczyk, Michal; Grebbin, Britta Moyo; Luo, Huiyan; Zhang, Kang] Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA. [Grebbin, Britta Moyo; Farin, Henner F.] German Canc Consortium, D-69120 Heidelberg, Germany. [Grebbin, Britta Moyo; Farin, Henner F.] Georg Speyer Haus, Inst Tumor Biol & Expt Therapy, D-60596 Frankfurt, Germany. [Farin, Henner F.] German Canc Res Ctr, D-69120 Heidelberg, Germany. [Luo, Huiyan; Xu, Rui-hua] Sun Yat Sen Univ, Ctr Canc, Collaborat Innovat Ctr Canc Med, State Key Lab Oncol, Guangzhou 510060, Guangdong, Peoples R China. [Golob-Schwarzl, Nicole; Schweiger, Caroline; Haybaeck, Johannes] Med Univ Graz, Inst Pathol, A-8036 Graz, Austria. [Wang, Kepeng] Univ Connecticut, Ctr Hlth, Sch Med, Dept Immunol, Farmington, CT USA. [Feng, Ying; Fearon, Eric R.] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 48109 USA. [Fearon, Eric R.] Univ Michigan, Sch Med, Dept Human Genet, Ann Arbor, MI 48109 USA. [Fearon, Eric R.] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA. [Kenner, Lukas] Med Univ Vienna, Clin Inst Pathol, A-1090 Vienna, Austria. [Kenner, Lukas] Med Univ Vienna, Ludwig Boltzmann Inst Canc Res, A-1090 Vienna, Austria. [Kenner, Lukas] Univ Vet Med Vienna, Dept Pathol Lab Anim, A-1210 Vienna, Austria. [Haybaeck, Johannes] Otto von Guericke Univ, Dept Pathol, D-39120 Magdeburg, Germany. [Datz, Christian] Paracelsus Private Univ Salzburg, Teaching Hosp, Hosp Oberndorf, Dept Internal Med, A-5110 Oberndorf, Austria. [Karin, Michael] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. RP Karin, M (reprint author), Univ Calif San Diego, Lab Gene Regulat & Signal Transduct, La Jolla, CA 92093 USA.; Karin, M (reprint author), Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA.; Karin, M (reprint author), Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA.; Karin, M (reprint author), Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. EM karinoffice@ucsd.edu OI Kenner, Lukas/0000-0003-2184-1338; de Jong, Petrus/0000-0003-2321-1153 FU Japan Society for the Promotion of Science; Uehara Memorial Foundation Fellowship; Mochida Memorial Foundation for Medical and Pharmaceutical Research; Kanae Foundation for the Promotion of Medical Science; KAKENHI [15K21775]; "Kibou" Projects; Italian Association for Cancer Research; Marie Curie Actions European Union-People-COFUND; Crohn's and Colitis Foundation of America SRA [330251]; European Commission Marie Curie program; Austrian Science Funds FWF; Innovative Medicines Initiative Joint Undertaking [115234]; European Union's Seventh Framework Programme (FP7); European Federation of Pharmaceutical Industries and Associations companies; SPAR Austria; NIH [AI043477]; Incyte Inc; Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases; [P26011]; [P29251] FX We thank Drs. D. Pan (Johns Hopkins University) and S. Akira (Osaka University) for YapF/F and Stat3F/F mice, respectively; Drs. D. L. Gumucio (University of Michigan) for the 12.4- kb Villin promoter; C. A. O'Brien (University of Arkansas for Medical Sciences) for the gp130-luciferase plasmid; T. Sato (Keio University), H. Clevers (Hubrecht Institute), and Y. Hippo (National Cancer Center Research Institute) for protocols describing intestinal organoid culture; C. Kuo (Stanford University) for R-spondin1-producing cells; J. Zhao [University of California, San Diego (UCSD) Transgenic Mouse and Gene Targeting Core], L. Gapuz, R. Ly, and N. Varki (UCSD Histology Core), N. Hiramatsu, S. Yamachika, S. I. Grivennikov, A. Chang, and T. Lee for technical advice and assistance; and Cell Signaling, Santa Cruz Biotechnology, GeneTex, and Incyte for antibodies and reagents. This work was supported by Postdoctoral Fellowship for Research Abroad and Research Fellowship for Young Scientists from the Japan Society for the Promotion of Science, a Uehara Memorial Foundation Fellowship, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, the Kanae Foundation for the Promotion of Medical Science, KAKENHI (15K21775), and the "Kibou" Projects (all to K.T.); FIRC for Abroad and iCare fellowship funded from the Italian Association for Cancer Research and Marie Curie Actions European Union-People-COFUND (G.D.C.); and Crohn's and Colitis Foundation of America SRA#330251 (to E.R.). L.K. is supported by the European Commission Marie Curie 2020 program as a Co-Coordinator within the "ALKATRAS' project as well as by the Austrian Science Funds FWF; and Grants P26011 and P29251. TMA generation was supported by the Innovative Medicines Initiative Joint Undertaking under Grant 115234 (OncoTrack), resources of which are composed of financial contributions from the European Union's Seventh Framework Programme (FP7/2007-2013) and European Federation of Pharmaceutical Industries and Associations companies' in-kind contribution (www.imi.europa.eu) (to J.H.). C.D. was supported by SPAR Austria. Research at UCSD was supported by the NIH (AI043477) and Incyte Inc. M. Karin is an American Cancer Society Research Professor and holder of the Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases. NR 47 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 FEB 14 PY 2017 VL 114 IS 7 BP 1643 EP 1648 DI 10.1073/pnas.1620290114 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EK5TR UT WOS:000393989300071 PM 28130546 ER PT J AU Tomasi, DG Shokri-Kojori, E Volkow, ND AF Tomasi, Dardo G. Shokri-Kojori, Ehsan Volkow, Nora D. TI Brain Network Dynamics Adhere to a Power Law SO FRONTIERS IN NEUROSCIENCE LA English DT Article DE FCDM; ALFF; lFCD; functional connectivity (FC); graph theory analysis; brain networks; Taylor's law; numerical simulations ID HUMAN CONNECTOME PROJECT; FUNCTIONAL CONNECTIVITY; RESTING-STATE; BINOCULAR-RIVALRY; DECISION-MAKING; FMRI; MRI; PATTERNS; TRACKING; CORTEX AB The temporal dynamics of complex networks such as the Internet is characterized by a power scaling between the temporal mean and dispersion of signals at each network node. Here we tested the hypothesis that the temporal dynamics of the brain networks is characterized by a similar power law. This realization could be useful to assess the effects of randomness and external modulators on the brain network dynamics. Simulated data using a well-stablished random diffusion model allowed us to predict that the temporal dispersion of the amplitude of low frequency fluctuations (ALFF) and that of the local functional connectivity density (lFCD) scale with their temporal means. We tested this hypothesis in open-access resting-state functional magnetic resonance imaging datasets from 66 healthy subjects. A robust power law emerged from the temporal dynamics of ALFF and lFCD metrics, which was insensitive to the methods used for the computation of the metrics. The scaling exponents (ALFF: 0.8 +/- 0.1; lFCD: 1.1 +/- 0.1; mean +/- SD) decreased with age and varied significantly across brain regions; multimodal cortical areas exhibited lower scaling exponents, consistent with a stronger influence of external inputs, than limbic and subcortical regions, which exhibited higher scaling exponents, consistent with a stronger influence of internal randomness. Findings are consistent with the notion that external inputs govern neuronal communication in the brain and that their relative influence differs between brain regions. Further studies will assess the potential of this metric as biomarker to characterize neuropathology. C1 [Tomasi, Dardo G.; Shokri-Kojori, Ehsan; Volkow, Nora D.] NIAAA, Bethesda, MD 20892 USA. [Volkow, Nora D.] Natl Inst Drug Abuse, Bethesda, MD USA. RP Tomasi, DG (reprint author), NIAAA, Bethesda, MD 20892 USA. EM tomasidg@mail.nih.gov FU 16 NIH Institutes and Centers [1U54MH091657]; McDonnell Center for Systems Neuroscience at Washington University; National Institute on Alcohol Abuse and Alcoholism [Y1AA-3009] FX Data was provided by the Human Connectome Project (HCP), WU-Minn Consortium (Principal Investigators: David Van Essen and Kamil Ugurbil; 1U54MH091657) funded by the 16 NIH Institutes and Centers that support the NIH Blueprint for Neuroscience Research and by the McDonnell Center for Systems Neuroscience at Washington University. This work was accomplished with support from the National Institute on Alcohol Abuse and Alcoholism (Y1AA-3009). NR 44 TC 0 Z9 0 U1 1 U2 1 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-453X J9 FRONT NEUROSCI-SWITZ JI Front. Neurosci. PD FEB 14 PY 2017 VL 11 AR 72 DI 10.3389/fnins.2017.00072 PG 9 WC Neurosciences SC Neurosciences & Neurology GA EK4RS UT WOS:000393915100001 PM 28261049 ER PT J AU Woo, CW Schmidt, L Krishnan, A Jepma, M Roy, M Lindquist, MA Atlas, LY Wager, TD AF Woo, Choong-Wan Schmidt, Liane Krishnan, Anjali Jepma, Marieke Roy, Mathieu Lindquist, Martin A. Atlas, Lauren Y. Wager, Tor D. TI Quantifying cerebral contributions to pain beyond nociception SO NATURE COMMUNICATIONS LA English DT Article ID NUCLEUS-ACCUMBENS; NEUROPATHIC PAIN; FUNCTIONAL CONNECTIVITY; PHYSICAL PAIN; BACK-PAIN; PREFRONTAL CORTEX; BRAIN MEDIATORS; BASAL GANGLIA; FMRI; MECHANISMS AB Cerebral processes contribute to pain beyond the level of nociceptive input and mediate psychological and behavioural influences. However, cerebral contributions beyond nociception are not yet well characterized, leading to a predominant focus on nociception when studying pain and developing interventions. Here we use functional magnetic resonance imaging combined with machine learning to develop a multivariate pattern signature-termed the stimulus intensity independent pain signature-1 (SIIPS1)-that predicts pain above and beyond nociceptive input in four training data sets (Studies 1-4, N = 137). The SIIPS1 includes patterns of activity in nucleus accumbens, lateral prefrontal and parahippocampal cortices, and other regions. In cross-validated analyses of Studies 1-4 and in two independent test data sets (Studies 5-6, N = 46), SIIPS1 responses explain variation in trial-by-trial pain ratings not captured by a previous fMRI-based marker for nociceptive pain. In addition, SIIPS1 responses mediate the pain-modulating effects of three psychological manipulations of expectations and perceived control. The SIIPS1 provides an extensible characterization of cerebral contributions to pain and specific brain targets for interventions. C1 [Woo, Choong-Wan; Wager, Tor D.] Univ Colorado, Dept Psychol & Neurosci, Boulder, CO 80309 USA. [Woo, Choong-Wan; Wager, Tor D.] Univ Colorado, Inst Cognit Sci, Boulder, CO 80309 USA. [Schmidt, Liane] INSEAD, F-77300 Fontainebleau, France. [Schmidt, Liane] Ecole Normale Super, INSERM U960, Dept Cognit Sci, Cognit Neurosci Lab, F-75005 Paris, France. [Krishnan, Anjali] CUNY Brooklyn Coll, Dept Psychol, Brooklyn, NY 11210 USA. [Jepma, Marieke] Leiden Univ, Inst Psychol, Cognit Psychol Unit, NL-2300 Leiden, Netherlands. [Jepma, Marieke] Leiden Univ, Leiden Inst Brain & Cognit, NL-2300 Leiden, Netherlands. [Roy, Mathieu] McGill Univ, Dept Psychol, Montreal, PQ H3A 0G4, Canada. [Lindquist, Martin A.] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21211 USA. [Atlas, Lauren Y.] NIH, Natl Ctr Complementary & Integrat Hlth, Bethesda, MD 20892 USA. [Atlas, Lauren Y.] NIDA, NIH, Rockville, MD 20852 USA. [Woo, Choong-Wan] Inst Basic Sci, Ctr Neurosci Imaging Res, Suwon 16419, South Korea. [Woo, Choong-Wan] Sungkyunkwan Univ, Dept Biomed Engn, Suwon 16419, South Korea. RP Wager, TD (reprint author), Univ Colorado, Dept Psychol & Neurosci, Boulder, CO 80309 USA.; Wager, TD (reprint author), Univ Colorado, Inst Cognit Sci, Boulder, CO 80309 USA. EM tor.wager@colorado.edu OI Woo, Choong-Wan/0000-0002-7423-5422 FU NIH [R01DA035484, R01MH076136]; Intramural Research program of the NIH's National Center for Complementary and Integrative Health; VENI grant of the Netherlands Organization for Scientific Research FX This work was funded by NIH R01DA035484 and R01MH076136 (T.D.W.), the Intramural Research program of the NIH's National Center for Complementary and Integrative Health (L.Y.A) and the VENI grant of the Netherlands Organization for Scientific Research (M.J.). NR 75 TC 0 Z9 0 U1 4 U2 4 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 FEB 14 PY 2017 VL 8 AR 14211 DI 10.1038/ncomms14211 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EK3VV UT WOS:000393857400001 PM 28195170 ER PT J AU Webster, DE Suver, C Doerr, M Mounts, E Domenico, L Petrie, T Leachman, SA Trister, AD Bot, BM AF Webster, Dan E. Suver, Christine Doerr, Megan Mounts, Erin Domenico, Lisa Petrie, Tracy Leachman, Sancy A. Trister, Andrew D. Bot, Brian M. TI Data Descriptor: The Mole Mapper Study, mobile phone skin imaging and melanoma risk data collected using ResearchKit SO SCIENTIFIC DATA LA English DT Article AB Sensor-embedded phones are an emerging facilitator for participant-driven research studies. Skin cancer research is particularly amenable to this approach, as phone cameras enable self-examination and documentation of mole abnormalities that may signal a progression towards melanoma. Aggregation and open sharing of this participant-collected data can be foundational for research and the development of early cancer detection tools. Here we describe data from Mole Mapper, an iPhone-based observational study built using the Apple ResearchKit framework. The Mole Mapper app was designed to collect participant-provided images and measurements of moles, together with demographic and behavioral information relating to melanoma risk. The study cohort includes 2,069 participants who contributed 1,920 demographic surveys, 3,274 mole measurements, and 2,422 curated mole images. Survey data recapitulates associations between melanoma and known demographic risks, with red hair as the most significant factor in this cohort. Participant-provided mole measurements indicate an average mole size of 3.95 mm. These data have been made available to engage researchers in a collaborative, multidisciplinary effort to better understand and prevent melanoma. C1 [Webster, Dan E.] NCI, Bethesda, MD 20892 USA. [Suver, Christine; Doerr, Megan; Mounts, Erin; Trister, Andrew D.; Bot, Brian M.] Sage Bionetworks, Seattle, WA 98109 USA. [Domenico, Lisa; Petrie, Tracy; Leachman, Sancy A.] Oregon Hlth & Sci Univ, Portland, OR 97239 USA. RP Bot, BM (reprint author), Sage Bionetworks, Seattle, WA 98109 USA.; Leachman, SA (reprint author), Oregon Hlth & Sci Univ, Portland, OR 97239 USA. EM leachmas@ohsu.edu; brian.bot@sagebase.org NR 9 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2052-4463 J9 SCI DATA JI Sci. Data PD FEB 14 PY 2017 VL 4 DI 10.1038/sdata.2017.5 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EK3VJ UT WOS:000393856200001 ER PT J AU Khan, JM Schenke, WH Sonmez, M Lederman, RJ AF Khan, Jaffar M. Schenke, William H. Sonmez, Merdim Lederman, Robert J. TI Guidewire Electrosurgery Optimization For LAMPOON SO JACC-CARDIOVASCULAR INTERVENTIONS LA English DT Meeting Abstract C1 [Khan, Jaffar M.; Schenke, William H.; Sonmez, Merdim; Lederman, Robert J.] NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-8798 EI 1876-7605 J9 JACC-CARDIOVASC INTE JI JACC-Cardiovasc. Interv. PD FEB 13 PY 2017 VL 10 IS 3 SU S MA CRT-800.45 BP S76 EP S76 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EP2MJ UT WOS:000397217000207 ER PT J AU Le, MT Kasprzak, WK Kim, T Gao, F Young, MYL Yuan, XF Shapiro, BA Seog, J Simon, AE AF Le, My-Tra Kasprzak, Wojciech K. kim, Taejin Gao, Feng Young, Megan Y. L. Yuan, Xuefeng Shapiro, Bruce A. Seog, Joonil Simon, Anne E. TI Folding behavior of a T-shaped, ribosome-binding translation enhancer implicated in a wide-spread conformational switch SO ELIFE LA English DT Article ID TURNIP-CRINKLE-VIRUS; PARTICLE MESH EWALD; OPTICAL TWEEZERS; NUCLEIC-ACIDS; MOLECULAR-DYNAMICS; GENETIC-CONTROL; METAL-IONS; VIRAL-RNA; RIBOSWITCHES; FORCE AB Turnip crinkle virus contains a T-shaped, ribosome-binding, translation enhancer (TSS) in its 3'UTR that serves as a hub for interactions throughout the region. The viral RNA-dependent RNA polymerase (RdRp) causes the TSS/surrounding region to undergo a conformational shift postulated to inhibit translation. Using optical tweezers (OT) and steered molecular dynamic simulations (SMD), we found that the unusual stability of pseudoknotted element H4a/psi(3) required five upstream adenylates, and H4a/psi(3) was necessary for cooperative association of two other hairpins (H5/H4b) in Mg2+. SMD recapitulated the TSS unfolding order in the absence of Mg2+, showed dependence of the resistance to pulling on the 3D orientation and gave structural insights into the measured contour lengths of the TSS structure elements. Adenylate mutations eliminated one-site RdRp binding to the 3'UTR, suggesting that RdRp binding to the adenylates disrupts H4a/psi(3), leading to loss of H5/H4b interaction and promoting a conformational switch interrupting translation and promoting replication. C1 [Le, My-Tra; Gao, Feng; Young, Megan Y. L.; Yuan, Xuefeng; Simon, Anne E.] Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. [Kasprzak, Wojciech K.] Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, Bas Sci Program, Frederick, MD USA. [kim, Taejin; Shapiro, Bruce A.] Natl Canc Inst, RNA Biol Lab, Ctr Canc Res, Frederick, MD USA. [Seog, Joonil] Univ Maryland, Dept Mat Sci & Engn, College Pk, MD 20742 USA. RP Le, MT; Simon, AE (reprint author), Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. EM my.letra@gmail.com; simona@umd.edu FU National Science Foundation [MCB-1411836]; National Institutes of Health [R21A1117882-01, 2T32A1051967-06A1]; National Cancer Institute FX National Science Foundation MCB-1411836 My-Tra Le Feng Gao Megan Y L Young Xuefeng Yuan Anne E Simon; National Institutes of Health R21A1117882-01 My-Tra Le Feng Gao Anne E Simon; National Cancer Institute Intramural Wojciech K Kasprzak Taejin Kim Bruce A Shapiro; National Institutes of Health 2T32A1051967-06A1 Megan Y L Young Anne E Simon NR 64 TC 0 Z9 0 U1 4 U2 4 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD FEB 13 PY 2017 VL 6 AR e22883 DI 10.7554/eLife.22883 PG 24 WC Biology SC Life Sciences & Biomedicine - Other Topics GA EN5ZG UT WOS:000396083700001 ER PT J AU Dewan, R Pemov, A Dutra, AS Pak, ED Edwards, NA Ray-Chaudhury, A Hansen, NF Chandrasekharappa, SC Mullikin, JC Asthagiri, AR Heiss, JD Stewart, DR Germanwala, AV AF Dewan, Ramita Pemov, Alexander Dutra, Amalia S. Pak, Evgenia D. Edwards, Nancy A. Ray-Chaudhury, Abhik Hansen, Nancy F. Chandrasekharappa, Settara C. Mullikin, James C. Asthagiri, Ashok R. Heiss, John D. Stewart, Douglas R. Germanwala, Anand V. CA NISC Comparative Sequencing Progra TI First insight into the somatic mutation burden of neurofibromatosis type 2-associated grade I and grade II meningiomas: a case report comprehensive genomic study of two cranial meningiomas with vastly different clinical presentation SO BMC CANCER LA English DT Article DE Whole exome sequencing; Single nucleotide polymorphism; Spectral karyotyping; NF2 gene; Somatic mutation; Case report ID CANCER; TUMORS; VARIANTS; FEATURES; CELLS; AKT1; SMO; NF2 AB Background: Neurofibromatosis type 2 (NF2) is a rare autosomal dominant nervous system tumor predisposition disorder caused by constitutive inactivation of one of the two copies of NF2. Meningiomas affect about one half of NF2 patients, and are associated with a higher disease burden. Currently, the somatic mutation landscape in NF2-associated meningiomas remains largely unexamined. Case presentation: Here, we present an in-depth genomic study of benign and atypical meningiomas, both from a single NF2 patient. While the grade I tumor was asymptomatic, the grade II tumor exhibited an unusually high growth rate: expanding to 335 times its initial volume within one year. The genomes of both tumors were examined by whole-exome sequencing (WES) complemented with spectral karyotyping (SKY) and SNP-array copy-number analyses. To better understand the clonal composition of the atypical meningioma, the tumor was divided in four sections and each section was investigated independently. Both tumors had second copy inactivation of NF2, confirming the central role of the gene in meningioma formation. The genome of the benign tumor closely resembled that of a normal diploid cell and had only one other deleterious mutation (EPHB3). In contrast, the chromosomal architecture of the grade II tumor was highly re-arranged, yet uniform among all analyzed fragments, implying that this large and fast growing tumor was composed of relatively few clones. Besides multiple gains and losses, the grade II meningioma harbored numerous chromosomal translocations. WES analysis of the atypical tumor identified deleterious mutations in two genes: ADAMTSL3 and CAPN5 in all fragments, indicating that the mutations were present in the cell undergoing fast clonal expansion Conclusions: This is the first WES study of NF2-associated meningiomas. Besides second NF2 copy inactivation, we found low somatic burden in both tumors and high level of genomic instability in the atypical meningioma. Genomic instability resulting in altered gene dosage and compromised structural integrity of multiple genes may be the primary reason of the high growth rate for the grade II tumor. Further study of ADAMTSL3 and CAPN5 may lead to elucidation of their molecular implications in meningioma pathogenesis. C1 [Germanwala, Anand V.] Loyola Univ, Stritch Sch Med, Dept Neurol Surg, Maywood, IL 60153 USA. [Germanwala, Anand V.] Edward Hines Jr VA Hosp, Dept Otolaryngol, 2160 South First Ave, Maywood, IL 60153 USA. [Dewan, Ramita; Edwards, Nancy A.; Ray-Chaudhury, Abhik; Heiss, John D.] NINDS, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Pemov, Alexander; Stewart, Douglas R.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Dutra, Amalia S.; Pak, Evgenia D.] NHGRI, NIH, Genet Dis Res Branch, Bethesda, MD USA. [Hansen, Nancy F.; Chandrasekharappa, Settara C.; Mullikin, James C.] NHGRI, NIH, Canc Genet & Comparat Genom Branch, Bethesda, MD USA. [Mullikin, James C.] NHGRI, NIH, NIH Intramural Sequencing Ctr, Rockville, MD USA. [Asthagiri, Ashok R.] Univ Virginia, Sch Med, Dept Neurol Surg, Charlottesville, VA 22908 USA. RP Germanwala, AV (reprint author), Loyola Univ, Stritch Sch Med, Dept Neurol Surg, Maywood, IL 60153 USA.; Germanwala, AV (reprint author), Edward Hines Jr VA Hosp, Dept Otolaryngol, 2160 South First Ave, Maywood, IL 60153 USA. EM agermanwala@gmail.com FU Intramural Research Program of the National Institute of Neurologic Disease and Stroke (NINDS); Division of Cancer Epidemiology and Genetics of the National Cancer Institute (NCI); National Human Genome Research Institute (NHGRI) FX This study was supported by funding from the Intramural Research Program of the National Institute of Neurologic Disease and Stroke (NINDS), the Division of Cancer Epidemiology and Genetics of the National Cancer Institute (NCI), and the National Human Genome Research Institute (NHGRI). The roles of each funding body were as follows: NINDS for study design, collection of data, and writing of the manuscript; NCI for study design, collection, analysis, and interpretation of data, and writing of the manuscript; and NHGRI for collection, analysis, and interpretation of data. NR 33 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD FEB 13 PY 2017 VL 17 AR 127 DI 10.1186/s12885-017-3127-6 PG 10 WC Oncology SC Oncology GA EK3QX UT WOS:000393842100004 PM 28193203 ER PT J AU Arca, B Lombardo, F Struchiner, CJ Ribeiro, JMC AF Arca, Bruno Lombardo, Fabrizio Struchiner, Claudio J. Ribeiro, Jose M. C. TI Anopheline salivary protein genes and gene families: an evolutionary overview after the whole genome sequence of sixteen Anopheles species SO BMC GENOMICS LA English DT Article DE Salivary glands; Salivary proteins; Anophelines; Mosquito saliva; Vector biology; Evolution; Salivary markers; Human exposure to malaria vectors; Positive selection ID ADULT FEMALE MOSQUITO; FLY LUTZOMYIA-LONGIPALPIS; RICH SECRETORY PROTEINS; INDUCED PLATELET-AGGREGATION; IMMUNO-EPIDEMIOLOGIC TOOL; EVALUATING HUMAN EXPOSURE; MALARIA VECTOR MOSQUITO; VON-WILLEBRAND-FACTOR; AEDES-AEGYPTI; ANTIBODY-RESPONSE AB Background: Mosquito saliva is a complex cocktail whose pharmacological properties play an essential role in blood feeding by counteracting host physiological response to tissue injury. Moreover, vector borne pathogens are transmitted to vertebrates and exposed to their immune system in the context of mosquito saliva which, in virtue of its immunomodulatory properties, can modify the local environment at the feeding site and eventually affect pathogen transmission. In addition, the host antibody response to salivary proteins may be used to assess human exposure to mosquito vectors. Even though the role of quite a few mosquito salivary proteins has been clarified in the last decade, we still completely ignore the physiological role of many of them as well as the extent of their involvement in the complex interactions taking place between the mosquito vectors, the pathogens they transmit and the vertebrate host. The recent release of the genomes of 16 Anopheles species offered the opportunity to get insights into function and evolution of salivary protein families in anopheline mosquitoes. Results: Orthologues of fifty three Anopheles gambiae salivary proteins were retrieved and annotated from 18 additional anopheline species belonging to the three subgenera Cellia, Anopheles, and Nyssorhynchus. Our analysis included 824 full-length salivary proteins from 24 different families and allowed the identification of 79 novel salivary genes and re-annotation of 379 wrong predictions. The comparative, structural and phylogenetic analyses yielded an unprecedented view of the anopheline salivary repertoires and of their evolution over 100 million years of anopheline radiation shedding light on mechanisms and evolutionary forces that contributed shaping the anopheline sialomes. Conclusions: We provide here a comprehensive description, classification and evolutionary overview of the main anopheline salivary protein families and identify two novel candidate markers of human exposure to malaria vectors worldwide. This anopheline sialome catalogue, which is easily accessible as hyperlinked spreadsheet, is expected to be useful to the vector biology community and to improve the capacity to gain a deeper understanding of mosquito salivary proteins facilitating their possible exploitation for epidemiological and/or pathogen-vector-host interaction studies. C1 [Arca, Bruno; Lombardo, Fabrizio] Sapienza Univ, Dept Publ Hlth & Infect Dis, Div Parasitol, Piazzale Aldo Moro 5, I-00185 Rome, Italy. [Struchiner, Claudio J.] Fundacao Oswaldo Cruz, Ave Brasil, BR-4365 Rio De Janeiro, Brazil. [Struchiner, Claudio J.] Univ Estado Rio de Janeiro, Inst Med Social, Rio De Janeiro, Brazil. [Ribeiro, Jose M. C.] NIAID, Lab Malaria & Vector Res, 12735 Twinbrook Pkwy, Rockville, MD 20852 USA. RP Arca, B (reprint author), Sapienza Univ, Dept Publ Hlth & Infect Dis, Div Parasitol, Piazzale Aldo Moro 5, I-00185 Rome, Italy. EM bruno.arca@uniroma1.it FU European Union [228421]; Ministry of Education, University and Research (MIUR) [2010C2LKKJ_004]; Brazilian Research Council (CNPq); FAPERJ; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institute of Health, USA FX BA was supported by funds from the European Union grant INFRAVEC (228421) and from the Ministry of Education, University and Research (MIUR) grant SKINFLAM (2010C2LKKJ_004). JMCR by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institute of Health, USA. CJS was supported by Brazilian Research Council (CNPq) and FAPERJ. NR 152 TC 0 Z9 0 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD FEB 13 PY 2017 VL 18 AR 153 DI 10.1186/s12864-017-3579-8 PG 27 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA EL1MQ UT WOS:000394384900002 PM 28193177 ER PT J AU Araya, RE Goldszmid, RS AF Araya, Romina E. Goldszmid, Romina S. TI IFNAR1 Degradation: A New Mechanism for Tumor Immune Evasion? SO CANCER CELL LA English DT Editorial Material ID I INTERFERON; DENDRITIC CELLS AB Type I interferons have been shown to play a major role in anti-cancer immunity. In this issue of Cancer Cell, Katlinski et al. describe tumor-induced degradation of type I interferon receptor IFNAR1 chain as a new immune-evasion mechanism in colorectal cancers. Stabilizing IFNAR1 inhibits tumor growth and improves immunotherapy efficacy. C1 [Araya, Romina E.; Goldszmid, Romina S.] NCI, Inflammatory Cell Dynam Sect, Canc & Inflammat Program, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Goldszmid, RS (reprint author), NCI, Inflammatory Cell Dynam Sect, Canc & Inflammat Program, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM rgoldszmid@mail.nih.gov FU intramural research program of the NCI FX This work was supported by the intramural research program of the NCI. We are grateful to Juan Pablo Borrelli for help with the illustration. 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 1535-6108 EI 1878-3686 J9 CANCER CELL JI Cancer Cell PD FEB 13 PY 2017 VL 31 IS 2 BP 161 EP 163 DI 10.1016/j.ccell.2017.01.012 PG 3 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EL1WG UT WOS:000394411500002 PM 28196588 ER PT J AU Fishbein, L Leshchiner, I Walter, V Danilova, L Robertson, AG Johnson, AR Lichtenberg, TM Murray, BA Ghayee, HK Else, T Ling, SY Jefferys, SR de Cubas, AA Wenz, B Korpershoek, E Amelio, AL Makowski, L Rathmell, WK Gimenez-Roqueplo, AP Giordano, TJ Asa, SL Tischler, AS Pacak, K Nathanson, KL Wilkerson, MD AF Fishbein, Lauren Leshchiner, Ignaty Walter, Vonn Danilova, Ludmila Robertson, A. Gordon Johnson, Amy R. Lichtenberg, Tara M. Murray, Bradley A. Ghayee, Hans K. Else, Tobias Ling, Shiyun Jefferys, Stuart R. de Cubas, Aguirre A. Wenz, Brandon Korpershoek, Esther Amelio, Antonio L. Makowski, Liza Rathmell, W. Kimryn Gimenez-Roqueplo, Anne-Paule Giordano, Thomas J. Asa, Sylvia L. Tischler, Arthur S. Pacak, Karel Nathanson, Katherine L. Wilkerson, Matthew D. CA Canc Genome Atlas Res Network TI Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma SO CANCER CELL LA English DT Article ID RNA-BINDING PROTEIN; SPORADIC PHEOCHROMOCYTOMA; SOMATIC MUTATIONS; GENE-EXPRESSION; STEM-CELLS; CANCER; TUMORS; CARCINOMA; RET; DIFFERENTIATION AB We report a comprehensive molecular characterization of pheochromocytomas and paragangliomas (PCCs/PGLs), a rare tumor type. Multi-platform integration revealed that PCCs/PGLs are driven by diverse alterations affecting multiple genes and pathways. Pathogenic germline mutations occurred in eight PCC/PGL susceptibility genes. We identified CSDE1 as a somatically mutated driver gene, complementing four known drivers (HRAS, RET, EPAS1, and NF1). We also discovered fusion genes in PCCs/PGLs, involving MAML3, BRAF, NGFR, and NF1. Integrated analysis classified PCCs/PGLs into four molecularly defined groups: a kinase signaling subtype, a pseudohypoxia subtype, a Wnt-altered subtype, driven by MAML3 and CSDE1, and a cortical admixture subtype. Correlates of metastatic PCCs/PGLs included the MAML3 fusion gene. This integrated molecular characterization provides a comprehensive foundation for developing PCC/PGL precision medicine. C1 [Fishbein, Lauren] Univ Penn, Perelman Sch Med, Div Endocrinol Diabet & Metab, Dept Med, Philadelphia, PA 19104 USA. [Leshchiner, Ignaty] Eli & Edythe L Broad Inst Massachusetts Inst Tech, Cambridge, MA 02142 USA. [Leshchiner, Ignaty] Harvard Univ, Cambridge, MA 02142 USA. [Walter, Vonn; Jefferys, Stuart R.; de Cubas, Aguirre A.; Amelio, Antonio L.; Makowski, Liza; Rathmell, W. Kimryn; Wilkerson, Matthew D.] Univ North Carolina Chapel Hill, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Danilova, Ludmila] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21287 USA. [Robertson, A. Gordon] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 4S6, Canada. [Johnson, Amy R.] Univ North Carolina Chapel Hill, Dept Nutr, Chapel Hill, NC 27599 USA. [Lichtenberg, Tara M.] Nationwide Childrens Hosp, Res Inst, Columbus, OH 43205 USA. [Ghayee, Hans K.] Univ Florida, Coll Med, Dept Med, Div Endocrinol & Metab, Gainesville, FL 32608 USA. [Ghayee, Hans K.] Malcom Randall VA Med Ctr, Gainesville, FL 32608 USA. [Else, Tobias] Univ Michigan Hlth Syst, Div Metab Endocrinol & Diabet, Dept Internal Med, Ann Arbor, MI 48109 USA. [Ling, Shiyun] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [de Cubas, Aguirre A.; Rathmell, W. Kimryn] Univ North Carolina Chapel Hill, Dept Med, Div Hematol & Oncol, Chapel Hill, NC 27599 USA. [Wenz, Brandon; Nathanson, Katherine L.] Univ Penn, Perelman Sch Med, Dept Med, Div Translat Med & Human Genet, Philadelphia, PA 19104 USA. [Korpershoek, Esther] Erasmus MC Univ Med Ctr Rotterdam, Dept Pathol, Wytemaweg 80, NL-3015 CN Rotterdam, Netherlands. [Gimenez-Roqueplo, Anne-Paule] INSERM, Paris Cardiovasc Res Ctr, UMR970, F-75015 Paris, France. [Giordano, Thomas J.] Univ Michigan Hlth Syst, Dept Pathol, Ann Arbor, MI 48109 USA. [Asa, Sylvia L.] Univ Hlth Network, Dept Pathol, Toronto, ON M5G 2C4, Canada. [Asa, Sylvia L.] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5G 2C4, Canada. [Tischler, Arthur S.] Tufts Med Ctr, Dept Pathol & Lab Med, Boston, MA 02111 USA. [Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, Bethesda, MD 20892 USA. [Nathanson, Katherine L.] Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Wilkerson, Matthew D.] Univ North Carolina Chapel Hill, Dept Genet, Chapel Hill, NC 27599 USA. [Fishbein, Lauren] Univ Colorado, Sch Med, Dept Med, Div Endocrinol Metab & Diabet, Aurora, CO 80045 USA. [Fishbein, Lauren; de Cubas, Aguirre A.; Rathmell, W. Kimryn] Vanderbilt Univ, Div Hematol & Oncol, Dept Med, Sch Med,Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA. [Wilkerson, Matthew D.] Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, Collaborat Hlth Initiat Res Program, Amer Genome Ctr, Bethesda, MD 20814 USA. RP Wilkerson, MD (reprint author), Univ North Carolina Chapel Hill, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA.; Nathanson, KL (reprint author), Univ Penn, Perelman Sch Med, Dept Med, Div Translat Med & Human Genet, Philadelphia, PA 19104 USA.; Pacak, K (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, Bethesda, MD 20892 USA.; Nathanson, KL (reprint author), Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA.; Wilkerson, MD (reprint author), Univ North Carolina Chapel Hill, Dept Genet, Chapel Hill, NC 27599 USA.; Wilkerson, MD (reprint author), Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, Collaborat Hlth Initiat Res Program, Amer Genome Ctr, Bethesda, MD 20814 USA. EM karel@mail.nih.gov; knathans@exchange.upenn.edu; mdwilkerson@outlook.com RI Marra, Marco/B-5987-2008; Holt, Robert/C-3303-2009; OI Zelinka, Tomas/0000-0003-3395-8373; Gehlenborg, Nils/0000-0003-0327-8297 FU NIH [U54 HG003273, U54 HG003067, U54 HG003079, U24 CA143799, U24 CA143835, U24 CA143840, U24 CA143843, U24 CA143845, U24 CA143848, U24 CA14385, U24 CA143866, U24 CA143867, U24 CA143882, U24 CA143883, U24 CA144025, P30 CA016672]; Bayer AG FX We thank all of the patients and families who contributed to the study, Ina Felau for project management, and Jill Dolinsky, MS, CGC, at Ambry Genetics, Inc., for sharing mutation classification and frequency data. This study was supported by NIH grants U54 HG003273, U54 HG003067, U54 HG003079, U24 CA143799, U24 CA143835, U24 CA143840, U24 CA143843, U24 CA143845, U24 CA143848, U24 CA143858, U24 CA143866, U24 CA143867, U24 CA143882, U24 CA143883, U24 CA144025, and P30 CA016672. S.L.A. is part of the pathology imaging medical advisory board of Leica Biosystems. Andrew D. Cherniack and Matthew Meyerson received research support from Bayer AG. NR 54 TC 1 Z9 1 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 EI 1878-3686 J9 CANCER CELL JI Cancer Cell PD FEB 13 PY 2017 VL 31 IS 2 BP 181 EP 193 DI 10.1016/j.ccell.2017.01.001 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EL1WG UT WOS:000394411500008 PM 28162975 ER PT J AU Rossey, I Gilman, MSA Kabeche, SC Sedeyn, K Wrapp, D Kanekiyo, M Chen, M Mas, V Spitaels, J Melero, JA Graham, BS Schepens, B McLellan, JS Saelens, X AF Rossey, Iebe Gilman, Morgan S. A. Kabeche, Stephanie C. Sedeyn, Koen Wrapp, Daniel Kanekiyo, Masaru Chen, Man Mas, Vicente Spitaels, Jan Melero, Jose A. Graham, Barney S. Schepens, Bert McLellan, Jason S. Saelens, Xavier TI Potent single-domain antibodies that arrest respiratory syncytial virus fusion protein in its prefusion state SO NATURE COMMUNICATIONS LA English DT Article ID HUMANIZED MONOCLONAL-ANTIBODY; PICHIA-PASTORIS; IN-VITRO; INFECTION; GLYCOPROTEIN; MOTAVIZUMAB; SOFTWARE; RISK AB Human respiratory syncytial virus (RSV) is the main cause of lower respiratory tract infections in young children. The RSV fusion protein (F) is highly conserved and is the only viral membrane protein that is essential for infection. The prefusion conformation of RSV F is considered the most relevant target for antiviral strategies because it is the fusion-competent form of the protein and the primary target of neutralizing activity present in human serum. Here, we describe two llama-derived single-domain antibodies (VHHs) that have potent RSV-neutralizing activity and bind selectively to prefusion RSV F with picomolar affinity. Crystal structures of these VHHs in complex with prefusion F show that they recognize a conserved cavity formed by two F protomers. In addition, the VHHs prevent RSV replication and lung infiltration of inflammatory monocytes and T cells in RSV-challenged mice. These prefusion F-specific VHHs represent promising antiviral agents against RSV. C1 [Rossey, Iebe; Sedeyn, Koen; Spitaels, Jan; Schepens, Bert; Saelens, Xavier] VIB, Ctr Med Biotechnol, Technol Pk 927, B-9052 Ghent, Belgium. [Rossey, Iebe; Sedeyn, Koen; Spitaels, Jan; Schepens, Bert; Saelens, Xavier] Univ Ghent, Dept Biomed Mol Biol, B-9052 Ghent, Belgium. [Gilman, Morgan S. A.; Kabeche, Stephanie C.; Wrapp, Daniel; McLellan, Jason S.] Geisel Sch Med Dartmouth, Dept Biochem & Cell Biol, Hanover, NH 03755 USA. [Kanekiyo, Masaru; Chen, Man; Graham, Barney S.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Mas, Vicente; Melero, Jose A.] Inst Salud Carlos III, Ctr Nacl Microbiol, Madrid 28220, Spain. [Mas, Vicente; Melero, Jose A.] Inst Salud Carlos III, CIBER Enfermedades Resp, Madrid 28220, Spain. RP Schepens, B; Saelens, X (reprint author), VIB, Ctr Med Biotechnol, Technol Pk 927, B-9052 Ghent, Belgium.; Schepens, B; Saelens, X (reprint author), Univ Ghent, Dept Biomed Mol Biol, B-9052 Ghent, Belgium.; McLellan, JS (reprint author), Geisel Sch Med Dartmouth, Dept Biochem & Cell Biol, Hanover, NH 03755 USA. EM Bert.Schepens@vib-ugent.be; Jason.S.McLellan@dartmouth.edu; xavier.saelens@vib-ugent.be RI Mas, Vicente/M-4776-2015 OI Mas, Vicente/0000-0002-0887-0743 FU IWT-Vlaanderen; National Institute of General Medical Sciences of the National Institutes of Health [T32GM008704, P20GM113132]; FWO-Vlaanderen; Ghent University [BOF12/GOA/014]; Interuniversity Attraction Poles programme (IAP7, BELVIR); VIB; Mineco (Spain) [SAF2015-67033-R]; U.S. Department of Energy, Office of Biological and Environmental Research [DE-AC02-06CH11357]; National Cancer Institute [ACB-12002]; National Institute of General Medical Sciences [AGM-12006] FX We thank Amanda Goncalves and Eef Parthoens from VIB Bio Imaging Core, Liesbeth Vande Ginste, Lien Van Hoecke, Soraya Van Cauwenberghe and Emilie Shipman for excellent technical assistance and Dr Florencia Linero for providing the control VHH. This study was supported by IWT-Vlaanderen (Ph.D. student fellowship to I.R.), National Institute of General Medical Sciences of the National Institutes of Health award T32GM008704 (M.S.A.G.) and P20GM113132 (J.S.M.), FWO-Vlaanderen (Postdoctoral fellowship to B.S.), Ghent University Special Research Grant BOF12/GOA/014, Interuniversity Attraction Poles programme (IAP7, BELVIR), VIB and Mineco (Spain) Grant SAF2015-67033-R (J.A.M.). Results shown in this report are derived in part from work performed at Argonne National Laboratory, Structural Biology Center at the Advanced Photon Source. Argonne is operated by UChicago Argonne, LLC, for the U.S. Department of Energy, Office of Biological and Environmental Research under contract DE-AC02-06CH11357. Data in this report were also obtained at GM/CA@APS, which has been funded in whole or in part with Federal funds from the National Cancer Institute (ACB-12002) and the National Institute of General Medical Sciences (AGM-12006). NR 47 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD FEB 13 PY 2017 VL 8 AR 14158 DI 10.1038/ncomms14158 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EK8DE UT WOS:000394153300001 PM 28194013 ER PT J AU Bulea, TC Stanley, CJ Damiano, DL AF Bulea, Thomas C. Stanley, Christopher J. Damiano, Diane L. TI Part 2: Adaptation of Gait Kinematics in Unilateral Cerebral Palsy Demonstrates Preserved Independent Neural Control of Each Limb SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE neural circuits; after-effects; brain injury; knee angle; local dynamic stability; neurorehabilitation ID SPLIT-BELT; LOCOMOTOR ADAPTATION; HUMAN WALKING; DYNAMIC STABILITY; PRISM ADAPTATION; INTERLIMB COORDINATION; TREADMILL WALKING; STROKE; VARIABILITY; REHABILITATION AB Motor adaptation, or alteration of neural control in response to a perturbation, is a potential mechanism to facilitate motor learning for rehabilitation. Central nervous system deficits are known to affect locomotor adaptation; yet we demonstrated that similar to adults following stroke, children with unilateral brain injuries can adapt step length in response to unilateral leg weighting. Here, we extend our analysis to explore kinematic strategies underlying step length adaptation and utilize dynamical systems approaches to elucidate how neural control may differ in those with hemiplegic CP across legs and compared to typically developing controls. Ten participants with hemiplegic CP and ten age-matched controls participated in this study. Knee and hip joint kinematics were analyzed during unilateral weighting of each leg in treadmill walking to assess adaptation and presence and persistence of after-effects. Peak joint angle displacement was used to represent changes in joint angles during walking. We examined baseline and task-specific variability and local dynamic stability to evaluate neuromuscular control across groups and legs. In contrast to controls, children with unilateral CP had asymmetries in joint angle variability and local dynamic stability at baseline, showing increased variability and reduced stability in the dominant limb. Kinematic variability increased and local stability decreased during weighting of ipsilateral and contralateral limbs in both groups compared to baseline. After weight removal both measures returned to baseline. Analogous to the temporal-spatial results, children with unilateral CP demonstrated similar capability as controls to adapt kinematics to unilateral leg weighting, however, the group with CP differed across sides after weight removal with dominant limb after-effects fading more quickly than in controls. The change in kinematics did not completely return to baseline in the non-dominant limb of the CP group, producing a transient improvement in joint angle symmetry. Recent studies demonstrate that neural control of gait is multi-layered with distinct circuits for different types of walking and for each leg. Remarkably, our results demonstrate that children with unilateral brain injury retain these separate circuits for each leg during walking and, importantly, that those networks can be adapted independently from one another to improve symmetry in the short term. C1 [Bulea, Thomas C.; Stanley, Christopher J.; Damiano, Diane L.] NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Bldg 10, Bethesda, MD 20892 USA. RP Bulea, TC (reprint author), NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Bldg 10, Bethesda, MD 20892 USA. EM thomas.bulea@nih.gov FU NIH Clinical Center FX This work was funded by the Intramural Research Program of the NIH Clinical Center. NR 48 TC 0 Z9 0 U1 1 U2 1 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 FEB 13 PY 2017 VL 11 AR 50 DI 10.3389/fnhum.2017.00050 PG 12 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA EK1WK UT WOS:000393716300001 PM 28243195 ER PT J AU Chinen, M Lei, EP AF Chinen, Madoka Lei, Elissa P. TI Drosophila Argonaute2 turnover is regulated by the ubiquitin proteasome pathway SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Argonaute; RNAi; Protein stability; Ubiquitin; Proteasome ID DISTINCT ROLES; HUMAN-CELLS; STABILITY; PROTEINS; GENE; COMPLEXES; RNAI AB Argonaute (AGO) proteins play a central role in the RNA interference (RNAi) pathway, which is a cytoplasmic mechanism important for post-transcriptional regulation of gene expression. In Drosophila, AGO2 also functions in the nucleus to regulate chromatin insulator activity and transcription. Although there are a number of studies focused on AGO2 function, the regulation of AGO2 turnover is not well understood. We found that mutation of T1149 or R1158 in the conserved PIWI domain causes AGO2 protein instability, but only T1149 affects RNAi activity. Mass spec analysis shows that several proteasome components co-purify with both wildtype and mutant AGO2, and knockdown of two proteasome pathway components results in AGO2 protein accumulation. Finally, AGO2 protein levels increase after treatment with the proteasome inhibitor MG132. Our results indicate that the ubiquitin-proteasome pathway is involved in AGO2 protein turnover. Published by Elsevier Inc. C1 [Chinen, Madoka; Lei, Elissa P.] NIDDK, Nucl Org & Gene Express Sect, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Lei, EP (reprint author), NIDDK, Nucl Org & Gene Express Sect, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. EM leielissa@niddk.nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health [DK015602] FX We thank M. Siomi, H. Siomi, and Q. Liu for anti-AG02; E.C. Lai and SW. Shin for discussions; and A. Haase and members of the Lei laboratory for comments on the manuscript. This work was funded by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases DK015602, National Institutes of Health. NR 22 TC 0 Z9 0 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD FEB 12 PY 2017 VL 483 IS 3 BP 951 EP 957 DI 10.1016/j.bbrc.2017.01.039 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA EK1ZI UT WOS:000393726400008 PM 28087276 ER PT J AU Hanley, DF Lane, K McBee, N Ziai, W Tuhrim, S Lees, KR Dawson, J Gandhi, D Ullman, N Mould, WA Mayo, SW Mendelow, AD Gregson, B Butcher, K Vespa, P Wright, DW Kase, CS Carhuapoma, JR Keyl, PM Diener-West, M Muschelli, J Betz, JF Thompson, CB Sugar, EA Yenokyan, G Janis, S John, S Harnof, S Lopez, GA Aldrich, EF Harrigan, MR Ansari, S Jallo, J Caron, JL LeDoux, D Adeoye, O Zuccarello, M Adams, HP Rosenblum, M Thompson, RE Awad, IA AF Hanley, Daniel F. Lane, Karen McBee, Nichol Ziai, Wendy Tuhrim, Stanley Lees, Kennedy R. Dawson, Jesse Gandhi, Dheeraj Ullman, Natalie Mould, W. Andrew Mayo, Steven W. Mendelow, A. David Gregson, Barbara Butcher, Kenneth Vespa, Paul Wright, David W. Kase, Carlos S. Carhuapoma, J. Ricardo Keyl, Penelope M. Diener-West, Marie Muschelli, John Betz, Joshua F. Thompson, Carol B. Sugar, Elizabeth A. Yenokyan, Gayane Janis, Scott John, Sayona Harnof, Sagi Lopez, George A. Aldrich, E. Francois Harrigan, Mark R. Ansari, Safdar Jallo, Jack Caron, Jean-Louis LeDoux, David Adeoye, Opeolu Zuccarello, Mario Adams, Harold P. Rosenblum, Michael Thompson, Richard E. Awad, Issam A. CA ClEAR III Investigators TI Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial SO LANCET LA English DT Article ID SPONTANEOUS INTRACEREBRAL HEMORRHAGE; PLASMINOGEN-ACTIVATOR; CLINICAL-TRIAL; RESOLUTION; UPDATE; BLOOD AB Background Intraventricular haemorrhage is a subtype of intracerebral haemorrhage, with 50% mortality and serious disability for survivors. We aimed to test whether attempting to remove intraventricular haemorrhage with alteplase versus saline irrigation improved functional outcome. Methods In this randomised, double-blinded, placebo-controlled, multiregional trial (CLEAR III), participants with a routinely placed extraventricular drain, in the intensive care unit with stable, non-traumatic intracerebral haemorrhage volume less than 30 mL, intraventricular haemorrhage obstructing the 3rd or 4th ventricles, and no underlying pathology were adaptively randomly assigned (1: 1), via a web-based system to receive up to 12 doses, 8 h apart of 1 mg of alteplase or 0.9% saline via the extraventricular drain. The treating physician, clinical research staff, and participants were masked to treatment assignment. CT scans were obtained every 24 h throughout dosing. The primary efficacy outcome was good functional outcome, defined as a modified Rankin Scale score (mRS) of 3 or less at 180 days per central adjudication by blinded evaluators. This study is registered with ClinicalTrials.gov,NCT00784134. Findings Between Sept 18, 2009, and Jan 13, 2015, 500 patients were randomised: 249 to the alteplase group and 251 to the saline group. 180-day follow-up data were available for analysis from 246 of 249 participants in the alteplase group and 245 of 251 participants in the placebo group. The primary efficacy outcome was similar in each group (good outcome in alteplase group 48% vs saline 45%; risk ratio [RR] 1.06 [95% CI 0.88-1.28; p=0.554]). A difference of 3.5% (RR 1.08 [95% CI 0.90-1.29], p= 0.420) was found after adjustment for intraventricular haemorrhage size and thalamic intracerebral haemorrhage. At 180 days, the treatment group had lower case fatality (46 [18%] vs saline 73 [29%], hazard ratio 0.60 [95% CI 0.41-0.86], p= 0.006), but a greater proportion with mRS 5 (42 [17%] vs 21 [9%]; RR 1.99 [95% CI 1.22-3.26], p= 0.007). Ventriculitis (17 [7%] alteplase vs 31 [12%] saline; RR 0.55 [95% CI 0.31-0.97], p= 0.048) and serious adverse events (114 [46%] alteplase vs 151 [60%] saline; RR 0.76 [95% CI 0.64-0.90], p= 0.002) were less frequent with alteplase treatment. Symptomatic bleeding (six [2%] in the alteplase group vs five [2%] in the saline group; RR 1.21 [95% CI 0.37-3.91], p=0.771) was similar. Interpretation In patients with intraventricular haemorrhage and a routine extraventricular drain, irrigation with alteplase did not substantially improve functional outcomes at the mRS 3 cutoff compared with irrigation with saline. Protocolbased use of alteplase with extraventricular drain seems safe. Future investigation is needed to determine whether a greater frequency of complete intraventricular haemorrhage removal via alteplase produces gains in functional status. C1 [Hanley, Daniel F.; Lane, Karen; McBee, Nichol; Ziai, Wendy; Ullman, Natalie; Mould, W. Andrew; Carhuapoma, J. Ricardo; Keyl, Penelope M.] Johns Hopkins Univ, Sch Med, Brain Injury Outcomes Div, Baltimore, MD USA. [Tuhrim, Stanley] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Lees, Kennedy R.; Dawson, Jesse] Univ Glasgow, Glasgow, Lanark, Scotland. [Gandhi, Dheeraj; Aldrich, E. Francois] Univ Maryland, Baltimore, MD 21201 USA. [Mayo, Steven W.] Emissary Int LLC, Austin, TX USA. [Mendelow, A. David; Gregson, Barbara] Newcastle Univ, Newcastle Upon Tyne, Tyne & Wear, England. [Butcher, Kenneth] Univ Alberta, Edmonton, AB, Canada. [Vespa, Paul] Univ Calif Los Angeles, Los Angeles, CA USA. [Wright, David W.] Emory Univ, Atlanta, GA 30322 USA. [Kase, Carlos S.] Boston Univ, Boston, MA 02215 USA. [Diener-West, Marie; Muschelli, John; Betz, Joshua F.; Thompson, Carol B.; Sugar, Elizabeth A.; Yenokyan, Gayane; Rosenblum, Michael; Thompson, Richard E.] Johns Hopkins Univ Bloomberg, Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Janis, Scott] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [John, Sayona] Rush Univ, Chicago, IL 60612 USA. [Harnof, Sagi] Chaim Sheba Med Ctr, Ramat Gan, Israel. [Lopez, George A.] Univ Texas Houston, Houston, TX USA. [Harrigan, Mark R.] Univ Alabama Birmingham, Birmingham, AL USA. [Ansari, Safdar] Univ Utah, Salt Lake City, UT USA. [Jallo, Jack] Thomas Jefferson Univ Hosp, Philadelphia, PA 19107 USA. [Caron, Jean-Louis] Univ Texas San Antonio, San Antonio, TX USA. [LeDoux, David] North Shore Long Isl Jewish Med Ctr, Manhasset, NY USA. [Adeoye, Opeolu; Zuccarello, Mario] Univ Cincinnati, Cincinnati, OH USA. [Adams, Harold P.] Univ Iowa, Iowa City, IA USA. [Awad, Issam A.] Univ Chicago, Chicago, IL 60637 USA. RP Hanley, DF (reprint author), Johns Hopkins Univ, Acute Care Neurol, Div Brain Injury Outcomes, Baltimore, MD 21231 USA. EM dhanley@jhmi.edu FU National Institute of Neurological Disorders and Stroke FX National Institute of Neurological Disorders and Stroke. NR 25 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD FEB 11 PY 2017 VL 389 IS 10069 BP 603 EP 611 DI 10.1016/S0140-6736(16)32410-2 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA EL9AF UT WOS:000394910800029 PM 28081952 ER PT J AU Lin, W Zhang, PP Chen, H Chen, Y Yang, HX Zheng, WJ Zhang, X Zhang, FX Zhang, W Lipsky, PE AF Lin, Wei Zhang, Panpan Chen, Hua Chen, Yu Yang, Hongxian Zheng, Wenjie Zhang, Xuan Zhang, Fengxiao Zhang, Wen Lipsky, Peter E. TI Circulating plasmablasts/plasma cells: a potential biomarker for IgG4-related disease SO ARTHRITIS RESEARCH & THERAPY LA English DT Article DE IgG4-RD; Biomarker; Autoimmunity; CD19(+) CD24(-) CD38(hi) plasmablast/plasma cell ID IMMUNOGLOBULIN G4-RELATED DISEASE; PLASMA-CELLS; B-CELLS; RECEPTOR STIMULATION; CD86; DIFFERENTIATION; EXPRESSION; TRANSCRIPTION; SUBSETS AB Background: Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a multisystem fibroinflammatory disease. We previously reported that a circulating cell population expressing CD19(+) CD24(-)CD38(hi) was increased in patients with IgG4-RD. In this study, we aimed to document that this cell population represented circulating plasmablasts/plasma cells, to identify the detailed phenotype and gene expression profile of these IgG4-secreting plasmablasts/plasma cells, and to determine whether this B-cell lineage subset could be a biomarker in IgG4-related disease (IgG4-RD). Methods: A total of 42 untreated patients with IgG4-RD were evaluated. Peripheral B-cell subsets, including CD19(+) CD24(-) CD38(hi) plasmablasts/plasma cells, CD19(+) CD24(+) CD38(-) memory B cells, CD19(+) CD24(int)CD38(int) naive B cells, and CD19(+) CD24(hi)CD38(hi) regulatory B cells, were assessed and sorted by flow cytometry. Microarray analysis was used to measure gene expression of circulating B-cell lineage subsets. Further characterization of CD19(+) CD24 (-)CD38(hi) plasmablasts/plasma cells was carried out by evaluating additional surface markers, including CD27, CD95, and human leukocyte antigen (HLA)-DR, by flow cytometric assay. In addition, various B-cell lineage subsets were cultured in vitro and IgG4 concentrations were measured by cytometric bead array. Results: In untreated patients with IgG4-RD, the peripheral CD19(+) CD24(-)CD38(hi) plasmablast/plasma cell subset was increased and positively correlated with serum IgG4 levels, the number of involved organs, and the IgG4-related Disease Responder Index. It decreased after treatment with glucocorticoids. Characterization of the plasmablast/ plasma cell population by gene expression profiling documented a typical plasmablast/plasma cell signature with higher expression of X-box binding protein 1 and IFN regulatory factor 4, but lower expression of paired box gene 5 and B-cell lymphoma 6 protein. In addition, CD27, CD95, and HLA-DR were highly expressed on CD19(+) CD24(-)CD38(hi) plasmablasts/plasma cells from patients with IgG4-RD. Furthermore, CD19(+) CD24(-)CD38(hi) plasmablasts/ plasma cells secreted more IgG4 than other B-cell populations. Conclusions: Circulating CD19(+) CD24(-)CD38(hi) plasmablasts/plasma cells are elevated in active IgG4-RD and decreased after glucocorticoid treatment. This IgG4-secreting plasmablast/plasma cell population might be a potentially useful biomarker for diagnosis and assessing response to treatment. C1 [Lin, Wei; Zhang, Panpan; Chen, Hua; Chen, Yu; Yang, Hongxian; Zheng, Wenjie; Zhang, Xuan; Zhang, Wen] Chinese Acad Med Sci, Key Lab Rheumatol & Clin Immunol, Peking Union Med Coll Hosp, Dept Rheumatol,Minist Educ, Beijing 100730, Peoples R China. [Lin, Wei; Zhang, Fengxiao] Hebei Gen Hosp, Dept Rheumatol, Shijiazhuang, Peoples R China. [Lipsky, Peter E.] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Zhang, W (reprint author), Chinese Acad Med Sci, Key Lab Rheumatol & Clin Immunol, Peking Union Med Coll Hosp, Dept Rheumatol,Minist Educ, Beijing 100730, Peoples R China.; Lipsky, PE (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM zhangwen91@sina.com; peterlipsky@comcast.net OI zhang, xuan/0000-0001-8775-1699 FU National Natural Science Foundation of China [81373190, 81571587] FX This work was supported by grants from the National Natural Science Foundation of China (grant numbers 81373190, 81571587). NR 39 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-6354 EI 1478-6362 J9 ARTHRITIS RES THER JI Arthritis Res. Ther. PD FEB 10 PY 2017 VL 19 AR 25 DI 10.1186/s13075-017-1231-2 PG 14 WC Rheumatology SC Rheumatology GA EN8UC UT WOS:000396274300002 PM 28183334 ER PT J AU Erikson, JM Valente, AJ Mummidi, S Kandikattu, HK DeMarco, VG Bender, SB Fay, WP Siebenlist, U Chandrasekar, B AF Erikson, John M. Valente, Anthony J. Mummidi, Srinivas Kandikattu, Hemanth Kumar DeMarco, Vincent G. Bender, Shawn B. Fay, William P. Siebenlist, Ulrich Chandrasekar, Bysani TI Targeting TRAF3IP2 by Genetic and Interventional Approaches Inhibits Ischemia/Reperfusion- induced Myocardial Injury and Adverse Remodeling SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ISCHEMIA-REPERFUSION INJURY; NF-KAPPA-B; IMPROVES CARDIAC-FUNCTION; ACTIVATED PROTEIN-KINASE; MICROBUBBLE DESTRUCTION; NITRIC-OXIDE; IN-VIVO; ENDOTHELIAL DYSFUNCTION; CARDIOMYOCYTE APOPTOSIS; ALBUMIN MICROBUBBLES AB Re-establishing blood supply is the primary goal for reducing myocardial injury in subjects with ischemic heart disease. Paradoxically, reperfusion results in nitroxidative stress and a marked inflammatory response in the heart. TRAF3IP2 (TRAF3 Interacting Protein 2; previously known as CIKS or Act1) is an oxidative stress-responsive cytoplasmic adapter molecule that is an upstream regulator of both I kappa B kinase (IKK) and c-Jun N-terminal kinase (JNK), and an important mediator of autoimmune and inflammatory responses. Here we investigated the role of TRAF3IP2 in ischemia/reperfusion (I/R)-induced nitroxidative stress, inflammation, myocardial dysfunction, injury, and adverse remodeling. Our data show that I/R up-regulates TRAF3IP2 expression in the heart, and its gene deletion, in a conditional cardiomyocyte-specific manner, significantly attenuates I/R-induced nitroxidative stress, IKK/NF-kappa B and JNK/AP-1 activation, inflammatory cytokine, chemokine, and adhesion molecule expression, immune cell infiltration, myocardial injury, and contractile dysfunction. Furthermore, Traf3ip2 gene deletion blunts adverse remodeling 12 weeks post-I/R, as evidenced by reduced hypertrophy, fibrosis, and contractile dysfunction. Supporting the genetic approach, an interventional approach using ultrasound-targeted microbubble destruction-mediated delivery of phosphorothioated TRAF3IP2 antisense oligonucleotides into the LV in a clinically relevant time frame significantly inhibits TRAF3IP2 expression and myocardial injury in wild type mice post-I/R. Furthermore, ameliorating myocardial damage by targeting TRAF3IP2 appears to be more effective to inhibiting its downstream signaling intermediates NF-kappa B and JNK. Therefore, TRAF3IP2 could be a potential therapeutic target in ischemic heart disease. C1 [Erikson, John M.; Valente, Anthony J.; Mummidi, Srinivas] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Kandikattu, Hemanth Kumar; DeMarco, Vincent G.; Fay, William P.; Chandrasekar, Bysani] Univ Missouri, Dept Med, Sch Med, Columbia, MO 65211 USA. [Kandikattu, Hemanth Kumar; DeMarco, Vincent G.; Fay, William P.; Chandrasekar, Bysani] Harry S Truman Mem Vet Hosp, Res Serv, Columbia, MO 65201 USA. [DeMarco, Vincent G.; Bender, Shawn B.; Fay, William P.; Chandrasekar, Bysani] Univ Missouri, Sch Med, Dept Med Pharmacol & Physiol, Columbia, MO 65211 USA. [Bender, Shawn B.; Siebenlist, Ulrich] Univ Missouri, Sch Med, Dept Biomed Sci, Columbia, MO 65211 USA. [Bender, Shawn B.; Chandrasekar, Bysani] Dalton Cardiovasc Res Ctr, Columbia, MO 65201 USA. [Siebenlist, Ulrich] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Chandrasekar, B (reprint author), Univ Missouri, Sch Med, Med Cardiol, 1 Hosp Dr, Columbia, MO 65212 USA. EM chandrasekarb@health.missouri.edu FU United States Department of Veterans Affairs, Office of Research and Development-Biomedical Laboratory Research and Development [I01-BX002255] FX The work was supported in part by United States Department of Veterans Affairs, Office of Research and Development-Biomedical Laboratory Research and Development (ORD-BLRD) Service Award I01-BX002255. The authors declare that they have no conflicts of interest with the contents of this article. The contents of this report do not represent the views of the Department of Veterans Affairs or the United States government. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 61 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 10 PY 2017 VL 292 IS 6 BP 2345 EP 2358 DI 10.1074/jbc.M116.764522 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EM7ZG UT WOS:000395530300025 PM 28053087 ER PT J AU Zhai, XH Gao, YG Mishra, SK Simanshu, DK Boldyrev, IA Benson, LM Bergen, HR Malinina, L Mundy, J Molotkovsky, JG Patel, DJ Brown, RE AF Zhai, Xiuhong Gao, Yong-Guang Mishra, Shrawan K. Simanshu, Dhirendra K. Boldyrev, Ivan A. Benson, Linda M. Bergen, H. Robert, III Malinina, Lucy Mundy, John Molotkovsky, Julian G. Patel, Dinshaw J. Brown, Rhoderick E. TI Phosphatidylserine Stimulates Ceramide 1-Phosphate (C1P) Intermembrane Transfer by C1P Transfer Proteins SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GLYCOLIPID TRANSFER PROTEIN; OXYSTEROL-BINDING PROTEINS; PROGRAMMED CELL-DEATH; AMPHITROPIC PROTEINS; MEMBRANE INTERACTION; GLYCOSPHINGOLIPID SYNTHESIS; TRANSBILAYER DISTRIBUTION; TRYPTOPHAN FLUORESCENCE; PHOSPHOLIPID-BINDING; MEDIATED TRANSFER AB Genetic models for studying localized cell suicide that halt the spread of pathogen infection and immune response activation in plants include Arabidopsis accelerated-cell-death 11 mutant (acd11). In this mutant, sphingolipid homeostasis is disrupted via depletion of ACD11, a lipid transfer protein that is specific for ceramide 1-phosphate (C1P) and phyto-C1P. The C1P binding site in ACD11 and in human ceramide-1-phosphate transfer protein (CPTP) is surrounded by cationic residues. Here, we investigated the functional regulation of ACD11 and CPTP by anionic phosphoglycerides and found that 1-palmitoyl-2-oleoyl-phosphatidic acid or 1-palmitoyl-2-oleoyl-phosphatidylglycerol (<= 15 mol %) in C1P source vesicles depressed C1P intermembrane transfer. Bycontrast, replacement with 1-palmitoyl-2-oleoyl-phosphatidylserine stimulated C1P transfer by ACD11 and CPTP. Notably, "soluble" phosphatidylserine (dihexanoyl-phosphatidylserine) failed to stimulate C1P transfer. Also, none of the anionic phosphoglycerides affected transfer action by human glycolipid lipid transfer protein (GLTP), which is glycolipid-specific and has few cationic residues near its glycolipid binding site. These findings provide the first evidence for a potential phosphoglyceride headgroup-specific regulatory interaction site(s) existing on the surface of any GLTP-fold and delineate new differences between GLTP superfamily members that are specific for C1P versus glycolipid. C1 [Zhai, Xiuhong; Gao, Yong-Guang; Mishra, Shrawan K.; Malinina, Lucy; Brown, Rhoderick E.] Univ Minnesota, Hormel Inst, 801 16th Ave NE, Austin, MN 55912 USA. [Simanshu, Dhirendra K.; Patel, Dinshaw J.] Mem Sloan Kettering Canc Ctr, Struct Biol Program, New York, NY 10065 USA. [Boldyrev, Ivan A.; Molotkovsky, Julian G.] Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, Moscow 117997, Russia. [Benson, Linda M.; Bergen, H. Robert, III] Mayo Fdn, Med Genom Facil, Prote Core, Rochester, MN 55905 USA. [Mundy, John] Univ Copenhagen, BioCtr, Dept Biol, DK-2200 Copenhagen N, Denmark. [Simanshu, Dhirendra K.] NCI Frederick, Frederick Natl Lab Canc Res, NIH, 8560 Progress Dr,C1012, Frederick, MD 21702 USA. RP Zhai, XH; Brown, RE (reprint author), Univ Minnesota, Hormel Inst, 801 16th Ave NE, Austin, MN 55912 USA. EM zhai@hi.umn.edu; reb@umn.edu FU NIGMS, National Institutes of Health (NIH) [GM45928]; NHLBI, NIH [HL125353, NCI CA121493]; Russian Foundation for Basic Research [015-04-07415]; Danish Strategic Research Council [09-067148]; Abby Rockefeller Mauze Trust; Maloris and Hormel Foundations FX This work was supported in whole or part by NIGMS, National Institutes of Health (NIH), Grant GM45928 and NHLBI, NIH, Grants HL125353 and NCI CA121493; Russian Foundation for Basic Research Grant 015-04-07415; Danish Strategic Research Council Grant 09-067148; the Abby Rockefeller Mauze Trust; and the Maloris and Hormel Foundations. Portions of this work were presented at the 2015 American Chemical Society and 2015 American Society for Biochemistry and Molecular Biology Annual Meetings. 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 73 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 10 PY 2017 VL 292 IS 6 BP 2531 EP 2541 DI 10.1074/jbc.M116.760256 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EM7ZG UT WOS:000395530300039 PM 28011644 ER PT J AU Carroll, YI Eichwald, J Scinicariello, F Hoffman, HJ Deitchman, S Radke, MS Themann, CL Breysse, P AF Carroll, Yulia I. Eichwald, John Scinicariello, Franco Hoffman, Howard J. Deitchman, Scott Radke, Marilyn S. Themann, Christa L. Breysse, Patrick TI Vital Signs: Noise-Induced Hearing Loss Among Adults - United States 2011-2012 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article ID HEALTH AB Introduction: The 2016 National Academies of Sciences report "Hearing Health Care for Adults: Priorities for Improving Access and Affordability" included a call to action for government agencies to strengthen efforts to collect, analyze, and disseminate population-based data on hearing loss in adults. Methods: CDC analyzed the most recent available data collected both by questionnaire and audiometric tests of adult participants aged 20-69 years in the 2011-2012 National Health. and Nutrition Examination Survey (NHANES) to determine the presence of audiometric notches indicative of noise-induced hearing loss. Prevalence of both unilateral and,bilateral audiometric notches and their association with sociodemographics and self-reported exposure to loud noise were calculated. Results: Nearly one in four adults (24%) had audiometric notches, suggesting a high prevalence of noise-induced hearing loss. The prevalence of notches was higher among males. Almost one in four U.S. adults who reported excellent or good hearing had audiometric notches (5.5% bilateral and 18.0% unilateral). Among participants who reported exposure to loud noise at work, almost one third had a notch. Conclusions and Implications for Public Health Practice: Noise-induced hearing loss is a significant, often unrecognized health problem among U.S. adults. Discussions between patients and personal health care providers about hearing loss symptoms, tests, and ways to protect hearing might help with early diagnosis of hearing loss and provide opportunities to prevent harmful noise expoSures. Avoiding prolonged exposure to loud environments and using personal hearing protection devices can prevent noise-induced hearing loss. C1 [Carroll, Yulia I.; Eichwald, John] CDC, Off Sci, Natl Ctr Environm Hlth, Atlanta, GA 30333 USA. [Scinicariello, Franco] Agcy Toxic Subst & Dis Registry, Div Toxicol & Human Hlth Serv, Atlanta, GA USA. [Hoffman, Howard J.] NIDCD, NIH, Bethesda, MD USA. [Deitchman, Scott; Breysse, Patrick] CDC, Off Director, Natl Ctr Environm Hlth, Atlanta, GA 30333 USA. [Radke, Marilyn S.] CDC, Div Emergency & Environm Hlth Serv, Natl Ctr Environm Hlth, Atlanta, GA 30333 USA. [Themann, Christa L.] CDC, NIOSH, Atlanta, GA 30333 USA. RP Carroll, YI (reprint author), CDC, Off Sci, Natl Ctr Environm Hlth, Atlanta, GA 30333 USA. EM YCarroll@cdc.gov NR 16 TC 0 Z9 0 U1 1 U2 1 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 0149-2195 EI 1545-861X J9 MMWR-MORBID MORTAL W JI MMWR-Morb. Mortal. Wkly. Rep. PD FEB 10 PY 2017 VL 66 IS 5 BP 139 EP 144 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EL1US UT WOS:000394407400005 PM 28182600 ER PT J AU Koonin, EV AF Koonin, Eugene V. TI Evolution of RNA- and DNA-guided antivirus defense systems in prokaryotes and eukaryotes: common ancestry vs convergence SO BIOLOGY DIRECT LA English DT Review ID CRISPR-CAS SYSTEMS; ADAPTIVE IMMUNITY; ARGONAUTE PROTEINS; CRYSTAL-STRUCTURE; STRUCTURAL INSIGHTS; BACTERIAL ARGONAUTE; GENOME EVOLUTION; NONCODING RNA; CENTRAL DOGMA; FOREIGN DNA AB Complementarity between nucleic acid molecules is central to biological information transfer processes. Apart from the basal processes of replication, transcription and translation, complementarity is also employed by multiple defense and regulatory systems. All cellular life forms possess defense systems against viruses and mobile genetic elements, and in most of them some of the defense mechanisms involve small guide RNAs or DNAs that recognize parasite genomes and trigger their inactivation. The nucleic acid-guided defense systems include prokaryotic Argonaute (pAgo)-centered innate immunity and CRISPR-Cas adaptive immunity as well as diverse branches of RNA interference (RNAi) in eukaryotes. The archaeal pAgo machinery is the direct ancestor of eukaryotic RNAi that, however, acquired additional components, such as Dicer, and enormously diversified through multiple duplications. In contrast, eukaryotes lack any heritage of the CRISPR-Cas systems, conceivably, due to the cellular toxicity of some Cas proteins that would get activated as a result of operon disruption in eukaryotes. The adaptive immunity function in eukaryotes is taken over partly by the PIWI RNA branch of RNAi and partly by protein-based immunity. In this review, I briefly discuss the interplay between homology and analogy in the evolution of RNA-and DNA-guided immunity, and attempt to formulate some general evolutionary principles for this ancient class of defense systems. C1 [Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov FU US Department of Health and Human Services FX The author's research is supported by intramural funds of the US Department of Health and Human Services (to the National Library of Medicine). NR 137 TC 0 Z9 0 U1 6 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD FEB 10 PY 2017 VL 12 AR 5 DI 10.1186/s13062-017-0177-2 PG 14 WC Biology SC Life Sciences & Biomedicine - Other Topics GA EM8YB UT WOS:000395595900001 PM 28187792 ER PT J AU Xu, C Yang, XY Fu, X Tian, R Jacobson, O Wang, ZT Lu, N Liu, YJ Fan, WP Zhang, FW Niu, G Hu, S Ali, IU Chen, XY AF Xu, Can Yang, Xiangyu Fu, Xiao Tian, Rui Jacobson, Orit Wang, Zhantong Lu, Nan Liu, Yijing Fan, Wenpei Zhang, Fuwu Niu, Gang Hu, Shuo Ali, Iqbal Unnisa Chen, Xiaoyuan TI Converting Red Blood Cells to Efficient Microreactors for Blood Detoxification SO ADVANCED MATERIALS LA English DT Article ID ATOMIC-FORCE MICROSCOPY; URIC-ACID; MOUSE ERYTHROCYTES; HYPOTONIC HEMOLYSIS; DRUG-DELIVERY; DEGRADATION; PEROXIDASE; CARRIERS; ENZYME; MICROPARTICLES AB A simple method to convert red blood cells (RBCs) into efficient microreactors is reported. Triton X-100 is employed at finely tuned concentrations to render RBCs highly permeable to substrates, while low concentrations of glutaraldehyde are used to stabilize cells. The ability for blood detoxification of these micro-reactors is demonstrated. C1 [Xu, Can; Hu, Shuo] Cent S Univ, Xiangya Hosp, Dept PET Ctr, Changsha 410008, Hunan, Peoples R China. [Xu, Can; Yang, Xiangyu; Fu, Xiao; Tian, Rui; Jacobson, Orit; Wang, Zhantong; Lu, Nan; Liu, Yijing; Fan, Wenpei; Zhang, Fuwu; Niu, Gang; Ali, Iqbal Unnisa; Chen, Xiaoyuan] NIBIB, LOMIN, NIH, Bethesda, MD 20892 USA. RP Hu, S (reprint author), Cent S Univ, Xiangya Hosp, Dept PET Ctr, Changsha 410008, Hunan, Peoples R China.; Ali, IU; Chen, XY (reprint author), NIBIB, LOMIN, NIH, Bethesda, MD 20892 USA. EM iqbal.ali@nih.gov; shawn.chen@nih.gov FU National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health; National Science Foundation of China [NSFC 81471689] FX This research was supported in part by the Intramural Research Program, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, and the National Science Foundation of China (NSFC 81471689). All experiments with live animals were conducted in accordance with a protocol approved by the National Institutes of Health Clinical Center Animal Care and Use Committee (NIH CC/ACUC). NR 59 TC 0 Z9 0 U1 7 U2 7 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 0935-9648 EI 1521-4095 J9 ADV MATER JI Adv. Mater. PD FEB 10 PY 2017 VL 29 IS 6 AR UNSP 1603673 DI 10.1002/adma.201603673 PG 12 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA EN6WB UT WOS:000396143000009 ER PT J AU Zhou, WC Marinelli, F Nief, C Faraldo-Gomez, JD AF Zhou, Wenchang Marinelli, Fabrizio Nief, Corrine Faraldo-Gomez, Jose D. TI Atomistic simulations indicate the c-subunit ring of the F1Fo ATP synthase is not the mitochondrial permeability transition pore SO ELIFE LA English DT Article ID HIGH-RESOLUTION STRUCTURE; ROTOR RING; ILYOBACTER-TARTARICUS; FORCE-FIELD; MECHANISM; OPTIMIZATION; DYNAMICS; CHANNEL; BINDING AB Pathological metabolic conditions such as ischemia induce the rupture of the mitochondrial envelope and the release of pro-apoptotic proteins, leading to cell death. At the onset of this process, the inner mitochondrial membrane becomes depolarized and permeable to osmolytes, proposedly due to the opening of a non-selective protein channel of unknown molecular identity. A recent study purports that this channel, referred to as Mitochondrial Permeability Transition Pore (MPTP), is formed within the c-subunit ring of the ATP synthase, upon its dissociation from the catalytic domain of the enzyme. Here, we examine this claim for two c-rings of different lumen width, through calculations of their ion conductance and selectivity based on all-atom molecular dynamics simulations. We also quantify the likelihood that the lumen of these c-rings is in a hydrated, potentially conducting state rather than empty or blocked by lipid molecules. These calculations demonstrate that the structure and biophysical properties of a correctly assembled c-ring are inconsistent with those attributed to the MPTP. C1 [Zhou, Wenchang; Marinelli, Fabrizio; Nief, Corrine; Faraldo-Gomez, Jose D.] NHLBI, Theoret Mol Biophys Sect, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Marinelli, F; Faraldo-Gomez, JD (reprint author), NHLBI, Theoret Mol Biophys Sect, NIH, Bldg 10, Bethesda, MD 20892 USA. EM marinelli@nih.gov; jose.faraldo@nih.gov FU National Heart, Lung, and Blood Institute FX National Heart, Lung, and Blood Institute Wenchang Zhou Fabrizio Marinelli Jose D Faraldo-Gomez.; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 39 TC 0 Z9 0 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 FEB 10 PY 2017 VL 6 AR e23781 DI 10.7554/eLife.23781 PG 11 WC Biology SC Life Sciences & Biomedicine - Other Topics GA EM3WA UT WOS:000395244100001 ER PT J AU Weldon, CB Madenci, AL Boikos, SA Janeway, KA George, S von Mehren, M Pappo, AS Schiffman, JD Wright, J Trent, JC Pacak, K Stratakis, CA Helman, LJ La Quaglia, MP AF Weldon, Christopher B. Madenci, Arin L. Boikos, Sosipatros A. Janeway, Katherine A. George, Suzanne von Mehren, Margaret Pappo, Alberto S. Schiffman, Joshua D. Wright, Jennifer Trent, Jonathan C. Pacak, Karel Stratakis, Constantine A. Helman, Lee J. La Quaglia, Michael P. TI Surgical Management of Wild-Type Gastrointestinal Stromal Tumors: A Report From the National Institutes of Health Pediatric and Wildtype GIST Clinic SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID KINASE INHIBITOR THERAPY; TERM-FOLLOW-UP; PROGNOSTIC-FACTORS; THE-LITERATURE; YOUNG-ADULTS; MUTATIONS; RECURRENCE; RESECTION; KIT; DIAGNOSIS AB Purpose Wild-type gastrointestinal stromal tumors (WT-GISTs) that lack KIT or PDGFRA mutations represent a unique subtype of GIST that predominantly affects children. We sought to determine the effect on event-free survival (EFS) of staging variables, extent of resection, and repeat resection of tumors. Methods In 2008, a WT-GIST clinic was established at the National Cancer Institute, allowing the development of a large clinical database. We included participants who underwent resection of WT-GIST. Associations with EFS (ie, freedom from disease progression or recurrence) were evaluated using the Kaplan-Meier method and Cox proportional hazards modeling. Results Among 76 participants with WT-GISTs, the median follow-up was 4.1 years. Overall EFS (6 SE) was 72.6 +/- 5.4% at 1 year, 57.6 +/- 6.2% at 2 years, 23.7 +/- 6.0% at 5 years, and 16.3 +/- 6 5.5% at 10 years postoperatively. Hazard of disease progression or recurrence was significantly increased for patients with metastatic disease (adjusted hazard ratio [AHR], 2.3; 95% CI, 1.0 to 5.1; P 5.04) and. 5 mitoses per 50 high-power fields (AHR, 2.5; 95% CI, 1.1 to 6.0; P = .03), whereas there was no significant effect of negative microscopic resection margins (AHR, 0.9; 95% CI, 0.4 to 2.2; P = 0.86). There was no association between type of gastric resection (ie, anatomic v partial/wedge) and EFS (P = .67). Repeated resection after the initial resection was significantly associated with decreasing postoperative EFS (P < .01). Five patients (6%) died after initial enrollment in 2008. Conclusion WT-GIST is an indolent disease, and most patients survive with disease progression. We found no improvement in EFS with more extensive or serial resections. Disease progression or recurrence may be more closely related to tumor biology than surgical management. These data suggest that resections for WT-GISTs be restricted to the initial procedure and that subsequent resections be performed only to address symptoms such as obstruction or bleeding. (C) 2016 by American Society of Clinical Oncology C1 [Weldon, Christopher B.; Madenci, Arin L.] Boston Childrens Hosp, Boston, MA USA. [Weldon, Christopher B.; Madenci, Arin L.; Janeway, Katherine A.; George, Suzanne] Harvard Med Sch, Boston, MA USA. [Weldon, Christopher B.; Janeway, Katherine A.; George, Suzanne] Dana Farber Boston Childrens Canc & Blood Disorde, Boston, MA USA. [Madenci, Arin L.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Boikos, Sosipatros A.] Virginia Commonwealth Univ, Massey Canc Ctr, Richmond, VA USA. [von Mehren, Margaret] Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Pappo, Alberto S.] St Jude Childrens Res Hosp, 332 N Lauderdale St, Memphis, TN 38105 USA. [Schiffman, Joshua D.; Wright, Jennifer] Huntsman Canc Inst, Salt Lake City, UT USA. [Trent, Jonathan C.] Sylvester Comprehens Canc Ctr, Miami, FL USA. [Pacak, Karel; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Helman, Lee J.] NCI, Bethesda, MD 20892 USA. [La Quaglia, Michael P.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [La Quaglia, Michael P.] Weill Cornell Med Coll, New York, NY USA. RP Weldon, CB (reprint author), Dept Surg, 300 Longwood Ave,Fegan 3, Boston, MA 02115 USA. EM christopher.weldon@childrens.harvard.edu FU ArQule; Janssen; Morphotek FX ArQule; ArQule; Janssen, Morphotek NR 28 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 FEB 10 PY 2017 VL 35 IS 5 BP 523 EP + DI 10.1200/JCO.2016.68.6733 PG 8 WC Oncology SC Oncology GA EL2KB UT WOS:000394447400001 ER PT J AU Bradley, CJ Yabroff, KR Mariotto, AB Zeruto, C Tran, Q Warren, JL AF Bradley, Cathy J. Yabroff, K. Robin Mariotto, Angela B. Zeruto, Christopher Tran, Quyen Warren, Joan L. TI Antineoplastic Treatment of Advanced-Stage Non-Small-Cell Lung Cancer: Treatment, Survival, and Spending (2000 to 2011) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PHASE-III TRIAL; CHEMOTHERAPY USE; THERAPY; BEVACIZUMAB; ERLOTINIB; MEDICARE; COST; ONCOLOGY; UTILITY; CARE AB Purpose Multiple agents for advanced non-small-cell lung cancer (NSCLC) have been approved in the past decade, but little is known about their use and associated spending and survival. Methods We used SEER-Medicare data for elderly patients with a new diagnosis of advanced-stage NSCLC and were treated with antineoplastic agents between 2000 and 2011 (N = 22,163). We estimated the adjusted percentage of patients who received each agent, days while on treatment, survival, and spending in the 12 months after diagnosis. Results During the 12-year study period, a marked shift in treatment occurred along with a rapid adoption of pemetrexed (39.2%), erlotinib (20.3%), and bevacizumab (18.9%) and a decline in paclitaxel (38.7%), gemcitabine (17.0%), and vinorelbine (5.7%; all P < .05). The average total days on therapy increased by 5 days (from 103 to 108 days). Patients who received bevacizumab, erlotinib, or pemetrexed had the longest treatment durations on average (approximately 146 days v 75 days for those who did not receive these agents). Approximately 44% of patients received antineoplastic agents in the last 30 days of life throughout the study period. Acute inpatient spending declined (from $29,376 to $23,731), whereas outpatient spending increased 23% (from $37,931 to $46,642). Median survival gains of 1.5 months were observed. Conclusion Considerable shifts in the treatment of advanced-stage NSCLC occurred along with modest gains in survival and total Medicare spending. More precise outcome information is needed to inform value-based treatment decisions for advanced-stage NSCLC. (C) 2017 by American Society of Clinical Oncology C1 [Bradley, Cathy J.] Univ Colorado, Aurora, CO USA. [Yabroff, K. Robin] US Dept HHS, Washington, DC 20201 USA. [Mariotto, Angela B.; Tran, Quyen; Warren, Joan L.] NCI, Bethesda, MD 20892 USA. [Zeruto, Christopher] Informat Management Serv Inc, Beltsville, MD USA. RP Bradley, CJ (reprint author), Univ Colorado, Ctr Canc, Dept Hlth Syst Management & Policy, 13001 E 17th Pl,B119,Bldg 500,Room N6203L, Aurora, CO 80045 USA. EM cathy.bradley@ucdenver.edu NR 24 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 FEB 10 PY 2017 VL 35 IS 5 BP 529 EP + DI 10.1200/JCO.2016.69.4166 PG 8 WC Oncology SC Oncology GA EL2KB UT WOS:000394447400002 ER PT J AU Shea, AA Bernhards, RC Cote, CK Chase, CJ Koehler, JW Klimko, CP Ladner, JT Rozak, DA Wolcott, MJ Fetterer, DP Kern, SJ Koroleva, GI Lovett, SP Palacios, GF Toothman, RG Bozue, JA Worsham, PL Welkos, SL AF Shea, A. A. Bernhards, R. C. Cote, C. K. Chase, C. J. Koehler, J. W. Klimko, C. P. Ladner, J. T. Rozak, D. A. Wolcott, M. J. Fetterer, D. P. Kern, S. J. Koroleva, G. I. Lovett, S. P. Palacios, G. F. Toothman, R. G. Bozue, J. A. Worsham, P. L. Welkos, S. L. TI Two stable variants of Burkholderia pseudomallei strain MSHR5848 express broadly divergent in vitro phenotypes associated with their virulence differences SO PLOS ONE LA English DT Article ID COLONY MORPHOLOGY VARIATION; ANTIGENIC VARIATION; PSEUDOMONAS-PSEUDOMALLEI; CAPSULAR POLYSACCHARIDE; OXIDATIVE STRESS; ANTIMICROBIAL PEPTIDES; CYSTIC-FIBROSIS; MICROARRAY DATA; D-SERINE; MELIOIDOSIS AB Burkholderia pseudomallei (Bp), the agent of melioidosis, causes disease ranging from acute and rapidly fatal to protracted and chronic. Bp is highly infectious by aerosol, can cause severe disease with nonspecific symptoms, and is naturally resistant to multiple antibiotics. However, no vaccine exists. Unlike many Bp strains, which exhibit random variability in traits such as colony morphology, Bp strain MSHR5848 exhibited two distinct and relatively stable colony morphologies on sheep blood agar plates: a smooth, glossy, pale yellow colony and a flat, rough, white colony. Passage of the two variants, designated "Smooth" and "Rough", under standard laboratory conditions produced cultures composed of > 99.9% of the single corresponding type; however, both could switch to the other type at different frequencies when incubated in certain nutritionally stringent or stressful growth conditions. These MSHR5848 derivatives were extensively characterized to identify variant-associated differences. Microscopic and colony morphology differences on six differential media were observed and only the Rough variant metabolized sugars in selective agar. Antimicrobial susceptibilities and lipopolysaccharide (LPS) features were characterized and phenotype microarray profiles revealed distinct metabolic and susceptibility disparities between the variants. Results using the phenotype microarray system narrowed the 1,920 substrates to a subset which differentiated the two variants. Smooth grew more rapidly in vitro than Rough, yet the latter exhibited a nearly 10-fold lower lethal dose for mice than Smooth. Finally, the Smooth variant was phagocytosed and replicated to a greater extent and was more cytotoxic than Rough in macrophages. In contrast, multiple locus sequence type (MLST) analysis, ribotyping, and whole genome sequence analysis demonstrated the variants' genetic conservation; only a single consistent genetic difference between the two was identified for further study. These distinct differences shown by two variants of a Bp strain will be leveraged to better understand the mechanism of Bp phenotypic variability and to possibly identify in vitro markers of infection. C1 [Shea, A. A.; Chase, C. J.; Koehler, J. W.; Rozak, D. A.; Wolcott, M. J.] USAMRIID, Diagnost Syst Div, Frederick, MD USA. [Bernhards, R. C.; Cote, C. K.; Klimko, C. P.; Toothman, R. G.; Bozue, J. A.; Worsham, P. L.; Welkos, S. L.] USAMRIID, Bacteriol Div, Frederick, MD 21702 USA. [Ladner, J. T.; Koroleva, G. I.; Lovett, S. P.; Palacios, G. F.] USAMRIID, Ctr Genome Sci, Frederick, MD USA. [Fetterer, D. P.; Kern, S. J.] USAMRIID, Biostat Serv Div, Frederick, MD USA. [Bernhards, R. C.] Edgewood Chem Biol Ctr, Aberdeen Proving Ground, MD USA. [Kern, S. J.] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Welkos, SL (reprint author), USAMRIID, Bacteriol Div, Frederick, MD 21702 USA. EM susan.l.welkos.civ@mail.mil OI Palacios, Gustavo/0000-0001-5062-1938 FU Joint Science & Technology Office for Chemical & Biological Defense (JSTO-CBD), Defense Threat Reduction Agency (DTRA) [CB3846PPE-1, CB10246] FX This research was funded by the Joint Science & Technology Office for Chemical & Biological Defense (JSTO-CBD), Defense Threat Reduction Agency (DTRA) - (1) Project CCAR# CB3846PPE-1 Burkholderia (PatriciaWorsham). (2) Project CB10246: High Speed Sequencing for Rapid Response and Countermeasure Development (GustavoPalacios) http://www.dtra. mil/Research/Chemical-Biological-TechnologyD epartment/. NR 98 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 FEB 10 PY 2017 VL 12 IS 2 AR e0171363 DI 10.1371/journal.pone.0171363 PG 32 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EK9KV UT WOS:000394244300022 ER PT J AU Shi, Y Lai, XR Ye, LY Chen, KQ Cao, Z Gong, WH Jin, LL Wang, CY Liu, MY Liao, Y Wang, JMM Zhou, NM AF Shi, Ying Lai, Xiangru Ye, Lingyan Chen, Keqiang Cao, Zheng Gong, Wanghua Jin, Lili Wang, Chunyan Liu, Mingyong Liao, Yuan Wang, Ji Ming Zhou, Naiming TI Activated niacin receptor HCA2 inhibits chemoattractant-mediated macrophage migration via G beta gamma/PKC/ERK1/2 pathway and heterologous receptor desensitization SO SCIENTIFIC REPORTS LA English DT Article ID NICOTINIC-ACID RECEPTOR; SUPPRESSES COLONIC INFLAMMATION; PUMA-G; PROTEIN-KINASE; MOLECULAR-IDENTIFICATION; CROSS-DESENSITIZATION; CHEMOKINE RECEPTORS; ARTERIAL BIOLOGY; PHOSPHOLIPASE-C; GAMMA-SUBUNITS AB The niacin receptor HCA2 is implicated in controlling inflammatory host responses with yet poorly understood mechanistic basis. We previously reported that HCA2 in A431 epithelial cells transduced G beta gamma-protein kinase C-and G beta gamma-metalloproteinase/EGFR-dependent MAPK/ERK signaling cascades. Here, we investigated the role of HCA2 in macrophage-mediated inflammation and the underlying mechanisms. We found that proinflammatory stimulants LPS, IL-6 and IL-1 beta up-regulated the expression of HCA2 on macrophages. Niacin significantly inhibited macrophage chemotaxis in response to chemoattractants fMLF and CCL2 by disrupting polarized distribution of F-actin and G beta protein. Niacin showed a selected additive effect on chemoattractant-induced activation of ERK1/2, JNK and PI3K pathways, but only the MEK inhibitor UO126 reduced niacin-mediated inhibition of macrophage chemotaxis, while activation of ERK1/2 by EGF alone did not inhibit fMLF-mediated migration of HEK293T cells co-expressing HCA2 and fMLF receptor FPR1. In addition, niacin induced heterologous desensitization and internalization of FPR1. Furthermore, niacin rescued mice from septic shock by diminishing inflammatory symptoms and the effect was abrogated in HCA2(-/-)mice. These results suggest that G beta gamma/PKC-dependent ERK1/2 activation and heterologous desensitization of chemoattractant receptors are involved in the inhibition of chemoattractant-induced migration of macrophages by niacin. Thus, HCA2 plays a critical role in host protection against pro-inflammatory insults. C1 [Shi, Ying; Lai, Xiangru; Ye, Lingyan; Cao, Zheng; Jin, Lili; Liao, Yuan; Zhou, Naiming] Zhejiang Univ, Coll Life Sci, Yu Hang Tang Load 388, Hangzhou, Zhejiang, Peoples R China. [Chen, Keqiang; Gong, Wanghua; Wang, Chunyan; Liu, Mingyong; Wang, Ji Ming] NCI, Canc & Inflammat Program, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Wang, Chunyan] Xuzhou Yes Biotech Labs Ltd, Xuzhou, Jiangsu, Peoples R China. [Liu, Mingyong] Third Mil Med Univ, Daping Hosp, Dept Spine Surg, Chongqing, Peoples R China. RP Zhou, NM (reprint author), Zhejiang Univ, Coll Life Sci, Yu Hang Tang Load 388, Hangzhou, Zhejiang, Peoples R China.; Wang, JMM (reprint author), NCI, Canc & Inflammat Program, Ctr Canc Res, NIH, Frederick, MD 21702 USA. EM wangji@mail.nih.gov; zhounaiming@zju.edu.cn FU Ministry of Science and Technology of China [2012CB910402, 2012AA020303]; National Natural Science Foundation of China [81173106, 31200621]; Zhejiang Provincial Natural Science Foundation of China [LY15C050001]; Siyuan Foundation; National Cancer Institute, National Institutes of Health [HSN261200800001E]; Intramural Research Program of the NCI,NIH FX We thank Dr. Stefan Offermanns of Max-Planck-Institute for Heart and Lung Research, Germany for providing Hca2 KO (C57BL) breeders, and We also thank the staff of Immunohistochemistry Facility of College of Pharmacological Science for preparation of frozen sections. This work was supported by grants from the Ministry of Science and Technology of China (2012CB910402 and 2012AA020303), the National Natural Science Foundation of China (81173106 and 31200621), Zhejiang Provincial Natural Science Foundation of China (LY15C050001) and Siyuan Foundation. This project was also funded in part by federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HSN261200800001E and was supported in part by the Intramural Research Program of the NCI, NIH. NR 71 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD FEB 10 PY 2017 VL 7 AR 42279 DI 10.1038/srep42279 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EK7IM UT WOS:000394099500001 PM 28186140 ER PT J AU Choi, YJ Lin, CP Risso, D Chen, S Kim, TA Tan, MH Li, JB Wu, YL Chen, CF Xuan, ZY Macfarlan, T Peng, WQ Lloyd, KCK Kim, SY Speed, TP He, L AF Choi, Yong Jin Lin, Chao-Po Risso, Davide Chen, Sean Kim, Thomas Aquinas Tan, Meng How Li, Jin Billy Wu, Yalei Chen, Caifu Xuan, Zhenyu Macfarlan, Todd Peng, Weiqun Lloyd, K. C. Kent Kim, Sang Yong Speed, Terence P. He, Lin TI Deficiency of microRNA miR-34a expands cell fate potential in pluripotent stem cells SO SCIENCE LA English DT Article ID STAGE MOUSE BLASTOMERES; GENE-EXPRESSION; MUERV-L; EMBRYOS; DIFFERENTIATION; P53; CONTRIBUTES; APOPTOSIS; ENDODERM; BIOLOGY AB Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) efficiently generate all embryonic cell lineages but rarely generate extraembryonic cell types. We found that microRNA miR-34a deficiency expands the developmental potential of mouse pluripotent stem cells, yielding both embryonic and extraembryonic lineages and strongly inducing MuERV-L (MERVL) endogenous retroviruses, similar to what is seen with features of totipotent two-cell blastomeres. miR-34a restricts the acquisition of expanded cell fate potential in pluripotent stem cells, and it represses MERVL expression through transcriptional regulation, at least in part by targeting the transcription factor Gata2. Our studies reveal a complex molecular network that defines and restricts pluripotent developmental potential in cultured ESCs and iPSCs. C1 [Choi, Yong Jin; Lin, Chao-Po; Chen, Sean; Kim, Thomas Aquinas; He, Lin] Univ Calif Berkeley, Div Cellular & Dev Biol, Dept Mol & Cell Biol, Berkeley, CA 94705 USA. [Risso, Davide] Univ Calif Berkeley, Sch Publ Hlth, Div Biostat, Berkeley, CA 94720 USA. [Tan, Meng How; Li, Jin Billy] Stanford Univ, Dept Genet, Stanford, CA 94305 USA. [Wu, Yalei] Thermo Fisher Sci, 180 Oyster Point Blvd, San Francisco, CA 94080 USA. [Chen, Caifu] Integrated DNA Technol, 200 Chesapeake Dr, Redwood City, CA 94063 USA. [Xuan, Zhenyu] Univ Texas Dallas, Dept Mol & Cell Biol, Richardson, TX 75080 USA. [Macfarlan, Todd] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. [Peng, Weiqun] George Washington Univ, Dept Phys, Washington, DC 20052 USA. [Lloyd, K. C. Kent] Univ Calif Davis, Mouse Biol Program, Davis, CA 95616 USA. [Kim, Sang Yong] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA. [Speed, Terence P.] Univ Calif Berkeley, Dept Stat, Berkeley, CA 94720 USA. [Speed, Terence P.] Univ Melbourne, Dept Math & Stat, Parkville, Vic 3010, Australia. [Speed, Terence P.] Walter & Eliza Hall Inst Med Res, Bioinformat Div, Parkville, Vic 3052, Australia. RP Lin, CP; He, L (reprint author), Univ Calif Berkeley, Div Cellular & Dev Biol, Dept Mol & Cell Biol, Berkeley, CA 94705 USA. EM newcplin@gmail.com; lhe@berkeley.edu OI Lin, Chao-Po/0000-0002-1457-1635; Kim, Sang Yong /0000-0001-7326-7505 FU NIH [S10RR029668, S10RR027303, U01MH105979]; California Institute for Regenerative Medicine (CIRM) [RN2-00923-1]; National Cancer Institute [R01 CA139067]; National Institute of General Medical Sciences [R01GM114414]; Howard Hughes Medical Institute; CIRM predoctoral fellowship; Cancer Research Coordinating Committee (CRCC) predoctoral fellowship; Siebel postdoctoral fellowship; CIRM postdoctoral fellowship; UT Dallas faculty startup fund FX We thank V. Prideaux, W. Wang, R. Huang, K. N. Li, H. Aaron, J.-Y. Lee, W. Xu, J. Ong, P. Cheung, B. Zaghi, M. Chung, J. Choi, A. Li, A. Perez, W. Bao, S. Tindall, K. Zhao, K. Cui, B. Xue, O. Tam, K. Heydari, A. Valeros, M. J. Bennett, C. Cattoglio, D. Young, N. Anchell, J. A. Wood, A. Y.-F. Lee, and H. Noller for technical assistance; L. Xie, V. A. Modzelewski, and R. Song for discussion and input; T. Heidmann, J. Rossant, A. Li, V. Krizhanovsky, M. Stadtfeld, M. C. Lorincz, Y. Shinkai, D. Trono, T. Chen, and R. Jaenisch for sharing valuable reagents; P. Margolis for carefully reading the manuscript; and M. Rape and N. Patel for sharing the use of an Olympus Revolution XD spinning disk confocal microscope and a Zeiss LSM 700 confocal microscope. This work used the Vincent J. Coates Genomics Sequencing Laboratory at UC Berkeley (supported by NIH S10 instrumentation grants S10RR029668 and S10RR027303) and the computing resource provided by the Center for Systems Biology, UT Dallas. Supported by California Institute for Regenerative Medicine (CIRM) new faculty award RN2-00923-1, National Cancer Institute grant R01 CA139067, National Institute of General Medical Sciences grant R01GM114414, and a Howard Hughes Medical Institute faculty scholar award (L. H.); a CIRM predoctoral fellowship and a Cancer Research Coordinating Committee (CRCC) predoctoral fellowship (S. C.); a Siebel postdoctoral fellowship and a CIRM postdoctoral fellowship (C-P. L.); NIH grant U01MH105979 (D. R.); and the UT Dallas faculty startup fund (Z.X.). The RNA sequencing data are publicly available at the NCBI Gene Expression Omnibus with accession number GSE69484. The annotation of retrotransposons in GFF format is available as supplementary data. NR 53 TC 1 Z9 1 U1 12 U2 12 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD FEB 10 PY 2017 VL 355 IS 6325 BP 596 EP + DI 10.1126/science.aag1927 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EK0SF UT WOS:000393636700040 ER PT J AU Solanki, S Dube, PR Birnbaumer, L Vazquez, G AF Solanki, Sumeet Dube, Prabhatchandra R. Birnbaumer, Lutz Vazquez, Guillermo TI Reduced Necrosis and Content of Apoptotic M1 Macrophages in Advanced Atherosclerotic Plaques of Mice With Macrophage-Specific Loss of Trpc3 SO SCIENTIFIC REPORTS LA English DT Article ID FOAM CELL-FORMATION; CARDIOVASCULAR-DISEASE; KNOCKOUT MOUSE; MURINE MODELS; CHANNELS; LESIONS; RUPTURE; ROLES; EFFEROCYTOSIS; EXPRESSION AB In previous work we reported that ApoeKO mice transplanted with bone marrow cells deficient in the Transient Receptor Potential Canonical 3 (TRPC3) channel have reduced necrosis and number of apoptotic macrophages in advanced atherosclerotic plaques. Also, in vitro studies with polarized macrophages derived from mice with macrophage-specific loss of TRPC3 showed that M1, but not M2 macrophages, deficient in Trpc3 are less susceptible to ER stress-induced apoptosis than Trpc3 expressing cells. The questions remained (a) whether the plaque phenotype in transplanted mice resulted from a genuine effect of Trpc3 on macrophages, and (b) whether the reduced necrosis and macrophage apoptosis in plaques of these mice was a manifestation of the selective effect of TRPC3 on apoptosis of M1 macrophages previously observed in vitro. Here, we addressed these questions using Ldlr knockout (Ldlr(-/-)) mice with macrophage-specific loss of Trpc3 (MacTrpc3(-/-)/Ldlr(-/-)-> Ldlr(-/-)). Compared to controls, we observed decreased plaque necrosis and number of apoptotic macrophages in MacTrpc3(-/-)/Ldlr(-/-)-> Ldlr(-/-) mice. Immunohistochemical analysis revealed a reduction in apoptotic M1, but not apoptotic M2 macrophages. These findings confirm an effect of TRPC3 on plaque necrosis and support the notion that this is likely a reflection of the reduced susceptibility of Trpc3-deficient M1 macrophages to apoptosis. C1 [Solanki, Sumeet; Dube, Prabhatchandra R.; Vazquez, Guillermo] Univ Toledo, Coll Med & Life Sci, Dept Physiol & Pharmacol, Hlth Sci Campus,3000 Transverse Dr, Toledo, OH 43614 USA. [Solanki, Sumeet; Dube, Prabhatchandra R.; Vazquez, Guillermo] Univ Toledo, Coll Med & Life Sci, Ctr Hypertens & Personalized Med, Hlth Sci Campus,3000 Transverse Dr, Toledo, OH 43614 USA. [Birnbaumer, Lutz] NIEHS, Neurobiol Lab, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. [Birnbaumer, Lutz] Fac Med Sci, BIOMED UCA CONICET, Inst Biomed Res, Av Alicia Moreau de Justo 1600,C1107AFF, Buenos Aires, Aires, Argentina. RP Vazquez, G (reprint author), Univ Toledo, Coll Med & Life Sci, Dept Physiol & Pharmacol, Hlth Sci Campus,3000 Transverse Dr, Toledo, OH 43614 USA.; Vazquez, G (reprint author), Univ Toledo, Coll Med & Life Sci, Ctr Hypertens & Personalized Med, Hlth Sci Campus,3000 Transverse Dr, Toledo, OH 43614 USA. EM Guillermo.Vazquez@utoledo.edu FU NIH grant [R01HL111877-04]; University of Toledo College of Medicine and Life Sciences; Intramural Research Program of the NIH Project [Z01-ES-101864]; American Heart Association (Great Rivers Affiliate) Pre-doctoral fellowship [15PRE24700002] FX Work was supported by NIH grant R01HL111877-04 (to G.V.), the University of Toledo College of Medicine and Life Sciences (G.V.), the Intramural Research Program of the NIH Project Z01-ES-101864 (to L.B.) and American Heart Association (Great Rivers Affiliate) Pre-doctoral fellowship 15PRE24700002 (to S.S.). NR 47 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 2045-2322 J9 SCI REP-UK JI Sci Rep PD FEB 10 PY 2017 VL 7 AR 42526 DI 10.1038/srep42526 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EK2UY UT WOS:000393783400001 PM 28186192 ER PT J AU Alsuliman, A Muftuoglu, M Khoder, A Ahn, YO Basar, R Verneris, MR Muranski, P Barrett, AJ Liu, E Li, L Stringaris, K Armstrong-James, D Shaim, H Kondo, K Imahashi, N Andersson, B Marin, D Champlin, RE Shpall, EJ Rezvani, K AF Alsuliman, Abdullah Muftuoglu, Muharrem Khoder, Ahmad Ahn, Yong-Oon Basar, Rafet Verneris, Michael R. Muranski, Pawel Barrett, A. John Liu, Enli Li, Li Stringaris, Kate Armstrong-James, Darius Shaim, Hila Kondo, Kayo Imahashi, Nobuhiko Andersson, Borje Marin, David Champlin, Richard E. Shpall, Elizabeth J. Rezvani, Katayoun TI A subset of virus-specific CD161(+) T cells selectively express the multidrug transporter MDR1 and are resistant to chemotherapy in AML SO BLOOD LA English DT Article ID HEMATOPOIETIC STEM-CELLS; P-GLYCOPROTEIN; TH17 CELLS; MYELOID-LEUKEMIA; MEMORY; LYMPHOCYTES; IMMUNITY; NAIVE; BET; DIFFERENTIATION AB The establishment of long-lived pathogen-specific T cells is a fundamental property of the adaptive immune response. However, the mechanisms underlying long-term persistence of antigen-specific CD4(+) T cells are not well-defined. Here we identify a subset of memory CD4(+) T cells capable of effluxing cellular toxins, including rhodamine (Rho), through the multidrug efflux protein MDR1 (also known as P-glycoprotein and ABCB1). Drug-effluxing CD4(+) T cells were characterized as CD161(+)CD95(+)CD45RA(-)CD127(hi)CD28(+)CD25(int) cells with a distinct chemokine profile and a Th1-polarized pro-inflammatory phenotype. CD4(+) CD161(+) Rho-effluxing T cells proliferated vigorously in response to stimulation with antiCD3/CD28 beads and gave rise to CD161(-) progeny in vitro. These cells were also capable of self-renewal and maintained their phenotypic and functional characteristics when cultured with homeostatic cytokines. Multidrug-effluxing CD4(+) CD161(+) T cells were enriched within the viral-specific Th1 repertoire of healthy donors and patients with acute myeloid leukemia (AML) and survived exposure to daunorubicin chemotherapy in vitro. Multidrug-effluxing CD4(+) CD161(+) T cells also resisted chemotherapy-induced cytotoxicity in vivo and underwent significant expansion in AML patients rendered lymphopenic after chemotherapy, contributing to the repopulation of anti-CMV immunity. Finally, after influenza vaccination, the proportion of influenza-specific CD4(+) T cells coexpressing CD161 was significantly higher after 2 years compared with 4 weeks after immunization, suggesting CD161 is a marker for long-lived antigen-specific memory T cells. These findings suggest that CD4(+) CD161 1 T cells with rapid efflux capacity contribute to the maintenance of viral-specific memory T cells. These data provide novel insights into mechanisms that preserve antiviral immunity in patients undergoing chemotherapy and have implications for the development of novel immunotherapeutic approaches. C1 [Alsuliman, Abdullah; Muftuoglu, Muharrem; Basar, Rafet; Liu, Enli; Li, Li; Shaim, Hila; Kondo, Kayo; Imahashi, Nobuhiko; Andersson, Borje; Marin, David; Champlin, Richard E.; Shpall, Elizabeth J.; Rezvani, Katayoun] MD Anderson Canc Ctr, Stem Cell Transplantat & Cellular Therapy, Houston, TX USA. [Khoder, Ahmad; Stringaris, Kate] Imperial Coll London, Dept Hematol, London, England. [Ahn, Yong-Oon; Verneris, Michael R.] Univ Minnesota, Dept Pediat, Div Hematol Oncol, Minneapolis, MN USA. [Muranski, Pawel; Barrett, A. John] Natl Inst Hlth, Natl Heart Lung & Blood Inst, Hematol Branch, Bethesda, MD USA. [Armstrong-James, Darius] Imperial Coll London, Natl Heart & Lung Inst, Fac Med, London, England. RP Rezvani, K (reprint author), MD Anderson Canc Ctr, Stem Cell Transplantat & Cellular Therapy, Houston, TX USA. EM krezvani@mdanderson.org FU National Institutes of Health, National Cancer Institute grants [P01 CA148600-02, RO1 CA061508-18]; National Institutes of Health through M. D. Anderson's Cancer Center Support Grant [CA016672] FX This work was funded in part by National Institutes of Health, National Cancer Institute grants P01 CA148600-02 and RO1 CA061508-18. The flow studies were performed in the Flow Cytometry & Cellular Imaging Facility, which is supported in part by the National Institutes of Health through M. D. Anderson's Cancer Center Support Grant CA016672. NR 36 TC 1 Z9 1 U1 1 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD FEB 9 PY 2017 VL 129 IS 6 BP 740 EP 758 DI 10.1182/blood-2016-05-713347 PG 19 WC Hematology SC Hematology GA EO9OD UT WOS:000397017100013 PM 27821506 ER PT J AU Tubbs, A Nussenzweig, A AF Tubbs, Anthony Nussenzweig, Andre TI Endogenous DNA Damage as a Source of Genomic Instability in Cancer SO CELL LA English DT Review ID DOUBLE-STRAND BREAKS; REGIONAL MUTATION-RATES; SOMATIC MUTATIONS; PROSTATE-CANCER; CHROMOSOMAL REARRANGEMENTS; TRANSCRIPTION STRESS; SEQUENCING REVEALS; SUPER-ENHANCERS; TOPOISOMERASE 1; STEM-CELLS AB Genome instability, defined as higher than normal rates of mutation, is a double-edged sword. As a source of genetic diversity and natural selection, mutations are beneficial for evolution. On the other hand, genomic instability can have catastrophic consequences for age-related diseases such as cancer. Mutations arise either from inactivation of DNA repair pathways or in a repair-competent background due to genotoxic stress from celluar processes such as transcription and replication that overwhelm high-fidelity DNA repair. Here, we review recent studies that shed light on endogenous sources of mutation and epigenomic features that promote genomic instability during cancer evolution. C1 [Tubbs, Anthony; Nussenzweig, Andre] NIH, Lab Genome Integr, Bldg 10, Bethesda, MD 20892 USA. RP Nussenzweig, A (reprint author), NIH, Lab Genome Integr, Bldg 10, Bethesda, MD 20892 USA. EM andre_nussenzweig@nih.gov FU NIH; National Cancer Institute; Center for Cancer Research; US Department of Defense [BC133858, BC151331]; Ellison Foundation; Alex's Lemonade Stand Foundation; American Cancer Society [PF-16-037-01-DMC] FX We are especially grateful to Joshua Waterfall, Ferenc Livak, Avinash Bhandoola, and Sam John for comments on the manuscript and to Jiri Lukas, Keith Caldecott, and Yossi Shiloh for discussions. This work was supported by the Intramural Research Program of the NIH, the National Cancer Institute, and the Center for Cancer Research. A.N. was also supported by the US Department of Defense (BCRP DOD Idea Expansion Award BC133858 and BCRP Breakthrough Award BC151331), the Ellison Foundation Award for Aging Research, and Alex's Lemonade Stand Foundation Reach Award. A.T. has been supported by a fellowship from the American Cancer Society (PF-16-037-01-DMC). NR 92 TC 0 Z9 0 U1 8 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD FEB 9 PY 2017 VL 168 IS 4 DI 10.1016/j.cell.2017.01.002 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EN8VJ UT WOS:000396277600015 PM 28187286 ER PT J AU Haft, DR Haft, DH AF Haft, David Renfrew Haft, Daniel H. TI A comprehensive software suite for protein family construction and functional site prediction SO PLOS ONE LA English DT Article ID COMPARATIVE GENOMICS; MICROBIOLOGY; ANNOTATION AB In functionally diverse protein families, conservation in short signature regions may outperform full-length sequence comparisons for identifying proteins that belong to a subgroup within which one specific aspect of their function is conserved. The SIMBAL workflow (Sites Inferred by Metabolic Background Assertion Labeling) is a data-mining procedure for finding such signature regions. It begins by using clues from genomic context, such as co-occurrence or conserved gene neighborhoods, to build a useful training set from a large number of uncharacterized but mutually homologous proteins. When training set construction is successful, the YES partition is enriched in proteins that share function with the user's query sequence, while the NO partition is depleted. A selected query sequence is then mined for short signature regions whose closest matches overwhelmingly favor proteins from the YES partition. High-scoring signature regions typically contain key residues critical to functional specificity, so proteins with the highest sequence similarity across these regions tend to share the same function. The SIMBAL algorithm was described previously, but significant manual effort, expertise, and a supporting software infrastructure were required to prepare the requisite training sets. Here, we describe a new, distributable software suite that speeds up and simplifies the process for using SIMBAL, most notably by providing tools that automate training set construction. These tools have broad utility for comparative genomics, allowing for flexible collection of proteins or protein domains based on genomic context as well as homology, a capability that can greatly assist in protein family construction. Armed with this new software suite, SIMBAL can serve as a fast and powerful in silico alternative to direct experimentation for characterizing proteins and their functional interactions. C1 [Haft, David Renfrew] J Craig Venter Inst, Rockville, MD USA. [Haft, Daniel H.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Haft, DH (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM daniel.haft@nih.gov FU National Science Foundationunder [1458808] FX This work was supported by the National Science Foundationunder Grant No.1458808 to the J.Craig Venter Institute and by the Intramural Research Program of the NIH, National Library of Medicine. The funders had no role in study design data collection and analysis, decision to publish, or preparation of the manuscript. NR 22 TC 0 Z9 0 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 FEB 9 PY 2017 VL 12 IS 2 AR e0171758 DI 10.1371/journal.pone.0171758 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EK9GJ UT WOS:000394231800102 PM 28182651 ER PT J AU Kugelman, JR Wiley, MR Nagle, ER Reyes, D Pfeffer, BP Kuhn, JH Sanchez-Lockhart, M Palacios, GF AF Kugelman, Jeffrey R. Wiley, Michael R. Nagle, Elyse R. Reyes, Daniel Pfeffer, Brad P. Kuhn, Jens H. Sanchez-Lockhart, Mariano Palacios, Gustavo F. TI Error baseline rates of five sample preparation methods used to characterize RNA virus populations SO PLOS ONE LA English DT Article ID LIBRARY PREPARATION; SEQUENCING DATA; QUALITY-CONTROL; EBOLA-VIRUS; GENOMES; REPLICATION; VARIANTS; COLI AB Individual RNA viruses typically occur as populations of genomes that differ slightly from each other due to mutations introduced by the error-prone viral polymerase. Understanding the variability of RNA virus genome populations is critical for understanding virus evolution because individual mutant genomes may gain evolutionary selective advantages and give rise to dominant sub populations, possibly even leading to the emergence of viruses resistant to medical countermeasures. Reverse transcription of virus genome populations followed by next-generation sequencing is the only available method to characterize variation for RNA viruses. However, both steps may lead to the introduction of artificial mutations, thereby skewing the data. To better understand how such errors are introduced during sample preparation, we determined and compared error baseline rates of five different sample preparation methods by analyzing in vitro transcribed Ebola virus RNA from an artificial plasmid-based system. These methods included: shotgun sequencing from plasmid DNA or in vitro transcribed RNA as a basic "no amplification" method, amplicon sequencing from the plasmid DNA or in vitro transcribed RNA as a "targeted" amplification method, sequenceindependent single-primer amplification (SISPA) as a "random" amplification method, rolling circle reverse transcription sequencing (CirSeq) as an advanced "no amplification" method, and Illumina TruSeq RNA Access as a "targeted" enrichment method. The measured error frequencies indicate that RNA Access offers the best tradeoff between sensitivity and sample preparation error (1.4(-5)) of all compared methods. C1 [Kugelman, Jeffrey R.; Wiley, Michael R.; Nagle, Elyse R.; Reyes, Daniel; Pfeffer, Brad P.; Sanchez-Lockhart, Mariano; Palacios, Gustavo F.] US Army, Med Res Inst Infect Dis, Ctr Genome Sci, Frederick, MD 21702 USA. [Kuhn, Jens H.] NIAID, Integrated Res Facil Ft Detrick IRF Frederick, NIH, Frederick, MD USA. RP Palacios, GF (reprint author), US Army, Med Res Inst Infect Dis, Ctr Genome Sci, Frederick, MD 21702 USA. EM gustavo.f.palacios.ctr@mail.mil OI Palacios, Gustavo/0000-0001-5062-1938 FU Defense Threat Reduction Agency; Battelle Memorial Institute's prime; US National Institute of Allergy and Infectious Diseases (NIAID) [HHSN272200700016I]; Tunnell Government Services, Inc. FX This work was supported by Defense Threat Reduction Agency and 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. NR 34 TC 0 Z9 0 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 FEB 9 PY 2017 VL 12 IS 2 AR e0171333 DI 10.1371/journal.pone.0171333 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EK9GJ UT WOS:000394231800055 PM 28182717 ER PT J AU Taye, M Kim, J Yoon, SH Lee, W Hanotte, O Dessie, T Kemp, S Mwai, OA Caetano-Anolles, K Cho, S Oh, SJ Lee, HK Kim, H AF Taye, Mengistie Kim, Jaemin Yoon, Sook Hee Lee, Wonseok Hanotte, Olivier Dessie, Tadelle Kemp, Stephen Mwai, Okeyo Ally Caetano-Anolles, Kelsey Cho, Seoae Oh, Sung Jong Lee, Hak-Kyo Kim, Heebal TI Whole genome scan reveals the genetic signature of African Ankole cattle breed and potential for higher quality beef SO BMC GENETICS LA English DT Article DE African cattle; Ankole cattle; Meat quality; Sanga cattle; XP-CLR; XP-EHH ID RESIDUAL FEED-INTAKE; DIFFERENTIALLY EXPRESSED GENES; INTRAMUSCULAR FAT-CONTENT; PORCINE SKELETAL-MUSCLE; LARGE WHITE-PIGS; MEAT QUALITY; CANDIDATE GENES; FUNCTIONAL-ANALYSIS; POSITIVE SELECTION; WIDE ASSOCIATION AB Background: Africa is home to numerous cattle breeds whose diversity has been shaped by subtle combinations of human and natural selection. African Sanga cattle are an intermediate type of cattle resulting from interbreeding between Bos taurus and Bos indicus subspecies. Recently, research has asserted the potential of Sanga breeds for commercial beef production with better meat quality as compared to Bos indicus breeds. Here, we identified meat quality related gene regions that are positively selected in Ankole (Sanga) cattle breeds as compared to indicus (Boran, Ogaden, and Kenana) breeds using cross-population (XP-EHH and XP-CLR) statistical methods. Results: We identified 238 (XP-EHH) and 213 (XP-CLR) positively selected genes, of which 97 were detected from both statistics. Among the genes obtained, we primarily reported those involved in different biological process and pathways associated with meat quality traits. Genes (CAPZB, COL9A2, PDGFRA, MAP3K5, ZNF410, and PKM2) involved in muscle structure and metabolism affect meat tenderness. Genes (PLA2G2A, PARK2, ZNF410, MAP2K3, PLCD3, PLCD1, and ROCK1) related to intramuscular fat (IMF) are involved in adipose metabolism and adipogenesis. MB and SLC48A1 affect meat color. In addition, we identified genes (TIMP2, PKM2, PRKG1, MAP3K5, and ATP8A1) related to feeding efficiency. Among the enriched Gene Ontology Biological Process (GO BP) terms, actin cytoskeleton organization, actin filament-based process, and protein ubiquitination are associated with meat tenderness whereas cellular component organization, negative regulation of actin filament depolymerization and negative regulation of protein complex disassembly are involved in adipocyte regulation. The MAPK pathway is responsible for cell proliferation and plays an important role in hyperplastic growth, which has a positive effect on meat tenderness. Conclusion: Results revealed several candidate genes positively selected in Ankole cattle in relation to meat quality characteristics. The genes identified are involved in muscle structure and metabolism, and adipose metabolism and adipogenesis. These genes help in the understanding of the biological mechanisms controlling beef quality characteristics in African Ankole cattle. These results provide a basis for further research on the genomic characteristics of Ankole and other Sanga cattle breeds for quality beef. C1 [Taye, Mengistie; Yoon, Sook Hee; Lee, Wonseok; Kim, Heebal] Seoul Natl Univ, Dept Agr Biotechnol, Anim Biotechnol & Res Inst Agr & Life Sci, Seoul 151921, South Korea. [Taye, Mengistie] Bahir Dar Univ, Coll Agr & Environm Sci, POB 79, Bahir Dar, Ethiopia. [Kim, Jaemin] NHGRI, NIH, 50 South Dr,Bldg 50,Room 5351, Bethesda, MD 20892 USA. [Hanotte, Olivier] Univ Nottingham, Sch Life Sci, Nottingham NG7 2RD, England. [Hanotte, Olivier; Dessie, Tadelle] ILRI, POB 5689, Addis Ababa, Ethiopia. [Kemp, Stephen; Mwai, Okeyo Ally] ILRI, POB 30709-00100, Nairobi, Kenya. [Kemp, Stephen] Univ Edinburgh, Roslin Inst, Ctr Trop Livestock Genet & Hlth, Easter Bush Campus, Roslin EH25 9RG, Midlothian, Scotland. [Caetano-Anolles, Kelsey] Univ Illinois, Dept Anim Sci, Urbana, IL 61801 USA. [Cho, Seoae; Kim, Heebal] C&K Genom, Main Bldg 514,SNU Res Pk, Seoul 151919, South Korea. [Oh, Sung Jong] RDA, Natl Inst Anim Sci, Wonju, South Korea. [Lee, Hak-Kyo] Chonbuk Natl Univ, Dept Anim Biotechnol, Anim Mol Genet & Breeding Ctr, Jeonju 561756, South Korea. [Kim, Heebal] Shinshu Univ, Inst Biomed Sci, Nagano, Japan. RP Kim, H (reprint author), Seoul Natl Univ, Dept Agr Biotechnol, Anim Biotechnol & Res Inst Agr & Life Sci, Seoul 151921, South Korea.; Kim, H (reprint author), C&K Genom, Main Bldg 514,SNU Res Pk, Seoul 151919, South Korea. EM heebal@snu.ac.kr FU Next-Generation BioGreen 21 Program, Rural Development Administration (RDA), Republic of Korea [PJ01134905] FX This work was supported by a grant from the Next-Generation BioGreen 21 Program (Project No. PJ01134905), Rural Development Administration (RDA), Republic of Korea. NR 96 TC 0 Z9 0 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2156 J9 BMC GENET JI BMC Genet. PD FEB 9 PY 2017 VL 18 AR 11 DI 10.1186/s12863-016-0467-1 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA EK7UW UT WOS:000394131700001 PM 28183280 ER PT J AU Carmona-Rivera, C Purmalek, MM Moore, E Waldman, M Walter, PJ Garraffo, HM Phillips, KA Preston, KL Graf, J Kaplan, MJ Grayson, PC AF Carmona-Rivera, Carmelo Purmalek, Monica M. Moore, Erica Waldman, Meryl Walter, Peter J. Garraffo, H. Martin Phillips, Karran A. Preston, Kenzie L. Graf, Jonathan Kaplan, Mariana J. Grayson, Peter C. TI A role for muscarinic receptors in neutrophil extracellular trap formation and levamisole-induced autoimmunity SO JCI INSIGHT LA English DT Article ID ACETYLCHOLINE-RECEPTORS; NETTING NEUTROPHILS; RHEUMATIC-DISEASES; VAGUS NERVE; MICE; COCAINE; CONTRACTION; ANTIBODIES; VASCULITIS; AORTA AB Levamisole, an anthelmintic drug with cholinergic properties, has been implicated in cases of drug-induced vasculitis when added to cocaine for profit purposes. Neutrophil extracellular trap (NET) formation is a cell death mechanism characterized by extrusion of chromatin decorated with granule proteins. Aberrant NET formation and degradation have been implicated in idiopathic autoimmune diseases that share features with levamisole-induced autoimmunity as well as in drug-induced autoimmunity. This study's objective was to determine how levamisole modulates neutrophil biology and its putative effects on the vasculature. Murine and human neutrophils exposed to levamisole demonstrated enhanced NET formation through engagement of muscarinic subtype 3 receptor. Levamisole-induced NETosis required activation of Akt and the RAF/MEK/ERK pathway, ROS induction through the nicotinamide adenine dinucleotide phosphate oxidase, and peptidylarginine deiminase activation. Sera from two cohorts of patients actively using levamisole-adulterated cocaine displayed autoantibodies against NET components. Cutaneous biopsy material obtained from individuals exposed to levamisole suggests that neutrophils produce NETs in areas of vasculitic inflammation and thrombosis. NETs generated by levamisole were toxic to endothelial cells and impaired endothelium-dependent vasorelaxation. Stimulation of muscarinic receptors on neutrophils by cholinergic agonists may contribute to the pathophysiology observed in drug-induced autoimmunity through the induction of inflammatory responses and neutrophil-induced vascular damage. C1 [Carmona-Rivera, Carmelo; Purmalek, Monica M.; Moore, Erica; Kaplan, Mariana J.; Grayson, Peter C.] Natl Inst Arthrit & Musculoskeletal & Skin Dis NI, Syst Autoimmun Branch, Bethesda, MD USA. [Waldman, Meryl; Walter, Peter J.; Garraffo, H. Martin] NIDDK, NIH, Bethesda, MD USA. [Phillips, Karran A.; Preston, Kenzie L.] NIDA, NIH, Baltimore, MD USA. [Graf, Jonathan] UCSF, Div Rheumatol, San Francisco, CA USA. RP Kaplan, MJ (reprint author), NIAMSD, Syst Autoimmun Branch, NIH, 10 Ctr Dr,6D-47C, Bethesda, MD 20892 USA. EM mariana.kaplan@nih.gov FU Intramural Research Program at the NIAMS [NIH ZIA AR041199] FX This research was supported by the Intramural Research Program at the NIAMS (NIH ZIA AR041199). Cl-amidine was provided by Paul Thompson and Venkataraman Subramaniam. Ann Biehl performed calculations to determine physiologic concentrations of levamisole. We also thank Jorge Irizarry-Caro for technical support. NR 58 TC 0 Z9 0 U1 3 U2 3 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD FEB 9 PY 2017 VL 2 IS 3 AR e89780 DI 10.1172/jci.insight.89780 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EK1TN UT WOS:000393708800008 PM 28194438 ER PT J AU Iyer, MR Cinar, R Katz, A Gao, M Erdelyi, K Jourdan, T Coffey, NJ Pacher, P Kunos, G AF Iyer, Malliga R. Cinar, Resat Katz, Alexis Gao, Michael Erdelyi, Katalin Jourdan, Tony Coffey, Nathan J. Pacher, Pal Kunos, George TI Design, Synthesis, and Biological Evaluation of Novel, Non-Brain-Penetrant, Hybrid Cannabinoid CB1R Inverse Agonist/Inducible Nitric Oxide Synthase (iNOS) Inhibitors for the Treatment of Liver Fibrosis SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID RECEPTOR ANTAGONISTS; DRUG DISCOVERY; RIMONABANT; OBESITY; FUTURE; POTENT; DERIVATIVES; RESISTANCE; BLOCKERS; SYSTEM AB We report the design, synthesis, and structure-activity relationships of novel dual-target compounds with antagonist/inverse agonist activity at cannabinoid receptor type 1 (CB1R) and inhibitory effect on inducible nitric oxide synthase (iNOS). A series of 3,4-diarylpyrazolinecarboximidamides were synthesized and evaluated in CB1 receptor (CB1R) binding assays and iNOS activity assays. The novel compounds, designed to have limited brain penetrance, elicited potent in vitro CB1R antagonist activities and iNOS inhibitory activities. Some key compounds displayed high CB1R binding affinities. Compound 7 demonstrated potent in vivo pharmacological activities such as reduction of food intake mediated by the antagonism of the CB(1)Rs and antifibrotic effect in the animal models of fibrosis mediated by iNOS inhibition and CB1R antagonism. C1 [Iyer, Malliga R.; Cinar, Resat; Katz, Alexis; Gao, Michael; Jourdan, Tony; Coffey, Nathan J.; Kunos, George] NIAAA, Lab Physiol Studies, NIH, 5625 Fishers Lane, Rockville, MD 20852 USA. [Erdelyi, Katalin; Pacher, Pal] NIAAA, Lab Cardiovasc Physiol & Tissue Injury, NIH, 5625 Fishers Lane, Rockville, MD 20852 USA. RP Iyer, MR; Kunos, G (reprint author), NIAAA, Lab Physiol Studies, NIH, 5625 Fishers Lane, Rockville, MD 20852 USA. EM Malliga.Iyer@nih.gov; George.Kunos@nih.gov OI CINAR, RESAT/0000-0002-8597-7253 FU National Institute on Alcohol Abuse and Alcoholism (NIAAA) FX This work was supported by intramural funds from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) to M.R.I, RC, P.P., and G.K. Resources from National Institute on Drug Abuse (NIDA) is gratefully acknowledged. Helpful advice and suggestions from Dr. Kenner C. Rice are acknowledged. John Lloyd, Noel Whittaker, and Bill Leister are acknowledged for supplying MS data and providing help with LC/MS data. NR 38 TC 0 Z9 0 U1 3 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD FEB 9 PY 2017 VL 60 IS 3 BP 1126 EP 1141 DI 10.1021/acs.jmedchem.6b01504 PG 16 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA EK4WM UT WOS:000393928300018 PM 28085283 ER PT J AU Marouli, E Graff, M Medina-Gomez, C Lo, KS Wood, AR Kjaer, TR Fine, RS Lu, YC Schurmann, C Highland, HM Rueger, S Thorleifsson, G Justice, AE Lamparter, D Stirrups, KE Turcot, V Young, KL Winkler, TW Esko, T Karaderi, T Locke, AE Masca, NGD Ng, MCY Mudgal, P Rivas, MA Vedantam, S Mahajan, A Guo, XQ Abecasis, G Aben, KK Adair, LS Alam, DS Albrecht, E Allin, KH Allison, M Amouyel, P Appel, EV Arveiler, D Asselbergs, FW Auer, PL Balkau, B Banas, B Bang, LE Benn, M Bergmann, S Bielak, LF Bluher, M Boeing, H Boerwinkle, E Boger, CA Bonnycastle, LL Bork-Jensen, J Bots, ML Bottinger, EP Bowden, DW Brandslund, I Breen, G Brilliant, MH Broer, L Burt, AA Butterworth, AS Carey, DJ Caulfield, MJ Chambers, JC Chasman, DI Chen, YDI Chowdhury, R Christensen, C Chu, AY Cocca, M Collins, FS Cook, JP Corley, J Galbany, JC Cox, AJ Cuellar-Partida, G Danesh, J Davies, G de Bakker, PIW de Borst, GJ de Denus, S de Groot, MCH de Mutsert, R Deary, IJ Dedoussis, G Demerath, EW den Hollander, AI Dennis, JG Di Angelantonio, E Drenos, F Du, MM Dunning, AM Easton, DF Ebeling, T Edwards, TL Ellinor, PT Elliott, P Evangelou, E Farmaki, AE Faul, JD Feitosa, MF Feng, S Ferrannini, E Ferrario, MM Ferrieres, J Florez, JC Ford, I Fornage, M Franks, PW Frikke-Schmidt, R Galesloot, TE Gan, W Gandin, I Gasparini, P Giedraitis, V Giri, A Girotto, G Gordon, SD Gordon-Larsen, P Gorski, M Grarup, N Grove, ML Gudnason, V Gustafsson, S Hansen, T Harris, KM Harris, TB Hattersley, AT Hayward, C He, L Heid, IM Heikkila, K Helgeland, O Hernesniemi, J Hewitt, AW Hocking, LJ Hollensted, M Holmen, OL Hovingh, GK Howson, JMM Hoyng, CB Huang, PL Hveem, K Ikram, MA Ingelsson, E Jackson, AU Jansson, JH Jarvik, GP Jensen, GB Jhun, MA Jia, YC Jiang, XJ Johansson, S Jorgensen, ME Jorgensen, T Jousilahti, P Jukema, JW Kahali, B Kahn, RS Kahonen, M Kamstrup, PR Kanoni, S Kaprio, J Karaleftheri, M Kardia, SLR Karpe, F Kee, F Keeman, R Kiemeney, LA Kitajima, H Kluivers, KB Kocher, T Komulainen, P Kontto, J Kooner, JS Kooperberg, C Kovacs, P Kriebel, J Kuivaniemi, H Kury, S Kuusisto, J La Bianca, M Laakso, M Lakka, TA Lange, EM Lange, LA Langefeld, CD Langenberg, C Larson, EB Lee, IT Lehtimaki, T Lewis, CE Li, HX Li, J Li-Gao, R Lin, HH Lin, LA Lin, X Lind, L Lindstrom, J Linneberg, A Liu, YH Liu, YM Lophatananon, A Luan, J Lubitz, SA Lyytikainen, LP Mackey, DA Madden, PAF Manning, AK Mannisto, S Marenne, G Marten, J Martin, NG Mazul, AL Meidtner, K Metspalu, A Mitchell, P Mohlke, KL Mook-Kanamori, DO Morgan, A Morris, AD Morris, AP Muller-Nurasyid, M Munroe, PB Nalls, MA Nauck, M Nelson, CP Nelson, CP Neville, M Nielsen, SF Nikus, K Njolstad, PR Nordestgaard, BG Ntalla, I O'Connel, JR Oksa, H Loohuis, LMO Ophoff, RA Owen, KR Packard, CJ Padmanabhan, S Palmer, CNA Pasterkamp, G Patel, AP Pattie, A Pedersen, O Peissig, PL Peloso, GM Pennell, CE Perola, M Perry, JA Perry, JRB Person, TN Pirie, A Polasek, O Posthuma, D Raitakari, OT Rasheed, A Rauramaa, R Reilly, DF Reiner, AP Renstrom, F Ridker, PM Rioux, JD Robertson, N Robino, A Rolandsson, O Rudan, I Ruth, KS Saleheen, D Salomaa, V Samani, NJ Sandow, K Sapkota, Y Sattar, N Schmidt, MK Schreiner, PJ Schulze, MB Scott, RA Segura-Lepe, MP Shah, S Sim, XL Sivapalaratnam, S Small, KS Smith, AV Smith, JA Southam, L Spector, TD Speliotes, EK Starr, JM Steinthorsdottir, V Stringham, HM Stumvoll, M Surendran, P 't Hart, LM Tansey, KE Tardif, JC Taylor, KD Teumer, A Thompson, DJ Thorsteinsdottir, U Thuesen, BH Tonjes, A Tromp, G Trompet, S Tsafantakis, E Tuomilehto, J Tybjaerg-Hansen, A Tyrer, JP Uher, R Uitterlinden, AG Ulivi, S van der Laan, SW Van Der Leij, AR van Duijn, CM van Schoor, NM van Setten, J Varbo, A Varga, TV Varma, R Edwards, DRV Vermeulen, SH Vestergaard, H Vitart, V Vogt, TF Vozzi, D Walker, M Wang, FJ Wang, CA Wang, S Wang, YQ Wareham, NJ Warren, HR Wessel, J Willems, SM Wilson, JG Witte, DR Woods, MO Wu, Y Yaghootkar, H Yao, J Yao, P Yerges-Armstrong, LM Young, R Zeggini, E Zhan, XW Zhang, WH Zhao, JH Zhao, W Zhao, W Zheng, H Zhou, W Rotter, JI Boehnke, M Kathiresan, S McCarthy, MI Willer, CJ Stefansson, K Borecki, IB Liu, DJ North, KE Heard-Costa, NL Pers, TH Lindgren, CM Oxvig, C Kutalik, Z Rivadeneira, F Loos, RJF Frayling, TM Hirschhorn, JN Deloukas, P Lettre, G AF Marouli, Eirini Graff, Mariaelisa Medina-Gomez, Carolina Lo, Ken Sin Wood, Andrew R. Kjaer, Troels R. Fine, Rebecca S. Lu, Yingchang Schurmann, Claudia Highland, Heather M. Rueger, Sina Thorleifsson, Gudmar Justice, Anne E. Lamparter, David Stirrups, Kathleen E. Turcot, Valerie Young, Kristin L. Winkler, Thomas W. Esko, Tonu Karaderi, Tugce Locke, Adam E. Masca, Nicholas G. D. Ng, Maggie C. Y. Mudgal, Poorva Rivas, Manuel A. Vedantam, Sailaja Mahajan, Anubha Guo, Xiuqing Abecasis, Goncalo Aben, Katja K. Adair, Linda S. Alam, Dewan S. Albrecht, Eva Allin, Kristine H. Allison, Matthew Amouyel, Philippe Appel, Emil V. Arveiler, Dominique Asselbergs, Folkert W. Auer, Paul L. Balkau, Beverley Banas, Bernhard Bang, Lia E. Benn, Marianne Bergmann, Sven Bielak, Lawrence F. Blueher, Matthias Boeing, Heiner Boerwinkle, Eric Boeger, Carsten A. Bonnycastle, Lori L. Bork-Jensen, Jette Bots, Michiel L. Bottinger, Erwin P. Bowden, Donald W. Brandslund, Ivan Breen, Gerome Brilliant, Murray H. Broer, Linda Burt, Amber A. Butterworth, Adam S. Carey, David J. Caulfield, Mark J. Chambers, John C. Chasman, Daniel I. Chen, Yii-Der Ida Chowdhury, Rajiv Christensen, Cramer Chu, Audrey Y. Cocca, Massimiliano Collins, Francis S. Cook, James P. Corley, Janie Galbany, Jordi Corominas Cox, Amanda J. Cuellar-Partida, Gabriel Danesh, John Davies, Gail de Bakker, Paul I. W. de Borst, Gert J. de Denus, Simon de Groot, Mark C. H. de Mutsert, Renee Deary, Ian J. Dedoussis, George Demerath, Ellen W. den Hollander, Anneke I. Dennis, Joe G. Di Angelantonio, Emanuele Drenos, Fotios Du, Mengmeng Dunning, Alison M. Easton, Douglas F. Ebeling, Tapani Edwards, Todd L. Ellinor, Patrick T. Elliott, Paul Evangelou, Evangelos Farmaki, Aliki-Eleni Faul, Jessica D. Feitosa, Mary F. Feng, Shuang Ferrannini, Ele Ferrario, Marco M. Ferrieres, Jean Florez, Jose C. Ford, Ian Fornage, Myriam Franks, Paul W. Frikke-Schmidt, Ruth Galesloot, Tessel E. Gan, Wei Gandin, Ilaria Gasparini, Paolo Giedraitis, Vilmantas Giri, Ayush Girotto, Giorgia Gordon, Scott D. Gordon-Larsen, Penny Gorski, Mathias Grarup, Niels Grove, Megan L. Gudnason, Vilmundur Gustafsson, Stefan Hansen, Torben Harris, Kathleen Mullan Harris, Tamara B. Hattersley, Andrew T. Hayward, Caroline He, Liang Heid, Iris M. Heikkila, Kauko Helgeland, Oyvind Hernesniemi, Jussi Hewitt, Alex W. Hocking, Lynne J. Hollensted, Mette Holmen, Oddgeir L. Hovingh, G. Kees Howson, Joanna M. M. Hoyng, Carel B. Huang, Paul L. Hveem, Kristian Ikram, M. Arfan Ingelsson, Erik Jackson, Anne U. Jansson, Jan-Hakan Jarvik, Gail P. Jensen, Gorm B. Jhun, Min A. Jia, Yucheng Jiang, Xuejuan Johansson, Stefan Jorgensen, Marit E. Jorgensen, Torben Jousilahti, Pekka Jukema, J. Wouter Kahali, Bratati Kahn, Rene S. Kahonen, Mika Kamstrup, Pia R. Kanoni, Stavroula Kaprio, Jaakko Karaleftheri, Maria Kardia, Sharon L. R. Karpe, Fredrik Kee, Frank Keeman, Renske Kiemeney, Lambertus A. Kitajima, Hidetoshi Kluivers, Kirsten B. Kocher, Thomas Komulainen, Pirjo Kontto, Jukka Kooner, Jaspal S. Kooperberg, Charles Kovacs, Peter Kriebel, Jennifer Kuivaniemi, Helena Kury, Sebastien Kuusisto, Johanna La Bianca, Martina Laakso, Markku Lakka, Timo A. Lange, Ethan M. Lange, Leslie A. Langefeld, Carl D. Langenberg, Claudia Larson, Eric B. Lee, I-Te Lehtimaki, Terho Lewis, Cora E. Li, Huaixing Li, Jin Li-Gao, Ruifang Lin, Honghuang Lin, Li-An Lin, Xu Lind, Lars Lindstrom, Jaana Linneberg, Allan Liu, Yeheng Liu, Yongmei Lophatananon, Artitaya Luan, Jian'an Lubitz, Steven A. Lyytikainen, Leo-Pekka Mackey, David A. Madden, Pamela A. F. Manning, Alisa K. Mannisto, Satu Marenne, Gaelle Marten, Jonathan Martin, Nicholas G. Mazul, Angela L. Meidtner, Karina Metspalu, Andres Mitchell, Paul Mohlke, Karen L. Mook-Kanamori, Dennis O. Morgan, Anna Morris, Andrew D. Morris, Andrew P. Mueller-Nurasyid, Martina Munroe, Patricia B. Nalls, Mike A. Nauck, Matthias Nelson, Christopher P. Nelson, Christopher P. Neville, Matt Nielsen, Sune F. Nikus, Kjell Njolstad, Pal R. Nordestgaard, Borge G. Ntalla, Ioanna O'Connel, Jeffrey R. Oksa, Heikki Loohuis, Loes M. Olde Ophoff, Roel A. Owen, Katharine R. Packard, Chris J. Padmanabhan, Sandosh Palmer, Colin N. A. Pasterkamp, Gerard Patel, Aniruddh P. Pattie, Alison Pedersen, Oluf Peissig, Peggy L. Peloso, Gina M. Pennell, Craig E. Perola, Markus Perry, James A. Perry, John R. B. Person, Thomas N. Pirie, Ailith Polasek, Ozren Posthuma, Danielle Raitakari, Olli T. Rasheed, Asif Rauramaa, Rainer Reilly, Dermot F. Reiner, Alex P. Renstrom, Frida Ridker, Paul M. Rioux, John D. Robertson, Neil Robino, Antonietta Rolandsson, Olov Rudan, Igor Ruth, Katherine S. Saleheen, Danish Salomaa, Veikko Samani, Nilesh J. Sandow, Kevin Sapkota, Yadav Sattar, Naveed Schmidt, Marjanka K. Schreiner, Pamela J. Schulze, Matthias B. Scott, Robert A. Segura-Lepe, Marcelo P. Shah, Svati Sim, Xueling Sivapalaratnam, Suthesh Small, Kerrin S. Smith, Albert Vernon Smith, Jennifer A. Southam, Lorraine Spector, Timothy D. Speliotes, Elizabeth K. Starr, John M. Steinthorsdottir, Valgerdur Stringham, Heather M. Stumvoll, Michael Surendran, Praveen 't Hart, Leen M. Tansey, Katherine E. Tardif, Jean-Claude Taylor, Kent D. Teumer, Alexander Thompson, Deborah J. Thorsteinsdottir, Unnur Thuesen, Betina H. Toenjes, Anke Tromp, Gerard Trompet, Stella Tsafantakis, Emmanouil Tuomilehto, Jaakko Tybjaerg-Hansen, Anne Tyrer, Jonathan P. Uher, Rudolf Uitterlinden, Andre G. Ulivi, Sheila van der Laan, Sander W. Van Der Leij, Andries R. van Duijn, Cornelia M. van Schoor, Natasja M. van Setten, Jessica Varbo, Anette Varga, Tibor V. Varma, Rohit Edwards, Digna R. Velez Vermeulen, Sita H. Vestergaard, Henrik Vitart, Veronique Vogt, Thomas F. Vozzi, Diego Walker, Mark Wang, Feijie Wang, Carol A. Wang, Shuai Wang, Yiqin Wareham, Nicholas J. Warren, Helen R. Wessel, Jennifer Willems, Sara M. Wilson, James G. Witte, Daniel R. Woods, Michael O. Wu, Ying Yaghootkar, Hanieh Yao, Jie Yao, Pang Yerges-Armstrong, Laura M. Young, Robin Zeggini, Eleftheria Zhan, Xiaowei Zhang, Weihua Zhao, Jing Hua Zhao, Wei Zhao, Wei Zheng, He Zhou, Wei Rotter, Jerome I. Boehnke, Michael Kathiresan, Sekar McCarthy, Mark I. Willer, Cristen J. Stefansson, Kari Borecki, Ingrid B. Liu, Dajiang J. North, Kari E. Heard-Costa, Nancy L. Pers, Tune H. Lindgren, Cecilia M. Oxvig, Claus Kutalik, Zoltan Rivadeneira, Fernando Loos, Ruth J. F. Frayling, Timothy M. Hirschhorn, Joel N. Deloukas, Panos Lettre, Guillaume CA EPIC-InterAct Consortium EPIC-CVD Consortium CHD Exome Consortium ExomeBP Consortium T2D-Genes Consortium GoT2D Genes Consortium Global Lipids Genetics Consortium ReproGen Consortium MAGIC Investigators TI Rare and low-frequency coding variants alter human adult height SO NATURE LA English DT Article ID GENOME-WIDE ASSOCIATION; MISSING HERITABILITY; GENETIC ARCHITECTURE; INTERLEUKIN-11; MUTATIONS; MICE AB Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways. 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[Butterworth, Adam S.; Chowdhury, Rajiv; Danesh, John; Di Angelantonio, Emanuele; Howson, Joanna M. M.; Surendran, Praveen; Young, Robin] Univ Cambridge, Dept Publ Hlth & Primary Care, MRC BHF Cardiovasc Epidemiol Unit, Cambridge CB1 8RN, England. [Butterworth, Adam S.; Danesh, John; Di Angelantonio, Emanuele] Univ Cambridge, NIHR Blood & Transplant Res Unit Donor Hlth Genom, Cambridge CB1 8RN, England. [Carey, David J.; Kuivaniemi, Helena; Tromp, Gerard] Sigfried & Janet Weis Ctr Res, Danville, PA 17822 USA. [Caulfield, Mark J.; Munroe, Patricia B.; Warren, Helen R.] Queen Mary Univ, Barts & London Sch Med & Dent, NIHR Barts Cardiovasc Res Unit, London EC1M 6BQ, England. [Chambers, John C.; Kooner, Jaspal S.; Zhang, Weihua] London North West Healthcare NHS Trust, Ealing Hosp, Dept Cardiol, Middlesex UB1 3HW, England. [Chambers, John C.; Evangelou, Evangelos; Segura-Lepe, Marcelo P.; Zhang, Weihua] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London W2 1PG, England. [Chambers, John C.; Kooner, Jaspal S.] Univ London Imperial Coll Sci Technol & Med, Healthcare NHS Trust, London W12 0HS, England. [Chasman, Daniel I.] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Chasman, Daniel I.; Patel, Aniruddh P.; Ridker, Paul M.; Kathiresan, Sekar] Harvard Med Sch, Boston, MA 02115 USA. [Chasman, Daniel I.; Chu, Audrey Y.; Ridker, Paul M.] Brigham & Womens & Harvard Med Sch, Div Prevent Med, Boston, MA 02115 USA. [Christensen, Cramer] Lillebaelt Hosp, Dept Med, DK-7100 Vejle, Denmark. [Chu, Audrey Y.; Heard-Costa, Nancy L.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Cocca, Massimiliano] Univ Trieste, Dept Med Surg & Hlth Sci, I-34100 Trieste, Italy. [Cook, James P.; Morris, Andrew P.] Univ Liverpool, Dept Biostat, Liverpool L69 3GL, Merseyside, England. [Corley, Janie; Davies, Gail; Deary, Ian J.; Starr, John M.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland. [Corley, Janie; Davies, Gail; Deary, Ian J.; Pattie, Alison] Univ Edinburgh, Dept Psychol, 7 George Sq, Edinburgh EH8 9JZ, Midlothian, Scotland. [Galbany, Jordi Corominas] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6500 HB Nijmegen, Netherlands. [Cox, Amanda J.] Griffith Univ, Menzies Hlth Inst Queensland, Southport, Qld, Australia. [Cuellar-Partida, Gabriel] Univ Queensland, Diamantina Inst, Brisbane, Qld 4072, Australia. [Cuellar-Partida, Gabriel; Gordon, Scott D.; Martin, Nicholas G.; Sapkota, Yadav] QIMR Berghofer Med Res Inst, Brisbane, Qld 4006, Australia. [Danesh, John; Marenne, Gaelle; Southam, Lorraine; Zeggini, Eleftheria] Wellcome Trust Sanger Inst, Wellcome Genome Campus, Cambridge CB10 1SA, England. [Danesh, John] Univ Cambridge, Dept Med, Cambridge Escellence, British Heart Fdn, Cambridge CB2 0QQ, England. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Ctr Mol Med, Dept Genet, NL-3584 CX Utrecht, Netherlands. [de Borst, Gert J.] Univ Med Ctr Utrecht, Dept Vasc Surg, Div Surg Specialties, NL-3584 CX Utrecht, Netherlands. [de Denus, Simon] Univ Montreal, Fac Pharm, Montreal, PQ H3T 1J4, Canada. [de Groot, Mark C. H.] Univ Med Ctr Utrecht, Div Lab & Pharm, Dept Clin Chem & Haematol, NL-3508 GA Utrecht, Netherlands. [de Groot, Mark C. H.] Univ Utrecht, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht Inst Pharmaceut Sci, NL-3508 TB Utrecht, Netherlands. [de Mutsert, Renee; Li-Gao, Ruifang; Mook-Kanamori, Dennis O.] Leiden Univ, Med Ctr, Dept Clin Epidemiol, NL-2300 RC Leiden, Netherlands. [Dedoussis, George; Farmaki, Aliki-Eleni] Harokopio Univ, Sch Hlth Sci & Educ, Dept Nutr & Dietet, Athens 17671, Greece. [Demerath, Ellen W.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55454 USA. [den Hollander, Anneke I.; Hoyng, Carel B.] Radbound Univ Med Ctr, Dept Ophthalmol, NL-6500 HB Nijmegen, Netherlands. [Dennis, Joe G.; Easton, Douglas F.; Thompson, Deborah J.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England. [Drenos, Fotios] UCL, Inst Cardiovasc Sci, London WC1E 6JF, England. [Drenos, Fotios] Univ Bristol, Sch Social & Community Med, MRC Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England. [Du, Mengmeng] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Du, Mengmeng] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10017 USA. [Dunning, Alison M.; Easton, Douglas F.; Pirie, Ailith; Tyrer, Jonathan P.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England. [Ebeling, Tapani] Oulu Univ Hosp, Dept Med, Oulu 90029, Finland. [Ebeling, Tapani] Univ Oulu, Res Unit Internal Med, FI-90014 Oulu, Finland. [Edwards, Todd L.; Giri, Ayush] Vanderbilt Univ, Vanderbilt Genet Inst, Inst Med & Publ Hlth, Dept Med,Div Epidemiol, Nashville, TN 37203 USA. [Ellinor, Patrick T.; Florez, Jose C.; Huang, Paul L.; Lubitz, Steven A.; Manning, Alisa K.; Patel, Aniruddh P.; Peloso, Gina M.; Sivapalaratnam, Suthesh; Kathiresan, Sekar] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ellinor, Patrick T.; Florez, Jose C.; Lubitz, Steven A.; Manning, Alisa K.; Peloso, Gina M.] Broad Inst, Med & Populat Genet Program, Cambridge, MA 02141 USA. [Elliott, Paul] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, Dept Epidemiol & Biostat, London W2 1PG, England. [Evangelou, Evangelos] Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, GR-45110 Ioannina, Greece. [Faul, Jessica D.] Univ Michigan, Inst Social Res, Survey Res Ctr, Ann Arbor, MI 48104 USA. [Feitosa, Mary F.; Borecki, Ingrid B.] Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63108 USA. [Ferrannini, Ele] CNR Inst Clin Physiol, Pisa, Italy. [Ferrannini, Ele] Univ Pisa, Dept Clin & Expt Med, Pisa, Italy. [Ferrario, Marco M.] Univ Insubria, Dept Clin & Expt Med, Res Ctr Epidemiol & Prevent Med, I-21100 Varese, Italy. [Ferrieres, Jean] Toulouse Univ, Sch Med, F-31059 Toulouse, France. [Florez, Jose C.; Manning, Alisa K.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Ford, Ian; Packard, Chris J.; Padmanabhan, Sandosh; Sattar, Naveed; Young, Robin] Univ Glasgow, Glasgow G12 8QQ, Lanark, Scotland. [Fornage, Myriam; Lin, Li-An] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA. [Franks, Paul W.; Renstrom, Frida; Varga, Tibor V.] Lund Univ, Dept Clin Sci, Genet & Mol Epidemiol Unit, SE-20502 Malmo, Sweden. [Franks, Paul W.] Harvard Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Franks, Paul W.] Umea Univ, Med Unit, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden. [Frikke-Schmidt, Ruth; Tybjaerg-Hansen, Anne] Copenhagen Univ Hosp, Rigshosp, Dept Clin Biochem, DK-2100 Copenhagen, Denmark. [Gandin, Ilaria; Gasparini, Paolo; Girotto, Giorgia; Morgan, Anna] Univ Trieste, Dept Med Sci, I-34137 Trieste, Italy. [Gasparini, Paolo; Girotto, Giorgia; Vozzi, Diego] Sidra Med & Res Ctr, Div Expt Genet, Doha 26999, Qatar. [Giedraitis, Vilmantas] Uppsala Univ, Dept Publ Hlth, Geriat, S-75185 Uppsala, Sweden. [Gordon-Larsen, Penny; Harris, Kathleen Mullan] Univ N Carolina, Caroline Populat Ctr, Chapel Hill, NC 27514 USA. [Gordon-Larsen, Penny] Univ N Carolina, Dept Nutr, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27514 USA. [Gudnason, Vilmundur; Smith, Albert Vernon; Thorsteinsdottir, Unnur; Stefansson, Kari] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. [Gudnason, Vilmundur; Smith, Albert Vernon] Icelandic Heart Assoc, IS-201 Kopavogur, Iceland. [Gustafsson, Stefan; Ingelsson, Erik] Uppsala Univ, Dept Med Sci, Mol Epidemiol & Sci Life Lab, S-75141 Uppsala, Sweden. [Harris, Kathleen Mullan] Univ N Carolina, Dept Sociol, Chapel Hill, NC 27514 USA. [Harris, Tamara B.] NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Hattersley, Andrew T.] Univ Exeter, Univ Exeter Med Sch, Exeter EX2 5DW, Devon, England. [Hayward, Caroline; Marten, Jonathan; Vitart, Veronique] Univ Edinburgh, Inst Genet & Mol Med, MRCHGU, Edinburgh EH4 2XU, Midlothian, Scotland. [He, Liang] Duke Univ, Social Sci Res Inst, Biodemog Aging Res Unit, Durham, NC 27708 USA. [He, Liang; Heikkila, Kauko; Kaprio, Jaakko] Univ Helsinki, Dept Publ Hlth, FI-00014 Helsinki, Finland. [Dunning, Alison M.; Heikkila, Kauko; Kaprio, Jaakko] Univ Helsinki, Inst Mol Med Finland FIMM, FI-00014 Helsinki, Finland. [Helgeland, Oyvind; Njolstad, Pal R.] Haukeland Hosp, Dept Pediat, N-5021 Bergen, Norway. [Helgeland, Oyvind; Johansson, Stefan; Njolstad, Pal R.] Univ Bergen, Dept Clin Sci, KG Jebson Ctr Diabet Res, N-5020 Bergen, Norway. [Hernesniemi, Jussi] Tampere Univ Hosp, Dept Cardiol, Ctr Heart, FI-33521 Tampere, Finland. [Hernesniemi, Jussi; Lehtimaki, Terho; Lyytikainen, Leo-Pekka] Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland. [Hernesniemi, Jussi; Lehtimaki, Terho; Lyytikainen, Leo-Pekka] Univ Tampere, Sch Med, Dept Clin Chem, Tampere 33014, Finland. [Hewitt, Alex W.] Univ Melbourne, Royal Victorian Eye & Ear Hosp, Ctr Eye Res Australia, Melbourne, Vic 3002, Australia. [Hewitt, Alex W.; Mackey, David A.] Univ Western Australia, Lions Eye Inst, Ctr Ophthalmol & Vis Sci, Perth, WA 6009, Australia. [Hewitt, Alex W.] Univ Tasmania, Menzies Res Inst Tasmania, Hobart, Tas 7000, Australia. [Hocking, Lynne J.] Univ Edinburgh, Ctr Genom & Expt Med, Generat Scotland, Edinburgh EH4 2XU, Midlothian, Scotland. [Hocking, Lynne J.] Univ Aberdeen, Div Appl Med, Musculoskeletal Res Programme, Aberdeen AB25 2ZD, Scotland. [Holmen, Oddgeir L.] Norwegian Univ Sci & Technol, NTNU, Dept Publ Hlth, KG Jebsen Ctr Genet Epidemiol, N-7600 Trondheim, Norway. [Hovingh, G. Kees] AMC, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands. [Hveem, Kristian] Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, HUNT Res Ctr, N-7600 Levanger, Norway. [Ikram, M. Arfan] Erasmus Sch Ctr, Dept Neurol, NL-3015 GE Rotterdam, Netherlands. [Ikram, M. Arfan] Erasmus Sch Ctr, Dept Radiol, NL-3015 GE Rotterdam, Netherlands. [Ingelsson, Erik] Stanford Univ, Sch Med, Div Cardiovasc Med, Dept Med, Stanford, CA 94305 USA. [Jansson, Jan-Hakan; Rolandsson, Olov] Umea Univ, Dept Publ Hlth & Clin Med, SE-90185 Umea, Sweden. [Jansson, Jan-Hakan] Res Unit Skelleftea, SE-93141 Skelleftea, Sweden. [Jarvik, Gail P.] Univ Washington, Dept Genom Sci, Seattle, WA 98195 USA. [Jensen, Gorm B.] Frederiksberg Univ Hosp, Copenhagen City Heart Study, DK-2000 Frederiksberg, Denmark. [Jiang, Xuejuan] Univ Calif Los Angeles, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA. [Jiang, Xuejuan; Varma, Rohit] Univ Southern Calif, Keck Sch Med, Dept Ophthalmol, USC Roski Eye Inst, Los Angeles, CA 90089 USA. [Johansson, Stefan] Haukeland Hosp, Ctr Med Genet & Mol Med, N-5021 Bergen, Norway. [Jorgensen, Marit E.] Univ Southern Denmark, Natl Inst Publ Hlth, DK-1353 Copenhagen, Denmark. [Jorgensen, Marit E.] Steno Diabet Ctr, DK-2820 Gentofte, Denmark. [Jorgensen, Torben] Aalborg Hosp, DK-9000 Aalborg, Denmark. [Jorgensen, Torben; Linneberg, Allan; Thuesen, Betina H.] Capital Reg Denmark, Res Ctr Prevent & Hlth, DK-2600 Glostrup, Denmark. [Jousilahti, Pekka; Kaprio, Jaakko; Kontto, Jukka; Lindstrom, Jaana; Mannisto, Satu; Perola, Markus; Salomaa, Veikko; Tuomilehto, Jaakko] Natl Inst Hlth & Welf, FI-00271 Helsinki, Finland. [Jukema, J. Wouter; Trompet, Stella] Leiden Univ Med Ctr, Dept Cardiol, NL-2333 Leiden, Netherlands. [Jukema, J. Wouter] Interuniv Cardiol Inst Netherlands, NL-2333 Utrecht, Netherlands. [Kahali, Bratati; Speliotes, Elizabeth K.; Zhou, Wei; Willer, Cristen J.] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Kahali, Bratati; Speliotes, Elizabeth K.; Zhou, Wei; Willer, Cristen J.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Kahali, Bratati; Speliotes, Elizabeth K.] Univ Michigan, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Kahn, Rene S.; Ophoff, Roel A.] Ctr Med Univ Utrecht, Brain Ctr Rudolf Magnus, Dept Psychiat, NL-3584 CG Utrecht, Netherlands. [Kahonen, Mika] Univ Tampere, Sch Med, Dept Clin Physiol, Tampere 33014, Finland. [Karaleftheri, Maria] Echinos Med Ctr, Echinos, Greece. [Karpe, Fredrik; Neville, Matt; Owen, Katharine R.; Robertson, Neil; McCarthy, Mark I.] Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabetes Endocrinol & Metab, Oxford OX3 7LE, England. [Karpe, Fredrik; Neville, Matt; Owen, Katharine R.; McCarthy, Mark I.] Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford OX3 7LE, England. [Kee, Frank] Queens Univ Belfast, UKCRC Ctr Excellence Publ Hlth Res, Belfast BT12 6BJ, Antrim, North Ireland. [Keeman, Renske; Schmidt, Marjanka K.] Netherlands Canc Inst, Antoni van Leewenhoek Hosp, NL-1066 CX Amsterdam, Netherlands. [Kocher, Thomas] Univ Med Greifswald, Dept Restorat Dent Periodontol & Endodontol, D-17475 Greifswald, Germany. [Komulainen, Pirjo; Lakka, Timo A.; Manning, Alisa K.; Rauramaa, Rainer] Kuopio Res Inst Exercise Med, Fdn Res Hlth Exercise & Nutr, Kuopio 70100, Finland. [Kooner, Jaspal S.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Hammersmith Hosp Campus, London W12 0NN, England. [Kooperberg, Charles; Reiner, Alex P.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Kriebel, Jennifer; Meidtner, Karina; Schulze, Matthias B.] German Ctr Diabet Res, D-85764 Munich, Germany. [Kriebel, Jennifer] Helmholtz Zentrum Munchen German Res Ctr Environm, Inst Epidemiol 2, D-85764 Neuherberg, Germany. [Kriebel, Jennifer] Helmholtz Zentrum Munchen German Res Ctr Environm, Res Unit Mol Epidemiol, D-85764 Neuherberg, Germany. [Kuivaniemi, Helena] Univ Stellenbosch, Fac Med & Hlth Sci, Dept Biomed Sci, Dept Psychiat, ZA-7505 Tygerberg, Western Cape, South Africa. [Kuivaniemi, Helena] Univ Stellenbosch, Fac Med & Hlth Sci, Dept Biomed Sci, Div Mol Biol & Human Genet, ZA-7505 Tygerberg, Western Cape, South Africa. [Kury, Sebastien] CHU Nantes, Serv Genet Med, F-44093 Nantes, France. [Kuusisto, Johanna; Laakso, Markku] Univ Eastern Finland, Inst Clin Med, Internal Med, Kuopio 70210, Finland. [Kuusisto, Johanna; Laakso, Markku] Kuopio Univ Hosp, SF-70210 Kuopio, Finland. [La Bianca, Martina; Robino, Antonietta; Ulivi, Sheila] Inst Maternal & Child Hlth IRCCS Burlo Garofolo, I-34137 Trieste, Italy. [Lakka, Timo A.] Univ Eastern Finland, Inst Biomed & Physiol, Kuopio 70210, Finland. [Lange, Ethan M.; Lange, Leslie A.; Mohlke, Karen L.; Wu, Ying] Univ N Carolina, Dept Genet, Chapel Hill, NC 27514 USA. [Langefeld, Carl D.] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC 27157 USA. [Langefeld, Carl D.] Wake Forest Sch Med, Ctr Publ Hlth Genom, Winston Salem, NC 27157 USA. [Langenberg, Claudia; Luan, Jian'an; Perry, John R. B.; Scott, Robert A.; Wareham, Nicholas J.; Willems, Sara M.; Zhao, Jing Hua] Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 0QQ, England. [Larson, Eric B.] Grp Hlth Res Inst, Seattle, WA 98101 USA. [Larson, Eric B.] Univ Washington, Dept Hlth Serv, Seattle, WA 98101 USA. [Lee, I-Te] Taichung Vet Gen Hosp, Dept Internal Med, Div Endocrinol & Metab, Taichung 407, Taiwan. [Lee, I-Te] Natl Yang Ming Univ, Sch Med, Taipei 112, Taiwan. [Lee, I-Te] Chung Shan Med Univ, Sch Med, Taichung 402, Taiwan. [Lewis, Cora E.] Univ Alabama Birmingham, Div Prevent Med, Birmingham, AL 35205 USA. [Li, Huaixing; Lin, Xu; Wang, Feijie; Wang, Yiqin; Yao, Pang; Zheng, He] Chinese Acad Sci, Univ Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Nutr Sci,Key Lab Nutr & Metab, Shanghai 200031, Peoples R China. [Li, Jin] Stanford Univ, Sch Med, Div Cardiovasc Med, Dept Med, Palo Alto, CA 94305 USA. [Lin, Honghuang; Teumer, Alexander] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Lind, Lars] Uppsala Univ, S-75185 Uppsala, Sweden. [Linneberg, Allan] Rigshosp, Dept Expt Med, DK-2200 Copenhagen, Denmark. [Liu, Yongmei] Wake Forest Sch Med, Div Publ Hlth Sci, Winston Salem, NC 27157 USA. [Lophatananon, Artitaya] Warsaw Acad Med & Hosp, Div Hlth Sci, Coventry CV4 7AL, W Midlands, England. [Madden, Pamela A. F.] Washington Univ, Dept Psychiat, St Louis, MO 63110 USA. [Meidtner, Karina; Schulze, Matthias B.] German Inst Human Nutr Potsdam Rehbruecke DIfE, Dept Mol Epidemiol, D-14558 Nuthetal, Germany. [Mitchell, Paul] Univ Sydney, Ctr Vis Res, Westmead Millennium Inst Med Res, Sydney, NSW 2022, Australia. [Mitchell, Paul] Univ Sydney, Dept Ophthalmol, Sydney, NSW 2022, Australia. [Mook-Kanamori, Dennis O.] Leiden Univ, Med Ctr, Dept Publ Hlth & Primary Care, NL-2300 RC Leiden, Netherlands. [Morris, Andrew D.; Polasek, Ozren; Rudan, Igor] Univ Edinburgh, Ctr Global Hlth Res, Ushar Inst Populat Hlth Sci & Informat, Edinburgh EH8 9AG, Midlothian, Scotland. [Mueller-Nurasyid, Martina] Univ Munich, Dept Med 1, D-81377 Munich, Germany. [Mueller-Nurasyid, Martina] DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, D-80802 Munich, Germany. [Nalls, Mike A.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Nauck, Matthias] DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, D-17475 Greifswald, Germany. [Nauck, Matthias] Univ Med Greifswald, Inst Clin Chem, D-17475 Greifswald, Germany. [Nauck, Matthias] Univ Med Greifswald, Lab Med, D-17475 Greifswald, Germany. [Nikus, Kjell] Univ Tampere, Tampere Univ Hosp, Dept Cardiol, Ctr Heart, Tampere 33521, Finland. [Nikus, Kjell] Univ Tampere, Sch Med, Tampere 33521, Finland. [O'Connel, Jeffrey R.; Perry, James A.; Yerges-Armstrong, Laura M.] Univ Maryland, Sch Med, Dept Med, Program Personalized Med, Baltimore, MD 21201 USA. [Oksa, Heikki] Tampere Univ Hosp, Dept Med, Tampere 33521, Finland. [Loohuis, Loes M. Olde; Ophoff, Roel A.] Univ Calif Los Angeles, Ctr Neurobehav Genet, Los Angeles, CA 90095 USA. [Palmer, Colin N. A.] Ninewells Hosp & Med Sch, Med Res Inst, Pat Macpherson Ctr Pharmacogenet & Pharmacogenom, Dundee DD1 9SY, Scotland. [Pasterkamp, Gerard] Univ Med Ctr Utrecht, Div Labs & Pharm, Lab Clin Chem & Hematol, NL-3584 CX Utrecht, Netherlands. [van der Laan, Sander W.] Univ Med Ctr Utrecht, Div Heart & Lungs, Lab Expt Cardiol, NL-3584 CX Utrecht, Netherlands. [Pennell, Craig E.; Wang, Carol A.] Univ Western Australia, Sch Womens & Infants Hlth, Perth, WA 6009, Australia. [Perola, Markus] Univ Helsinki, Inst Mol Med FIMM, FI-00014 Helsinki, Finland. [Perola, Markus] Univ Helsinki, Diabet & Obes Res Program, FI-00014 Helsinki, Finland. [Perola, Markus] Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia. [Polasek, Ozren] Univ Split, Sch Med, Split 21000, Croatia. [Posthuma, Danielle] Vrije Univ Amsterdam, Dept Complex Trait Genet, Ctr Neurogenom & Cognit Res, NL-1081 HV Amsterdam, Netherlands. [Posthuma, Danielle] Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, Neurosci Campus Amsterdam, NL-1081 HV Amsterdam, Netherlands. [Raitakari, Olli T.] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku 20521, Finland. [Raitakari, Olli T.] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, FIN-20520 Turku, Finland. [Rasheed, Asif; Saleheen, Danish] Ctr Noncommunicable Dis, Karachi, Pakistan. [Rauramaa, Rainer] Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, SF-70210 Kuopio, Finland. [Reilly, Dermot F.] MRL Merck & Co Inc, Genet & Pharmacogenom, Boston, MA 02115 USA. [Reiner, Alex P.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Renstrom, Frida] Umea Univ, Dept Biobank Res, SE-90187 Umea, Sweden. [Ridker, Paul M.] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. [Rioux, John D.; Tardif, Jean-Claude; Lettre, Guillaume] Univ Montreal, Fac Med, Dept Med, Montreal, PQ H3T 1J4, Canada. [Rolandsson, Olov] Umea Univ, Unit Family Med, Dept Publ Hlth & Clin Med, S-90185 Umea, Sweden. [Saleheen, Danish; Zhao, Wei] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Schreiner, Pamela J.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN 55454 USA. [Shah, Svati] Duke Univ, Durham, NC 27703 USA. [Sim, Xueling] Natl Univ Singapore, Natl Univ Hlth Syst, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore. [Sivapalaratnam, Suthesh] Univ Cambridge, Dept Haematol, Cambridge CB2 0PT, England. [Sivapalaratnam, Suthesh] AMC, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands. [Small, Kerrin S.; Spector, Timothy D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England. [Starr, John M.] Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh EH8 9JZ, Midlothian, Scotland. ['t Hart, Leen M.; van Schoor, Natasja M.] Vrije Univ Amsterdam Med Ctr, Dept Epidemiol & Biostat, NL-1007 MB Amsterdam, Netherlands. ['t Hart, Leen M.] Leiden Univ, Med Ctr, Dept Mol & Cell Biol, NL-2333 ZC Leiden, Netherlands. ['t Hart, Leen M.] Leiden Univ, Med Ctr, Dept Mol Epidemiol, NL-2333 ZC Leiden, Netherlands. [Tansey, Katherine E.] Cardiff Univ, Coll Biomed & Life Sci, Cardiff CF14 4EP, S Glam, Wales. [Tansey, Katherine E.] Univ Bristol, Dept Social & Community Med, MRC Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England. [Teumer, Alexander] Univ Med Greifswald, Inst Community Med, D-17475 Greifswald, Germany. [Toenjes, Anke] Univ Leipzig, Dept Womens & Child Hlth, Ctr Pediat Res, D-04103 Leipzig, Germany. [Tromp, Gerard] Univ Stellenbosch, Fac Med & Hlth Sci, Dept Biomed Sci, Div Human Genet & Mol Biol, ZA-7505 Tygerberg, Western Cape, South Africa. [Trompet, Stella] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, NL-2333 Leiden, Netherlands. [Tsafantakis, Emmanouil] Anogia Med Ctr, Anogia, Greece. [Tuomilehto, Jaakko] Danube Univ Krems, Ctr Vasc Prevent, A-3500 Krems, Austria. [Tuomilehto, Jaakko] Dasman Diabet Inst, Dasman 15462, Kuwait. [Tuomilehto, Jaakko] King Abdulaziz Univ, Diabet Res Grp, Jeddah 21589, Saudi Arabia. [Uher, Rudolf] Dalhousie Univ, Dept Psychiat, Halifax, NS B3H 4R2, Canada. [Van Der Leij, Andries R.] Univ Amsterdam, Dept Brain & Cognit, NL-1018 WS Amsterdam, Netherlands. [Edwards, Digna R. Velez] Vanderbilt Univ, Vanderbilt Genet Inst, Inst Med & Publ Hlth, Dept Obstet & Gynecol, Nashville, TN 37203 USA. [Vogt, Thomas F.] MRL Merck Co Inc, Cardiometab Dis, Kenilworth, NJ 07033 USA. [Walker, Mark] Newcastle Univ, Sch Med, Inst Cellular Med, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. [Wang, Shuai] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Wessel, Jennifer] Indiana Univ, Fairbanks Sch Publ Hlth, Diabet Translat Res Ctr, Dept Epidemiol & Med, Indianapolis, IN 46202 USA. [Wessel, Jennifer] Indiana Univ, Sch Med, Indianapolis, IN 46202 USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Witte, Daniel R.] Danish Diabet Acad, DK-5000 Odense, Denmark. [Witte, Daniel R.] Aarhus Univ, Dept Publ Hlth, DK-8000 Aarhus, Denmark. [Woods, Michael O.] Mem Univ Newfoundland, Fac Med, Discipline Genet, St John, NF A1B 3V6, Canada. [Yerges-Armstrong, Laura M.] GlaxoSmithKlein, King Of Prussia, PA 19406 USA. [Zhan, Xiaowei] Univ Texas Southwestern Med Ctr Dallas, Quantitat Biomed Res Ctr, Ctr Genet Host Def, Dept Clin Sci, Dallas, TX 75390 USA. [Willer, Cristen J.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Liu, Dajiang J.] Penn State Univ, Coll Med, Inst Personalized Med, Dept Publ Hlth Sci, Hershey, PA 17033 USA. [North, Kari E.] Dept Epidemiol, Chapel Hill, NC 27514 USA. [North, Kari E.] Carolina Ctr Genome Sci, Chapel Hill, NC 27514 USA. [Heard-Costa, Nancy L.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Pers, Tune H.] Statens Serum Inst, Dept Epidemiol Res, DK-2200 Copenhagen, Denmark. [Lindgren, Cecilia M.] Univ Oxford, Big Data Inst, Li Ka Shing Ctr Hlth Informat & Discovery, Oxford OX3 7BN, England. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10069 USA. [Hirschhorn, Joel N.] Harvard Med Sch, Dept Pediat & Genet, Boston, MA 02115 USA. [Deloukas, Panos] King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah 21589, Saudi Arabia. RP Deloukas, P (reprint author), Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London EC1M 6BQ, England.; Lettre, G (reprint author), Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada.; Hirschhorn, JN (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.; Hirschhorn, JN (reprint author), Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA.; Hirschhorn, JN (reprint author), Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA 02115 USA.; Lettre, G (reprint author), Univ Montreal, Fac Med, Dept Med, Montreal, PQ H3T 1J4, Canada.; Hirschhorn, JN (reprint author), Harvard Med Sch, Dept Pediat & Genet, Boston, MA 02115 USA.; Deloukas, P (reprint author), King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah 21589, Saudi Arabia. EM joelh@broadinstitute.org; p.deloukas@qmul.ac.uk; guillaume.lettre@umontreal.ca RI Polasek, Ozren/B-6002-2011; Feitosa, Mary/K-8044-2012; Mackey, David/H-5340-2014; Rioux, John/A-9599-2015; OI Ewing, Ailith/0000-0002-2272-1277; Bergmann, Sven/0000-0002-6785-9034; Linneberg, Allan/0000-0002-0994-0184; Polasek, Ozren/0000-0002-5765-1862; Feitosa, Mary/0000-0002-0933-2410; Mackey, David/0000-0001-7914-4709; Smith, Jennifer/0000-0002-3575-5468; Rioux, John/0000-0001-7560-8326; Jorgensen, Torben/0000-0001-9453-2830; Small, Kerrin/0000-0003-4566-0005; Medina-Gomez, Carolina/0000-0001-7999-5538; Varga, Tibor/0000-0002-2383-699X; Kaprio, Jaakko/0000-0002-3716-2455; Evangelou, Evangelos/0000-0002-5488-2999; Kontto, Jukka/0000-0003-3899-9852 FU Doris Duke Charitable Foundation [2014105]; Medical Research Council [G0600237, MC_PC_15018, MR/K006584/1, MR/K026992/1, MR/L01341X/1, MR/L01632X/1]; NCATS NIH HHS [UL1 TR000124, UL1 TR001881]; NCI NIH HHS [P30 CA008748]; NHLBI NIH HHS [HHSN268201100046C, HHSN268201300046C, K23 HL114724, K99 HL130580, N01 HC095159]; NICHD NIH HHS [P2C HD050924]; NIDDK NIH HHS [P30 DK063491, R01 DK075787, R01 DK089256] NR 29 TC 0 Z9 0 U1 11 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD FEB 9 PY 2017 VL 542 IS 7640 BP 186 EP 190 DI 10.1038/nature21039 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EK2DJ UT WOS:000393737500031 PM 28146470 ER PT J AU Wang, YJ Patel, BA Anreddy, N Zhang, YK Zhang, GN Alqahtani, S Singh, S Shukla, S Kaddoumi, A Ambudkar, SV Talele, TT Chen, ZS AF Wang, Yi-Jun Patel, Bhargav A. Anreddy, Nagaraju Zhang, Yun-Kai Zhang, Guan-Nan Alqahtani, Saeed Singh, Satyakam Shukla, Suneet Kaddoumi, Amal Ambudkar, Suresh V. Talele, Tanaji T. Chen, Zhe-Sheng TI Thiazole-valine peptidomimetic (TTT-28) antagonizes multidrug resistance in vitro and in vivo by selectively inhibiting the efflux activity of ABCB1 SO SCIENTIFIC REPORTS LA English DT Article ID DRUG-RESISTANCE; P-GLYCOPROTEIN; HEART-FAILURE; CANCER-CELLS; TRANSPORTERS; PACLITAXEL; PROTEIN; ABCG2; POLYMORPHISMS; DOXORUBICIN AB Multidrug resistance (MDR) attenuates the chemotherapy efficacy and increases the probability of cancer recurrence. The accelerated drug efflux mediated by ATP-binding cassette (ABC) transporters is one of the major MDR mechanisms. This study investigated if TTT-28, a newly synthesized thiazolevaline peptidomimetic, could reverse ABCB1-mediated MDR in vitro and in vivo. TTT-28 reversed the ABCB1-mediated MDR and increased the accumulation of [H-3]-paclitaxel in ABCB1 overexpressing cells by selectively blocking the efflux function of ABCB1, but not interfering with the expression level and localization of ABCB1. Animal study revealed that TTT-28 enhanced the intratumoral concentration of paclitaxel and promoted apoptosis, thereby potently inhibiting the growth of ABCB1 overexpressing tumors. But TTT-28 did not induce the toxicity (cardiotoxicity/myelosuppression) of paclitaxel in mice. In this study, we synthesized and evaluated a novel selective inhibitor of ABCB1 (TTT-28) with high efficacy and low toxicity. The identification and characterization of this new thiazole-valine peptidomimetic will facilitate design and synthesis of a new generation of ABCB1 inhibitors, leading to further research on multidrug resistance and combination chemotherapy. Furthermore, the strategy that co-administer MDR-ABCB1 inhibitor to overcome the resistance of one FDA approved, widely used chemotherapeutic paclitaxel, may be promising direction for the field of adjuvant chemotherapy. C1 [Wang, Yi-Jun; Patel, Bhargav A.; Anreddy, Nagaraju; Zhang, Yun-Kai; Zhang, Guan-Nan; Singh, Satyakam; Talele, Tanaji T.; Chen, Zhe-Sheng] St Johns Univ, Coll Pharm & Hlth Sci, Dept Pharmaceut Sci, Queens, NY 11439 USA. [Alqahtani, Saeed; Kaddoumi, Amal] Univ Louisiana Monroe, Sch Pharm, Dept Basic Pharmaceut Sci, Monroe, LA 71201 USA. [Shukla, Suneet; Ambudkar, Suresh V.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. RP Chen, ZS (reprint author), St Johns Univ, Coll Pharm & Hlth Sci, Dept Pharmaceut Sci, Queens, NY 11439 USA. EM chenz@stjohns.edu FU NIH [1R15CA143701]; St. John's University Research Seed Grant [579-1110-7002]; Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This work was supported by funds from NIH (No. 1R15CA143701) and St. John's University Research Seed Grant (No. 579-1110-7002) to Z.S. Chen. SS and SVA were supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. We thank Drs. Susan E. Bates and Robert W. Robey (NCI, NIH, Bethesda, MD) for providing SW620 and SW620/Ad300 cell lines. NR 36 TC 0 Z9 0 U1 6 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD FEB 9 PY 2017 VL 7 AR 42106 DI 10.1038/srep42106 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EK3MY UT WOS:000393831700001 PM 28181548 ER PT J AU McManus, DD Rong, J Huan, TX Lacey, S Tanriverdi, K Munson, PJ Larson, MG Joehanes, R Murthy, V Shah, R Freedman, JE Levy, D AF McManus, David D. Rong, Jian Huan, Tianxiao Lacey, Sean Tanriverdi, Kahraman Munson, Peter J. Larson, Martin G. Joehanes, Roby Murthy, Venkatesh Shah, Ravi Freedman, Jane E. Levy, Daniel TI Messenger RNA and MicroRNA transcriptomic signatures of cardiometabolic risk factors SO BMC GENOMICS LA English DT Article DE Cardiovascular disease risk factors; Epidemiology; Circulation; mRNA; microRNA ID VASCULAR SMOOTH-MUSCLE; CORONARY-HEART-DISEASE; METABOLIC SYNDROME; CARDIOVASCULAR-DISEASE; GENE-EXPRESSION; ASSOCIATION; HYPERTENSION; CELLS; POLYMORPHISMS; VARIANTS AB Background: Cardiometabolic (CM) risk factors are heritable and cluster in individuals. We hypothesized that CM risk factors are associated with multiple shared and unique mRNA and microRNA (miRNA) signatures. We examined associations of mRNA and miRNA levels with 6 CM traits: body mass index, HDL-cholesterol and triglycerides, fasting glucose, and systolic and diastolic blood pressures through cross-sectional analysis of 2812 Framingham Heart Study who had whole blood collection for RNA isolation for mRNA and miRNA expression studies and who consented to genetic research. We excluded participants taking medication for hypertension, dyslipidemia, or diabetes. We measured mRNA (n = 17,318; using the Affymetrix GeneChip Human Exon 1.0 ST Array) and miRNA (n = 315; using qRT-PCR) expression in whole blood. We used linear regression for mRNA analyses and a combination of linear and logistic regression for miRNA analyses. We conducted miRNA-mRNA coexpression and gene ontology enrichment analyses to explore relations between pleiotropic miRNAs, mRNA expression, and CM trait clustering. Results: We identified hundreds of significant associations between mRNAs, miRNAs, and individual CM traits. Four mRNAs (FAM13A, CSF2RB, HIST1H2AC, WNK1) were associated with all 6 CM traits (FDR < 0.001) and four miRNAs (miR-197-3p, miR-328, miR-505-5p, miR-145-5p) were associated with four CM traits (FDR < 0.05). Twelve mRNAs, including WNK1, that were coexpressed with the four most pleiotropic miRNAs, were also miRNA targets. mRNAs coexpressed with pleiotropic miRNAs were enriched for RNA metabolism (miR-505-5p), ubiquitin-dependent protein catabolism (miR-197-3p, miR-328) and chromatin assembly (miR-328). Conclusions: We identified mRNA and miRNA signatures of individual CM traits and their clustering. Implicated transcripts may play causal roles in CM risk or be downstream consequences of CM risk factors on the transcriptome. Studies are needed to establish whether or not pleiotropic circulating transcripts illuminate causal pathways for CM risk. C1 [McManus, David D.; Freedman, Jane E.] Univ Massachusetts, Sch Med, Dept Med, Div Cardiol, Worcester, MA 01003 USA. [McManus, David D.; Rong, Jian; Huan, Tianxiao; Lacey, Sean; Larson, Martin G.; Levy, Daniel] NHLBI, Framingham, MA 02215 USA. [McManus, David D.; Rong, Jian; Huan, Tianxiao; Lacey, Sean; Larson, Martin G.; Levy, Daniel] Boston Univ Framingham Heart Study, Framingham, MA 20892 USA. [McManus, David D.] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Div Epidemiol, Worcester, MA 01605 USA. [Rong, Jian; Lacey, Sean; Larson, Martin G.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Rong, Jian; Levy, Daniel] Boston Univ, Sch Med, Dept Med, Div Neurol, Boston, MA 02215 USA. [Huan, Tianxiao; Joehanes, Roby; Levy, Daniel] NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA. [Huan, Tianxiao; Joehanes, Roby; Levy, Daniel] NHLBI, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Munson, Peter J.; Joehanes, Roby] NIH, Ctr Informat Technol, Mathemat & Stat Comp Lab, Bethesda, MD 20892 USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Joehanes, Roby] Hebrew SeniorLife, Boston, MA USA. [Joehanes, Roby] Harvard Med Sch, Boston, MA USA. [Murthy, Venkatesh] Univ Michigan, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. [Shah, Ravi] Beth Israel Deaconess Med Ctr, Dept Med, Div Cardiol, Boston, MA USA. [McManus, David D.] 1355 Lake Ave North, Worcester, MA 01655 USA. RP McManus, DD (reprint author), Univ Massachusetts, Sch Med, Dept Med, Div Cardiol, Worcester, MA 01003 USA.; McManus, DD (reprint author), NHLBI, Framingham, MA 02215 USA.; McManus, DD (reprint author), Boston Univ Framingham Heart Study, Framingham, MA 20892 USA.; McManus, DD (reprint author), Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Div Epidemiol, Worcester, MA 01605 USA.; McManus, DD (reprint author), 1355 Lake Ave North, Worcester, MA 01655 USA. EM mcmanusd@ummhc.org FU National Institutes of Health [N01-HC-25195]; Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD; NIH [N01-HC-25195]; Division of Intramural Research, National Heart, Lung, and Blood Institute; Center for Information Technology, National Institutes of Health, Bethesda, MD; National Heart, Lung and Blood Institute of the National Institutes of Health, Bethesda, MA [KL2RR031981, 1R01HL126911-01A1, 1R15HL121761-01A1, 1UH2TR000921-02] FX The Framingham Heart Study is funded by National Institutes of Health contract N01-HC-25195. The laboratory work for this investigation was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD and by NIH contract N01-HC-25195. The analytical component of this project was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, and the Center for Information Technology, National Institutes of Health, Bethesda, MD. DDM's time was supported by KL2RR031981, 1R01HL126911-01A1, 1R15HL121761-01A1, and 1UH2TR000921-02 from the National Heart, Lung and Blood Institute of the National Institutes of Health, Bethesda, MA. NR 43 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD FEB 8 PY 2017 VL 18 AR 139 DI 10.1186/s12864-017-3533-9 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA EL1MG UT WOS:000394383900002 PM 28178938 ER PT J AU Doulatov, S Vo, LT Macari, ER Wahlster, L Kinney, MA Taylor, AM Barragan, J Gupta, M McGrath, K Lee, HY Humphries, JM DeVine, A Narla, A Alter, BP Beggs, AH Agarwal, S Ebert, BL Gazda, HT Lodish, HF Sieff, CA Schlaeger, TM Zon, LI Daley, GQ AF Doulatov, Sergei Vo, Linda T. Macari, Elizabeth R. Wahlster, Lara Kinney, Melissa A. Taylor, Alison M. Barragan, Jessica Gupta, Manav McGrath, Katherine Lee, Hsiang-Ying Humphries, Jessica M. DeVine, Alex Narla, Anupama Alter, Blanche P. Beggs, Alan H. Agarwal, Suneet Ebert, Benjamin L. Gazda, Hanna T. Lodish, Harvey F. Sieff, Colin A. Schlaeger, Thorsten M. Zon, Leonard I. Daley, George Q. TI Drug discovery for Diamond-Blackfan anemia using reprogrammed hematopoietic progenitors SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID PLURIPOTENT STEM-CELLS; RIBOSOMAL-PROTEIN S19; AUTOPHAGY; GENE; ERYTHROPOIESIS; DYSFUNCTION; PRECURSORS; GENERATION; MUTATIONS; REGULATOR AB Diamond-Blackfan anemia (DBA) is a congenital disorder characterized by the failure of erythroid progenitor differentiation, severely curtailing red blood cell production. Because many DBA patients fail to respond to corticosteroid therapy, there is considerable need for therapeutics for this disorder. Identifying therapeutics for DBA requires circumventing the paucity of primary patient blood stem and progenitor cells. To this end, we adopted a reprogramming strategy to generate expandable hematopoietic progenitor cells from induced pluripotent stem cells (iPSCs) from DBA patients. Reprogrammed DBA progenitors recapitulate defects in erythroid differentiation, which were rescued by gene complementation. Unbiased chemical screens identified SMER28, a small-molecule inducer of autophagy, which enhanced erythropoiesis in a range of in vitro and in vivo models of DBA. SMER28 acted through autophagy factor ATG5 to stimulate erythropoiesis and up-regulate expression of globin genes. These findings present an unbiased drug screen for hematological disease using iPSCs and identify autophagy as a therapeutic pathway in DBA. C1 [Doulatov, Sergei; Vo, Linda T.; Macari, Elizabeth R.; Wahlster, Lara; Kinney, Melissa A.; Taylor, Alison M.; Barragan, Jessica; Gupta, Manav; McGrath, Katherine; Humphries, Jessica M.; DeVine, Alex; Agarwal, Suneet; Schlaeger, Thorsten M.; Zon, Leonard I.; Daley, George Q.] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Doulatov, Sergei; Vo, Linda T.; Macari, Elizabeth R.; Wahlster, Lara; Kinney, Melissa A.; Taylor, Alison M.; Barragan, Jessica; Gupta, Manav; McGrath, Katherine; Humphries, Jessica M.; DeVine, Alex; Agarwal, Suneet; Schlaeger, Thorsten M.; Zon, Leonard I.; Daley, George Q.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Doulatov, Sergei; Vo, Linda T.; Macari, Elizabeth R.; Wahlster, Lara; Kinney, Melissa A.; Taylor, Alison M.; Barragan, Jessica; Gupta, Manav; McGrath, Katherine; Humphries, Jessica M.; DeVine, Alex; Narla, Anupama; Agarwal, Suneet; Sieff, Colin A.; Schlaeger, Thorsten M.; Zon, Leonard I.; Daley, George Q.] Boston Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA. [Taylor, Alison M.; Beggs, Alan H.; Agarwal, Suneet; Ebert, Benjamin L.; Gazda, Hanna T.; Sieff, Colin A.; Zon, Leonard I.; Daley, George Q.] Harvard Med Sch, Boston, MA 02115 USA. [Lee, Hsiang-Ying; Lodish, Harvey F.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Lee, Hsiang-Ying; Lodish, Harvey F.] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02142 USA. [Lee, Hsiang-Ying; Lodish, Harvey F.] MIT, Dept Biol Engn, Cambridge, MA 02142 USA. [Narla, Anupama; Ebert, Benjamin L.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Alter, Blanche P.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Beggs, Alan H.; Gazda, Hanna T.] Boston Childrens Hosp, Div Genet & Genom, Boston, MA 02115 USA. [Beggs, Alan H.; Agarwal, Suneet; Gazda, Hanna T.; Daley, George Q.] Manton Ctr Orphan Dis Res, Boston, MA 02115 USA. [Doulatov, Sergei] Univ Washington, Dept Med, Seattle, WA 98195 USA. RP Zon, LI; Daley, GQ (reprint author), Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA.; Zon, LI; Daley, GQ (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA.; Zon, LI; Daley, GQ (reprint author), Boston Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA.; Zon, LI; Daley, GQ (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Daley, GQ (reprint author), Manton Ctr Orphan Dis Res, Boston, MA 02115 USA. EM zon@enders.tch.harvard.edu; george.daley@childrens.harvard.edu FU NIH National Institute of Diabetes and Digestive and Kidney Diseases [R24-DK092760, R24-DK49216, U54DK110805]; National Heart, Lung, and Blood Institute (NHLBI) Progenitor Cell Biology Consortium [UO1-HL100001, U01HL134812]; NHLBI [R01HL04880, 1K99HL123484, R00HL123484-03, R01HL107558]; NIH [R24OD017870-01, K02HL111156]; Alex's Lemonade Stand Foundation; Taub Foundation Grants Program for MDS Research; Doris Duke Medical Foundation; Division of Cancer Epidemiology and Genetics, NCI, NIH; Helen Hay Whitney Foundation; NSF Graduate Research Fellowship; NIH NHLBI [1F32HL124948-01]; University of Heidelberg Medical School; Brigham and Women's Hospital; Charles H. Hood Foundation FX This work was supported by grants from the NIH National Institute of Diabetes and Digestive and Kidney Diseases (R24-DK092760, R24-DK49216, and U54DK110805) and National Heart, Lung, and Blood Institute (NHLBI) Progenitor Cell Biology Consortium (UO1-HL100001 and U01HL134812) (NHLBI R01HL04880 and NIH R24OD017870-01); Alex's Lemonade Stand Foundation; The Taub Foundation Grants Program for MDS Research; and the Doris Duke Medical Foundation. This study was funded in part by the intramural research program of the Division of Cancer Epidemiology and Genetics, NCI, NIH (B.P.A.). G.Q.D. is an associate member of the Broad Institute and an investigator of the Howard Hughes Medical Institute and the Manton Center for Orphan Disease Research. S.D. was supported by NHLBI 1K99HL123484, R00HL123484-03, and the Helen Hay Whitney Foundation. H.T.G. was supported by NIH K02HL111156 and NHLBI R01HL107558. L.T.V. was supported by an NSF Graduate Research Fellowship. E.R.M. was supported by NIH NHLBI 1F32HL124948-01. L.W. was supported by a Career Development Award from the University of Heidelberg Medical School. M.A.K. was supported by a T32 hematology training grant from Brigham and Women's Hospital. H.-Y.L. was supported by a postdoctoral fellowship from the Charles H. Hood Foundation. NR 44 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD FEB 8 PY 2017 VL 9 IS 376 AR eaah5645 DI 10.1126/scitranslmed.aah5645 PG 11 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA EL2LE UT WOS:000394450400002 ER PT J AU Rainwater-Lovett, K Ziemniak, C Watson, D Luzuriaga, K Siberry, G Petru, A Chen, YH Uprety, P McManus, M Ho, YC Lamers, SL Persaud, D AF Rainwater-Lovett, Kaitlin Ziemniak, Carrie Watson, Douglas Luzuriaga, Katherine Siberry, George Petru, Ann Chen, YaHui Uprety, Priyanka McManus, Margaret Ho, Ya-Chi Lamers, Susanna L. Persaud, Deborah TI Paucity of Intact Non-Induced Provirus with Early, Long-Term Antiretroviral Therapy of Perinatal HIV Infection SO PLOS ONE LA English DT Article ID VIRUS TYPE-1 RECOMBINATION; CD4(+) T-CELLS; LATENT RESERVOIR; HIV-1-INFECTED CHILDREN; VIROLOGICAL CONTROL; PERIPHERAL-BLOOD; IMMUNE-RESPONSES; REPLICATION; SUPPRESSION; CURE AB The latent reservoir is a major barrier to HIV eradication. Reservoir size is emerging as an important biomarker to assess the likelihood of HIV remission in the absence of antiretroviral therapy (ART) and may be reduced by earlier initiation of ART that restricts HIV spread into CD4+ T cells. Reservoir size is traditionally measured with a quantitative viral outgrowth assay (QVOA) that induces replication-competent HIV production through in vitro stimulation of resting CD4+ T cells. However, the recent identification of replication-intact, non-induced proviral genomes (NIPG) suggests the QVOA significantly underestimates (by 62-fold) latent reservoir size in chronically-infected adults. Whether formation and persistence of Intact, NIPG is thwarted by early ART initiation and long-term virologic suppression in perinatal infection is unclear. Here, we show that the latent reservoir in 11 early treated, long-term suppressed perinatally infected children and adolescents was not inducible by QVOA and dominated by defective, NIPG. Single genome analysis of 164 NIPG from 232 million cultured resting CD4+ T cells revealed no replication-intact, near-full length sequences. Forty-three (26%) NIPG contained APOBEC3G-mediated hypermutation, 115 (70%) NIPG contained large internal deletions, one NIPG contained nonsense mutations and indels, and 5 (3%) NIPG were assigned as "Not Evaluable" due to multiple failed sequencing attempts that precluded further classification. The lack of replication competent inducible provirus and intact NIPG in this cohort indicate early, long-term ART of perinatal infection leads to marked diminution of replication-competent HIV-1 reservoirs, creating a favorable state towards interventions aimed at virologic remission. C1 [Rainwater-Lovett, Kaitlin; Ziemniak, Carrie; Chen, YaHui; Uprety, Priyanka; Persaud, Deborah] Johns Hopkins Univ, Sch Med, Dept Pediat Infect Dis, Baltimore, MD 21218 USA. [Watson, Douglas] Univ Maryland, Dept Pediat, Baltimore, MD 21201 USA. [Luzuriaga, Katherine; McManus, Margaret] Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA USA. [Siberry, George] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, Rockville, MD USA. [Petru, Ann] Childrens Hosp & Res Ctr Oakland, Dept Pediat Infect Dis, Oakland, CA USA. [Ho, Ya-Chi] Johns Hopkins Univ, Sch Med, Dept Med Infect Dis, Baltimore, MD USA. [Lamers, Susanna L.] Bioinfoexperts LLC, Thibodaux, LA USA. RP Persaud, D (reprint author), Johns Hopkins Univ, Sch Med, Dept Pediat Infect Dis, Baltimore, MD 21218 USA. EM dpers@jhmi.edu FU NIAID; NICHD [R01 HD080474]; Johns Hopkins Center for AIDS Research [P30 A1094189]; International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network; NIAID [UM1 Al068632, UM1 Al068616, UM1 Al106716]; NICHD; NIMH FX This study was supported by the NIAID and NICHD (R01 HD080474 to DP), the Johns Hopkins Center for AIDS Research (P30 A1094189), and subspecialty laboratory funding to DP from the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network. Overall support for IMPAACT was provided by NIAID (UM1 Al068632, UM1 Al068616, and UM1 Al106716) with co-funding from NICHD and NIMH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The funder provided support in the form of salaries for authors [SL], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section. NR 45 TC 0 Z9 0 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 FEB 8 PY 2017 VL 12 IS 2 AR e0170548 DI 10.1371/journal.pone.0170548 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EK1UY UT WOS:000393712500008 PM 28178277 ER PT J AU Damiano, DL Stanley, CJ Bulea, TC Park, HS AF Damiano, Diane L. Stanley, Christopher J. Bulea, Thomas C. Park, Hyung Soon TI Motor Learning Abilities Are Similar in Hemiplegic Cerebral Palsy Compared to Controls as Assessed by Adaptation to Unilateral Leg-Weighting during Gait: Part I SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE asymmetry; aftereffects; cerebellar deficits; brain injury; children ID SPLIT-BELT TREADMILL; LOCOMOTOR ADAPTATION; HUMAN WALKING; REHABILITATION; STROKE; POSTSTROKE; CHILDREN; LIMB AB Introduction: Individuals with cerebral palsy (CP) demonstrate high response variability to motor training insufficiently accounted for by age or severity. We propose here that differences in the inherent ability to learn new motor tasks may explain some of this variability. Damage to motor pathways involving the cerebellum, which may be a direct or indirect effect of the brain injury for many with CP, has been shown to adversely affect the ability to learn new motor tasks and may be a potential explanation. Classic adaptation paradigms that evaluate cerebellar integrity have been utilized to assess adaptation to gait perturbations in adults with stroke, traumatic brain injury and other neurological injuries but not in children with CP. Materials and Methods: A case-control study of 10 participants with and 10 without hemiplegic CP within the age range of 5-20 years was conducted. Mean age of participants in the CP group was slightly but not significantly higher than controls. Step length and swing time adaptation, defined as gradual accommodation to a perturbation, and aftereffects, or maintenance of the accommodation upon removal of the perturbation, to unilateral leg weighing during treadmill gait were quantified to assess group differences in learning. Results: Adaptation and aftereffects were demonstrated in step length across groups with no main effect for group. In CP, the dominant leg had a greater response when either leg was weighted. Swing time accommodated immediately (no adaptation) in the weighted leg only, with the non-dominant leg instead showing a more pronounced response in CP. Discussion: This group of participants with unilateral CP did not demonstrate poorer learning or retention similar to reported results in adult stroke. Deficits, while not found here, may become evident in those with other etiologies or greater severity of CP. Our data further corroborate an observation from the stroke literature that repeated practice of exaggerating the asymmetry (error augmentation), in this case by weighting the more involved or shorter step leg, vs. minimizing it by weighting the less involved or longer step leg (error reduction) may be a useful training strategy to improve step symmetry in unilateral CP. C1 [Damiano, Diane L.; Stanley, Christopher J.; Bulea, Thomas C.] NIH, Funct & Appl Biomech Sect, Bldg 10, Bethesda, MD 20892 USA. [Park, Hyung Soon] Korea Adv Inst Sci & Technol, Dept Mech Engn, Daejeon, South Korea. RP Damiano, DL (reprint author), NIH, Funct & Appl Biomech Sect, Bldg 10, Bethesda, MD 20892 USA. EM damianod@cc.nih.gov FU Intramural Research Program of the NIH Clinical Center FX This work was funded by the Intramural Research Program of the NIH Clinical Center. NR 22 TC 1 Z9 1 U1 6 U2 6 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 FEB 8 PY 2017 VL 11 AR 49 DI 10.3389/fnhum.2017.00049 PG 9 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA EJ9LF UT WOS:000393546900001 PM 28228720 ER PT J AU Nguyen, TA Cisse, OH Wong, JY Zheng, P Hewitt, D Nowrousian, M Stajich, JE Jedd, G AF Tu Anh Nguyen Cisse, Ousmane H. Wong, Jie Yun Zheng, Peng Hewitt, David Nowrousian, Minou Stajich, Jason E. Jedd, Gregory TI Innovation and constraint leading to complex multicellularity in the Ascomycota SO NATURE COMMUNICATIONS LA English DT Article ID GENOME REVEALS; ANIMAL DEVELOPMENT; SEXUAL DEVELOPMENT; HIGH-THROUGHPUT; EVOLUTION; PROTEIN; PEROXISOMES; DYNEIN; DYNACTIN; DOMAIN AB The advent of complex multicellularity (CM) was a pivotal event in the evolution of animals, plants and fungi. In the fungal Ascomycota, CM is based on hyphal filaments and arose in the Pezizomycotina. The genus Neolecta defines an enigma: phylogenetically placed in a related group containing mostly yeasts, Neolecta nevertheless possesses Pezizomycotina-like CM. Here we sequence the Neolecta irregularis genome and identify CM-associated functions by searching for genes conserved in Neolecta and the Pezizomycotina, which are absent or divergent in budding or fission yeasts. This group of 1,050 genes is enriched for functions related to diverse endomembrane systems and their organization. Remarkably, most show evidence for divergence in both yeasts. Using functional genomics, we identify new genes involved in fungal complexification. Together, these data show that rudimentary multicellularity is deeply rooted in the Ascomycota. Extensive parallel gene divergence during simplification and constraint leading to CM suggest a deterministic process where shared modes of cellular organization select for similarly configured organelle- and transport-related machineries. C1 [Tu Anh Nguyen; Wong, Jie Yun; Zheng, Peng; Jedd, Gregory] Natl Univ Singapore, Temasek Life Sci Lab, Singapore 117604, Singapore. [Tu Anh Nguyen; Wong, Jie Yun; Zheng, Peng; Jedd, Gregory] Natl Univ Singapore, Dept Biol Sci, Singapore 117604, Singapore. [Cisse, Ousmane H.; Stajich, Jason E.] Univ Calif Riverside, Inst Integrat Genome Biol, Dept Plant Pathol & Microbiol, Riverside, CA 92521 USA. [Hewitt, David] Acad Nat Sci Philadelphia, Dept Bot, Philadelphia, PA 19103 USA. [Nowrousian, Minou] Ruhr Univ Bochum, Lehrstuhl Allgemeine & Mol Bot, D-44780 Bochum, Germany. [Cisse, Ousmane H.] Natl Inst Hlth, Dept Crit Care Med, Bethesda, MD 20814 USA. RP Jedd, G (reprint author), Natl Univ Singapore, Temasek Life Sci Lab, Singapore 117604, Singapore.; Jedd, G (reprint author), Natl Univ Singapore, Dept Biol Sci, Singapore 117604, Singapore.; Stajich, JE (reprint author), Univ Calif Riverside, Inst Integrat Genome Biol, Dept Plant Pathol & Microbiol, Riverside, CA 92521 USA. EM jason.stajich@ucr.edu; gregory@tll.org.sg OI Cisse, Ousmane/0000-0002-2990-2185; Stajich, Jason/0000-0002-7591-0020 FU Temasek Life Sciences Laboratory; Singapore Millennium Foundation; A.P. Sloan Foundation; USDA Agriculture Experimental Station at the University of California-Riverside; NIFA Hatch project [CA-R-PPA-5062-H]; German Research Foundation [DFG NO407/5-1]; Department of General and Molecular Botany; Swiss National Science Foundation [151780]; National Institutes of Health [P01 GM068087] FX Research in the Jedd group is funded by the Temasek Life Sciences Laboratory and Singapore Millennium Foundation. J.E.S. was supported by the A.P. Sloan Foundation, USDA Agriculture Experimental Station at the University of California-Riverside and NIFA Hatch project CA-R-PPA-5062-H. M.N. was supported by the German Research Foundation (DFG NO407/5-1) and thanks Ulrich Kuck for his support at the Department of General and Molecular Botany. O.H.C was supported by the Swiss National Science Foundation fellowship grant no. 151780. We thank Zhang Louxin for insightful discussion, Dillon McDonald and Katherine Borkovich for help with Saitoella experiments, Don Pfister, Pete and Kitty Griffith for help with Neolecta fruiting bodies collection, and gratefully acknowledge use of deletion mutants generated by National Institutes of Health Grant P01 GM068087 'Functional Analysis of a Model Filamentous Fungus'. NR 88 TC 0 Z9 0 U1 11 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD FEB 8 PY 2017 VL 8 AR 14444 DI 10.1038/ncomms14444 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EJ8EU UT WOS:000393458800001 PM 28176784 ER PT J AU Jin, LL Liu, Y Sun, FY Collins, MT Blackwell, K Woo, AS Reichenberger, EJ Hu, Y AF Jin, Lingling Liu, Yi Sun, Fanyue Collins, Michael T. Blackwell, Keith Woo, Albert S. Reichenberger, Ernst J. Hu, Ying TI Three novel ANO5 missense mutations in Caucasian and Chinese families and sporadic cases with gnathodiaphyseal dysplasia SO SCIENTIFIC REPORTS LA English DT Article ID FIBROOSSEOUS LESIONS; MUSCULAR-DYSTROPHY; BONE; GENE; PROTEIN; DIFFERENTIATION; MINERALIZATION; EXPRESSION AB Gnathodiaphyseal dysplasia (GDD; MIM#166260) is an autosomal dominant syndrome with characteristic cemento-osseous lesions of jawbones, bone fragility, and diaphyseal sclerosis of tubular bones. To date, only five mutations in the proposed calcium-activated chloride channel ANO5/TMEM16E gene have been identified. In this study, we describe two families and two singular patients with three new mutations. One Caucasian family with seven affected members exhibited frequent bone fractures and florid osseous dysplasia (p. Cys356Tyr), while one Chinese family with two affected members suffered from cementoma and purulent osteomyelitis (p. Cys360Tyr). In addition, two different novel mutations (p. Gly518Glu and p. Arg215Gly) were identified in sporadic patients without family history. In vitro studies overexpressing GDD mutations (p. Cys356Tyr and p. Cys360Tyr) showed significantly reduced ANO5 protein. It appears that all GDD mutations known so far locate in an extracellular domain following the first transmembrane domain or in the 4th putative transmembrane domain. Both wildtype and mutant ANO5 protein localize to the endoplasmic reticulum. After Ano5 gene knock-down with shRNA in MC3T3-E1 osteoblast precursors we saw elevated expression of osteoblast-related genes such as Col1a1, osteocalcin, osterix and Runx2 as well as increased mineral nodule formation in differentiating cells. Our data suggest that ANO5 plays a role in osteoblast differentiation. C1 [Jin, Lingling; Hu, Ying] Capital Med Univ, Beijing Stomatol Hosp, Beijing Inst Dent Res, Beijing, Peoples R China. [Liu, Yi] Capital Med Univ, Beijing Stomatol Hosp, Dept Maxillofacial Surg, Beijing, Peoples R China. [Sun, Fanyue; Reichenberger, Ernst J.] Univ Connecticut Hlth, Ctr Regenerat Med & Skeletal Dev, Dept Reconstruct Sci, Farmington, CT 06030 USA. [Collins, Michael T.] Natl Inst Dent & Craniofacial Res NIDCR, Bethesda, MD 20892 USA. [Blackwell, Keith] Univ Calif Los Angeles, Dept Head & Neck Surg, Los Angeles, CA 90095 USA. [Woo, Albert S.] Brown Univ, Warren Alpert Med Sch, Div Plast Craniofacial & Pediat Surg, Providence, RI 02903 USA. RP Hu, Y (reprint author), Capital Med Univ, Beijing Stomatol Hosp, Beijing Inst Dent Res, Beijing, Peoples R China.; Reichenberger, EJ (reprint author), Univ Connecticut Hlth, Ctr Regenerat Med & Skeletal Dev, Dept Reconstruct Sci, Farmington, CT 06030 USA. EM reichenberger@uchc.edu; hyshuai@ccmu.edu.cn FU School of Stomatology, Capital Medical University; UCH; National Natural Science Foundation of China [81570958]; High-level Talents of Beijing Health System [2013-3-036]; Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry [2015-1098]; DIR NIDCR; CRC (University of Connecticut Clinical Research Center (NIH grant) [M01RR006192] FX We thank all individuals for participating in this study and for institutional support from the School of Stomatology, Capital Medical University and UCH. We thank Drs P.G. Robey and S. Kuznetsov for providing patient cells for genetic analysis. This work was supported by the National Natural Science Foundation of China (Grant #81570958); High-level Talents of Beijing Health System (grant # 2013-3-036); Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry (grant # 2015-1098); the DIR NIDCR; and the CRC (University of Connecticut Clinical Research Center, (NIH grant # M01RR006192)). NR 29 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD FEB 8 PY 2017 VL 7 AR 40935 DI 10.1038/srep40935 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EK0GE UT WOS:000393604000001 PM 28176803 ER PT J AU Dai, JQ Voloshin, O Potapova, S Camerini-Otero, RD AF Dai, Jieqiong Voloshin, Oleg Potapova, Svetlana Camerini-Otero, R. Daniel TI Meiotic Knockdown and Complementation Reveals Essential Role of RAD51 in Mouse Spermatogenesis SO CELL REPORTS LA English DT Article ID DOUBLE-STRAND BREAKS; RECA HOMOLOGS RAD51; CHROMOSOME SYNAPSIS; SACCHAROMYCES-CEREVISIAE; PROPHASE ARREST; GENE-TRANSFER; IN-VIVO; DMC1; RECOMBINATION; MEIOSIS AB Meiotic homologous recombination (HR) is important for proper chromosomal segregation during gametogenesis and facilitates evolutionary adaptation via genomic reshuffling. In most eukaryotes, HR is mediated by two recombinases, the ubiquitous RAD51 and the meiosis- specific DMC1. The role of RAD51 in mammalian meiosis is unclear and study of its function is limited due to embryonic lethality of RAD51 knockouts. Here, we developed an in vivo meiotic knockdown and protein complementation system to study RAD51 during mouse spermatogenesis. We show that RAD51 is crucial during meiotic prophase and its loss leads to depletion of late prophase I spermatocytes through a p53- dependent apoptotic pathway. This phenotype is distinct from that observed in the DMC1 knockdown. Our meiotic knockdown and complementation system establishes an experimental platform for mechanistic studies of meiotic proteins with unknown functions or essential genes for which a testis- specific knockout is not possible. C1 [Dai, Jieqiong; Voloshin, Oleg; Camerini-Otero, R. Daniel] NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. [Potapova, Svetlana] NIDDK, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Camerini-Otero, RD (reprint author), NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. EM rdcamerini@mail.nih.gov FU NIDDK Intramural Research Program FX We are grateful to G. Petukhova (Uniformed Services University of Health Sciences), P. Hsieh, F. Pratto, and K. Brick (National Institute of Diabetes and Digestive and Kidney Diseases) for valuable comments and discussion of the manuscript. We also thank M. A. Handel (The Jackson Laboratory) for the H1t antibody. This work was supported by the NIDDK Intramural Research Program (to R.D.C.-O.). NR 45 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD FEB 7 PY 2017 VL 18 IS 6 BP 1383 EP 1394 DI 10.1016/j.celrep.2017.01.024 PG 12 WC Cell Biology SC Cell Biology GA EP4AR UT WOS:000397323400005 PM 28178517 ER PT J AU Flici, H Schnitzler, CE Millane, RC Govinden, G Houlihan, A Boomkamp, SD Shen, SB Baxevanis, AD Frank, U AF Flici, Hakima Schnitzler, Christine E. Millane, R. Cathriona Govinden, Graham Houlihan, Amy Boomkamp, Stephanie D. Shen, Sanbing Baxevanis, Andreas D. Frank, Uri TI An Evolutionarily Conserved SoxB-Hdac2 Crosstalk Regulates Neurogenesis in a Cnidarian SO CELL REPORTS LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; HISTONE DEACETYLASES 1; EMBRYONIC STEM-CELLS; MULTIPLE SOX GENES; NEMATOSTELLA-VECTENSIS; TRANSCRIPTION FACTOR; BRAIN-DEVELOPMENT; PROGENITOR CELLS; BETA-CATENIN; DIFFERENTIATION AB SoxB transcription factors and histone deacetylases (HDACs) are each major players in the regulation of neurogenesis, but a functional link between them has not been previously demonstrated. Here, we show that SoxB2 and Hdac2 act together to regulate neurogenesis in the cnidarian Hydractinia echinata during tissue homeostasis and head regeneration. We find that misexpression of SoxB genes modifies the number of neural cells in all life stages and interferes with head regeneration. Hdac2 was coexpressed with SoxB2, and its downregulation phe-nocopied SoxB2 knockdown. We also show that SoxB2 and Hdac2 promote each other's transcript levels, but Hdac2 counteracts this amplification cycle by deacetylating and destabilizing SoxB2 protein. Finally, we present evidence for conservation of these interactions in human neural progenitors. We hypothesize that crosstalk between SoxB transcription factors and Hdac2 is an ancient feature of metazoan neurogenesis and functions to stabilize the correct levels of these multifunctional proteins. C1 [Flici, Hakima; Millane, R. Cathriona; Govinden, Graham; Houlihan, Amy; Frank, Uri] Natl Univ Ireland, Sch Nat Sci, CCB, Galway H91 CF50, Ireland. [Schnitzler, Christine E.] Univ Florida, Whitney Lab Marine Biosci, St Augustine, FL 32080 USA. [Schnitzler, Christine E.] Univ Florida, Dept Biol, Gainesville, FL 32611 USA. [Schnitzler, Christine E.; Baxevanis, Andreas D.] NHGRI, Computat & Stat Genom Branch, NIH, Bethesda, MD 20892 USA. [Boomkamp, Stephanie D.; Shen, Sanbing] Natl Univ Ireland, Regenerat Med Inst REMEDI, Galway H91 CF50, Ireland. RP Frank, U (reprint author), Natl Univ Ireland, Sch Nat Sci, CCB, Galway H91 CF50, Ireland. EM uri.frank@nuigalway.ie FU Science Foundation Ireland (SFI) [11/PI/1020]; Intramural Research Program of the National Human Genome Research Institute,NIH FX We thank members of the Frank lab for advice and assistance. HDAC2 inhibitors BRD4884 and BRD6688 were a kind gift from F.F. Wagner and E.B. Holson, Broad Institute of Harvard and MIT. Class I Hdac inhibitor RGFP966 was kindly provided by Bob Lahue, Centre for Chromosome Biology, NUI Galway. Ncol3 antibody was a kind gift from SuatO " zbek, University of Heidelberg.Katya McDonagh and Martin Madill, REMEDI, NUI Galway, are kindly acknowledged for providing human neural progenitors. This work was supported by Science Foundation Ireland (SFI) through grant number 11/PI/1020 to U.F. This work was also supported in part by the Intramural Research Program of the National Human Genome Research Institute,NIH NR 56 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD FEB 7 PY 2017 VL 18 IS 6 BP 1395 EP 1409 DI 10.1016/j.celrep.2017.01.019 PG 15 WC Cell Biology SC Cell Biology GA EP4AR UT WOS:000397323400006 PM 28178518 ER PT J AU Russell, RA Chojnacki, J Jones, DM Johnson, E Do, T Eggeling, C Padilla-Parra, S Sattentau, QJ AF Russell, Rebecca A. Chojnacki, Jakub Jones, Daniel M. Johnson, Errin Do, Thao Eggeling, Christian Padilla-Parra, Sergi Sattentau, Quentin J. TI Astrocytes Resist HIV-1 Fusion but Engulf Infected Macrophage Material SO CELL REPORTS LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN FETAL ASTROCYTES; CENTRAL-NERVOUS-SYSTEM; HUMAN GLIAL-CELLS; LASER CAPTURE MICRODISSECTION; CHEMOKINE RECEPTORS; POTENTIAL ROLE; PRODUCTIVE INFECTION; SITU HYBRIDIZATION; TYPE-1 INFECTION AB HIV-1 disseminates to diverse tissues and establishes long-lived viral reservoirs. These reservoirs include the CNS, in which macrophage-lineage cells, and as suggested by many studies, astrocytes, may be infected. Here, we have investigated astrocyte infection by HIV-1. We confirm that astrocytes trap and internalize HIV-1 particles for subsequent release but find no evidence that these particles infect the cell. Astrocyte infection was not observed by cell-free or cell-to-cell routes using diverse approaches, including luciferase and GFP reporter viruses, fixed and live-cell fusion assays, multispectral flow cytometry, and super-resolution imaging. By contrast, we observed intimate interactions between HIV-1-infected macrophages and astrocytes leading to signals that might be mistaken for astrocyte infection using less stringent approaches. These results have implications for HIV-1 infection of the CNS, viral reservoir formation, and antiretroviral therapy. C1 [Russell, Rebecca A.; Johnson, Errin; Sattentau, Quentin J.] Univ Oxford, Sir William Dunn Sch Pathol, South Parks Rd, Oxford OX1 3RE, England. [Chojnacki, Jakub; Eggeling, Christian] Univ Oxford, Weatherall Inst Mol Med, MRC Human Immunol Unit, Oxford OX3 9DS, England. [Jones, Daniel M.; Padilla-Parra, Sergi] Univ Oxford, Henry Wellcome Bldg Genom Med, Div Struct Biol, Oxford OX3 7BN, England. [Jones, Daniel M.; Padilla-Parra, Sergi] Univ Oxford, Wellcome Trust Ctr Human Genet, Cellular Imaging Core, Oxford OX3 7BN, England. [Do, Thao] NIH, Natl Canc Inst, Ctr Canc Res, Cell Biol Lab, Bethesda, MD 20892 USA. RP Sattentau, QJ (reprint author), Univ Oxford, Sir William Dunn Sch Pathol, South Parks Rd, Oxford OX1 3RE, England. EM quentin.sattentau@path.ox.ac.uk FU Medical Research Council [MC_UU_12010, G0902418, MC_UU_12025]; Wolfson Foundation [18272]; MRC/BBSRC/EPSRC [MR/K01577X/1]; Wellcome Trust [104924/14/Z/14]; Deutsche Forschungsgemeinschaft [1905]; Nuffield Department of Medicine Leadership Fellowship from Oxford University; Wellcome Trust Centre for Human Genetics is supported by Wellcome Trust [090532/Z/09/Z]; Cellular Imaging Core from the Wellcome Trust Centre for Human Genetics; Wolfson Imaging Centre at the Weatherall Institute of Molecular Medicine FX J.C. and C.E. were supported by The Medical Research Council (grant MC_UU_12010 and unit programs G0902418 and MC_UU_12025), the Wolfson Foundation (grant 18272), MRC/BBSRC/EPSRC (grant MR/K01577X/1), Wellcome Trust (grant 104924/14/Z/14), and the Deutsche Forschungsgemeinschaft (grant 1905, Research unit 1905, "Structure and Function of the Peroxisomal Translocon''). The S.P.-P. research group is funded by the Nuffield Department of Medicine Leadership Fellowship from Oxford University. The Wellcome Trust Centre for Human Genetics is supported by Wellcome Trust (grant 090532/Z/09/Z). We thank the Cellular Imaging Core from the Wellcome Trust Centre for Human Genetics and the Wolfson Imaging Centre at the Weatherall Institute of Molecular Medicine for their support and input. Q. J. S. is a Jenner investigator and a James Martin senior fellow. Electron microscopy was performed at the Dunn School EM Facility, and we are grateful to Anna Pielach for preparing the EM samples. NR 59 TC 0 Z9 0 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD FEB 7 PY 2017 VL 18 IS 6 BP 1473 EP 1483 DI 10.1016/j.celrep.2017.01.027 PG 11 WC Cell Biology SC Cell Biology GA EP4AR UT WOS:000397323400012 PM 28178524 ER PT J AU Gill, J Merchant-Borna, K Jeromin, A Livingston, W Bazarian, J AF Gill, Jessica Merchant-Borna, Kian Jeromin, Andreas Livingston, Whitney Bazarian, Jeffrey TI Acute plasma tau relates to prolonged return to play after concussion SO NEUROLOGY LA English DT Article ID TRAUMATIC BRAIN-INJURY; SPORTS-RELATED CONCUSSION; ICE HOCKEY PLAYERS; CEREBROSPINAL-FLUID; NEUROTROPHIC FACTOR; EXERCISE; ENCEPHALOPATHY; BIOMARKERS; MANAGEMENT; IMPACT AB Objective: To determine whether tau changes after sport-related concussion (SRC) relate to return to play (RTP). Methods: Collegiate athletes underwent preseason plasma sampling and cognitive testing and were followed. After a SRC (n = 46), athletes and controls (n 5 37) had sampling at 6 hours, and at 24 hours, 72 hours, and 7 days after SRC. A sample of 21 nonathlete controls were compared at baseline. SRC athletes were grouped by long (. 10 days, n = 23) and short (< 10 days, n = 18) RTP. Total tau was measured using an ultrasensitive immunoassay. Results: Both SRC and athlete controls had significantly higher mean tau at baseline compared to nonathlete healthy controls (F-101,(3) = 19.644, p, < 0.01). Compared to SRC athletes with short RTP, those with long RTP had higher tau concentrations overall, after controlling for sex (F-39,1 = 3.59, p = 0.022), compared to long RTP athletes, at 6 (p, 0.01), 24 (p, 0.01), and 72 hours (p = 0.02). Receiver operator characteristic analyses showed that higher plasma tau 6 hours postSRC was a significant predictor of RTP.10 days (area under the curve 0.81; 95% confidence interval 0.62-0.97, p = 0.01). Conclusions: Elevated plasma tau concentration within 6 hours following a SRC was related to having a prolonged RTP, suggesting that tau levels may help inform RTP. C1 [Gill, Jessica; Livingston, Whitney] NINR, NIH, Bethesda, MD 20892 USA. [Merchant-Borna, Kian; Bazarian, Jeffrey] Univ Rochester, Sch Med & Dent, Dept Emergency Med, Rochester, NY USA. [Jeromin, Andreas] Quanterix Corp, Lexington, MA USA. RP Gill, J (reprint author), NINR, NIH, Bethesda, MD 20892 USA. EM gillj@mail.nih.gov FU NIH/NICHD [K24HD064754]; NIH; National Institute of Nursing Research Intramural Research Program FX This work was supported by funds from the NIH/NICHD (award no.K24HD064754) and the NIH, National Institute of Nursing Research Intramural Research Program. NR 35 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 7 PY 2017 VL 88 IS 6 BP 595 EP 602 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA EP4HR UT WOS:000397342100015 PM 28062722 ER PT J AU Thompson, PM Ramachandran, S Case, LB Tolbert, CE Tandon, A Pershad, M Dokholyan, NV Waterman, CM Campbell, SL AF Thompson, Peter M. Ramachandran, Srinivas Case, Lindsay B. Tolbert, Caitlin E. Tandon, Arpit Pershad, Mihir Dokholyan, Nikolay V. Waterman, Clare M. Campbell, Sharon L. TI A Structural Model for Vinculin Insertion into PIP2-Containing Membranes and the Effect of Insertion on Vinculin Activation and Localization SO STRUCTURE LA English DT Article ID DISCRETE MOLECULAR-DYNAMICS; CELL MECHANICAL-PROPERTIES; PROTEIN-KINASE-C; F-ACTIN-BINDING; FOCAL ADHESION; TAIL DOMAIN; I-GAMMA; INTRAMOLECULAR ASSOCIATION; PTDINS(4,5)P-2 SYNTHESIS; NANOSCALE ARCHITECTURE AB Vinculin, a scaffolding protein that localizes to focal adhesions (FAs) and adherens junctions, links the actin cytoskeleton to the adhesive super-structure. While vinculin binds to a number of cytoskeletal proteins, it can also associate with phosphatidylinositol 4,5-bisphosphate (PIP2) to drive membrane association. To generate a structural model for PIP2-dependent interaction of vinculin with the lipid bilayer, we conducted lipid-association, nuclear magnetic resonance, and computational modeling experiments. We find that two basic patches on the vinculin tail drive membrane association: the basic collar specifically recognizes PIP2, while the basic ladder drives association with the lipid bilayer. Vinculin mutants with defects in PIP2-dependent liposome association were then expressed in vinculin knockout murine embryonic fibroblasts. Results from these analyses indicate that PIP2 binding is not required for localization of vinculin to FAs or FA strengthening, but is required for vinculin activation and turnover at FAs to promote its association with the force transduction FA nanodomain. C1 [Thompson, Peter M.; Ramachandran, Srinivas; Tandon, Arpit; Dokholyan, Nikolay V.; Campbell, Sharon L.] Univ North Carolina Chapel Hill, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. [Case, Lindsay B.; Waterman, Clare M.] NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. [Tolbert, Caitlin E.] Univ North Carolina Chapel Hill, Dept Cell Biol & Physiol, Chapel Hill, NC 27599 USA. [Pershad, Mihir] Univ North Carolina Chapel Hill, Dept Chem, Chapel Hill, NC 27599 USA. [Dokholyan, Nikolay V.; Campbell, Sharon L.] Univ North Carolina Chapel Hill, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Thompson, Peter M.] NIEHS, Lab Genome Integr & Struct Biol, POB 12233, Res Triangle Pk, NC 27709 USA. [Ramachandran, Srinivas] Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98109 USA. [Case, Lindsay B.; Waterman, Clare M.] Univ Texas Southwestern Med Ctr Dallas, Dept Biophys, Dallas, TX 75390 USA. [Tolbert, Caitlin E.] Francis Crick Inst, Cellular Signaling & Cytoskeletal Funct Lab, London NW1 1AT, England. RP Campbell, SL (reprint author), Univ North Carolina Chapel Hill, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA.; Campbell, SL (reprint author), Univ North Carolina Chapel Hill, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. EM campbesl@med.unc.edu OI Ramachandran, Srinivas/0000-0003-2929-1377 FU American Heart Association [12PRE11820012]; NIH [1R01GM115597, GM029860] FX P.M.T. was supported by the American Heart Association (12PRE11820012). Funding to S.L.C. and N.V.D. was supported by the NIH (1R01GM115597). Funding to C.E.T. was supported by the NIH (GM029860). The authors wish to thank Evan Nelsen, Greg Young, and Paul Sapienza for their assistance with methods as well as Keith Burridge for his feedback on the manuscript. NR 58 TC 0 Z9 0 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 EI 1878-4186 J9 STRUCTURE JI Structure PD FEB 7 PY 2017 VL 25 IS 2 BP 264 EP 275 DI 10.1016/j.str.2016.12.002 PG 12 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA EO4ZL UT WOS:000396702700008 PM 28089450 ER PT J AU Markovic-Mueller, S Stuttfeld, E Asthana, M Weinert, T Bliven, S Goldie, KN Kisko, K Capitani, G Ballmer-Hofer, K AF Markovic-Mueller, Sandra Stuttfeld, Edward Asthana, Mayanka Weinert, Tobias Bliven, Spencer Goldie, Kenneth N. Kisko, Kaisa Capitani, Guido Ballmer-Hofer, Kurt TI Structure of the Full-length VEGFR-1 Extracellular Domain in Complex with VEGF-A SO STRUCTURE LA English DT Article ID ENDOTHELIAL-GROWTH-FACTOR; RECEPTOR TYROSINE KINASE; STEM-CELL FACTOR; LIGAND-BINDING; CRYSTAL-STRUCTURE; FLT-1 RECEPTOR; ACTIVATION; ANGIOGENESIS; DIMERIZATION; CONTACTS AB Vascular endothelial growth factors (VEGFs) regulate blood and lymph vessel development upon activation of three receptor tyrosine kinases: VEGFR-1, -2, and -3. Partial structures of VEGFR/VEGF complexes based on single-particle electron microscopy, small-angle X-ray scattering, and X-ray crystallography revealed the location of VEGF binding and domain arrangement of individual receptor subdomains. Here, we describe the structure of the full-length VEGFR-1 extracellular domain in complex with VEGF-A at 4 angstrom resolution. We combined X-ray crystallography, single-particle electron microscopy, and molecular modeling for structure determination and validation. The structure reveals the molecular details of ligand-induced receptor dimerization, in particular of homotypic receptor interactions in immunoglobulin homology domains 4, 5, and 7. Functional analyses of ligand binding and receptor activation confirm the relevance of these homotypic contacts and identify them as potential therapeutic sites to allosterically inhibit VEGFR-1 activity. C1 [Markovic-Mueller, Sandra; Asthana, Mayanka; Weinert, Tobias; Bliven, Spencer; Kisko, Kaisa; Capitani, Guido; Ballmer-Hofer, Kurt] Paul Scherrer Inst, Lab Biomol Res, CH-5232 Villigen, Switzerland. [Stuttfeld, Edward] Univ Basel, Biozentrum, CH-4056 Basel, Switzerland. [Goldie, Kenneth N.] Univ Basel, Biozentrum, C CINA, CH-4056 Basel, Switzerland. [Bliven, Spencer] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Markovic-Mueller, Sandra] LeadXpro AG, Pk Innovaare, CH-5234 Villigen, Switzerland. RP Ballmer-Hofer, K (reprint author), Paul Scherrer Inst, Lab Biomol Res, CH-5232 Villigen, Switzerland. EM kurt.ballmer-hofer@unibas.ch FU Swiss National Science Foundation [31003A-130463]; Oncosuisse [OC2 01200-08-2007]; Intramural Research Program of the NCBI; National Library of Medicine; NIH (United States) FX K.B.-H. thanks the Swiss National Science Foundation (grant 31003A-130463) and Oncosuisse (grant OC2 01200-08-2007) for continuous support of his research. S.B. was supported by the Intramural Research Program of the NCBI, National Library of Medicine, and NIH (United States). We are also grateful to Thomas Schleier, Kate Thieltges, and Julia Kostin for technical assistance and the staff of the X06SA and X06DA beamlines of the Swiss Light Source for their support during data collection. We thank the Foldit players and Firas Khatib for modeling D1 and D6 (https://fold.it/portal/info/credits). NR 58 TC 0 Z9 0 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 EI 1878-4186 J9 STRUCTURE JI Structure PD FEB 7 PY 2017 VL 25 IS 2 BP 341 EP 352 DI 10.1016/j.str.2016.12.012 PG 12 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA EO4ZL UT WOS:000396702700015 PM 28111021 ER PT J AU Song, H Fang, XY Jin, L Shaw, GX Wang, YX Ji, XH AF Song, He Fang, Xianyang Jin, Lan Shaw, Gary X. Wang, Yun-Xing Ji, Xinhua TI The Functional Cycle of Rnt1p: Five Consecutive Steps of Double-Stranded RNA Processing by a Eukaryotic RNase III SO STRUCTURE LA English DT Article ID SMALL-ANGLE SCATTERING; MOLECULAR-STRUCTURE DETERMINATION; X-RAY-SCATTERING; RIBONUCLEASE-III; BIOLOGICAL MACROMOLECULES; STRUCTURAL BASIS; XPLOR-NIH; MECHANISM; DICER; COMPLEX AB Double-stranded RNA (dsRNA)-specific RNase III proteins are required for RNA maturation and gene regulation. The mechanism of prokaryotic RNase IIIs has been well characterized, but how eukaryotic RNase IIIs (exemplified by Rnt1p, Drosha, and Dicer) work is less clear. Recently, we reported the crystal structure of Rnt1p in complex with RNA, revealing a double-ruler mechanism for substrate selection. Here, we present more structures of Rnt1p, either RNA free or RNA bound, featuring two major conformations of the enzyme. Using these structures with existing data, we describe the functional cycle of Rnt1p in five steps, selecting, loading, locking, cleavage, and releasing. We also describe atomic details of the two-Mg2+-ion catalytic mechanism that is applicable to all eukaryotic RNase III enzymes. Overall, our results indicate that substrate selection is achieved independent of cleavage, allowing the recognition of substrates with different structures while preserving the basic mechanism of cleavage. C1 [Song, He; Jin, Lan; Shaw, Gary X.; Ji, Xinhua] NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. [Fang, Xianyang; Wang, Yun-Xing] NCI, Struct Biophys Lab, Frederick, MD 21702 USA. [Fang, Xianyang] Tsinghua Univ, Sch Life Sci, Beijing 100084, Peoples R China. RP Ji, XH (reprint author), NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. EM jix@mail.nih.gov FU Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357, 22978]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX We thank Dr. Xiaobing Zuo for assistance with the SAXS experiments and Drs. Sherif Abou Elela, Donald Court, and Alexander Wlodawer for critical reading of the manuscript and insightful discussions. X-ray diffraction data were collected at the SER-CAT beamlines of the Advanced Photon Source (APS), Argonne National Laboratory (ANL). SAXS data were collected at the APS beamline 12-ID-B, ANL. Use of the APS was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract no. DE-AC02-06CH11357 and under the Partner User Proposal PUP no. 22978. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 48 TC 0 Z9 0 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 EI 1878-4186 J9 STRUCTURE JI Structure PD FEB 7 PY 2017 VL 25 IS 2 BP 353 EP 363 DI 10.1016/j.str.2016.12.013 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA EO4ZL UT WOS:000396702700016 PM 28111020 ER PT J AU Dalgard, C Eidelman, O Jozwik, C Olsen, CH Srivastava, M Biswas, R Eudy, Y Rothwell, SW Mueller, GP Yuan, P Drevets, WC Manji, HK Vythlingam, M Charney, DS Neumeister, A Ursano, RJ Jacobowitz, DM Pollard, HB Bonne, O AF Dalgard, C. Eidelman, O. Jozwik, C. Olsen, C. H. Srivastava, M. Biswas, R. Eudy, Y. Rothwell, S. W. Mueller, G. P. Yuan, P. Drevets, W. C. Manji, H. K. Vythlingam, M. Charney, D. S. Neumeister, A. Ursano, R. J. Jacobowitz, D. M. Pollard, H. B. Bonne, O. TI The MCP-4/MCP-1 ratio in plasma is a candidate circadian biomarker for chronic post-traumatic stress disorder SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID CEREBROSPINAL-FLUID; MONOCYTES; SLEEP; INFLAMMATION; DEPRESSION; CHEMOKINE; TRAUMA; RHYTHM; CLOCK AB Post-traumatic stress disorder (PTSD) is psychiatric disease, which can occur following exposure to traumatic events. PTSD may be acute or chronic, and can have a waxing and waning course of symptoms. It has been hypothesized that proinflammatory cytokines and chemokines in the cerebrospinal fluid (CSF) or plasma might be mediators of the psychophysiological mechanisms relating a history of trauma exposure to changes in behavior and mental health disorders, and medical morbidity. Here we test the cytokine/ chemokine hypothesis for PTSD by examining levels of 17 classical cytokines and chemokines in CSF, sampled at 0900 hours, and in plasma sampled hourly for 24 h. The PTSD and healthy control patients are from the NIMH Chronic PTSD and healthy control cohort, initially described by Bonne et al. (2011), in which the PTSD patients have relatively low comorbidity for major depressive disorder (MDD), drug or alcohol use. We find that in plasma, but not CSF, the bivariate MCP4 (CCL13)/MCP1(CCL2) ratio is ca. twofold elevated in PTSD patients compared with healthy controls. The MCP-4/MCP-1 ratio is invariant over circadian time, and is independent of gender, body mass index or the age at which the trauma was suffered. By contrast, MIP-1 alpha is a candidate biomarker for PTSD only in females, whereas TARC is a candidate biomarker for PTSD only in males. It remains to be discovered whether these disease-specific differences in circadian expression for these specific immune signaling molecules are biomarkers, surrogates, or drivers for PTSD, or whether any of these analytes could contribute to therapy. C1 [Dalgard, C.; Eidelman, O.; Srivastava, M.; Biswas, R.; Eudy, Y.; Rothwell, S. W.; Mueller, G. P.; Jacobowitz, D. M.; Pollard, H. B.] Uniformed Serv Univ Hlth Sci, Uniformed Serv Univ Sch Med, Dept Anat Physiol & Genet, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. [Dalgard, C.; Jozwik, C.; Srivastava, M.; Biswas, R.; Mueller, G. P.; Jacobowitz, D. M.; Pollard, H. B.] Uniformed Serv Univ Hlth Sci, Uniformed Serv Univ Sch Med, CHIRP, Bethesda, MD 20814 USA. [Jozwik, C.] Henry M Jackson Fdn Mil Med, Bethesda, MD USA. [Olsen, C. H.] Uniformed Serv Univ Hlth Sci, Uniformed Serv Univ Sch Med, Dept Prevent Med & Biometr, Bethesda, MD 20814 USA. [Yuan, P.] NIMH, Mood & Anxiety Disorders Branch, Bethesda, MD 20892 USA. [Rothwell, S. W.; Mueller, G. P.] LLC, Janssen Res & Dev, Johnson & Johnson, Titusville, NJ USA. [Vythlingam, M.] United States Dept Def, Washington, DC USA. [Vythlingam, M.; Charney, D. S.] Mt Sinai Sch Med, Office Dean, New York, NY USA. [Neumeister, A.] Mitsubishi Tanabe Pharma Dev Amer, Jersey City, NJ USA. [Ursano, R. J.] Uniformed Serv Univ Hlth Sci, Uniformed Serv Univ Sch Med, Dept Psychiat, Bethesda, MD 20814 USA. [Ursano, R. J.] Uniformed Serv Univ Hlth Sci, Uniformed Serv Univ Sch Med, Ctr Study Traumat Stress, Bethesda, MD 20814 USA. [Bonne, O.] Hadassah Med Ctr, Dept Psychiat, Jerusalem, Israel. RP Pollard, HB (reprint author), Uniformed Serv Univ Hlth Sci, Uniformed Serv Univ Sch Med, Dept Anat Physiol & Genet, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM Harvey.pollard@usuhs.edu; bonne@hadassah.org.il FU CDMRP [W81WH-08-2-0201]; Center for Neurology and Regenerative Medicine (CNRM); Center for Studies on Traumatic Stress (CSTS); Collaborative Health Initiative Research Program (CHIRP) FX We acknowledge support from CDMRP No. W81WH-08-2-0201, PI: HBP); the Center for Neurology and Regenerative Medicine (CNRM; PI: HBP); and Center for Studies on Traumatic Stress (CSTS, PI: RJU); and Collaborative Health Initiative Research Program (CHIRP, PI: HBP). We also acknowledge the National Institute of Mental Health (NIMH, NIH) clinical study for which both NIH and USUHS Institutional Investigational Review Board (IRB) approvals made samples of CSF and plasma available for this study (Protocol 02-M-0317; PI: OB). NR 32 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 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD FEB 7 PY 2017 VL 7 AR e1025 DI 10.1038/tp.2016.285 PG 11 WC Psychiatry SC Psychiatry GA EP2KY UT WOS:000397213200003 PM 28170001 ER PT J AU Crowley, MJ Diamantidis, CJ McDuffie, JR Cameron, CB Stanifer, JW Mock, CK Wang, XW Tang, S Nagi, A Kosinski, AS Williams, JW AF Crowley, Matthew J. Diamantidis, Clarissa J. McDuffie, Jennifer R. Cameron, C. Blake Stanifer, John W. Mock, Clare K. Wang, Xianwei Tang, Shuang Nagi, Avishek Kosinski, Andrzej S. Williams, John W., Jr. TI Clinical Outcomes of Metformin Use in Populations With Chronic Kidney Disease, Congestive Heart Failure, or Chronic Liver Disease A Systematic Review SO ANNALS OF INTERNAL MEDICINE LA English DT Review ID CARDIOVASCULAR EVENTS; DIABETES-MELLITUS; SERUM CREATININE; OLDER-ADULTS; MORTALITY; METAANALYSIS; TRIALS; COHORT; RISK; ASSOCIATION AB Background: Recent changes to the U.S. Food and Drug Administration boxed warning for metformin will increase its use in persons with historical contraindications or precautions. Prescribers must understand the clinical outcomes of metformin use in these populations. Purpose: To synthesize data addressing outcomes of metformin use in populations with type 2 diabetes and moderate to severe chronic kidney disease (CKD), congestive heart failure (CHF), or chronic liver disease (CLD) with hepatic impairment. Data Sources: MEDLINE (via PubMed) from January 1994 to September 2016, and Cochrane Library, EMBASE, and International Pharmaceutical Abstracts from January 1994 to November 2015. Study Selection: English-language studies that: 1) examined adults with type 2 diabetes and CKD (with estimated glomerular filtration rate less than 60 mL/min/1.73 m(2)), CHF, or CLD with hepatic impairment; 2) compared diabetes regimens that included metformin with those that did not; and 3) reported all-cause mortality, major adverse cardiovascular events, and other outcomes of interest. Data Extraction: 2 reviewers abstracted data and independently rated study quality and strength of evidence. Data Synthesis: On the basis of quantitative and qualitative syntheses involving 17 observational studies, metformin use is associated with reduced all-cause mortality in patients with CKD, CHF, or CLD with hepatic impairment, and with fewer heart failure readmissions in patients with CKD or CHF. Limitations: Strength of evidence was low, and data on multiple outcomes of interest were sparse. Available studies were observational and varied in follow-up duration. Conclusion: Metformin use in patients with moderate CKD, CHF, or CLD with hepatic impairment is associated with improvements in key clinical outcomes. Our findings support the recent changes in metformin labeling. C1 [Nagi, Avishek] Durham Vet Affairs Med Ctr, 508 Fulton St, Durham, NC 27705 USA. Duke Univ, Sch Med, Durham, NC USA. [Crowley, Matthew J.] Durham Vet Affairs Med Ctr, Hlth Serv Res & Dev 152, 508 Fulton St, Durham, NC 27705 USA. [Diamantidis, Clarissa J.; Williams, John W., Jr.] 411 West Chapel Hill St,Suite 500, Durham, NC 27701 USA. [McDuffie, Jennifer R.] 411 West Chapel Hill St,Suite 6, Durham, NC 27701 USA. [Cameron, C. Blake] 2424 Erwin Rd,Suite 605, Durham, NC 27705 USA. [Stanifer, John W.] Duke Clin Res Inst, 2400 Pratt St, Durham, NC 27705 USA. [Mock, Clare K.] Univ N Carolina, Hillsborough Hosp, 430 Waterstone Dr, Hillsborough, NC 27278 USA. [Wang, Xianwei] Capital Med Univ, Beijing Tiantan Hosp, Dept Neurol, 6 Tiantan Xili, Beijing 100050, Peoples R China. [Tang, Shuang] NIEHS, Signal Transduct Lab, Res Triangle Pk, NC 27709 USA. [Kosinski, Andrzej S.] Duke Clin Res Inst, Room 7058,POB 17969, Durham, NC 27715 USA. RP Crowley, MJ (reprint author), Durham Vet Affairs Med Ctr, Hlth Serv Res & Dev 152, 508 Fulton St, Durham, NC 27705 USA. EM matthew.crowley@dm.duke.edu FU VHA Evidence-based Synthesis Program [09-009]; Career Development Award from VHA Health Services Research and Development [CDA 13-261]; Mentored Patient-Oriented Research Career Development Award from the National Institute of Diabetes and Digestive and Kidney Diseases [K23-DK099385] FX This project was supported by the VHA Evidence-based Synthesis Program (project 09-009). Dr. Crowley is supported by a Career Development Award from VHA Health Services Research and Development (CDA 13-261). Dr. Diamantidis is supported by a Mentored Patient-Oriented Research Career Development Award from the National Institute of Diabetes and Digestive and Kidney Diseases (K23-DK099385). NR 52 TC 1 Z9 1 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD FEB 7 PY 2017 VL 166 IS 3 BP 191 EP + DI 10.7326/M16-1901 PG 21 WC Medicine, General & Internal SC General & Internal Medicine GA EL7DL UT WOS:000394781200008 PM 28055049 ER PT J AU Friend, DM Devarakonda, K O'Neal, TJ Skirzewski, M Papazoglou, I Kaplan, AR Liow, JS Guo, J Rane, SG Rubinstein, M Alvarez, VA Hall, KD Kravitz, AV AF Friend, Danielle M. Devarakonda, Kavya O'Neal, Timothy J. Skirzewski, Miguel Papazoglou, Ioannis Kaplan, Alanna R. Liow, Jeih-San Guo, Juen Rane, Sushil G. Rubinstein, Marcelo Alvarez, Veronica A. Hall, Kevin D. Kravitz, Alexxai V. TI Basal Ganglia Dysfunction Contributes to Physical Inactivity in Obesity SO CELL METABOLISM LA English DT Article ID DIET-INDUCED OBESITY; DOPAMINE-RECEPTOR GENE; HIGH-FAT DIET; LOW-ENERGY INTAKE; Y GASTRIC BYPASS; SEDENTARY BEHAVIOR; OVERWEIGHT WOMEN; EATING BEHAVIOR; D2 RECEPTORS; WEIGHT-LOSS AB Obesity is associated with physical inactivity, which exacerbates the health consequences of weight gain. However, the mechanisms that mediate this association are unknown. We hypothesized that deficits in dopamine signaling contribute to physical inactivity in obesity. To investigate this, we quantified multiple aspects of dopamine signaling in lean and obese mice. We found that D2-type receptor (D2R) binding in the striatum, but not D1-type receptor binding or dopamine levels, was reduced in obese mice. Genetically removing D2Rs from striatal medium spiny neurons was sufficient to reduce motor activity in lean mice, whereas restoring G(i) signaling in these neurons increased activity in obese mice. Surprisingly, although mice with low D2Rs were less active, they were not more vulnerable to diet-induced weight gain than control mice. We conclude that deficits in striatal D2R signaling contribute to physical inactivity in obesity, but inactivity is more a consequence than a cause of obesity. C1 [Friend, Danielle M.; Devarakonda, Kavya; O'Neal, Timothy J.; Papazoglou, Ioannis; Guo, Juen; Rane, Sushil G.; Hall, Kevin D.; Kravitz, Alexxai V.] Eunice Shriver Kennedy Natl Inst Child Hlth & Hum, Natl Inst Diabet & Digest & Kidney Dis, NIH, Bethesda, MD 20892 USA. [Kaplan, Alanna R.; Alvarez, Veronica A.] Eunice Shriver Kennedy Natl Inst Child Hlth & Hum, NIAID, NIH, Bethesda, MD 20892 USA. [Kravitz, Alexxai V.] Eunice Shriver Kennedy Natl Inst Child Hlth & Hum, NIDA, NIH, Bethesda, MD 20892 USA. [Liow, Jeih-San] Eunice Shriver Kennedy Natl Inst Child Hlth & Hum, NIMH, NIH, Bethesda, MD 20892 USA. [Skirzewski, Miguel] Eunice Shriver Kennedy Natl Inst Child Hlth & Hum, Sect Mol Neurobiol, NIH, Bethesda, MD 20892 USA. [Rubinstein, Marcelo] Consejo Nacl Invest Cient & Tecn, Inst Invest Ingn Genet & Biol Mol, C1428ADN, Buenos Aires, DF, Argentina. [Rubinstein, Marcelo] Univ Buenos Aires, FCEN, Dept Physiol Mol & Cellular Biol, C1428EGA, Buenos Aires, DF, Argentina. [Rubinstein, Marcelo] Univ Michigan, Sch Med, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA. RP Kravitz, AV (reprint author), Eunice Shriver Kennedy Natl Inst Child Hlth & Hum, Natl Inst Diabet & Digest & Kidney Dis, NIH, Bethesda, MD 20892 USA.; Kravitz, AV (reprint author), Eunice Shriver Kennedy Natl Inst Child Hlth & Hum, NIDA, NIH, Bethesda, MD 20892 USA. EM lex.kravitz@nih.gov FU Intramural Research Program of the NIH, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) FX This work was supported by the Intramural Research Program of the NIH, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). We would like to thank the Mouse Metabolism Core at the NIDDK for assessing serum metabolites and hormones, Andres Buonanno with his assistance in designing dopamine microdialysis experiments, and Dr. Judith Walters, Dr. Kristin Dupre, and Dr. Claire Delaville for assistance with HPLC dopamine tissue content analysis. We would also like to thank Dr. Scott Young for the use of his laboratory equipment and assistance with binding studies. Thanks also to the members of the A.V.K. laboratory, Marc Reitman, and Nick Ryba for input on experimental design and careful reading of the manuscript. NR 71 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD FEB 7 PY 2017 VL 25 IS 2 BP 312 EP 321 DI 10.1016/j.cmet.2016.12.001 PG 10 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA EN9YB UT WOS:000396354400013 PM 28041956 ER PT J AU Visweswaraiah, J Hinnebusch, AG AF Visweswaraiah, Jyothsna Hinnebusch, Alan G. TI Interface between 40S exit channel protein uS7/Rps5 and eIF2 alpha modulates start codon recognition in vivo SO ELIFE LA English DT Article ID EUKARYOTIC TRANSLATION INITIATION; FACTOR 1 EIF1; SACCHAROMYCES-CEREVISIAE; PREINITIATION COMPLEX; SCANNING MECHANISM; RIBOSOMAL-SUBUNIT; SELECTION; ELEMENTS; BINDING; ACCURACY AB The eukaryotic pre-initiation complex (PIC) bearing the eIF2.GTP.Met-tRNA(i)(Met) ternary complex (TC) scans the mRNA for an AUG codon in favorable context. AUG recognition evokes rearrangement of the PIC from an open, scanning to a closed, arrested conformation. Cryo-EM reconstructions of yeast PICs suggest remodeling of the interface between 40S protein Rps5/uS7 and eIF2 alpha between open and closed states; however, its importance was unknown. uS7 substitutions disrupting eIF2 alpha contacts favored in the open complex increase initiation at suboptimal sites, and uS7-S223D stabilizes TC binding to PICs reconstituted with a UUG start codon, indicating inappropriate rearrangement to the closed state. Conversely, uS7-D215 substitutions, perturbing uS7-eIF2 alpha interaction in the closed state, confer the opposite phenotypes of hyperaccuracy and (for D215L) accelerated TC dissociation from reconstituted PICs. Thus, remodeling of the uS7/eIF2 alpha interface appears to stabilize first the open, and then the closed state of the PIC to promote accurate AUG selection in vivo. C1 [Visweswaraiah, Jyothsna; Hinnebusch, Alan G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Hinnebusch, AG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. EM ahinnebusch@nih.gov FU National Institutes of Health Intramural Program [HD001004] FX National Institutes of Health Intramural Program HD001004 Alan G Hinnebusch; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 32 TC 0 Z9 0 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 FEB 7 PY 2017 VL 6 AR e22572 DI 10.7554/eLife.22572 PG 22 WC Biology SC Life Sciences & Biomedicine - Other Topics GA EM3HC UT WOS:000395204100001 ER PT J AU Greenbaum, AB Babaliaros, VC Chen, MY Stine, AM Rogers, T O'Neill, WW Paone, G Thourani, VH Muhammad, KI Leonardi, RA Ramee, S Troendle, JF Lederman, RJ AF Greenbaum, Adam B. Babaliaros, Vasilis C. Chen, Marcus Y. Stine, Annette M. Rogers, Toby O'Neill, William W. Paone, Gaetano Thourani, Vinod H. Muhammad, Kamran I. Leonardi, Robert A. Ramee, Stephen Troendle, James F. Lederman, Robert J. TI Transcaval Access and Closure for Transcatheter Aortic Valve Replacement A Prospective Investigation SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE caval-aortic access; nontransfemoral access; structural heart disease; transcatheter aortic valve replacement; transcaval; vascular access ID INTERMEDIATE-RISK PATIENTS; IMPLANTATION; REGISTRY; STENOSIS; BIOPROSTHESIS; EXPERIENCE; OUTCOMES; SURGERY AB BACKGROUND Transcaval access may enable fully percutaneous transcatheter aortic valve replacement (TAVR) without the hazards and discomfort of transthoracic (transapical or transaortic) access. OBJECTIVES The authors performed a prospective, independently adjudicated, multicenter, single-arm trial of transcaval access for TAVR in patients who were ineligible for femoral artery access and had high or prohibitive risk of complications from transthoracic access. METHODS A total of 100 patients underwent attempted percutaneous transcaval access to the abdominal aorta by electrifying a caval guidewire and advancing it into a pre-positioned aortic snare. After exchanging for a rigid guidewire, conventional TAVR was performed through transcaval introducer sheaths. Transcaval access ports were closed with nitinol cardiac occluders. A core laboratory analyzed pre-discharge and 30-day abdominal computed tomograms. The Society of Thoracic Surgeons predicted risk of mortality was 9.6 +/- 6.3%. RESULTS Transcaval access was successful in 99 of 100 patients. Device success (access and closure with a nitinol cardiac occluder without death or emergency surgical rescue) occurred 98 of 99 patients; 1 subject had closure with a covered stent. Inpatient survival was 96%, and 30-day survival was 92%. Second Valve Academic Research Consortium (VARC-2) life-threatening bleeding and modified VARC-2 major vascular complications possibly related to transcaval access were 7% and 13%, respectively. Median length of stay was 4 days (range 2 to 6 days). There were no vascular complications after discharge. CONCLUSIONS Transcaval access enabled TAVR in patients who were not good candidates for transthoracic access. Bleeding and vascular complications, using permeable nitinol cardiac occluders to close the access ports, were common but acceptable in this high-risk cohort. Transcaval access should be investigated in patients who are eligible for transthoracic access. Purpose-built closure devices are in development that may simplify the procedure and reduce bleeding. (Transcaval Access for Transcatheter Aortic Valve Replacement in People With No Good Options for Aortic Access; NCT02280824) Published by Elsevier on behalf of the American College of Cardiology Foundation. C1 [Greenbaum, Adam B.; O'Neill, William W.; Paone, Gaetano] Henry Ford Hosp, Detroit, MI 48202 USA. [Babaliaros, Vasilis C.; Thourani, Vinod H.] Emory Univ, Atlanta, GA 30322 USA. [Chen, Marcus Y.; Stine, Annette M.; Rogers, Toby; Troendle, James F.; Lederman, Robert J.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Muhammad, Kamran I.] Oklahoma Heart Inst, Tulsa, OK USA. [Leonardi, Robert A.] Lexington Med Ctr, W Columbia, SC USA. [Ramee, Stephen] Ochsner Med Ctr, New Orleans, LA USA. RP Lederman, RJ (reprint author), NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bldg 10,Room 2c713,MSC 1538, Bethesda, MD 20892 USA. EM lederman@nih.gov FU NHLBI Division of Intramural Research [Z01-HL006040]; St. Jude Medical; Edwards Lifesciences; Abbott Vascular; Medtronic; Boston Scientific; Abbott Medical FX This study was supported by the NHLBI Division of Intramural Research Z01-HL006040. Dr. Greenbaum is a proctor for Edwards Lifesciences and St. Jude Medical; and his employer receives research support from St. Jude Medical. Dr. Babaliaros is a researcher and consultant for Edwards Lifesciences and Abbott Vascular; and his employer receives research support from Edwards Lifesciences, Abbott Vascular, Medtronic, St. Jude Medical, and Boston Scientific. Dr. O'Neill is a consultant for Edwards Lifesciences, Medtronic, St. Jude Medical, and Boston Scientific. Dr. Paone is a consultant and proctor for Edwards Lifesciences. Dr. Thourani is a consultant for Edwards Lifesciences and Abbott Vascular; and his employer receives research support from Edwards Lifesciences, Boston Scientific, Medtronic, St. Jude Medical, and Abbott Medical. Dr. Muhammad is a consultant for Edwards Lifesciences and Abiomed. Dr. Leonardi is a consultant for St. Jude Medical; and a paid speaker for Edwards Lifesciences. Dr. Ramee is an investigator for Edwards Lifesciences and St. Jude Medical; and has received honoraria from Edwards Lifesciences and Medtronic. Drs. Greenbaum, Rogers, and Lederman are co-inventors of devices, not tested in this protocol, intended to close transcaval access. The other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 26 TC 2 Z9 2 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB 7 PY 2017 VL 69 IS 5 BP 511 EP 521 DI 10.1016/j.jacc.2016.10.024 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EJ1UE UT WOS:000392994900007 PM 27989885 ER PT J AU Lacy, ME Wellenius, GA Sumner, AE Correa, A Carnethon, MR Liem, RI Wilson, JG Sacks, DB Jacobs, DR Carson, AP Luo, X Gjelsvik, A Reiner, AP Naik, RP Liu, SM Musani, SK Eaton, CB Wu, WC AF Lacy, Mary E. Wellenius, Gregory A. Sumner, Anne E. Correa, Adolfo Carnethon, Mercedes R. Liem, Robert I. Wilson, James G. Sacks, David B. Jacobs, David R., Jr. Carson, April P. Luo, Xi Gjelsvik, Annie Reiner, Alexander P. Naik, Rakhi P. Liu, Simin Musani, Solomon K. Eaton, Charles B. Wu, Wen-Chih TI Association of Sickle Cell Trait With Hemoglobin A(1c) in African Americans SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID UNITED-STATES; LIFE-SPAN; A1C; GLUCOSE; ADULTS; PREVALENCE; DISPARITIES; HBA(1C) AB IMPORTANCE Hemoglobin A(1c) (HbA(1c)) reflects past glucose concentrations, but this relationship may differ between those with sickle cell trait (SCT) and those without it. OBJECTIVE To evaluate the association between SCT and HbA(1c) for given levels of fasting or 2-hour glucose levels among African Americans. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study using data collected from 7938 participants in 2 community-based cohorts, the Coronary Artery Risk Development in Young Adults (CARDIA) study and the Jackson Heart Study (JHS). From the CARDIA study, 2637 patients contributed a maximum of 2 visits (2005-2011); from the JHS, 5301 participants contributed a maximum of 3 visits (2000-2013). All visits were scheduled at approximately 5-year intervals. Participants without SCT data, those without any concurrent HbA(1c) and glucose measurements, and those with hemoglobin variants HbSS, HbCC, or HbAC were excluded. Analysis of the primary outcome was conducted using generalized estimating equations (GEE) to examine the association of SCT with HbA(1c) levels, controlling for fasting or 2-hour glucose measures. EXPOSURES Presence of SCT. MAIN OUTCOMES AND MEASURES Hemoglobin A(1c) stratified by the presence or absence of SCT was the primary outcome measure. RESULTS The analytic sample included 4620 participants (mean age, 52.3 [SD, 11.8] years; 2835 women [61.3%]; 367 [7.9%] with SCT) with 9062 concurrent measures of fasting glucose and HbA(1c) levels. In unadjusted GEE analyses, for a given fasting glucose, HbA(1c) values were statistically significantly lower in those with (5.72%) vs those without (6.01%) SCT (mean HbA(1c) difference, -0.29%; 95% CI, -0.35% to -0.23%). Findings were similar in models adjusted for key risk factors and in analyses using 2001 concurrent measures of 2-hour glucose and HbA(1c) concentration for those with SCT (mean, 5.35%) vs those without SCT (mean, 5.65%) for a mean HbA(1c) difference of -0.30% (95% CI, -0.39% to -0.21%). The HbA(1c) difference by SCT was greater at higher fasting (P=.02 for interaction) and 2-hour (P=.03) glucose concentrations. The prevalence of prediabetes and diabetes was statistically significantly lower among participants with SCT when defined using HbA(1c) values (29.2% vs 48.6% for prediabetes and 3.8% vs 7.3% for diabetes in 572 observations from participants with SCT and 6877 observations from participants without SCT; P<. 001 for both comparisons). CONCLUSIONS AND RELEVANCE Among African Americans from 2 large, well-established cohorts, participants with SCT had lower levels of HbA(1c) at any given concentration of fasting or 2-hour glucose compared with participants without SCT. These findings suggest that HbA(1c) may systematically underestimate past glycemia in black patients with SCT and may require further evaluation. C1 [Lacy, Mary E.; Wellenius, Gregory A.; Gjelsvik, Annie; Liu, Simin; Eaton, Charles B.; Wu, Wen-Chih] Brown Univ, Sch Publ Hlth, Dept Epidemiol, 121 S Main St,POB G, Providence, RI 02906 USA. [Sumner, Anne E.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Sumner, Anne E.] Natl Inst Minor Hlth & Hlth Dispar, NIH, Bethesda, MD USA. [Correa, Adolfo; Musani, Solomon K.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Carnethon, Mercedes R.] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Liem, Robert I.] Ann & Robert H Lurie Childrens Hosp, Div Hematol Oncol & SCT, Chicago, IL USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Sacks, David B.] NIH, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Jacobs, David R., Jr.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Carson, April P.] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA. [Luo, Xi] Brown Univ, Sch Publ Hlth, Dept Biostat, Providence, RI 02912 USA. [Reiner, Alexander P.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Naik, Rakhi P.] Johns Hopkins Univ, Dept Med, Div Hematol, Baltimore, MD USA. [Wu, Wen-Chih] Providence Vet Affairs Med Ctr, Ctr Innovat Long Term Serv & Support, Providence, RI USA. [Wu, Wen-Chih] Providence Vet Affairs Med Ctr, Div Cardiol, Providence, RI USA. [Liu, Simin; Wu, Wen-Chih] Brown Univ, Alpert Med Sch, Dept Med, Providence, RI 02912 USA. RP Lacy, ME (reprint author), Brown Univ, Sch Publ Hlth, Dept Epidemiol, 121 S Main St,POB G, Providence, RI 02906 USA. EM mary_lacy@brown.edu FU National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, HHSN26820090004]; Intramural Research Program of the National Institute on Aging (NIA); NIA [AG0005]; NHLBI [AG0005, HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C, K08HL125100]; National Institute on Minority Health and Health Disparities; Center of Innovation in Long-Term Services and Support, Providence VA Medical Center; NIDDK; NIMHD; NIH; [F31DK105791]; [K01DK095928]; [R01HL107816] FX CARDIA is supported by contracts HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, and HHSN26820090004 from the National Heart, Lung, and Blood Institute (NHLBI), the Intramural Research Program of the National Institute on Aging (NIA), and an intra-agency agreement between NIA and NHLBI (AG0005). The JHS is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, and HHSN268201300050C from the NHLBI and the National Institute on Minority Health and Health Disparities. Dr Lacy was supported by F31DK105791 (Drs Wu and Wellenius are cosponsors of this grant). Dr Wu was supported by the Center of Innovation in Long-Term Services and Support, Providence VA Medical Center. Dr Carson was supported by K01DK095928. Dr Sumner is supported by the intramural program of NIDDK and NIMHD. Dr Sacks is supported by the Intramural Research Program of the NIH. Dr Naik was supported by NHLBI grant K08HL125100. Joint calling of exome sequence data in JHS was supported by R01HL107816 to S. Kathiresan, who was the principal investigator of the ancillary study that obtained the SCT data on JHS participants. NR 35 TC 1 Z9 1 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 7 PY 2017 VL 317 IS 5 BP 507 EP 515 DI 10.1001/jama.2016.21035 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA EJ9RN UT WOS:000393564200019 PM 28170479 ER PT J AU Thomason, ME Marusak, HA AF Thomason, Moriah E. Marusak, Hilary A. TI TOWARD UNDERSTANDING THE IMPACT OF TRAUMA ON THE EARLY DEVELOPING HUMAN BRAIN SO NEUROSCIENCE LA English DT Review DE adversity; maltreatment; abuse; neural; children; adolescents ID POSTTRAUMATIC-STRESS-DISORDER; EARLY-LIFE STRESS; NEURAL DEVELOPMENT DEPRIVATION; ADVERSE CHILDHOOD EXPERIENCES; DEFAULT NETWORK CONNECTIVITY; HUMAN CEREBRAL-CORTEX; HIPPOCAMPAL VOLUME; HOUSEHOLD DYSFUNCTION; MATERNAL-DEPRIVATION; FEAR CIRCUITRY AB Traumatic experiences early in life predispose animals and humans to later cognitive-behavioral, emotional, and somatic problems. In humans, traumatic experiences are strong predictors of psychiatric illness. A growing body of research has emphasized alterations in neurological structure and function that underscore phenotypic changes following trauma. However, results are mixed and imprecise. We argue that future translation of neurological findings to clinical practice will require: (1) discovery of neurobehavioral associations within a longitudinal context, (2) dissociation of trauma types and of trauma versus chronic stress, and (3) better localization of neural sequelae considerate of the fine resolution of neural circuitry. We provide a brief overview of early brain development and highlight the role of longitudinal research in unearthing brain-behavior relations in youth. We relay an emergent framework in which dissociable trauma types are hypothesized to impact distinct, rationally informed neural systems. In line with this, we discuss the long-standing challenge of separating effects of chronic stress and trauma, as these are often intertwined. We bring to light inconsistencies in localization of neural correlates of trauma, emphasizing results in medial prefrontal regions. We assert that more precise spatial brain localization will help to advance prevailing models of trauma pathways and inform future research. (C) 2016 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Thomason, Moriah E.; Marusak, Hilary A.] Wayne State Univ, Merrill Palmer Skillman Inst Child & Family Dev, Detroit, MI USA. [Thomason, Moriah E.] Wayne State Univ, Sch Med, Dept Pediat, Detroit, MI 48201 USA. [Thomason, Moriah E.] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Marusak, Hilary A.] Wayne State Univ, Sch Med, Dept Psychiat & Behav Neurosci, Detroit, MI USA. RP Thomason, ME (reprint author), Wayne State Univ, Merrill Palmer Skillman Inst, 71 E Ferry St, Detroit, MI 48009 USA. EM moriah@wayne.edu FU NIH National Institute of Environmental Health Sciences [P30 ES020957, R21 ES026022] FX This work was supported by the NIH National Institute of Environmental Health Sciences awards P30 ES020957 and R21 ES026022 (MET). NR 125 TC 1 Z9 1 U1 9 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 EI 1873-7544 J9 NEUROSCIENCE JI Neuroscience PD FEB 7 PY 2017 VL 342 SI SI BP 55 EP 67 DI 10.1016/j.neuroscience.2016.02.022 PG 13 WC Neurosciences SC Neurosciences & Neurology GA EJ0LC UT WOS:000392899100005 PM 26892294 ER PT J AU Kelleher, AM Peng, W Pru, JK Pru, CA DeMayo, FJ Spencer, TE AF Kelleher, Andrew M. Peng, Wang Pru, James K. Pru, Cindy A. DeMayo, Francesco J. Spencer, Thomas E. TI Forkhead box a2 (FOXA2) is essential for uterine function and fertility SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE uterus; gland; FOXA2; pregnancy; LIF ID LEUKEMIA INHIBITORY FACTOR; MOUSE UTERUS; EMBRYO IMPLANTATION; BLASTOCYST IMPLANTATION; PROGESTERONE-RECEPTOR; TRANSCRIPTION FACTORS; ENDOMETRIAL GLANDS; HYPERPLASIA FORMATION; BIOLOGICAL ROLES; EARLY-PREGNANCY AB Establishment of pregnancy is a critical event, and failure of embryo implantation and stromal decidualization in the uterus contribute to significant numbers of pregnancy losses in women. Glands of the uterus are essential for establishment of pregnancy inmice and likely in humans. Forkhead box a2 (FOXA2) is a transcription factor expressed specifically in the glands of the uterus and is a critical regulator of postnatal uterine gland differentiation in mice. In this study, we conditionally deleted FOXA2 in the adult mouse uterus using the lactotransferrin Cre (Ltf-Cre) model and in the neonatal mouse uterus using the progesterone receptor Cre (Pgr-Cre) model. The uteri of adult FOXA2-deleted mice were morphologically normal and contained glands, whereas the uteri of neonatal FOXA2-deleted mice were completely aglandular. Notably, adult FOXA2-deleted mice are completely infertile because of defects in blastocyst implantation and stromal cell decidualization. Leukemia inhibitory factor (LIF), a critical implantation factor of uterine gland origin, was not expressed during early pregnancy in adult FOXA2-deleted mice. Intriguingly, i.p. injections of LIF initiated blastocyst implantation in the uteri of both gland-containing and glandless adult FOXA2-deleted mice. Although pregnancy was rescued by LIF and was maintained to term in uterine gland-containing adult FOXA2-deleted mice, pregnancy failed by day 10 in neonatal FOXA2-deleted mice lacking uterine glands. These studies reveal a previously unrecognized role for FOXA2 in regulation of adult uterine function and fertility and provide original evidence that uterine glands and, by inference, their secretions play important roles in blastocyst implantation and stromal cell decidualization. C1 [Kelleher, Andrew M.; Peng, Wang; Spencer, Thomas E.] Univ Missouri, Dept Anim Sci, Columbia, MO 65211 USA. [Pru, James K.; Pru, Cindy A.] Washington State Univ, Dept Anim Sci, Pullman, WA 99164 USA. [DeMayo, Francesco J.] NIEHS, Pregnancy & Female Reprod Grp, POB 12233, Res Triangle Pk, NC 27709 USA. RP Spencer, TE (reprint author), Univ Missouri, Dept Anim Sci, Columbia, MO 65211 USA. EM spencerte@missouri.edu FU Eunice Kennedy Shriver National Institute of Child Health and Development [R21 HD076347] FX This work was supported by Grant R21 HD076347 from the Eunice Kennedy Shriver National Institute of Child Health and Development (to T.E.S.). NR 80 TC 1 Z9 1 U1 2 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 7 PY 2017 VL 114 IS 6 BP E1018 EP E1026 DI 10.1073/pnas.1618433114 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EJ7SH UT WOS:000393422200016 PM 28049832 ER PT J AU Perni, M Galvagnion, C Maltsev, A Meisl, G Muller, MBD Challa, PK Kirkegaard, JB Flagmeier, P Cohen, SIA Cascella, R Chen, SW Limboker, R Sormanni, P Heller, GT Aprile, FA Cremades, N Cecchi, C Chiti, F Nollen, EAA Knowles, TPJ Vendruscolo, M Bax, A Zasloff, M Dobson, CM AF Perni, Michele Galvagnion, Celine Maltsev, Alexander Meisl, Georg Mueller, Martin B. D. Challa, Pavan K. Kirkegaard, Julius B. Flagmeier, Patrick Cohen, Samuel I. A. Cascella, Roberta Chen, Serene W. Limboker, Ryan Sormanni, Pietro Heller, Gabriella T. Aprile, Francesco A. Cremades, Nunilo Cecchi, Cristina Chiti, Fabrizio Nollen, Ellen A. A. Knowles, Tuomas P. J. Vendruscolo, Michele Bax, Adriaan Zasloff, Michael Dobson, Christopher M. TI A natural product inhibits the initiation of alpha-synuclein aggregation and suppresses its toxicity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Parkinson's disease; protein aggregation; amyloid formation; toxic oligomers; drug development ID PROTEIN MISFOLDING DISEASES; PARKINSONS-DISEASE; CAENORHABDITIS-ELEGANS; AMPLIFICATION STEPS; NMR-SPECTROSCOPY; SURFACE-CHARGE; LEWY BODIES; SQUALAMINE; BINDING; PHOSPHORYLATION AB The self-assembly of alpha-synuclein is closely associated with Parkinson's disease and related syndromes. We show that squalamine, a natural product with known anticancer and antiviral activity, dramatically affects alpha-synuclein aggregation in vitro and in vivo. We elucidate the mechanism of action of squalamine by investigating its interaction with lipid vesicles, which are known to stimulate nucleation, and find that this compound displaces alpha-synuclein from the surfaces of such vesicles, thereby blocking the first steps in its aggregation process. We also show that squalamine almost completely suppresses the toxicity of alpha-synuclein oligomers in human neuroblastoma cells by inhibiting their interactions with lipid membranes. We further examine the effects of squalamine in a Caenorhabditis elegans strain overexpressing alpha-synuclein, observing a dramatic reduction of alpha-synuclein aggregation and an almost complete elimination of muscle paralysis. These findings suggest that squalamine could be a means of therapeutic intervention in Parkinson's disease and related conditions. C1 [Perni, Michele; Galvagnion, Celine; Meisl, Georg; Mueller, Martin B. D.; Challa, Pavan K.; Flagmeier, Patrick; Cohen, Samuel I. A.; Chen, Serene W.; Limboker, Ryan; Sormanni, Pietro; Heller, Gabriella T.; Aprile, Francesco A.; Knowles, Tuomas P. J.; Vendruscolo, Michele; Dobson, Christopher M.] Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England. [Perni, Michele; Mueller, Martin B. D.; Nollen, Ellen A. A.] Univ Groningen, Univ Med Ctr Groningen, European Res Inst Biol Aging, NL-9713 AV Groningen, Netherlands. [Maltsev, Alexander; Bax, Adriaan] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Kirkegaard, Julius B.] Univ Cambridge, Dept Appl Math & Theoret Phys, Cambridge CB3 0WA, England. [Cascella, Roberta; Cecchi, Cristina; Chiti, Fabrizio] Univ Florence, Dept Expt & Clin Biomed Sci, I-50134 Florence, Italy. [Cremades, Nunilo] Univ Zaragoza, Biocomputat & Complex Syst Phys Inst BIFI Joint U, Zaragoza 50018, Spain. [Zasloff, Michael] Georgetown Univ, MedStar Georgetown Transplant Inst, Sch Med, Washington, DC 20010 USA. RP Vendruscolo, M; Dobson, CM (reprint author), Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England.; Bax, A (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA.; Zasloff, M (reprint author), Georgetown Univ, Sch Med, MedStar Georgetown Transplant Inst, Washington, DC 20010 USA. EM mv245@cam.ac.uk; bax@nih.gov; maz5@georgetown.edu; cmd44@cam.ac.uk FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), US National Institutes of Health; Boehringer Ingelheim Fonds; European Research Council; Cambridge Centre for Misfolding Diseases; Agency for Science, Technology, and Research, Singapore FX The authors thank Alfonso de Simone, Sam Casford, Mandy Koopman, and Maarten C. Hardenberg for valuable advice and discussions. This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), US National Institutes of Health (A.M. and A.B.); by the Boehringer Ingelheim Fonds (P.F.); by a European Research Council starting grant (to M.B.D.M. and E.A.A.N.); and by The Cambridge Centre for Misfolding Diseases. N.C. thanks the Spanish Ministry of Economy and Competitiveness (RYC-2012-12068). S.W.C. thanks the Agency for Science, Technology, and Research, Singapore for support. NR 55 TC 2 Z9 2 U1 18 U2 18 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 7 PY 2017 VL 114 IS 6 BP E1009 EP E1017 DI 10.1073/pnas.1610586114 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EJ7SH UT WOS:000393422200015 PM 28096355 ER PT J AU Tebebi, PA Kim, SJ Williams, RA Milo, B Frenkel, V Burks, SR Frank, JA AF Tebebi, Pamela A. Kim, Saejeong J. Williams, Rashida A. Milo, Blerta Frenkel, Victor Burks, Scott R. Frank, Joseph A. TI Improving the therapeutic efficacy of mesenchymal stromal cells to restore perfusion in critical limb ischemia through pulsed focused ultrasound SO SCIENTIFIC REPORTS LA English DT Article ID PERIPHERAL ARTERIAL-DISEASE; ENDOTHELIAL PROGENITOR CELLS; ACUTE HINDLIMB ISCHEMIA; BONE-MARROW-CELLS; STEM-CELLS; SKELETAL-MUSCLE; MOUSE MODEL; ANGIOGENESIS; TRANSPLANTATION; MICE AB Mesenchymal stem cells (MSC) are promising therapeutics for critical limb ischemia (CLI). Mechanotransduction from pulsed focused ultrasound (pFUS) upregulates local chemoattractants to enhance homing of intravenously (IV)-infused MSC and improve outcomes. This study investigated whether pFUS exposures to skeletal muscle would improve local homing of iv-infused MSCs and their therapeutic efficacy compared to iv-infused MSCs alone. CLI was induced by external iliac arterial cauterization in 10-12-month-old mice. pFUS/MSC treatments were delayed 14 days, when surgical inflammation subsided. Mice were treated with iv-saline, pFUS alone, IV-MSC, or pFUS and IV-MSC. Proteomic analyses revealed pFUS upregulated local chemoattractants and increased MSC tropism to CLI muscle. By 7 weeks post-treatment, pFUS + MSC significantly increased perfusion and CD31 expression, while reducing fibrosis compared to saline. pFUS or MSC alone reduced fibrosis, but did not increase perfusion or CD31. Furthermore, MSCs homing to pFUS-treated CLI muscle expressed more vascular endothelial growth factor (VEGF) and interleukin-10 (IL-10) than MSCs homing to non-pFUS-treated muscle. pFUS + MSC improved perfusion and vascular density in this clinically-relevant CLI model. The molecular effects of pFUS increased both MSC homing and MSC production of VEGF and IL-10, suggesting microenvironmental changes from pFUS also increased potency of MSCs in situ to further enhance their efficacy. C1 [Tebebi, Pamela A.; Kim, Saejeong J.; Williams, Rashida A.; Milo, Blerta; Burks, Scott R.; Frank, Joseph A.] NIH, Ctr Clin, Radiol & Imaging Sci Dept, Frank Lab, Bethesda, MD 20892 USA. [Tebebi, Pamela A.] Catholic Univ Amer, Dept Biomed Engn, Washington, DC 20064 USA. [Frenkel, Victor] Univ Maryland, Sch Med, Dept Diagnost Radiol & Nucl Med, Baltimore, MD 21201 USA. [Frank, Joseph A.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. RP Frank, JA (reprint author), NIH, Ctr Clin, Radiol & Imaging Sci Dept, Frank Lab, Bethesda, MD 20892 USA.; Frank, JA (reprint author), Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. EM jfrank@helix.nih.gov FU Intramural Research Program of the National Institutes of Health Clinical Center; National Institute of Biomedical Imaging and Bioengineering FX This research was funded by the Intramural Research Program of the National Institutes of Health Clinical Center and the National Institute of Biomedical Imaging and Bioengineering. NR 52 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD FEB 7 PY 2017 VL 7 AR 41550 DI 10.1038/srep41550 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EJ8VR UT WOS:000393505400001 PM 28169278 ER PT J AU Staunton, JR Blehm, B Devine, A Tanner, K AF Staunton, Jack R. Blehm, Ben Devine, Alexus Tanner, Kandice TI In situ calibration of position detection in an optical trap for active microrheology in viscous materials SO OPTICS EXPRESS LA English DT Article ID FOCAL-PLANE INTERFEROMETRY; MECHANICAL-PROPERTIES; EX-VIVO; TWEEZERS; FORCE; COLLAGEN; DISPLACEMENTS; SPECTROSCOPY; ELASTICITY; MICROSCOPY AB In optical trapping, accurate determination of forces requires calibration of the position sensitivity relating displacements to the detector readout via the V-nm conversion factor (beta). Inaccuracies in measured trap stiffness (k) and dependent calculations of forces and material properties occur if beta is assumed to be constant in optically heterogeneous materials such as tissue, necessitating calibration at each probe. For solid-like samples in which probes are securely positioned, calibration can be achieved by moving the sample with a nanopositioning stage and stepping the probe through the detection beam. However, this method may be applied to samples only under select circumstances. Here, we introduce a simple method to find a in any material by steering the detection laser beam while the probe is trapped. We demonstrate the approach in the yolk of living Danio rerio (zebrafish) embryos and measure the viscoelastic properties over an order of magnitude of stress-strain amplitude. (C) 2017 Optical Society of America C1 [Staunton, Jack R.; Blehm, Ben; Devine, Alexus; Tanner, Kandice] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Tanner, K (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM kandice.tanner@nih.gov FU Intramural Research Program of the National Institutes of Health, the National Cancer Institute FX This effort was supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute. NR 54 TC 0 Z9 0 U1 0 U2 0 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1094-4087 J9 OPT EXPRESS JI Opt. Express PD FEB 6 PY 2017 VL 25 IS 3 BP 1746 EP 1761 DI 10.1364/OE.25.001746 PG 16 WC Optics SC Optics GA EP3XI UT WOS:000397314600013 ER PT J AU Cahan, A Cimino, JJ AF Cahan, Amos Cimino, James J. TI Improving precision medicine using individual patient data from trials SO CANADIAN MEDICAL ASSOCIATION JOURNAL LA English DT Article ID RANDOMIZED CONTROLLED-TRIALS; EXTERNAL VALIDITY; CLINICAL-PRACTICE; SUBGROUP ANALYSIS; GUIDELINES; EXPERIENCE AB Our first commitment as clinicians is to our patients as individuals. This understanding lies at the heart of the precision medicine initiative, which aims to customize treatments based not only on a patient's clinical picture but also on their genetic, demographic and environmental profile. (1) Clinical trials are rigid by design, typically assessing the effect of one intervention. In a reality of complex patients and polypharmacy, clinical trials cannot provide all the answers that clinicians are seeking. It is widely accepted that the uniquely complex health care environment requires the implementation at scale of informatics tools to help physicians navigate through the huge volume of medical data, and technology is being developed and refined to support this need. Whereas data from electronic health records are routinely reused in research to generate evidence-based recommendations for patient care, databases of clinical trial populations are not. The potential of individual-level data of participants in completed clinical trials to facilitate evidence-personalized treatment decisions has not yet been fully realized. C1 [Cahan, Amos] IBM TJ Watson Res Ctr, Yorktown Hts, NY 10598 USA. [Cimino, James J.] NIH, Natl Lib Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Cimino, James J.] Univ Alabama Birmingham, Sch Med, Inst Informat, Birmingham, AL USA. RP Cahan, A (reprint author), IBM TJ Watson Res Ctr, Yorktown Hts, NY 10598 USA. EM acahan@us.ibm.com FU Research Participation Program for the Centers for Disease Control and Prevention; National Center for Environmental Health; Division of Laboratory Sciences (DLS); National Library of Medicine and the National Institues of Health (NIH) Clinical Center; Informatics Institute at the University of Alabama School of Medicine, Birmingham FX Amos Cahan was supported by an appointment to the Research Participation Program for the Centers for Disease Control and Prevention, National Center for Environmental Health, Division of Laboratory Sciences (DLS),administered by the Oak Ridge Institute for Science and Education through an agreement between the US Department of Energy and DLS. Amos Cahan is currently employed by IBM. James Cimino was supported in part by research funds from the National Library of Medicine and the National Institues of Health (NIH) Clinical Center, and is currently supported by the Informatics Institute at the University of Alabama School of Medicine, Birmingham. NR 19 TC 0 Z9 0 U1 0 U2 0 PU CMA-CANADIAN MEDICAL ASSOC PI OTTAWA PA 1867 ALTA VISTA DR, OTTAWA, ONTARIO K1G 5W8, CANADA SN 0820-3946 EI 1488-2329 J9 CAN MED ASSOC J JI Can. Med. Assoc. J. PD FEB 6 PY 2017 VL 189 IS 5 BP E204 EP E207 DI 10.1503/cmaj.160267 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA EM7RF UT WOS:000395509300005 PM 27573743 ER PT J AU Vijayakumar, P Hoyer, A Nelson, RG Brinks, R Pavkov, ME AF Vijayakumar, Pavithra Hoyer, Annika Nelson, Robert G. Brinks, Ralph Pavkov, Meda E. TI Estimation of chronic kidney disease incidence from prevalence and mortality data in American Indians with type 2 diabetes SO PLOS ONE LA English DT Article ID PIMA-INDIANS; RISK-FACTORS; MELLITUS; ESRD; MICROALBUMINURIA; ALBUMINURIA; POPULATION; ANTIBODIES; REMISSION; EQUATION AB The objective was to estimate chronic kidney disease (CKD) incidence rates from prevalence and mortality data, and compare the estimates with observed (true) incidence rates in a well-characterized population with diabetes. Pima Indians aged 20 years and older with type 2 diabetes were followed from 1982 through 2007. CKD was defined by estimated GFR (eGFR) <60 ml/min/1.72 m(2) or albumin-to-creatinine ratio (ACR) >= 30 mg/g. True CKD incidence and mortality rates were computed for the whole study period, and prevalence for the intervals 1982-1994 and 1995-2007. Estimated age-sex stratified CKD incidence rates were computed using illness-death models of the observed prevalences, and of the whole period mortality rate ratio of CKD to non-CKD persons. Among 1201 participants, 616 incident events of CKD occurred during a median follow-up of 5.6 years. Observed CKD prevalence was 56.9% (95%X153.7-60.0) and 48.0% (95%X145.2-50.8) in women; 54.0% (95% CI 49.9-58.1) and 49.6% (95%C 46.0-53.3) in men, across the two periods. Mortality rate was 2.5 (95%CI 11.9-3.3) times as high in women with CKD and 1.6 (95%Cl 1.3-2.1) times as high in men with CKD, compared to women or men without CKD. In women, estimated CKD incidence increased linearly from 25.6 (95%CI14.2-53.0) to 128.6 (95%CI177.1-196.6) with each 5-year age group up to 69 years, and to 99.8 (95% CI 38.7-204.7) at age >= 70. In men, estimated CKD incidence increased form 28.5 (95% CI13.8-71.2) at age 20-24 years to 118.7 (95%CI123.6-336.7) at age >= 70. Age-sex-stratified estimated incidence reflected the magnitude and directional trend of the true incidence and were similar to the true incidence rates (p>0.05 for difference) except for age 20-24 in women (p = 0.008) and age 2529 in men (p = 0.002). In conclusion, the estimated and observed incidence rates of CKD agree well over 25 years of observation in this well characterized population with type 2 diabetes. C1 [Vijayakumar, Pavithra; Nelson, Robert G.] NIDDK, NIH, Phoenix, AZ USA. [Hoyer, Annika; Brinks, Ralph] German Diabet Ctr Duesseldorf, Inst Epidemiol & Biometry, Dusseldorf, Germany. [Pavkov, Meda E.] Ctr Dis Control & Prevent, Div Diabet Translat, Atlanta, GA 30333 USA. [Pavkov, Meda E.] Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. RP Pavkov, ME (reprint author), Ctr Dis Control & Prevent, Div Diabet Translat, Atlanta, GA 30333 USA.; Pavkov, ME (reprint author), Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. EM mpavkov@cdc.gov OI Pavkov, Meda/0000-0002-6203-1772 FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported in part by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. The authors received no specific funding for this work. There was no additional external funding received for this study. NR 27 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 FEB 6 PY 2017 VL 12 IS 2 AR e0171027 DI 10.1371/journal.pone.0171027 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EK1QH UT WOS:000393700100020 PM 28166298 ER PT J AU O'Neal, TJ Friend, DM Guo, JE Hall, KD Kravitz, AV AF O'Neal, Timothy J. Friend, Danielle M. Guo, Juen Hall, Kevin D. Kravitz, Alexxai V. TI Increases in Physical Activity Result in Diminishing Increments in Daily Energy Expenditure in Mice SO CURRENT BIOLOGY LA English DT Article ID WEIGHT-LOSS; COMPENSATORY RESPONSES; VOLUNTARY EXERCISE; SEDENTARY TIME; OBESITY; DIET; INTERVENTIONS; TEMPERATURE; LOCOMOTION; BALANCE AB Exercise is a common component of weight loss strategies, yet exercise programs are associated with surprisingly small changes in body weight [1-4]. This may be due in part to compensatory adaptations, in which calories expended during exercise are counteracted by decreases in other aspects of energy expenditure [1, 5-10]. Here we examined the relationship between a rodent model of voluntary exercise wheel running and total daily energy expenditure. Use of a running wheel for 3 to 7 days increased daily energy expenditure, resulting in a caloric deficit of similar to 1 kcal/day; however, total daily energy expenditure remained stable after the first week of wheel access, despite further increases in wheel use. We hypothesized that compensatory mechanisms accounted for the lack of increase in daily energy expenditure after the first week. Supporting this idea, we observed a decrease in off-wheel ambulation when mice were using the wheels, indicating behavioral compensation. Finally, we asked whether individual variation in wheel use within a group of mice would be associated with different levels of daily energy expenditure. Despite a large variation in wheel running, we did not observe a significant relationship between the amount of daily wheel running and total daily energy expenditure or energy intake across mice. Together, our experiments support a model in which the transition from sedentary to light activity is associated with an increase in daily energy expenditure, but further increases in physical activity produce diminishingly small increments in daily energy expenditure. C1 [O'Neal, Timothy J.; Friend, Danielle M.; Kravitz, Alexxai V.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [O'Neal, Timothy J.; Guo, Juen; Hall, Kevin D.] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. [Kravitz, Alexxai V.] NIDA, NIH, Baltimore, MD 21224 USA. RP Kravitz, AV (reprint author), NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA.; Kravitz, AV (reprint author), NIDA, NIH, Baltimore, MD 21224 USA. EM lex.kravitz@nih.gov FU Intramural Research Program of the NIH, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [1ZIADK075096] FX This research was supported by the Intramural Research Program of the NIH, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK; grant no. 1ZIADK075096). We would like to thank the Mouse Metabolism Core at the National Institute of Diabetes and Digestive and Kidney Diseases for assistance with indirect calorimetry experiments. We thank members of the A.V.K. lab, Marc Reitman, and Oksana Gavrilova for helpful discussions and insight on the manuscript. NR 38 TC 0 Z9 0 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 EI 1879-0445 J9 CURR BIOL JI Curr. Biol. PD FEB 6 PY 2017 VL 27 IS 3 BP 423 EP 430 DI 10.1016/j.cub.2016.12.009 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EK1ZH UT WOS:000393726300029 PM 28111149 ER PT J AU Law, PJ Berndt, SI Speedy, HE Camp, NJ Sava, GP Skibola, CF Holroyd, A Joseph, V Sunter, NJ Nieters, A Bea, S Monnereau, A Martin-Garcia, D Goldin, LR Clot, G Teras, LR Quintela, I Birmann, BM Jayne, S Cozen, W Majid, A Smedby, KE Lan, Q Dearden, C Brooks-Wilson, AR Hall, AG Purdue, MP Mainou-Fowler, T Vajdic, CM Jackson, GH Cocco, P Marr, H Zhang, YW Zheng, TZ Giles, GG Lawrence, C Call, TG Liebow, M Melbye, M Glimelius, B Mansouri, L Glenn, M Curtin, K Diver, WR Link, BK Conde, L Bracci, PM Holly, EA Jackson, RD Tinker, LF Benavente, Y Boffetta, P Brennan, P Maynadie, M McKay, J Albanes, D Weinstein, S Wang, ZM Caporaso, NE Morton, LM Severson, RK Riboli, E Vineis, P Vermeulen, RCH Southey, MC Milne, RL Clavel, J Topka, S Spinelli, JJ Kraft, P Ennas, MG Summerfield, G Ferri, GM Harris, RJ Miligi, L Pettitt, AR North, KE Allsup, DJ Fraumeni, JF Bailey, JR Offit, K Pratt, G Hjalgrim, H Pepper, C Chanock, SJ Fegan, C Rosenquist, R de Sanjose, S Carracedo, A Dyer, MJS Catovsky, D Campo, E Cerhan, JR Allan, JM Rothman, N Houlston, R Slager, SL AF Law, Phillip J. Berndt, Sonja I. Speedy, Helen E. Camp, Nicola J. Sava, Georgina P. Skibola, Christine F. Holroyd, Amy Joseph, Vijai Sunter, Nicola J. Nieters, Alexandra Bea, Silvia Monnereau, Alain Martin-Garcia, David Goldin, Lynn R. Clot, Guillem Teras, Lauren R. Quintela, Ines Birmann, Brenda M. Jayne, Sandrine Cozen, Wendy Majid, Aneela Smedby, Karin E. Lan, Qing Dearden, Claire Brooks-Wilson, Angela R. Hall, Andrew G. Purdue, Mark P. Mainou-Fowler, Tryfonia Vajdic, Claire M. Jackson, Graham H. Cocco, Pierluigi Marr, Helen Zhang, Yawei Zheng, Tongzhang Giles, Graham G. Lawrence, Charles Call, Timothy G. Liebow, Mark Melbye, Mads Glimelius, Bengt Mansouri, Larry Glenn, Martha Curtin, Karen Diver, W. Ryan Link, Brian K. Conde, Lucia Bracci, Paige M. Holly, Elizabeth A. Jackson, Rebecca D. Tinker, Lesley F. Benavente, Yolanda Boffetta, Paolo Brennan, Paul Maynadie, Marc McKay, James Albanes, Demetrius Weinstein, Stephanie Wang, Zhaoming Caporaso, Neil E. Morton, Lindsay M. Severson, Richard K. Riboli, Elio Vineis, Paolo Vermeulen, Roel C. H. Southey, Melissa C. Milne, Roger L. Clavel, Jacqueline Topka, Sabine Spinelli, John J. Kraft, Peter Ennas, Maria Grazia Summerfield, Geoffrey Ferri, Giovanni M. Harris, Robert J. Miligi, Lucia Pettitt, Andrew R. North, Kari E. Allsup, David J. Fraumeni, Joseph F., Jr. Bailey, James R. Offit, Kenneth Pratt, Guy Hjalgrim, Henrik Pepper, Chris Chanock, Stephen J. Fegan, Chris Rosenquist, Richard de Sanjose, Silvia Carracedo, Angel Dyer, Martin J. S. Catovsky, Daniel Campo, Elias Cerhan, James R. Allan, James M. Rothman, Nathanial Houlston, Richard Slager, Susan L. TI Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia SO NATURE COMMUNICATIONS LA English DT Article ID TRANSCRIPTION FACTORS; COMMON VARIATION; BREAST-CANCER; RISK; DISEASE; METAANALYSIS; IMPUTATION; CHROMATIN; VARIANTS; LOCI AB Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We identify nine risk loci at 1p36.11 (rs34676223, P = 5.04 X 10 (-) (13)), 1q42.13 (rs41271473, P = 1.06 X 10 (-) (10)), 4q24 (rs71597109, P = 1.37 X 10 (-) (10)), 4q35.1 (rs57214277, P = 3.69 X 10 (-) (8)), 6p21.31 (rs3800461, P = 1.97 X 10 (-) (8)), 11q23.2 (rs61904987, P = 2.64 X 10 (-) (11)), 18q21.1 (rs1036935, P = 3.27 X 10 (-) (8)), 19p13.3 (rs7254272, P = 4.67 X 10 (-) (8)) and 22q13.33 (rs140522, P = 2.70 X 10 (-) (9)). These new and established risk loci map to areas of active chromatin and show an over-representation of transcription factor binding for the key determinants of B-cell development and immune response. C1 [Law, Phillip J.; Speedy, Helen E.; Sava, Georgina P.;