FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Hoppin, JA Umbach, DM Long, S Rinsky, JL Henneberger, PK Salo, PM Zeldin, DC London, SJ Alavanja, MCR Blair, A Freeman, LEB Sandler, DP AF Hoppin, Jane A. Umbach, David M. Long, Stuart Rinsky, Jessica L. Henneberger, Paul K. Salo, Paivi M. Zeldin, Darryl C. London, Stephanie J. Alavanja, Michael C. R. Blair, Aaron Freeman, Laura E. Beane Sandler, Dale P. TI Respiratory disease in United States farmers SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID OBSTRUCTIVE PULMONARY-DISEASE; INDUCED AIRWAY HYPERREACTIVITY; ADULT-ONSET ASTHMA; CHRONIC-BRONCHITIS; AGRICULTURAL HEALTH; PESTICIDE APPLICATORS; NATIONAL-HEALTH; ANIMAL FARMERS; SYMPTOMS; RISK AB Objectives Farmers may be at increased risk for adverse respiratory outcomes compared with the general population due to their regular exposures to dusts, animals and chemicals. However, early life farm exposures to microbial agents may result in reduced risk. Understanding respiratory disease risk among farmers and identifying differences between farmers and other populations may lead to better understanding of the contribution of environmental exposures to respiratory disease risk in the general population. Methods We compared the prevalence of self-reported respiratory outcomes in 43548 participants from the Agricultural Health Study (AHS), a prospective cohort of farmers and their spouses from Iowa and North Carolina, with data from adult participants in the National Health and Nutrition Examination Survey (NHANES) over the same period (2005-2010). Results AHS participants had lower prevalences of respiratory diseases (asthma, adult-onset asthma, chronic bronchitis and emphysema), but higher prevalences of current respiratory symptoms (wheeze, cough and phlegm) even after controlling for smoking, body mass index and population characteristics. The overall prevalence of asthma in the AHS (7.2%, 95% CI 6.9 to 7.4) was 52% of that in NHANES (13.8%, 95% CI 13.3 to 14.3), although the prevalence of adult-onset asthma among men did not differ (3.6% for AHS, 3.7% for NHANES). Conversely, many respiratory symptoms were more common in the AHS than NHANES, particularly among men. Conclusions These findings suggest that farmers and their spouses have lower risk for adult-onset respiratory diseases compared with the general population, and potentially higher respiratory irritation as evidenced by increased respiratory symptoms. C1 [Hoppin, Jane A.; London, Stephanie J.; Sandler, Dale P.] NIEHS, Epidemiol Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Hoppin, Jane A.] N Carolina State Univ, Dept Biol Sci, Raleigh, NC 27695 USA. [Umbach, David M.] NIEHS, Biostat Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Long, Stuart] Westat Corp, Durham, NC USA. [Rinsky, Jessica L.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Henneberger, Paul K.] NIOSH, Div Resp Dis Studies, CDC, DHHS, Morgantown, WV 26505 USA. [Salo, Paivi M.; Zeldin, Darryl C.] NIEHS, Lab Resp Biol, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Alavanja, Michael C. R.; Blair, Aaron; Freeman, Laura E. Beane] NCI, Occupat & Environm Epidemiol Branch, NIH, DHHS, Rockville, MD USA. RP Hoppin, JA (reprint author), N Carolina State Univ, Dept Biol Sci, CB 7633, Raleigh, NC 27695 USA. EM jahoppin@ncsu.edu RI Beane Freeman, Laura/C-4468-2015; OI Beane Freeman, Laura/0000-0003-1294-4124; Sandler, Dale/0000-0002-6776-0018; London, Stephanie/0000-0003-4911-5290 FU Intramural Research Program of the National Institutes of Health; National Institute of Environmental Health Sciences [Z01-ES025041, T32ES007018]; National Cancer Institute [Z01-CP010119] FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (Z01-ES025041) and National Cancer Institute (Z01-CP010119). JLR was supported by the National Institute of Environmental Health Sciences (award no. T32ES007018). NR 37 TC 16 Z9 16 U1 0 U2 6 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 EI 1470-7926 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD JUL PY 2014 VL 71 IS 7 BP 484 EP 491 DI 10.1136/oemed-2013-101983 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AJ7YP UT WOS:000337918300006 PM 24913223 ER PT J AU Axelsen, JB Yaari, R Grenfell, BT Stone, L AF Axelsen, Jacob Bock Yaari, Rami Grenfell, Bryan T. Stone, Lewi TI Multiannual forecasting of seasonal influenza dynamics reveals climatic and evolutionary drivers SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE model forecasting; infectious disease; climate; Bayesian epidemic model; predictive model ID PANDEMIC INFLUENZA; EPIDEMIC; TRANSMISSION; MODEL; VIRUS; FLU AB Human influenza occurs annually in most temperate climatic zones of the world, with epidemics peaking in the cold winter months. Considerable debate surrounds the relative role of epidemic dynamics, viral evolution, and climatic drivers in driving year-to-year variability of outbreaks. The ultimate test of understanding is prediction; however, existing influenza models rarely forecast beyond a single year at best. Here, we use a simple epidemiological model to reveal multiannual predictability based on high-quality influenza surveillance data for Israel; the model fit is corroborated by simple metapopulation comparisons within Israel. Successful forecasts are driven by temperature, humidity, antigenic drift, and immunity loss. Essentially, influenza dynamics are a balance between large perturbations following significant antigenic jumps, interspersed with nonlinear epidemic dynamics tuned by climatic forcing. C1 [Axelsen, Jacob Bock; Yaari, Rami; Stone, Lewi] Tel Aviv Univ, Fac Life Sci, Dept Zool, Biomath Unit, IL-69978 Ramat Aviv, Israel. [Yaari, Rami] Tel Aviv Univ, Porter Sch Environm Studies, IL-69978 Ramat Aviv, Israel. [Grenfell, Bryan T.] Princeton Univ, Woodrow Wilson Sch Publ & Int Affairs, Princeton, NJ 08544 USA. [Grenfell, Bryan T.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Stone, Lewi] RMIT Univ, Sch Math & Geospatial Sci, Melbourne, Vic 3001, Australia. RP Stone, L (reprint author), Tel Aviv Univ, Fac Life Sci, Dept Zool, Biomath Unit, IL-69978 Ramat Aviv, Israel. EM lewistone2@gmail.com FU European Union FP7 EPIWORK grant; Israel Science Foundation; Israel Ministry of Health; Carlsberg Foundation; Israel National Institute for Health Policy and Health Services Research; Bill and Melinda Gates Foundation; Science and Technology Directorate, Department of Homeland Security [HSHQDC-12-C-00058]; Research and Policy in Infectious Disease Dynamics program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX We thank Drs. Jodie McVernon, James McCaw, Haggai Katriel, and Amit Huppert. We are grateful for the support of the European Union FP7 EPIWORK grant, the Israel Science Foundation, and the Israel Ministry of Health. J.B.A. is supported by the Carlsberg Foundation. R.Y. is supported by the Israel National Institute for Health Policy and Health Services Research. We appreciate the support of Maccabi Health Care Services for providing the ILI data. B. T. G. was supported by the Bill and Melinda Gates Foundation, the Science and Technology Directorate, Department of Homeland Security Contract HSHQDC-12-C-00058, and the Research and Policy in Infectious Disease Dynamics program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. NR 30 TC 14 Z9 14 U1 2 U2 13 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 1 PY 2014 VL 111 IS 26 BP 9538 EP 9542 DI 10.1073/pnas.1321656111 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK0QG UT WOS:000338118900053 PM 24979763 ER PT J AU Chen, AK Sengupta, P Waki, K Van Engelenburg, SB Ochiya, T Ablan, SD Freed, EO Lippincott-Schwartz, J AF Chen, Antony K. Sengupta, Prabuddha Waki, Kayoko Van Engelenburg, Schuyler B. Ochiya, Takahiro Ablan, Sherimay D. Freed, Eric O. Lippincott-Schwartz, Jennifer TI MicroRNA binding to the HIV-1 Gag protein inhibits Gag assembly and virus production SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID RNA; CELLS; BIOGENESIS; RETROVIRUS; TYPE-1; RECOGNITION; MICROSCOPY; PARTICLES; ELEMENT; PLASMA AB MicroRNAs (miRNAs) are small, 18-22 nt long, noncoding RNAs that act as potent negative gene regulators in a variety of physiological and pathological processes. To repress gene expression, miRNAs are packaged into RNA-induced silencing complexes (RISCs) that target mRNAs for degradation and/or translational repression in a sequence-specific manner. Recently, miRNAs have been shown to also interact with proteins outside RISCs, impacting cellular processes through mechanisms not involving gene silencing. Here, we define a previously unappreciated activity of miRNAs in inhibiting RNA-protein interactions that in the context of HIV-1 biology blocks HIV virus budding and reduces virus infectivity. This occurs by miRNA binding to the nucleocapsid domain of the Gag protein, the main structural component of HIV-1 virions. The resulting miRNA-Gag complexes interfere with viral-RNA-mediated Gag assembly and viral budding at the plasma membrane, with imperfectly assembled Gag complexes endocytosed and delivered to lysosomes. The blockade of virus production by miRNA is reversed by adding the miRNA's target mRNA and stimulated by depleting Argonaute-2, suggesting that when miRNAs are not mediating gene silencing, they can block HIV-1 production through disruption of Gag assembly on membranes. Overall, our findings have significant implications for understanding how cells modulate HIV-1 infection by miRNA expression and raise the possibility that miRNAs can function to disrupt RNA-mediated protein assembly processes in other cellular contexts. C1 [Chen, Antony K.; Sengupta, Prabuddha; Van Engelenburg, Schuyler B.; Lippincott-Schwartz, Jennifer] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Chen, Antony K.] Peking Univ, Coll Engn, Dept Biomed Engn, Beijing 100871, Peoples R China. [Waki, Kayoko; Ablan, Sherimay D.; Freed, Eric O.] NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Ctr Canc Res, Frederick, MD 21702 USA. [Ochiya, Takahiro] Natl Canc Ctr, Res Inst, Div Mol & Cellular Med, Tokyo 1040045, Japan. RP Lippincott-Schwartz, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. EM lippincj@mail.nih.gov OI CHEN, ANTONY/0000-0002-4105-9741 FU National Natural Science Foundation of China [81371613]; China's 1000 Young Talent Award program FX The authors thank Dr. Nobuyoshi Kosaka for providing the miR-146a and its reporter plasmids and the members of J.L.-S.'s laboratory for helpful discussions. This project was supported in part by the National Natural Science Foundation of China (Grant 81371613 to A.K.C.) and China's 1000 Young Talent Award program (A.K.C.). NR 36 TC 20 Z9 22 U1 3 U2 23 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 JUL 1 PY 2014 VL 111 IS 26 BP E2676 EP E2683 DI 10.1073/pnas.1408037111 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK0QG UT WOS:000338118900010 PM 24938790 ER PT J AU Cuss, SM AF Cuss, Steven M. TI Systemic flaws cannot be fixed with minor tweaks SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Letter C1 NCI, Ctr Canc Res, NIH, Frederick, MD 21702 USA. RP Cuss, SM (reprint author), NCI, Ctr Canc Res, NIH, Frederick, MD 21702 USA. EM cusssm@mail.nih.gov NR 1 TC 0 Z9 0 U1 2 U2 11 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 JUL 1 PY 2014 VL 111 IS 26 BP E2635 EP E2635 DI 10.1073/pnas.1407402111 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK0QG UT WOS:000338118900005 PM 24920597 ER PT J AU Reiner, RC Stoddard, ST Forshey, BM King, AA Ellis, AM Lloyd, AL Long, KC Rocha, C Vilcarromero, S Astete, H Bazan, I Lenhart, A Vazquez-Prokopec, GM Paz-Soldan, VA McCall, PJ Kitron, U Elder, JP Halsey, ES Morrison, AC Kochel, TJ Scott, TW AF Reiner, Robert C., Jr. Stoddard, Steven T. Forshey, Brett M. King, Aaron A. Ellis, Alicia M. Lloyd, Alun L. Long, Kanya C. Rocha, Claudio Vilcarromero, Stalin Astete, Helvio Bazan, Isabel Lenhart, Audrey Vazquez-Prokopec, Gonzalo M. Paz-Soldan, Valerie A. McCall, Philip J. Kitron, Uriel Elder, John P. Halsey, Eric S. Morrison, Amy C. Kochel, Tadeusz J. Scott, Thomas W. TI Time-varying, serotype-specific force of infection of dengue virus SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE disease ecology; emerging infections; arthropod-borne virus ID HEMORRHAGIC-FEVER; TRANSMISSION; EPIDEMIC; DISEASE; THAILAND; BANGKOK; PERU; INTEREPIDEMIC; INAPPARENT; EMERGENCE AB Infectious disease models play a key role in public health planning. These models rely on accurate estimates of key transmission parameters such as the force of infection (FoI), which is the percapita risk of a susceptible person being infected. The FoI captures the fundamental dynamics of transmission and is crucial for gauging control efforts, such as identifying vaccination targets. Dengue virus (DENV) is a mosquito-borne, multiserotype pathogen that currently infects similar to 390 million people a year. Existing estimates of the DENV FoI are inaccurate because they rely on the unrealistic assumption that risk is constant over time. Dengue models are thus unreliable for designing vaccine deployment strategies. Here, we present to our knowledge the first time-varying (daily), serotype-specific estimates of DENV FoIs using a spline-based fitting procedure designed to examine a 12-y, longitudinal DENV serological dataset from Iquitos, Peru (11,703 individuals, 38,416 samples, and 22,301 serotype-specific DENV infections from 1999 to 2010). The yearly DENV FoI varied markedly across time and serotypes (0-0.33), as did daily basic reproductive numbers (0.49-4.72). During specific time periods, the FoI fluctuations correlated across serotypes, indicating that different DENV serotypes shared common transmission drivers. The marked variation in transmission intensity that we detected indicates that intervention targets based on one-time estimates of the FoI could underestimate the level of effort needed to prevent disease. Our description of dengue virus transmission dynamics is unprecedented in detail, providing a basis for understanding the persistence of this rapidly emerging pathogen and improving disease prevention programs. C1 [Reiner, Robert C., Jr.; Stoddard, Steven T.; King, Aaron A.; Ellis, Alicia M.; Lloyd, Alun L.; Vazquez-Prokopec, Gonzalo M.; Kitron, Uriel; Scott, Thomas W.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Reiner, Robert C., Jr.; Stoddard, Steven T.; Long, Kanya C.; Morrison, Amy C.; Scott, Thomas W.] Univ Calif Davis, Dept Entomol & Nematol, Davis, CA 95616 USA. [Forshey, Brett M.; Rocha, Claudio; Vilcarromero, Stalin; Astete, Helvio; Bazan, Isabel; Halsey, Eric S.; Morrison, Amy C.; Kochel, Tadeusz J.] US Naval Med Res Unit 6 Lima & Iquitos, Lima, Peru. [King, Aaron A.] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. [Ellis, Alicia M.] Univ Vermont, Rubenstein Sch Environm & Nat Resources, Burlington, VT 05405 USA. [Lloyd, Alun L.] N Carolina State Univ, Dept Math, Raleigh, NC 27695 USA. [Lloyd, Alun L.] N Carolina State Univ, Biomath Grad Program, Raleigh, NC 27695 USA. [Long, Kanya C.] Andrews Univ, Dept Biol, Berrien Springs, MI 49104 USA. [Lenhart, Audrey; McCall, Philip J.] Univ Liverpool, Liverpool Sch Trop Med, Liverpool L3 5QA, Merseyside, England. [Lenhart, Audrey] Ctr Dis Control & Prevent, Entomol Branch, Div Parasit Dis & Malaria, Ctr Global Hlth, Atlanta, GA 30333 USA. [Vazquez-Prokopec, Gonzalo M.; Kitron, Uriel] Emory Univ, Dept Environm Sci, Atlanta, GA 30322 USA. [Paz-Soldan, Valerie A.] Tulane Univ, Sch Publ Hlth & Trop Med, New Orleans, LA 70112 USA. [Elder, John P.] San Diego State Univ, Grad Sch Publ Hlth, Inst Behav & Community Hlth, San Diego, CA 92182 USA. RP Reiner, RC (reprint author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM rcreiner@ucdavis.edu OI Vilcarromero, Stalin/0000-0002-9097-0638 FU Research and Policy for Infectious Disease Dynamics program of the Science and Technology Directory, Department of Homeland Security; Fogarty International Center, National Institutes of Health (NIH); NIH [RO1 AI-42332, RO1 AI069341, R01AI091980]; Innovative Vector Control Consortium; US Department of Defense Global Emerging Infections Systems Research Program [847705.82000.25GB.B0016]; Military Infectious Disease Research Program [6000 RAD1.S.B0302, S0002 04 LI, DOD S0017 03LI, DOD 32519, S0088 06 NM]; Deployed Warfighter Protection Program [DOD S0002 04]; Wellcome Trust [08571]; National Science Foundation [DMS 1246991] FX We thank Neil Ferguson and an anonymous reviewer for comments that improved this manuscript. In particular, we acknowledge Dr. Ferguson's helpful suggestions regarding our calculations of R0. We thank Tom Lindstrom for insightful comments on our Bayesian approach. This work was supported by the Research and Policy for Infectious Disease Dynamics program of the Science and Technology Directory, Department of Homeland Security, and Fogarty International Center, National Institutes of Health (NIH); NIH Grants RO1 AI-42332 and RO1 AI069341; Innovative Vector Control Consortium; US Department of Defense Global Emerging Infections Systems Research Program Work Unit 847705.82000.25GB.B0016; Military Infectious Disease Research Program Work Units 6000 RAD1.S.B0302, S0002 04 LI, DOD S0017 03LI, DOD 32519, and S0088 06 NM; Deployed Warfighter Protection Program DOD S0002 04; and Wellcome Trust Grant 08571. A.L.L. acknowledges support from NIH Grant R01AI091980 and National Science Foundation Grant DMS 1246991. E.S.H. and T.J.K. are military service members and B.M.F., S.V., H.A., I.B., A.L., and A.C.M. are employees of the US Government. This work was prepared as part of their official duties. Title 17 U.S.C. 105 provides that "Copyright protection under this title is not available for any work of the United States Government." Title 17 U.S.C. 101 defines a US Government work as a work prepared by a military service members or employees of the US Government as part of those persons' official duties. NR 56 TC 25 Z9 25 U1 2 U2 19 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 JUL 1 PY 2014 VL 111 IS 26 BP E2694 EP E2702 DI 10.1073/pnas.1314933111 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK0QG UT WOS:000338118900012 PM 24847073 ER PT J AU Wickner, RB Bezsonov, E Bateman, DA AF Wickner, Reed B. Bezsonov, Evgeny Bateman, David A. TI Normal levels of the antiprion proteins Btn2 and Cur1 cure most newly formed [URE3] prion variants SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Bmh1; Sis1; prion seed sequestration ID DISEASE-RELATED PROTEIN; DE-NOVO APPEARANCE; SACCHAROMYCES-CEREVISIAE; BATTEN-DISEASE; PSI+ PRION; YEAST PRION; GUANIDINE-HYDROCHLORIDE; QUALITY-CONTROL; MISFOLDED PROTEINS; SPECIES BARRIERS AB [URE3] is an amyloid prion of the Saccharomyces cerevisiae Ure2p, a regulator of nitrogen catabolism. Overproduction of Btn2p, involved in late endosome to Golgi protein transport, or its paralog Cur1p, cures [URE3]. Btn2p, in curing, is colocalized with Ure2p in a single locus, suggesting sequestration of Ure2p amyloid filaments. We find that most [URE3] variants generated in a btn2 cur1 double mutant are cured by restoring normal levels of Btn2p and Cur1p, with both proteins needed for efficient curing. The [URE3] variants cured by normal levels of Btn2p and Cur1p all have low seed number, again suggesting a seed sequestration mechanism. Hsp42 overproduction also cures [URE3], and Hsp42p aids Btn2 overproduction curing. Cur1p is needed for Hsp42 overproduction curing of [URE3], but neither Btn2p nor Cur1p is needed for overproduction curing by the other. Although hsp42 Delta strains stably propagate [URE3-1], hsp26 Delta destabilizes this prion. Thus, Btn2p and Cur1p are antiprion system components at their normal levels, acting with Hsp42. Btn2p is related in sequence to human Hook proteins, involved in aggresome formation and other transport activities. C1 [Wickner, Reed B.; Bezsonov, Evgeny; Bateman, David A.] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Wickner, RB (reprint author), NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. EM wickner@helix.nih.gov FU Intramural Program of the NIDDK of the National Institutes of Health FX We thank Daniel Masison, Kevin O'Connell, and Michael Reidy [all of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)] and Frank Shewmaker and Dmitry Kryndushkin [Uniformed Services University of the Health Sciences (USUHS)] for reading the manuscript; and Herman Edskes (NIDDK), Michael Reidy (NIDDK), and Dmitry Kryndushkin (USUHS) for strains and plasmids. This work was supported by the Intramural Program of the NIDDK of the National Institutes of Health. NR 63 TC 13 Z9 13 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 1 PY 2014 VL 111 IS 26 BP E2711 EP E2720 DI 10.1073/pnas.1409582111 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK0QG UT WOS:000338118900014 PM 24938787 ER PT J AU Naim, R Wald, I Lior, A Pine, DS Fox, NA Sheppes, G Halpern, P Bar-Haim, Y AF Naim, R. Wald, I. Lior, A. Pine, D. S. Fox, N. A. Sheppes, G. Halpern, P. Bar-Haim, Y. TI Perturbed threat monitoring following a traumatic event predicts risk for post-traumatic stress disorder SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Anxiety; attention bias; dissociation; PTSD ID ATTENTIONAL BIAS; PERITRAUMATIC DISSOCIATION; ACCIDENT VICTIMS; TRAIT ANXIETY; TIME-COURSE; SYMPTOMS; PTSD; INFORMATION; DEPRESSION; SEVERITY AB Background. Post-traumatic stress disorder (PTSD) is a chronic and difficult to treat psychiatric disorder. Objective, performance-based diagnostic markers that uniquely index risk for PTSD above and beyond subjective self-report markers could inform attempts to improve prevention and early intervention. We evaluated the predictive value of threat-related attention bias measured immediately after a potentially traumatic event, as a risk marker for PTSD at a 3-month follow-up. We measured the predictive contribution of attentional threat bias above and beyond that of the more established marker of risk for PTSD, self-reported psychological dissociation. Method. Dissociation symptoms and threat-related attention bias were measured in 577 motor vehicle accident (MVA) survivors (mean age= 35.02 years, 356 males) within 24 h of admission to an emergency department (ED) of a large urban hospital. PTSD symptoms were assessed at a 3-month follow-up using the Clinician-Administered PTSD Scale (CAPS). Results. Self-reported dissociation symptoms significantly accounted for 16% of the variance in PTSD at follow-up, and attention bias toward threat significantly accounted for an additional 4% of the variance in PTSD. Conclusions. Threat-related attention bias can be reliably measured in the context of a hospital ED and significantly predicts risk for later PTSD. Possible mechanisms underlying the association between threat bias following a potentially traumatic event and risk for PTSD are discussed. The potential application of an attention bias modification treatment (ABMT) tailored to reduce risk for PTSD is suggested. C1 [Naim, R.; Wald, I.; Sheppes, G.; Bar-Haim, Y.] Tel Aviv Univ, Sch Psychol Sci, IL-69978 Tel Aviv, Israel. [Lior, A.; Halpern, P.] Tel Aviv Med Ctr & Sch Med, Dept Emergency Med, Tel Aviv, Israel. [Pine, D. S.] NIMH, Bethesda, MD 20892 USA. [Fox, N. A.] Univ Maryland, Dept Human Dev, College Pk, MD 20742 USA. [Halpern, P.] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Bar-Haim, Y.] Tel Aviv Univ, Sagol Sch Neurosci, IL-69978 Tel Aviv, Israel. RP Naim, R (reprint author), Tel Aviv Univ, Sch Psychol Sci, IL-69978 Tel Aviv, Israel. EM reutnaim@post.tau.ac.il FU Israel Insurance Association; Association of Life Insurance Companies of Israel [0610714692] FX This work was supported by the Israel Insurance Association, Association of Life Insurance Companies of Israel (0610714692). Professor Y. Bar-Haim is independent of any commercial funder and had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. NR 61 TC 3 Z9 3 U1 4 U2 12 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 EI 1469-8978 J9 PSYCHOL MED JI Psychol. Med. PD JUL PY 2014 VL 44 IS 10 BP 2077 EP 2084 DI 10.1017/S0033291713002456 PG 8 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA AJ5UP UT WOS:000337755100006 PM 24131552 ER PT J AU Matsuo, M Matsumoto, S Mitchell, JB Krishna, MC Camphausen, K AF Matsuo, Masayuki Matsumoto, Shingo Mitchell, James B. Krishna, Murali C. Camphausen, Kevin TI Magnetic Resonance Imaging of the Tumor Microenvironment in Radiotherapy: Perfusion, Hypoxia, and Metabolism SO SEMINARS IN RADIATION ONCOLOGY LA English DT Article ID CONTRAST-ENHANCED MRI; CERVICAL-CANCER; RADIATION-THERAPY; CYCLING HYPOXIA; PROSTATE-CANCER; OXYGENATION; BIOLOGY; GLYCOLYSIS; EXPRESSION; CARCINOMA AB The tumor microenvironment is characterized by hypoxia, low pH, and high interstitial fluid pressure. Hypoxic regions in tumors with low partial pressure of oxygen (pO(2)) levels can result in resistance to radiotherapy, thus causing local failure. Therefore, it would be desirable to noninvasively measure pO(2) levels in the tumor before, during, and after treatment to better customize therapy and follow treatment response. Several techniques used in preclinical and clinical studies to obtain the pO(2) status of tissue, such as dynamic contrast-enhanced magnetic resonance imaging, blood oxygen level dependent imaging, and electron paramagnetic resonance imaging, are reviewed. Furthermore, the ability to hyperpolarize specific metabolic substrates that are isotopically labeled with C-13 coupled with magnetic resonance spectroscopy enables noninvasive imaging of tissue metabolism, such as glycolysis. Published by Elsevier Inc. C1 [Matsuo, Masayuki; Matsumoto, Shingo; Mitchell, James B.; Krishna, Murali C.] NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Camphausen, Kevin] NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Camphausen, K (reprint author), 9000 Rockville Pike, Bethesda, MD 20892 USA. EM camphauk@mail.nih.gov FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH FX This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH. NR 39 TC 11 Z9 11 U1 1 U2 23 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1053-4296 EI 1532-9461 J9 SEMIN RADIAT ONCOL JI Semin. Radiat. Oncol. PD JUL PY 2014 VL 24 IS 3 BP 210 EP 217 DI 10.1016/j.semradonc.2014.02.002 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AJ8VS UT WOS:000337986800013 PM 24931096 ER PT J AU Gail, MH AF Gail, Mitchell H. TI Using absolute risks to assess the risks and benefits of treatment SO THORAX LA English DT Editorial Material ID BREAST-CANCER C1 NCI, Biostat Branch, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. RP Gail, MH (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 7E-138, Rockville, MD 20850 USA. EM gailm@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 4 TC 3 Z9 3 U1 1 U2 4 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0040-6376 EI 1468-3296 J9 THORAX JI Thorax PD JUL PY 2014 VL 69 IS 7 BP 604 EP 605 DI 10.1136/thoraxjnl-2014-205175 PG 2 WC Respiratory System SC Respiratory System GA AJ7ZJ UT WOS:000337920700002 PM 24550059 ER PT J AU Laast, VA Larsen, T Allison, N Hoenerhoff, MJ Boorman, GA AF Laast, Victoria A. Larsen, Thomas Allison, Neil Hoenerhoff, Mark J. Boorman, Gary A. TI Distinguishing Cystic Degeneration from Other Aging Lesions in the Adrenal Cortex of Sprague-Dawley Rats SO TOXICOLOGIC PATHOLOGY LA English DT Review DE Sprague-Dawley rat; adrenal cortex; cystic degeneration; aging lesions AB Cystic degeneration of the adrenal cortex is a common age-related finding in the Sprague-Dawley (SD) rat strain occurring more frequently in females. Compression of the adjacent cortex, a common hallmark of benign adrenal cortical tumors, often accompanies foci of cystic degeneration, creating a diagnostic challenge. Accurately differentiating these relatively common degenerative changes from proliferative lesions is critical in safety assessment studies. Cystic degeneration typically arises in the zona fasciculata of the adrenal cortex and often causes compression along the margin of the lesion. The degenerating cells are large, with abundant eosinophilic cytoplasm, or contain clear cytoplasmic vacuoles. Mitotic figures are generally uncommon. In many cases, cystic degeneration appears to arise in areas of hypertrophy in the zona fasciculata. In contrast, adrenal cortical hyperplasia and adrenal cortical adenoma are frequently comprised of smaller cells that cause compression of adjacent cortex, and in some cases mitotic figures are observed. Cytological detail and growth patterns should be considered more useful criteria than compression alone for separating degenerative cystic lesions from proliferative lesions in the adrenal cortex of SD rats. C1 [Laast, Victoria A.] Covance Pharmaceut R&D Shanghai Co Ltd, Nonclin Safety Assessment, Shanghai 201318, Peoples R China. [Larsen, Thomas; Boorman, Gary A.] Covance Labs Inc, Nonclin Safety Assessment, Chantilly, VA USA. [Allison, Neil] Expt Pathol Labs Inc, Res Triangle Pk, NC USA. [Hoenerhoff, Mark J.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Laast, VA (reprint author), Covance Pharmaceut R&D Shanghai Co Ltd, Nonclin Safety Assessment, Bldg 3,3377 Kangxin Rd, Shanghai 201318, Peoples R China. EM victoria.laast@covance.com FU National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS) FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported (in part) by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS). This article may be the work product of an employee or group of employees of the National Toxicology Program (NTP), NIEHS, NIH; however, the statements, opinions, or conclusions contained therein do not necessarily represent the statements, opinions, or conclusions of NTP, NIEHS, NIH, or the U.S. Government. NR 12 TC 4 Z9 4 U1 1 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 EI 1533-1601 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUL PY 2014 VL 42 IS 5 BP 823 EP 829 DI 10.1177/0192623313502258 PG 7 WC Pathology; Toxicology SC Pathology; Toxicology GA AJ9GX UT WOS:000338017200005 PM 24970856 ER PT J AU Rider, CV Nyska, A Cora, MC Kissling, GE Smith, C Travlos, GS Hejtmancik, MR Fomby, LM Colleton, CA Ryan, MJ Kooistra, L Morrison, JP Chan, PC AF Rider, Cynthia V. Nyska, Abraham Cora, Michelle C. Kissling, Grace E. Smith, Cynthia Travlos, Gregory S. Hejtmancik, Milton R. Fomby, Laurene M. Colleton, Curtis A. Ryan, Michael J. Kooistra, Linda Morrison, James P. Chan, Po C. TI Toxicity and Carcinogenicity Studies of Ginkgo biloba Extract in Rat and Mouse: Liver, Thyroid, and Nose Are Targets SO TOXICOLOGIC PATHOLOGY LA English DT Article DE herbal; natural medicine; hepatocarcinogenicity; thyroid tumors; nasal lesions ID PREGNANE X RECEPTOR; RESPIRATORY-TRACT LESIONS; QUALITY-CONTROL; INDIVIDUAL GINKGOLIDES; RISK; TOXICOLOGY; LEAVES; SUPPLEMENTS; METABOLISM; INDUCTION AB Ginkgo biloba extract (GBE) is a popular herbal supplement that is used to improve circulation and brain function. In spite of widespread human exposure to relatively high doses over potentially long periods of time, there is a paucity of data from animal studies regarding the toxicity and carcinogenicity associated with GBE. In order to fill this knowledge gap, 3-month and 2-year toxicity and carcinogenicity studies with GBE administered by oral gavage to B6C3F1/N mice and F344/N rats were performed as part of the National Toxicology Program's Dietary Supplements and Herbal Medicines Initiative. The targets of GBE treatment were the liver, thyroid, and nose. These targets were consistent across exposure period, sex, and species, albeit with varying degrees of effect observed among studies. Key findings included a notably high incidence of hepatoblastomas in male and female mice and evidence of carcinogenic potential in the thyroid gland of both mice and rats. Various nonneoplastic lesions were observed beyond control levels in the liver, thyroid gland, and nose of rats and mice administered GBE. Although these results cannot be directly extrapolated to humans, the findings fill an important data gap in assessing risk associated with GBE use. C1 [Rider, Cynthia V.; Cora, Michelle C.; Kissling, Grace E.; Smith, Cynthia; Travlos, Gregory S.; Chan, Po C.] NIEHS, Durham, NC USA. [Nyska, Abraham] Integrated Lab Syst Inc, Res Triangle Pk, NC USA. [Hejtmancik, Milton R.; Fomby, Laurene M.; Colleton, Curtis A.; Ryan, Michael J.] Battelle Mem Inst, Columbus, OH USA. [Morrison, James P.] Charles River Labs, Pathol Associates, Durham, NC USA. RP Rider, CV (reprint author), 111 TW Alexander Dr,POB 12233,MD K2-12, Res Triangle Pk, NC 27709 USA. EM ridercv@niehs.nih.gov FU Intramural NIH HHS [Z01 ES045004-11, Z99 ES999999] NR 51 TC 2 Z9 2 U1 1 U2 11 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 EI 1533-1601 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUL PY 2014 VL 42 IS 5 BP 830 EP 843 DI 10.1177/0192623313501235 PG 14 WC Pathology; Toxicology SC Pathology; Toxicology GA AJ9GX UT WOS:000338017200006 PM 23960164 ER PT J AU Blackshear, PE Pandiri, AR Ton, TVT Clayton, NP Shockley, KR Peddada, SD Gerrish, KE Sills, RC Hoenerhoff, MJ AF Blackshear, Pamela E. Pandiri, Arun R. Ton, Thai-Vu T. Clayton, Natasha P. Shockley, Keith R. Peddada, Shyamal D. Gerrish, Kevin E. Sills, Robert C. Hoenerhoff, Mark J. TI Spontaneous Mesotheliomas in F344/N Rats Are Characterized by Dysregulation of Cellular Growth and Immune Function Pathways SO TOXICOLOGIC PATHOLOGY LA English DT Article DE mesothelioma; F344/N rat; National Toxicology Program; microarray; gene expression; mesothelial cell; Fred-PE cells ID MALIGNANT PLEURAL MESOTHELIOMA; GENE-EXPRESSION ANALYSIS; TGF-BETA; PULMONARY ADENOCARCINOMA; PROBE LEVEL; CELLS; CANCER; PROGRESSION; ASBESTOS; CARCINOGENESIS AB Aged male Fischer 344/N rats are prone to developing spontaneous peritoneal mesotheliomas that arise predominantly from the tunica vaginalis of the testes. A definitive cause for the predominance of this neoplasm in F344/N rats is unknown. Investigation of the molecular alterations that occur in spontaneous rat mesotheliomas may provide insight into their pathogenesis as well enable a better understanding regarding the mechanisms underlying chemically induced mesothelioma in rodents. Mesothelial cell function represents a complex interplay of pathways related to host defense mechanisms and maintenance of cellular homeostasis. Global gene expression profiles of spontaneous mesotheliomas from vehicle control male F344/N rats from 2-year National Toxicology Program carcinogenicity bioassays were analyzed to determine the molecular features of these tumors and elucidate tumor-specific gene expression profiles. The resulting gene expression pattern showed that spontaneous mesotheliomas are associated with upregulation of various growth factors, oncogenes, cytokines, pattern recognition response receptors, and pathogen-associated molecular patterns receptors, and the production of reactive oxygen and nitrogen species, as well as downregulation of apoptosis pathways. Alterations in these pathways in turn trigger molecular responses that stimulate cell proliferation and promote tumor survival and progression. C1 [Blackshear, Pamela E.] Integrated Lab Syst Inc, Res Triangle Pk, NC USA. [Pandiri, Arun R.] Expt Pathol Labs Inc, Res Triangle Pk, NC USA. [Ton, Thai-Vu T.; Clayton, Natasha P.; Sills, Robert C.; Hoenerhoff, Mark J.] NIEHS, Cellular & Mol Pathol Branch, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Shockley, Keith R.; Peddada, Shyamal D.] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Gerrish, Kevin E.] NIEHS, Microarray Core, Toxicol & Pharmacol Branch, Res Triangle Pk, NC 27709 USA. RP Hoenerhoff, MJ (reprint author), NIEHS, Invest Pathol Grp, Cellular & Mol Pathol Branch, B350 Rall Bldg,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM hoenerhm@niehs.nih.gov FU National Institutes of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH); Division of the National Toxicology Program (DNTP) FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Institutes of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), and The Division of the National Toxicology Program (DNTP). NR 80 TC 2 Z9 2 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 EI 1533-1601 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUL PY 2014 VL 42 IS 5 BP 863 EP 876 DI 10.1177/0192623313501894 PG 14 WC Pathology; Toxicology SC Pathology; Toxicology GA AJ9GX UT WOS:000338017200009 PM 23980201 ER PT J AU Herman, EH Knapton, A Liu, YM Lipshultz, SE Estis, J Todd, J Woodward, RA Cochran, T Zhang, J Poirier, MC AF Herman, Eugene H. Knapton, Alan Liu, Yongmin Lipshultz, Steven E. Estis, Joel Todd, John Woodward, Ruth A. Cochran, Thomas Zhang, Jun Poirier, Miriam C. TI The Influence of Age on Serum Concentrations of Cardiac Troponin I: Results in Rats, Monkeys, and Commercial Sera SO TOXICOLOGIC PATHOLOGY LA English DT Article DE cardiac troponin I; Sprague-Dawley rats; patas monkeys; young age ID STAGE HEART-FAILURE; MYOCARDIAL-INFARCTION; EXPRESSION; RELEASE; MARKERS; INJURY; VALUES; ASSAY; CARDIOMYOCYTES; IMMUNOASSAYS AB Cardiac troponins serve as serum biomarkers of myocardial injury. The current study examined the influence of age on serum concentrations of cardiac troponin I (cTnI). An ultrasensitive immunoassay was used to monitor cTnI concentrations in Sprague-Dawley (SD) rats and Erythrocebus patas monkeys of different ages. The mean cTnI concentrations were highest in 10-day-old rats compared to 25-, 40-, and 80-day-old SD rats. Cardiomyocyte remodeling was apparent in hearts from 10-day-old SD rats as evident by hypercellularity, irregularly shaped nuclei, and moderate numbers of myocytes undergoing mitosis and apoptosis. The mean concentration of cTnI in 5 newborn monkeys was considerably higher than that of three 1-year-old monkeys. Evidence of cardiomyocyte remodeling was also observed in these newborn hearts (loss of myofibrils and cytoplasmic vacuolation). Commercial animal serum samples were also analyzed. The concentrations of cTnI detected in fetal equine and porcine serum were considerably higher than that found in adult equine and porcine serum samples Likewise, fetal bovine serum had higher cTnI concentrations (>2,400 pg/ml) than did adult caprine and laprine samples (2.5-2.7 pg/ml). The present study found age-related differences in cTnI concentrations, with higher levels occurring at younger ages. This effect was consistent across several animal species. C1 [Herman, Eugene H.; Knapton, Alan; Zhang, Jun] US FDA, Div Drug Safety Res, Silver Spring, MD 20993 USA. [Liu, Yongmin; Poirier, Miriam C.] NCI, NIH, Carcinogen DNA Interact Sect, Bethesda, MD 20892 USA. [Lipshultz, Steven E.; Cochran, Thomas] Univ Miami, Dept Pediat, Leonard M Miller Sch Med, Mailman Ctr Child Dev, Miami, FL 33152 USA. [Estis, Joel; Todd, John] Singulex Inc, Alameda, CA USA. [Woodward, Ruth A.] NIH, Shared Anim Facil, Anim Ctr, Dickerson, MD USA. RP Herman, EH (reprint author), US FDA, Div Drug Safety Res HFD 910, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. EM eugene.herman@fda.hhs.gov NR 39 TC 2 Z9 2 U1 1 U2 6 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 EI 1533-1601 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUL PY 2014 VL 42 IS 5 BP 888 EP 896 DI 10.1177/0192623313505154 PG 9 WC Pathology; Toxicology SC Pathology; Toxicology GA AJ9GX UT WOS:000338017200011 PM 24129761 ER PT J AU Elmore, SA Ryan, AM Wood, CE Crabbs, TA Sills, RC AF Elmore, Susan A. Ryan, Anne M. Wood, Charles E. Crabbs, Torrie A. Sills, Robert C. TI FutureTox II: Contemporary Concepts in Toxicology: "Pathways to Prediction: In Vitro and In Silico Models for Predictive Toxicology" SO TOXICOLOGIC PATHOLOGY LA English DT Article C1 [Elmore, Susan A.; Sills, Robert C.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Ryan, Anne M.] Pfizer Inc, Pfizer Global R&D, Groton, CT 06340 USA. [Wood, Charles E.] US EPA, Res Triangle Pk, NC 27711 USA. [Crabbs, Torrie A.] Expt Pathol Labs Inc, Res Triangle Pk, NC USA. RP Elmore, SA (reprint author), NIEHS, Natl Toxicol Program, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM elmore@niehs.nih.gov FU National Institutes of Health (NIH); National Institute of Environmental Health Sciences (NIEHS) FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported (in part) by the National Institutes of Health (NIH) and National Institute of Environmental Health Sciences (NIEHS). NR 5 TC 0 Z9 1 U1 0 U2 6 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 EI 1533-1601 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUL PY 2014 VL 42 IS 5 BP 940 EP 942 DI 10.1177/0192623314537135 PG 3 WC Pathology; Toxicology SC Pathology; Toxicology GA AJ9GX UT WOS:000338017200017 PM 24855144 ER PT J AU Sverrisson, EF Zens, MS Fei, DL Andrews, A Schned, A Robbins, D Kelsey, KT Li, H DiRenzo, J Karagas, MR Seigne, JD AF Sverrisson, Einar F. Zens, Michael S. Fei, Dennis Liang Andrews, Angeline Schned, Alan Robbins, David Kelsey, Karl T. Li, Hua DiRenzo, James Karagas, Margaret R. Seigne, John D. TI Clinicopathological correlates of Gli1 expression in a population-based cohort of patients with newly diagnosed bladder cancer SO UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS LA English DT Article DE Gil1; Bladder neoplasm ID SONIC HEDGEHOG; CARCINOMA; CLASSIFICATION; ACTIVATION AB Introduction: Dysregulation of the hedgehog signaling pathway has been linked to the development and progression of a variety of different human tumors including cancers of the skin, brain, colon, prostate, blood, and pancreas. We assessed the clinicopathological factors that are potentially related to expression of Gli1, the transcription factor that is thought to be the most reliable marker of hedgehog pathway activation in bladder cancer. Methods: Bladder cancer cases were identified from the New Hampshire State Cancer Registry as histologically confirmed primary bladder cancer diagnosed between January 1, 2002, and July 31, 2004. Immunohistochemical analysis was performed on a tissue microarray to detect Gli1 and p53 expression in these bladder tumors. We computed odds ratios (ORs) and their 95% CIs for Gil1 positivity for pathological category using T category (from TNM), invasiveness, and grade with both the World Health Organization 1973 and World Health Organization International Society of Urological Pathology criteria. We calculated hazard ratios and their 95% CI for Gli1 positivity and recurrence for both Ta-category and invasive bladder tumors (T1+). Results: A total of 194 men and 67 women, whose tumors were assessable for Gli1 staining, were included in the study. No appreciable differences in Gli1 staining were noted by sex, age, smoking status, or high-risk occupation. Ta-category tumors were more likely to stain for Gli1 as compared with T1-category tumors (adjusted OR = 0.38, CI: 0.17-0.87) Similarly, low-grade (grades 1-2) tumors were more likely to stain for Gli1 as compared with high-grade tumors (grade 3) (adjusted OR = 0.44, CI: 0.21-0.93). In a Cox proportional hazards regression analysis, non muscle-invasive bladder tumors expressing Gil1 were less likely to recur (adjusted hazard ratio = 0.48; CI: 0.28-0.82; P < 0.05) than those in which Gli1 was absent. Conclusion: Our findings indicate that Gli1 expression may be a marker of low-stage, low-grade bladder tumors and an indicator of a reduced risk of recurrence in this group. (C) 2014 Elsevier Inc. All rights reserved. C1 [Sverrisson, Einar F.; Seigne, John D.] Dartmouth Hitchcock Med Ctr, Dept Urol Surg, Lebanon, NH 03766 USA. [Zens, Michael S.; Andrews, Angeline; Karagas, Margaret R.] Geisel Sch Med Dartmouth, Dept Community & Family Med, Hanover, NH USA. [Fei, Dennis Liang] NIH, Canc Biol Sect, Bethesda, MD 20892 USA. [Schned, Alan] Dartmouth Hitchcock Med Ctr, Dept Pathol Urol, Lebanon, NH 03766 USA. [Robbins, David] Univ Miami, Dept Surg, Mol Oncol Program, Miami, FL USA. [Kelsey, Karl T.] Brown Univ, Dept Community Hlth, Providence, RI 02912 USA. [Li, Hua] Uniformed Serv Univ Hlth Sci, Ctr Prostate Dis Res, Bethesda, MD 20814 USA. [DiRenzo, James] Geisel Sch Med Dartmouth, Dept Pharmacol & Toxicol, Hanover, NH USA. RP Seigne, JD (reprint author), Dartmouth Hitchcock Med Ctr, Dept Urol Surg, Lebanon, NH 03766 USA. EM john.d.seigne@hitchcock.org FU NIH, USA [CA 023108, R01 CA057594, P42 ES007373, P01ES022832, P20 GM104416, K07 CA102327] FX All grants supported by NIH, USA: CA 023108, R01 CA057594, P42 ES007373, P01ES022832, P20 GM104416, and K07 CA102327. NR 21 TC 6 Z9 6 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1078-1439 EI 1873-2496 J9 UROL ONCOL-SEMIN ORI JI Urol. Oncol.-Semin. Orig. Investig. PD JUL PY 2014 VL 32 IS 5 BP 539 EP 545 DI 10.1016/j.urolonc.2014.03.006 PG 7 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA AK0GL UT WOS:000338090800004 PM 24856810 ER PT J AU Apolo, AB Kim, JW Bochner, BH Steinberg, SM Bajorin, DF Kelly, WK Agarwal, PK Koppie, TM Kaag, MG Quinn, DI Vogelzang, NJ Sridhar, SS AF Apolo, Andrea B. Kim, Joseph W. Bochner, Bernard H. Steinberg, Seth M. Bajorin, Dean F. Kelly, Wm. Kevin Agarwal, Piyush K. Koppie, Theresa M. Kaag, Matthew G. Quinn, David I. Vogelzang, Nicholas J. Sridhar, Srikala S. TI Examining the management of muscle-invasive bladder cancer by medical oncologists in the United States SO UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS LA English DT Article DE Adjuvant chemotherapy; Medical oncologist; Muscle-invasive bladder cancer; Neoadjuvant chemotherapy; Survey ID PHASE-III TRIAL; CISPLATIN-BASED CHEMOTHERAPY; UROTHELIAL TRACT TUMORS; NEOADJUVANT CHEMOTHERAPY; M-VAC; PERIOPERATIVE CHEMOTHERAPY; PLUS CYSTECTOMY; CARBOPLATIN; CARCINOMA; THERAPY AB Background: Neoadjuvant chemotherapy (NACT) for the treatment of muscle-invasive bladder cancer (MIBC) remains underutilized in the United States despite evidence supporting its use. Objectives: To examine the perioperative chemotherapy management of patients with MIBC by medical oncologists (MedOncs) to move toward standardization of practice Participants and methods: A 26-question survey was emailed to 92 MedOncs belonging to the Bladder Cancer Advocacy Network or the American Society of Clinical Oncology for completion from May to October 2011 Results: A total of 83 MedOncs completed the survey: 52% were based in academic centers. Most referrals were from urologists (79%). NACT for treatment of MIBC and high-grade upper-tract urothelial carcinoma is offered by 80% and 46% of respondents, respectively. Adjuvant chemotherapy for treatment of MIBC and upper-tract urothelial carcinoma is offered by 46% and 42% of respondents, respectively. NACT was not offered by 49%, 29%, and 35% of respondents if Eastern Cooperative Oncology Group performance status was 3 or greater, if patients had T2 lesions without lymphovascular invasion, and if the glomerular filtration rate was <50 ml/min, respectively. Chemotherapy regimens included gemcitabine/cisplatin (90%), methotrexate/vinblastine/adriamycin/cisplatin (30%), dose-dense methotrexate, vinblastine, adriamycin, and cisplatin (20%), and gemcitabine/carboplatin (37%). Conclusions: Most MedOncs (79%) in this survey offer perioperative chemotherapy to all patients with MIBC. This increased use of NACT is higher than previously reported, suggesting an increase in the adoption of recommendations that follow best evidence. Published by Elsevier Inc. C1 [Apolo, Andrea B.] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Kim, Joseph W.] Yale Univ, Sch Med, Dept Med, Yale Canc Ctr, New Haven, CT 06510 USA. [Bochner, Bernard H.] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10021 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. [Bajorin, Dean F.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Kelly, Wm. Kevin] Thomas Jefferson Univ, Kimmel Canc Ctr, Dept Med Oncol, Philadelphia, PA 19107 USA. [Agarwal, Piyush K.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Koppie, Theresa M.] Oregon Hlth & Sci Univ, Dept Urol, Portland, OR 97201 USA. [Kaag, Matthew G.] Penn State Hershey Med Ctr, Div Urol, Hershey, PA USA. [Quinn, David I.] Univ So Calif, Norris Comprehens Canc Ctr, Dev Therapeut Program, Los Angeles, CA USA. [Quinn, David I.] Univ So Calif, Norris Comprehens Canc Ctr, Genitourinary Canc Program, Los Angeles, CA USA. [Vogelzang, Nicholas J.] US Oncol Res, Houston, TX USA. [Vogelzang, Nicholas J.] Comprehens Canc Ctr Nevada, Las Vegas, NV USA. [Sridhar, Srikala S.] Princess Margaret Hosp, Dept Med Oncol & Hematol, Toronto, ON M4X 1K9, Canada. RP Apolo, AB (reprint author), NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. EM andrea.apolo@nih.gov RI Quinn, David/F-4343-2015; OI Quinn, David/0000-0002-1411-0417; Agarwal, Piyush/0000-0002-6042-6834 FU US Office of Management and Budget [0925-0046] FX The US Office of Management and Budget (0925-0046). NR 28 TC 13 Z9 13 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1078-1439 EI 1873-2496 J9 UROL ONCOL-SEMIN ORI JI Urol. Oncol.-Semin. Orig. Investig. PD JUL PY 2014 VL 32 IS 5 BP 637 EP 644 DI 10.1016/j.urolonc.2013.12.012 PG 8 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA AK0GL UT WOS:000338090800019 PM 24840869 ER PT J AU Auer, R Vittinghoff, E Kiefe, C Reis, JP Rodondi, N Khodneva, YA Kertesz, SG Cornuz, J Pletcher, MJ AF Auer, Reto Vittinghoff, Eric Kiefe, Catarina Reis, Jared P. Rodondi, Nicolas Khodneva, Yulia A. Kertesz, Stefan G. Cornuz, Jacques Pletcher, Mark J. TI Change in physical activity after smoking cessation: the Coronary Artery Risk Development in Young Adults (CARDIA) study SO ADDICTION LA English DT Article DE behavior change; marginal structural model; middle age; mixed longitudinal model; physical activity; smoking cessation; trajectory analysis; young adults ID HEALTH-RELATED BEHAVIORS; CIGARETTE-SMOKING; WEIGHT-GAIN; FOLLOW-UP; SELF-REPORTS; LIFE-STYLE; EXERCISE; WOMEN; DISEASE; MIDDLE AB Aims To estimate physical activity trajectories for people who quit smoking, and compare them to what would have been expected had smoking continued. Design, Setting and Participants A total of 5115 participants in the Coronary Artery Risk Development in Young Adults Study (CARDIA) study, a population-based study of African American and European American people recruited at age 18-30 years in 1985/6 and followed over 25 years. Measurements Physical activity was self-reported during clinical examinations at baseline (1985/6) and at years 2, 5, 7, 10, 15, 20 and 25 (2010/11); smoking status was reported each year (at examinations or by telephone, and imputed where missing). We used mixed linear models to estimate trajectories of physical activity under varying smoking conditions, with adjustment for participant characteristics and secular trends. Findings We found significant interactions by race/sex (P=0.02 for the interaction with cumulative years of smoking), hence we investigated the subgroups separately. Increasing years of smoking were associated with a decline in physical activity in black and white women and black men [e.g. coefficient for 10 years of smoking: -0.14; 95% confidence interval (CI)=-0.20 to -0.07, P<0.001 for white women]. An increase in physical activity was associated with years since smoking cessation in white men (coefficient 0.06; 95% CI=0 to 0.13, P=0.05). The physical activity trajectory for people who quit diverged progressively towards higher physical activity from the expected trajectory had smoking continued. For example, physical activity was 34% higher (95% CI=18 to 52%; P<0.001) for white women 10 years after stopping compared with continuing smoking for those 10 years (P=0.21 for race/sex differences). Conclusions Smokers who quit have progressively higher levels of physical activity in the years after quitting compared with continuing smokers. C1 [Auer, Reto; Vittinghoff, Eric; Pletcher, Mark J.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Kiefe, Catarina] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Worcester, MA USA. [Reis, Jared P.] NHLBI, Bethesda, MD 20892 USA. [Rodondi, Nicolas] Univ Bern, Inselspital, Dept Gen Internal Med, CH-3010 Bern, Switzerland. [Khodneva, Yulia A.; Kertesz, Stefan G.] Univ Alabama Birmingham, Birmingham Sch Publ Hlth, Dept Hlth Behav, Birmingham, AL USA. [Kertesz, Stefan G.] Birmingham VA Med Ctr, Ctr Surg Med & Acute Care Res, Birmingham, AL USA. [Kertesz, Stefan G.] Univ Alabama Birmingham, Div Prevent Med, Med Sch Birmingham, Birmingham, AL USA. [Cornuz, Jacques] Univ Lausanne Hosp, Dept Ambulatory & Community Med, Lausanne, Switzerland. RP Auer, R (reprint author), Univ Calif San Francisco, Dept Epidemiol & Biostat, 185 Berry St,Suite 5700, San Francisco, CA 94143 USA. EM reto.auer@ucsf.edu FU National Heart, Lung, and Blood Institute (NHLBI); University of Alabama at Birmingham [HHSN268201300025C, HHSN268201300026C]; Northwestern University [HHSN268201300027C]; University of Minnesota [HHSN268201300028C]; Kaiser Foundation Research Institute [HHSN268201300029C]; Johns Hopkins University School of Medicine [HHSN268200900041C]; National Institute on Aging (NIA); NIA; NHLBI [AG0005]; Swiss National Science Foundation [PBLAP3-136774]; Societe Academique Vaudoise; SICPA Foundation FX The Coronary Artery Risk Development in Young Adults Study (CARDIA) is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with the University of Alabama at Birmingham (HHSN268201300025C and HHSN268201300026C), Northwestern University (HHSN268201300027C), University of Minnesota (HHSN268201300028C), Kaiser Foundation Research Institute (HHSN268201300029C) and Johns Hopkins University School of Medicine (HHSN268200900041C). CARDIA is also partially supported by the Intramural Research Program of the National Institute on Aging (NIA) and an intra-agency agreement between NIA and NHLBI (AG0005). This manuscript has been reviewed by CARDIA for scientific content. Dr Auer's research on cardiovascular prevention is supported by a grant from the Swiss National Science Foundation PBLAP3-136774, the Societe Academique Vaudoise and the SICPA Foundation. NR 53 TC 3 Z9 3 U1 1 U2 20 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0965-2140 EI 1360-0443 J9 ADDICTION JI Addiction PD JUL PY 2014 VL 109 IS 7 BP 1172 EP 1183 DI 10.1111/add.12561 PG 12 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA AJ3LY UT WOS:000337569200025 PM 24690003 ER PT J AU Heller, T Rotman, Y Koh, C Clark, S Haynes-Williams, V Chang, R McBurney, R Schmid, P Albrecht, J Kleiner, DE Ghany, MG Liang, TJ Hoofnagle, JH AF Heller, T. Rotman, Y. Koh, C. Clark, S. Haynes-Williams, V. Chang, R. McBurney, R. Schmid, P. Albrecht, J. Kleiner, D. E. Ghany, M. G. Liang, T. J. Hoofnagle, J. H. TI Long-term therapy of chronic delta hepatitis with peginterferon alfa SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID VENOUS-PRESSURE GRADIENT; PEGYLATED INTERFERON-ALPHA-2B; PORTAL-HYPERTENSION; LIVER-DISEASE; VIRUS; INFECTION; CIRRHOSIS; PREVALENCE; DIAGNOSIS; EFFICACY AB Background Chronic delta hepatitis virus (HDV) infection rapidly progresses to cirrhosis. Treatment with peginterferon for up to 2 years is often without durable response. Aim To examine the efficacy and safety of long-term peginterferon in achieving a durable response. Methods Treatment was initiated with 180 mu g/week of peginterferon alfa-2a with titration to a maximal tolerable dose, for up to 5 years. Liver biopsies and hepatic venous pressure gradients (HVPG) were evaluated at baseline, 1, 3 and 5 years. The primary endpoint was histological improvement or loss of serum HDV and HBsAg at 3 years. Results Thirteen patients were treated for a median of 140 weeks (6-260) with an average peginterferon dose of 180 mu g/week (90-270). At baseline, most had advanced disease (median Ishak fibrosis = 3) with portal hypertension (HVPG = 10.2 +/- 6 mmHg). Five of 13 patients (39%) achieved the primary endpoint, with three seroconverting for HBsAg after 24, 37 and 202 weeks of treatment. Histological inflammation improved after 1 year, (median HAI: 10 vs. 7, P = 0.01) with persistence in 4/5 patients at 3 years (median HAI: 7.5). Greatest improvements occurred in the first year. Baseline bilirubin and HBsAg levels were significantly lower in virological responders than nonresponders. After 12 weeks, virological responders had a significant decline in HBsAg (1.5 log10 IU/mL, P = 0.05). Conclusion Despite increased doses and duration of therapy, treatment of chronic HDV with peginterferon remains unsatisfactory. Quantitative measures of HBsAg may be an important biomarker of early response to peginterferon therapy in chronic delta hepatitis virus infection. C1 [Heller, T.; Rotman, Y.; Koh, C.; Clark, S.; Haynes-Williams, V.; Ghany, M. G.; Liang, T. J.; Hoofnagle, J. H.] NIDDK, Liver Dis Branch, NIH, Bethesda, MD USA. [Chang, R.; McBurney, R.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Schmid, P.; Albrecht, J.] Natl Inst Genet, Los Angeles, CA USA. [Kleiner, D. E.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Heller, T (reprint author), 10 Ctr Dr,Bldg 10 Room 9B16 MSC 1800, Bethesda, MD 20892 USA. EM TheoH@intra.niddk.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Cancer Institute (NCI) of the National Institutes of Health (NIH) FX This research was funded by the Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Cancer Institute (NCI) of the National Institutes of Health (NIH). Peginterferon alfa-2a was provided by Hoffman La Roche (Genentech) under a Clinical Trial Agreement with the NIDDK. NR 42 TC 21 Z9 22 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-2813 EI 1365-2036 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD JUL PY 2014 VL 40 IS 1 BP 93 EP 104 DI 10.1111/apt.12788 PG 12 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA AJ4DN UT WOS:000337621500009 PM 24815494 ER PT J AU Keppler-Noreuil, KM Sapp, JC Lindhurst, MJ Parker, VER Blumhorst, C Darling, T Tosi, LL Huson, SM Whitehouse, RW Jakkula, E Grant, I Balasubramanian, M Chandler, KE Fraser, JL Gucev, Z Crow, YJ Brennan, LM Clark, R Sellars, EA Pena, LDM Krishnamurty, V Shuen, A Braverman, N Cunningham, ML Sutton, VR Tasic, V Graham, JM Geer, J Henderson, A Semple, RK Biesecker, LG AF Keppler-Noreuil, Kim M. Sapp, Julie C. Lindhurst, Marjorie J. Parker, Victoria E. R. Blumhorst, Cathy Darling, Thomas Tosi, Laura L. Huson, Susan M. Whitehouse, Richard W. Jakkula, Eveliina Grant, Ian Balasubramanian, Meena Chandler, Kate E. Fraser, Jamie L. Gucev, Zoran Crow, Yanick J. Brennan, Leslie Manace Clark, Robin Sellars, Elizabeth A. Pena, Loren D. M. Krishnamurty, Vidya Shuen, Andrew Braverman, Nancy Cunningham, Michael L. Sutton, V. Reid Tasic, Velibor Graham, John M., Jr. Geer, Joseph, Jr. Henderson, Alex Semple, Robert K. Biesecker, Leslie G. TI Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE somatic mosaicism; PIK3CA gene; fibroadipose overgrowth; segmental overgrowth; macrodactyly; CLOVES syndrome ID COLORECTAL-CANCER SURVIVAL; PIK3CA GENE; PROTEUS-SYNDROME; ACTIVATING MUTATIONS; CLOVES SYNDROME; MEGALENCEPHALY SYNDROMES; EPIDERMAL-NEVI; BREAST-CANCER; PATHWAY; ASPIRIN AB Somatic mutations in the phosphatidylinositol/AKT/mTOR pathway cause segmental overgrowth disorders. Diagnostic descriptors associated with PIK3CA mutations include fibroadipose overgrowth (FAO), Hemihyperplasia multiple Lipomatosis (HHML), Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi, Scoliosis/skeletal and spinal (CLOVES) syndrome, macrodactyly, and the megalencephaly syndrome, Megalencephaly-Capillary malformation (MCAP) syndrome. We set out to refine the understanding of the clinical spectrum and natural history of these phenotypes, and now describe 35 patients with segmental overgrowth and somatic PIK3CA mutations. The phenotypic data show that these previously described disease entities have considerable overlap, and represent a spectrum. While this spectrum overlaps with Proteus syndrome (sporadic, mosaic, and progressive) it can be distinguished by the absence of cerebriform connective tissue nevi and a distinct natural history. Vascular malformations were found in 15/35 (43%) and epidermal nevi in 4/35 (11%) patients, lower than in Proteus syndrome. Unlike Proteus syndrome, 31/35 (89%) patients with PIK3CA mutations had congenital overgrowth, and in 35/35 patients this was asymmetric and disproportionate. Overgrowth was mild with little postnatal progression in most, while in others it was severe and progressive requiring multiple surgeries. Novel findings include: adipose dysregulation present in all patients, unilateral overgrowth that is predominantly left-sided, overgrowth that affects the lower extremities more than the upper extremities and progresses in a distal to proximal pattern, and in the most severely affected patients is associated with marked paucity of adipose tissue in unaffected areas. While the current data are consistent with some genotype-phenotype correlation, this cannot yet be confirmed. (c) 2014 Wiley Periodicals, Inc. C1 [Keppler-Noreuil, Kim M.; Sapp, Julie C.; Lindhurst, Marjorie J.; Blumhorst, Cathy; Fraser, Jamie L.; Biesecker, Leslie G.] NHGRI, NIH, Bethesda, MD 20892 USA. [Parker, Victoria E. R.; Semple, Robert K.] Univ Cambridge, Metab Res Labs, Inst Metab Sci, Cambridge, England. [Darling, Thomas] Uniformed Serv Univ Hlth Sci, Dept Dermatol, Bethesda, MD 20814 USA. [Tosi, Laura L.] Childrens Natl Med Ctr, Div Orthopaed Surg & Sports Med, Washington, DC 20010 USA. [Huson, Susan M.; Chandler, Kate E.; Crow, Yanick J.] Univ Manchester, Cent Manchester Univ Hosp NHS Fdn Trust, Inst Human Dev,Fac Med & Human Sci, Manchester Ctr Genom Med,MAHSC, Manchester, Lancs, England. [Whitehouse, Richard W.] Manchester Royal Infirm, Cent Manchester Univ Hosp NHS Fdn Trust, Dept Radiol, Manchester M13 9WL, Lancs, England. [Jakkula, Eveliina] Univ Helsinki, Cent Hosp, Dept Clin Genet, Helsinki, Finland. [Grant, Ian] Cambridge Univ Hosp NHS Trust, Dept Plast Surg, Cambridge, England. [Balasubramanian, Meena] Sheffield Childrens NHS Fdn Trust, Sheffield Clin Genet Serv, Sheffield, S Yorkshire, England. [Gucev, Zoran] Univ Skopje, Dept Endocrinol & Genet, Skopje, Macedonia. [Brennan, Leslie Manace] Univ Calif San Francisco, Kaiser Permanente Oakland, San Francisco, CA 94143 USA. [Clark, Robin] Loma Linda Univ, Dept Pediat, Med Ctr, Div Med Genet, Loma Linda, CA 92350 USA. [Sellars, Elizabeth A.] Arkansas Childrens Hosp, Sect Genet & Metab, Little Rock, AR 72202 USA. [Pena, Loren D. M.] Duke Univ, Med Ctr, Dept Pediat, Div Genet, Durham, NC 27710 USA. [Krishnamurty, Vidya] Pediat Clin, Alpharetta, GA USA. [Krishnamurty, Vidya] Genet Clin, Alpharetta, GA USA. [Shuen, Andrew] McGill Univ, Dept Med Genet, Ctr Hlth, Montreal, PQ, Canada. [Braverman, Nancy] McGill Univ, Montreal Childrens Hosp, Res Inst, Dept Human Genet & Pediat, Montreal, PQ H3H 1P3, Canada. [Cunningham, Michael L.] Univ Washington, Sch Med, Div Craniofacial Med, Seattle, WA USA. [Sutton, V. Reid] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Tasic, Velibor] Univ Childrens Hosp, Sch Med, Skopje, Macedonia. [Graham, John M., Jr.] Harbor UCLA Med Ctr, Dept Pediat, Los Angeles, CA USA. [Geer, Joseph, Jr.] Greenwood Genet Ctr, Greenwood, SC 29646 USA. [Henderson, Alex] Newcastle Upon Tyne Hosp, Northern Genet Serv, Newcastle Upon Tyne, Tyne & Wear, England. RP Keppler-Noreuil, KM (reprint author), NHGRI, NIH, 49 Convent Dr 4A83, Bethesda, MD 20892 USA. EM kim.keppler-noreuil@nih.gov RI Crow, Yanick/N-6120-2014; OI Crow, Yanick/0000-0001-7211-7564; Semple, Robert/0000-0001-6539-3069; Balasubramanian, Meena/0000-0003-1488-3695; Darling, Thomas/0000-0002-5161-1974 FU National Human Genome Research Institute; Wellcome Trust (Senior Research Fellowship in Clinical Science) [098498/Z/12/Z]; Clinical Research Training Fellowship [097721/Z/11/Z]; UK National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre; UK Medical Research Council Centre for Obesity and Related Metabolic Diseases FX Grant sponsor: Intramural Research Program of the National Human Genome Research Institute; Grant sponsor: Wellcome Trust (Senior Research Fellowship in Clinical Science); Grant number: 098498/Z/12/Z; Grant sponsor: Clinical Research Training Fellowship; Grant number: 097721/Z/11/Z; Grant sponsor: UK National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre; Grant sponsor: UK Medical Research Council Centre for Obesity and Related Metabolic Diseases. NR 48 TC 45 Z9 45 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD JUL PY 2014 VL 164 IS 7 BP 1713 EP 1733 DI 10.1002/ajmg.a.36552 PG 21 WC Genetics & Heredity SC Genetics & Heredity GA AJ4HB UT WOS:000337633300017 PM 24782230 ER PT J AU Ferreira, C Poretti, A Cohen, J Hamosh, A Naidu, S AF Ferreira, Carlos Poretti, Andrea Cohen, Julie Hamosh, Ada Naidu, Sakkubai TI Novel TUBB4A mutations and expansion of the neuroimaging phenotype of hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE hypomyelination with atrophy of the basal ganglia and cerebellum; TUBB4A; tubulin beta 4 ID BETA-TUBULIN AB Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) has recently been associated with a single heterozygous p.D249N mutation in TUBB4A. We describe two novel mutations in this gene. A p.C239F mutation was found in one of the originally described H-ABC patients, for whom we provide follow-up 11 years after the original publication. The second novel mutation, p.R262H, was found in a patient with a typical clinical presentation for H-ABC, but with a novel neuroimaging phenotype, given the absence of atrophy of the putamen and caudate nucleus despite 7 years of follow-up. The recent recognition of TUBB4A mutations as the underlying etiology of H-ABC will likely lead to the identification of subtler clinical and neuroimaging presentations of this disorder, like in our third patient. Thus mutations in this gene should be suspected in any patient with hypomyelination, regardless of the long-term presence of neostriatal atrophy. (c) 2014 Wiley Periodicals, Inc. C1 [Ferreira, Carlos] NHGRI, NIH, Bethesda, MD 20892 USA. [Poretti, Andrea] Johns Hopkins Univ, Sch Med, Russell H Morgan Dept Radiol & Radiol Sci, Sect Pediat Neuroradiol,Div Pediat Radiol, Baltimore, MD USA. [Cohen, Julie] Kennedy Krieger Inst, Dept Neurol & Dev Med, Baltimore, MD USA. [Hamosh, Ada] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Naidu, Sakkubai] Kennedy Krieger Inst, Dept Neurogenet, Baltimore, MD 21205 USA. RP Naidu, S (reprint author), Kennedy Krieger Inst, Dept Neurogenet, 707 N Broadway, Baltimore, MD 21205 USA. EM naidu@kennedykrieger.org OI Poretti, Andrea/0000-0002-9594-3858 NR 17 TC 12 Z9 13 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD JUL PY 2014 VL 164 IS 7 BP 1802 EP 1807 DI 10.1002/ajmg.a.36526 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA AJ4HB UT WOS:000337633300029 PM 24706558 ER PT J AU Tzeng, M du Souich, C Cheung, HWH Boerkoel, CF AF Tzeng, Michael du Souich, Christele Cheung, Helen Wing-Hong Boerkoel, Cornelius F. TI Coffin-Siris syndrome: Phenotypic evolution of a novel SMARCA4 mutation SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE chromatin remodeling; intellectual disability; scoliosis; expressivity; choanal stenosis ID NICOLAIDES-BARAITSER SYNDROME; SWI/SNF COMPLEX; GENOME; PLURIPOTENT; COMPONENTS; CELLS; MAPS AB Coffin-Siris Syndrome (CSS) is an intellectual disability disorder caused by mutation of components of the SWI/SNF chromatin-remodeling complex. We describe the evolution of the phenotypic features for a male patient with CSS from birth to age 7 years and 9 months and by review of reported CSS patients, we expand the phenotype to include neonatal and infantile hypertonia and upper airway obstruction. The propositus had a novel de novo heterozygous missense mutation in exon 17 of SMARCA4 (NM_001128849.1:c.2434C>T (NP_001122321.1:p.Leu812Phe)). This is the first reported mutation within motif Ia of the SMARCA4 SNF2 domain. In summary, SMARCA4-associated CSS is a pleiotropic disorder in which the pathognomic clinical features evolve and for which the few reported individuals do not demonstrate a clear genotype-phenotype correlation. (c) 2014 Wiley Periodicals, Inc. C1 [Tzeng, Michael; Cheung, Helen Wing-Hong; Boerkoel, Cornelius F.] NIH Off Director, NIH Undiagnosed Dis Program, Common Fund, Bethesda, MD USA. [Tzeng, Michael; Cheung, Helen Wing-Hong; Boerkoel, Cornelius F.] NHGRI, Bethesda, MD 20892 USA. [du Souich, Christele; Boerkoel, Cornelius F.] Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada. [du Souich, Christele; Boerkoel, Cornelius F.] Childrens & Womens Hlth Ctr British Columbia, Child & Family Res Inst, Vancouver, BC, Canada. RP du Souich, C (reprint author), Childrens & Womens Hlth Ctr BC, Dept Med Genet, Prov Med Genet Program, 4500 Oak St,Rm C234, Vancouver, BC V6H 3N1, Canada. EM cdusouich@cw.bc.ca FU Common Fund, Office of the Director, the Intramural Research Program of the National Human Genome Research Institute (NIH, Bethesda, Maryland); Child & Family Research Institute FX We thank Rosemarie Rupps for critical review of the manuscript. This work was supported in part by the Common Fund, Office of the Director, the Intramural Research Program of the National Human Genome Research Institute (NIH, Bethesda, Maryland) and grants from the Child & Family Research Institute (C. F. B.). C. F. Boerkoel is a scholar of the Michael Smith Foundation for Health Research and a Clinical Investigator at the Child & Family Research Institute. NR 17 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD JUL PY 2014 VL 164 IS 7 BP 1808 EP 1814 DI 10.1002/ajmg.a.36533 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA AJ4HB UT WOS:000337633300030 PM 24700502 ER PT J AU Paul, RK Singh, NS Khadeer, M Moaddel, R Sanghvi, M Green, CE O'Loughlin, K Torjman, MC Bernier, M Wainer, IW AF Paul, Rajib K. Singh, Nagendra S. Khadeer, Mohammed Moaddel, Ruin Sanghvi, Mitesh Green, Carol E. O'Loughlin, Kathleen Torjman, Marc C. Bernier, Michel Wainer, Irving W. TI (R,S)-Ketamine Metabolites (R,S)-norketamine and (2S,6S)-hydroxynorketamine Increase the Mammalian Target of Rapamycin Function SO ANESTHESIOLOGY LA English DT Article ID NICOTINIC ACETYLCHOLINE-RECEPTORS; LIVER MICROSOMAL PREPARATIONS; RESISTANT BIPOLAR DEPRESSION; SERINE RACEMASE; KETAMINE; RAT; NORKETAMINE; PAIN; BIOTRANSFORMATION; ANTAGONISTS AB Background: Subanesthetic doses of (R,S)-ketamine are used in the treatment of neuropathic pain and depression. In the rat, the antidepressant effects of (R,S)-ketamine are associated with increased activity and function of mammalian target of rapamycin (mTOR); however, (R,S)-ketamine is extensively metabolized and the contribution of its metabolites to increased mTOR signaling is unknown. Methods: Rats (n = 3 per time point) were given (R,S)-ketamine, (R,S)-norketamine, and (2S,6S)-hydroxynorketamine and their effect on the mTOR pathway determined after 20, 30, and 60 min. PC-12 pheochromocytoma cells (n = 3 per experiment) were treated with escalating concentrations of each compound and the impact on the mTOR pathway was determined. Results: The phosphorylation of mTOR and its downstream targets was significantly increased in rat prefrontal cortex tissue by more than 2.5-, 25-, and 2-fold, respectively, in response to a 60-min postadministration of (R,S)-ketamine, (R,S)-norketamine, and (2S,6S)-hydroxynorketamine (P < 0.05, ANOVA analysis). In PC-12 pheochromocytoma cells, the test compounds activated the mTOR pathway in a concentration-dependent manner, which resulted in a significantly higher expression of serine racemase with 2-fold increases at 0.05 nM (2S,6S)-hydroxynorketamine, 10 nM (R,S)-norketamine, and 1,000 nM (R,S)-ketamine. The potency of the effect reflected antagonistic activity of the test compounds at the (7)-nicotinic acetylcholine receptor. Conclusions: The data demonstrate that (R,S)-norketamine and (2S,6S)-hydroxynorketamine have potent pharmacological activity both in vitro and in vivo and contribute to the molecular effects produced by subanesthetic doses of (R,S)-ketamine. The results suggest that the determination of the mechanisms underlying the antidepressant and analgesic effects of (R,S)-ketamine requires a full study of the parent compound and its metabolites. C1 [Paul, Rajib K.; Singh, Nagendra S.; Khadeer, Mohammed; Moaddel, Ruin; Sanghvi, Mitesh; Wainer, Irving W.] NIA, Clin Invest Lab, NIH, Baltimore, MD 21224 USA. [Bernier, Michel] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Green, Carol E.; O'Loughlin, Kathleen] SRI Int, SRI Biosci, Menlo Pk, CA 94025 USA. [Torjman, Marc C.; Wainer, Irving W.] Rowan Univ, Cooper Med Sch, Dept Anesthesiol, Camden, NJ USA. RP Wainer, IW (reprint author), NIA, Clin Invest Lab, NIH, Biomed Res Ctr, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. EM wainerir@grc.nia.nih.gov RI Singh, Nagendra/K-8966-2015; OI Bernier, Michel/0000-0002-5948-368X FU Intramural Research Program of the National Institute on Aging, National Institutes of Health (Baltimore, Maryland); National Institute on Aging [HHSN271201000008I] FX This work was supported by funding from the Intramural Research Program of the National Institute on Aging, National Institutes of Health (Baltimore, Maryland) and by National Institute on Aging Contract No. HHSN271201000008I. NR 23 TC 26 Z9 26 U1 2 U2 18 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD JUL PY 2014 VL 121 IS 1 BP 149 EP 159 DI 10.1097/ALN.0000000000000285 PG 11 WC Anesthesiology SC Anesthesiology GA AJ5VQ UT WOS:000337758500019 PM 24936922 ER PT J AU Wade, PA AF Wade, Paul A. TI Are genomic translocations predictable? SO BIOESSAYS LA English DT Editorial Material C1 NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Wade, PA (reprint author), NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. EM wadep2@niehs.nih.gov FU Intramural NIH HHS [ZIA ES101965-09]; NIEHS NIH HHS [Z01ES101965, Z01 ES101965] NR 3 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0265-9247 EI 1521-1878 J9 BIOESSAYS JI Bioessays PD JUL PY 2014 VL 36 IS 7 BP 633 EP 633 DI 10.1002/bies.201400050 PG 1 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA AJ4XK UT WOS:000337682800003 PM 24752810 ER PT J AU Novais, EA Commodaro, AG Santos, F Muccioli, C Maia, A Nascimento, H Moeller, CTA Rizzo, LV Grigg, ME Belfort, R AF Novais, Eduardo A. Commodaro, Alessandra G. Santos, Fabio Muccioli, Cristina Maia, Andre Nascimento, Heloisa Moeller, Cecilia T. A. Rizzo, Luiz V. Grigg, Michael E. Belfort, Rubens, Jr. TI Patients with diffuse uveitis and inactive toxoplasmic retinitis lesions test PCR positive for Toxoplasma gondii in their vitreous and blood SO BRITISH JOURNAL OF OPHTHALMOLOGY LA English DT Article ID POLYMERASE-CHAIN-REACTION; OCULAR TOXOPLASMOSIS; DIAGNOSIS; DISEASE; EPIDEMIOLOGY; HUMANS; BRAZIL; SAG1 AB Background/aims To determine if patients with inactive chorioretinitis lesions who experience chronic toxoplasmic uveitis test PCR positive for Toxoplasma in their ocular fluids. Methods Two patients undergoing long-term anti-toxoplasmic treatment developed chronic uveitis and vitritis. They underwent therapeutic and diagnostic pars plana vitrectomy. Patient specimens were tested for toxoplasmosis by real-time PCR and nested PCR. Patient specimens were also tested for the presence of Toxoplasma antibodies that recognise allelic peptide motifs to determine parasite serotype. Results Patients tested positive for Toxoplasma by real-time PCR at the B1 gene in the vitreous and aqueous humours of patient 1, but only the vitreous of patient 2. Patients were not parasitemic by real-time PCR in plasma and blood. During surgery, only old hyperpigmented toxoplasmic scars were observed; there was no sign of active retinitis. Multilocus PCR-DNA sequence genotyping at B1, NTS2 and SAG1 loci established that two different non-archetypal Toxoplasma strains had infected patients 1 and 2. A peptide-based serotyping ELISA confirmed the molecular findings. Conclusions No active lesions were observed, but both patients possessed sufficient parasite DNA in their vitreous to permit genotyping. Several hypotheses to explain the persistence of the vitritis and anterior uveitis in the absence of active retinitis are discussed. C1 [Novais, Eduardo A.; Commodaro, Alessandra G.; Santos, Fabio; Muccioli, Cristina; Maia, Andre; Nascimento, Heloisa; Moeller, Cecilia T. A.; Belfort, Rubens, Jr.] Univ Fed Sao Paulo, Dept Ophthalmol, BR-04023062 Sao Paulo, Brazil. [Commodaro, Alessandra G.; Grigg, Michael E.] NIAID, Parasit Dis Lab, Bethesda, MD 20892 USA. [Santos, Fabio; Rizzo, Luiz V.] Hosp Albert Einstein, Sao Paulo, Brazil. RP Novais, EA (reprint author), Univ Fed Sao Paulo, Dept Ophthalmol, Rua Botucatu 816, BR-04023062 Sao Paulo, Brazil. EM eduardo@novais.md FU National Institute of Allergy and Infectious Diseases, National Institutes of Health; CNPq [237252/2012] FX This work was supported in part by the National Institute of Allergy and Infectious Diseases, National Institutes of Health (MEG) and CNPq (AGC-Grant number 237252/2012). NR 22 TC 5 Z9 5 U1 0 U2 7 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0007-1161 EI 1468-2079 J9 BRIT J OPHTHALMOL JI Br. J. Ophthalmol. PD JUL PY 2014 VL 98 IS 7 BP 937 EP 940 DI 10.1136/bjophthalmol-2013-304184 PG 4 WC Ophthalmology SC Ophthalmology GA AJ2NH UT WOS:000337492500018 PM 24518074 ER PT J AU Miao, LY Liu, C Ge, JY Yang, WD Liu, JZ Sun, WB Yang, B Zheng, CY Sun, HC Hu, QG AF Miao, Leiying Liu, Chao Ge, Jiuyu Yang, Weidong Liu, Jinzhong Sun, Weibin Yang, Bai Zheng, Changyu Sun, Hongchen Hu, Qingang TI Antitumor Effect of TRAIL on Oral Squamous Cell Carcinoma using Magnetic Nanoparticle-Mediated Gene Expression SO CELL BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE Oral squamous cell carcinoma; Nanoparticles; Polyethylenimine; Apoptosis ID IRON-OXIDE NANOPARTICLES; REVERSE-TRANSCRIPTASE PROMOTER; ADENOID CYSTIC CARCINOMA; IN-VIVO; MULTIFUNCTIONAL NANOPARTICLES; DRUG-DELIVERY; CANCER-CELLS; APOPTOSIS; LIGAND; INDUCTION AB We developed a new magnetic nanovector to improve the efficiency and targeting of transgene therapy for oral squamous cell carcinoma (OSCC). Positively charged polymer PEI-modified Fe3O4 magnetic nanoparticles were tested as gene transfer vectors in the presence of a magnetic field. The Fe3O4 nanoparticles were prepared by a co-precipitation method and had good dispersibility in water. These nanoparticles modified by PEI were combined with negatively charged pACTERT-EGFP via electrostatic interaction. The transfection efficiency of the magnetic nano-gene vector with the magnetic field was determined by a fluorescence-inverted microscope and flow cytometry. The results showed significant improvement compared with the control group (p < 0.05). The magnetic complexes also exhibited up to 6-times higher transfection efficiency compared with commonly used PEI or lipofectin. On the basis of these results, the antitumor effect with suicide gene therapy using pACTERT-TRAIL in vitro and vivo was evaluated. In vitro apoptosis was determined with the Annexin V-FITC Apoptosis Detection Kit. The results suggested that PEI-modified Fe3O4 nanoparticles could mediate the killing of Tca83 cells. Furthermore, treatment with pACTERT-TRAIL delivered by magnetic nanoparticles showed a significant cytostatic effect through the induction of apoptosis in a xenograft model. This indicates that magnetic nano-gene vectors could improve the transgene efficiency for Tca83 cells and could exhibit antitumor functions with the plasmid pACTERT-TRAIL. This may be a new way to treat OSCC. C1 [Miao, Leiying; Liu, Chao; Ge, Jiuyu; Yang, Weidong; Sun, Weibin; Hu, Qingang] Nanjing Univ, Sch Med, Inst & Hosp Stomatol, Nanjing 210008, Jiangsu, Peoples R China. [Liu, Jinzhong; Sun, Hongchen] Jilin Univ, Sch Stomatol, Changchun 130041, Peoples R China. [Yang, Bai] Jilin Univ, State Key Lab Supramol Struct & Mat, Changchun 130041, Peoples R China. [Zheng, Changyu] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, DHHS, NIH, Bethesda, MD USA. RP Hu, QG (reprint author), Nanjing Univ, Sch Med, Inst & Hosp Stomatol, Nanjing 210008, Jiangsu, Peoples R China. EM drhcsun@163.com; Qghu@nju.edu.cn FU National Natural Science Foundation of China [81300852, 30672338, 30740420551, 30830108]; Jiangsu Province Natural Science Foundation of China [BK20130079]; Youth Start Fund of Nanjing City [2011-19-198*]; Third Level Fund for the Young Talents in the Health Field of Nanjing City FX This work was supported by grants from the National Natural Science Foundation of China (No: 81300852, 30672338, 30740420551 and 30830108), Jiangsu Province Natural Science Foundation of China (BK20130079), the Youth Start Fund of Nanjing City (No. 2011-19-198*), the Third Level Fund for the Young Talents in the Health Field of Nanjing City. We thank Dr. Shenglin Li at Peking University, China for a gift of the Tca83 cell line. NR 39 TC 3 Z9 3 U1 9 U2 41 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1085-9195 EI 1559-0283 J9 CELL BIOCHEM BIOPHYS JI Cell Biochem. Biophys. PD JUL PY 2014 VL 69 IS 3 BP 663 EP 672 DI 10.1007/s12013-014-9849-z PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA AJ6GC UT WOS:000337787700039 PM 24563116 ER PT J AU Dolton, G Lissina, A Skowera, A Ladell, K Tungatt, K Jones, E Kronenberg-Versteeg, D Akpovwa, H Pentier, JM Holland, CJ Godkin, AJ Cole, DK Neller, MA Miles, JJ Price, DA Peakman, M Sewell, AK AF Dolton, G. Lissina, A. Skowera, A. Ladell, K. Tungatt, K. Jones, E. Kronenberg-Versteeg, D. Akpovwa, H. Pentier, J. M. Holland, C. J. Godkin, A. J. Cole, D. K. Neller, M. A. Miles, J. J. Price, D. A. Peakman, M. Sewell, A. K. TI Comparison of peptide-major histocompatibility complex tetramers and dextramers for the identification of antigen-specific T cells SO CLINICAL AND EXPERIMENTAL IMMUNOLOGY LA English DT Article DE autoimmunity; diabetes; T cell receptors; T cells; tumour immunology ID MHC CLASS-I; KILL BETA-CELLS; CD8 CORECEPTOR; ANTI-CD8 ANTIBODIES; TCR-BINDING; RECEPTOR; ACTIVATION; AFFINITY; MULTIMERS; PROTEIN AB Fluorochrome-conjugated peptide-major histocompatibility complex (pMHC) multimers are widely used for flow cytometric visualization of antigen-specific T cells. The most common multimers, streptavidin-biotin-based tetramers', can be manufactured readily in the laboratory. Unfortunately, there are large differences between the threshold of T cell receptor (TCR) affinity required to capture pMHC tetramers from solution and that which is required for T cell activation. This disparity means that tetramers sometimes fail to stain antigen-specific T cells within a sample, an issue that is particularly problematic when staining tumour-specific, autoimmune or MHC class II-restricted T cells, which often display TCRs of low affinity for pMHC. Here, we compared optimized staining with tetramers and dextramers (dextran-based multimers), with the latter carrying greater numbers of both pMHC and fluorochrome per molecule. Most notably, we find that: (i) dextramers stain more brightly than tetramers; (ii) dextramers outperform tetramers when TCR-pMHC affinity is low; (iii) dextramers outperform tetramers with pMHC class II reagents where there is an absence of co-receptor stabilization; and (iv) dextramer sensitivity is enhanced further by specific protein kinase inhibition. Dextramers are compatible with current state-of-the-art flow cytometry platforms and will probably find particular utility in the fields of autoimmunity and cancer immunology. C1 [Dolton, G.; Lissina, A.; Ladell, K.; Tungatt, K.; Jones, E.; Akpovwa, H.; Pentier, J. M.; Holland, C. J.; Godkin, A. J.; Cole, D. K.; Miles, J. J.; Price, D. A.; Sewell, A. K.] Cardiff Univ, Inst Infect & Immun, Sch Med, Cardiff CF14 4XN, S Glam, Wales. [Skowera, A.; Kronenberg-Versteeg, D.; Peakman, M.] Kings Coll London, Dept Immunobiol, Sch Med, London WC2R 2LS, England. [Neller, M. A.; Miles, J. J.] Univ Queensland, QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia. [Miles, J. J.] Univ Queensland, Sch Med, Brisbane, Qld, Australia. [Price, D. A.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Sewell, AK (reprint author), Cardiff Univ, Inst Infect & Immun, Sch Med, Univ Hosp, Henry Wellcome Bldg, Cardiff CF14 4XN, S Glam, Wales. EM sewellak@cardiff.ac.uk RI Price, David/C-7876-2013; Ladell, Kristin/C-8301-2013; OI Price, David/0000-0001-9416-2737; Ladell, Kristin/0000-0002-9856-2938; Sewell, Andrew/0000-0003-3194-3135; Cole, David/0000-0003-0028-9396 FU Juvenile Diabetes Research Foundation [17-2012-352]; UK Department of Health via the National Institute for Health Research (NIHR) Biomedical Research Centre; King's College London; Australian National Health and Medical Research (NHMRC) FX The autoimmune T cell part of this work was made possible by the generous support of the Juvenile Diabetes Research Foundation award 17-2012-352. Work contributed by M. P. and A. S. was supported by the UK Department of Health via the National Institute for Health Research (NIHR) Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London, which also funds D. K.-V. via a PhD studentship. J. J. M. is funded by an Australian National Health and Medical Research (NHMRC) Career Development Fellowship. A. K. S. and D. A. P. are Wellcome Trust Senior Investigators. NR 40 TC 18 Z9 18 U1 1 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9104 EI 1365-2249 J9 CLIN EXP IMMUNOL JI Clin. Exp. Immunol. PD JUL PY 2014 VL 177 IS 1 BP 47 EP 63 DI 10.1111/cei.12339 PG 17 WC Immunology SC Immunology GA AJ3SW UT WOS:000337588700006 PM 24673376 ER PT J AU Opal, SM Dellinger, RP Vincent, JL Masur, H Angus, DC AF Opal, Steven M. Dellinger, R. Phillip Vincent, Jean-Louis Masur, Henry Angus, Derek C. TI The Next Generation of Sepsis Clinical Trial Designs: What Is Next After the Demise of Recombinant Human Activated Protein C? SO CRITICAL CARE MEDICINE LA English DT Article DE clinical trial design; intensive care units; sepsis; septic shock; severe sepsis; tumor necrosis factor antibody ID INTERLEUKIN-1 RECEPTOR ANTAGONIST; TUMOR-NECROSIS-FACTOR; SEPTIC SHOCK; DOUBLE-BLIND; MULTICENTER TRIAL; SURVIVING SEPSIS; GLOBAL HEALTH; ORGAN FAILURE; PHASE-III; EFFICACY AB Objective: The developmental pipeline for novel therapeutics to treat sepsis has diminished to a trickle compared to previous years of sepsis research. While enormous strides have been made in understanding the basic molecular mechanisms that underlie the pathophysiology of sepsis, a long list of novel agents have now been tested in clinical trials without a single immunomodulating therapy showing consistent benefit. The only antisepsis agent to successfully complete a phase III clinical trial was human recumbent activated protein C. This drug was taken off the market after a follow-up placebo-controlled trial (human recombinant activated Protein C Worldwide Evaluation of Severe Sepsis and septic Shock [PROWESS SHOCK]) failed to replicate the favorable results of the initial registration trial performed ten years earlier. We must critically reevaluate our basic approach to the preclinical and clinical evaluation of new sepsis therapies. Data Sources: We selected the major clinical studies that investigated interventional trials with novel therapies to treat sepsis over the last 30 years. Study Selection: Phase II and phase III trials investigating new treatments for sepsis and editorials and critiques of these studies. Data Extraction: Selected manuscripts and clinical study reports were analyzed from sepsis trials. Specific shortcomings and potential pit falls in preclinical evaluation and clinical study design and analysis were reviewed and synthesized. Data Synthesis: After review and discussion, a series of 12 recommendations were generated with suggestions to guide future studies with new treatments for sepsis. Conclusions: We need to improve our ability to define appropriate molecular targets for preclinical development and develop better methods to determine the clinical value of novel sepsis agents. Clinical trials must have realistic sample sizes and meaningful endpoints. Biomarker-driven studies should be considered to categorize specific at risk populations most likely to benefit from a new treatment. Innovations in clinical trial design such as parallel crossover design, alternative endpoints, or adaptive trials should be pursued to improve the outlook for future interventional trials in sepsis. C1 [Opal, Steven M.] Brown Univ, Div Infect Dis, Alpert Med Sch, Providence, RI 02912 USA. [Dellinger, R. Phillip] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Crit Care Dept, Camden, NJ 08103 USA. [Vincent, Jean-Louis] Erasme Univ Hosp, Crit Care Dept, B-1070 Brussels, Belgium. [Masur, Henry] NIH, Crit Care Dept, Bethesda, MD 20892 USA. [Angus, Derek C.] Univ Pittsburgh, Sch Med, Crit Care Dept, Pittsburgh, PA USA. RP Opal, SM (reprint author), Brown Univ, Div Infect Dis, Alpert Med Sch, Providence, RI 02912 USA. EM steven_opal@brown.edu FU Asahi Kasei; Sirtris; GSK; National Institutes of Health; Elsai Inc. FX Dr. Opal served as board member for Kenta biotech (advice on monoclonal antibody targets for bacterial infections) and Arsanis (advice on anti-LPS antibody targets), consulted for Medimmune (monoclonal antibody strategies), received royalties from Elsevier (book royalties for an infectious disease textbook), and disclosed DSMB for Tetraohase and DSMB for Achaogen (data review committee). His institution received grant support from Asahi Kasei, Sirtris, and GSK and he has patents with the University of Maryland (patent on a novel vaccine for endotoxin) and Prothera biologics (patent on a novel therapy for anthrax). Dr. Masur received support for article research from the National Institutes of Health. Dr. Angus consulted for Idaho Technology, Pfizer, Elsai, and Medimmune, LLC and disclosed that he has interest in Eli Lilly (member). His institution received grant support from Elsai Inc. (grant to the University of Pittsburgh Medical Center. Dr. Angus served as PI from 2006-2010 and served as co-investigator from 2010-2012). The remaining authors have disclosed that they do not have any potential conflicts of interest. NR 43 TC 51 Z9 53 U1 0 U2 15 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD JUL PY 2014 VL 42 IS 7 BP 1714 EP 1721 DI 10.1097/CCM.0000000000000325 PG 8 WC Critical Care Medicine SC General & Internal Medicine GA AJ5DU UT WOS:000337703000036 PM 24717456 ER PT J AU Elinoff, JM Suffredini, AF AF Elinoff, Jason M. Suffredini, Anthony F. TI Exploring the Boundaries of Systemic Inflammation SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE compartments; endotoxin; inflammation; intravenous administration; lung administration ID HUMAN ENDOTOXEMIA; HUMANS; MODEL C1 [Elinoff, Jason M.; Suffredini, Anthony F.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Elinoff, JM (reprint author), NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 CL999999] NR 12 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD JUL PY 2014 VL 42 IS 7 BP 1735 EP 1737 DI 10.1097/CCM.0000000000000365 PG 3 WC Critical Care Medicine SC General & Internal Medicine GA AJ5DU UT WOS:000337703000045 PM 24933053 ER PT J AU Jain, NA Lu, K Ito, S Muranski, P Hourigan, CS Haggerty, J Chokshi, PD Ramos, C Cho, E Cook, L Childs, R Battiwalla, M Barrett, AJ AF Jain, Natasha A. Lu, Kit Ito, Sawa Muranski, Pawel Hourigan, Christopher S. Haggerty, Janice Chokshi, Puja D. Ramos, Catalina Cho, Elena Cook, Lisa Childs, Richard Battiwalla, Minoo Barrett, A. John TI The clinical and financial burden of pre-emptive management of cytomegalovirus disease after allogeneic stem cell transplantation-implications for preventative treatment approaches SO CYTOTHERAPY LA English DT Article DE antiviral cellular therapy; CMV reactivation; economic cost; pre-emptive therapy ID BONE-MARROW-TRANSPLANTATION; CORD BLOOD TRANSPLANTATION; CYTOTOXIC T-LYMPHOCYTES; ACUTE MYELOID-LEUKEMIA; RELAPSE RISK EVIDENCE; VIRAL-INFECTIONS; PP65 ANTIGENEMIA; CMV REACTIVATION; TREATMENT STRATEGY; ADOPTIVE TRANSFER AB Background aims. Although cytomegalovirus (CMV) infection after allogeneic stem cell transplantation (SCT) is rarely fatal, the management of CMV by pre-emptive medication for viral reactivation has toxicity and carries a financial burden. New strategies to prevent CMV reactivation with vaccines and antiviral T cells may represent an advance over pre-emptive strategies but have yet to be justified in terms of transplantation outcome and cost. Methods. We compared outcomes and post-transplantation treatment cost in 44 patients who never required pre-emptive CMV treatment with 90 treated patients undergoing SCT at our institute between 2006 and 2012. Eighty-one subjects received CD34+ selected myeloablative SCT, 12 umbilical cord blood transplants, and 41 T-replete non-myeloablative SCT. One hundred nineteen patients (89%) were at risk for CMV because either the donor or recipient was seropositive. Of these, 90 patients (75.6%) reactivated CMV at a median of 30 (range 8-105) days after transplantation and received antivirals. Results. There was no difference in standard transplantation risk factors between the two groups. In multivariate modeling, CMV reactivation >250 copies/mL (odds ratio = 3, P < 0.048), total duration of inpatient IV antiviral therapy (odds ratio = 1.04, P < 0.001), type of transplantation (T-deplete vs. T-replete; odds ratio = 4.65, P < 0.017) were found to be significantly associated with increased non-relapse mortality. The treated group incurred an additional cost of antiviral medication and longer hospitalization within the first 6 months after SCT of $58,000 to $74,000 per patient. Conclusions. Our findings suggest that to prevent CMV reactivation, treatment should be given within 1 week of SCT. Preventative treatment may improve outcome and have significant cost savings. C1 [Jain, Natasha A.; Lu, Kit; Ito, Sawa; Muranski, Pawel; Hourigan, Christopher S.; Haggerty, Janice; Chokshi, Puja D.; Ramos, Catalina; Cho, Elena; Cook, Lisa; Childs, Richard; Battiwalla, Minoo; Barrett, A. John] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Battiwalla, M (reprint author), NHLBI, Hematol Branch, NIH, 10 CRC Room 3-5288,10 Ctr Dr, Bethesda, MD 20892 USA. EM minoo.battiwalla@nih.gov RI Hourigan, Christopher/S-2476-2016 OI Hourigan, Christopher/0000-0002-6189-8067 FU National Heart, Lung, and Blood Institute, National Institutes of Health FX This work was supported by the intramural research program of the National Heart, Lung, and Blood Institute, National Institutes of Health. NR 51 TC 7 Z9 9 U1 1 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1465-3249 EI 1477-2566 J9 CYTOTHERAPY JI Cytotherapy PD JUL PY 2014 VL 16 IS 7 BP 927 EP 933 DI 10.1016/j.jcyt.2014.02.010 PG 7 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA AJ4OK UT WOS:000337655500007 PM 24831837 ER PT J AU Kumar, A Lualdi, M Loncarek, J Cho, YW Lee, JE Ge, K Kuehn, MR AF Kumar, Amit Lualdi, Margaret Loncarek, Jadranka Cho, Young-Wook Lee, Ji-Eun Ge, Kai Kuehn, Michael R. TI Loss of Function of Mouse Pax-Interacting Protein 1-Associated Glutamate Rich Protein 1a (Pagr1a) Leads to Reduced Bmp2 Expression and Defects in Chorion and Amnion Development SO DEVELOPMENTAL DYNAMICS LA English DT Article DE chorion; amnion; amniochorionic fold; BMP signaling ID REVEALS; EMBRYOS; PTIP AB Background: Human PAX-Interacting Protein 1 (PAXIP1)-associated glutamate rich protein 1 (PAGR1, also known as PA1) originally was discovered as part of a complex containing PAXIP1 and histone H3K4 methyltransferases MLL3 and MLL4, suggesting a role in epigenetic gene regulation. Further in vitro studies suggested additional functions in DNA damage repair and transcription. However, in vivo analysis of PAGR1 function has been lacking. Results: Here we show that expression of the cognate mouse gene Pagr1a is found predominately in the extraembryonic and chorionic ectoderm from pregastrulation stages and is up-regulated within the embryo proper after gastrulation. Embryos with a germ line deletion of Pagr1a establish the anterior-posterior axis, and show normal neuroectodermal, mesodermal, and endodermal patterning, but fail to develop beyond the four-to five-somite stage or to undergo axial rotation. Pagr1a(-/-) embryos also show abnormal development of extraembryonic tissues with defects seen in the amnion, chorion and visceral yolk sac. At the molecular level, Pagr1a(-/-) embryos have reduced expression of BMP2, a known regulator of extraembryonic development. Conclusions: Loss of mouse Pagr1a function leads to defective extraembryonic development, likely due at least in part to altered BMP signaling, contributing to developmental arrest. (C) 2014 Wiley Periodicals, Inc. C1 [Kumar, Amit; Loncarek, Jadranka; Kuehn, Michael R.] NCI, Lab Prot Dynam & Signaling, NIH, Frederick, MD 21702 USA. [Lualdi, Margaret] Leidos Biomed Res Inc, Lab Anim Sci Program, Frederick, MD USA. [Cho, Young-Wook; Lee, Ji-Eun; Ge, Kai] NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. [Cho, Young-Wook] Chuncheon Ctr, Korea Basic Sci Inst, Chunchon, Kangwon, South Korea. RP Kuehn, MR (reprint author), NCI, Bldg 560,Room 12-90, Frederick, MD 21702 USA. EM mkuehn@mail.nih.gov RI Lee, Ji-Eun/F-7891-2011; Kuehn, Michael/A-4573-2014; OI Lee, Ji-Eun/0000-0002-3768-7016; Kuehn, Michael/0000-0002-7703-9160; Ge, Kai/0000-0002-7442-5138 FU Intramural Research Program of the NCI; NIDDK FX We thank Jennifer Matta and Lawrence Sternberg, Histopathology lab, Leidos Biomedical Research Inc. for assistance in embryo sectioning and scanning; Naiche Adler, Mark Lewandoski and Alan Perantoni for comments on the manuscript; An Zwijsen, for helpful suggestions; Janet Rossant, Pamela Hoodless, Leif Lundh, Yuji Mishina, Shankar Srinivas, Terry Yamaguchi, and Minoru Ko for providing plasmids for RNA probes. This work was supported in part by the Intramural Research Program of the NCI (M. R. K.) and NIDDK (K.G.). NR 21 TC 4 Z9 4 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1058-8388 EI 1097-0177 J9 DEV DYNAM JI Dev. Dyn. PD JUL PY 2014 VL 243 IS 7 BP 937 EP 947 DI 10.1002/DVDY.24125 PG 11 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA AJ5PR UT WOS:000337738100008 PM 24633704 ER PT J AU Merluzzi, AP Hurwitz, ZE Briscione, MA Cobuzzi, JL Wetzell, B Rice, KC Riley, AL AF Merluzzi, Andrew P. Hurwitz, Zachary E. Briscione, Maria A. Cobuzzi, Jennifer L. Wetzell, Bradley Rice, Kenner C. Riley, Anthony L. TI Age-Dependent MDPV-Induced Taste Aversions and Thermoregulation in Adolescent and Adult Rats SO DEVELOPMENTAL PSYCHOBIOLOGY LA English DT Article DE MDPV; bath salts; taste aversions; body temperature ID CONDITIONED PLACE PREFERENCE; BATH SALTS; LOCOMOTOR-ACTIVITY; UNITED-STATES; COCAINE; NICOTINE; METHAMPHETAMINE; AMPHETAMINE; RETENTION; MORPHINE AB Adolescent rats are more sensitive to the rewarding and less sensitive to the aversive properties of various drugs of abuse than their adult counterparts. Given a nationwide increase in use of "bath salts," the present experiment employed the conditioned taste aversion procedure to assess the aversive effects of 3,4-methylenedioxypyrovalerone (MDPV; 0, 1.0, 1.8, or 3.2 mg/kg), a common constituent in " bath salts," in adult and adolescent rats. As similar drugs induce thermoregulatory changes in rats, temperature was recorded following MDPV administration to assess if thermoregulatory changes were related to taste aversion conditioning. Both age groups acquired taste aversions, although these aversions were weaker and developed at a slower rate in the adolescent subjects. Adolescents increased and adults decreased body temperature following MDPV administration with no correlation to aversions. The relative insensitivity of adolescents to the aversive effects of MDPV suggests that MDPV may confer an increased risk in this population. (C) 2013 Wiley Periodicals, Inc. C1 [Merluzzi, Andrew P.; Hurwitz, Zachary E.; Briscione, Maria A.; Cobuzzi, Jennifer L.; Wetzell, Bradley; Riley, Anthony L.] Amer Univ, Dept Psychol, Psychopharmacol Lab, Washington, DC 20016 USA. [Rice, Kenner C.] NIDA, Chem Biol Res Branch, Bethesda, MD 20892 USA. RP Merluzzi, AP (reprint author), Amer Univ, Dept Psychol, Psychopharmacol Lab, 4400 Mass Ave, Washington, DC 20016 USA. EM andrewmerluzzi@gmail.com RI Wetzell, B Bradley/J-6802-2013 OI Wetzell, B Bradley/0000-0002-2723-5542 FU Mellon Foundation; American University Artists and Scholars Fellowship; Dean's Undergraduate Research Award; National Institute on Drug Abuse; National Institute on Alcohol Abuse and Alcoholism FX Contract grant sponsor: Mellon Foundation; Contract grant sponsor: American University Artists and Scholars Fellowship; Contract grant sponsor: Dean's Undergraduate Research Award; Contract grant sponsor: Intramural Research Programs of the National Institute on Drug Abuse; Contract grant sponsor: National Institute on Alcohol Abuse and Alcoholism NR 54 TC 9 Z9 9 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0012-1630 EI 1098-2302 J9 DEV PSYCHOBIOL JI Dev. Psychobiol. PD JUL PY 2014 VL 56 IS 5 BP 943 EP 954 DI 10.1002/dev.21171 PG 12 WC Developmental Biology; Psychology SC Developmental Biology; Psychology GA AJ4WW UT WOS:000337680900006 PM 24122728 ER PT J AU Simpson, EA Jakobsen, KV Fragaszy, DM Okada, K Frick, JE AF Simpson, Elizabeth A. Jakobsen, Krisztina V. Fragaszy, Dorothy M. Okada, Kazunori Frick, Janet E. TI The Development of Facial Identity Discrimination Through Learned Attention SO DEVELOPMENTAL PSYCHOBIOLOGY LA English DT Article DE facial identity; visual attention; facial feature; configural processing; discrimination; learned attention; perceptual narrowing; human infant; computation simulation method; systematically varied faces; monkey faces; sheep faces ID FACE RECOGNITION; VISUAL EXPERIENCE; HUMAN INFANTS; 1ST YEAR; PERCEPTION; INFORMATION; PREFERENCE; INVERSION; FEATURES; NOVELTY AB Learned attention models of perceptual discrimination predict that with age, sensitivity will increase for dimensions of stimuli useful for discrimination. We tested this prediction by examining the face dimensions 4- to 6-month-olds (n = 77), 9- to 12-month-olds (n = 66), and adults (n = 73) use for discriminating human, monkey, and sheep faces systematically varying in outer features (contour), inner features (eyes, mouth), or configuration (feature spacing). We controlled interindividual variability across species by varying faces within natural ranges and measured stimulus variability using computational image similarity. We found the most improvement with age in human face discrimination, and older participants discriminated more species and used more facial properties for discrimination, consistent with learned attention models. Older infants and adults discriminated human, monkey, and sheep faces; however, they used different facial properties for primates and sheep. Learned attention models may provide insight into the mechanisms underlying perceptual narrowing. (C) 2014 Wiley Periodicals, Inc. C1 [Simpson, Elizabeth A.] Univ Parma, Dipartimento Neurosci, I-43100 Parma, Italy. [Simpson, Elizabeth A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Dickerson, MD 20842 USA. [Jakobsen, Krisztina V.] James Madison Univ, Dept Psychol, St Harrisonburg, VA USA. [Fragaszy, Dorothy M.; Frick, Janet E.] Univ Georgia, Dept Psychol, Athens, GA 30602 USA. [Okada, Kazunori] San Francisco State Univ, Dept Comp Sci, San Francisco, CA 94132 USA. RP Simpson, EA (reprint author), Univ Parma, Dipartimento Neurosci, I-43100 Parma, Italy. EM simpsonea@mail.nih.gov OI Simpson, Elizabeth/0000-0003-2715-2533 FU University of Georgia Graduate School; NICHD [P01HD064653] FX We would like to thank the undergraduate researchers for their help with recruitment and data collection. Special thanks to Hysam Halabi for programming assistance. Thanks are also due to the Athens families who participated in this study. This research was supported in part by the J. William Fanning Fellowship and Dissertation Completion Award from the University of Georgia Graduate School and NICHD P01HD064653. Results from this experiment were presented at the 2011 Society for Research in Child Development Biennial Meeting, Montreal, Quebec, Canada. Part of this report was submitted by the first author in partial fulfillment of the Ph.D. degree in Psychology at the University of Georgia under the direction of the third and last authors. NR 86 TC 3 Z9 3 U1 2 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0012-1630 EI 1098-2302 J9 DEV PSYCHOBIOL JI Dev. Psychobiol. PD JUL PY 2014 VL 56 IS 5 BP 1083 EP 1101 DI 10.1002/dev.21194 PG 19 WC Developmental Biology; Psychology SC Developmental Biology; Psychology GA AJ4WW UT WOS:000337680900019 PM 24395087 ER PT J AU Muller, YL Piaggi, P Hoffman, D Huang, K Gene, B Kobes, S Thearle, MS Knowler, WC Hanson, RL Baier, LJ Bogardus, C AF Muller, Yunhua L. Piaggi, Paolo Hoffman, Duncan Huang, Ke Gene, Brittany Kobes, Sayuko Thearle, Marie S. Knowler, William C. Hanson, Robert L. Baier, Leslie J. Bogardus, Clifton TI Common genetic variation in the glucokinase gene (GCK) is associated with type 2 diabetes and rates of carbohydrate oxidation and energy expenditure SO DIABETOLOGIA LA English DT Article DE Carbohydrate oxidation; Energy expenditure; GCK; Thermic effect of food; Type 2 diabetes ID BETA-CELL GLUCOKINASE; PIMA-INDIANS; INSULIN-RESISTANCE; WEIGHT-GAIN; MELLITUS; GLUCOSE; RISK; THERMOGENESIS; VARIANTS; OBESITY AB Aims/hypothesis Glucokinase (GCK) plays a role in glucose metabolism and glucose-stimulated insulin secretion. Rare mutations in GCK cause MODY. We investigated whether common variation (minor allele frequency >= 0.01) in GCK is associated with metabolic traits and type 2 diabetes. Methods Four exonic single-nucleotide polymorphisms (SNPs) and three SNPs predicted to cause loss of promoter function were identified in whole-genome sequence data from 234 Pima Indians. These seven tag SNPs and rs4607517, a type 2 diabetes variant established in other studies, were analysed in 415 full-heritage non-diabetic Pima Indians characterised for metabolic traits, and 7,667 American Indians who had data on type 2 diabetes and BMI. Results A novel 3' untranslated region (3'UTR) SNP, chr7:44184184-G/A, was associated with the rate of carbohydrate oxidation post-absorptively (beta = 0.22 mg [kg estimated metabolic body size (EMBS)](-1) min(-1), p = 0.005) and during a hyperinsulinaemic-euglycaemic clamp (beta = 0.24 mg [kg EMBS](-1) min(-1), p = 0.0002), the rate of carbohydrate oxidation in a respiratory chamber (beta = 311 kJ/day, p = 0.03) and 24 h energy expenditure, which was attributable to the thermic effect of food (beta = 520 kJ/day, p = 3.39 x 10(-6)). This 3'UTR SNP was also associated with diabetes (OR 1.36, 95% CI 1.11, 1.65, p = 0.002), where the A allele (allele frequency 0.05) was associated with a lower rate of carbohydrate oxidation, lower 24 h energy expenditure and higher risk for diabetes. In a Cox proportional hazards model, a rate of insulin-stimulated carbohydrate oxidation lower than the mean rate at baseline predicted a higher risk for developing diabetes than for those above the mean (hazard rate ratio 2.2, 95% CI 1.3, 3.6, p = 0.002). Conclusion/interpretation Common variation in GCK influences the rate of carbohydrate oxidation, 24 h energy expenditure and diabetes risk in Pima Indians. C1 [Muller, Yunhua L.; Piaggi, Paolo; Hoffman, Duncan; Huang, Ke; Gene, Brittany; Kobes, Sayuko; Thearle, Marie S.; Knowler, William C.; Hanson, Robert L.; Baier, Leslie J.; Bogardus, Clifton] NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85004 USA. RP Bogardus, C (reprint author), NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, 445 North 5th St, Phoenix, AZ 85004 USA. EM cbogardus@phx.niddk.nih.gov RI Hanson, Robert/O-3238-2015; OI Hanson, Robert/0000-0002-4252-7068; Piaggi, Paolo/0000-0003-2774-9161 FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX This work was supported by the intramural research programme of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 23 TC 6 Z9 8 U1 1 U2 31 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD JUL PY 2014 VL 57 IS 7 BP 1382 EP 1390 DI 10.1007/s00125-014-3234-8 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AJ2OZ UT WOS:000337498700016 PM 24728127 ER PT J AU Kim, KY McShane, LM Conley, BA AF Kim, Kelly Y. McShane, Lisa M. Conley, Barbara A. TI Designing biomarker studies for head and neck cancer SO HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK LA English DT Review DE prognostic biomarkers; molecular markers; clinical utility; head and neck cancer; head and neck squamous cell carcinoma (HNSCC) ID SQUAMOUS-CELL CARCINOMA; OROPHARYNGEAL CANCER; NASOPHARYNGEAL CARCINOMA; HUMAN-PAPILLOMAVIRUS; BCL-2 EXPRESSION; DRUG DEVELOPMENT; CLINICAL-USE; VALIDATION; METASTASIS; SURVIVAL AB Although there is ample literature reporting on the identification of molecular biomarkers for head and neck squamous cell carcinoma, none is currently recommended for routine clinical use. A major reason for this lack of progress is the difficulty in designing studies in head and neck cancer to clearly establish the clinical utility of biomarkers. Consequently, biomarker studies frequently stall at the initial discovery phase. In this article, we focus on biomarkers for use in clinical management, including selection of therapy. Using several contemporary examples, we identify some of the common deficiencies in study design that hinder success in biomarker development for this disease area, and we suggest some potential solutions. The purpose of this article is to provide guidance that can assist investigators to more efficiently move promising biomarkers in head and neck cancer from discovery to clinical practice. (C) 2013 Wiley Periodicals, Inc. C1 [Kim, Kelly Y.; McShane, Lisa M.; Conley, Barbara A.] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Kim, KY (reprint author), NCI, Div Canc Treatment & Diag, 9609 Med Ctr Dr,Room 4W430,MSC 9730, Bethesda, MD 20892 USA. EM kimke@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 33 TC 4 Z9 4 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1043-3074 EI 1097-0347 J9 HEAD NECK-J SCI SPEC JI Head Neck-J. Sci. Spec. Head Neck PD JUL PY 2014 VL 36 IS 7 BP 1069 EP 1075 DI 10.1002/hed.23444 PG 7 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA AJ4CU UT WOS:000337618800024 PM 25072057 ER PT J AU Kaplan, R Horner, AJ Bandettini, PA Doeller, CF Burgess, N AF Kaplan, Raphael Horner, Aidan J. Bandettini, Peter A. Doeller, Christian F. Burgess, Neil TI Human hippocampal processing of environmental novelty during spatial navigation SO HIPPOCAMPUS LA English DT Article DE amygdala; fMRI; MTL; content; context ID MEDIAL TEMPORAL-LOBE; PERIRHINAL CORTEX; HUMAN AMYGDALA; RECOGNITION MEMORY; CAUDATE-NUCLEUS; PARAHIPPOCAMPAL CORTEX; SCENE REPRESENTATIONS; OBJECT RECOGNITION; FUNCTIONAL MRI; NEUTRAL FACES AB The detection and processing of novel information encountered as we explore our environment is crucial for learning and adaptive behavior. The human hippocampus has been strongly implicated in laboratory tests of novelty detection and episodic memory, but has been less well studied during more ethological tasks such as spatial navigation, typically used in animals. We examined fMRI BOLD activity as a function of environmental and object novelty as humans performed an object-location virtual navigation task. We found greater BOLD response to novel relative to familiar environments in the hippocampus and adjacent parahippocampal gyrus. Object novelty was associated with increased activity in the posterior parahippocampal/fusiform gyrus and anterior hippocampus extending into the amygdala and superior temporal sulcus. Importantly, whilst mid-posterior hippocampus was more sensitive to environmental novelty than object novelty, the anterior hippocampus responded similarly to both forms of novelty. Amygdala activity showed an increase for novel objects that decreased linearly over the learning phase. By investigating how participants learn and use different forms of information during spatial navigation, we found that medial temporal lobe (MTL) activity reflects both the novelty of the environment and of the objects located within it. This novelty processing is likely supported by distinct, but partially overlapping, sets of regions within the MTL. (c) 2014 The Authors. Hippocampus Published by Wiley Periodicals, Inc. C1 [Kaplan, Raphael] NIMH UCL Joint Grad Partnership Program Neurosci, Bethesda, MD USA. [Kaplan, Raphael; Horner, Aidan J.; Burgess, Neil] UCL, UCL Inst Cognit Neurosci, London WC1E 6BT, England. [Kaplan, Raphael; Horner, Aidan J.; Burgess, Neil] UCL, UCL Inst Neurol, London WC1E 6BT, England. [Kaplan, Raphael; Bandettini, Peter A.] NIMH, Sect Funct Imaging Methods, Lab Brain & Cognit, Bethesda, MD 20892 USA. [Doeller, Christian F.] Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6525 ED Nijmegen, Netherlands. RP Kaplan, R (reprint author), Wellcome Trust Ctr Neuroimaging, 12 Queen Sq, London WC1N 3BG, England. EM raphael.kaplan.09@ucl.ac.uk; n.burgess@ucl.ac.uk RI Burgess, Neil/B-2420-2009; OI Burgess, Neil/0000-0003-0646-6584; Kaplan, Raphael/0000-0002-5023-1566 FU European Research Council; MRC, UK; National Institute of Mental Health; Wellcome Trust; National Institutes of Health Graduate Partnership Program FX Grant sponsors: European Research Council; MRC, UK; National Institute of Mental Health; the Wellcome Trust; National Institutes of Health Graduate Partnership Program. NR 79 TC 12 Z9 12 U1 4 U2 22 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1050-9631 EI 1098-1063 J9 HIPPOCAMPUS JI Hippocampus PD JUL PY 2014 VL 24 IS 7 BP 740 EP 750 DI 10.1002/hipo.22264 PG 11 WC Neurosciences SC Neurosciences & Neurology GA AJ4TD UT WOS:000337668200003 PM 24550152 ER PT J AU Shiee, N Bazin, PL Cuzzocreo, JL Ye, CY Kishore, B Carass, A Calabresi, PA Reich, DS Prince, JL Pham, DL AF Shiee, Navid Bazin, Pierre-Louis Cuzzocreo, Jennifer L. Ye, Chuyang Kishore, Bhaskar Carass, Aaron Calabresi, Peter A. Reich, Daniel S. Prince, Jerry L. Pham, Dzung L. TI Reconstruction of the human cerebral cortex robust to white matter lesions: Method and validation SO HUMAN BRAIN MAPPING LA English DT Article DE cortical reconstruction; WM lesions; multiple sclerosis; lesion segmentation; cortical thickness ID IMPLICIT SURFACE EVOLUTION; AUTOMATED 3-D EXTRACTION; CORTICAL SURFACE; MULTIPLE-SCLEROSIS; HUMAN BRAIN; MRI; MORPHOMETRY; SEGMENTATION; THICKNESS; IMAGES AB Cortical atrophy has been reported in a number of diseases, such as multiple sclerosis and Alzheimer's disease, that are also associated with white matter (WM) lesions. However, most cortical reconstruction techniques do not account for these pathologies, thereby requiring additional processing to correct for the effect of WM lesions. In this work, we introduce CRUISE+, an automated process for cortical reconstruction from magnetic resonance brain images with WM lesions. The process extends previously well validated methods to allow for multichannel input images and to accommodate for the presence of WM lesions. We provide new validation data and tools for measuring the accuracy of cortical reconstruction methods on healthy brains as well as brains with multiple sclerosis lesions. Using this data, we validate the accuracy of CRUISE+ and compare it to another state-of-the-art cortical reconstruction tool. Our results demonstrate that CRUISE+ has superior performance in the cortical regions near WM lesions, and similar performance in other regions. Hum Brain Mapp 35:3385-3401, 2014. (c) 2013 Wiley Periodicals, Inc. C1 [Shiee, Navid; Cuzzocreo, Jennifer L.; Ye, Chuyang; Kishore, Bhaskar; Carass, Aaron; Prince, Jerry L.; Pham, Dzung L.] Johns Hopkins Univ, Dept Elect & Comp Engn, Image Anal & Commun Lab, Baltimore, MD 21218 USA. [Shiee, Navid; Pham, Dzung L.] Henry M Jackson Fdn Adv Mil Med, Ctr Neurosci & Regenerat Med, Bethesda, MD USA. [Bazin, Pierre-Louis] Max Planck Inst Human Cognit & Brain Sci, Dept Neurophys, Leipzig, Germany. [Calabresi, Peter A.; Reich, Daniel S.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Reich, Daniel S.] NINDS, Neuroimmunol Branch, Bethesda, MD 20892 USA. RP Shiee, N (reprint author), Ctr Neurosci & Regenerat Med, 10 Ctr Dr,Bldg 10,Room B1N264B, Bethesda, MD 20892 USA. EM navid@jhu.edu RI Reich, Daniel/E-5701-2010; OI Reich, Daniel/0000-0002-2628-4334; Carass, Aaron/0000-0003-4939-5085 FU National Institute of Neurological Disorders and Stroke [R01NS070906, R01NS054255, R01NS037747]; National Institute of Drug Abuse [K25DA025356]; National Multiple Sclerosis Society [TR3760A3] FX Contract grant sponsor: National Institute of Neurological Disorders and Stroke; Contract grant number: R01NS070906; R01NS054255; R01NS037747; Contract grant sponsor: National Institute of Drug Abuse; Contract grant number: K25DA025356; Contract grant sponsor: National Multiple Sclerosis Society; Contract grant number: TR3760A3. NR 45 TC 9 Z9 9 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 EI 1097-0193 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD JUL PY 2014 VL 35 IS 7 BP 3385 EP 3401 DI 10.1002/hbm.22409 PG 17 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA AJ5SC UT WOS:000337746800039 PM 24382742 ER PT J AU Lamont, PJ Wallefeld, W Hilton-Jones, D Udd, B Argov, Z Barboi, AC Bonneman, C Boycott, KM Bushby, K Connolly, AM Davies, N Beggs, AH Cox, GF Dastgir, J DeChene, ET Gooding, R Jungbluth, H Muelas, N Palmio, J Penttila, S Schmedding, E Suominen, T Straub, V Staples, C Van den Bergh, PYK Vilchez, JJ Wagner, KR Wheeler, PG Wraige, E Laing, NG AF Lamont, Phillipa J. Wallefeld, William Hilton-Jones, David Udd, Bjarne Argov, Zohar Barboi, Alexandru C. Bonneman, Carsten Boycott, Kym M. Bushby, Kate Connolly, Anne M. Davies, Nicholas Beggs, Alan H. Cox, Gerald F. Dastgir, Jahannaz DeChene, Elizabeth T. Gooding, Rebecca Jungbluth, Heinz Muelas, Nuria Palmio, Johanna Penttila, Sini Schmedding, Eric Suominen, Tiina Straub, Volker Staples, Christopher Van den Bergh, Peter Y. K. Vilchez, Juan J. Wagner, Kathryn R. Wheeler, Patricia G. Wraige, Elizabeth Laing, Nigel G. TI Novel Mutations Widen the Phenotypic Spectrum of Slow Skeletal/-Cardiac Myosin (MYH7) Distal Myopathy SO HUMAN MUTATION LA English DT Article DE MYH7; Laing distal myopathy; MPD1 ID FIBER-TYPE DISPROPORTION; STORAGE MYOPATHY; HEAVY-CHAIN; MISSENSE MUTATIONS; SEQUENCE VARIATION; STRIATED-MUSCLE; M-BAND; CARDIOMYOPATHY; GENE; DISEASE AB Laing early onset distal myopathy and myosin storage myopathy are caused by mutations of slow skeletal/-cardiac myosin heavy chain encoded by the gene MYH7, as is a common form of familial hypertrophic/dilated cardiomyopathy. The mechanisms by which different phenotypes are produced by mutations in MYH7, even in the same region of the gene, are not known. To explore the clinical spectrum and pathobiology, we screened the MYH7 gene in 88 patients from 21 previously unpublished families presenting with distal or generalized skeletal muscle weakness, with or without cardiac involvement. Twelve novel mutations have been identified in thirteen families. In one of these families, the father of the proband was found to be a mosaic for the MYH7 mutation. In eight cases, de novo mutation appeared to have occurred, which was proven in four. The presenting complaint was footdrop, sometimes leading to delayed walking or tripping, in members of 17 families (81%), with other presentations including cardiomyopathy in infancy, generalized floppiness, and scoliosis. Cardiac involvement as well as skeletal muscle weakness was identified in nine of 21 families. Spinal involvement such as scoliosis or rigidity was identified in 12 (57%). This report widens the clinical and pathological phenotypes, and the genetics of MYH7 mutations leading to skeletal muscle diseases. C1 [Lamont, Phillipa J.] Royal Perth Hosp, Dept Neurol, Neurogenet Unit, Perth, WA 6847, Australia. [Lamont, Phillipa J.; Wallefeld, William; Gooding, Rebecca; Laing, Nigel G.] Queen Elizabeth II Med Ctr, Pathwest, Diagnost Genom Lab, Nedlands, WA, Australia. [Hilton-Jones, David] John Radcliffe Hosp, Dept Clin Neurol, Oxford OX3 9DU, England. [Udd, Bjarne; Palmio, Johanna; Penttila, Sini; Suominen, Tiina] Tampere Univ, Neuromuscular Res Ctr, FIN-33101 Tampere, Finland. [Udd, Bjarne; Palmio, Johanna; Penttila, Sini; Suominen, Tiina] Tampere Univ Hosp, Tampere, Finland. [Udd, Bjarne] Univ Helsinki, Dept Med Genet, Folkhalsan Inst Genet, FIN-00014 Helsinki, Finland. [Udd, Bjarne] Vasa Cent Hosp, Dept Neurol, Vaasa, Finland. [Argov, Zohar] Hadassah Hebrew Univ, Med Ctr, Dept Neurol, Jerusalem, Israel. [Barboi, Alexandru C.] Rush Univ, Dept Neurol Sci, Chicago, IL 60612 USA. [Bonneman, Carsten; Dastgir, Jahannaz] Natl Inst Neurol Disorders, Neuromuscular & Neurogenet Disorders Childhood Se, Neurogenet Branch, Bethesda, MD USA. [Bonneman, Carsten; Dastgir, Jahannaz] Stroke NIH, Bethesda, MD USA. [Boycott, Kym M.] Childrens Hosp Eastern Ontario, Dept Genet, Ottawa, ON K1H 8L1, Canada. [Bushby, Kate; Straub, Volker] Int Ctr Life, Inst Human Genet, Newcastle Upon Tyne, Tyne & Wear, England. [Connolly, Anne M.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Davies, Nicholas; Wraige, Elizabeth] Univ Hosp Birmingham NHS Trust, Dept Neurol, Birmingham Muscle & Nerve Ctr, Birmingham, W Midlands, England. [Beggs, Alan H.; Cox, Gerald F.] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Genet & Genom,Manton Ctr Orphan Dis Res, Boston, MA USA. [DeChene, Elizabeth T.] Childrens Hosp Philadelphia, Div Human Genet, Philadelphia, PA 19104 USA. [Jungbluth, Heinz] St Thomas Hosp, Evelina Childrens Hosp, Neuromuscular Serv, Dept Paediat Neurol, London, England. [Jungbluth, Heinz] Kings Coll London, Muscle Signalling Sect, Randall Div Cell & Mol Biophys, London WC2R 2LS, England. [Jungbluth, Heinz] Kings Coll London, IOP, Clin Neurosci Div, London WC2R 2LS, England. [Muelas, Nuria; Vilchez, Juan J.] Hosp Univ & Politecn La Fe, Dept Neurol, Valencia, Spain. [Muelas, Nuria; Vilchez, Juan J.] Ctr Invest Biomed Red Enfermedades Neurodegenerar, Valencia, Spain. [Schmedding, Eric] Univ Ziekenhuis Brussel, Neuromusculair Referentie Centrum, Brussels, Belgium. [Staples, Christopher] Mater Adult & Womens Hosp, Dept Neurol, South Brisbane, Qld, Australia. [Van den Bergh, Peter Y. K.] Univ Louvain, Univ Hosp St Luc, Neuromuscular Reference Ctr, Brussels, Belgium. [Wagner, Kathryn R.] Johns Hopkins Sch Med, Kennedy Krieger Inst, Ctr Genet Muscle Disorders, Baltimore, MD USA. [Wagner, Kathryn R.] Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD USA. [Wagner, Kathryn R.] Johns Hopkins Sch Med, Dept Neurosci, Baltimore, MD USA. [Wheeler, Patricia G.] Nemours Childrens Clin, Div Genet, Orlando, FL USA. [Laing, Nigel G.] Univ Western Australia, Ctr Med Res, Harry Perkins Inst Med Res, QEII Med Ctr, Nedlands, WA, Australia. RP Lamont, PJ (reprint author), Royal Perth Hosp, Dept Neurol, Box X2213 GPO, Perth, WA 6847, Australia. EM phillipa.lamont@health.wa.gov.au RI Jungbluth, Heinz/B-8893-2012 FU Muscular Dystrophy Association (USA) [MDA201302]; National Institutes of Health [R01 AR044345]; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Australian National Health and Medical Research Council [APP1002147] FX Contract grant sponsors: Muscular Dystrophy Association (USA) (MDA201302); National Institutes of Health (R01 AR044345); National Institute of Arthritis and Musculoskeletal and Skin Diseases; Australian National Health and Medical Research Council Fellowship (APP1002147). NR 49 TC 25 Z9 26 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-7794 EI 1098-1004 J9 HUM MUTAT JI Hum. Mutat. PD JUL PY 2014 VL 35 IS 7 BP 868 EP 879 DI 10.1002/humu.22553 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA AJ5EQ UT WOS:000337705500013 PM 24664454 ER PT J AU Jennings, BL George, LW Pingili, AK Khan, NS Estes, AM Fang, XR Gonzalez, FJ Malik, KU AF Jennings, Brett L. George, L. Watson Pingili, Ajeeth K. Khan, Nayaab S. Estes, Anne M. Fang, Xiao R. Gonzalez, Frank J. Malik, Kafait U. TI Estrogen Metabolism by Cytochrome P450 1B1 Modulates the Hypertensive Effect of Angiotensin II in Female Mice SO HYPERTENSION LA English DT Article DE 2-methoxyestradiol; cytochrome P450 1B1; hypertension; ovariectomy; oxidative stress ID SALT-INDUCED HYPERTENSION; SEX-DIFFERENCES; ESTRADIOL HYDROXYLATION; BLOOD-PRESSURE; METHOXYESTRADIOLS MEDIATE; OXIDATIVE STRESS; AT(1) RECEPTOR; EXPRESSION; RATS; 17-BETA-ESTRADIOL AB To determine the role of cytochrome P450 (CYP) 1B1 in the sex difference in response to angiotensin II (Ang II)-induced hypertension, female Cyp1b1(+/+) and Cyp1b1(-/-) mice were infused with Ang II (700 ng/kg per minute) or vehicle with or without ovariectomy. In addition, mice were treated with the CYP1B1 inhibitor, 2,3,4,5-tetramethoxystilbene (TMS; 300 g/kg IP, every third day), and 17- estradiol metabolites, 2-hydroxyestradiol (2-OHE), 4-OHE, or 2-methoxyestradiol (1.5 mg/kg per day IP, for 2 weeks) and systolic blood pressure (SBP) measured. Ang II increased SBP more in Cyp1b1(-/-) than in Cyp1b1(+/+) mice (119 +/- 3-171 +/- 11 versus 120 +/- 4-149 +/- 4 mm Hg; P<0.05). Ang II caused cardiovascular remodeling and endothelial dysfunction and increased vascular reactivity and oxidative stress in Cyp1b1(-/-) but not in Cyp1b1(+/+)mice. The Ang II-induced increase in SBP was enhanced by ovariectomy and TMS in Cyp1b1(+/+) but not in Cyp1b1(-/-) mice. 2-OHE did not alter Ang II-induced increase in SBP in Cyp1b1(+/+) mice but minimized it in Cyp1b1(-/-) mice, whereas 4-OHE enhanced Ang II-induced increase in SBP in Cyp1b1(+/+) mice but did not alter the increased SBP in Cyp1b1(-/-) mice. 2-OHE-derived catechol-O-methyltransferase metabolite, 2-methoxyestradiol, inhibited Ang II-induced increase in SBP in Cyp1b1(-/-) mice. Ang II increased plasma levels of 2-methoxyestradiol in Cyp1b1(+/+) but not in Cyp1b1(-/-) mice and increased activity of cardiac extracellular signal-regulated kinase 1/2, p38 mitogen-activated kinase, c-Src, and Akt in Cyp1b1(-/-) but not in Cyp1b1(+/+) mice. These data suggest that CYP1B1 protects against Ang II-induced hypertension and associated cardiovascular changes in female mice, most likely mediated by 2-methoxyestradiol-inhibiting oxidative stress and the activity of these signaling molecules. C1 [Jennings, Brett L.; George, L. Watson; Pingili, Ajeeth K.; Khan, Nayaab S.; Estes, Anne M.; Fang, Xiao R.; Malik, Kafait U.] Univ Tennessee, Ctr Hlth Sci, Dept Pharmacol, Coll Med, Memphis, TN 38163 USA. [Gonzalez, Frank J.] NCI, Lab Metab, Bethesda, MD 20892 USA. RP Malik, KU (reprint author), Univ Tennessee, Ctr Hlth Sci, Dept Pharmacol, Coll Med, 874 Union Ave, Memphis, TN 38163 USA. EM kmalik@uthsc.edu FU National Institutes of Health-National Heart, Lung, and Blood Institute [R01-HL-19134-38]; American Heart Association; National Institutes of Health FX This work was supported by the National Institutes of Health-National Heart, Lung, and Blood Institute grant R01-HL-19134-38 (K.U. Malik). L.W. George was supported by a summer student fellowship from the American Heart Association and National Institutes of Health. NR 56 TC 16 Z9 17 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X EI 1524-4563 J9 HYPERTENSION JI Hypertension PD JUL PY 2014 VL 64 IS 1 BP 134 EP 140 DI 10.1161/HYPERTENSIONAHA.114.03275 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AJ5CY UT WOS:000337700400022 PM 24777982 ER PT J AU Belkaid, Y AF Belkaid, Yasmine TI Tailored immunity at mucosae SO IMMUNOLOGICAL REVIEWS LA English DT Review ID DISEASE; INNATE; CELLS C1 [Belkaid, Yasmine] NIAID, Program Barrier Immun & Repair, Bethesda, MD 20892 USA. [Belkaid, Yasmine] NIAID, Mucosal Immunol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Belkaid, Y (reprint author), NIAID, Mucosal Immunol Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ybelkaid@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 28 TC 2 Z9 2 U1 3 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-2896 EI 1600-065X J9 IMMUNOL REV JI Immunol. Rev. PD JUL PY 2014 VL 260 IS 1 SI SI BP 5 EP 7 DI 10.1111/imr.12197 PG 3 WC Immunology SC Immunology GA AJ4HV UT WOS:000337636200001 PM 24942677 ER PT J AU Cho, H Kelsall, BL AF Cho, Hyeseon Kelsall, Brian L. TI The role of type I interferons in intestinal infection, homeostasis, and inflammation SO IMMUNOLOGICAL REVIEWS LA English DT Review DE type I interferons; enteric microbial infection; intestinal inflammation ID DOUBLE-STRANDED-RNA; PLASMACYTOID DENDRITIC CELLS; INNATE IMMUNE-RESPONSE; LISTERIA-MONOCYTOGENES INFECTION; ENTERICA SEROVAR TYPHIMURIUM; MURINE NOROVIRUS REPLICATION; PERSISTENT LCMV INFECTION; ACTIVE ULCERATIVE-COLITIS; NATURAL-KILLER-CELLS; INDUCIBLE GENE-I AB Type I interferons are a widely expressed family of effector cytokines that promote innate antiviral and antibacterial immunity. Paradoxically, they can also suppress immune responses by driving production of anti-inflammatory cytokines, and dysregulation of these cytokines can contribute to host-mediated immunopathology and disease progression. Recent studies describe their anti-inflammatory role in intestinal inflammation and the locus containing IFNAR, a heterodimeric receptor for the type I interferons has been identified as a susceptibility region for human inflammatory bowel disease. This review focuses on the role of type I IFNs in the intestine in health and disease and their emerging role as immune modulators. Clear understanding of type I IFN-mediated immune responses may provide avenues for fine-tuning existing IFN treatment for infection and intestinal inflammation. C1 [Cho, Hyeseon; Kelsall, Brian L.] NIAID, Mucosal Immunobiol Sect, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Kelsall, BL (reprint author), NIAID, Lab Mol Immunol, Bldg 10,Room 11N104,10 Ctr Dr MSC 1886, Bethesda, MD 20892 USA. EM bkelsall@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA FX This study was supported by funding from the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. The authors have no conflicts of interest to declare. NR 251 TC 13 Z9 14 U1 2 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-2896 EI 1600-065X J9 IMMUNOL REV JI Immunol. Rev. PD JUL PY 2014 VL 260 IS 1 SI SI BP 145 EP 167 DI 10.1111/imr.12195 PG 23 WC Immunology SC Immunology GA AJ4HV UT WOS:000337636200012 PM 24942688 ER PT J AU Strober, W Asano, N Fuss, I Kitani, A Watanabe, T AF Strober, Warren Asano, Naoki Fuss, Ivan Kitani, Atsushi Watanabe, Tomohiro TI Cellular and molecular mechanisms underlying NOD2 risk-associated polymorphisms in Crohn's disease SO IMMUNOLOGICAL REVIEWS LA English DT Review DE NOD2; Crohn's disease; defensins; colitis; microbiome; IRF-4 ID INFLAMMATORY-BOWEL-DISEASE; INVASIVE ESCHERICHIA-COLI; ALPHA-DEFENSIN EXPRESSION; PANETH CELLS; DENDRITIC CELLS; ILEAL MUCOSA; ULCERATIVE-COLITIS; HUMAN MICROBIOTA; TRANSGENIC MICE; GUT MICROBIOTA AB The discovery that polymorphisms in the NOD2 (nucleotide-binding oligomerization domain containing 2) gene are associated with a greatly increased risk for the development of Crohn's disease has provided a means to achieve a deeper understanding of the dysregulation of mucosal immune responses to the commensal intestinal organisms that is thought to underlie this disease. NOD2 is a NOD-like receptor (NLR) family member that senses and responds to bacterial wall peptides; thus, the most widely held view of the relation of the NOD2 polymorphisms with Crohn's disease is that these polymorphisms lead to deficient immune responses to gut bacteria, and these, in turn, lead to quantitative or qualitative changes in the bacterial population in the gut lumen or lamina propria that cause inflammation at this site. Initially, this view was based mainly on the observation that defective NOD2 function can result in reduced -defensin production by intestinal Paneth cells and that such impairment leads to loss of host defense against gut bacteria. In this review, we reconsider this possibility and marshal evidence that it is not in fact likely to be a prime element of Crohn's disease causation. More recently, evidence has been accumulating that the NOD2 dysfunction leads to Crohn's inflammation by inducing changes in the gut microbiome that influence immune effector or regulatory function. We review the strengths and weaknesses of this emerging hypothesis. Finally, we consider the possibility that NOD2 dysfunction can lead to inflammation because of a second and somewhat overlooked aspect of its function, that as an immunoregulator of innate immune responses. In particular, we review the body of evidence that NOD2 stimulation activates a cross-tolerance response that downregulates and thus prevents excessive TLR responses that cause Crohn's inflammation. C1 [Strober, Warren; Fuss, Ivan; Kitani, Atsushi] NIAID, Mucosal Immun Sect, LHD, NIH, Bethesda, MD 20892 USA. [Asano, Naoki] Tohoku Univ, Grad Sch Med, Div Gastroenterol, Sendai, Miyagi 980, Japan. [Watanabe, Tomohiro] Kyoto Univ, Dept Gastroenterol & Hepatol, Grad Sch Med, Kyoto, Japan. RP Strober, W (reprint author), NIAID, Mucosal Immun Sect, LHD, NIH, Bldg 10 CRC,Room 5-3940,10 Ctr Dr, Bethesda, MD 20892 USA. EM Wstrober@niaid.nih.gov NR 60 TC 22 Z9 23 U1 1 U2 24 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-2896 EI 1600-065X J9 IMMUNOL REV JI Immunol. Rev. PD JUL PY 2014 VL 260 IS 1 SI SI BP 249 EP 260 DI 10.1111/imr.12193 PG 12 WC Immunology SC Immunology GA AJ4HV UT WOS:000337636200018 PM 24942694 ER PT J AU Gonzalez, FE Ortiz, C Reyes, M Dutzan, N Patel, V Pereda, C Gleisner, MA Lopez, MN Gutkind, JS Salazar-Onfray, F AF Gonzalez, Fermin E. Ortiz, Carolina Reyes, Montserrat Dutzan, Nicolas Patel, Vyomesh Pereda, Cristian Gleisner, Maria A. Lopez, Mercedes N. Gutkind, J. Silvio Salazar-Onfray, Flavio TI Melanoma cell lysate induces CCR7 expression and in vivo migration to draining lymph nodes of therapeutic human dendritic cells SO IMMUNOLOGY LA English DT Article DE CCR7; dendritic cells; immunotherapy; melanoma; migration; tumour lysates ID PRIMARY IMMUNE-RESPONSE; T-CELLS; CANCER-IMMUNOTHERAPY; GENE-EXPRESSION; TUMOR; CHEMOKINE; VACCINATION; DIFFERENTIATION; METASTASIS; ACTIVATION AB We have previously reported a novel method for the production of tumour-antigen-presenting cells (referred to as TAPCells) that are currently being used in cancer therapy, using an allogeneic melanoma-derived cell lysate (referred to as TRIMEL) as an antigen provider and activation factor. It was recently demonstrated that TAPCell-based immunotherapy induces T-cell-mediated immune responses resulting in improved long-term survival of stage IV melanoma patients. Clinically, dendritic cell (DC) migration from injected sites to lymph nodes is an important requirement for an effective anti-tumour immunization. This mobilization of DCs is mainly driven by the C-C chemokine receptor type 7 (CCR7), which is up-regulated on mature DCs. Using flow cytometry and immunohistochemistry, we investigated if TRIMEL was capable of inducing the expression of the CCR7 on TAPCells and enhancing their migration in vitro, as well as their in vivo relocation to lymph nodes in an ectopic xenograft animal model. Our results confirmed that TRIMEL induces a phenotypic maturation and increases the expression of surface CCR7 on melanoma patient-derived DCs, and also on the monocytic/macrophage cell line THP-1. Moreover, in vitro assays showed that TRIMEL-stimulated DCs and THP-1 cells were capable of migrating specifically in the presence of the CCR7 ligand CCL19. Finally, we demonstrated that TAPCells could migrate in vivo from the injection site into the draining lymph nodes. This work contributes to an increased understanding of the biology of DCs produced ex vivo allowing the design of new strategies for effective DC-based vaccines for treating aggressive melanomas. C1 [Gonzalez, Fermin E.; Ortiz, Carolina; Pereda, Cristian; Gleisner, Maria A.; Lopez, Mercedes N.; Salazar-Onfray, Flavio] Univ Chile, Millennium Inst Immunol & Immunotherapy, Santiago, Chile. [Gonzalez, Fermin E.; Dutzan, Nicolas] Univ Chile, Dept Conservat Dent, Fac Dent, Santiago 8380492, Chile. [Reyes, Montserrat] Univ Chile, Dept Pathol, Fac Dent, Santiago, Chile. [Patel, Vyomesh; Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. [Gleisner, Maria A.; Lopez, Mercedes N.; Salazar-Onfray, Flavio] Univ Chile, Inst Biomed Sci, Fac Med, Santiago 8380453, Chile. [Lopez, Mercedes N.] Univ Chile, Cell Therapy Lab, Blood Bank Serv, Clin Hosp, Santiago, Chile. RP Gonzalez, FE (reprint author), Univ Chile, Dept Conservat Dent, Fac Dent, Santiago 8380492, Chile. EM fgonzalez@u.uchile.cl; fsalazar@med.uchile.cl FU Chilean National Fund for Scientific and Technological Development [FONDECYT 1130320, 1130324, 11130607]; Fund for the Promotion of Scientific and Technological Development [FONDEF D11I1036]; National Commission of Scientific and Technological Research (CONICYT); Millennium Science Initiative from the Ministry for the Economy, Development and Tourism [P09/016-F] FX The authors thank Dr Maria Ines Becker (Biosonda) who kindly donated the anti-NK1.1 antibodies. We also thank Dr Alfredo Molinolo, Ramiro Iglesias-Bartolome and Constantinos Mikelis (NIH, NIDCR) for their expert assistance, and Dagoberto Donoso for technical support. We also thank Eugenio Rivas for artwork assistance. This work was supported by grants from the Chilean National Fund for Scientific and Technological Development (FONDECYT 1130320 FS-O, 1130324 MNL, and 11130607 FEG), the Fund for the Promotion of Scientific and Technological Development (FONDEF D11I1036 FS-O and MNL), the National Commission of Scientific and Technological Research (CONICYT, Advanced Human Capital Program, FEG) and the Millennium Science Initiative from the Ministry for the Economy, Development and Tourism (P09/016-F, FS-O). NR 36 TC 6 Z9 7 U1 4 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0019-2805 EI 1365-2567 J9 IMMUNOLOGY JI Immunology PD JUL PY 2014 VL 142 IS 3 BP 396 EP 405 DI 10.1111/imm.12264 PG 10 WC Immunology SC Immunology GA AJ3XF UT WOS:000337600500008 PM 24673602 ER PT J AU Ochoa-Cortes, F Linan-Rico, A Jacobson, KA Christofi, FL AF Ochoa-Cortes, Fernando Linan-Rico, Andromeda Jacobson, Kenneth A. Christofi, Fievos L. TI Potential for Developing Purinergic Drugs for Gastrointestinal Diseases SO INFLAMMATORY BOWEL DISEASES LA English DT Review DE purinergic drugs; clinical trials; inflammatory diarrhea; visceral pain; endogenous adenosine; A(3) receptors; P2X ion channels; inflammatory bowel disease; irritable bowel syndrome ID A(3) ADENOSINE RECEPTOR; INFLAMMATORY-BOWEL-DISEASE; INTESTINAL EPITHELIAL-CELLS; ENTERIC NERVOUS-SYSTEM; PIG SMALL-INTESTINE; INHIBITORY NEUROMUSCULAR-TRANSMISSION; TRINITROBENZENE SULFONIC-ACID; EXPERIMENTAL MURINE COLITIS; FUNCTIONAL GI DISORDERS; ROOT GANGLION NEURONS AB Treatments for inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), functional dyspepsia, or motility disorders are not adequate, and purinergic drugs offer exciting new possibilities. Gastrointestinal symptoms that could be targeted for therapy include visceral pain, inflammatory pain, dysmotility, constipation, and diarrhea. The focus of this review is on the potential for developing purinergic drugs for clinical trials to treat gastrointestinal symptoms. Purinergic receptors are divided into adenosine P1 (A(1), A(2A), A(2B), A(3)), ionotropic ATP-gated P2X ion channel (P2X(1-7)), or metabotropic P2Y(1,2,4,6,11-14) receptors. There is good experimental evidence for targeting A(2A), A(2B), A(3), P2X(7), and P2X(3) receptors or increasing endogenous adenosine levels to treat IBD, inflammatory pain, IBS/visceral pain, inflammatory diarrhea, and motility disorders. Purine genes are also potential biomarkers of disease. Advances in medicinal chemistry have an accelerated pace toward clinical trials: Methotrexate and sulfasalazine, used to treat IBD, act by stimulating CD73-dependent adenosine production. ATP protects against NSAID-induced enteropathy and has pain-relieving properties in humans. A P2X(7)R antagonist AZD9056 is in clinical trials for Crohn's disease. A(3) adenosine receptor drugs target inflammatory diseases (e.g., CF101, CF102). Dipyridamole, a nucleoside uptake inhibitor, is in trials for endotoxemia. Drugs for pain in clinical trials include P2X(3)/P2X(2/3) (AF-219) and P2X(7) (GSK1482160) antagonists and A(1) (GW493838) or A(2A) (BVT.115959) agonists. Iberogast is a phytopharmacon targeting purine mechanisms with efficacy in IBS and functional dyspepsia. Purinergic drugs have excellent safety/efficacy profile for prospective clinical trials in IBD, IBS, functional dyspepsia, and inflammatory diarrhea. Genetic polymorphisms and caffeine consumption may affect susceptibility to treatment. Further studies in animals can clarify mechanisms and test new generation drugs. Finally, there is still a huge gap in our knowledge of human pathophysiology of purinergic signaling. C1 [Ochoa-Cortes, Fernando; Linan-Rico, Andromeda; Christofi, Fievos L.] Ohio State Univ, Wexner Med Ctr, Dept Anesthesiol, Columbus, OH 43210 USA. [Jacobson, Kenneth A.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. RP Christofi, FL (reprint author), Ohio State Univ, Wexner Med Ctr, Dept Anesthesiol, Tzagournis Med Res Facil 226, 420 West 12th Ave, Columbus, OH 43210 USA. EM fedias.christofi@osumc.edu RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU National Institutes of Health [R01 DK093499]; strategic initiative research funds from the Department of Anesthesiology & Wexner Medical Center at The Ohio State University [R01 DK044179 11-15, DK04417915S]; NCRR [S10RR11434]; NIDDK, NIH FX Current support from the National Institutes of Health on R01 DK093499; strategic initiative research funds from the Department of Anesthesiology & Wexner Medical Center at The Ohio State University to F. L. Christofi; R01 DK044179 11-15; DK04417915S and NCRR S10RR11434 to F. L. Christofi. Support for from "the NIDDK, NIH Intramural Research Program" to K. A. Jacobson for research in the Laboratory of Bioorganic Chemistry & Molecular Recognition Section, Bethesda, MD. NR 239 TC 24 Z9 25 U1 2 U2 16 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1078-0998 EI 1536-4844 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD JUL PY 2014 VL 20 IS 7 BP 1259 EP 1287 DI 10.1097/MIB.0000000000000047 PG 29 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AJ5TC UT WOS:000337750000020 PM 24859298 ER PT J AU Morris, KM Kirby, K Beatty, JA Barrs, VR Cattley, S David, V O'Brien, SJ Menotti-Raymond, M Belov, K AF Morris, Katrina M. Kirby, Katherine Beatty, Julia A. Barrs, Vanessa R. Cattley, Sonia David, Victor O'Brien, Stephen J. Menotti-Raymond, Marilyn Belov, Katherine TI Development of MHC-Linked Microsatellite Markers in the Domestic Cat and Their Use to Evaluate MHC Diversity in Domestic Cats, Cheetahs, and Gir Lions SO JOURNAL OF HEREDITY LA English DT Article DE Acinonyx jubatus; Felis catus; major histocompatibility complex; Panthera leo ID MAJOR HISTOCOMPATIBILITY COMPLEX; CLASS-II DRB; FELIS-CATUS; ACINONYX-JUBATUS; POPULATION-SIZE; BLOOD TYPES; POLYMORPHISM; SELECTION; REGION; LOCI AB Diversity within the major histocompatibility complex (MHC) reflects the immunological fitness of a population. MHC-linked microsatellite markers provide a simple and an inexpensive method for studying MHC diversity in large-scale studies. We have developed 6 MHC-linked microsatellite markers in the domestic cat and used these, in conjunction with 5 neutral microsatellites, to assess MHC diversity in domestic mixed breed (n = 129) and purebred Burmese (n = 61) cat populations in Australia. The MHC of outbred Australian cats is polymorphic (average allelic richness = 8.52), whereas the Burmese population has significantly lower MHC diversity (average allelic richness = 6.81; P < 0.01). The MHC-linked microsatellites along with MHC cloning and sequencing demonstrated moderate MHC diversity in cheetahs (n = 13) and extremely low diversity in Gir lions (n = 13). Our MHC-linked microsatellite markers have potential future use in diversity and disease studies in other populations and breeds of cats as well as in wild felid species. C1 [Morris, Katrina M.; Kirby, Katherine; Beatty, Julia A.; Barrs, Vanessa R.; Belov, Katherine] Univ Sydney, Fac Vet Sci, Sydney, NSW 2006, Australia. [Cattley, Sonia] Univ Sydney, ANGIS, Sydney, NSW 2006, Australia. [David, Victor; Menotti-Raymond, Marilyn] NCI, Lab Genom Div, Frederick, MD 21702 USA. [O'Brien, Stephen J.] St Petersburg State Univ, Theodosius Dobzhansky Ctr Genome Bioinformat, St Petersburg 199034, Russia. [O'Brien, Stephen J.] Nova SE Univ, Oceanog Ctr, Ft Lauderdale, FL 33314 USA. RP Belov, K (reprint author), Univ Sydney, Fac Vet Sci, Sydney, NSW 2006, Australia. EM kathy.belov@sydney.edu.au OI O'Brien, Stephen J./0000-0001-7353-8301 FU Australian Companion Animal Health Foundation; Intramural Research Program of the National Institutes of Health; National Cancer Institute, Center for Cancer Research [N01-CO-12400]; Russian Ministry of Science [11.G34.31.0068] FX Australian Companion Animal Health Foundation; Intramural Research Program of the National Institutes of Health; National Cancer Institute, Center for Cancer Research (contract N01-CO-12400). Russian Ministry of Science (11.G34.31.0068 to S.J.O., Principal Investigator). NR 64 TC 0 Z9 0 U1 3 U2 31 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1503 EI 1465-7333 J9 J HERED JI J. Hered. PD JUL-AUG PY 2014 VL 105 IS 4 BP 493 EP 505 DI 10.1093/jhered/esu017 PG 13 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA AJ6KJ UT WOS:000337802400006 PM 24620003 ER PT J AU Reisin, E Graves, JW Yamal, JM Barzilay, JI Pressel, SL Einhorn, PT Dart, RA Retta, TM Saklayen, MG Davis, BR AF Reisin, Efrain Graves, John W. Yamal, Jose-Miguel Barzilay, Joshua I. Pressel, Sara L. Einhorn, Paula T. Dart, Richard A. Retta, Tamrat M. Saklayen, Mohammad G. Davis, Barry R. CA ALLHAT Collaborative Res Grp TI Blood pressure control and cardiovascular outcomes in normal-weight, overweight, and obese hypertensive patients treated with three different antihypertensives in ALLHAT SO JOURNAL OF HYPERTENSION LA English DT Article DE blood pressure control; hypertension; obesity; overweight ID LIPID-LOWERING TREATMENT; ATTACK TRIAL ALLHAT; RANDOMIZED CONTROLLED-TRIAL; ARTERIAL-HYPERTENSION; SYSTOLIC HYPERTENSION; METABOLIC SYNDROME; CLINICAL-OUTCOMES; BODY-MASS; RISK; AMLODIPINE AB Objective: Epidemiologically, there is a strong relationship between BMI and blood pressure (BP) levels. We prospectively examined randomization to first-step chlorthalidone, a thiazide-type diuretic; amlodipine, a calcium-channel blocker; and lisinopril, an angiotensin-converting enzyme inhibitor, on BP control and cardiovascular outcomes in a hypertensive cohort stratified by baseline BMI [ kg/m(2); normal weight (BMI < 25), overweight (BMI = 25-29.9), and obese (BMI > 30)]. Methods: In a randomized, double-blind, practice-based Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, 33 357 hypertensive participants, aged at least 55 years, were followed for an average of 4.9 years, for a primary outcome of fatal coronary heart disease or nonfatal myocardial infarction, and secondary outcomes of stroke, heart failure, combined cardiovascular disease, mortality, and renal failure. Results: Of participants, 37.9% were overweight and 42.1% were obese at randomization. For each medication, BP control (< 140/90 mmHg) was equivalent in each BMI stratum. At the fifth year, 66.1, 66.5, and 65.1% of normal-weight, overweight, and obese participants, respectively, were controlled. Those randomized to chlorthalidone had highest BP control (67.2, 68.3, and 68.4%, respectively) and to lisinopril the lowest (60.4, 63.2, and 59.6%, respectively) in each BMI stratum. A significant interaction (P = 0.004) suggests a lower coronary heart disease risk in the obese for lisinopril versus chlorthalidone (hazard ratio 0.85, 95% confidence interval 0.74-0.98) and a significant interaction (P = 0.011) suggests a higher risk of end-stage renal disease for amlodipine versus chlorthalidone in obese participants (hazard ratio 1.49, 95% confidence interval 1.06-2.08). However, these results were not consistent among other outcomes. Conclusion: BMI status does not modify the effects of antihypertensive medications on BP control or cardiovascular disease outcomes. C1 [Reisin, Efrain] Louisiana State Univ, Hlth Sci Ctr, Sect Nephrol & Hypertens, New Orleans, LA USA. [Graves, John W.] Mayo Clin, Div Nephrol Hypertens, Rochester, MN USA. [Yamal, Jose-Miguel; Pressel, Sara L.; Davis, Barry R.] Univ Texas Sch Publ Hlth, Coordinating Ctr Clin Trials, Houston, TX 77030 USA. [Barzilay, Joshua I.] Kaiser Permanente Georgia, Div Endocrinol, Atlanta, GA USA. [Barzilay, Joshua I.] Emory Univ, Sch Med, Atlanta, GA USA. [Einhorn, Paula T.] NHLBI, Bethesda, MD 20892 USA. [Dart, Richard A.] Marshfield Clin Res Fdn, Ctr Human Genet, Marshfield, WI USA. [Retta, Tamrat M.] Howard Univ, Hypertens & Lipid Clin, Howard Univ Hosp, Washington, DC 20059 USA. [Saklayen, Mohammad G.] Vet Affairs Med Ctr, Dayton, OH USA. [Saklayen, Mohammad G.] Wright State Univ, Dayton, OH 45435 USA. RP Yamal, JM (reprint author), Univ Texas Sch Publ Hlth, Coordinating Ctr Clin Trials, 1200 Pressler St, Houston, TX 77030 USA. EM Jose-Miguel.Yamal@uth.tmc.edu FU National Heart, Lung, and Blood Institute [NO1-HC-35130, HHSN268201100036C]; Pfizer, Inc. FX The National Heart, Lung, and Blood Institute contracts NO1-HC-35130 and HHSN268201100036C supported this study. ALLHAT investigators acknowledge medications contributed by Pfizer, Inc. (amlodipine and doxazosin), AstraZeneca (atenolol and lisinopril), and Bristol-Myers Squibb (pravastatin), and financial support provided by Pfizer, Inc. NR 28 TC 7 Z9 7 U1 0 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0263-6352 EI 1473-5598 J9 J HYPERTENS JI J. Hypertens. PD JUL PY 2014 VL 32 IS 7 BP 1503 EP 1513 DI 10.1097/HJH.0000000000000204 PG 11 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AJ0NP UT WOS:000337351400023 PM 24842697 ER PT J AU Sherman-Baust, CA Kuhn, E Valle, BL Shih, LM Kurman, RJ Wang, TL Amano, T Ko, MSH Miyoshi, I Araki, Y Lehrmann, E Zhang, YQ Becker, KG Morin, PJ AF Sherman-Baust, Cheryl A. Kuhn, Elisabetta Valle, Blanca L. Shih, Le-Ming Kurman, Robert J. Wang, Tian-Li Amano, Tomokazu Ko, Minoru S. H. Miyoshi, Ichiro Araki, Yoshihiko Lehrmann, Elin Zhang, Yongqing Becker, Kevin G. Morin, Patrice J. TI A genetically engineered ovarian cancer mouse model based on fallopian tube transformation mimics human high-grade serous carcinoma development SO JOURNAL OF PATHOLOGY LA English DT Article DE transgenic mouse model; ovarian cancer; fallopian tube; intraepithelial carcinoma; p53; Top2a ID TOPOISOMERASE-II-ALPHA; INTRAEPITHELIAL CARCINOMA; SURFACE EPITHELIUM; BREAST-CANCER; CONDITIONAL INACTIVATION; COMPREHENSIVE ANALYSIS; CANDIDATE PRECURSOR; TP53 MUTATIONS; P53 SIGNATURE; EXPRESSION AB Recent evidence suggests that ovarian high-grade serous carcinoma (HGSC) originates from the epithelium of the fallopian tube. However, most mouse models are based on the previous prevailing view that ovarian cancer develops from the transformation of the ovarian surface epithelium. Here, we report the extensive histological and molecular characterization of the mogp-TAg transgenic mouse, which expresses the SV40 large T-antigen (TAg) under the control of the mouse mullerian-specific Ovgp-1 promoter. Histological analysis of the fallopian tubes of mogp-TAg mice identified a variety of neoplastic lesions analogous to those described as precursors to ovarian HGSC. We identified areas of normal-appearing p53-positive epithelium that are similar to p53 signatures' in the human fallopian tube. More advanced proliferative lesions with nuclear atypia and epithelial stratification were also identified that were morphologically and immunohistochemically reminiscent of human serous tubal intraepithelial carcinoma (STIC), a potential precursor of ovarian HGSC. Beside these non-invasive precursor lesions, we also identified invasive adenocarcinoma in the ovaries of 56% of the mice. Microarray analysis revealed several genes differentially expressed between the fallopian tube of mogp-TAg and wild-type (WT) C57BL/6. One of these genes, Top2a, which encodes topoisomerase II, was shown by immunohistochemistry to be concurrently expressed with elevated p53 and was specifically elevated in mouse STICs but not in the surrounding tissues. TOP2A protein was also found elevated in human STICs, low-grade and high-grade serous carcinoma. The mouse model reported here displays a progression from normal tubal epithelium to invasive HGSC in the ovary, and therefore closely simulates the current emerging model of human ovarian HGSC pathogenesis. This mouse therefore has the potential to be a very useful new model for elucidating the mechanisms of serous ovarian tumourigenesis, as well as for developing novel approaches for the prevention, diagnosis and therapy of this disease. Published 2014. This article has been contributed to by US Government employees and their work is in the public domain in the USA. C1 [Sherman-Baust, Cheryl A.; Morin, Patrice J.] NIA, Lab Mol Biol & Immunol, Baltimore, MD 21224 USA. [Amano, Tomokazu; Ko, Minoru S. H.; Lehrmann, Elin; Zhang, Yongqing; Becker, Kevin G.] NIA, Genet Lab, Baltimore, MD 21224 USA. [Miyoshi, Ichiro] Nagoya City Univ, Grad Sch Med Sci, Ctr Expt Anim Sci, Nagoya, Aichi, Japan. [Araki, Yoshihiko] Juntendo Univ, Grad Sch Med, Inst Environm & Gender Specif Med, Urayasu, Chiba, Japan. [Kuhn, Elisabetta; Shih, Le-Ming; Kurman, Robert J.; Wang, Tian-Li; Morin, Patrice J.] Johns Hopkins Med Inst, Dept Pathol Oncol & Gynecol & Obstet, Baltimore, MD 21205 USA. [Valle, Blanca L.] Johns Hopkins Med Inst, Dept Otolaryngol, Baltimore, MD 21205 USA. RP Morin, PJ (reprint author), Amer Assoc Canc Res, 615 Chestnut St,17th Floor, Philadelphia, PA 19106 USA. EM pat.morin@aacr.org OI Lehrmann, Elin/0000-0002-9869-9475; Ko, Minoru/0000-0002-3530-3015 FU Intramural Research Programme of the NIH; National Institute on Aging; US Department of Defense [W81XWH-11-2-0230/OC100517] FX We thank the members of our laboratory for useful comments on the manuscript. This research was supported in part by the Intramural Research Programme of the NIH, the National Institute on Aging and the US Department of Defense (Grant No. W81XWH-11-2-0230/OC100517). NR 46 TC 32 Z9 32 U1 1 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3417 EI 1096-9896 J9 J PATHOL JI J. Pathol. PD JUL PY 2014 VL 233 IS 3 BP 228 EP 237 DI 10.1002/path.4353 PG 10 WC Oncology; Pathology SC Oncology; Pathology GA AJ3WW UT WOS:000337599600004 PM 24652535 ER PT J AU Collins, FS Hudson, KL Briggs, JP Lauer, MS AF Collins, Francis S. Hudson, Kathy L. Briggs, Josephine P. Lauer, Michael S. TI PCORnet: turning a dream into reality SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Editorial Material C1 [Collins, Francis S.; Hudson, Kathy L.] NIH, Bethesda, MD 20892 USA. [Briggs, Josephine P.] NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. [Lauer, Michael S.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Hudson, KL (reprint author), NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM kathy.hudson@nih.gov NR 5 TC 22 Z9 23 U1 4 U2 9 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1067-5027 EI 1527-974X J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD JUL PY 2014 VL 21 IS 4 SI SI BP 576 EP 577 DI 10.1136/amiajnl-2014-002864 PG 2 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA AJ4QJ UT WOS:000337660600002 PM 24821744 ER PT J AU Min, H Ohira, R Collins, MA Bondy, J Avis, NE Tchuvatkina, O Courtney, PK Moser, RP Shaikh, AR Hesse, BW Cooper, M Reeves, D Lanese, B Helba, C Miller, SM Ross, EA AF Min, Hua Ohira, Riki Collins, Michael A. Bondy, Jessica Avis, Nancy E. Tchuvatkina, Olga Courtney, Paul K. Moser, Richard P. Shaikh, Abdul R. Hesse, Bradford W. Cooper, Mary Reeves, Dianne Lanese, Bob Helba, Cindy Miller, Suzanne M. Ross, Eric A. TI Sharing behavioral data through a grid infrastructure using data standards SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID ELECTRONIC HEALTH RECORDS; SUBJECTIVE NUMERACY SCALE; MEANINGFUL USE; NCI THESAURUS; SCIENCE; PROGRESS; TOOLKIT; SYSTEMS; PHENX AB Objective In an effort to standardize behavioral measures and their data representation, the present study develops a methodology for incorporating measures found in the National Cancer Institute's (NCI) grid-enabled measures (GEM) portal, a repository for behavioral and social measures, into the cancer data standards registry and repository (caDSR). Methods The methodology consists of four parts for curating GEM measures into the caDSR: (1) develop unified modeling language (UML) models for behavioral measures; (2) create common data elements (CDE) for UML components; (3) bind CDE with concepts from the NCI thesaurus; and (4) register CDE in the caDSR. Results UML models have been developed for four GEM measures, which have been registered in the caDSR as CDE. New behavioral concepts related to these measures have been created and incorporated into the NCI thesaurus. Best practices for representing measures using UML models have been utilized in the practice (eg, caDSR). One dataset based on a GEM-curated measure is available for use by other systems and users connected to the grid. Conclusions Behavioral and population science data can be standardized by using and extending current standards. A new branch of CDE for behavioral science was developed for the caDSR. It expands the caDSR domain coverage beyond the clinical and biological areas. In addition, missing terms and concepts specific to the behavioral measures addressed in this paper were added to the NCI thesaurus. A methodology was developed and refined for curation of behavioral and population science data. C1 [Min, Hua] George Mason Univ, Coll Hlth & Human Serv, Dept Hlth Adm & Policy, Fairfax, VA 22030 USA. [Min, Hua; Collins, Michael A.; Tchuvatkina, Olga; Miller, Suzanne M.; Ross, Eric A.] Temple Univ Hlth, Fox Chase Canc Ctr, Philadelphia, PA USA. [Ohira, Riki] Booz Allen Hamilton, Rockville, MD USA. [Bondy, Jessica] Univ Colorado Denver, Denver, CO USA. [Avis, Nancy E.] Wake Forest Univ, Bowman Gray Sch Med, Dept Social Sci & Hlth Policy, Winston Salem, NC USA. [Courtney, Paul K.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Moser, Richard P.; Hesse, Bradford W.] NCI, Behav Res Program, Rockville, MD USA. [Shaikh, Abdul R.] PricewaterhouseCoopers LLP, Mclean, VA USA. [Cooper, Mary] Sci Applicat Int Corp, Mclean, VA 22102 USA. [Reeves, Dianne] NCI, Rockville, MD USA. [Lanese, Bob] Case Western Reserve Univ, Ireland Canc Ctr, Cleveland, OH 44106 USA. [Helba, Cindy] Westat Corp, Rockville, MD USA. RP Min, H (reprint author), George Mason Univ, Coll Hlth & Human Serv, Dept Hlth Adm & Policy, 4400 Univ Dr,MS1J3, Fairfax, VA 22030 USA. EM gmu3@gmu.edu OI Lanese, Robert/0000-0002-6246-9475; Hesse, Bradford/0000-0003-1142-1161 NR 34 TC 4 Z9 4 U1 2 U2 16 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1067-5027 EI 1527-974X J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD JUL PY 2014 VL 21 IS 4 SI SI BP 642 EP 649 DI 10.1136/amiajnl-2013-001763 PG 8 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA AJ4QJ UT WOS:000337660600016 PM 24076749 ER PT J AU Duyn, JH Barbara, TM AF Duyn, Jeff H. Barbara, Thomas M. TI Sphere of Lorentz and Demagnetization Factors in White Matter SO MAGNETIC RESONANCE IN MEDICINE LA English DT Letter ID GRADIENT-ECHO MRI; MAGNETIC-SUSCEPTIBILITY; BIOPHYSICAL MECHANISMS; IN-VIVO; NMR; CONTRAST; BRAIN; ORIENTATION; RELAXATION; FREQUENCY C1 [Duyn, Jeff H.] NINDS, Adv MRI Sect, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Barbara, Thomas M.] Oregon Hlth & Sci Univ, Adv Imaging Res Ctr, Portland, OR 97201 USA. RP Duyn, JH (reprint author), Lab Funct & Mol Imaging, Bldg 10,Room B1D728,9000 Rockville Pike, Bethesda, MD 20892 USA. EM jhd@helix.nih.gov OI barbara, thomas/0000-0002-1494-0541 FU Intramural NIH HHS [ZIA NS002990-14] NR 21 TC 3 Z9 3 U1 1 U2 45 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD JUL PY 2014 VL 72 IS 1 BP 1 EP 3 DI 10.1002/mrm.25021 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AJ4EK UT WOS:000337624400001 PM 24764306 ER PT J AU Triplett, WT Baligand, C Forbes, SC Willcocks, RJ Lott, DJ DeVos, S Pollaro, J Rooney, WD Sweeney, HL Bonnemann, CG Wang, DJ Vandenborne, K Walter, GA AF Triplett, William T. Baligand, Celine Forbes, Sean C. Willcocks, Rebecca J. Lott, Donovan J. DeVos, Soren Pollaro, Jim Rooney, William D. Sweeney, H. Lee Boennemann, Carsten G. Wang, Dah-Jyuu Vandenborne, Krista Walter, Glenn A. TI Chemical Shift-Based MRI to Measure Fat Fractions in Dystrophic Skeletal Muscle SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE Duchenne muscular dystrophy; collagen VI; skeletal muscle; magnetic resonance spectroscopy; congenital muscular dystrophy; muscle composition; fat water imaging ID DUCHENNE MUSCULAR-DYSTROPHY; 3-POINT DIXON TECHNIQUE; WATER/FAT SEPARATION; QUANTITATIVE ASSESSMENT; CLINICAL-ASSESSMENTS; DISEASE PROGRESSION; HEPATIC STEATOSIS; LIVER FAT; QUANTIFICATION; SPECTROSCOPY AB Purpose: The relationship between fat fractions (FFs) determined based on multiple TE, unipolar gradient echo images and H-1 magnetic resonance spectroscopy (MRS) was evaluated using different models for fat-water decomposition, signal-to-noise ratios, and excitation flip angles. Methods: A combination of single-voxel proton spectroscopy(H-1-MRS) and gradient echo imaging was used to determine muscle FFs in both normal and dystrophic muscles. In order to cover a large range of FFs, the soleus and vastus lateralis muscles of 22 unaffected control subjects, 16 subjects with collagen VI deficiency (COL6), and 71 subjects with Duchenne muscular dystrophy (DMD) were studied. H-1-MRS-based FF were corrected for the increased muscle (H2OT1)-H-1 and T-2 values observed in dystrophic muscles. Results: Excellent agreement was found between coregistered FFs derived from gradient echo images fit to a multipeak model with noise bias correction and the relaxation-corrected H-1-MRS FFs (y = 0.93x + 0.003; R-2 = 0.96) across the full range of FFs. Relaxation-corrected H-1-MRS FFs and imaging-based FFs were significantly elevated (P < 0.01) in the muscles of COL6 and DMD subjects. Conclusion: FFs, T-2, and T-1 were all sensitive to muscle involvement in dystrophic muscle. MRI offered an additional advantage over single-voxel spectroscopy in that the tissue heterogeneity in FFs could be readily determined. (C) 2013 Wiley Periodicals, Inc. C1 [Triplett, William T.; Baligand, Celine; Walter, Glenn A.] Univ Florida, Dept Physiol & Funct Genom, Gainesville, FL 32610 USA. [Forbes, Sean C.; Willcocks, Rebecca J.; Lott, Donovan J.; DeVos, Soren; Vandenborne, Krista] Univ Florida, Dept Phys Therapy, Gainesville, FL 32610 USA. [Pollaro, Jim; Rooney, William D.] Oregon Hlth & Sci Univ, Adv Imaging Res Ctr, Portland, OR 97201 USA. [Sweeney, H. Lee] Univ Penn, Dept Physiol, Philadelphia, PA 19104 USA. [Boennemann, Carsten G.] NINDS, NIH, Bethesda, MD 20892 USA. [Wang, Dah-Jyuu] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. RP Walter, GA (reprint author), Univ Florida, Dept Physiol & Funct Genom, POB 100274, Gainesville, FL 32610 USA. EM glennw@ufl.edu OI Triplett, William/0000-0002-9546-1306 FU National Institute of Arthritis and Musculoskeletal and Skin Diseases/National Institute of Neurological Disorders and Stroke [R01AR056973]; National Institutes of Health [P01HL59412]; Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Centers [U54AR052646]; Parent Project Muscular Dystrophy; National Science Foundation [DMR-0654118]; State of Florida FX Grant sponsor: National Institute of Arthritis and Musculoskeletal and Skin Diseases/National Institute of Neurological Disorders and Stroke; Grant number: R01AR056973; Grant sponsor: National Institutes of Health; Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Centers; Grant number: U54AR052646; Grant sponsor: National Institutes of Health; Grant number: P01HL59412; Grant sponsor: Parent Project Muscular Dystrophy. A portion of this work was performed at the National High Magnetic Field Laboratory, which is supported by National Science Foundation Cooperative Agreement No. DMR-0654118 and the State of Florida. NR 61 TC 17 Z9 17 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD JUL PY 2014 VL 72 IS 1 BP 8 EP 19 DI 10.1002/mrm.24917 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AJ4EK UT WOS:000337624400003 PM 24006208 ER PT J AU Rajan, S Herbertson, L Bernardo, M Choyke, P AF Rajan, Sunder Herbertson, Luke Bernardo, Marcelino Choyke, Peter TI A Dialyzer-Based Flow System for Validating Dynamic Contrast Enhanced MR Image Acquisition SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE flow-phantom; DCE-MRI; dialyzer; polysulfone ID PHANTOM AB Purpose: Dynamic contrast enhanced magnetic resonance imaging (MRI) has proven to be quite sensitive for the characterization of masses and early response to therapy. However, it is fraught with a number of procedural challenges as well as a lack of standardization. In this article, we describe the use of a simple dialyzer-based flow system to evaluate reproducibility of dynamic contrast enhanced MRI under active flow conditions. Methods: The MR signal during a bolus injection of Gd-DTPA was analyzed to test the precision and variability of contrast agent kinetics during a typical dynamic contrast enhanced MRI sequence. A simple model allows an estimation of the washout rate constant of Gd-DTPA through the polysulfone tubules of the dialyzer. Results: The simple flow phantom described here provided reproducible measurements of the washout rate constants. The washout rate increased from 0.20 +/- 0.005 min(-1) to 0.25 +/- 0.008 min(-1) over 32 weeks. Measurements were also made at week 24 using dynamic computed tomography and found to be 0.27 +/- 0.006 min(-1). Overall, the computed tomography derived rate constants results were found be similar to 12% higher than the corresponding MRI values. Conclusion: In this study, we show that a simple dialyzer-based flow phantom can be used for testing dynamic contrast enhanced MRI pulse sequences and also allows for short-term reproducibility testing of rate constants. (C) 2013 Wiley Periodicals, Inc. C1 [Rajan, Sunder; Herbertson, Luke] US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Bernardo, Marcelino] SAIC Frederick, Frederick, MD USA. [Choyke, Peter] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. RP Rajan, S (reprint author), 10903 New Hampshire Ave,WO 62,Room 1113, Silver Spring, MD 20993 USA. EM sunder.rajan@fda.hhs.gov NR 11 TC 1 Z9 1 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD JUL PY 2014 VL 72 IS 1 BP 41 EP 48 DI 10.1002/mrm.24887 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AJ4EK UT WOS:000337624400007 PM 23907806 ER PT J AU Graessl, A Renz, W Hezel, F Dieringer, MA Winter, L Oezerdem, C Rieger, J Kellman, P Santoro, D Lindel, TD Frauenrath, T Pfeiffer, H Niendorf, T AF Graessl, Andreas Renz, Wolfgang Hezel, Fabian Dieringer, Matthias A. Winter, Lukas Oezerdem, Celal Rieger, Jan Kellman, Peter Santoro, Davide Lindel, Tomasz D. Frauenrath, Tobias Pfeiffer, Harald Niendorf, Thoralf TI Modular 32-Channel Transceiver Coil Array for Cardiac MRI at 7.0T SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE ultrahigh-field MRI; cardiovascular MRI; transceiver array; parallel imaging ID CARDIOVASCULAR MAGNETIC-RESONANCE; TO-NOISE RATIO; 7 TESLA; HEAD COIL; DESIGN; SYNCHRONIZATION; FEASIBILITY; ELEMENT; SNR AB Purpose: To design and evaluate a modular transceiver coil array with 32 independent channels for cardiac MRI at 7.0T. Methods: The modular coil array comprises eight independent building blocks, each containing four transceiver loop elements. Numerical simulations were used for B-1(+) field homogenization and radiofrequency (RF) safety validation. RF characteristics were examined in a phantom study. The array's suitability for accelerated high spatial resolution two-dimensional (2D) FLASH CINE imaging of the heart was examined in a volunteer study. Results: Transmission field adjustments and RF characteristics were found to be suitable for the volunteer study. The signal-to-noise intrinsic to 7.0T together with the coil performance afforded a spatial resolution of 1.1 X 1.1 X 2.5 mm(3) for 2D CINE FLASH MRI, which is by a factor of 6 superior to standardized CINE protocols used in clinical practice at 1.5T. The 32-channel transceiver array supports one-dimensional acceleration factors of up to R = 4 without impairing image quality significantly. Conclusion: The modular 32-channel transceiver cardiac array supports accelerated and high spatial resolution cardiac MRI. The array is compatible with multichannel transmission and provides a technological basis for future clinical assessment of parallel transmission techniques at 7.0T. (C) 2013 Wiley Periodicals, Inc. C1 [Graessl, Andreas; Hezel, Fabian; Dieringer, Matthias A.; Winter, Lukas; Oezerdem, Celal; Rieger, Jan; Santoro, Davide; Lindel, Tomasz D.; Frauenrath, Tobias; Pfeiffer, Harald; Niendorf, Thoralf] Max Delbruck Ctr Mol Med, Berlin Ultrahigh Field Facil, D-13125 Berlin, Germany. [Renz, Wolfgang] Siemens Healthcare, Erlangen, Germany. [Rieger, Jan] MRI TOOLS GmbH, Berlin, Germany. [Kellman, Peter] NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. [Lindel, Tomasz D.; Pfeiffer, Harald] Phys Tech Bundesanstalt, Berlin, Germany. [Dieringer, Matthias A.; Niendorf, Thoralf] Charite Med Fac, Expt & Clin Res Ctr, Berlin, Germany. [Dieringer, Matthias A.; Niendorf, Thoralf] Max Delbruck Ctr Mol Med, D-13125 Berlin, Germany. RP Niendorf, T (reprint author), Max Delbruck Ctr Mol Med, Berlin Ultrahigh Field Facil, Robert Roessle Str 10, D-13125 Berlin, Germany. EM thoralf.niendorf@mdc-berlin.de RI Niendorf, Thoralf/H-7738-2013; OI Niendorf, Thoralf/0000-0001-7584-6527; Winter, Lukas/0000-0002-4381-275X NR 57 TC 30 Z9 30 U1 1 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD JUL PY 2014 VL 72 IS 1 BP 276 EP 290 DI 10.1002/mrm.24903 PG 15 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AJ4EK UT WOS:000337624400031 PM 23904404 ER PT J AU Persoskie, A Leyva, B Ferrer, RA AF Persoskie, Alexander Leyva, Bryan Ferrer, Rebecca A. TI Mode Effects in Assessing Cancer Worry and Risk Perceptions: Is Social Desirability Bias at Play? SO MEDICAL DECISION MAKING LA English DT Article DE perceived risk; worry; cancer; social desirability; survey mode ID QUALITY-OF-LIFE; TRENDS SURVEY HINTS; BREAST-CANCER; SENSITIVE QUESTIONS; DATA-COLLECTION; PERCEIVED RISK; OVARIAN-CANCER; COMMUNICATION; INFORMATION; IMPACT AB Background. Risk perceptions and worry are important determinants of health behavior. Despite extensive research on these constructs, it is unknown whether people's self-reports of perceived risk and worry are biased by their concerns about being viewed negatively by others (social desirability). Methods. In this study, we examined whether reports of perceived risk and worry about cancer varied across survey modes differing in the salience of social desirability cues. We used data from the National Cancer Institute's 2007 Health Information National Trends Survey, which assessed perceived cancer risk and worry in 1 of 2 survey modes: an interviewer-administered telephone survey (higher likelihood of socially desirable responding; n = 3678) and a self-administered mail survey (lower likelihood of socially desirable responding; n = 3445). Data were analyzed by regressing perceived risk and worry on survey mode and demographic factors. Results. Analyses showed no effect of survey mode on cancer risk perceptions (B = 0.02, P = 0.55, d = 0.02). However, cancer worry was significantly higher in the self-administered mode than in the interviewer-administered mode (B = 0.24, P < 0.001, d = 0.26). Education moderated this effect, with respondents lower in education exhibiting a stronger mode effect. When cancer worry was dichotomized, the odds of reporting cancer worry were approximately twice as high in the self-administered mode compared with the interviewer-administered mode (OR = 2.13, P < 0.001). Conclusions. These results bolster the veracity of self-reported cancer risk perceptions. They also suggest that interviewer-administered surveys may underestimate the frequency of cancer worry, particularly for samples lower in socioeconomic status. Studies are needed to test for this effect in clinical contexts. C1 [Persoskie, Alexander; Leyva, Bryan; Ferrer, Rebecca A.] NCI, Behav Res Program, Bethesda, MD 20892 USA. RP Persoskie, A (reprint author), NCI, Behav Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,Room 3E204,MSC 9761, Bethesda, MD 20892 USA. EM persoskieai@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 52 TC 3 Z9 3 U1 2 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0272-989X EI 1552-681X J9 MED DECIS MAKING JI Med. Decis. Mak. PD JUL PY 2014 VL 34 IS 5 BP 583 EP 589 DI 10.1177/0272989X14527173 PG 7 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA AJ3NB UT WOS:000337572300004 PM 24718657 ER PT J AU van der Berg, JD Bosma, H Caserotti, P Eiriksdottir, G Arnardottir, NY Martin, KR Brychta, RJ Chen, KY Sveinsson, T Johannsson, E Launer, LJ Gudnason, V Jonsson, PV Stehouwer, CDA Harris, TB Koster, A AF van der Berg, Julianne D. Bosma, Hans Caserotti, Paolo Eiriksdottir, Gudny Arnardottir, Nanna Yr Martin, Kathryn R. Brychta, Robert J. Chen, Kong Y. Sveinsson, Thorarinn Johannsson, Erlingur Launer, Lenore J. Gudnason, Vilmundur Jonsson, Palmi V. Stehouwer, Coen D. A. Harris, Tamara B. Koster, Annemarie TI Midlife Determinants Associated with Sedentary Behavior in Old Age SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE ACCELEROMETRY; SEDENTARY LIFESTYLE; OLDER ADULTS; LONGITUDINAL STUDIES; SOCIOECONOMIC FACTORS; BIOMEDICAL FACTORS ID ALL-CAUSE MORTALITY; PHYSICAL-ACTIVITY; LIFE-STYLE; CARDIOVASCULAR-DISEASE; SITTING TIME; WHITEHALL II; VIEWING TIME; US ADULTS; OBESITY; SPENT AB Background: Sedentary behavior is associated with adverse health effects. Insights into associated determinants are essential to prevent sedentary behavior and limit health risks. Sedentary behavior should be viewed as a distinct health behavior; therefore, its determinants should be independently identified. Purpose: This study examines the prospective associations between a wide range of midlife determinants and objectively measured sedentary time in old age. Methods: Data from 565 participants (age 73-92 yr) of the AGESII-Reykjavik Study were used. Participants wore an accelerometer (ActiGraph GT3X) on the right hip for seven consecutive days. On average, 31 yr earlier (during midlife), demographic, socioeconomic, lifestyle, and biomedical factors were collected. Linear regression models were used to examine prospective associations between midlife determinants and sedentary time (<100 counts per minute) in old age. Results: After adjustment for sex, age, follow-up time, minutes of moderate to vigorous physical activity, body mass index, health status, mobility limitation, and joint pain in old age, the midlife determinants not being married, primary education, living in a duplex or living in an apartment (vs villa), being obese, and having a heart disease were associated with, on average, 15.3, 12.4, 13.5, 13.3, 21.8, and 38.9 sedentary minutes more per day in old age, respectively. Conclusions: This study shows that demographic, socioeconomic, and biomedical determinants in midlife were associated with considerably more sedentary time per day in old age. These results can indicate the possibility of predicting sedentariness in old age, which could be used to identify target groups for prevention programs reducing sedentary time in older adults. C1 [van der Berg, Julianne D.; Bosma, Hans; Koster, Annemarie] Maastricht Univ, CAPHRI Sch Publ Hlth & Primary Care, Dept Social Med, Maastricht, Netherlands. [Caserotti, Paolo] Univ Southern Denmark, Inst Sports Sci & Clin Biomech, Odense, Denmark. [Eiriksdottir, Gudny; Arnardottir, Nanna Yr; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Arnardottir, Nanna Yr; Sveinsson, Thorarinn] Univ Iceland, Res Ctr Movement Sci, Reykjavik, Iceland. [Martin, Kathryn R.; Launer, Lenore J.; Harris, Tamara B.] NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, Bethesda, MD 20892 USA. [Brychta, Robert J.; Chen, Kong Y.] NIDDK, Diabet Endocrinol & Obes Branch, Bethesda, MD 20892 USA. [Johannsson, Erlingur] Iceland Univ Educ, Ctr Sport & Hlth Sci, Laugarvatn, Iceland. [Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Jonsson, Palmi V.] Univ Iceland, Fac Med, Reykjavik, Iceland. [Jonsson, Palmi V.] Landspitali Natl Univ Hosp, Dept Geriatr, Reykjavik, Iceland. [Stehouwer, Coen D. A.] Maastricht Univ, Med Ctr, Dept Internal Med, Cardiovasc Res Inst Maastricht CARIM, Maastricht, Netherlands. RP van der Berg, JD (reprint author), POB 616, NL-6200 MD Maastricht, Netherlands. EM j.vanderberg@maastrichtuniversity.nl RI Koster, Annemarie/E-7438-2010; Gudnason, Vilmundur/K-6885-2015; Sveinsson, Thorarinn/F-7554-2010; van der Berg, Julianne/M-7172-2016; Bosma, Hans/A-6184-2013; OI Gudnason, Vilmundur/0000-0001-5696-0084; Sveinsson, Thorarinn/0000-0001-8989-5514; van der Berg, Julianne/0000-0001-9513-683X; Chen, Kong/0000-0002-0306-1904 FU National Institutes of Health [N01-AG-12100]; NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); European Union [PCIG09-GA-2011-293621] FX This study has been funded by the National Institutes of Health contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). A Koster has received funding from the European Union Seventh Framework Programme (FP7-PEOPLE-2011-CIG) under grant agreement PCIG09-GA-2011-293621. NR 32 TC 8 Z9 8 U1 3 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 EI 1530-0315 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD JUL PY 2014 VL 46 IS 7 BP 1359 EP 1365 DI 10.1249/MSS.0000000000000246 PG 7 WC Sport Sciences SC Sport Sciences GA AJ5EO UT WOS:000337705300011 PM 24389522 ER PT J AU Brochard, S Alter, K Damiano, D AF Brochard, Sylvain Alter, Katharine Damiano, Diane TI Shoulder strength profiles in children with and without brachial PLEXUS PALSY SO MUSCLE & NERVE LA English DT Article DE children; brachial plexus palsy; shoulder; strength; imbalance ID HAND-HELD DYNAMOMETER; BIRTH PALSY; MUSCLE STRENGTH; CEREBRAL-PALSY; RELIABILITY; DEFORMITY; MANAGEMENT; STABILITY; PEOPLE AB Introduction: We characterized bilateral shoulder strength and the balance of antagonist/agonist muscle pairs in children with brachial plexus palsy (BPP) and with typical development (TD). Methods: In 15 children with unilateral BPP and 11 with TD, bilateral maximal isometric shoulder strength in flexion/extension, internal/external rotation, and abduction/adduction was recorded using a hand-held dynamometer. Correlation between strength and active range of motion were evaluated using the Mallet score. Results: Children with BPP had strength asymmetry in all muscles, whereas children with TD had significant strength asymmetry for flexors and abductors. In children with BPP, extensors and external rotators were the weakest muscles, leading to sagittal and transverse plane muscle imbalances. Higher strength values were related to better active range of motion. Conclusions: This study highlights the importance of documenting shoulder strength profiles in children with BPP which may help predict deformity development. Muscle Nerve 50: 60-66, 2014 C1 [Brochard, Sylvain] CHRU Brest, Hop Morvan, F-29609 Brest, France. [Alter, Katharine; Damiano, Diane] NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. RP Brochard, S (reprint author), CHRU Brest, Hop Morvan, 5 Ave Foch, F-29609 Brest, France. EM sylvain.brochard@chu-brest.fr RI Damiano, Diane/B-3338-2010 OI Damiano, Diane/0000-0002-2770-5356 FU University Hospital of Brest; French Society of Physical Medicine and Rehabilitation (SOFMER); French Society of Research in Children with Disabilities (SFERHE); Intramural Research Program of the National Institutes of Health Clinical Center, Bethesda, MD, USA FX This work was funded by grants awarded to Dr Brochard from the University Hospital of Brest, the French Society of Physical Medicine and Rehabilitation (SOFMER), the French Society of Research in Children with Disabilities (SFERHE) and by the Intramural Research Program of the National Institutes of Health Clinical Center, Bethesda, MD, USA. NR 32 TC 6 Z9 6 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0148-639X EI 1097-4598 J9 MUSCLE NERVE JI Muscle Nerve PD JUL PY 2014 VL 50 IS 1 BP 60 EP 66 DI 10.1002/mus.24099 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AJ4IU UT WOS:000337639600008 PM 24307245 ER PT J AU Luckey, MA Kimura, MY Waldman, AT Feigenbaum, L Singer, A Park, JH AF Luckey, Megan A. Kimura, Motoko Y. Waldman, Adam T. Feigenbaum, Lionel Singer, Alfred Park, Jung-Hyun TI The transcription factor ThPOK suppresses Runx3 and imposes CD4(+) lineage fate by inducing the SOCS suppressors of cytokine signaling SO NATURE IMMUNOLOGY LA English DT Article ID CD8(+) T-CELLS; POSITIVE SELECTION; COMMITMENT; DIFFERENTIATION; THYMOCYTES; PROTEINS; CHOICE; EXPRESSION; REPRESSION; PATHWAY AB Lineage fate in the thymus is determined by mutually exclusive expression of the transcription factors ThPOK and Runx3, with ThPOK imposing the CD4(+) lineage fate and Runx3 promoting the CD8(+) lineage fate. While it is known that cytokine signals induce thymocytes to express Runx3, it is not known how ThPOK prevents thymocytes from expressing Runx3 and adopting the CD8(+) lineage fate, nor is it understood why ThPOK itself imposes the CD4(+) lineage fate on thymocytes. We now report that genes encoding members of the SOCS (suppressor of cytokine signaling) family are critical targets of ThPOK and that their induction by ThPOK represses Runx3 expression and promotes the CD4(+) lineage fate. Thus, induction of SOCS-encoding genes is the main mechanism by which ThPOK imposes the CD4(+) lineage fate in the thymus. C1 [Luckey, Megan A.; Kimura, Motoko Y.; Waldman, Adam T.; Singer, Alfred; Park, Jung-Hyun] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Feigenbaum, Lionel] Leidos Biomed Res, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Park, JH (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM parkhy@mail.nih.gov RI Park, Jung Hyun /B-5712-2015; Davis, Megan/F-5339-2015 OI Park, Jung Hyun /0000-0002-9547-9055; FU Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research FX We thank D. Singer and R. Hodes for critical review of this manuscript; R. Bosselut (National Cancer Institute) for Thpok-/- and ThPOK-Tg (C8) mice; J. Ihle (St. Jude Children's Research Hospital) for mice with germline deficiency in Socs1 and Ifng; D. Kappes (Fox Chase Cancer Center) for Thpokhd/hd mice; T. Kay (St. Vincent's Institute of Medical Research) for human CD4-Socs1 reporter mice; and M. Kubo (RIKEN) for SOCS1-Tg mice. Supported by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 28 TC 6 Z9 6 U1 2 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD JUL PY 2014 VL 15 IS 7 BP 638 EP 645 DI 10.1038/ni.2917 PG 8 WC Immunology SC Immunology GA AJ5IJ UT WOS:000337715600010 PM 24880459 ER PT J AU Steinke, FC Yu, SY Zhou, XY He, B Yang, WJ Zhou, B Kawamoto, H Zhu, J Tan, K Xue, HH AF Steinke, Farrah C. Yu, Shuyang Zhou, Xinyuan He, Bing Yang, Wenjing Zhou, Bo Kawamoto, Hiroshi Zhu, Jun Tan, Kai Xue, Hai-Hui TI TCF-1 and LEF-1 act upstream of Th-POK to promote the CD4(+) T cell fate and interact with Runx3 to silence Cd4 in CD8(+) T cells SO NATURE IMMUNOLOGY LA English DT Article ID TRANSCRIPTION FACTORS TCF-1; LINEAGE CHOICE; THYMOCYTE DIFFERENTIATION; CYTOTOXIC-LINEAGE; GENE-EXPRESSION; DEFICIENT MICE; THPOK; SPECIFICATION; COMMITMENT; REPRESSION AB The transcription factors TCF-1 and LEF-1 are essential for early T cell development, but their roles beyond the CD4(+)CD8(+) double-positive (DP) stage are unknown. By specific ablation of these factors in DP thymocytes, we demonstrated that deficiency in TCF-1 and LEF-1 diminished the output of CD4(+) T cells and redirected CD4(+) T cells to a CD8(+) T cell fate. The role of TCF-1 and LEF-1 in the CD4-versus-CD8 lineage 'choice' was mediated in part by direct positive regulation of the transcription factor Th-POK. Furthermore, loss of TCF-1 and LEF-1 unexpectedly caused derepression of CD4 expression in T cells committed to the CD8(+) lineage without affecting the expression of Runx transcription factors. Instead, TCF-1 physically interacted with Runx3 to cooperatively silence Cd4. Thus, TCF-1 and LEF-1 adopted distinct genetic 'wiring' to promote the CD4(+) T cell fate and establish CD8(+) T cell identity. C1 [Steinke, Farrah C.; Zhou, Bo; Xue, Hai-Hui] Univ Iowa, Dept Microbiol, Carver Coll Med, Iowa City, IA 52242 USA. [Steinke, Farrah C.; Xue, Hai-Hui] Univ Iowa, Carver Coll Med, Interdisciplinary Immunol Grad Program, Iowa City, IA 52242 USA. [Yu, Shuyang] China Agr Univ, Coll Biol Sci, State Key Lab Agrobiotechnol, Beijing 100094, Peoples R China. [Zhou, Xinyuan] Third Mil Med Univ, Inst Immunol, Chongqing, Peoples R China. [He, Bing] Univ Iowa, Carver Coll Med, Interdisciplinary Grad Program Genet, Iowa City, IA 52242 USA. [Yang, Wenjing; Zhu, Jun] NHLBI, Ctr Dev Biol, NIH, Bethesda, MD 20892 USA. [Kawamoto, Hiroshi] Kyoto Univ, Inst Frontier Med Sci, Dept Immunol, Kyoto, Japan. [Tan, Kai] Univ Iowa, Dept Internal Med, Carver Coll Med, Iowa City, IA 52242 USA. RP Xue, HH (reprint author), Univ Iowa, Dept Microbiol, Carver Coll Med, Iowa City, IA 52242 USA. EM hai-hui-xue@uiowa.edu FU American Cancer Society [RSG-11-161-01-MPC]; US National Institutes of Health [HL095540, AI105351, HG006130, AI007485, P30CA086862, 1S10 RR027219] FX We thank R. Bosselut (National Cancer Institute of the US National Institutes of Health) for mice expressing the transgene encoding Th-POK; S.-C. Bae (Chungbuh National University) for the Myc-tagged Runx3 expression plasmid; B.J. Fowlkes for input and discussions; Y. Wakabayashi and Y. Luo (NHLBI) for high-throughput sequencing and data processing; T. Zhao for animal husbandry; the Flow Cytometry Core facility at the University of Iowa (J. Fishbaugh, H. Vignes and G. Rasmussen) for support for cell sorting; and Radiation Core facility at the University of Iowa (A. Kalen) for mouse irradiation. Supported by the American Cancer Society (RSG-11-161-01-MPC to H.-H.X.) and the US National Institutes of Health (HL095540 and AI105351 to H.-H.X.; HG006130 to K.T.; AI007485 (for support of F.C.S.); and P30CA086862 and 1S10 RR027219 to the Flow Core Facility at the University of Iowa). The content is solely the responsibility of the authors and does not necessarily represent the official views of the US National Institutes of Health. NR 47 TC 29 Z9 30 U1 3 U2 11 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD JUL PY 2014 VL 15 IS 7 BP 646 EP 656 DI 10.1038/ni.2897 PG 11 WC Immunology SC Immunology GA AJ5IJ UT WOS:000337715600011 PM 24836425 ER PT J AU Zhu, H Pleil, KE Urban, DJ Moy, SS Kash, TL Roth, BL AF Zhu, Hu Pleil, Kristen E. Urban, Daniel J. Moy, Sheryl S. Kash, Thomas L. Roth, Bryan L. TI Chemogenetic Inactivation of Ventral Hippocampal Glutamatergic Neurons Disrupts Consolidation of Contextual Fear Memory SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID LONG-TERM-MEMORY; DIFFERENT ANTEROGRADE AMNESIAS; ANISOMYCIN-INDUCED AMNESIA; 2 TIME WINDOWS; DORSAL HIPPOCAMPUS; ADENYLYL-CYCLASE; BASOLATERAL AMYGDALA; INHIBITORY AVOIDANCE; SYNAPTIC PLASTICITY; MOLECULAR-BIOLOGY AB Synaptic consolidation is a process thought to consolidate memory in the brain. Although lesion studies have mainly implicated the hippocampus (HPC) in this process, it is unknown which cell type(s) or regions of the HPC might be essential for synaptic consolidation. To selectively and reversibly suppress hippocampal neuronal activity during this process, we developed a new Gi-DREADD (hM4Di) transgenic mouse for in vivo manipulation of neuronal activity in freely moving animals. We found that CAI pyramidal neurons could be dose-dependently inactivated by clozapine-n-oxide (CNO). Inactivation of hippocampal neurons within 6 h immediately after conditioned fear training successfully impaired the consolidation of contextual memory, without disturbing cued memory. To anatomically define the brain subregion critical for the behavioral effects, hM4Di viral vectors were transduced and selectively expressed in the glutamatergic neurons in either the dorsal or ventral HPC. Significantly, we found that selective inactivation of ventral but not dorsal glutamatergic hippocampal neurons suppressed the synaptic consolidation of contextual memory. C1 [Zhu, Hu; Pleil, Kristen E.; Urban, Daniel J.; Kash, Thomas L.; Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Pleil, Kristen E.; Kash, Thomas L.] Univ N Carolina, Sch Med, Bowles Ctr Alcohol Studies, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Moy, Sheryl S.; Roth, Bryan L.] Univ N Carolina, Carolina Inst Dev Disabil, Chapel Hill, NC 27599 USA. [Moy, Sheryl S.] Univ N Carolina, Sch Med, Dept Psychiat, Chapel Hill, NC 27599 USA. [Roth, Bryan L.] Univ N Carolina, Program Neurosci, Chapel Hill, NC 27599 USA. [Roth, Bryan L.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Roth, Bryan L.] Univ N Carolina, Sch Pharm, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA. [Roth, Bryan L.] Univ N Carolina, NIMH Psychoact Drug Screening Program, Chapel Hill, NC 27599 USA. RP Roth, BL (reprint author), Univ N Carolina, Sch Med, Dept Pharmacol, 4072 Genet Med Bldg,120 Mason Farm Rd, Chapel Hill, NC 27599 USA. EM bryan_roth@med.unc.edu RI Roth, Bryan/F-3928-2010 FU Michael Hooker Chair of Pharmacology; Confocal and Multiphoton Imaging Core of NINDS Center [P30 NS045892]; [U19MH82441]; [RO1MH61887] FX This work was supported by U19MH82441 and RO1MH61887 to Dr Roth as well as the Michael Hooker Chair of Pharmacology to Dr Roth. Imaging was supported by the Confocal and Multiphoton Imaging Core of NINDS Center Grant P30 NS045892. Dr Roth has consulted for Otsuka Pharmaceuticals, Merck, Sunovion, Albany Molecular Research, Pfizer Pharmaceuticals, Finnegan, Henderson, Farabow, Garrett And Dunner, L.I.p, Venrock, Sea Change Pharmaceuticals, and RuiYi Pharmaceuticals. Dr Roth also receives compensation for serving as Associate Editor of the Journal of Clinical Investigation. The remaining authors declare no conflict of interest. NR 61 TC 22 Z9 22 U1 1 U2 20 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 JUL PY 2014 VL 39 IS 8 BP 1880 EP 1892 DI 10.1038/npp.2014.35 PG 13 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA AJ3EZ UT WOS:000337550600010 PM 24525710 ER PT J AU Krasnova, IN Marchant, NJ Ladenheim, B McCoy, MT Panlilio, LV Bossert, JM Shaham, Y Cadet, JL AF Krasnova, Irina N. Marchant, Nathan J. Ladenheim, Bruce McCoy, Michael T. Panlilio, Leigh V. Bossert, Jennifer M. Shaham, Yavin Cadet, Jean L. TI Incubation of Methamphetamine and Palatable Food Craving after Punishment-Induced Abstinence SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID MEDIAL PREFRONTAL CORTEX; STRESS-INDUCED REINSTATEMENT; TIME-DEPENDENT CHANGES; CUE-INDUCED REINSTATEMENT; COCAINE-SEEKING; NUCLEUS-ACCUMBENS; INDUCED RELAPSE; HEROIN-SEEKING; DRUG SEEKING; RAT MODEL AB In a rat model of drug craving and relapse, cue-induced drug seeking progressively increases after withdrawal from methamphetamine and other drugs, a phenomenon termed 'incubation of drug craving'. However, current experimental procedures used to study incubation of drug craving do not incorporate negative consequences of drug use, which is a common factor promoting abstinence in humans. Here, we studied whether incubation of methamphetamine craving is observed after suppression of drug seeking by adverse consequences (punishment). We trained rats to self-administer methamphetamine or palatable food for 9 h per day for 14 days; reward delivery was paired with a tone-light cue. Subsequently, for one group within each reward type, 50% of the lever-presses were punished by mild footshock for 9-10 days, whereas for the other group lever-presses were not punished. Shock intensity was gradually increased overtime. Next, we assessed cue-induced reward seeking in 1-h extinction sessions on withdrawal days 2 and 21. Response-contingent punishment suppressed extended-access methamphetamine or food self-administration; surprisingly, food-trained rats showed greater resistance to punishment than methamphetamine-trained rats. During the relapse tests, both punished and unpunished methamphetamine- and food-trained rats showed significantly higher cue-induced reward seeking on withdrawal day 21 than on day 2. These results demonstrate that incubation of both methamphetamine and food craving occur after punishment-induced suppression of methamphetamine or palatable food self-administration. Our procedure can be used to investigate mechanisms of relapse to drug and palatable food seeking under conditions that more closely approximate the human condition. C1 [Krasnova, Irina N.; Ladenheim, Bruce; McCoy, Michael T.; Cadet, Jean L.] NIDA, Mol Neuropsychiatry Res Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. [Marchant, Nathan J.; Panlilio, Leigh V.; Bossert, Jennifer M.; Shaham, Yavin] NIDA, Behav Neurosci Res Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. [Marchant, Nathan J.] Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Parkville, Vic 3052, Australia. RP Cadet, JL (reprint author), NIDA, Mol Neuropsychiatry Res Branch, NIH, Intramural Res Program, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM jcadet@intra.nida.nih.gov OI Marchant, Nathan/0000-0001-8269-0532 FU National Institute on Drug Abuse, Intramural Research Program FX Research was supported by the National Institute on Drug Abuse, Intramural Research Program. The authors declare no conflict of interests (financial or otherwise) related to the data presented in this manuscript. NR 72 TC 21 Z9 21 U1 2 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JUL PY 2014 VL 39 IS 8 BP 2008 EP 2016 DI 10.1038/npp.2014.50 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA AJ3EZ UT WOS:000337550600022 PM 24584329 ER PT J AU Huang, MC Schwandt, ML Chester, JA Kirchhoff, AM Kao, CF Liang, TB Tapocik, JD Ramchandani, VA George, DT Hodgkinson, CA Goldman, D Heilig, M AF Huang, Ming-Chyi Schwandt, Melanie L. Chester, Julia A. Kirchhoff, Aaron M. Kao, Chung-Feng Liang, Tiebing Tapocik, Jenica D. Ramchandani, Vijay A. George, David T. Hodgkinson, Colin A. Goldman, David Heilig, Markus TI FKBP5 Moderates Alcohol Withdrawal Severity: Human Genetic Association and Functional Validation in Knockout Mice SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; CHILDHOOD TRAUMA; DELIRIUM-TREMENS; GLUCOCORTICOID-RECEPTOR; POLYMORPHISMS; DEPENDENCE; RISK; SYMPTOMS; EXPRESSION; INCREASES AB Alcohol withdrawal is associated with hypothalamic pituitary adrenal (HPA) axis dysfunction. The FKBP5 gene codes for a cochaperone, FK506-binding protein 5, that exerts negative feedback on HPA axis function. This study aimed to examine the effects of single-nucleotide polymorphisms (SNPs) of the FKBP5 gene in humans and the effect of Fkbp5 gene deletion in mice on alcohol withdrawal severity. We genotyped six FKBP5 SNPs (rs3800373, rs9296I58, rs3777747, rs9380524, rs I 360780, and rs9470080) in 399 alcohol-dependent inpatients with alcohol consumption 48 h before admission and recorded scores from the Clinical Institute Withdrawal Assessment-Alcohol revised (CIWA-Ar). Fkbp5 gene knockout (KO) and wild-type (WT) mice were assessed for alcohol withdrawal using handling-induced convulsions (HICs) following both acute and chronic alcohol exposure. We found the minor alleles of rs3800373 (G), rs9296I58 (A), rsI360780 (T), and rs9470080 (T) were significantly associated with lower CIWA-Ar scores whereas the minor alleles of rs3777747 (G) and rs9380524 (A) were associated with higher scores. The haplotype-based analyses also showed an association with alcohol withdrawal severity. Fkbp5 KO mice showed significantly greater HICs during withdrawal from chronic alcohol exposure compared with WT controls. This study is the first to show a genetic effect of FKBP5 on the severity of alcohol withdrawal syndrome. In mice, the absence of the Fkbp5 gene enhances sensitivity to alcohol withdrawal. We suggest that FKBP5 variants may trigger different adaptive changes in HPA axis regulation during alcohol withdrawal with concomitant effects on withdrawal severity. C1 [Huang, Ming-Chyi] Taipei City Hosp, Taipei City Psychiat Ctr, Dept Psychiat, Taipei, Taiwan. [Huang, Ming-Chyi] Taipei Med Univ, Sch Med, Dept Psychiat, Taipei, Taiwan. [Schwandt, Melanie L.; Tapocik, Jenica D.; Ramchandani, Vijay A.; George, David T.; Heilig, Markus] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. [Chester, Julia A.; Kirchhoff, Aaron M.; Liang, Tiebing] Purdue Univ, Dept Psychol Sci, W Lafayette, IN 47907 USA. [Chester, Julia A.; Kirchhoff, Aaron M.; Liang, Tiebing] Indiana Univ, Sch Med, Dept Med, Indianapolis, IN USA. [Kao, Chung-Feng] Coll Publ Hlth, Dept Publ Hlth, Taipei, Taiwan. [Kao, Chung-Feng] Coll Publ Hlth, Inst Epidemiol & Prevent Med, Taipei, Taiwan. [Hodgkinson, Colin A.; Goldman, David] NIAAA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA. RP Heilig, M (reprint author), NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. EM markus.heilig@mail.nih.gov RI Goldman, David/F-9772-2010; Schwandt, Melanie/L-9866-2016; OI Goldman, David/0000-0002-1724-5405; Heilig, Markus/0000-0003-2706-2482 FU NIAAA NIH HHS [P60 AA007611] NR 55 TC 15 Z9 15 U1 1 U2 9 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 JUL PY 2014 VL 39 IS 8 BP 2029 EP 2038 DI 10.1038/npp.2014.55 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA AJ3EZ UT WOS:000337550600024 PM 24603855 ER PT J AU Laughon, SK Berghella, V Reddy, UM Sundaram, R Lu, Z Hoffman, MK AF Laughon, S. Katherine Berghella, Vincenzo Reddy, Uma M. Sundaram, Rajeshwari Lu, Zhaohui Hoffman, Matthew K. TI Neonatal and Maternal Outcomes With Prolonged Second Stage of Labor SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID 2ND STAGE; NULLIPAROUS WOMEN; DURATION; MORBIDITY; TERM AB OBJECTIVE:To assess neonatal and maternal outcomes when the second stage of labor was prolonged according to American College of Obstetricians and Gynecologists guidelines.METHODS:Electronic medical record data from a retrospective cohort (2002-2008) from 12 U.S. clinical centers (19 hospitals), including 43,810 nulliparous and 59,605 multiparous singleton deliveries at 36 weeks of gestation or greater, vertex presentation, who reached 10-cm cervical dilation were analyzed. Prolonged second stage was defined as: nulliparous women with epidural greater than 3 hours and without greater than 2 hours and multiparous women with epidural greater than 2 hours and without greater than 1 hour. Maternal and neonatal outcomes were compared and adjusted odds ratios calculated controlling for maternal race, body mass index, insurance, and region.RESULTS:Prolonged second stage occurred in 9.9% and 13.9% of nulliparous and 3.1% and 5.9% of multiparous women with and without an epidural, respectively. Vaginal delivery rates with prolonged second stage compared with within guidelines were 79.9% compared with 97.9% and 87.0% compared with 99.4% for nulliparous women with and without epidural, respectively, and 88.7% compared with 99.7% and 96.2% compared with 99.9% for multiparous women with and without epidural, respectively (P<.001 for all comparisons). Prolonged second stage was associated with increased chorioamnionitis and third-degree or fourth-degree perineal lacerations. Neonatal morbidity with prolonged second stage included sepsis in nulliparous women (with epidural: 2.6% compared with 1.2% [adjusted odds ratio (OR) 2.08, 95% confidence interval (CI) 1.60-2.70]; without epidural: 1.8% compared with 1.1% [adjusted OR 2.34, 95% CI 1.28-4.27]); asphyxia in nulliparous women with epidural (0.3% compared with 0.1% [adjusted OR 2.39, 95% CI 1.22-4.66]) and perinatal mortality without epidural (0.18% compared with 0.04% for nulliparous women [adjusted OR 5.92, 95% CI 1.43-24.51]); and 0.21% compared with 0.03% for multiparous women (adjusted OR 6.34, 95% CI 1.32-30.34). However, among the offspring of women with epidurals whose second stage was prolonged (3,533 nulliparous and 1,348 multiparous women), there were no cases of hypoxic-ischemic encephalopathy or perinatal death.CONCLUSIONS:Benefits of increased vaginal delivery should be weighed against potential small increases in maternal and neonatal risks with prolonged second stage. C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, NIH, Bethesda, MD 20892 USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, NIH, Bethesda, MD 20892 USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Glotech Inc, Div Intramural Populat Hlth Res, NIH, Bethesda, MD 20892 USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, NIH, Bethesda, MD 20892 USA. Thomas Jefferson Univ, Div Maternal Fetal Med, Dept Obstet & Gynecol, Philadelphia, PA 19107 USA. Christiana Care Hlth Syst, Div Res & Educ, Dept Obstet & Gynecol, Newark, DE USA. RP Laughon, SK (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd Room 7B03, Bethesda, MD 20892 USA. EM laughonsk@mail.nih.gov OI Sundaram, Rajeshwari/0000-0002-6918-5002; Grantz, Katherine/0000-0003-0276-8534; Berghella, Vincenzo/0000-0003-2854-0239 FU Intramural Research Program of the National Institutes ofHealth, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Intramural Research Program of the NICHD [HHSN267200603425C] FX Supported by the Intramural Research Program of the National Institutes ofHealth, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). The Consortium on Safe Labor was funded by the Intramural Research Program of the NICHD through Contract No. HHSN267200603425C. NR 20 TC 30 Z9 31 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 EI 1873-233X J9 OBSTET GYNECOL JI Obstet. Gynecol. PD JUL PY 2014 VL 124 IS 1 BP 57 EP 67 DI 10.1097/AOG.0000000000000278 PG 11 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AJ5OK UT WOS:000337734000010 PM 24901265 ER PT J AU Maheshwari, A Schelonka, RL Dimmitt, RA Carlo, WA Munoz-Hernandez, B Das, A McDonald, SA Thorsen, P Skogstrand, K Hougaard, DM Higgins, RD AF Maheshwari, Akhil Schelonka, Robert L. Dimmitt, Reed A. Carlo, Waldemar A. Munoz-Hernandez, Breda Das, Abhik McDonald, Scott A. Thorsen, Poul Skogstrand, Kristin Hougaard, David M. Higgins, Rosemary D. CA Eunice Kennedy Shriver Natl Inst C TI Cytokines associated with necrotizing enterocolitis in extremely-low-birth-weight infants SO PEDIATRIC RESEARCH LA English DT Article ID GROWTH-FACTOR-BETA; PATHOGENETIC CONCEPTS; BINDING-PROTEIN; PRETERM INFANTS; INFLAMMATION; OUTCOMES; NEWBORN; PLASMA; INTESTINE; MARKERS AB BACKGROUND: The goal was to identify cytokines associated with necrotizing enterocolitis (NEC). Based on our earlier reports of decreased tissue expression of transforming growth factor (TGF)-beta, we hypothesized that infants with NEC also have low blood TGF-beta levels. We further hypothesized that because fetal inflammation increases the risk of NEC, infants who develop NEC have elevated blood cytokine levels in early neonatal period. METHODS: Data on 104 extremely-low-birth-weight infants with NEC and 893 without NEC from 17 centers were analyzed. Clinical information was correlated with blood cytokine levels on postnatal day 1 (D1), D3, D7, D14, and D21. RESULTS: Male gender, non-Caucasian/non-African American ethnicity, sepsis, lower blood TGF-beta and interleukin (IL)-2 levels, and higher IL-8 levels were associated with NEC. The NEC group had lower TGF-beta levels than controls since D1. The diagnosis of NEC was associated with elevated IL-1 beta, IL-6, IL-8, IL-10, monocyte chemoattractant protein-1/CC-motif ligand-2, macrophage inflammatory protein-1 beta/CC-motif ligand-3, and C-reactive protein. CONCLUSION: Clinical characteristics, such as gender and ethnicity, and low blood TGF-beta levels are associated with higher risk of NEC. Infants who developed NEC did not start with high blood levels of inflammatory cytokines, but these rose mainly after the onset of NEC. C1 [Maheshwari, Akhil; Schelonka, Robert L.; Dimmitt, Reed A.; Carlo, Waldemar A.] Univ Alabama Birmingham, Dept Pediat, Birmingham, AL 35294 USA. [Maheshwari, Akhil] Univ Illinois, Dept Pediat, Chicago, IL USA. [Schelonka, Robert L.] Oregon Hlth & Sci Univ, Dept Pediat, Portland, OR 97201 USA. [Munoz-Hernandez, Breda; Das, Abhik; McDonald, Scott A.] RTI Int, Stat & Epidemiol Unit, Res Triangle Pk, NC USA. [Thorsen, Poul] Lillebaelt Hosp, Dept Obstet & Gynecol, Kolding, Denmark. [Skogstrand, Kristin; Hougaard, David M.] Statens Serum Inst, Dept Clin Biochem & Immunol, DK-2300 Copenhagen, Denmark. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Maheshwari, A (reprint author), Univ Alabama Birmingham, Dept Pediat, Birmingham, AL 35294 USA. EM akhil1@uic.edu OI Skogstrand, Kristin/0000-0002-0026-3711 FU National Institutes of Health (NIH), Bethesda, MD (General Clinical Research Center) [M01 RR30, M01 RR32, M01 RR39, M01 RR70, M01 RR80, M01 RR633, M01 RR750, M01 RR997, M01 RR6022, M01 RR7122, M01 RR8084, M01 RR16587]; Eunice Kennedy Shriver National Institute of Child Health and Human Development; NIH [U01 HD36790, U10 HD21364, U10 HD21373, U10 HD21385, U10 HD21397, U10 HD21415, U10 HD27851, U10 HD27853, U10 HD27856, U10 HD27871, U10 HD27880, U10 HD27881, U10 HD27904, U10 HD34216, U10 HD40461, U10 HD40492, U10 HD40498, U10 HD40689, R01HD059142]; US Centers for Disease Control and Prevention, Atlanta, GA [Y1-HD-5000-01] FX The National Institutes of Health (NIH), Bethesda, MD (General Clinical Research Center grants M01 RR30, M01 RR32, M01 RR39, M01 RR70, M01 RR80, M01 RR633, M01 RR750, M01 RR997, M01 RR6022, M01 RR7122, M01 RR8084, M01 RR16587), Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH (grants U01 HD36790, U10 HD21364, U10 HD21373, U10 HD21385, U10 HD21397, U10 HD21415, U10 HD27851, U10 HD27853, U10 HD27856, U10 HD27871, U10 HD27880, U10 HD27881,U10 HD27904, U10 HD34216, U10 HD40461, U10 HD40492, U10 HD40498, U10 HD40689), and the US Centers for Disease Control and Prevention, Atlanta, GA (interagency agreement Y1-HD-5000-01) provided grant support for recruitment during 1999-2001 and data analysis for the Neonatal Research Network's Cytokine Study. The funding agencies provided overall oversight for study conduct, but all data analysis and interpretation were independent of the funding agencies. The study was made possible in part by the NIH grant R01HD059142 (awarded to A.M.). NR 40 TC 25 Z9 26 U1 1 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0031-3998 EI 1530-0447 J9 PEDIATR RES JI Pediatr. Res. PD JUL PY 2014 VL 76 IS 1 BP 100 EP 108 DI 10.1038/pr.2014.48 PG 9 WC Pediatrics SC Pediatrics GA AJ4RQ UT WOS:000337663900014 PM 24732104 ER PT J AU Bereszczak, JZ Watts, NR Wingfield, PT Steven, AC Heck, AJR AF Bereszczak, Jessica Z. Watts, Norman R. Wingfield, Paul T. Steven, Alasdair C. Heck, Albert J. R. TI Assessment of differences in the conformational flexibility of hepatitis B virus core-antigen and e-antigen by hydrogen deuterium exchange-mass spectrometry SO PROTEIN SCIENCE LA English DT Article DE hepatitis B virus; e-antigen; hydrogen deuterium exchange mass spectrometry; EX1 kinetics ID OF-FLIGHT INSTRUMENT; CAPSID PROTEIN; ELECTRON CRYOMICROSCOPY; VIRAL REPLICATION; ESCHERICHIA-COLI; PRECORE-REGION; RESOLUTION; DYNAMICS; SERUM; IDENTIFICATION AB Hepatitis B virus core-antigen (capsid protein) and e-antigen (an immune regulator) have almost complete sequence identity, yet the dimeric proteins (termed Cp149d and Cp(-10)149d, respectively) adopt quite distinct quaternary structures. Here we use hydrogen deuterium exchange-mass spectrometry (HDX-MS) to study their structural properties. We detect many regions that differ substantially in their HDX dynamics. Significantly, whilst all regions in Cp(-10)149d exchange by EX2-type kinetics, a number of regions in Cp149d were shown to exhibit a mixture of EX2- and EX1-type kinetics, hinting at conformational heterogeneity in these regions. Comparison of the HDX of the free Cp149d with that in assembled capsids (Cp149c) indicated increased resistance to exchange at the C-terminus where the inter-dimer contacts occur. Furthermore, evidence of mixed exchange kinetics were not observed in Cp149c, implying a reduction in flexibility upon capsid formation. Cp(-10)149d undergoes a drastic structural change when the intermolecular disulphide bridge is reduced, adopting a Cp149d-like structure, as evidenced by the detected HDX dynamics being more consistent with Cp149d in many, albeit not all, regions. These results demonstrate the highly dynamic nature of these similar proteins. To probe the effect of these structural differences on the resulting antigenicity, we investigated binding of the antibody fragment (Fab E1) that is known to bind a conformational epitope on the four-helix bundle. Whilst Fab E1 binds to Cp149c and Cp149d, it does not bind non-reduced and reduced Cp(-10)149d, despite unhindered access to the epitope. These results imply a remarkable sensitivity of this epitope to its structural context. C1 [Bereszczak, Jessica Z.; Heck, Albert J. R.] Univ Utrecht, Bijvoet Ctr Biomol Res, NL-3584 CH Utrecht, Netherlands. [Bereszczak, Jessica Z.; Heck, Albert J. R.] Univ Utrecht, Utrecht Inst Pharmaceut Sci, NL-3584 CH Utrecht, Netherlands. [Bereszczak, Jessica Z.; Heck, Albert J. R.] Netherlands Prote Ctr, Utrecht, Netherlands. [Watts, Norman R.; Wingfield, Paul T.] NIAMSD, Prot Express Lab, NIH, Bethesda, MD 20892 USA. [Steven, Alasdair C.] NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. RP Heck, AJR (reprint author), Univ Utrecht, Bijvoet Ctr Biomol Res, Padualaan 8, NL-3584 CH Utrecht, Netherlands. EM a.j.r.heck@uu.nl RI Heck, Albert/D-7098-2011 OI Heck, Albert/0000-0002-2405-4404 FU Netherlands Organization for Scientific Research (NWO); ALW-ECHO [819.02.10]; Netherlands Proteomics Centre; Netherlands Genomics Initiative; Intramural Research Program of the National Institute of Arthritis, Musculoskeletal and Skin Diseases at the National Institutes of Health FX Grant sponsor: Netherlands Organization for Scientific Research (NWO) with ALW-ECHO; Grant number: 819.02.10; Grant sponsor: Netherlands Proteomics Centre, embedded in the Netherlands Genomics Initiative, Intramural Research Program of the National Institute of Arthritis, Musculoskeletal and Skin Diseases at the National Institutes of Health. NR 72 TC 8 Z9 8 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD JUL PY 2014 VL 23 IS 7 BP 884 EP 896 DI 10.1002/pro.2470 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AJ4TS UT WOS:000337669800004 PM 24715628 ER PT J AU Israeli, M Roelen, DL Carrington, M Petersdorf, EW Claas, FHJ Oudshoorn, M AF Israeli, Moshe Roelen, Dave L. Carrington, Mary Petersdorf, Effie W. Claas, Frans H. J. Oudshoorn, Machteld TI ASSOCIATION BETWEEN CTL PRECURSOR FREQUENCY TO HLA-C MISMATCHES AND HLA-C ANTIGEN CELL SURFACE EXPRESSION SO TISSUE ANTIGENS LA English DT Meeting Abstract CT 28th EFI European Immunogenetics and Histocompatibility Conference CY JUN 25-28, 2014 CL Stockholm, SWEDEN SP EFI C1 [Israeli, Moshe; Roelen, Dave L.; Claas, Frans H. J.] Leiden Univ, Med Ctr, Leiden, Netherlands. [Carrington, Mary] NCI, Frederick, MD 21701 USA. [Petersdorf, Effie W.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Oudshoorn, Machteld] Europdonor Fdn, Leiden, Netherlands. EM israelimoshe@yahoo.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0001-2815 EI 1399-0039 J9 TISSUE ANTIGENS JI Tissue Antigens PD JUL PY 2014 VL 84 IS 1 BP 42 EP 42 PG 1 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA AJ3DN UT WOS:000337546000088 ER PT J AU Kuranov, AB Vavilov, MN Akilzhanova, AR Nurkina, ZM Tarlykov, PV Zholdybayeva, EV Muller, CA Momynaliev, KT AF Kuranov, Alexandr B. Vavilov, Mikhail N. Akilzhanova, Ainur R. Nurkina, Zhannur M. Tarlykov, Pavel V. Zholdybayeva, Elena V. Mueller, Claudia A. Momynaliev, Kuvat T. TI HLA-DRB1 CLASS II GENES IN NAIMANS FROM EAST KAZAKHSTAN SO TISSUE ANTIGENS LA English DT Meeting Abstract CT 28th EFI European Immunogenetics and Histocompatibility Conference CY JUN 25-28, 2014 CL Stockholm, SWEDEN SP EFI C1 [Kuranov, Alexandr B.; Mueller, Claudia A.] Univ Tubingen, Tubingen, Germany. [Vavilov, Mikhail N.] Chelyabinsk Reg Blood Ctr, Chelyabinsk, Russia. [Akilzhanova, Ainur R.; Nurkina, Zhannur M.; Tarlykov, Pavel V.; Zholdybayeva, Elena V.; Momynaliev, Kuvat T.] Natl Biotechnol Ctr, Astana, Kazakhstan. EM iskander.kuranov@gmail.com RI Tarlykov, Pavel/C-2587-2012 OI Tarlykov, Pavel/0000-0003-2075-307X NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0001-2815 EI 1399-0039 J9 TISSUE ANTIGENS JI Tissue Antigens PD JUL PY 2014 VL 84 IS 1 BP 137 EP 137 PG 1 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA AJ3DN UT WOS:000337546000332 ER PT J AU Kuranov, AB Vavilov, MN Abisheva, ST Muller, CA Momynaliev, KT AF Kuranov, Alexandr B. Vavilov, Mikhail N. Abisheva, Saule T. Mueller, Claudia A. Momynaliev, Kuvat T. TI ASSOCIATION OF HLA-DRB1 ALLELES WITH RHEUMATOID ARTHRITIS IN KAZAKH POPULATION SO TISSUE ANTIGENS LA English DT Meeting Abstract CT 28th EFI European Immunogenetics and Histocompatibility Conference CY JUN 25-28, 2014 CL Stockholm, SWEDEN SP EFI C1 [Kuranov, Alexandr B.; Mueller, Claudia A.] Univ Tubingen, Tubingen, Germany. [Vavilov, Mikhail N.] Chelyabinsk Reg Blood Ctr, Chelyabinsk, Russia. [Abisheva, Saule T.] Sci Res Inst Traumatol & Orthoped, Astana, Kazakhstan. [Momynaliev, Kuvat T.] Natl Biotechnol Ctr, Astana, Kazakhstan. EM iskander.kuranov@gmail.com NR 0 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0001-2815 EI 1399-0039 J9 TISSUE ANTIGENS JI Tissue Antigens PD JUL PY 2014 VL 84 IS 1 BP 153 EP 153 PG 1 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA AJ3DN UT WOS:000337546000373 ER PT J AU Ellis, RJ Patel, D Prodanov, T Nilubol, N Pacak, K Kebebew, E AF Ellis, Ryan J. Patel, Dhaval Prodanov, Tamara Nilubol, Naris Pacak, Karel Kebebew, Electron TI The Presence of SDHB Mutations Should Modify Surgical Indications for Carotid Body Paragangliomas SO ANNALS OF SURGERY LA English DT Article DE carotid body tumor; genetics; metastasis; paraganglioma; surgery ID MALIGNANT PHEOCHROMOCYTOMA; NECK PARAGANGLIOMAS; GENE-MUTATIONS; HEAD; CARRIERS AB Objective: The aim of this study was to determine whether the genetic background of the disease should be incorporated into treatment decision making. Background: Carotid body paragangliomas are rare tumors that often affect patients with genetic mutations of the succinate dehydrogenase complex (SDHx). Despite growing evidence that germ line genetic mutations alter the aggressiveness of paragangliomas, treatment decisions are currently based only on clinical symptoms and tumor size in patients with carotid body paragangliomas. Methods: Retrospective analysis of 34 patients with carotid body paragangliomas who underwent genetic testing and surgical treatment. Recurrence was defined by the return of locoregional disease and/or development of distant metastases. Clinical characteristics and genetic testing results were analyzed as predictors of patient outcomes. Results: Thirty-four patients underwent 41 primary carotid body paraganglioma resections (median follow-up time of 42 months, range: 1-293). Overall survival was 91.2%. Twelve patients had germ line mutations in SDHB, 17 in SDHD, and 5 carried no known mutation. Surgical resection of larger tumors was associated with higher operative complications (odds ratio: 5.4, P = 0.05). Tumor size at resection was significantly smaller in patients with SDHB mutations than in patients with non-SDHB mutations (2.1 vs 3.3 cm, P = 0.02). Patients with a mutation in the SDHB gene also had significantly worse disease-free survival compared with patients without an SDHB gene mutation (P = 0.03). Conclusions: Mutations in the SDHB gene are associated with worse disease-free survival after resection in patients with carotid body paragangliomas despite earlier intervention. This suggests that a more aggressive surgical approach is warranted in patients with SDHB mutations. C1 [Ellis, Ryan J.; Patel, Dhaval; Nilubol, Naris; Kebebew, Electron] NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. [Ellis, Ryan J.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Prodanov, Tamara; Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. RP Kebebew, E (reprint author), NCI, Endocrine Oncol Branch, NIH, Bldg 10-CRC,Room 3-5581, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov OI Patel, Dhaval/0000-0002-5744-568X FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX Supported by the intramural research program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. The authors declare no conflicts of interest. NR 24 TC 10 Z9 11 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD JUL PY 2014 VL 260 IS 1 BP 158 EP 162 DI 10.1097/SLA.0000000000000283 PG 5 WC Surgery SC Surgery GA AI9XD UT WOS:000337297900025 PM 24169168 ER PT J AU Saba, N Wiestner, A AF Saba, Nakhle Wiestner, Adrian TI Do mantle cell lymphomas have an 'Achilles heel'? SO CURRENT OPINION IN HEMATOLOGY LA English DT Review DE B-cell lymphoma 2; B-cell receptor; cyclin-D1; ibrutinib; mantle cell lymphoma ID CHRONIC LYMPHOCYTIC-LEUKEMIA; BRUTON TYROSINE KINASE; NON-HODGKIN-LYMPHOMA; CYCLIN D1; BORTEZOMIB RESISTANCE; ANTICANCER THERAPY; ANTITUMOR-ACTIVITY; TARGETING BTK; PHASE-II; INHIBITION AB Purpose of review Mantle cell lymphoma (MCL) is a mature B-cell malignancy that continues to have a high mortality rate. In this article, we discuss key pathogenic pathways in MCL biology and their possible therapeutic targeting. Recent findings In addition to cyclin-D1, the transcription factor SOX-11 emerged as a common characteristic of MCL. Genomic studies have identified a number of recurrently mutated genes; in order of descending frequency these include ATM, CCND1, UBR5, TP53, BIRC3, NOTCH1/2 and TRAF2. However, no clear oncogenic driver has been identified. In contrast, several observations indicate that MCL cells are antigen-experienced cells and that the tumor microenvironment and B-cell receptor engagement are important. This is underscored by the impressive clinical responses achieved with the Bruton's tyrosine kinase inhibitor ibrutinib. Recently identified activating mutations in the noncanonical nuclear factor-kappa B pathway could give rise to ibrutinib resistance. Poly-ADP ribose polymerase and aurora kinase inhibitors may be synthetic lethal with the common aberrations in DNA damage pathways found in MCL. Also, ABT-199, a potent and selective inhibitor of B-cell lymphoma 2, has promising activity in early studies. Summary MCL is a heterogeneous disease, and no single Achilles heel has been identified. Nevertheless, genomic, molecular and clinical studies have revealed vulnerabilities that can be exploited for effective therapy. C1 [Saba, Nakhle; Wiestner, Adrian] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Wiestner, A (reprint author), NHLBI, Lymphoid Malignancies Sect, Hematol Branch, NIH, Bld 10,CRC 3-5140,10 Ctr Dr, Bethesda, MD 20892 USA. EM wiestnea@nhlbi.nih.gov FU intramural research program of the Heart, Lung, and Blood Institute, National Institutes of Health FX The authors are supported by the intramural research program of the Heart, Lung, and Blood Institute, National Institutes of Health. NR 61 TC 6 Z9 6 U1 2 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1065-6251 EI 1531-7048 J9 CURR OPIN HEMATOL JI Curr. Opin. Hematol. PD JUL PY 2014 VL 21 IS 4 BP 350 EP 357 DI 10.1097/MOH.0000000000000057 PG 8 WC Hematology SC Hematology GA AI8IJ UT WOS:000337155600014 PM 24857884 ER PT J AU Wang, Y Yue, XY Kiesewetter, DO Niu, G Teng, GJ Chen, XY AF Wang, Yu Yue, Xuyi Kiesewetter, Dale O. Niu, Gang Teng, Gaojun Chen, Xiaoyuan TI PET imaging of neuroinflammation in a rat traumatic brain injury model with radiolabeled TSPO ligand DPA-714 SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Article DE Traumatic brain injury (TBI); Translocator protein (TSPO); [F-18]DPA-714; PET; Molecular imaging ID PERIPHERAL BENZODIAZEPINE-RECEPTOR; POSITRON-EMISSION-TOMOGRAPHY; TRANSLOCATOR PROTEIN; IN-VIVO; ACTIVATED MICROGLIA; NERVOUS-SYSTEM; ASTROCYTES; EXPRESSION; ALZHEIMERS; DISEASE AB Purpose The inflammatory response in injured brain parenchyma after traumatic brain injury (TBI) is crucial in the pathological process. In order to follow microglia activation and neuroinflammation after TBI, we performed PET imaging in a rat model of TBI using F-18-labeled DPA-714, a ligand of the 18-kDa translocator protein (TSPO). Methods TBI was induced in male SD rats by a controlled cortical impact. The success of the TBI model was confirmed by MRI. [F-18]DPA-714 was synthesized using a slightly modified TRACERLab FX-FN module and an automated procedure. In vivo PET imaging was performed at different time points after surgery using an Inveon small-animal PET scanner. The specificity of [F-18]DPA-714 was confirmed by a displacement study with an unlabeled competitive TSPO ligand, PK11195. Ex vivo autoradiography as well as immunofluorescence staining was carried out to confirm the in vivo PET results. Results Both in vivo T-2-weighted MR images and ex vivo TTC staining results revealed successful establishment of the TBI model. Compared with the sham-treated group, [F-18]DPA-714 uptake was significantly higher in the injured brain area on PET images. Increased lesion-to-normal ratios of [F-18]DPA-714 were observed in the brain of TBI rats on day 2 after surgery. Ratios peaked around day 6 (2.65 +/- 0.36) and then decreased gradually to nearly normal levels on day 28. The displacement study using PK11195 confirmed the specific binding of [F-18]DPA-714 to TSPO. The results of ex vivo autoradiography were consistent with in vivo PET results. Immunofluorescence staining showed the time course of TSPO expression after TBI and the temporal and the spatial distribution of microglia in the damaged brain area. Conclusion TSPO-targeted PET using [F-18]DPA-714 as the imaging probe can be used to dynamically monitor the inflammatory response after TBI in a noninvasive manner. This method will not only facilitate a better understanding of the inflammatory process after TBI, but also provide a useful in vivo monitoring strategy for antiinflammation therapy of TBI. C1 [Wang, Yu; Teng, Gaojun] Southeast Univ, Jiangsu Key Lab Mol Imaging & Funct Imaging, Dept Radiol, Zhongda Hosp,Med Sch, Nanjing 210009, Jiangsu, Peoples R China. [Wang, Yu; Yue, Xuyi; Kiesewetter, Dale O.; Niu, Gang; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. RP Teng, GJ (reprint author), 87 Dingjiaqiao Rd, Nanjing 210009, Jiangsu, Peoples R China. EM niug@mail.nih.gov; gjteng@vip.sina.com; shawn.chen@nih.gov FU National Basic Research Program of China (973 program) [2013CB733803, 2013CB733802]; Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH) FX This work was supported by the National Basic Research Program of China (973 program, 2013CB733803, 2013CB733802), and the Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH). NR 34 TC 14 Z9 14 U1 1 U2 18 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1619-7070 EI 1619-7089 J9 EUR J NUCL MED MOL I JI Eur. J. Nucl. Med. Mol. Imaging PD JUL PY 2014 VL 41 IS 7 BP 1440 EP 1449 DI 10.1007/s00259-014-2727-5 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AI9UR UT WOS:000337286200020 PM 24615467 ER PT J AU Coleman, CN AF Coleman, C. Norman TI Bringing Cancer Care to the Underserved Globally: A Challenging Problem for Which Radiation Oncology Can Pioneer Novel Solutions SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID NONCOMMUNICABLE DISEASES; INCOME COUNTRIES; HEALTH C1 [Coleman, C. Norman] Int Canc Expert Corps, Chevy Chase, MD USA. [Coleman, C. Norman] Int Canc Expert Corps, Wilmington, DE USA. RP Coleman, CN (reprint author), NCI, Div Canc Treatment & Diag, EPN Room 6014,6130 Execut Blvd, Bethesda, MD 20892 USA. EM ccoleman@mail.nih.gov NR 13 TC 8 Z9 8 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 1 PY 2014 VL 89 IS 3 BP 443 EP 445 DI 10.1016/j.ijrobp.2014.04.002 PG 3 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AI9AX UT WOS:000337219400002 PM 24929152 ER PT J AU Burkeen, J Coleman, CN Daphtary, M Vikram, B AF Burkeen, Jeffrey Coleman, C. Norman Daphtary, Maithili Vikram, Bhadrasain TI The Medical Student Perspective on Global Health Care in Radiation Oncology: Opportunities, Barriers to Sustainability, and Future Directions SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID MIDDLE-INCOME COUNTRIES; RADIOTHERAPY C1 [Burkeen, Jeffrey] Texas A&M Univ, Sch Med, Bryan, TX USA. [Coleman, C. Norman; Daphtary, Maithili; Vikram, Bhadrasain] NCI, Radiat Res Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Burkeen, Jeffrey; Coleman, C. Norman] NCI, Radiat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Burkeen, J (reprint author), NCI, Bldg 10 Hatfield CRC,Room B2-3561, Bethesda, MD 20892 USA. EM ccoleman@mail.nih.gov NR 10 TC 3 Z9 3 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 1 PY 2014 VL 89 IS 3 BP 492 EP 494 DI 10.1016/j.ijrobp.2013.10.013 PG 3 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AI9AX UT WOS:000337219400011 PM 24929160 ER PT J AU Li, BS Tsoi, LC Swindell, WR Gudjonsson, JE Tejasvi, T Johnston, A Ding, J Stuart, PE Xing, XY Kochkodan, JJ Voorhees, JJ Kang, HM Nair, RP Abecasis, GR Elder, JT AF Li, Bingshan Tsoi, Lam C. Swindell, William R. Gudjonsson, Johann E. Tejasvi, Trilokraj Johnston, Andrew Ding, Jun Stuart, Philip E. Xing, Xianying Kochkodan, James J. Voorhees, John J. Kang, Hyun M. Nair, Rajan P. Abecasis, Goncalo R. Elder, James T. TI Transcriptome Analysis of Psoriasis in a Large Case-Control Sample: RNA-Seq Provides Insights into Disease Mechanisms SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID FOLLICLE STEM-CELLS; GENE-EXPRESSION; HAIR FOLLICLE; EPIDERMAL DIFFERENTIATION; TUMOR SUSCEPTIBILITY; HUMAN KERATINOCYTES; NETWORK ANALYSIS; INNATE IMMUNITY; T-CELL; SKIN AB To increase our understanding of psoriasis, we used high-throughput complementary DNA sequencing (RNA-seq) to assay the transcriptomes of lesional psoriatic and normal skin. We sequenced polyadenylated RNA-derived complementary DNAs from 92 psoriatic and 82 normal punch biopsies, generating an average of similar to 38 million single-end 80-bp reads per sample. Comparison of 42 samples examined by both RNA-seq and microarray revealed marked differences in sensitivity, with transcripts identified only by RNA-seq having much lower expression than those also identified by microarray. RNA-seq identified many more differentially expressed transcripts enriched in immune system processes. Weighted gene coexpression network analysis (WGCNA) revealed multiple modules of coordinately expressed epidermal differentiation genes, overlapping significantly with genes regulated by the long noncoding RNA TINCR, its target gene, staufen-1 (STAU1), the p63 target gene ZNF750, and its target KLF4. Other coordinately expressed modules were enriched for lymphoid and/or myeloid signature transcripts and genes induced by IL-17 in keratinocytes. Dermally expressed genes were significantly downregulated in psoriatic biopsies, most likely because of expansion of the epidermal compartment. These results show the power of WGCNA to elucidate gene regulatory circuits in psoriasis, and emphasize the influence of tissue architecture in both differential expression and coexpression analysis. C1 [Li, Bingshan] Vanderbilt Univ, Dept Mol Physiol & Biophys, Ctr Human Genet Res, Nashville, TN 37232 USA. [Li, Bingshan; Tsoi, Lam C.; Ding, Jun; Kang, Hyun M.; Abecasis, Goncalo R.] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Swindell, William R.; Gudjonsson, Johann E.; Tejasvi, Trilokraj; Johnston, Andrew; Stuart, Philip E.; Xing, Xianying; Kochkodan, James J.; Voorhees, John J.; Nair, Rajan P.; Elder, James T.] Univ Michigan, Dept Dermatol, Ann Arbor, MI 48109 USA. [Tejasvi, Trilokraj; Elder, James T.] Univ Michigan, Ann Arbor Vet Affairs Hosp, Ann Arbor, MI 48109 USA. [Ding, Jun] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. RP Elder, JT (reprint author), Univ Michigan, Sch Med, 7412 Med Sci Bldg 1,1301 E Catherine, Ann Arbor, MI 48109 USA. EM goncalo@umich.edu; jelder@umich.edu OI Johnston, Andrew/0000-0002-1313-9402; Tsoi, Lam Cheung/0000-0003-1627-5722 FU NIH [R01 AR042742, R01 AR050511, AR054966, K08 AR060802, K01 AR064765-01]; Ann Arbor Veterans Affairs Hospital; Dermatology Foundation; Frances and Kenneth Eisenberg Emerging Scholar Fund; National Psoriasis Foundation; Dawn and Dudley Holmes Memorial Fund; Babcock Endowment Fund FX We thank the many volunteers who provided skin biopsies for this study. This research was supported by NIH grants R01 AR042742, R01 AR050511, and AR054966 to JTE, K08 AR060802 to JEG, and K01 AR064765-01 to AJ. JTE and TT are supported by the Ann Arbor Veterans Affairs Hospital, AJ is supported by the Dermatology Foundation, and JEG is supported by the Frances and Kenneth Eisenberg Emerging Scholar Fund and the National Psoriasis Foundation. We also acknowledge generous support from the Dawn and Dudley Holmes Memorial Fund and the Babcock Endowment Fund to the Department of Dermatology at the University of Michigan. NR 82 TC 50 Z9 51 U1 5 U2 39 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD JUL PY 2014 VL 134 IS 7 BP 1828 EP 1838 DI 10.1038/jid.2014.28 PG 11 WC Dermatology SC Dermatology GA AJ0IA UT WOS:000337333000011 PM 24441097 ER PT J AU Kocarnik, JM Park, SL Han, JL Dumitrescu, L Cheng, I Wilkens, LR Schumacher, FR Kolonel, L Carlson, CS Crawford, DC Goodloe, RJ Dilks, H Baker, P Richardson, D Ambite, JL Song, FJ Quresh, AA Zhang, MF Duggan, D Hutter, C Hindorff, LA Bush, WS Kooperberg, C Le Marchand, L Peters, U AF Kocarnik, Jonathan M. Park, Sungshim Lani Han, Jiali Dumitrescu, Logan Cheng, Iona Wilkens, Lynne R. Schumacher, Fredrick R. Kolonel, Laurence Carlson, Chris S. Crawford, Dana C. Goodloe, Robert J. Dilks, Holli Baker, Paxton Richardson, Danielle Ambite, Jose Luis Song, Fengju Quresh, Abrar A. Zhang, Mingfeng Duggan, David Hutter, Carolyn Hindorff, Lucia A. Bush, William S. Kooperberg, Charles Le Marchand, Loic Peters, Ulrike TI Replication of Associations between GWAS SNPs and Melanoma Risk in the Population Architecture Using Genomics and Epidemiology (PAGE) Study SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Letter ID WIDE ASSOCIATION; MALIGNANT-MELANOMA; HUMAN MELANOCYTES; PIGMENTATION; VARIANTS; GENE; POLYMORPHISMS; LOCI C1 [Kocarnik, Jonathan M.; Carlson, Chris S.; Kooperberg, Charles; Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Park, Sungshim Lani; Wilkens, Lynne R.; Kolonel, Laurence; Le Marchand, Loic] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. [Han, Jiali; Song, Fengju] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Lab,Dept Med, Boston, MA 02115 USA. [Han, Jiali] Indiana Univ, Simon Canc Ctr, Fairbanks Sch Publ Hlth, Dept Epidemiol, Indianapolis, IN 46204 USA. [Dumitrescu, Logan; Crawford, Dana C.; Goodloe, Robert J.; Dilks, Holli; Baker, Paxton; Richardson, Danielle; Bush, William S.] Vanderbilt Univ, Ctr Human Genet Res, Nashville, TN 37235 USA. [Dumitrescu, Logan; Crawford, Dana C.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Cheng, Iona] Canc Prevent Inst Calif, Fremont, CA USA. [Schumacher, Fredrick R.] Univ So Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA 90033 USA. [Ambite, Jose Luis] Univ So Calif, Inst Informat Sci, Marina Del Rey, CA 90292 USA. [Song, Fengju] Tianjin Med Univ Canc Inst & Hosp, Dept Epidemiol, Tianjin, Peoples R China. [Quresh, Abrar A.; Zhang, Mingfeng] Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA. [Duggan, David] Translat Genom Res Inst, Phoenix, AZ USA. [Hutter, Carolyn] NCI, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Hindorff, Lucia A.] NHGRI, Div Genom Med, NIH, Bethesda, MD 20892 USA. [Bush, William S.] Vanderbilt Univ, Dept Biomed Informat, Nashville, TN 37235 USA. RP Kocarnik, JM (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. EM jkocarni@fhcrc.org; upeters@fhcrc.org OI Bush, William/0000-0002-9729-6519 FU NCATS NIH HHS [UL1 TR000445]; NCI NIH HHS [P01 CA033619, P01 CA055075, T32 CA009168, R01 CA122838, R01 CA049449, U01 CA098758, P30 CA071789, P01CA33619, P50 CA093459, P01 CA087969, P30 CA015704, R01 CA063464, R01 CA100264, R01 CA63464, R25 CA094880, R37 CA054281, R37CA54281, U01 CA049449, U01 CA136792, U01CA136792, U01CA98758]; NHGRI NIH HHS [U01 HG004801, U01 HG004803, U01 HG007376, U01 HG007419, U01 HG004802, U01HG004798, U01HG004802, U01 HG007416, U01HG004798-01, U01 HG004798, U01HG004790, U01 HG004790, U01HG004801, U01HG00480]; NHLBI NIH HHS [HHSN268201100001I, HHSN268201100046C, HHSN268201100004I, HHSN268201100002I]; NIA NIH HHS [HHSN271201100004C]; NIGMS NIH HHS [T32 GM080178]; PHS HHS [HHSN268201100003C, HHSN268201100002C, HHSN268201100004C, HHSN268201100046C, HHSN271201100004C, HHSN268201100001C]; WHI NIH HHS [HHSN268201100002C, HHSN268201100004C, HHSN268201100003C, HHSN268201100001C] NR 18 TC 8 Z9 8 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD JUL PY 2014 VL 134 IS 7 BP 2049 EP 2052 DI 10.1038/jid.2014.53 PG 4 WC Dermatology SC Dermatology GA AJ0IA UT WOS:000337333000038 PM 24480881 ER PT J AU Mukherjee, S Dowd, KA Manhart, CJ Ledgerwood, JE Durbin, AP Whitehead, SS Pierson, TC AF Mukherjee, Swati Dowd, Kimberly A. Manhart, Carolyn J. Ledgerwood, Julie E. Durbin, Anna P. Whitehead, Stephen S. Pierson, Theodore C. TI Mechanism and Significance of Cell Type-Dependent Neutralization of Flaviviruses SO JOURNAL OF VIROLOGY LA English DT Article ID WEST-NILE-VIRUS; ANTIBODY-MEDIATED NEUTRALIZATION; TICK-BORNE ENCEPHALITIS; DENGUE VIRUS; MONOCLONAL-ANTIBODIES; ANTIGENIC STRUCTURE; VERO CELLS; INFECTION; VACCINE; GLYCOPROTEIN AB The production of neutralizing antibodies (NAbs) is a correlate of protection for many human vaccines, including currently licensed vaccines against flaviviruses. NAbs are typically measured using a plaque reduction neutralization test (PRNT). Despite its extensive use, parameters that impact the performance of the PRNT have not been investigated from a mechanistic perspective. The results of a recent phase IIb clinical trial of a tetravalent dengue virus (DENV) vaccine suggest that NAbs, as measured using a PRNT performed with Vero cells, do not correlate with protection. This surprising finding highlights the importance of understanding how well the PRNT captures the complexity of the NAb response to DENV. In this study, we demonstrated that the structural heterogeneity of flaviviruses arising from inefficient virion maturation impacts the results of neutralization assays in a cell type-dependent manner. Neutralization titers of several monoclonal antibodies were significantly reduced when assayed on Vero cells compared to Raji cells expressing DC-SIGNR. This pattern can be explained by differences in the efficiency with which partially mature flaviviruses attach to each cell type, rather than a differential capacity of antibody to block infection. Vero cells are poorly permissive to the fraction of virions that are most sensitive to neutralization. Analysis of sera from recipients of live-attenuated monovalent DENV vaccine candidates revealed a strong correlation between the sensitivity of serum antibodies to the maturation state of DENV and cell type-dependent patterns of neutralization. Cross-reactive patterns of neutralization may be underrepresented by the "gold-standard" PRNT that employs Vero cells. C1 [Mukherjee, Swati; Dowd, Kimberly A.; Manhart, Carolyn J.; Pierson, Theodore C.] NIH, Viral Pathogenesis Sect, Viral Dis Lab, Bethesda, MD 20892 USA. [Ledgerwood, Julie E.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Durbin, Anna P.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Ctr Immunizat Res, Baltimore, MD USA. [Whitehead, Stephen S.] NIH, Emerging Resp Virus Sect, Infect Dis Lab, Bethesda, MD 20892 USA. RP Pierson, TC (reprint author), NIH, Viral Pathogenesis Sect, Viral Dis Lab, Bldg 10, Bethesda, MD 20892 USA. EM piersontc@mail.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases FX This work was funded by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases. NR 63 TC 18 Z9 18 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JUL PY 2014 VL 88 IS 13 BP 7210 EP 7220 DI 10.1128/JVI.03690-13 PG 11 WC Virology SC Virology GA AI9GN UT WOS:000337240700009 PM 24741083 ER PT J AU Abram, ME Ferris, AL Das, K Quinones, O Shao, W Tuske, S Alvord, WG Arnold, E Hughes, SH AF Abram, Michael E. Ferris, Andrea L. Das, Kalyan Quinones, Octavio Shao, Wei Tuske, Steven Alvord, W. Gregory Arnold, Eddy Hughes, Stephen H. TI Mutations in HIV-1 Reverse Transcriptase Affect the Errors Made in a Single Cycle of Viral Replication SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; AMINO-ACID SUBSTITUTIONS; MURINE LEUKEMIA-VIRUS; IN-VITRO; DRUG-RESISTANT; DNA-SYNTHESIS; COMBINATION THERAPY; MISPAIR EXTENSION; 3TC RESISTANCE; LAMIVUDINE 3TC AB The genetic variation in HIV-1 in patients is due to the high rate of viral replication, the high viral load, and the errors made during viral replication. Some of the mutations in reverse transcriptase (RT) that alter the deoxynucleoside triphosphate (dNTP)binding pocket, including those that confer resistance to nucleoside/nucleotide analogs, affect dNTP selection during replication. The effects of mutations in RT on the spectrum (nature, position, and frequency) of errors made in vivo are poorly understood. We previously determined the mutation rate and the frequency of different types of mutations and identified hot spots for mutations in a lacZ alpha (the alpha complementing region of lacZ) reporter gene carried by an HIV-1 vector that replicates using wild-type RT. We show here that four mutations (Y115F, M184V, M184I, and Q151M) in the dNTP-binding pocket of RT that had relatively small effects on the overall HIV-1 mutation rate (less than 3-fold compared to the wild type) significantly increased mutations at some specific positions in the lacZ alpha reporter gene. We also show that changes in a sequence that flanks the reporter gene can affect the mutations that arise in the reporter. These data show that changes either in HIV-1 RT or in the sequence of the nucleic acid template can affect the spectrum of mutations made during viral replication. This could, by implication, affect the generation of drug-resistant mutants and immunological-escape mutants in patients. C1 [Abram, Michael E.; Ferris, Andrea L.; Hughes, Stephen H.] NCI, Ctr Canc Res, HIV Drug Resistance Program, Frederick, MD 21701 USA. [Das, Kalyan; Tuske, Steven; Arnold, Eddy] Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. [Das, Kalyan; Tuske, Steven; Arnold, Eddy] Rutgers State Univ, Dept Chem & Chem Biol, Piscataway, NJ USA. [Quinones, Octavio; Alvord, W. Gregory] Frederick Natl Lab Canc Res, Data Management Serv, Frederick, MD USA. [Shao, Wei] Leidos Frederick Inc, Frederick Natl Lab Canc Res, Adv Biomed Comp Ctr, Frederick, MD USA. RP Hughes, SH (reprint author), NCI, Ctr Canc Res, HIV Drug Resistance Program, Frederick, MD 21701 USA. EM hughesst@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; R37 MERIT Award [AI 27690] FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and an R37 MERIT Award (AI 27690) to E.A. NR 78 TC 9 Z9 9 U1 0 U2 13 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JUL PY 2014 VL 88 IS 13 BP 7589 EP 7601 DI 10.1128/JVI.00302-14 PG 13 WC Virology SC Virology GA AI9GN UT WOS:000337240700041 PM 24760888 ER PT J AU Kiss, G Holl, JM Williams, GM Alonas, E Vanover, D Lifland, AW Gudheti, M Guerrero-Ferreira, RC Nair, V Yi, H Graham, BS Santangelo, PJ Wright, ER AF Kiss, Gabriella Holl, Jens M. Williams, Grant M. Alonas, Eric Vanover, Daryll Lifland, Aaron W. Gudheti, Manasa Guerrero-Ferreira, Ricardo C. Nair, Vinod Yi, Hong Graham, Barney S. Santangelo, Philip J. Wright, Elizabeth R. TI Structural Analysis of Respiratory Syncytial Virus Reveals the Position of M2-1 between the Matrix Protein and the Ribonucleoprotein Complex SO JOURNAL OF VIROLOGY LA English DT Article ID DEFECTIVE INTERFERING PARTICLES; ELECTRON-MICROSCOPY; MEASLES-VIRUS; SENDAI-VIRUS; PARAINFLUENZA VIRUS; FILAMENT FORMATION; RNA; CELLS; TOMOGRAPHY; ADULTS AB Respiratory syncytial virus (RSV), a member of the Paramyxoviridae family of nonsegmented, negative-sense, single-stranded RNA genome viruses, is a leading cause of lower respiratory tract infections in infants, young children, and the elderly or immunocompromised. There are many open questions regarding the processes that regulate human RSV (hRSV) assembly and budding. Here, using cryo-electron tomography, we identified virus particles that were spherical, filamentous, and asymmetric in structure, all within the same virus preparation. The three particle morphologies maintained a similar organization of the surface glycoproteins, matrix protein (M), M2-1, and the ribonucleoprotein (RNP). RNP filaments were traced in three dimensions (3D), and their total length was calculated. The measurements revealed the inclusion of multiple full-length genome copies per particle. RNP was associated with the membrane whenever the M layer was present. The amount of M coverage ranged from 24% to 86% in the different morphologies. Using fluorescence light microscopy (fLM), direct stochastic optical reconstruction microscopy (dSTORM), and a proximity ligation assay (PLA), we provide evidence illustrating that M2-1 is located between RNP and M in isolated viral particles. In addition, regular spacing of the M2-1 densities was resolved when hRSV viruses were imaged using Zernike phase contrast (ZPC) cryo-electron tomography. Our studies provide a more complete characterization of the hRSV virion structure and substantiation that M and M2-1 regulate virus organization. C1 [Kiss, Gabriella; Holl, Jens M.; Williams, Grant M.; Guerrero-Ferreira, Ricardo C.; Wright, Elizabeth R.] Emory Univ, Sch Med, Dept Pediat, Div Pediat Infect Dis,Childrens Healthcare Atlant, Atlanta, GA 30322 USA. [Alonas, Eric; Vanover, Daryll; Santangelo, Philip J.] Georgia Inst Technol, Wallace H Coulter Dept Biomed Engn, Atlanta, GA 30332 USA. [Alonas, Eric; Vanover, Daryll; Santangelo, Philip J.] Emory Univ, Atlanta, GA 30322 USA. [Lifland, Aaron W.; Gudheti, Manasa] Vutara Inc, Salt Lake City, UT USA. [Nair, Vinod] NIAID, Res Technol Branch, Microscopy Unit, Rocky Mt Labs,NIH, Hamilton, MT USA. [Yi, Hong; Wright, Elizabeth R.] Emory Univ, Robert P Apkarian Integrated Electron Microscopy, Atlanta, GA 30322 USA. [Graham, Barney S.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Wright, ER (reprint author), Emory Univ, Sch Med, Dept Pediat, Div Pediat Infect Dis,Childrens Healthcare Atlant, Atlanta, GA 30322 USA. EM erwrigh@emory.edu OI Guerrero-Ferreira, Ricardo/0000-0002-3664-8277 FU Emory University; Center for AIDS Research at Emory University [P30 AI050409]; Georgia Research Alliance; James B. Pendleton Charitable Trust; NSF [0923395]; public health service grants [R21AI101775, R01GM094198]; Children's Healthcare of Atlanta FX This work was supported in part by Emory University, Children's Healthcare of Atlanta, the Center for AIDS Research at Emory University (P30 AI050409), the Georgia Research Alliance, and the James B. Pendleton Charitable Trust to E.R.W., NSF grant 0923395 to E.R.W., and public health service grants R21AI101775 to E.R.W. and R01GM094198 to P.J.S. NR 83 TC 16 Z9 16 U1 2 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JUL PY 2014 VL 88 IS 13 BP 7602 EP 7617 DI 10.1128/JVI.00256-14 PG 16 WC Virology SC Virology GA AI9GN UT WOS:000337240700042 PM 24760890 ER PT J AU Boi, S Kolokithas, A Shepard, J Linwood, R Rosenke, K Van Dis, E Malik, F Evans, LH AF Boi, Stefano Kolokithas, Angelo Shepard, Joyce Linwood, Rebecca Rosenke, Kyle Van Dis, Erik Malik, Frank Evans, Leonard H. TI Incorporation of Mouse APOBEC3 into Murine Leukemia Virus Virions Decreases the Activity and Fidelity of Reverse Transcriptase SO JOURNAL OF VIROLOGY LA English DT Article ID RETROVIRUS; INFECTION; PATHOGENESIS; RESTRICTION; DEAMINATION; MUTATION; GENE; DNA AB APOBEC3 proteins are restriction factors that induce G -> A hypermutation in retroviruses during replication as a result of cytidine deamination of minus-strand DNA transcripts. However, the mechanism of APOBEC inhibition of murine leukemia viruses (MuLVs) does not appear to be G -> A hypermutation and is unclear. In this report, the incorporation of mA3 in virions resulted in a loss in virion reverse transcriptase (RT) activity and RT fidelity that correlated with the loss of virion-specific infectivity. C1 [Boi, Stefano; Kolokithas, Angelo; Shepard, Joyce; Linwood, Rebecca; Rosenke, Kyle; Van Dis, Erik; Malik, Frank; Evans, Leonard H.] NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. [Boi, Stefano] Univ Cagliari, Dept Biomed Sci, Cagliari, Italy. RP Evans, LH (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. EM levans@niaid.nih.gov OI Van Dis, Erik S/0000-0003-4773-379X FU Intramural Research Program of the NIH, NIAID; Department of Biomedical Sciences, University of Cagliari, Monserrato (Cagliari), Italy FX This research was supported by the Intramural Research Program of the NIH, NIAID, and the Department of Biomedical Sciences, University of Cagliari, Monserrato (Cagliari), Italy. NR 23 TC 4 Z9 4 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JUL PY 2014 VL 88 IS 13 BP 7659 EP 7662 DI 10.1128/JVI.00967-14 PG 4 WC Virology SC Virology GA AI9GN UT WOS:000337240700046 PM 24719421 ER PT J AU Free, RB Chun, LS Moritz, AE Miller, BN Doyle, TB Conroy, JL Padron, A Meade, JA Xiao, JB Hu, X Dulcey, AE Han, Y Duan, LH Titus, S Bryant-Genevier, M Barnaeva, E Ferrer, M Javitch, JA Beuming, T Shi, L Southall, NT Marugan, JJ Sibley, DR AF Free, R. Benjamin Chun, Lani S. Moritz, Amy E. Miller, Brittney N. Doyle, Trevor B. Conroy, Jennie L. Padron, Adrian Meade, Julie A. Xiao, Jingbo Hu, Xin Dulcey, Andres E. Han, Yang Duan, Lihua Titus, Steve Bryant-Genevier, Melanie Barnaeva, Elena Ferrer, Marc Javitch, Jonathan A. Beuming, Thijs Shi, Lei Southall, Noel T. Marugan, Juan J. Sibley, David R. TI Discovery and Characterization of a G Protein-Biased Agonist That Inhibits beta-Arrestin Recruitment to the D2 Dopamine Receptor SO MOLECULAR PHARMACOLOGY LA English DT Article ID MUSCARINIC ACETYLCHOLINE-RECEPTOR; FUNCTIONAL SELECTIVITY; COUPLED-RECEPTOR; D3 RECEPTOR; MOLECULAR DETERMINANTS; ALLOSTERIC MODULATION; CRYSTAL-STRUCTURE; LITHIUM ACTION; ACTIVATION; EFFICACY AB A high-throughput screening campaign was conducted to interrogate a 380,000+ small-molecule library for novel D2 dopamine receptor modulators using a calcium mobilization assay. Active agonist compounds from the primary screen were examined for orthogonal D2 dopamine receptor signaling activities including cAMP modulation and beta-arrestin recruitment. Although the majority of the subsequently confirmed hits activated all signaling pathways tested, several compounds showed a diminished ability to stimulate beta-arrestin recruitment. One such compound (MLS1547; 5-chloro-7-[(4-pyridin-2-ylpiperazin-1-yl)methyl]quinolin-8-ol) is a highly efficacious agonist at D2 receptor-mediated G protein-linked signaling, but does not recruit beta-arrestin as demonstrated using two different assays. This compound does, however, antagonize dopamine-stimulated beta-arrestin recruitment to the D2 receptor. In an effort to investigate the chemical scaffold of MLS1547 further, we characterized a set of 24 analogs of MLS1547 with respect to their ability to inhibit cAMP accumulation or stimulate beta-arrestin recruitment. A number of the analogs were similar to MLS1547 in that they displayed agonist activity for inhibiting cAMP accumulation, but did not stimulate beta-arrestin recruitment (i.e., they were highly biased). In contrast, other analogs displayed various degrees of G protein signaling bias. These results provided the basis to use pharmacophore modeling and molecular docking analyses to build a preliminary structure-activity relationship of the functionally selective properties of this series of compounds. In summary, we have identified and characterized a novel G protein-biased agonist of the D2 dopamine receptor and identified structural features that may contribute to its biased signaling properties. C1 [Free, R. Benjamin; Chun, Lani S.; Moritz, Amy E.; Miller, Brittney N.; Doyle, Trevor B.; Conroy, Jennie L.; Padron, Adrian; Meade, Julie A.; Sibley, David R.] NINDS, Mol Neuropharmacol Sect, NIH, Bethesda, MD 20892 USA. [Xiao, Jingbo; Hu, Xin; Dulcey, Andres E.; Titus, Steve; Bryant-Genevier, Melanie; Barnaeva, Elena; Ferrer, Marc; Southall, Noel T.; Marugan, Juan J.] NIH, Natl Ctr Adv Translat Sci, Rockville, MD USA. [Chun, Lani S.] Johns Hopkins Univ, Cellular Mol Dev Biol & Biophys Program, Baltimore, MD USA. [Han, Yang; Duan, Lihua; Javitch, Jonathan A.] Columbia Univ Coll Phys & Surg, Ctr Mol Recognit, New York, NY 10032 USA. [Han, Yang; Duan, Lihua; Javitch, Jonathan A.] Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. [Han, Yang; Duan, Lihua; Javitch, Jonathan A.] Columbia Univ Coll Phys & Surg, Dept Pharmacol, New York, NY 10032 USA. [Han, Yang; Duan, Lihua; Javitch, Jonathan A.] New York State Psychiat Inst & Hosp, Div Mol Therapeut, New York, NY 10032 USA. [Beuming, Thijs] Schrodinger Inc, New York, NY USA. [Shi, Lei] Cornell Univ, Weill Med Coll, Dept Physiol & Biophys, New York, NY 10021 USA. [Shi, Lei] Cornell Univ, Weill Med Coll, Inst Computat Biomed, New York, NY 10021 USA. RP Free, RB (reprint author), NINDS, Mol Neuropharmacol Sect, NIH, 5625 Fishers Lane,Room 4S-04, Bethesda, MD 20892 USA. EM freeb@ninds.nih.gov RI Southall, Noel/H-8991-2012 OI Southall, Noel/0000-0003-4500-880X FU Intramural Research Program of the National Institutes of Health [National Institute of Neurological Disorders and Stroke] FX This work was supported, in part, by the Intramural Research Program of the National Institutes of Health [National Institute of Neurological Disorders and Stroke]. NR 44 TC 21 Z9 22 U1 2 U2 17 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X EI 1521-0111 J9 MOL PHARMACOL JI Mol. Pharmacol. PD JUL PY 2014 VL 86 IS 1 BP 96 EP 105 DI 10.1124/mol.113.090563 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AI9GW UT WOS:000337242100010 PM 24755247 ER PT J AU Chen, G Li, JY Ying, Q Sherman, S Perkins, N Rajeshwari, S Mendola, P AF Chen, Gang Li, Jingyi Ying, Qi Sherman, Seth Perkins, Neil Rajeshwari, Sundaram Mendola, Pauline TI Evaluation of observation-fused regional air quality model results for population air pollution exposure estimation SO SCIENCE OF THE TOTAL ENVIRONMENT LA English DT Article DE Community Multiscale Air Quality (CMAQ) model; Data fusing; Inverse distance weighting; Model performance; Exposure; Population weighted average ID UNITED-STATES; TRANSPORT MODEL; OZONE; PM2.5; SIMULATION; RESOLUTION; MORTALITY; EMISSIONS; SULFATE; SYSTEM AB In this study, Community Multiscale Air Quality (CMAQ) model was applied to predict ambient gaseous and particulate concentrations during 2001 to 2010 in 15 hospital referral regions (HRRs) using a 36-km horizontal resolution domain. An inverse distance weighting based method was applied to produce exposure estimates based on observation-fused regional pollutant concentration fields using the differences between observations and predictions at grid cells where air quality monitors were located. Although the raw CMAQ model is capable of producing satisfying results for O-3 and PM2.5 based on EPA guidelines, using the observation data fusing technique to correct CMAQ predictions leads to significant improvement of model performance for all gaseous and particulate pollutants. Regional average concentrations were calculated using five different methods: 1) inverse distance weighting of observation data alone, 2) raw CMAQ results, 3) observation-fused CMAQ results, 4) population-averaged raw CMAQ results and 5) population-averaged fused CMAQ results. It shows that while O-3 (as well as NOx) monitoring networks in the HRRs are dense enough to provide consistent regional average exposure estimation based on monitoring data alone, PM2.5 observation sites (as well as monitors for CO, SO2, PM10 and PM2.5 components) are usually sparse and the difference between the average concentrations estimated by the inverse distance interpolated observations, raw CMAQ and fused CMAQ results can be significantly different. Population-weighted average should be used to account for spatial variation in pollutant concentration and population density. Using raw CMAQ results or observations alone might lead to significant biases in health outcome analyses. (C) 2014 Elsevier B.V. All rights reserved. C1 [Chen, Gang; Li, Jingyi; Ying, Qi] Texas A&M Univ, Zachry Dept Civil, College Stn, TX 77843 USA. [Sherman, Seth] EMMES Corp, Rockville, MD 20850 USA. [Perkins, Neil; Rajeshwari, Sundaram; Mendola, Pauline] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20852 USA. RP Ying, Q (reprint author), Texas A&M Univ, Zachry Dept Civil, College Stn, TX 77843 USA. EM qying@civil.tamu.edu OI Perkins, Neil/0000-0002-6802-4733; Sherman, Seth/0000-0003-3667-9898; Mendola, Pauline/0000-0001-5330-2844; Sundaram, Rajeshwari/0000-0002-6918-5002 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; Air Quality and Reproductive Health [HHSN275200800002I] FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. The data included in this paper were obtained from the Air Quality and Reproductive Health study supported through the Contract No. HHSN275200800002I and Task Order No. HHSN27500008 awarded to The EMMES Corporation. The authors have no conflicts of interests to disclose. The authors want to acknowledge the Texas A&M Supercomputing Facility (http://sc.tamu.edu) and the Texas Advanced Computing Center (http://www.tacc.utexas.edu/) for providing computing resources essential for completing the research reported in this paper. NR 30 TC 10 Z9 10 U1 2 U2 24 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 JUL 1 PY 2014 VL 485 BP 563 EP 574 DI 10.1016/j.scitotenv.2014.03.107 PG 12 WC Environmental Sciences SC Environmental Sciences & Ecology GA AI9NJ UT WOS:000337259000059 PM 24747248 ER PT J AU Brinton, LA Smith, L Gierach, GL Pfeiffer, RM Nyante, SJ Sherman, ME Park, Y Hollenbeck, AR Dallal, CM AF Brinton, Louise A. Smith, Llewellyn Gierach, Gretchen L. Pfeiffer, Ruth M. Nyante, Sarah J. Sherman, Mark E. Park, Yikyung Hollenbeck, Albert R. Dallal, Cher M. TI Breast cancer risk in older women: results from the NIH-AARP Diet and Health Study SO CANCER CAUSES & CONTROL LA English DT Article DE Breast cancer; Risk; Age; Older women ID HORMONE-RECEPTOR STATUS; POSTMENOPAUSAL WOMEN; TUMOR CHARACTERISTICS; ELDERLY-WOMEN; REPRODUCTIVE FACTORS; POOLED ANALYSIS; WEIGHT CHANGE; AGE; POPULATION; MENOPAUSE AB Divergent risk factors exist for premenopausal and postmenopausal breast cancers, but it is unclear whether differences by age exist among postmenopausal women. We examined relationships among 190,872 postmenopausal women, ages 50-71 years recruited during 1995-1996 for the NIH-AARP Diet and Health Study, in whom 7,384 incident invasive breast carcinomas were identified through 2006. Multivariable Cox regression hazard ratios (HRs) and 95 % confidence intervals (CIs) were estimated for breast cancer risk factors by age (50-59, 60-69, a parts per thousand yen70 years). The only factor showing significant statistical heterogeneity by age (p (het) = 0.001) was menopausal hormone therapy duration, but trends were apparent across all ages and the strongest association prevailed among women 60-69 years. Although other risk factors did not show statistically significant heterogeneity by age, we did observe attenuated relations for parity and late age at first birth among older women [e.g., HR for age at first birth a parts per thousand yen30 vs. 20-24 = 1.62 (95 % CI 1.23-2.14) for women 50-59 years vs. 1.12 (0.96-1.31) for a parts per thousand yen70 years]. In contrast, risk estimates associated with alcohol consumption and BMI tended to be slightly stronger among the oldest subjects [e.g., HR for BMI a parts per thousand yen35 vs. 18.5-24.9 = 1.24 (95 % CI 0.97-1.58) for 50-59 years vs. 1.46 (1.26-1.70) for a parts per thousand yen70 years]. These differences were somewhat more pronounced for estrogen receptor positive and ductal cancers, tumors predominating among older women. Breast cancer family history, physical activity, and previous breast biopsies did not show divergent associations by age. Although breast cancer risk factor differences among older women were not large, they may merit further consideration with respect to individualized risk prediction. C1 [Brinton, Louise A.; Smith, Llewellyn; Gierach, Gretchen L.; Pfeiffer, Ruth M.; Nyante, Sarah J.; Park, Yikyung; Dallal, Cher M.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Sherman, Mark E.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. RP Brinton, LA (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM brinton@nih.gov RI Brinton, Louise/G-7486-2015; Gierach, Gretchen/E-1817-2016; OI Brinton, Louise/0000-0003-3853-8562; Gierach, Gretchen/0000-0002-0165-5522; Park, Yikyung/0000-0002-6281-489X FU Intramural Research Program of the National Cancer Institute at the National Institutes of Health; Cancer Prevention Fellowship Program, National Institutes of Health, Bethesda, MD FX This research was supported in part by the Intramural Research Program of the National Cancer Institute at the National Institutes of Health. Dr. Cher Dallal was supported by the Cancer Prevention Fellowship Program, National Institutes of Health, Bethesda, MD. Cancer incidence data from the collected by the Georgia Center for Cancer Statistics, Department of Epidemiology, Rollins School of Public Health, Emory University (for the Atlanta metropolitan area); the California Department of Health Services, Cancer Surveillance Section; the Michigan Cancer Surveillance Program, Community Health Administration, State of Michigan (for the Detroit metropolitan area); the Florida Cancer Data System (FCDC) under contract with the Florida Department of Health (FDOH); the Louisiana Tumor Registry, Louisiana State University Medical Center in New Orleans; the New Jersey State Cancer Registry, Cancer Epidemiology Services, New Jersey State Department of Health and Senior Services; the North Carolina Central Cancer Registry; the Division of Health Statistics and Research, Pennsylvania Department of Health, Harrisburg, Pennsylvania; the Arizona Cancer Registry, Division of Public Health Services, Arizona Department of Health Services; and the Texas Cancer Registry, Cancer Epidemiology and Surveillance Branch, Texas Department of State Health Services. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations, or conclusions. The views expressed herein are solely those of the authors and do not necessarily reflect those of the FCDC or FDOH. We are indebted to the participants in the NIH-AARP Diet and Health Study for their outstanding cooperation. We also thank Sigurd Hermansen and Kerry Grace Morrissey from Westat for study outcomes ascertainment and management and Leslie Carroll at Information Management Services for data support and analysis. NR 45 TC 4 Z9 4 U1 1 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 EI 1573-7225 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD JUL PY 2014 VL 25 IS 7 BP 843 EP 857 DI 10.1007/s10552-014-0385-3 PG 15 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AI6XM UT WOS:000337020700007 PM 24810653 ER PT J AU Brodie, FL Ruggiero, J Ghodasra, DH Eftekhari, K Hui, JZ Brucker, AJ VanderBeek, BL AF Brodie, Frank L. Ruggiero, Jason Ghodasra, Devon H. Eftekhari, Kian Hui, James Z. Brucker, Alexander J. VanderBeek, Brian L. TI A Novel Method for the Measurement of Reflux from Intravitreal Injections: Data from 20 Porcine Eyes SO CURRENT EYE RESEARCH LA English DT Article DE Intravitreal injection; reflux ID PRECISION; ACCURACY AB Background: Reflux following intravitreal injection is a common phenomenon, but it is unknown how much, if any, medication is lost as a result. Reflux is known to be a combination of vitreous and the injected agent, but the relative composition is unknown. This article describes a novel method for the measurement of the volume and composition of reflux and presents data from porcine eyes. Methods: Twenty porcine eyes were injected with 0.05 ml of dye at intraocular pressures (IOPs) of 15, 20, 25 and 30mmHg (five eyes per subgroup). Reflux was captured on filter paper and the area of saturation and color intensity of the dye were digitally analyzed. Total refluxed volume and proportion of dye versus vitreous fluid were calculated from linear regression lines created from known standards. Results: Average (median) total volume of reflux from all eyes was 1.19 mu l (0.93 mu l), volume of injected dye refluxed was 0.47 mu l (0.11 mu l) and composition of reflux was 20.8% dye (15.5%). Less than 1% of the injected dye was lost to reflux. There were no differences between IOP groups in the total volume refluxed, the total amount of dye refluxed, the average composition of the reflux or the amount of injected dye refluxed (df = 3 for all comparisons; p = 0.58, p = 0.51, p = 0.55, p = 0.51, respectively). Conclusions: This novel method allows for measurement of quantity and composition of reflux following intravitreal injection in vitro. While reflux occurs frequently, it is predominantly composed of vitreous, not the injected agent. In fact, <1% of the original injection was lost to reflux. C1 [Brodie, Frank L.; Ruggiero, Jason; Ghodasra, Devon H.; Eftekhari, Kian; Brucker, Alexander J.; VanderBeek, Brian L.] Univ Penn, Scheie Eye Inst, Perelman Sch Med, Dept Ophthalmol, Philadelphia, PA 19104 USA. [Hui, James Z.] Univ Penn, Penn HHMI NIBIB Interface Program Biomed Imaging, Dept Bioengn, Philadelphia, PA 19104 USA. [VanderBeek, Brian L.] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. RP VanderBeek, BL (reprint author), Univ Penn, Scheie Eye Inst, 51 N 39th St, Philadelphia, PA 19104 USA. EM brian.vanderbeek@uphs.upenn.edu OI VanderBeek, Brian L./0000-0003-4953-118X FU National Institutes of Health [K12-EY015398]; Research to Prevent Blindness; Paul and Evanina Mackall Foundation; HHMI-NIBIB Biomedical Interface Program Training Grant FX The authors report no conflicts of interest. Hope for Vision and The Richard H. Chartrand Eye Research Foundation; National Institutes of Health K12 Award, K12-EY015398; Additional funding was provided by Research to Prevent Blindness and the Paul and Evanina Mackall Foundation, HHMI-NIBIB Biomedical Interface Program Training Grant. NR 16 TC 5 Z9 5 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0271-3683 EI 1460-2202 J9 CURR EYE RES JI Curr. Eye Res. PD JUL PY 2014 VL 39 IS 7 BP 752 EP 757 DI 10.3109/02713683.2013.864774 PG 6 WC Ophthalmology SC Ophthalmology GA AI6OS UT WOS:000336995500014 PM 24256543 ER PT J AU Fertig, E Fureman, BE Bergey, GK Brodie, MA Hesdorffer, DC Hirtz, D Kossoff, EH LaFrance, WC Versavel, M French, J AF Fertig, Evan Fureman, Brandy E. Bergey, Gregory K. Brodie, Mary Ann Hesdorffer, Dale C. Hirtz, Deborah Kossoff, Eric H. LaFrance, W. Curt, Jr. Versavel, Mark French, Jacqueline TI Inclusion and exclusion criteria for epilepsy clinical trials-Recommendations from the April 30, 2011 NINDS workshop SO EPILEPSY RESEARCH LA English DT Review DE Participant selection criteria; Clinical trial methodology; Recruitment; Comorbidity ID QUALITY STANDARDS SUBCOMMITTEE; AMERICAN-ACADEMY; ILAE COMMISSION; CONSENSUS; NEUROLOGY; SOCIETY AB On April 30th, 2011 the National Institute of Neurological Disorders and Stroke (NINDS) held a workshop to identify key problems in recent epilepsy clinical trials and propose approaches to address the barriers that impede development of new therapeutic options for epilepsy. Preliminary recommendations were made for selection criteria for subjects entered into epilepsy trials that maximize the scientific impact of the trial and increase the ability to recruit appropriate subjects efficiently and safely. These recommendations were further refined by the authors following the workshop, and subsequently shared with all HINDS workshop participants and with the participants of the 2011 AED XI workshop on epilepsy trials (approximately 200 participants) for further comment. The working group agreed to a final set of criteria that include updated considerations of subject age, clinical semiology, EEG and imaging results, use of prior and current therapies, co-occurring conditions, and suicidality, among others. Published by Elsevier B.V. C1 [Fertig, Evan] Northeast Reg Epilepsy Grp, Hackensack, NJ USA. [Fureman, Brandy E.; Hirtz, Deborah] NINDS, NIH, Bethesda, MD 20892 USA. [Bergey, Gregory K.; Kossoff, Eric H.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Brodie, Mary Ann; French, Jacqueline] Epilepsy Study Consortium, New York, NY USA. [Hesdorffer, Dale C.] Columbia Univ, Dept Epidemiol, New York, NY USA. [Kossoff, Eric H.] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. [LaFrance, W. Curt, Jr.] Rhode Isl Hosp, Dept Psychiat, Brown Med Sch, Providence, RI USA. [LaFrance, W. Curt, Jr.] Rhode Isl Hosp, Brown Med Sch, Dept Neurol Res, Providence, RI USA. [Versavel, Mark] Sunovion Pharmaceut Inc, Marlborough, MA USA. [French, Jacqueline] NYU, Dept Neurol, New York, NY 10016 USA. RP Fureman, BE (reprint author), NINDS, 6001 Execut Blvd, Bethesda, MD 20892 USA. EM furemanb@ninds.nih.gov RI French, Jacqueline/G-6795-2013 OI French, Jacqueline/0000-0003-2242-8027 FU Epilepsy Consortium; Cyberonics; Eisai Medical Research; GlaxoSmithKline; Icagen, Inc.; Johnson Johnson; Marinus; Neurotherapeutics; NeuroVista Corporation; Ono Pharma USA, Inc.; Lundbeck; Pfizer; Sepracor; Sunovion; SK Life Science; Supernus Pharmaceuticals; UCB Inc/Schwarz Pharma; Upsher Smith; Valeant; Vertex; International League Against Epillepsy; CDC; NINDS; NICHD; Epilepsy Study Consortium; Epilepsy Foundation of America; American Epilepsy Society; Epilepsy Foundation; Brown University; Siravo Foundation; Entra Pharmaceuticals FX Evan Fertig is an employee of the Northeast Regional Epilepsy Group. He has received research support from Pfizer, UCB, Lundbeck, Vertex, Supernus, and Esai.; Mary Ann Brodie is an employee of the Epilepsy Study Consortium. Within the past year, the Epilepsy Consortium has received funding for research support, meeting support and services provided from the following companies: Cyberonics, Eisai Medical Research, GlaxoSmithKline, Icagen, Inc., Johnson & Johnson, Marinus, Neurotherapeutics, NeuroVista Corporation, Ono Pharma USA, Inc., Lundbeck, Pfizer, Sepracor, Sunovion, SK Life Science, Supernus Pharmaceuticals, UCB Inc/Schwarz Pharma, Upsher Smith, Valeant, Vertex.; Dale C. Hesdorffer is an employee of GH Sergievsky Center and Department of Epidemiology, Columbia University. She has received travel funding from GlaxoSmithKline and the International League Against Epillepsy, and grant funding from the CDC, the NINDS, NICHD, the Epilepsy Study Consortium, and the Epilepsy Foundation of America.; W. Curt LaFrance, Jr. is employed by Rhode Island Hospital. He has received grant support from NINDS, the American Epilepsy Society, the Epilepsy Foundation, Brown University and the Siravo Foundation. He receives book royalties for Gates and Rowan's Nonepileptic Seizures, 3rd Edition, Cambridge University Press.; Mark Versavel is an employee of Sunovion Inc. Jackie French serves as the president of The Epilepsy Study Consortium, a non-profit organization. NYU receives a fixed amount from the Epilepsy Study Consortium toward her salary. The money is for work performed by her on behalf of The Epilepsy Study Consortium, for consulting and clinical trial related activities. She receives no personal income for these activities. Within the past year, The Epilepsy Study Consortium received payments from: Cyberonics, Eisai Medical Research, Entra Pharmaceuticals, GlaxoSmithKline, Icagen, Inc., Johnson & Johnson, Marinus, Neurotherapeutics, NeuroVista Corporation, Ono Pharma USA, Inc., Lundbeck, Pfizer, Sepracor, Sunovion, SK Life Science, Supernus Pharmaceuticals, UCB Inc./Schwarz Pharma, Upsher Smith, Valeant, Vertex. NR 19 TC 0 Z9 0 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-1211 EI 1872-6844 J9 EPILEPSY RES JI Epilepsy Res. PD JUL PY 2014 VL 108 IS 5 BP 825 EP 832 DI 10.1016/j.eplsyres.2014.02.011 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA AI6VJ UT WOS:000337014800001 PM 24702822 ER PT J AU Romero, R Yoon, BH Chaemsaithong, P Cortez, J Park, CW Gonzalez, R Behnke, E Hassan, SS Gotsch, F Yeo, L Chaiworapongsa, T AF Romero, Roberto Yoon, Bo Hyun Chaemsaithong, Piya Cortez, Josef Park, Chan-Wook Gonzalez, Rogelio Behnke, Ernesto Hassan, Sonia S. Gotsch, Francesca Yeo, Lami Chaiworapongsa, Tinnakorn TI Secreted phospholipase A(2) is increased in meconium-stained amniotic fluid of term gestations: potential implications for the genesis of meconium aspiration syndrome SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE Acute phase protein reactant; interleukin-6; intra-amniotic inflammation/infection; prostaglandins; sPLA(2) ID GROUP-II PHOSPHOLIPASE-A2; HUMAN LUNG MACROPHAGES; PULMONARY SURFACTANT FUNCTION; ACID-BASE STATUS; PRETERM LABOR; HUMAN PARTURITION; SYNOVIAL-FLUID; INFLAMMATORY RESPONSE; HUMAN NEUTROPHILS; RISK-FACTORS AB Background: Meconium-stained amniotic fluid (MSAF) represents the passage of fetal colonic content into the amniotic cavity. Meconium aspiration syndrome (MAS) is a complication that occurs in a subset of infants with MSAF. Secreted phospholipase A(2) (sPLA(2)) is detected in meconium and is implicated in the development of MAS. The purpose of this study was to determine if sPLA(2) concentrations are increased in the amniotic fluid of women in spontaneous labor at term with MSAF. Materials and methods: This was a cross-sectional study of patients in spontaneous term labor who underwent amniocentesis (n = 101). The patients were divided into two study groups: (1) MSAF (n = 61) and (2) clear fluid (n = 40). The presence of bacteria and endotoxin as well as interleukin-6 (IL-6) and sPLA(2) concentrations in the amniotic fluid were determined. Statistical analyses were performed to test for normality and bivariate analysis. The Spearman correlation coefficient was used to study the relationship between sPLA(2) and IL-6 concentrations in the amniotic fluid. Results: Patients with MSAF have a higher median sPLA(2) concentration (ng/mL) in amniotic fluid than those with clear fluid [1.7 (0.98-2.89) versus 0.3 (0-0.6), p < 0.001]. Among patients with MSAF, those with either microbial invasion of the amniotic cavity (MIAC, defined as presence of bacteria in the amniotic cavity), or bacterial endotoxin had a significantly higher median sPLA(2) concentration (ng/mL) in amniotic fluid than those without MIAC or endotoxin [2.4 (1.7-6.0) versus 1.7 (1.3-2.5), p<0.05]. There was a positive correlation between sPLA2 and IL-6 concentrations in the amniotic fluid (Spearman Rho = 0.3, p < 0.05). Conclusion: MSAF that contains bacteria or endotoxin has a higher concentration of sPLA(2), and this may contribute to induce lung inflammation when meconium is aspirated before birth. C1 [Romero, Roberto; Yoon, Bo Hyun; Chaemsaithong, Piya; Cortez, Josef; Hassan, Sonia S.; Gotsch, Francesca; Yeo, Lami; Chaiworapongsa, Tinnakorn] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Romero, Roberto; Yoon, Bo Hyun; Chaemsaithong, Piya; Cortez, Josef; Hassan, Sonia S.; Gotsch, Francesca; Yeo, Lami; Chaiworapongsa, Tinnakorn] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Yoon, Bo Hyun; Park, Chan-Wook] Seoul Natl Univ, Coll Med, Dept Obstet & Gynecol, Seoul, South Korea. [Chaemsaithong, Piya; Hassan, Sonia S.; Yeo, Lami; Chaiworapongsa, Tinnakorn] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Cortez, Josef] Wayne State Univ, Dept Pediat, Detroit, MI 48201 USA. [Gonzalez, Rogelio] Pontificia Univ Catolica Chile, Hosp Dr Sotero del Rio, Ctr Perinatal Diag & Res CEDIP, Puente Alto, Chile. [Behnke, Ernesto] Hosp Dr Sotero del Rio, Dept Obstet & Gynecol, Ctr Perinatal Diag & Res CEDIP, Santiago, Chile. [Gotsch, Francesca] Azienda Osped Univ, Integrata Verona, Verona, Italy. RP Romero, R (reprint author), Wayne State Univ, NICHD, Perinatol Res Branch, NIH,DHHS,Hutzel Womens Hosp, 3990 John R,Box 4, Detroit, MI 48201 USA. EM romeror@mail.nih.gov FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH); NICHD, NIH [HHSN275201300006C]; Walter Scott Foundation for Medical Research FX This research was supported, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH); and, in part, with Federal funds from NICHD, NIH under Contract No. HHSN275201300006C. The research was also supported by a grant from the Walter Scott Foundation for Medical Research. NR 231 TC 4 Z9 4 U1 1 U2 9 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1476-7058 EI 1476-4954 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD JUL PY 2014 VL 27 IS 10 BP 975 EP 983 DI 10.3109/14767058.2013.847918 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AI7MQ UT WOS:000337076100001 PM 24063538 ER PT J AU Chan, CYX Wang, D Cadeiras, M Deng, MC Ping, PP AF Chan, C. Y. X'avia Wang, Ding Cadeiras, Martin Deng, Mario C. Ping, Peipei TI S-nitrosylation of TRIM72 mends the broken heart: A molecular modifier-mediated cardioprotection SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Editorial Material ID PERCUTANEOUS CORONARY INTERVENTION; ACUTE MYOCARDIAL-INFARCTION; MITOCHONDRIAL COMPLEX-I; NITRIC-OXIDE; REPERFUSION INJURY; O-GLCNAC; OXIDATIVE STRESS; CROSS-TALK; CYSTEINE; PHOSPHORYLATION C1 [Chan, C. Y. X'avia; Wang, Ding; Ping, Peipei] Univ Calif Los Angeles, NHLBI, Prote Ctr, Dept Physiol,David Geffen Sch Med, Los Angeles, CA 90095 USA. [Chan, C. Y. X'avia; Wang, Ding; Ping, Peipei] Univ Calif Los Angeles, Dept Med, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Cadeiras, Martin; Deng, Mario C.] Univ Calif Los Angeles, Med Ctr, Ronald Reagan UCLA Med Ctr, Santa Monica, CA USA. RP Chan, CYX (reprint author), Univ Calif Los Angeles, Dept Physiol, NHLBI, Prote Ctr,Sch Med, Los Angeles, CA 90095 USA. EM xaviachan@mednet.ucla.edu; DingWang@mednet.ucla.edu; MCadeiras@mednet.ucla.edu; MDeng@mednet.ucla.edu OI Ping, Peipei/0000-0003-3583-3881 NR 65 TC 1 Z9 1 U1 1 U2 12 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD JUL PY 2014 VL 72 BP 292 EP 295 DI 10.1016/j.yjmcc.2014.04.004 PG 4 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA AI7YU UT WOS:000337119700032 ER PT J AU Kim, W Lee, Y McKenna, ND Yi, M Simunovic, F Wang, YL Kong, B Rooney, RJ Seo, H Stephens, RM Sonntag, KC AF Kim, Woori Lee, Yenarae McKenna, Noah D. Yi, Ming Simunovic, Filip Wang, Yulei Kong, Benjamin Rooney, Robert J. Seo, Hyemyung Stephens, Robert M. Sonntag, Kai C. TI miR-126 contributes to Parkinson's disease by dysregulating the insulin-like growth factor/phosphoinositide 3-kinase signaling SO NEUROBIOLOGY OF AGING LA English DT Article DE miRNAs; miR-126; Dopamine neurons; Parkinson's disease; Insulin; IGF-1 signaling; PI3K; Laser capture microdissection; Postmortem; 6-OHDA neurotoxicity; Cell systems ID ALPHA-SYNUCLEIN EXPRESSION; GENE-EXPRESSION; ALZHEIMERS-DISEASE; DOPAMINE NEURONS; POSTTRANSCRIPTIONAL REGULATION; HUNTINGTONS-DISEASE; VASCULAR INTEGRITY; MICRORNA TARGETS; NERVOUS-SYSTEM; MUTANT MICE AB Dopamine (DA) neurons in sporadic Parkinson's disease (PD) display dysregulated gene expression networks and signaling pathways that are implicated in PD pathogenesis. Micro (mi) RNAs are regulators of gene expression, which could be involved in neurodegenerative diseases. We determined the miRNA profiles in laser microdissected DA neurons from postmortem sporadic PD patients' brains and age-matched controls. DA neurons had a distinctive miRNA signature and a set of miRNAs was dysregulated in PD. Bioinformatics analysis provided evidence for correlations of miRNAs with signaling pathways relevant to PD, including an association of miR-126 with insulin/IGF-1/PI3K signaling. In DA neuronal cell systems, enhanced expression of miR-126 impaired IGF-1 signaling and increased vulnerability to the neurotoxin 6-OHDA by downregulating factors in IGF-1/PI3K signaling, including its targets p85 beta, IRS-1, and SPRED1. Blocking of miR-126 function increased IGF-1 trophism and neuroprotection to 6-OHDA. Our data imply that elevated levels of miR-126 may play a functional role in DA neurons and in PD pathogenesis by downregulating IGF-1/PI3K/AKT signaling and that its inhibition could be a mechanism of neuroprotection. (C) 2014 Elsevier Inc. All rights reserved. C1 [Kim, Woori; Lee, Yenarae; McKenna, Noah D.; Simunovic, Filip; Sonntag, Kai C.] Harvard Univ, McLean Hosp, Sch Med, Dept Psychiat, Belmont, MA 02478 USA. [Yi, Ming; Stephens, Robert M.] NCI, Adv Biomed Comp Ctr, Bioinformat Support Grp, Frederick, MD 21701 USA. [Wang, Yulei; Kong, Benjamin] Life Technol, Foster City, CA USA. [Rooney, Robert J.] Genome Explorat Inc, Memphis, TN USA. [Kim, Woori; Seo, Hyemyung] Hanyang Univ, Coll Sci & Technol, Div Mol & Life Sci, Seoul 133791, South Korea. RP Sonntag, KC (reprint author), Harvard Univ, McLean Hosp, Sch Med, Dept Psychiat, MRC 223,115 Mill St, Belmont, MA 02478 USA. EM ksonntag@mclean.harvard.edu FU Massachusetts' Alzheimer's Disease Research Center and the Harvard NeuroDiscovery Center; National Institute of Neurological Disorders and Stroke [R21NS067335]; Korean Government, Ministry of Science, Information communication technology and future Planning (MSIP) [2011-0030775] FX financial support and resources. Kai C Sonntag was involved in all aspects of the study, including conception, design, data acquisition, analysis, interpretation, presentation, and write-up for publication; Woori Kim, Yenarae Lee, Noah D McKenna, Filip Simunovic, and Hyemyung Seo were directly involved with data acquisition and/or manuscript preparation; Benjamin Kong and Yulei Wang performed the microRNA profiling, Ming Yi and Robert Stephens the bioinformatics analyses, and Robert J Rooney additional computational microRNA quantification. This research was supported by a grant from the Massachusetts' Alzheimer's Disease Research Center and the Harvard NeuroDiscovery Center, and National Institute of Neurological Disorders and Stroke R21NS067335 (Kai C Sonntag), and the National Research Foundation of Korea and a grant of the Korean Government, Ministry of Science, Information communication technology and future Planning (MSIP) No 2011-0030775 to Hyemyung Seo. NR 60 TC 17 Z9 19 U1 5 U2 18 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2014 VL 35 IS 7 BP 1712 EP 1721 DI 10.1016/j.neurobiolaging.2014.01.021 PG 10 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA AI0XX UT WOS:000336575100025 PM 24559646 ER PT J AU Lodge, NJ Li, YW Chin, FT Dischino, DD Zoghbi, SS Deskus, JA Mattson, RJ Imaizumi, M Pieschl, R Molski, TF Fujita, M Dulac, H Zaczek, R Bronson, JJ Macor, JE Innis, RB Pike, VW AF Lodge, Nicholas J. Li, Yu-Wen Chin, Frederick T. Dischino, Douglas D. Zoghbi, Sami S. Deskus, Jeffrey A. Mattson, Ronald J. Imaizumi, Masao Pieschl, Rick Molski, Thaddeus F. Fujita, Masahiro Dulac, Heidi Zaczek, Robert Bronson, Joanne J. Macor, John E. Innis, Robert B. Pike, Victor W. TI Synthesis and evaluation of candidate PET radioligands for corticotropin-releasing factor type-1 receptors SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE Corticotropin-releasing factor (CRF); Autoradiography; Positron emission tomography (PET); [C-11]BMS-709460; [F-18]BMS-721313; [F-18]BMS-732098; Rhesus monkey ID FACTOR BINDING-SITES; CRF1 RECEPTOR; IN-VIVO; AUTORADIOGRAPHIC LOCALIZATION; IMAGING AGENTS; ANTAGONIST; STRESS; BRAIN; DEPRESSION; ANXIETY AB Introduction: A radioligand for measuring the density of corticotropin-releasing factor subtype-1 receptors (CRF1 receptors) in living animal and human brain with positron emission tomography (PET) would be a useful tool for neuropsychiatric investigations and the development of drugs intended to interact with this target. This study was aimed at discovery of such a radioligand from a group of CAF(1), receptor ligands based on a core 3-(phenylamino)-pyrazin-2(1H)-one scaffold. Methods: CRF1 receptor ligands were selected for development as possible PET radioligands based on their binding potency at CRF1 receptors (displacement of [I-128]CRF from rat cortical membranes), measured lipophilicity, autoradiographic binding profile in rat and rhesus monkey brain sections, rat biodistribution, and suitability for radiolabeling with carbon-11 or fluorine-18. Two identified candidates (BMS-721313 and BMS-732098) were labeled with fluorine-18. A third candidate (BMS-709460) was labeled with carbon-11 and all three radioligands were evaluated in PET experiments in rhesus monkey. CRF1 receptor density (B-rnax) was assessed in rhesus brain cortical and cerebellum membranes with the CRF1 receptor ligand, [H-3]BMS-728300. Results: The three ligands selected for development showed high binding affinity (IC50 values, 0.3-8 nM) at CRF1 receptors and moderate lipophilicity (LogD, 2.8-4.4). [H-3]BMS-728300 and the two F-18-labeled ligands showed region-specific binding in rat and rhesus monkey brain autoradiography, namely higher binding density in the frontal and limbic cortex, and cerebellum than in thalamus and brainstem. CRF1 receptor B-max, in rhesus brain was found to be 50-120 fmol/mg protein across cortical regions and cerebellum. PET experiments in rhesus monkey showed that the radioligands [F-18]BMS-721313, [F-18]BMS-732098 and [C-11]BMS-709460 gave acceptably high brain radioactivity uptake but no indication of the specific binding as seen in vitro. Conclusions: Candidate CRF1 receptor PET radioligands were identified but none proved to be effective for imaging monkey brain CRF1 receptors. Higher affinity radioligands are likely required for successful PET imaging of CRF1 receptors. (c) 2014 Elsevier Inc. All rights reserved. C1 [Lodge, Nicholas J.; Li, Yu-Wen; Pieschl, Rick; Molski, Thaddeus F.; Zaczek, Robert] Bristol Myers Squibb Co, Dept Neurosci Biol, Wallingford, CT 06492 USA. [Deskus, Jeffrey A.; Mattson, Ronald J.; Bronson, Joanne J.; Macor, John E.] Bristol Myers Squibb Co, Dept Neurosci Chem, Wallingford, CT 06492 USA. [Dischino, Douglas D.] Bristol Myers Squibb Co, Dept Radiochem, Wallingford, CT 06492 USA. [Dulac, Heidi] Bristol Myers Squibb Co, Dept Vet Sci, Wallingford, CT 06492 USA. [Chin, Frederick T.; Zoghbi, Sami S.; Imaizumi, Masao; Fujita, Masahiro; Innis, Robert B.; Pike, Victor W.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. [Chin, Frederick T.] Stanford Univ, Sch Med, Mol Imaging Program Stanford, Dept Radiol, Stanford, CA 94305 USA. RP Li, YW (reprint author), Bristol Myers Squibb Co, Dept Neurosci Biol, 5 Res Pkwy, Wallingford, CT 06492 USA. FU Intramural Research Program of the NIH (National Institute of Mental Health; NIMH) FX The authors are indebted to Yuan Tian (Dept. of Radiochemistry, Bristol-Myers Squibb) for providing the [3H]BMS-728300. Authors affiliated to the National Institutes of Health (NIH) were supported by the Intramural Research Program of the NIH (National Institute of Mental Health; NIMH). This project was conducted under a cooperative research and development agreement (CRADA) between Bristol-Myers-Squibb Research Laboratories and the NIMH. NR 43 TC 4 Z9 4 U1 2 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0969-8051 EI 1872-9614 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD JUL PY 2014 VL 41 IS 6 BP 524 EP 535 DI 10.1016/j.nucmedbio.2014.03.005 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AI5YH UT WOS:000336946400013 PM 24793011 ER PT J AU Zhang, Y Duan, X Xiong, B Cui, XS Kim, NH Rui, R Sun, SC AF Zhang, Yu Duan, Xing Xiong, Bo Cui, Xiang-Shun Kim, Nam-Hyung Rui, Rong Sun, Shao-Chen TI ROCK inhibitor Y-27632 prevents porcine oocyte maturation SO THERIOGENOLOGY LA English DT Article DE Y-27632; Rho-associated protein kinase; Actin; Oocyte maturation; Spindle migration ID RHO-ASSOCIATED KINASE; FORMING PROTEIN-KINASE; MEIOTIC SPINDLE; MOUSE OOCYTES; ACTIN CYTOSKELETON; MYOSIN PHOSPHATASE; FOCAL ADHESIONS; STRESS FIBERS; LIM-KINASE; ROK-ALPHA AB The inhibitor Y-27632 is a specific selective inhibitor of Rho-associated protein kinases (ROCKs), which are downstream effectors of Rho guanosine triphosphatease (GTPases) and regulate Rho-associated cellular functions, including actin cytoskeletal organization. Little is known regarding the effects of Y-27632 on mammalian oocyte maturation. In the present study, we investigated the effects of Y-27632 on porcine oocyte meiosis and possible regulatory mechanisms of ROCK during porcine oocyte maturation. We found that ROCK accumulated not only at spindles, but also at the cortex in porcine oocytes. Y-27632 treatment reduced ROCK expression, and inhibited porcine oocyte meiotic maturation, which might be because of the impairment of actin expression and actin-related spindle positioning. Y-27632 treatment also disrupted the formation of actin cap and cortical granule-free domain, which further confirmed a spindle positioning failure. Thus, Y-27632 has significant effects on the meiotic competence of mammalian oocytes by reducing ROCK expression, and the regulation is related to its effects on actin-mediated spindle positioning. (C) 2014 Elsevier Inc. All rights reserved. C1 [Zhang, Yu; Duan, Xing; Sun, Shao-Chen] Nanjing Agr Univ, Coll Anim Sci & Technol, Nanjing, Jiangsu, Peoples R China. [Zhang, Yu; Rui, Rong] Nanjing Agr Univ, Coll Vet Med, Nanjing, Jiangsu, Peoples R China. [Xiong, Bo] NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. [Cui, Xiang-Shun; Kim, Nam-Hyung] Chungbuk Natl Univ, Dept Anim Sci, Cheongju, Chungbuk, South Korea. RP Sun, SC (reprint author), Nanjing Agr Univ, Coll Anim Sci & Technol, Nanjing, Jiangsu, Peoples R China. EM sunsc@njau.edu.cn FU National Basic Research Program of China [2014CB138503]; Natural Science Foundation of Jiangsu Province, China [BK20130671]; Biogreen 21 Program, RDA, Republic of Korea [PJ009594, PJ00909801] FX This work was supported by the National Basic Research Program of China (2014CB138503), the Natural Science Foundation of Jiangsu Province (BK20130671), China; and the Biogreen 21 Program (PJ009594 & PJ00909801), RDA, Republic of Korea. NR 43 TC 7 Z9 7 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0093-691X EI 1879-3231 J9 THERIOGENOLOGY JI Theriogenology PD JUL 1 PY 2014 VL 82 IS 1 BP 49 EP 56 DI 10.1016/j.theriogenology.2014.02.020 PG 8 WC Reproductive Biology; Veterinary Sciences SC Reproductive Biology; Veterinary Sciences GA AI6SA UT WOS:000337006100007 PM 24681214 ER PT J AU Scoccia, B Moghissi, K Westhoff, C Niwa, S Ruggieri, D Trabert, B Lamb, E Brinton, L AF Scoccia, B. Moghissi, K. Westhoff, C. Niwa, S. Ruggieri, D. Trabert, B. Lamb, E. Brinton, L. TI Long-term relationship of ovulation-stimulating drugs to breast and gynecologic cancers SO HUMAN REPRODUCTION LA English DT Meeting Abstract CT 30th Annual Meeting of the European-Society-of-Human-Reproduction-and-Embryology (ESHRE) CY JUN 29-JUL 02, 2014 CL Munich, GERMANY SP European Soc Human Reprod & Embryol C1 [Scoccia, B.] Univ Illinois, Obstet & Gynecol, Chicago, IL USA. [Moghissi, K.] Wayne State Univ, Obstet & Gynecol, Detroit, MI USA. [Westhoff, C.] Columbia Univ, Obstet & Gynecol, New York, NY USA. [Niwa, S.] Westat Corp, Rockville, MD USA. [Ruggieri, D.] IMS Inc, Rockville, MD USA. [Trabert, B.; Brinton, L.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Lamb, E.] Stanford Univ, Dept Obstet & Gynecol, Stanford, CA 94305 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 EI 1460-2350 J9 HUM REPROD JI Hum. Reprod. PD JUL PY 2014 VL 29 SU 1 MA O-064 BP 27 EP 27 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CP2YZ UT WOS:000359745300065 ER PT J AU Mueller, SC Cornwell, BR Grillon, C MacIntyre, J Gorodetsky, E Goldman, D Pine, DS Ernst, M AF Mueller, Sven C. Cornwell, Brian R. Grillon, Christian MacIntyre, Jessica Gorodetsky, Elena Goldman, David Pine, Daniel S. Ernst, Monique TI Evidence of MAOA genotype involvement in spatial ability in males SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Monoamine-oxidase; Virtual maze; Spatial navigation; Spatial memory; Learning; Gene ID MONOAMINE-OXIDASE; GENE PROMOTER; FUNCTIONAL POLYMORPHISM; VAL66MET POLYMORPHISM; MOLECULAR-GENETICS; MAJOR DEPRESSION; NAVIGATION TASK; PANIC DISORDER; PERFORMANCE; ANXIETY AB Although the monoamine oxidase-A (MAOA) gene has been linked to spatial learning and memory in animal models, convincing evidence in humans is lacking. Performance on an ecologically-valid, virtual computer-based equivalent of the Morris Water Maze task was compared between 28 healthy males with the low MAOA transcriptional activity and 41 healthy age- and IQ-matched males with the high MAOA transcriptional activity. The results revealed consistently better performance (reduced heading error, shorter path length, and reduced failed trials) for the high MAOA activity individuals relative to the low activity individuals. By comparison, groups did not differ on pre-task variables or strategic measures such as first-move latency. The results provide novel evidence of MAOA gene involvement in human spatial navigation using a virtual analogue of the Morris Water Maze task. (C) 2014 Elsevier B.V. All rights reserved. C1 [Mueller, Sven C.] Univ Ghent, Dept Expt Clin & Hlth Psychol, B-9000 Ghent, Belgium. [Mueller, Sven C.; MacIntyre, Jessica; Pine, Daniel S.; Ernst, Monique] NIMH, Sect Dev & Affect Neurosci, NIH, Bethesda, MD 20892 USA. [Cornwell, Brian R.] Swinburne Univ, Hawthorn, Vic 3122, Australia. [Grillon, Christian] NIMH, Sect Neurobiol Fear & Anxiety, NIH, Bethesda, MD 20892 USA. [Gorodetsky, Elena] NIMH, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. [Goldman, David] NIAAA, NIH, Bethesda, MD 20892 USA. RP Mueller, SC (reprint author), Univ Ghent, Dept Expt Clin & Hlth Psychol, B-9000 Ghent, Belgium. EM Sven.Mueller@UGent.be RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU Intramural Research Programme of the NIMH, NIH; Ghent University (Multidisciplinary Research Partnership: "The integrative neuroscience of behavioural control") FX This research was supported, in part, by the Intramural Research Programme of the NIMH, NIH. We would also like to acknowledge the support of Ghent University (Multidisciplinary Research Partnership: "The integrative neuroscience of behavioural control"). None of the authors has a conflict of interest to declare. NR 36 TC 1 Z9 2 U1 0 U2 10 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 JUL 1 PY 2014 VL 267 BP 106 EP 110 DI 10.1016/j.bbr.2014.03.025 PG 5 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA AI2UK UT WOS:000336713400014 PM 24671068 ER PT J AU Qi, HB Jin, M Duan, YQ Du, XL Zhang, YQ Ren, FL Wang, YY Tian, QY Wang, XF Wang, Q Zhu, Y Xie, YL Liu, CJ Cao, X Mishina, Y Chen, D Deng, CX Chang, ZJ Chen, L AF Qi, Huabing Jin, Min Duan, Yaqi Du, Xiaolan Zhang, Yuanquan Ren, Fangli Wang, Yinyin Tian, Qingyun Wang, Xiaofeng Wang, Quan Zhu, Ying Xie, Yangli Liu, Chuanju Cao, Xu Mishina, Yuji Chen, Di Deng, Chu-xia Chang, Zhijie Chen, Lin TI FGFR3 induces degradation of BMP type I receptor to regulate skeletal development SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH LA English DT Article DE FGFR3; BMPR1; Achondroplasia; Smurf1; Chondrocyte ID GROWTH-FACTOR RECEPTOR-3; TGF-BETA; UBIQUITIN LIGASE; BONE-DEVELOPMENT; CHONDROCYTE PROLIFERATION; ACHONDROPLASIA; ACTIVATION; CARTILAGE; MUTATION; DIFFERENTIATION AB Fibroblast growth factors (FGFs) and their receptors (FGFRs) play significant roles in vertebrate organogenesis and morphogenesis. FGFR3 is a negative regulator of chondrogenesis and multiple mutations with constitutive activity of FGFR3 result in achondroplasia, one of the most common dwarfisms in humans, but the molecular mechanism remains elusive. In this study, we found that chondrocyte-specific deletion of BMP type I receptor a (Bmpr1 a) rescued the bone overgrowth phenotype observed in Fgfr3 deficient mice by reducing chondrocyte differentiation. Consistently, using in vitro chondrogenic differentiation assay system, we demonstrated that FGFR3 inhibited BMPR1a-mediated chondrogenic differentiation. Furthermore, we showed that FGFR3 hyper-activation resulted in impaired BMP signaling in chondrocytes of mouse growth plates. We also found that FGFR3 inhibited BMP-2-or constitutively activated BMPR1-induced phosphorylation of Smads through a mechanism independent of its tyrosine kinase activity. We found that FGFR3 facilitates BMPR1a to degradation through Smurf1-mediated ubiquitination pathway. We demonstrated that down-regulation of BMP signaling by BMPR1 inhibitor dorsomorphin led to the retardation of chondrogenic differentiation, which mimics the effect of FGF-2 on chondrocytes and BMP-2 treatment partially rescued the retarded growth of cultured bone rudiments from thanatophoric dysplasia type II mice. Our findings reveal that FGFR3 promotes the degradation of BMPR1a, which plays an important role in the pathogenesis of FGFR3-related skeletal dysplasia. (C) 2014 Elsevier B.V. All rights reserved. C1 [Qi, Huabing; Jin, Min; Duan, Yaqi; Du, Xiaolan; Wang, Xiaofeng; Wang, Quan; Zhu, Ying; Xie, Yangli; Chen, Lin] Third Mil Med Univ, Doping Hosp, Inst Surgeiy Res, Ctr Trauma,CBMR, Chongqing 400042, Peoples R China. [Du, Xiaolan; Chen, Lin] Third Mil Med Univ, State Key Lab Trauma Burns & Combined Injury, Chongqing 400042, Peoples R China. [Chen, Lin] Third Mil Med Univ, Daping Hosp, Dept Rehabil Med, Chongqing 400042, Peoples R China. [Zhang, Yuanquan; Ren, Fangli; Wang, Yinyin; Chang, Zhijie] Tsinghua Univ, Sch Med, State Key Lab Biomembrane & Membrane Biotechnol, Beijing 100084, Peoples R China. [Tian, Qingyun; Xie, Yangli] NYU, Sch Med, Dept Cell Biol, New York, NY 10016 USA. [Tian, Qingyun; Liu, Chuanju] NYU, Sch Med, Dept Orthopaed Surg, New York, NY 10003 USA. [Tian, Qingyun; Liu, Chuanju] NYU, Hosp Joint Dis, New York, NY 10003 USA. [Cao, Xu] Johns Hopkins Univ, Sch Med, Dept Orthopaed Surg, Baltimore, MD 21205 USA. [Mishina, Yuji] Univ Michigan, Sch Dent, Dept Biol & Mat Sci, Ann Arbor, MI 48109 USA. [Chen, Di] Rush Univ, Dept Biochem, Chicago, IL 60612 USA. [Deng, Chu-xia] Natl Inst Diabet & Digest & Kidney Dis, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Chang, ZJ (reprint author), Tsinghua Univ, Sch Med, State Key Lab Biomembrane & Membrane Biotechnol, Beijing 100084, Peoples R China. EM zhijiec@tsinghua.edu.cn; linchen70@163.com RI Tian, Qingyun/L-7723-2014; deng, chuxia/N-6713-2016; OI liu, chuanju/0000-0002-7181-8032 FU Tsinghua Internal Research Foundation [20091081322]; National Natural Science Foundation of China [81030036, 30800652]; Special Funds for Major State Basic Research Program of China (973 program) [2012CB518100]; Foundation of the State Key Laboratory of Trauma, Burns and Combined Injury [SKLZZ200902] FX We thank Drs. Pavel Krejci (Masaryk University, Czech Republic), Yeguang Chen (Tsinghua University, China) and Lingqiang Zhang (Beijing Institute of Radiation Medicine, China) for providing constructs. The work was supported by the Tsinghua Internal Research Foundation (20091081322), the National Natural Science Foundation of China (No. 81030036, No. 30800652), the Special Funds for Major State Basic Research Program of China (973 program) (No. 2012CB518100), and the Foundation of the State Key Laboratory of Trauma, Burns and Combined Injury (No. SKLZZ200902). NR 66 TC 12 Z9 13 U1 0 U2 22 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4889 EI 0006-3002 J9 BBA-MOL CELL RES JI Biochim. Biophys. Acta-Mol. Cell Res. PD JUL PY 2014 VL 1843 IS 7 BP 1237 EP 1247 DI 10.1016/j.bbamcr.2014.03.011 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AI2UM UT WOS:000336713600001 PM 24657641 ER PT J AU Brinton, LA Felix, AS AF Brinton, Louise A. Felix, Ashley S. TI Menopausal hormone therapy and risk of endometrial cancer SO JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE Menopausal hormone therapy; Endometrial cancer; Risk; Epidemiology ID ESTROGEN REPLACEMENT THERAPY; BODY-MASS INDEX; POSTMENOPAUSAL WOMEN; LONG-TERM; UNITED-STATES; EXOGENOUS ESTROGENS; PROGESTIN THERAPY; PLUS PROGESTIN; FOLLOW-UP; CARCINOMA AB Endometrial cancer is clearly a hormonally responsive tumor, with a critical role played by estrogens unopposed by progestins. Numerous epidemiologic studies have shown substantial risk increases associated with use of unopposed estrogens, especially among thin women. This risk, however, can be reduced if progestins are added to the therapy. The manner in which progestins are prescribed is a critical determinant of risk. Most studies show that women who have ever used progestins continuously (>25 days/months) are at somewhat reduced risk relative to non-users (meta-analysis relative risk, RR, based on observational studies = 0.78, 95 confidence intervals, CI, 0.72-0.86). The reduced risk in greatest among heavy women. In contrast, women who have ever used progestins sequentially for <10 days each month are at increased risk, with meta-analysis results showing on overall RR of 1.76 (1.51-2.05); in contrast, progestins given for 10-24 days/month appear unrelated to risk (RR= 1.07,0.92-1.24). These risks were based on varying patterns of usage, with little information available regarding how endometrial cancer risk is affected by duration of use, type and/or dose of estrogen or progestin, or mode of administration. Effects may also vary by clinical characteristics (e.g., differences for Type I vs. II tumors). Further resolution of many of these relationships may be dependent on pooling data from multiple studies to derive sufficient power for subgroups of users. With changing clinical practices, it will be important for future studies to monitor a wide range of exposures and to account for divergent effects of different usage patterns. This article is part of a Special Issue entitled 'Menopause'. Published by Elsevier Ltd. C1 [Brinton, Louise A.; Felix, Ashley S.] NCI, Hormonal & Reprod Epidemiol Branch, Rockville, MD 20852 USA. RP Brinton, LA (reprint author), 6120 Execut Blvd,Room 5018, Rockville, MD USA. EM brinton@nih.gov RI Brinton, Louise/G-7486-2015; Felix, Ashley/A-3240-2016 OI Brinton, Louise/0000-0003-3853-8562; FU Intramural NIH HHS [Z01 CP010126-13] NR 58 TC 12 Z9 13 U1 0 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-0760 J9 J STEROID BIOCHEM JI J. Steroid Biochem. Mol. Biol. PD JUL PY 2014 VL 142 SI SI BP 83 EP 89 DI 10.1016/j.jsbmb.2013.05.001 PG 7 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA AI2RA UT WOS:000336704600013 PM 23680641 ER PT J AU Shao, W Kearney, MF Boltz, VF Spindler, JE Mellors, JW Maldarelli, F Coffin, JM AF Shao, Wei Kearney, Mary F. Boltz, Valerie F. Spindler, Jonathan E. Mellors, John W. Maldarelli, Frank Coffin, John M. TI PAPNC, a novel method to calculate nucleotide diversity from large scale next generation sequencing data SO JOURNAL OF VIROLOGICAL METHODS LA English DT Article DE HIV-1; Viral population diversity calculation; Next generation sequencing ID DRUG-RESISTANCE MUTATIONS; DISEASE PROGRESSION; GENETIC DIVERSITY; HIV-1 PROTEASE; ALIGNMENT; MULTIPLE; EVOLUTION; INFECTION; ACCURACY AB Estimating viral diversity in infected patients can provide insight into pathogen evolution and emergence of drug resistance. With the widespread adoption of deep sequencing, it is important to develop tools to accurately calculate population diversity from very large datasets. Current methods for estimating diversity that are based on multiple alignments are not practical to apply to such data. In this study, the authors report a novel method (Pairwise Alignment Positional Nucleotide Counting, PAPNC) for estimating population diversity from 454 sequence data. The diversity measurements determined using this method were comparable to those calculated by average pairwise difference (APD) of multiply aligned sequences using MEGA5. Diversities were estimated for 9 patient plasma HIV samples sequenced with Titanium 454 technology and by single-genome sequencing (SGS). Diversities calculated from deep sequencing using PAPNC ranged from 0.002 to 0.021 while APD measurements calculated from SGS data ranged proximately from 0.001 to 0.018, with the difference being attributable to PCR error (contributing background diversity of 0.0016 in a control sample). Comparison of APDs estimated from 100 sets of sequences drawn at random from 454 generated data and from corresponding SGS data showed very close correlation between the two methods with R-2 of 0.96, and differing on average by about 1% (after correction for PCR error). The authors have developed a novel method that is good for calculating genetic diversities for large scale datasets from next generation sequencing. It can be implemented easily as a function in available variation calling programs like SAMtools or haplotype reconstruction software for nucleotide genetic diversity calculation. A Perl script implementing this method is available upon request. (C) 2014 Elsevier B.V. All rights reserved. C1 [Shao, Wei] Leidos Biomed Res Inc, Adv Biomed Comp Ctr, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Kearney, Mary F.; Boltz, Valerie F.; Spindler, Jonathan E.; Maldarelli, Frank] NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. [Mellors, John W.] Univ Pittsburgh, Div Infect Dis, Pittsburgh, PA USA. [Coffin, John M.] Tufts Univ, Dept Mol Biol & Microbiol, Boston, MA 02111 USA. RP Shao, W (reprint author), Leidos Biomed Res Inc, Adv Biomed Comp Ctr, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. EM shaow@mail.nih.gov FU National Cancer Institute's intramural Center for Cancer Research; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; George Kirby Foundation FX The authors thank Ann Wiegand and Natalia Volfovsky for useful discussions; Claudia Stewart and Alex Levitsky for 454 sequencing and data processing; Elizabeth Anderson for helping with the construction of figures, and Connie Kinna, Susan Jones, and Sue Toms for administrative support. Funding for this research was provided by the National Cancer Institute's intramural Center for Cancer Research and in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. JMC was a research professor of the American Cancer Society, with support from the George Kirby Foundation. 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 29 TC 4 Z9 4 U1 0 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-0934 EI 1879-0984 J9 J VIROL METHODS JI J. Virol. Methods PD JUL PY 2014 VL 203 BP 73 EP 80 DI 10.1016/j.jviromet.2014.03.008 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Virology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Virology GA AI2SP UT WOS:000336708700011 PM 24681054 ER PT J AU De-La-Torre, A Pfaff, AW Grigg, ME Villard, O Candolfi, E Gomez-Marin, JE AF de-la-Torre, Alejandra Pfaff, Alexander W. Grigg, Michael E. Villard, Odile Candolfi, Ermanno Gomez-Marin, Jorge E. TI Ocular cytokinome is linked to clinical characteristics in ocular toxoplasmosis SO CYTOKINE LA English DT Article DE Toxoplasma gondii; Uveitis; Th2; Colombia; Intraocular cytokines ID AQUEOUS-HUMOR; TH17 CELLS; UVEITIS; GONDII; AGE; LYMPHOCYTES; PROFILES; COLOMBIA; SURVIVAL; ALLELES AB Purpose: To determine the cytokine levels in aqueous humor (AH) of Colombian patients with active ocular toxoplasmosis (OT), and to correlate them with their clinical characteristics. Methods: 27 Cytokines/chemokines were assayed in 15 AH samples (nine patients with diagnosis of OT biologically-confirmed and six controls that underwent cataract surgery). Correlations were assessed between cytokine/chemokine levels, type of inflammatory response (Th1, Th2, Th17, Treg), and clinical characteristics. Results: Th2 predominant response was related to more severe clinical features. The presence of VEGF and IL-5 was related to higher number of recurrences. Growth factors (VEGF, FGF, PDGF-beta), were related to higher number of lesions. Patients infected by type-I/III strains had a particular intraocular cytokinepattern. Conclusions: Th2 response was related to more severe clinical characteristics in patients infected by Type strains. IL-5 and VEGF were associated with recurrences. We correlate for the first time, specific cytokine-patterns with clinical characteristics and with the infecting Toxoplasma strain. (C) 2014 Elsevier Ltd. All rights reserved. C1 [de-la-Torre, Alejandra] Univ Rosario, Escuela Med & Ciencias Salud, Dept Inmunol, Bogota, Colombia. [Pfaff, Alexander W.; Villard, Odile; Candolfi, Ermanno] Univ Strasbourg, Fed Med Translat Strasbourg, Inst Parasitol & Pathol Trop, Strasbourg, France. [Grigg, Michael E.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Gomez-Marin, Jorge E.] Univ Quindio, GEPAMOL, Fac Ciencias Salud, Ctr Invest Biomed, Armenia, Colombia. RP Gomez-Marin, JE (reprint author), Univ Quindio, GEPAMOL, Fac Ciencias Salud, Ctr Invest Biomed, Ave Bolivar 12N, Armenia, Colombia. EM gepamol2@uniquindio.edu.co RI Gomez-Marin, Jorge/L-9793-2013; de-la-Torre, Alejandra/G-6436-2016 OI Gomez-Marin, Jorge/0000-0001-6472-3329; de-la-Torre, Alejandra/0000-0003-0684-1989 FU Colciencias [111345921861]; Ecos Nord Program; Fondation pour la Recherche Medicale; NIAID FX This work was supported by Colciencias [Grant 111345921861], the Ecos Nord Program, Fondation pour la Recherche Medicale, and the Intramural Research Program of the National Institutes of Health and NIAID. NR 41 TC 9 Z9 9 U1 1 U2 32 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 EI 1096-0023 J9 CYTOKINE JI Cytokine PD JUL PY 2014 VL 68 IS 1 BP 23 EP 31 DI 10.1016/j.cyto.2014.03.005 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA AH9ON UT WOS:000336471800004 PM 24787053 ER PT J AU Tatari-Calderone, Z Fasano, RM Miles, MR Pinto, LA Luban, NLC Vukmanovic, S AF Tatari-Calderone, Zohreh Fasano, Ross M. Miles, Megan R. Pinto, Ligia A. Luban, Naomi L. C. Vukmanovic, Stanislav TI High multi-cytokine levels are not a predictive marker of alloimmunization in transfused sickle cell disease patients SO CYTOKINE LA English DT Article DE Sickle cell disease; Red blood cell transfusion; Antibodies; Cytokines; Inflammation ID TUMOR-NECROSIS-FACTOR; RED-BLOOD-CELLS; CIRCULATING CYTOKINES; CLINICAL-SIGNIFICANCE; GENE-EXPRESSION; STEADY-STATE; SERUM-LEVELS; IN-VIVO; CHILDREN; INFLAMMATION AB Patients with sickle cell disease (SCD) receive multiple red blood cell (RBC) transfusions for both prevention of and therapy for disease-related complications. In some patients, transfusion results in development of both allo- and auto-antibodies to RBC antigens. What precipitates the antibody formation is currently unclear. It has been hypothesized that a pro-inflammatory state preceding the therapeutic transfusion may be a predisposing factor. Plasma levels of ten cytokines were evaluated upon recruitment to the study of 83 children with SCD undergoing therapeutic RBC transfusiops. The levels of cytokines were correlated with development of anti-RBC antibodies prior, or during seven years post recruitment. Twelve subjects displayed significantly higher levels of all cytokines examined, with pro-, as well as anti-inflammatory properties. Surprisingly, the elevated levels of cytokines were preferentially found in patients without anti-RBC allo- and/or auto-antibodies. Further, presence of high cytokine levels was not predictive of anti-RBC antibody development during the subsequent seven year follow up. These data suggest that the increased concentration of multiple cytokines is not a biomarker of either the presence of or susceptibility to the development of RBC alloimmunization. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Tatari-Calderone, Zohreh; Vukmanovic, Stanislav] Childrens Natl Med Ctr, Sheikh Zayed Inst Pediat Surg Innovat, Washington, DC 20010 USA. [Tatari-Calderone, Zohreh; Fasano, Ross M.; Luban, Naomi L. C.; Vukmanovic, Stanislav] George Washington Univ, Sch Med, Dept Pediat, Washington, DC 20052 USA. [Fasano, Ross M.; Luban, Naomi L. C.] Childrens Natl Med Ctr, Div Hematol & Oncol, Washington, DC 20010 USA. [Fasano, Ross M.; Miles, Megan R.; Luban, Naomi L. C.] Childrens Natl Med Ctr, Dept Lab Med, Washington, DC 20010 USA. [Pinto, Ligia A.] Frederick Natl Lab Canc Res, HPV Immunol Lab, Frederick, MD USA. RP Vukmanovic, S (reprint author), Childrens Natl Med Ctr, Sheikh Zayed Inst Pediat Surg Innovat, 111 Michigan Ave NW, Washington, DC 20010 USA. EM svukmano@childrensnational.org NR 39 TC 4 Z9 4 U1 0 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 EI 1096-0023 J9 CYTOKINE JI Cytokine PD JUL PY 2014 VL 68 IS 1 BP 59 EP 64 DI 10.1016/j.cyto.2014.03.008 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA AH9ON UT WOS:000336471800008 PM 24746244 ER PT J AU Fouladi, M Perentesis, JP Phillips, CL Leary, S Reid, JM McGovern, RM Ingle, AM Ahern, CH Ames, MM Houghton, P Doyle, LA Weigel, B Blaney, SM AF Fouladi, Maryam Perentesis, John P. Phillips, Christine L. Leary, Sarah Reid, Joel M. McGovern, Renee M. Ingle, Ashish M. Ahern, Charlotte H. Ames, Matthew M. Houghton, Peter Doyle, L. Austin Weigel, Brenda Blaney, Susan M. TI A Phase I Trial of MK-2206 in Children with Refractory Malignancies: A Children's Oncology Group Study SO PEDIATRIC BLOOD & CANCER LA English DT Article DE antimicrobial drug resistance; catheter-associated infections; bacterial infections and mycoses; neoplasms; child; neutropenia ID INHIBITOR MK-2206; CLINICAL-TRIAL; BREAST-CANCER; AKT2 ONCOGENE; SOLID TUMORS; PATHWAY; ACTIVATION; AMPLIFICATION; SURVIVAL; TARGET AB Background Cancer is the second most common cause of childhood deaths in the United Kingdom and infection contributes to a quarter of all cancer-related deaths. This study aimed to estimate the risk, aetiology and outcome of bloodstream bacterial and fungal infections in children with cancer within a geographically defined region in South-West London over a 3-year period. Methods Web-based questionnaires were completed using case records of children with positive blood cultures admitted to five London hospitals during 2009-2011. Results A total of 112 children with a median age of 5.4 (IQR 3.6-11.2) years had 266 significant blood cultures during 149 infection episodes. Haematological malignancy affected 68 patients (60.7%) and solid tumours 44 (39.3%). The overall bloodstream infection rate was 1.5 episodes per 1,000 days-at-risk (95% CI, 1.2-1.8) and was similar for those with haematological malignancies and solid tumours. Most episodes were attributed to central venous catheter infection (120/149, 80.5%). Coagulase-negative staphylococci were isolated in almost half the bloodstream infections (127/266; 47.7%), while Gram-negative organisms accounted for a further quarter (64/266; 24.1%). Fungal isolates from blood were uncommon (8/112 children, 7.1%) but significantly associated with neutropenia (18/149 [12.1%] vs. 1/114 [0.9%], P = 0.0004). Six children (5.4%) died, including three (2.7%; 95% CI, 0.6-7.6%) whose deaths were infection-related. Conclusions This study provides an updated risk estimate for bloodstream infections in children with cancer and adds to the framework for developing evidence-based guidance for management of suspected infections in this highly vulnerable group. Pediatr Blood Cancer 2014;61:1239-1245. (c) 2014 Wiley Periodicals, Inc. C1 [Fouladi, Maryam; Perentesis, John P.; Phillips, Christine L.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Leary, Sarah] Childrens Hosp & Reg Med Ctr, Seattle, WA USA. [Reid, Joel M.; McGovern, Renee M.; Ames, Matthew M.] Mayo Clin, Coll Med, Rochester, MN USA. [Ingle, Ashish M.; Ahern, Charlotte H.] Childrens Oncol Grp, Arcadia, CA USA. [Houghton, Peter] Nationwide Childrens Hosp, Columbus, OH USA. [Doyle, L. Austin] NCI, Rockville, MD USA. [Weigel, Brenda] Univ Minnesota, Minneapolis, MN USA. [Blaney, Susan M.] Texas Childrens Canc Ctr, Houston, TX USA. RP Fouladi, M (reprint author), Cincinnati Childrens Hosp Med Ctr, Div Oncol, 3333 Burnet Ave, Cincinnati, OH 45229 USA. EM maryam.fouladi@cchmc.org FU National Cancer Institute [U01 CA97452]; Cancerfree KIDS FX Grant sponsor: National Cancer Institute; Grant numbers: U01 CA97452; Grant sponsor: Cancerfree KIDS NR 20 TC 17 Z9 17 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUL PY 2014 VL 61 IS 7 BP 1246 EP 1251 DI 10.1002/pbc.24995 PG 6 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AG1TG UT WOS:000335198400023 PM 24664955 ER PT J AU Abraham, AG Mak, RH Mitsnefes, M White, C Moxey-Mims, M Warady, B Furth, SL AF Abraham, Alison G. Mak, Robert H. Mitsnefes, Mark White, Colin Moxey-Mims, Marva Warady, Bradley Furth, Susan L. TI Protein energy wasting in children with chronic kidney disease SO PEDIATRIC NEPHROLOGY LA English DT Article DE Cachexia inflammation syndrome; Hospitalization; Chronic kidney disease; Malnutrition; Growth; Glomerular filtration rate ID GLOMERULAR-FILTRATION-RATE; NONTRADITIONAL RISK-FACTORS; STAGE RENAL-DISEASE; PLASMA CREATININE; MORTALITY; INFANTS; COHORT; DEATH; CKD; GFR AB In adults with chronic kidney disease (CKD), protein-energy wasting (PEW) is a risk factor for hospitalization and death. However, PEW in children with CKD is not well characterized or defined. Using data from the Chronic Kidney Disease in Children study, we assessed three alternate definitions of PEW using biochemical parameters, body and muscle mass measurements, and reported appetite as described in adults: (1) a minimal PEW definition (a parts per thousand yen2 of the four criteria); (2) a standard PEW definition (a parts per thousand yen3 of the four criteria); (3) a modified PEW definition (a parts per thousand yen3 of the four criteria plus a pediatric-focused criterion of short stature or poor growth). Of the 528 children analyzed in this study (median age 12 years, median glomerular filtration rate 45 mL/min/1.73 m(2), 39 % female, 18 % African American), 7-20 % met the spectrum of definitions for PEW. The unadjusted incidence rates for incident hospitalizations were 1.9-, 2.1-, and 2.2-fold higher for those children diagnosed with PEW using the minimal, standard, and modified definitions, respectively (P = 0.08, 0.09 and 0.03). Following adjustment, only the modified PEW definition, which added short stature or poor growth as a criterion, showed modest significance (P = 0.06). The inclusion of a criterion based on growth may augment the definition of PEW and improve risk discrimination in children with CKD. C1 [Abraham, Alison G.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Mak, Robert H.] UC San Diego Sch Med, Dept Pediat, San Diego, CA USA. [Mitsnefes, Mark] Cincinnati Childrens Hosp, Dept Pediat, Cincinnati, OH USA. [White, Colin] Univ British Columbia, Dept Pediat, Vancouver, BC V6T 1W5, Canada. [Moxey-Mims, Marva] NIDDK, Div Kidney Urol & Hematol, NIH, Bethesda, MD 20892 USA. [Warady, Bradley] Childrens Mercy Hosp & Clin, Dept Pediat, Kansas City, MO USA. [Furth, Susan L.] Univ Penn, Dept Pediat & Epidemiol, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Abraham, AG (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, 615 North Wolfe St, Baltimore, MD 21205 USA. EM aabraham@jhsph.edu 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 DK82194, U01-DK-66143, U01-DK-66174, U01-DK-66116] FX The authors would like to acknowledge the efforts of Derek Ng and Rachel Zack in the analysis of the data presented in this manuscript. Data in this manuscript were collected by the Chronic Kidney Disease in children prospective cohort study (CKiD) with clinical coordinating centers (Principal Investigators) at Children's Mercy Hospital and the University of Missouri-Kansas City (Bradley Warady, MD) and Children's Hospital of Philadelphia (Susan Furth, MD, Ph.D.), data coordinating center at the Johns Hopkins Bloomberg School of Public Health (Alvaro Munoz, PhD), and the Central Biochemistry Laboratory at the University of Rochester (George J. Schwartz, MD). The CKiD is funded by the 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 (U01 DK82194, U01-DK-66143, U01-DK-66174, and U01-DK-66116). The CKID website is located at http://www.statepi.jhsph.edu/ckid. NR 33 TC 5 Z9 6 U1 0 U2 2 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 JUL PY 2014 VL 29 IS 7 BP 1231 EP 1238 DI 10.1007/s00467-014-2768-9 PG 8 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA AH9BQ UT WOS:000336434600015 PM 24504731 ER PT J AU Striano, BM Barker, DJ Pawlak, AP Root, DH Fabbricatore, AT Coffey, KR Stamos, JP West, MO AF Striano, Brendan M. Barker, David J. Pawlak, Anthony P. Root, David H. Fabbricatore, Anthony T. Coffey, Kevin R. Stamos, Joshua P. West, Mark O. TI Olfactory Tubercle Neurons Exhibit Slow-Phasic Firing Patterns During Cocaine Self-Administration SO SYNAPSE LA English DT Article DE addiction; dopamine; ventral striatum; cocaine ID NUCLEUS-ACCUMBENS NEURONS; DOPAMINE; RAT C1 [Striano, Brendan M.; Barker, David J.; Pawlak, Anthony P.; Root, David H.; Fabbricatore, Anthony T.; West, Mark O.] Rutgers State Univ, Dept Psychol, Piscataway, NJ 08854 USA. [Root, David H.] NIDA, Neural Networks Sect, Integrat Neurosci Res Branch, Baltimore, MD 21224 USA. RP West, MO (reprint author), Rutgers State Univ, Dept Psychol, 152 Frelinghuysen Rd, Piscataway, NJ 08854 USA. EM markwest@rutgers.edu OI Root, David/0000-0002-1927-2175 FU National Institute on Drug Abuse Grants [DA006886, DA032270] FX Contract grant sponsor: National Institute on Drug Abuse Grants; Contract grant numbers: DA006886 (MOW) and DA032270 (DJB). NR 14 TC 3 Z9 3 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0887-4476 EI 1098-2396 J9 SYNAPSE JI Synapse PD JUL PY 2014 VL 68 IS 7 BP 321 EP 323 DI 10.1002/syn.21744 PG 3 WC Neurosciences SC Neurosciences & Neurology GA AG8DG UT WOS:000335648400005 PM 24700541 ER PT J AU Burbelo, PD Arnbatipudi, K Alevizos, I AF Burbelo, Peter D. Arnbatipudi, Kiran Alevizos, Ilias TI Genome-wide association studies in Sjogren's syndrome: What do the genes tell us about disease pathogenesis? SO AUTOIMMUNITY REVIEWS LA English DT Review DE Autoimmune disease; Candidate genes; Genetics; Genome-wide association studies; Polymorphisms; Sjogren's syndrome; SNP ID CLASSIFICATION CRITERIA; AUTOIMMUNE-DISEASE; EMERGING ROLES; RISK-FACTOR; CELLS; IRF5; SUSCEPTIBILITY; EXPRESSION; STAT4; POLYMORPHISM AB The pathogenesis of Sjogren's syndrome (SS) likely involves complex interactions between genes and the environment. While the candidate gene approach has been previously used to identify several genes associated with SS, two recent large-scale genome-wide association studies (GWAS) have implicated many more loci as genetic risk factors. Of particular relevance, was the significant association of SS with additional immune-related genes including IL12A, BLK, and CXCR5. GWAS has also uncovered other loci and suggestive gene associations in SS, but none are related to genes encoding salivary or lacrimal components, secretion machinery and neuronal proteins involved in innervations of the glands, respectively. In this review, we discuss these genetic findings with particular attention paid to the genes identified, the strength of associations, and how the SS-associated genes compare to what has been discovered previously in systemic lupus erythematosus (SLE). We also summarize the potential impact of these associated gene products on NF kappa B and immune pathways and describe how this new information might be integrated further for identifying clinical subsets and understanding the pathogenesis of SS. Published by Elsevier B.V. C1 [Burbelo, Peter D.] Natl Inst Dent & Craniofacial Res, Dent Clin Res Core, NIH, Bethesda, MD USA. [Arnbatipudi, Kiran] Natl Inst Dent & Craniofacial Res, Secretory Mech & Dysfunct Sect, NIH, Bethesda, MD USA. RP Burbelo, PD (reprint author), Bldg 10,Room 5N102,10 Ctr Dr, Bethesda, MD 20892 USA. EM burbelop@nidcr.nih.gov FU NIH; NIDCR FX This research was supported by the intramural research program of NIH and NIDCR. NR 43 TC 24 Z9 25 U1 1 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-9972 EI 1873-0183 J9 AUTOIMMUN REV JI Autoimmun. Rev. PD JUL PY 2014 VL 13 IS 7 BP 756 EP 761 DI 10.1016/j.autrev.2014.02.002 PG 6 WC Immunology SC Immunology GA AH0JS UT WOS:000335805800008 PM 24657515 ER PT J AU Nanes, JA Xia, YL Dassanayake, RMAPS Jones, RM Li, A Stodgell, CJ Walker, CK Szabo, S Leuthner, S Durkin, MS Moye, J Miller, RK AF Nanes, Jessica A. Xia, Yulin Dassanayake, R. M. A. Priyanthi S. Jones, Rachael M. Li, An Stodgell, Christopher J. Walker, Cheryl K. Szabo, Sara Leuthner, Steve Durkin, Maureen S. Moye, Jack Miller, Richard K. CA Natl Children's Study Placenta Con TI Selected persistent organic pollutants in human placental tissue from the United States SO CHEMOSPHERE LA English DT Article DE Persistent organic pollutants; Human placenta; Polybrominated diphenyl ethers (PBDEs); Polychlorinated biphenyls (PCBs); Dichlorodiphenyldichloroethylene (DDE); National Children's Study (NCS) ID POLYBROMINATED DIPHENYL ETHERS; DIBENZO-P-DIOXINS; POLYCHLORINATED-BIPHENYLS; PREGNANT-WOMEN; BREAST-MILK; CORD SERUM; PBDES; EXPOSURE; METABOLITES; CALIFORNIA AB Emerging and legacy environmental pollutants such as polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs) and organochlorine pesticide metabolite DDE are found in human placenta, indicating prenatal exposure, but data from the United States are sparse. We sought to determine concentrations of these compounds in human placentae as part of a formative research project conducted by the National Children's Study Placenta Consortium. A total of 169 tissue specimens were collected at different time points post delivery from 43 human placentae at three U.S. locations, and analyzed by gas chromatography coupled with mass spectrometry following extraction using matrix solid phase dispersion. PBDEs, PCBs, and DDE were detected in all specimens. The concentrations of 10 PBDEs (Sigma 10PBDEs), 32 PCBs (Sigma 32PCBs) and p,p(1)-DDE were 43-1723,76-856 and 10-1968 pg g-1 wet weight, respectively, in specimens collected shortly after delivery. Significant geographic differences in PBDEs were observed, with higher concentrations in placentae collected in Davis, CA than in those from Rochester, NY or Milwaukee, WI. We combined these with other published data and noted first-order declining trends for placental PCB and DDE concentrations over the past decades, with half-lives of about 5 and 8 years, respectively. The effect of time to tissue collection from refrigerated placentae on measured concentrations of these three classes of persistent organic pollutants was additionally examined, with no significant effect observed up to 120 h. The results of this work indicate that widespread prenatal exposure to persistent organic pollutants in the United States continues.(c) 2014 Elsevier Ltd. All rights reserved. C1 [Nanes, Jessica A.; Xia, Yulin; Dassanayake, R. M. A. Priyanthi S.; Jones, Rachael M.; Li, An] Univ Illinois, Sch Publ Hlth, Chicago, IL USA. [Stodgell, Christopher J.; Miller, Richard K.] Univ Rochester, Sch Med & Dent, Dept Obstet Gynecol, Rochester, NY USA. [Walker, Cheryl K.] Univ Calif Davis, Sch Med, Dept Obstet & Gynecol, Davis, CA USA. [Szabo, Sara; Leuthner, Steve] Med Coll Wisconsin, Dept Pathol, Milwaukee, WI 53226 USA. [Szabo, Sara; Leuthner, Steve] Med Coll Wisconsin, Dept Pediat, Milwaukee, WI 53226 USA. [Durkin, Maureen S.] Univ Wisconsin, Madison Sch Med & Publ Hlth, Dept Populat Hlth Sci, Madison, WI USA. [Durkin, Maureen S.] Univ Wisconsin, Madison Sch Med & Publ Hlth, Dept Pediat, Madison, WI USA. [Moye, Jack] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Natl Childrens Study, NIH, Bethesda, MD USA. RP Li, A (reprint author), UIC MC 922, SPH, EOHS, 2121 W Taylor St, Chicago, IL 60612 USA. EM anli@uic.edu RI Durkin, Maureen/B-7834-2015; Li, An/A-3395-2008; OI Li, An/0000-0002-8476-8783; Stodgell, Christopher/0000-0002-1666-5299; moye, john/0000-0001-9976-8586 FU National Children's Study Placenta Consortium (NCS formative research project) [LOI2-BIO-18]; Eunice Kennedy Shriver National Institute of Child Health and Human Development; Office of the Director of the National Institutes of Health; NICHD [HHSN267200700027C, HHSN275201100002C, HHSN275200503396C] FX This work is part of the National Children's Study Placenta Consortium (NCS formative research project LOI2-BIO-18). This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and funded, through its appropriation, by the Office of the Director of the National Institutes of Health, with NICHD Contracts HHSN267200700027C, HHSN275201100002C, and HHSN275200503396C. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the National Institutes of Health or the U.S. Department of Health and Human Services. NR 39 TC 9 Z9 11 U1 4 U2 67 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0045-6535 EI 1879-1298 J9 CHEMOSPHERE JI Chemosphere PD JUL PY 2014 VL 106 BP 20 EP 27 DI 10.1016/j.chemosphere.2013.12.080 PG 8 WC Environmental Sciences SC Environmental Sciences & Ecology GA AE6VR UT WOS:000334136600002 PM 24485817 ER PT J AU Ali, T Nakajima, T Sano, K Sato, K Choyke, PL Kobayashi, H AF Ali, Towhid Nakajima, Takahito Sano, Kohei Sato, Kazuhide Choyke, Peter L. Kobayashi, Hisataka TI Dynamic fluorescent imaging with indocyanine green for monitoring the therapeutic effects of photoimmunotherapy SO CONTRAST MEDIA & MOLECULAR IMAGING LA English DT Article DE photoimmunothearpy; cancer fluorescence imaging; indocyanine green; super-enhanced permeability and retention effect ID BREAST-CANCER; HEPATOCELLULAR-CARCINOMA; CLINICAL-EXPERIENCE; NAVIGATION SURGERY; GUIDED SURGERY; LIGHT; RECONSTRUCTION; FEASIBILITY; TIME; CHOLANGIOGRAPHY AB A new type of monoclonal antibody (mAb)-based, highly specific phototherapy (photoimmunotherapy; PIT) that uses a near-infrared (NIR) phthalocyanine dye, IRDye700DX (IR700) conjugated with an mAb, has recently been described. NIR light exposure leads to immediate, target-selective necrotic cell death. However, tumor shrinkage takes several days to occur, making it difficult to detect earlier changes in the tumor. In this study, Panitumumab targeting the epidermal growth factor receptor (EGFR1) conjugated to IR700 was used to treat EGFR-expressing A431 tumor cells and in vivo xenografts. PIT was performed at varying doses of NIR light (10, 30, 50 and 100Jcm(-2)) in xenograft tumors in mice. Indocyanine green (ICG) dynamic imaging was evaluated for monitoring cytotoxic effects for the first hour after PIT. Our results demonstrated a statistical difference (p<0.05) in ICG intensity between control and PIT treated tumors in the higher light exposure groups (50Jcm(-2): 2.94 +/- 0.35 vs 5.22 +/- 0.92, p=0.02; and 100Jcm(-2): 3.56 +/- 0.96 vs 5.71 +/- 1.43, p=0.008) as early as 20min post ICG injection. However, no significant difference (p>0.05) in ICG intensity between control and PIT treated tumors was evident in the lower light exposure group at any time points up to 60min (10Jcm(-2): 1.92 +/- 0.49 vs 1.71 +/- 0.3, p=0.44; and 30Jcm(-2): 1.57 +/- 0.35 vs 2.75 +/- 0.59, p=0.07). Similarly, the retention index (background to corrected uptake ratio of ICG) varied with light exposure. In conclusion, ICG may serve as a potential indicator of acute cytotoxic effects of mAb-IR700-induced PIT even before morphological changes can be seen in targeted tumors. Published 2014. This article is a U.S. Government work and is in the public domain in the USA. C1 [Ali, Towhid; Nakajima, Takahito; Sano, Kohei; Sato, Kazuhide; Choyke, Peter L.; Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM Kobayash@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; NIH through the National Institutes of Health (NIH) Medical Research Scholars Program, a public-private partnership FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. This research was made possible through the National Institutes of Health (NIH) Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer Inc., The Leona M. and Harry B. Helmsley Charitable Trust, and the Howard Hughes Medical Institute, as well as other private donors. For a complete list, please visit the Foundation website at http://www.fnih.org/work/programs-development/medical-research-scholars- program. NR 45 TC 3 Z9 3 U1 1 U2 44 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1555-4309 EI 1555-4317 J9 CONTRAST MEDIA MOL I JI Contrast Media Mol. Imaging PD JUL PY 2014 VL 9 IS 4 BP 276 EP 282 DI 10.1002/cmmi.1570 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AE2TG UT WOS:000333825300003 PM 24706611 ER PT J AU Guariento, AH Furtado, KS de Conti, A Campos, A Purgatto, E Carrilho, J Shinohara, EMG Tryndyak, V Han, T Fuscoe, JC Ross, SA Beland, FA Pogribny, IP Moreno, FS AF Guariento, Aline H. Furtado, Kelly S. de Conti, Aline Campos, Adriana Purgatto, Eduardo Carrilho, Jessica Guerra Shinohara, Elvira Maria Tryndyak, Volodymyr Han, Tao Fuscoe, James C. Ross, Sharon A. Beland, Frederick A. Pogribny, Igor P. Moreno, Fernando S. TI Transcriptomic responses provide a new mechanistic basis for the chemopreventive effects of folic acid and tributyrin in rat liver carcinogenesis SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE angiogenesis; folic acid; tributyrin; hepatocarcinogenesis; chemoprevention ID ENDOTHELIAL GROWTH-FACTOR; HEPATOCELLULAR-CARCINOMA; CANCER PREVENTION; HEPATOCARCINOGENESIS; ANGIOGENESIS; EXPRESSION; CELLS; INHIBITORS; NEOPLASIA; PROMOTION AB The steady increase in the incidence and mortality of hepatocellular carcinoma (HCC) signifies a crucial need to understand better its pathogenesis to improve clinical management and prevention of the disease. The aim of this study was to investigate molecular mechanisms for the chemopreventive effects of folic acid and tributyrin alone or in combination on rat hepatocarcinogenesis. Male Wistar rats were subjected to a classic "resistant hepatocyte" model of liver carcinogenesis and treated with folic acid and tributyrin alone or in combination for 5 weeks during promotion stage. Treatment with folic acid and tributyrin alone or in combination strongly inhibited the development of glutathione-S-transferase placental form (GSTP)-positive foci. Microarray analysis showed significant changes in gene expression. A total of 498, 655 and 940 of differentially expressed genes, involved in cell cycle, p53-signaling, angiogenesis and Wnt pathways, was identified in the livers of rats treated with folic acid, tributyrin or folic acid and tributyrin. A detailed analysis of these differentially expressed genes revealed that treatments inhibited angiogenesis in the preneoplastic livers. This was evidenced by the fact that 30 out of 77 differentially expressed genes common to all three treatments are involved in the regulation of the angiogenesis pathway. The inhibition of angiogenesis was confirmed by reduced levels of CD34 protein. In conclusion, the tumor-suppressing activity of folic acid and tributyrin is associated with inhibition of angiogenesis at early stages of rat liver carcinogenesis. Importantly, the combination of folic acid and tributyrin has stronger chemopreventive effect than each of the compounds alone. C1 [Guariento, Aline H.; Furtado, Kelly S.; Campos, Adriana; Moreno, Fernando S.] Univ Sao Paulo, Lab Diet Nutr & Canc, Dept Food & Expt Nutr, Sao Paulo, Brazil. [de Conti, Aline; Tryndyak, Volodymyr; Beland, Frederick A.; Pogribny, Igor P.] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Purgatto, Eduardo] Univ Sao Paulo, Lab Food Chem & Biochem, Dept Food & Expt Nutr, Sao Paulo, Brazil. [Carrilho, Jessica; Guerra Shinohara, Elvira Maria] Univ Sao Paulo, Fac Pharmaceut Sci, Hematol Lab, Dept Clin & Toxicol Anal, Sao Paulo, Brazil. [Han, Tao; Fuscoe, James C.] Natl Ctr Toxicol Res, Div Syst Biol, Jefferson, AR 72079 USA. [Ross, Sharon A.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Moreno, FS (reprint author), Univ Sao Paulo, Lab Diet Nutr & Canc, Sao Paulo, Brazil. EM igor.pogribny@fda.hhs.gov; rmoreno@usp.br RI Purgatto, Eduardo/C-7707-2009; Guerra-Shinohara, Elvira/E-5610-2012; Moreno, Fernando/I-1943-2013 OI Purgatto, Eduardo/0000-0002-7372-1197; Guerra-Shinohara, Elvira/0000-0001-6681-2210; FU Intramural NIH HHS [Z99 CA999999] NR 46 TC 3 Z9 4 U1 1 U2 26 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 JUL 1 PY 2014 VL 135 IS 1 BP 7 EP 18 DI 10.1002/ijc.28642 PG 12 WC Oncology SC Oncology GA AE9TR UT WOS:000334353500002 PM 24302446 ER PT J AU Matsuda, S Yan, T Mizutani, A Sota, T Hiramoto, Y Prieto-Vila, M Chen, L Satoh, A Kudoh, T Kasai, T Murakami, H Fu, L Salomon, DS Seno, M AF Matsuda, Shuichi Yan, Ting Mizutani, Akifumi Sota, Tatsuyuki Hiramoto, Yuki Prieto-Vila, Marta Chen, Ling Satoh, Ayano Kudoh, Takayuki Kasai, Tomonari Murakami, Hiroshi Fu, Li Salomon, David S. Seno, Masaharu TI Cancer stem cells maintain a hierarchy of differentiation by creating their niche SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE niche; cancer stem cell; vascular endothelium; differentiation; self-renewal ID ENDOTHELIAL-CELLS; SELF-RENEWAL; GLIOBLASTOMA CELLS; NOTCH; PATHWAY; PLASTICITY; SURVIVAL; PROMOTES; HEDGEHOG; GROWTH AB The self-renewal and differentiation properties of cancer stem cells (CSCs) are regulated and maintained by the CSC niche. However, the mechanism of this maintenance, especially the maintenance contributed by differentiated cancer cells, remains to be fully elucidated. Recently, we have established a model of CSCs, miPS-LLCcm, from mouse induced pluripotent stem cells (miPSCs). In vitro cultured miPS-LLCcm cells were autonomously balanced with stem-like cells and differentiated cells including vascular endothelial cells. Under these conditions, the CSC properties appeared to be stable in the presence of the factor(s) secreted by the differentiated cells. The factor(s) activated Notch signaling and promoted self-renewal of CSCs. In addition, the secreted factor(s) appeared to regulate the differentiation lineage of CSCs. Our results indicate that the differentiated progenies of CSCs containing vascular endothelium play important roles for regulating the CSC's properties. Therefore, miPS-LLCcm cells create their own in vitro niche to maintain themselves in the hierarchy of differentiating CSCs. C1 [Matsuda, Shuichi; Yan, Ting; Mizutani, Akifumi; Sota, Tatsuyuki; Hiramoto, Yuki; Prieto-Vila, Marta; Satoh, Ayano; Kudoh, Takayuki; Kasai, Tomonari; Murakami, Hiroshi; Seno, Masaharu] Okayama Univ, Grad Sch Nat Sci & Technol, Dept Biotechnol, Okayama 7008530, Japan. [Chen, Ling] Tianjin Cent Hosp Gynecol Obstet, Dept Pathol, Tianjin, Peoples R China. [Fu, Li] Tianjin Med Univ, Canc Hosp, State Key Lab Breast Canc Res, Dept Breast Canc Pathol, Tianjin, Peoples R China. [Fu, Li] Tianjin Med Univ, Canc Hosp, Res Lab, Tianjin, Peoples R China. [Salomon, David S.] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21701 USA. RP Mizutani, A (reprint author), Okayama Univ, Grad Sch Nat Sci & Technol, Dept Biotechnol, Kita Ku, 3-1-1 Tsushima Naka, Okayama 7008530, Japan. EM mizut-a@okayama-u.ac.jp RI SENO, Masaharu /B-2092-2011; OI SENO, Masaharu /0000-0001-8547-6259; SATOH, Ayano/0000-0003-3736-1283 FU Advanced Research Training program; [23650598]; [21300179]; [24501315] FX Grant sponsor: Grant-in-Aid for Challenging Exploratory Research; Grant number: 23650598; Grant sponsor: Grant-in-Aid for Scientific Research B); Grant number: 21300179; Grant sponsor: Grant-in-Aid for Scientific Research C); Grant number: 24501315; Grant sponsor: Advanced Research Training program NR 29 TC 6 Z9 6 U1 0 U2 65 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 JUL 1 PY 2014 VL 135 IS 1 BP 27 EP 36 DI 10.1002/ijc.28648 PG 10 WC Oncology SC Oncology GA AE9TR UT WOS:000334353500004 PM 24323788 ER PT J AU Virtamo, J Taylor, PR Kontto, J Mannisto, S Utriainen, M Weinstein, SJ Huttunen, J Albanes, D AF Virtamo, Jarmo Taylor, Phil R. Kontto, Jukka Mannisto, Satu Utriainen, Meri Weinstein, Stephanie J. Huttunen, Jussi Albanes, Demetrius TI Effects of alpha-tocopherol and beta-carotene supplementation on cancer incidence and mortality: 18-Year postintervention follow-up of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE post-trial; mortality; beta-carotene; alpha-tocopherol; cancer ID RANDOMIZED CONTROLLED-TRIAL; LONG-TERM SUPPLEMENTATION; RETINOL EFFICACY TRIAL; DIETARY VITAMIN-E; PROSTATE-CANCER; LUNG-CANCER; CARDIOVASCULAR-DISEASE; RISK; MEN; SELENIUM AB In the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study among 29,133 Finnish male smokers aged 50-69 years, daily alpha-tocopherol (50 mg) for a median of 6.1 years decreased the risk of prostate cancer, whereas beta-carotene (20 mg) increased risk of lung cancer and overall mortality. To determine the postintervention effects of alpha-tocopherol and beta-carotene, 25,563 men were followed 18 years for cancer incidence and all causes of mortality through national registers. Neither supplement had significant effects on post-trial cancer incidence. Relative risk (RR) for lung cancer (n = 2,881) was 1.04 (95% confidence interval [CI], 0.96-1.11) among beta-carotene recipients compared with nonrecipients. For prostate cancer (n = 2,321), RR was 0.97 (95% CI, 0.89-1.05) among alpha-tocopherol recipients compared with nonrecipients with the preventive effect of alpha-tocopherol continuing similar to 8 years postintervention. Body mass index significantly modified the effect of alpha-tocopherol on prostate cancer (p for interaction = 0.01) RR 1.00 (95% CI, 0.88-1.14) in normal-weight men, 0.87 (95% CI, 0.77-0.98) in overweight men, and 1.25 (95% CI, 1.01-1.55) in obese men. The post-trial relative mortality (based on 16,686 deaths) was 1.02 (95% CI, 0.98-1.05) for alpha-tocopherol recipients compared with nonrecipients and 1.02 (95% CI, 0.99-1.05) for beta-carotene recipients compared with nonrecipients. alpha-Tocopherol decreased post-trial prostate cancer mortality (RR, 0.84; 95% CI, 0.70-0.99), whereas beta-carotene increased it (RR, 1.20; 95% CI, 1.01-1.42). In conclusion, supplementation with alpha-tocopherol and beta-carotene appeared to have no late effects on cancer incidence. The preventive effect of moderate-dose alpha-tocopherol on prostate cancer continued several years post-trial and resulted in lower prostate cancer mortality. C1 [Virtamo, Jarmo; Kontto, Jukka; Mannisto, Satu; Huttunen, Jussi] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, FI-00271 Helsinki, Finland. [Taylor, Phil R.; Weinstein, Stephanie J.; Albanes, Demetrius] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Utriainen, Meri] Univ Helsinki, Cent Hosp, Dept Oncol, Helsinki, Finland. RP Virtamo, J (reprint author), Natl Inst Hlth & Welf, Dept Chron Dis Prevent, POB 30, FI-00271 Helsinki, Finland. EM jarmo.virtamo@thl.fi RI Albanes, Demetrius/B-9749-2015; OI Mannisto, Satu/0000-0002-8668-3046 FU National Cancer Institute at the National Institutes of Health (U.S. Public Health Service) [N01-CN-45165, N01-RC-45035, N01-RC-37004, HHSN261201000006C] FX Grant sponsor: Intramural Research Program of the National Cancer Institute at the National Institutes of Health (U.S. Public Health Service); Grant numbers: N01-CN-45165, N01-RC-45035, N01-RC-37004 and HHSN261201000006C NR 33 TC 17 Z9 19 U1 1 U2 20 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 JUL 1 PY 2014 VL 135 IS 1 BP 178 EP 185 DI 10.1002/ijc.28641 PG 8 WC Oncology SC Oncology GA AE9TR UT WOS:000334353500019 PM 24338499 ER PT J AU Turner, MA Catapano, M Hirschfeld, S Giaquinto, C AF Turner, M. A. Catapano, M. Hirschfeld, S. Giaquinto, C. CA GRiP Global Res Paediat TI Paediatric drug development: The impact of evolving regulations SO ADVANCED DRUG DELIVERY REVIEWS LA English DT Review DE Children's medicine; Regulatory framework; Pharmaceutical development; Risk benefit ratio; Extrapolation; Pharmacokinetics; Pharmacodynamics ID EUROPEAN MEDICINES AGENCY; CLINICAL-TRIALS; CHILDREN; INITIATIVES; PRODUCTS; THERAPY; INFANTS; HEALTH; EXCLUSIVITY; PERSPECTIVE AB Children deserve medicines that are adapted to their needs. The need to include children in drug development has been recognised increasingly over the past few decades. Legal and regulatory frameworks are well established in the EU and US. The amount of work done to study medicines for children is significantly greater than it was 10 years go. Proof-of-concept has been demonstrated for all segments of the paediatric drug development pipeline. It is now time-to examine how the practice of developing medicines for children has evolved within those frameworks and to determine how that work should be generalised. This review describes the development of medicines for children and critically appraises the work that has been done within those frameworks. Significant effort is needed to realize the potential provided by the current regulatory framework. Using the work programme of the Global Research in Paediatrics (GRiP) Network of Excellence as a template we outline current work and future growing points. (C) 2014 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). C1 [Turner, M. A.] Univ Liverpool, Liverpool Womens NHS Fdn Trust, Dept Womens & Childrens Hlth, Inst Translat Med, Liverpool L8 7SS, Merseyside, England. [Catapano, M.] Univ Pavia, Italian Grp Study Pharmacoecon GISF, I-27100 Pavia, Italy. [Hirschfeld, S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. [Giaquinto, C.] Azienda Osped Padova AOPD, Dept Paediat, I-35128 Padua, Italy. RP Turner, MA (reprint author), Liverpool Womens NHS Fdn Trust, Crown St, Liverpool L8 7SS, Merseyside, England. EM mark.turner@liv.ac.uk; mariana.c@libero.it; hirschfs@mail.nih.gov; carlog@pediatria.unipd.it RI Hirschfeld, Steven/E-2987-2016; OI Hirschfeld, Steven/0000-0003-0627-7249; Turner, Mark/0000-0002-5299-8656 FU European Union [261060]; Global Research in Paediatrics Network (GRiP) FX The research leading to these results has received funding from the European Union Seventh Framework Programme FP7/2007-2013 under grant agreement no. 261060. The Global Research in Paediatrics Network (GRiP) has been funded in order to implement an infrastructure matrix to stimulate and facilitate the development and safe use of medicine in children. GRiP aims to create consensus on international standards, methodologies and tools for paediatric research. NR 88 TC 20 Z9 20 U1 1 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-409X EI 1872-8294 J9 ADV DRUG DELIVER REV JI Adv. Drug Deliv. Rev. PD JUN 30 PY 2014 VL 73 BP 2 EP 13 DI 10.1016/j.addr.2014.02.003 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AL0IY UT WOS:000338811800002 PM 24556465 ER PT J AU McMahon, PM Meza, R Plevritis, SK Black, WC Tammemagi, CM Erdogan, A ten Haaf, K Hazelton, W Holford, TR Jeon, J Clarke, L Kong, CY Choi, SE Munshi, VN Han, SS van Rosmalen, J Pinsky, PF Moolgavkar, S de Koning, HJ Feuer, EJ AF McMahon, Pamela M. Meza, Rafael Plevritis, Sylvia K. Black, William C. Tammemagi, C. Martin Erdogan, Ayca ten Haaf, Kevin Hazelton, William Holford, Theodore R. Jeon, Jihyoun Clarke, Lauren Kong, Chung Yin Choi, Sung Eun Munshi, Vidit N. Han, Summer S. van Rosmalen, Joost Pinsky, Paul F. Moolgavkar, Suresh de Koning, Harry J. Feuer, Eric J. TI Comparing Benefits from Many Possible Computed Tomography Lung Cancer Screening Programs: Extrapolating from the National Lung Screening Trial Using Comparative Modeling SO PLOS ONE LA English DT Article ID THORACIC-SURGERY GUIDELINES; DECISION-MAKING; AMERICAN ASSOCIATION; POTENTIAL BENEFITS; ELDERLY-PATIENTS; TASK-FORCE; RISK MODEL; SMOKING; MORTALITY; PROSTATE AB Background. The National Lung Screening Trial (NLST) demonstrated that in current and former smokers aged 55 to 74 years, with at least 30 pack-years of cigarette smoking history and who had quit smoking no more than 15 years ago, 3 annual computed tomography (CT) screens reduced lung cancer-specific mortality by 20% relative to 3 annual chest X-ray screens. We compared the benefits achievable with 576 lung cancer screening programs that varied CT screen number and frequency, ages of screening, and eligibility based on smoking. Methods and Findings: We used five independent microsimulation models with lung cancer natural history parameters previously calibrated to the NLST to simulate life histories of the US cohort born in 1950 under all 576 programs. 'Efficient' (within model) programs prevented the greatest number of lung cancer deaths, compared to no screening, for a given number of CT screens. Among 120 'consensus efficient (identified as efficient across models) programs, the average starting age was 55 years, the stopping age was 80 or 85 years, the average minimum pack-years was 27, and the maximum years since quitting was 20. Among consensus efficient programs, 11% to 40% of the cohort was screened, and 153 to 846 lung cancer deaths were averted per 100,000 people. In all models, annual screening based on age and smoking eligibility in NLST was not efficient; continuing screening to age 80 or 85 years was more efficient. Conclusions:Consensus results from five models identified a set of efficient screening programs that include annual CT lung cancer screening using criteria like NLST eligibility but extended to older ages. Guidelines for screening should also consider harms of screening and individual patient characteristics. C1 [McMahon, Pamela M.; Kong, Chung Yin; Choi, Sung Eun; Munshi, Vidit N.] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [McMahon, Pamela M.; Kong, Chung Yin] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Meza, Rafael] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Plevritis, Sylvia K.; Erdogan, Ayca; Han, Summer S.] Stanford Univ, Dept Radiol, Stanford, CA 94305 USA. [Black, William C.] Dartmouth Coll, Hitchcock Med Ctr, Dartmouth Med Sch, Dept Radiol, Hanover, NH 03756 USA. [Tammemagi, C. Martin] Brock Univ, Dept Community Hlth Sci, St Catharines, ON L2S 3A1, Canada. [ten Haaf, Kevin; van Rosmalen, Joost; de Koning, Harry J.] Erasmus MC, Dept Publ Hlth, Rotterdam, Netherlands. [Hazelton, William] Fred Hutchinson Canc Res Ctr, Program Computat Biol, Seattle, WA 98104 USA. [Holford, Theodore R.] Yale Univ, Sch Publ Hlth, Dept Biostat, New Haven, CT USA. [Jeon, Jihyoun; Moolgavkar, Suresh] Fred Hutchinson Canc Res Ctr, Dept Biostat & Biomath, Seattle, WA 98104 USA. [Clarke, Lauren] Cornerstone Syst Northwest Inc, Lynden, WA USA. [Pinsky, Paul F.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Moolgavkar, Suresh] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Feuer, Eric J.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP McMahon, PM (reprint author), Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. EM pamela@mgh-ita.org OI van Rosmalen, Joost/0000-0002-9187-244X FU Agency for Healthcare Research and Quality FX This report is based on research conducted by the Cancer Intervention and Surveillance Modeling Network under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Administrative Supplement to U01 CA152956). The National Cancer Institute supported the infrastructure for the CISNET models. The Agency for Healthcare Research and Quality funded this work and provided review. The authors worked witah USPSTF members to specify the overall questions. The findings and conclusions in this document are those of the authors, who are responsible for its contents, and do not necessarily represent the views of AHRQ. No statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 11 Z9 11 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 30 PY 2014 VL 9 IS 6 AR e99978 DI 10.1371/journal.pone.0099978 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK5ZO UT WOS:000338506400012 PM 24979231 ER PT J AU Rego, ROM Bestor, A Stefka, J Rosa, PA AF Rego, Ryan O. M. Bestor, Aaron Stefka, Jan Rosa, Patricia A. TI Population Bottlenecks during the Infectious Cycle of the Lyme Disease Spirochete Borrelia burgdorferi SO PLOS ONE LA English DT Article ID SENSU-STRICTO; MAMMALIAN HOST; NORTH-AMERICA; PEROMYSCUS-LEUCOPUS; IXODES-RICINUS; TICKS; MICE; TRANSMISSION; DISSEMINATION; DIVERSITY AB Borrelia burgdorferi is a zoonotic pathogen whose maintenance in nature depends upon an infectious cycle that alternates between a tick vector and mammalian hosts. Lyme disease in humans results from transmission of B. burgdorferi by the bite of an infected tick. The population dynamics of B. burgdorferi throughout its natural infectious cycle are not well understood. We addressed this topic by assessing the colonization, dissemination and persistence of B. burgdorferi within and between the disparate mammalian and tick environments. To follow bacterial populations during infection, we generated seven isogenic but distinguishable B. burgdorferi clones, each with a unique sequence tag. These tags resulted in no phenotypic changes relative to wild type organisms, yet permitted highly sensitive and specific detection of individual clones by PCR. We followed the composition of the spirochete population throughout an experimental infectious cycle that was initiated with a mixed inoculum of all clones. We observed heterogeneity in the spirochete population disseminating within mice at very early time points, but all clones displayed the ability to colonize most mouse tissues by 3 weeks of infection. The complexity of clones subsequently declined as murine infection persisted. Larval ticks typically acquired a reduced and variable number of clones relative to what was present in infected mice at the time of tick feeding, and maintained the same spirochete population through the molt to nymphs. However, only a random subset of infectious spirochetes was transmitted to naive mice when these ticks next fed. Our results clearly demonstrate that the spirochete population experiences stochastic bottlenecks during both acquisition and transmission by the tick vector, as well as during persistent infection of its murine host. The experimental system that we have developed can be used to further explore the forces that shape the population of this vector-borne bacterial pathogen throughout its infectious cycle. C1 [Rego, Ryan O. M.; Bestor, Aaron; Rosa, Patricia A.] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Stefka, Jan] Univ South Bohemia, Fac Sci, Ceske Budejovice, Czech Republic. [Stefka, Jan] ASCR, Ctr Biol, Inst Parasitol, Ceske Budejovice, Czech Republic. RP Rego, ROM (reprint author), NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM ryanrego@paru.cas.cz RI Rego, Ryan/G-9773-2014; Stefka, Jan/G-9267-2014 OI Rego, Ryan/0000-0001-6932-0940; Stefka, Jan/0000-0002-1283-9730 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 74 TC 15 Z9 15 U1 0 U2 14 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 30 PY 2014 VL 9 IS 6 AR e101009 DI 10.1371/journal.pone.0101009 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK5ZO UT WOS:000338506400061 PM 24979342 ER PT J AU Stojmirovic, A Yu, YK AF Stojmirovic, Aleksandar Yu, Yi-Kuo TI Building a Hierarchical Organization of Protein Complexes Out of Protein Association Data SO PLOS ONE LA English DT Article ID SACCHAROMYCES-CEREVISIAE; MASS-SPECTROMETRY; LIQUID-CHROMATOGRAPHY; INTERACTION NETWORKS; INFORMATION-FLOW; YEAST; UPDATE; SUM; PURIFICATION; INTERACTOME AB Organizing experimentally determined protein associations as a hierarchy can be a good approach to elucidating the content of protein complexes and the modularity of subcomplexes. Several challenges exist. First, intrinsically sticky proteins, such as chaperones, are often falsely assigned to many functionally unrelated complexes. Second, the reported collections of proteins may not be true "complexes" in the sense that they bind together and perform a joint cellular function. Third, due to imperfect sensitivity of protein detection methods, both false positive and false negative assignments of a protein to complexes may occur. We mitigate the first issue by down-weighting sticky proteins by their occurrence frequencies. We approach the other two problems by merging nearly identical complexes and by constructing a directed acyclic graph (DAG) based on the relationship of partial inclusion. The constructed DAG, within which smaller complexes form parts of the larger, can reveal how different complexes are joined. By merging almost identical complexes one can deemphasize the influence of false positives, while allowing false negatives to be rescued by other nearly identical association data. We investigate several protein weighting schemes and compare their corresponding DAGs using yeast and human complexes. We find that the scheme incorporating weights based on information flow in the network of direct protein-protein interactions produces biologically most meaningful DAGs. In either yeast or human, isolated nodes form a large proportion of the final hierarchy. While most connected components encompass very few nodes, the largest one for each species contains a sizable portion of all nodes. By considering examples of subgraphs composed of nodes containing a specified protein, we illustrate that the graphs' topological features can correctly suggest the biological roles of protein complexes. The input data, final results and the source code are available at ftp://ftp.ncbi.nlm.nih.gov/pub/qmbpmn/ProteinComplexDAG/. C1 [Stojmirovic, Aleksandar; Yu, Yi-Kuo] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Yu, YK (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM yyu@ncbi.nlm.nih.gov FU Intramural Research Program of the National Library of Medicine at the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Library of Medicine at the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 0 Z9 0 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 30 PY 2014 VL 9 IS 6 AR e100098 DI 10.1371/journal.pone.0100098 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK5ZO UT WOS:000338506400020 PM 24978199 ER PT J AU Comeau, DC Batista-Navarro, RT Dai, HJ Dogan, RI Yepes, AJ Khare, R Lu, ZY Marques, H Mattingly, CJ Neves, M Peng, YF Rak, R Rinaldi, F Tsai, RTH Verspoor, K Wiegers, TC Wu, CH Wilbur, WJ AF Comeau, Donald C. Batista-Navarro, Riza Theresa Dai, Hong-Jie Dogan, Rezarta Islamaj Yepes, Antonio Jimeno Khare, Ritu Lu, Zhiyong Marques, Hernani Mattingly, Carolyn J. Neves, Mariana Peng, Yifan Rak, Rafal Rinaldi, Fabio Tsai, Richard Tzong-Han Verspoor, Karin Wiegers, Thomas C. Wu, Cathy H. Wilbur, W. John TI BioC interoperability track overview SO DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION LA English DT Article ID BIOMEDICAL TEXT; NORMALIZATION; DEFINITIONS; BIOSMILE; TOOL AB BioC is a new simple XML format for sharing biomedical text and annotations and libraries to read and write that format. This promotes the development of interoperable tools for natural language processing (NLP) of biomedical text. The interoperability track at the BioCreative IV workshop featured contributions using or highlighting the BioC format. These contributions included additional implementations of BioC, many new corpora in the format, biomedical NLP tools consuming and producing the format and online services using the format. The ease of use, broad support and rapidly growing number of tools demonstrate the need for and value of the BioC format. C1 [Comeau, Donald C.; Dogan, Rezarta Islamaj; Khare, Ritu; Lu, Zhiyong; Wilbur, W. John] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Batista-Navarro, Riza Theresa; Rak, Rafal] Univ Manchester, Natl Ctr Text Min, Manchester M1 7DN, Lancs, England. [Batista-Navarro, Riza Theresa; Rak, Rafal] Univ Manchester, Sch Comp Sci, Manchester M1 7DN, Lancs, England. [Dai, Hong-Jie] Taipei Med Univ, Grad Inst BioMed Informat, Coll Med Sci & Technol, Taipei 110, Taiwan. [Yepes, Antonio Jimeno; Verspoor, Karin] Univ Melbourne, Dept Comp & Informat Syst, Parkville, Vic 3010, Australia. [Marques, Hernani; Rinaldi, Fabio] Univ Zurich, Inst Computat Linguist, CH-8050 Zurich, Switzerland. [Mattingly, Carolyn J.; Wiegers, Thomas C.] N Carolina State Univ, Dept Biol Sci, Raleigh, NC 27695 USA. [Neves, Mariana] Humboldt Univ, Inst Comp Sci, WBI, D-10099 Berlin, Germany. [Neves, Mariana] Charite, Berlin Brandenburg Ctr Regenerat Therapies, D-13353 Berlin, Germany. [Peng, Yifan; Wu, Cathy H.] Univ Delaware, Dept Comp & Informat Sci, Newark, DE 19711 USA. [Tsai, Richard Tzong-Han] Natl Cent Univ, Dept Comp Sci & Informat Engn, Taoyuan 32001, Taiwan. [Verspoor, Karin] Univ Melbourne, Hlth & Biomed Informat Ctr, Parkville, Vic 3010, Australia. [Wu, Cathy H.] Univ Delaware, Ctr Bioinformat & Computat Biol, Newark, DE 19711 USA. RP Comeau, DC (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM comeau@ncbi.nlm.nih.gov RI Verspoor, Karin/G-6034-2016; Peng, Yifan/M-1605-2016; OI Verspoor, Karin/0000-0002-8661-1544; Peng, Yifan/0000-0001-9309-8331; Neves, Mariana/0000-0002-6488-2394; Jimeno Yepes, Antonio Jose/0000-0002-6581-094X; Rinaldi, Fabio/0000-0001-5718-5462 FU National Science Foundation [DBI-0850319]; National Institutes of Health, National Library of Medicine; NICTA; Australian Government through Department of Communications; Australian Research Council through ICT Centre of Excellence Program FX National Science Foundation [DBI-0850319] to The BioCreative IV Workshop; Intramural Research Program of the National Institutes of Health, National Library of Medicine to D.C.C., R.I.D., R.K., Z.L. and W.J.W; NICTA, which is funded by the Australian Government through the Department of Communications, and the Australian Research Council through the ICT Centre of Excellence Program to A.J.Y. and K.V. Funding for open access charge: Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 56 TC 5 Z9 5 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1758-0463 J9 DATABASE-OXFORD JI Database PD JUN 30 PY 2014 AR bau053 DI 10.1093/database/bau053 PG 12 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA AK7BG UT WOS:000338580400001 ER PT J AU Schoch, CL Robbertse, B Robert, V Vu, D Cardinali, G Irinyi, L Meyer, W Nilsson, RH Hughes, K Miller, AN Kirk, PM Abarenkov, K Aime, MC Ariyawansa, HA Bidartondo, M Boekhout, T Buyck, B Cai, Q Chen, J Crespo, A Crous, PW Damm, U De Beer, ZW Dentinger, BTM Divakar, PK Duenas, M Feau, N Fliegerova, K Garcia, MA Ge, ZW Griffith, G Groenewald, JZ Groenewald, M Grube, M Gryzenhout, M Gueidan, C Guo, LD Hambleton, S Hamelin, R Hansen, K Hofstetter, V Hong, SB Houbraken, J Hyde, KD Inderbitzin, P Johnston, PR Karunarathna, SC Koljalg, U Kovacs, GM Kraichak, E Krizsan, K Kurtzman, CP Larsson, KH Leavitt, S Letcher, PM Liimatainen, K Liu, JK Lodge, DJ Luangsa-ard, JJ Lumbsch, HT Maharachchikumbura, SSN Manamgoda, D Martin, MP Minnis, AM Moncalvo, JM Mule, G Nakasone, KK Niskanen, T Olariaga, I Papp, T Petkovits, T Pino-Bodas, R Powell, MJ Raja, HA Redecker, D Sarmiento-Ramirez, JM Seifert, KA Shrestha, B Stenroos, S Stielow, B Suh, SO Tanaka, K Tedersoo, L Telleria, MT Udayanga, D Untereiner, WA Uribeondo, JD Subbarao, KV Vagvolgyi, C Visagie, C Voigt, K Walker, DM Weir, BS Weiss, M Wijayawardene, NN Wingfield, MJ Xu, JP Yang, ZL Zhang, N Zhuang, WY Federhen, S AF Schoch, Conrad L. Robbertse, Barbara Robert, Vincent Duong Vu Cardinali, Gianluigi Irinyi, Laszlo Meyer, Wieland Nilsson, R. Henrik Hughes, Karen Miller, Andrew N. Kirk, Paul M. Abarenkov, Kessy Aime, M. Catherine Ariyawansa, Hiran A. Bidartondo, Martin Boekhout, Teun Buyck, Bart Cai, Qing Chen, Jie Crespo, Ana Crous, Pedro W. Damm, Ulrike De Beer, Z. Wilhelm Dentinger, Bryn T. M. Divakar, Pradeep K. Duenas, Margarita Feau, Nicolas Fliegerova, Katerina Garcia, Miguel A. Ge, Zai-Wei Griffith, GarethW. Groenewald, Johannes Z. Groenewald, Marizeth Grube, Martin Gryzenhout, Marieka Gueidan, Cecile Guo, Liangdong Hambleton, Sarah Hamelin, Richard Hansen, Karen Hofstetter, Valerie Hong, Seung-Beom Houbraken, Jos Hyde, Kevin D. Inderbitzin, Patrik Johnston, Peter R. Karunarathna, Samantha C. Koljalg, Urmas Kovacs, Gabor M. Kraichak, Ekaphan Krizsan, Krisztina Kurtzman, Cletus P. Larsson, Karl-Henrik Leavitt, Steven Letcher, Peter M. Liimatainen, Kare Liu, Jian-Kui Lodge, D. Jean Luangsa-ard, Janet Jennifer Lumbsch, H. Thorsten Maharachchikumbura, Sajeewa S. N. Manamgoda, Dimuthu Martin, Maria P. Minnis, Andrew M. Moncalvo, Jean-Marc Mule, Giuseppina Nakasone, Karen K. Niskanen, Tuula Olariaga, Ibai Papp, Tamas Petkovits, Tamas Pino-Bodas, Raquel Powell, Martha J. Raja, Huzefa A. Redecker, Dirk Sarmiento-Ramirez, J. M. Seifert, Keith A. Shrestha, Bhushan Stenroos, Soili Stielow, Benjamin Suh, Sung-Oui Tanaka, Kazuaki Tedersoo, Leho Teresa Telleria, M. Udayanga, Dhanushka Untereiner, Wendy A. Dieguez Uribeondo, Javier Subbarao, Krishna V. Vagvoelgyi, Csaba Visagie, Cobus Voigt, Kerstin Walker, Donald M. Weir, Bevan S. Weiss, Michael Wijayawardene, Nalin N. Wingfield, Michael J. Xu, J. P. Yang, Zhu L. Zhang, Ning Zhuang, Wen-Ying Federhen, Scott TI Finding needles in haystacks: linking scientific names, reference specimens and molecular data for Fungi SO DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION LA English DT Article ID INTERNAL TRANSCRIBED SPACER; ARBUSCULAR MYCORRHIZAL FUNGI; RIBOSOMAL DNA; INTERSPECIFIC HYBRIDIZATION; SEQUENCE ANALYSES; SPECIES COMPLEX; IDENTIFICATION; EVOLUTION; BARCODE; LIFE AB DNA phylogenetic comparisons have shown that morphology-based species recognition often underestimates fungal diversity. Therefore, the need for accurate DNA sequence data, tied to both correct taxonomic names and clearly annotated specimen data, has never been greater. Furthermore, the growing number of molecular ecology and microbiome projects using high-throughput sequencing require fast and effective methods for en masse species assignments. In this article, we focus on selecting and re-annotating a set of marker reference sequences that represent each currently accepted order of Fungi. The particular focus is on sequences from the internal transcribed spacer region in the nuclear ribosomal cistron, derived from type specimens and/or ex-type cultures. Re-annotated and verified sequences were deposited in a curated public database at the National Center for Biotechnology Information (NCBI), namely the RefSeq Targeted Loci (RTL) database, and will be visible during routine sequence similarity searches with NR_prefixed accession numbers. A set of standards and protocols is proposed to improve the data quality of new sequences, and we suggest how type and other reference sequences can be used to improve identification of Fungi. C1 [Schoch, Conrad L.; Robbertse, Barbara; Federhen, Scott] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Robert, Vincent; Duong Vu; Boekhout, Teun; Crespo, Ana; Crous, Pedro W.; Groenewald, Johannes Z.; Groenewald, Marizeth; Houbraken, Jos; Stielow, Benjamin; Visagie, Cobus] CBS KNAW Fungal Biodivers Ctr, NL-3508 AD Utrecht, Netherlands. [Cardinali, Gianluigi] Univ Perugia, Dept Pharmaceut Sci Microbiol, I-06100 Perugia, Italy. [Irinyi, Laszlo; Meyer, Wieland] Univ Sydney, Marie Bashir Inst Infect Dis & Biosecur, Mol Mycol Res Lab,Sydney Med Sch,Westmead Hosp, Westmead Millennium Inst,Ctr Infect Dis & Microbi, Westmead, NSW 2145, Australia. [Nilsson, R. Henrik] Univ Gothenburg, Dept Biol & Environm Sci, S-40530 Gothenburg, Sweden. [Hughes, Karen] Univ Tennessee, Knoxville, TN 37920 USA. [Miller, Andrew N.] Univ Illinois, Illinois Nat Hist Survey, Champaign, IL 61820 USA. [Kirk, Paul M.; Dentinger, Bryn T. M.] Royal Bot Gardens, Jodrell Lab, Mycol Sect, Richmond TW9 3DS, Surrey, England. [Abarenkov, Kessy; Koljalg, Urmas; Tedersoo, Leho] Univ Tartu, Nat Hist Museum, EE-51014 Tartu, Estonia. [Aime, M. Catherine] Purdue Univ, Dept Bot & Plant Pathol, W Lafayette, IN 47907 USA. [Ariyawansa, Hiran A.; Chen, Jie; Hyde, Kevin D.; Karunarathna, Samantha C.; Liu, Jian-Kui; Maharachchikumbura, Sajeewa S. N.; Manamgoda, Dimuthu; Udayanga, Dhanushka; Wijayawardene, Nalin N.] Mae Fah Luang Univ, Inst Excellence Fungal Res, Chiang Rai 57100, Thailand. [Ariyawansa, Hiran A.; Chen, Jie; Hyde, Kevin D.; Karunarathna, Samantha C.; Liu, Jian-Kui; Maharachchikumbura, Sajeewa S. N.; Manamgoda, Dimuthu; Udayanga, Dhanushka; Wijayawardene, Nalin N.] Mae Fah Luang Univ, Sch Sci, Chiang Rai 57100, Thailand. [Bidartondo, Martin] Imperial Coll London, Royal Bot Gardens, Richmond TW9 3DS, England. [Buyck, Bart] Museum Natl Hist Nat, Dept Systemat & Evolut CP39, UMR7205, F-75005 Paris, France. [Cai, Qing; Ge, Zai-Wei; Yang, Zhu L.] Chinese Acad Sci, Kunming Inst Bot, Kunming 650201, Yunnan, Peoples R China. [Crespo, Ana; Divakar, Pradeep K.] Univ Complutense Madrid, Fac Farm, Dept Biol Vegetal 2, E-28040 Madrid, Spain. [Damm, Ulrike] Senckenberg Museum Nat Hist Gorlitz, D-02806 Gorlitz, Germany. [De Beer, Z. Wilhelm; Wingfield, Michael J.] Univ Pretoria, Dept Microbiol & Plant Pathol, FABI, ZA-0001 Pretoria, South Africa. [Duenas, Margarita; Martin, Maria P.; Sarmiento-Ramirez, J. M.; Teresa Telleria, M.; Dieguez Uribeondo, Javier] CSIC, RJB, E-28014 Madrid, Spain. [Feau, Nicolas; Hamelin, Richard] Univ British Columbia, Fac Forestry, Dept Forest & Conservat Sci, Vancouver, BC V6T 1W5, Canada. [Fliegerova, Katerina] Acad Sci Czech Republic, Inst Anim Physiol & Genet, Vvi, Prague, Czech Republic. [Garcia, Miguel A.] Univ Toronto, Dept Biol, Mississauga, ON L5L 1C6, Canada. [Griffith, GarethW.] Prifysgol Aberystwyth, Inst Biol Environm & Rural Sci, Aberystwyth SY23 3DD, Ceredigion, Wales. [Grube, Martin] Karl Franzens Univ Graz, Inst Plant Sci, A-8010 Graz, Austria. [Gryzenhout, Marieka] Univ Orange Free State, Dept Plant Sci, ZA-9300 Bloemfontein, South Africa. [Gueidan, Cecile] CANBR, CSIRO Plant Ind, Canberra, ACT 2601, Australia. [Guo, Liangdong; Zhuang, Wen-Ying] Chinese Acad Sci, Inst Microbiol, State Key Lab Mycol, Beijing, Peoples R China. [Hambleton, Sarah; Seifert, Keith A.] Agr & Agri Food Canada, Biodivers Mycol & Microbiol, Ottawa, ON, Canada. [Hansen, Karen; Olariaga, Ibai] Swedish Museum Nat Hist, Dept Bot, SE-10405 Stockholm, Sweden. [Hofstetter, Valerie] Agroscope Changins Wadenswil Res Stn ACW, Dept Rech Protect Vegetaux Grandes Cultures & Vig, CH-1260 Nyon, Switzerland. [Hong, Seung-Beom] RDA, Korean Agr Culture Collect, Natl Acad Agr Sci, Suwon 441707, South Korea. [Inderbitzin, Patrik; Subbarao, Krishna V.] Univ Calif Davis, Dept Plant Pathol, Davis, CA 95616 USA. [Johnston, Peter R.; Weir, Bevan S.] Landcare Res, Auckland 1142, New Zealand. [Kovacs, Gabor M.] Eotvos Lorand Univ, Inst Biol, Dept Plant Anat, H-1117 Budapest, Hungary. [Kovacs, Gabor M.] Hungarian Acad Sci, Inst Plant Protect, Agr Res Ctr, H-1525 Budapest, Hungary. [Kraichak, Ekaphan; Leavitt, Steven; Lumbsch, H. Thorsten] Field Museum Nat Hist, Chicago, IL 60605 USA. [Krizsan, Krisztina; Papp, Tamas; Petkovits, Tamas; Vagvoelgyi, Csaba] Univ Szeged, Fac Sci & Informat, Dept Microbiol, H-6726 Szeged, Hungary. [Kurtzman, Cletus P.] ARS, Bacterial Foodborne Pathogens & Mycol Res Unit, USDA, Natl Ctr Agr Utilizat Res, Peoria, IL 61604 USA. [Larsson, Karl-Henrik] Nat Hist Museum, N-0318 Oslo, Norway. [Letcher, Peter M.; Powell, Martha J.] Univ Alabama, Dept Biol Sci, Tuscaloosa, AL 35487 USA. [Liimatainen, Kare; Niskanen, Tuula] Univ Helsinki, Dept Biosci, FIN-00014 Helsinki, Finland. [Lodge, D. Jean] US Forest Serv, USDA, NRS, Luquillo, PR USA. [Luangsa-ard, Janet Jennifer] Natl Ctr Genet Engn & Biotechnol BIOTEC, Pathum Thani 12120, Thailand. [Minnis, Andrew M.] Univ Wisconsin, Dept Med Microbiol & Immunol, Madison, WI 53706 USA. [Moncalvo, Jean-Marc] Univ Toronto, Royal Ontario Museum, Dept Nat Hist, Toronto, ON, Canada. [Moncalvo, Jean-Marc] Univ Toronto, Dept Ecol Evolutionary Biol, Toronto, ON, Canada. [Mule, Giuseppina] CNR, Inst Sci Food Prod, I-70126 Bari, Italy. [Nakasone, Karen K.] US Forest Serv, Ctr Forest Mycol Res, No Res Stn, Madison, WI 53726 USA. [Pino-Bodas, Raquel; Stenroos, Soili] Univ Helsinki, Finnish Museum Nat Hist, Bot Museum, FI-00014 Helsinki, Finland. [Raja, Huzefa A.] Univ N Carolina, Dept Chem & Biochem, Greensboro, NC 27402 USA. [Redecker, Dirk] Univ Bourgogne, Agroecol UMR1347, F-21000 Dijon, France. [Shrestha, Bhushan] Sungkyunkwan Univ, Inst Life Sci & Biotechnol, Suwon 440746, South Korea. [Suh, Sung-Oui] ATCC, Mycol & Bot Program, Manassas, VA 20110 USA. [Tanaka, Kazuaki] Hirosaki Univ, Fac Agr & Life Sci, Hirosaki, Aomori 0368561, Japan. [Untereiner, Wendy A.] Brandon Univ, Dept Biol, Brandon, MB R7A 6A9, Canada. [Voigt, Kerstin] Leibniz Inst Nat Prod Res & Infect Biol, Jena Microbial Resource Collect, Jena, Germany. [Voigt, Kerstin] Univ Jena, Jena, Germany. [Walker, Donald M.] Univ Findlay, Dept Nat Sci, Findlay, OH 45840 USA. [Weiss, Michael] Univ Tubingen, Inst Evolut & Ecol, D-72076 Tubingen, Germany. [Xu, J. P.] McMaster Univ, Dept Biol, Hamilton, ON L8S 4K1, Canada. [Zhang, Ning] Rutgers State Univ, Dept Plant Biol & Pathol, New Brunswick, NJ 08901 USA. RP Schoch, CL (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM schoch2@ncbi.nlm.nih.gov RI de Beer, Z. Wilhelm/B-6353-2008; Maharachchikumbura, Sajeewa/C-9403-2013; Zhang, Ning/K-3046-2012; Garcia, Miguel Angel/N-6275-2016; Martin, Maria /H-8069-2012; Divakar, Pradeep/E-5603-2014; Groenewald, Johannes/F-4667-2011; Crespo, Ana/N-6236-2014; Duenas, Margarita/H-4944-2015; Abarenkov, Kessy/H-9611-2015; Wingfield, Michael/A-9473-2008; Crous, Pedro/H-1489-2012; Ariyawansa, Hiran/C-2618-2015; Groenewald, Marizeth/G-4976-2012; WeiSS, Michael/F-6206-2012; Meyer, Wieland/G-1204-2015; Telleria, M. Teresa/H-4928-2015; Mule, Giuseppina/B-6478-2015 OI de Beer, Z. Wilhelm/0000-0001-9758-8987; Zhang, Ning/0000-0003-0755-2505; Garcia, Miguel Angel/0000-0002-0366-043X; Martin, Maria /0000-0002-1235-4418; Divakar, Pradeep/0000-0002-0300-0124; Raja, Huzefa/0000-0002-0824-9463; Nilsson, Henrik/0000-0002-8052-0107; Crespo, Ana/0000-0002-5271-0157; Duenas, Margarita/0000-0003-0621-8003; Abarenkov, Kessy/0000-0001-5526-4845; Crous, Pedro/0000-0001-9085-8825; Ariyawansa, Hiran/0000-0001-8836-2572; Groenewald, Marizeth/0000-0003-0835-5925; WeiSS, Michael/0000-0002-4869-9186; Meyer, Wieland/0000-0001-9933-8340; Telleria, M. Teresa/0000-0002-9876-6914; Mule, Giuseppina/0000-0002-9094-1888 FU National Center for Biotechnology Information, National Library of Medicine at the National Institutes of Health; National Human Genome Research Institute at the National Institutes of Health FX Funding for open access charge: The Intramural Research Programs of the National Center for Biotechnology Information, National Library of Medicine and the National Human Genome Research Institute, both at the National Institutes of Health. NR 99 TC 43 Z9 44 U1 6 U2 87 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1758-0463 J9 DATABASE-OXFORD JI Database PD JUN 30 PY 2014 AR bau061 DI 10.1093/database/bau061 PG 21 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA AK7AY UT WOS:000338579600001 ER PT J AU Mage, M AF Mage, Michael TI Without Scars SO NEW YORK TIMES BOOK REVIEW LA English DT Letter C1 NIH, Bethesda, MD 20892 USA. RP Mage, M (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NEW YORK TIMES PI NEW YORK PA 620 8TH AVE, NEW YORK, NY 10018 USA SN 0028-7806 J9 NY TIMES BK REV JI N. Y. Times Book Rev. PD JUN 29 PY 2014 VL 119 IS 26 BP 6 EP 6 PG 1 WC Humanities, Multidisciplinary SC Arts & Humanities - Other Topics GA AJ5JX UT WOS:000337719600004 ER PT J AU Liew, SL Santarnecchi, E Buch, ER Cohen, LG AF Liew, Sook-Lei Santarnecchi, Emilliano Buch, Ethan R. Cohen, Leonardo G. TI Non-invasive brain stimulation in neurorehabilitation: local and distant effects for motor recovery SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Review DE non-invasive brain stimulation; transcranial direct current stimulation (tDCS); transcranial magnetic stimulation; neurorehabilitation; stroke ID TRANSCRANIAL MAGNETIC STIMULATION; PAIRED ASSOCIATIVE STIMULATION; DORSOLATERAL PREFRONTAL CORTEX; THETA-BURST STIMULATION; CHRONIC STROKE PATIENTS; DORSAL PREMOTOR CORTEX; ACUTE ISCHEMIC-STROKE; CONCURRENT TMS-FMRI; RESTING HUMAN BRAIN; UPPER-LIMB AB Non-invasive brain stimulation (NIBS) may enhance motor recovery after neurological injury through the causal induction of plasticity processes. Neurological injury, such as stroke, often results in serious long-term physical disabilities, and despite intensive therapy, a large majority of brain injury survivors fail to regain full motor function. Emerging research suggests that NIBS techniques, such as transcranial magnetic (TMS) and direct current (tDCS) stimulation, in association with customarily used neurorehabilitative treatments, may enhance motor recovery. This paper provides a general review on TMS and tDCS paradigms, the mechanisms by which they operate and the stimulation techniques used in neurorehabilitation, specifically stroke. TMS and tDCS influence regional neural activity underlying the stimulation location and also distant interconnected network activity throughout the brain. We discuss recent studies that document NIBS effects on global brain activity measured with various neuroimaging techniques, which help to characterize better strategies for more accurate NIBS stimulation. These rapidly growing areas of inquiry may hold potential for improving the effectiveness of NIBS-based interventions for clinical rehabilitation. C1 [Liew, Sook-Lei; Buch, Ethan R.; Cohen, Leonardo G.] NINDS, Human Cort Physiol & Neurorehabil Sect, NIH, Bethesda, MD 20892 USA. [Santarnecchi, Emilliano] Univ Siena, Dept Med Surg & Neurosci, I-53100 Siena, Italy. [Buch, Ethan R.; Cohen, Leonardo G.] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD USA. RP Liew, SL (reprint author), NINDS, Human Cort Physiol & Neurorehabil Sect, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM lei.liew@nih.gov; cohenl@ninds.nih.gov FU US National Institute of Neurological Disorders and Stroke (NINDS); US National Institute of Neurological Disorders and Stroke (US National Institutes of Health); US Department of Defense in the Center for Neuroscience and Regenerative Medicine FX We thank Marco Sandrini for helpful feedback. This work was supported by the Intramural Research Program of the US National Institute of Neurological Disorders and Stroke (NINDS; US National Institutes of Health) and by funding from US Department of Defense in the Center for Neuroscience and Regenerative Medicine. NR 149 TC 37 Z9 39 U1 2 U2 29 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD JUN 27 PY 2014 VL 8 AR 378 DI 10.3389/fnhum.2014.00378 PG 15 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA AM6BH UT WOS:000339945300002 PM 25018714 ER PT J AU Zhang, XL Gierman, HJ Levy, D Plump, A Dobrin, R Goring, HHH Curran, JE Johnson, MP Blangero, J Kim, SK O'Donnell, CJ Emilsson, V Johnson, AD AF Zhang, Xiaoling Gierman, Hinco J. Levy, Daniel Plump, Andrew Dobrin, Radu Goring, Harald H. H. Curran, Joanne E. Johnson, Matthew P. Blangero, John Kim, Stuart K. O'Donnell, Christopher J. Emilsson, Valur Johnson, Andrew D. TI Synthesis of 53 tissue and cell line expression QTL datasets reveals master eQTLs SO BMC GENOMICS LA English DT Article DE eQTL; RNA; Gene expression; Genomics; Transcriptome; GWAS; Genome-wide; Tissue; Cis; Trans ID CORONARY-ARTERY-DISEASE; HUMAN GENE-EXPRESSION; REGULATORY VARIATION; MONOALLELIC EXPRESSION; POPULATION GENOMICS; SUSCEPTIBILITY LOCI; DNA METHYLATION; ASSOCIATION; EVOLUTION; ANNOTATION AB Background: Gene expression genetic studies in human tissues and cells identify cis- and trans-acting expression quantitative trait loci (eQTLs). These eQTLs provide insights into regulatory mechanisms underlying disease risk. However, few studies systematically characterized eQTL results across cell and tissues types. We synthesized eQTL results from >50 datasets, including new primary data from human brain, peripheral plaque and kidney samples, in order to discover features of human eQTLs. Results: We find a substantial number of robust cis-eQTLs and far fewer trans-eQTLs consistent across tissues. Analysis of 45 full human GWAS scans indicates eQTLs are enriched overall, and above nSNPs, among positive statistical signals in genetic mapping studies, and account for a significant fraction of the strongest human trait effects. Expression QTLs are enriched for gene centricity, higher population allele frequencies, in housekeeping genes, and for coincidence with regulatory features, though there is little evidence of 5' or 3' positional bias. Several regulatory categories are not enriched including microRNAs and their predicted binding sites and long, intergenic non-coding RNAs. Among the most tissue-ubiquitous cis-eQTLs, there is enrichment for genes involved in xenobiotic metabolism and mitochondrial function, suggesting these eQTLs may have adaptive origins. Several strong eQTLs (CDK5RAP2, NBPFs) coincide with regions of reported human lineage selection. The intersection of new kidney and plaque eQTLs with related GWAS suggest possible gene prioritization. For example, butyrophilins are now linked to arterial pathogenesis via multiple genetic and expression studies. Expression QTL and GWAS results are made available as a community resource through the NHLBI GRASP database [http://apps.nhlbi.nih.gov/grasp/]. Conclusions: Expression QTLs inform the interpretation of human trait variability, and may account for a greater fraction of phenotypic variability than protein-coding variants. The synthesis of available tissue eQTL data highlights many strong cis-eQTLs that may have important biologic roles and could serve as positive controls in future studies. Our results indicate some strong tissue-ubiquitous eQTLs may have adaptive origins in humans. Efforts to expand the genetic, splicing and tissue coverage of known eQTLs will provide further insights into human gene regulation. C1 [Zhang, Xiaoling; Levy, Daniel; O'Donnell, Christopher J.; Johnson, Andrew D.] NHLBI, Div Intramural Res, Cardiovasc Epidemiol & Human Genom Branch, Framingham, MA 01702 USA. [Gierman, Hinco J.; Kim, Stuart K.] Stanford Univ, Sch Med, Dept Dev Biol, Stanford, CA 94305 USA. [Plump, Andrew] Sanofi Aventis Pharmaceut, Bridgewater, NJ 08807 USA. [Dobrin, Radu] Johnson & Johnson Pharmaceut Res & Dev, Radnor, PA 19477 USA. [Goring, Harald H. H.; Curran, Joanne E.; Johnson, Matthew P.; Blangero, John] Texas Biomed Res Inst, Dept Genet, San Antonio, TX 78227 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Emilsson, Valur] Iceland Heart Assoc, Kopavogur, Iceland. RP Johnson, AD (reprint author), NHLBI, Div Intramural Res, Cardiovasc Epidemiol & Human Genom Branch, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM johnsonad2@nhlbi.nih.gov RI Johnson, Andrew/G-6520-2013; OI Dobrin, Radu/0000-0002-3336-0091 FU Glenn Center for Aging; National Institutes of Health; GTEx Portal [08/06/2013]; NCI; NHGRI; NHLBI; NIDA; NIMH; NINDS; NCI \SAIC-Frederick, Inc. (SAIC-F) [10XS170]; Roswell Park Cancer Institute [10XS171]; Science Care, Inc. [X10S172]; Laboratory, Data Analysis, and Coordinating Center (LDACC) through Broad Institute, Inc. [HHSN268201000029C]; SAIC-F subcontract to Van Andel Institute [10ST1035]; SAIC-F [HHSN261200800001E]; University of Miami [DA006227]; University of Geneva [MH090941]; University of Chicago [MH090951, MH090937]; University of North Carolina - Chapel Hill [MH090936]; Harvard University [MH090948] FX XZ and ADJ were supported by NIH Intramural Funds. The authors acknowledge Heather E. Wheeler for contribution to the kidney eQTL data. The kidney eQTL work was supported by the Glenn Center for Aging. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health (commonfund.nih.gov/GTEx). The GTEx datasets used for the analyses described in this manuscript were obtained from: GTEx Portal on 08/06/2013. Additional funds were provided by the NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Donors were enrolled at Biospecimen Source Sites funded by NCI \SAIC-Frederick, Inc. (SAIC-F) subcontracts to the National Disease Research Interchange (10XS170), Roswell Park Cancer Institute (10XS171), and Science Care, Inc. (X10S172). The Laboratory, Data Analysis, and Coordinating Center (LDACC) was funded through a contract (HHSN268201000029C) to the The Broad Institute, Inc. Biorepository operations were funded through an SAIC-F subcontract to Van Andel Institute (10ST1035). Additional data repository and project management were provided by SAIC-F (HHSN261200800001E). The Brain Bank was supported by a supplement to University of Miami grant DA006227. Statistical Methods development grants were made to the University of Geneva (MH090941), the University of Chicago (MH090951 & MH090937), the University of North Carolina - Chapel Hill (MH090936) and to Harvard University (MH090948). NR 94 TC 19 Z9 19 U1 0 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD JUN 27 PY 2014 VL 15 AR 532 DI 10.1186/1471-2164-15-532 PG 19 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA AL2JM UT WOS:000338951900001 PM 24973796 ER PT J AU Veiga, ABG Ribeiro, JMC Francischetti, IMB Xu, XQ Guimaraes, JA Andersen, JF AF Veiga, Ana B. G. Ribeiro, Jose M. C. Francischetti, Ivo M. B. Xu, Xueqing Guimaraes, Jorge A. Andersen, John F. TI Examination of the Ligand-Binding and Enzymatic Properties of a Bilin-Binding Protein from the Poisonous Caterpillar Lonomia obliqua SO PLOS ONE LA English DT Article ID OXYGENASE HMU O; MANDUCA-SEXTA L; CORYNEBACTERIUM-DIPHTHERIAE; PSEUDOMONAS-AERUGINOSA; HEMORRHAGIC SYNDROME; MOLECULAR-STRUCTURE; OXIDATIVE CLEAVAGE; COUPLED OXIDATION; CRYSTAL-STRUCTURE; TOBACCO HORNWORM AB The bilin-binding proteins (BBP) from lepidopteran insects are members of the lipocalin family of proteins and play a special role in pigmentation through the binding of biliverdin IX gamma. Lopap, a BBP-like protein from the venom of the toxic caterpillar Lonomia obliqua has been reported to act as a serine protease that activates the coagulation proenzyme prothrombin. Here we show that BBPLo, a variant of lopap from the same organism binds biliverdin IX gamma, forming a complex that is spectrally identical with previously described BBP proteins. Although BBPLo is nearly identical in sequence to lopap, no prothrombinase activity was detected in our recombinant preparations using reconstituted systems containing coagulation factors Xa and Va, as well as anionic phospholipids. In addition to biliverdin, BBPLo was found to form a 1:1 complex with heme prompting us to examine whether the unusual biliverdin IX gamma ligand of BBPs forms as a result of oxidation of bound heme in situ rather than by a conventional heme oxygenase. Using ascorbate or a NADPH+-ferredoxin reductase-ferredoxin system as a source of reducing equivalents, spectral changes are seen that suggest an initial reduction of heme to the Fe(II) state and formation of an oxyferrous complex. The complex then disappears and a product identified as a 5-coordinate carbonyl complex of verdoheme, an intermediate in the biosynthesis of biliverdin, is formed. However, further reaction to form biliverdin was not observed, making it unlikely that biliverdin IX gamma is formed by this pathway. C1 [Veiga, Ana B. G.; Ribeiro, Jose M. C.; Francischetti, Ivo M. B.; Xu, Xueqing; Andersen, John F.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Veiga, Ana B. G.; Guimaraes, Jorge A.] Univ Fed Rio Grande do Sul, Ctr Biotechnol, Porto Alegre, RS, Brazil. RP Andersen, JF (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. EM jandersen@niaid.nih.gov RI Ribeiro, Jose/J-7011-2015; OI Guimaraes, Jorge A./0000-0001-6354-6789; Ribeiro, Jose/0000-0002-9107-0818 FU intramural research program of the NIAID, National Institutes of Health FX This work was supported by the intramural research program of the NIAID, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 25 TC 0 Z9 0 U1 3 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 27 PY 2014 VL 9 IS 6 AR e95424 DI 10.1371/journal.pone.0095424 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK6BK UT WOS:000338512200003 PM 24972000 ER PT J AU Matsusue, K Aibara, D Hayafuchi, R Matsuo, K Takiguchi, S Gonzalez, FJ Yamano, S AF Matsusue, Kimihiko Aibara, Daisuke Hayafuchi, Risa Matsuo, Kohei Takiguchi, Soichi Gonzalez, Frank J. Yamano, Shigeru TI Hepatic PPAR gamma and LXR alpha independently regulate lipid accumulation in the livers of genetically obese mice SO FEBS LETTERS LA English DT Article DE Liver X receptor alpha; Peroxisome proliferator-activated receptor gamma; Fatty liver ID ELEMENT-BINDING PROTEIN; LEPTIN-DEFICIENT MICE; CHOLESTEROL EFFLUX; TARGET GENE; X RECEPTORS; EXPRESSION; LIPOGENESIS; STEATOSIS; MACROPHAGES; DISRUPTION AB The nuclear hormone receptors liver X receptor alpha (LXR alpha) and peroxisome proliferator-activated receptor gamma (PPAR gamma) play key roles in the development of fatty liver. To determine the link between hepatic PPAR gamma and LXR alpha signaling and the development of fatty liver, a LXR alpha-specific ligand, T0901317, was administered to normal OBIOB and genetically obese (ob/ob) mice lacking hepatic PPAR gamma (Ppar gamma(Delta H)). In ob/ob-Ppar gamma(Delta H) and OB/OB-Ppar gamma(Delta H) mice, as well as oblob-Pparywr and OB/OB-PparywT mice, the liver weights and hepatic triglyceride levels were markedly increased in response to T0901317 treatment. These results suggest that hepatic PPARy and LXRa signals independently contribute to the development of fatty liver. (C) 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. C1 [Matsusue, Kimihiko; Aibara, Daisuke; Hayafuchi, Risa; Matsuo, Kohei; Yamano, Shigeru] Fukuoka Univ, Fac Pharmaceut Sci, Jonan Ku, Fukuoka 8140180, Japan. [Takiguchi, Soichi] Kyushu Natl Canc Ctr, Inst Clin Res, Minami Ku, Fukuoka 8111395, Japan. [Gonzalez, Frank J.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Matsusue, K (reprint author), Fukuoka Univ, Fac Pharmaceut Sci, Jonan Ku, 8-19-1 Nanakuma, Fukuoka 8140180, Japan. EM matsusuk@fukuoka-u.ac.jp FU Mochida Memorial Foundation for Medical Research and a KAKENHI Grant [25460348] FX This work was supported by the Mochida Memorial Foundation for Medical Research and a KAKENHI Grant (No. 25460348). NR 17 TC 11 Z9 12 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 EI 1873-3468 J9 FEBS LETT JI FEBS Lett. PD JUN 27 PY 2014 VL 588 IS 14 BP 2277 EP 2281 DI 10.1016/j.febslet.2014.05.012 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA AK4NJ UT WOS:000338401100014 PM 24857376 ER PT J AU Gao, R Schellenberg, MJ Huang, SYN Abdelmalak, M Marchand, C Nitiss, KC Nitiss, JL Williams, RS Pommier, Y AF Gao, Rui Schellenberg, Matthew J. Huang, Shar-yin N. Abdelmalak, Monica Marchand, Christophe Nitiss, Karin C. Nitiss, John L. Williams, R. Scott Pommier, Yves TI Proteolytic Degradation of Topoisomerase II (Top2) Enables the Processing of Top2.DNA and Top2.RNA Covalent Complexes by Tyrosyl-DNA-Phosphodiesterase 2 (TDP2) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GENOME INTEGRITY; STRUCTURAL BASIS; CLEAVAGE; REPAIR; RIBONUCLEOTIDES; ANTICANCER; ETOPOSIDE; ADDUCTS; CHEMOTHERAPY; TOP3-BETA AB Eukaryotic type II topoisomerases (Top2 alpha and Top2 beta) are homodimeric enzymes; they are essential for altering DNA topology by the formation of normally transient double strand DNA cleavage. Anticancer drugs (etoposide, doxorubicin, and mitoxantrone) and also Top2 oxidation and DNA helical alterations cause potentially irreversible Top2.DNA cleavage complexes (Top2cc), leading to Top2-linked DNA breaks. Top2cc are the therapeutic mechanism for killing cancer cells. Yet Top2cc can also generate recombination, translocations, and apoptosis in normal cells. The Top2 protein-DNA covalent complexes are excised (in part) by tyrosyl-DNA-phosphodiesterase 2 (TDP2/TTRAP/EAP2/VPg unlinkase). In this study, we show that irreversible Top2cc induced in suicidal substrates are not processed by TDP2 unless they first undergo proteolytic processing or denaturation. We also demonstrate that TDP2 is most efficient when the DNA attached to the tyrosyl is in a single-stranded configuration and that TDP2 can efficiently remove a tyrosine linked to a single misincorporated ribonucleotide or to polyribonucleotides, which expands the TDP2 catalytic profile with RNA substrates. The 1.6-angstrom resolution crystal structure of TDP2 bound to a substrate bearing a 5'-ribonucleotide defines a mechanism through which RNA can be accommodated in the TDP2 active site, albeit in a strained conformation. C1 [Gao, Rui; Huang, Shar-yin N.; Abdelmalak, Monica; Marchand, Christophe; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Schellenberg, Matthew J.; Williams, R. Scott] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Nitiss, Karin C.; Nitiss, John L.] Univ Illinois, Coll Pharm, Dept Biopharmaceut Sci, Rockford, IL 61107 USA. RP Pommier, Y (reprint author), NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM pommier@nih.gov RI Williams, Robert/A-6059-2015 FU United States Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX We thank L. Pedersen of the National Institutes of Health, NIEHS, Collaborative Crystallography Group and the Advanced Photon Source (APS) Southeast Regional Collaborative Access Team (SER-CAT) for beamline access. Use of the Advanced Photon Source was supported by the United States Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract W-31-109-Eng-38. NR 45 TC 23 Z9 24 U1 0 U2 22 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 JUN 27 PY 2014 VL 289 IS 26 BP 17960 EP 17969 DI 10.1074/jbc.M114.565374 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AJ9OM UT WOS:000338042000001 PM 24808172 ER PT J AU Cho, HJ Hwang, YS Mood, K Ji, YJ Lim, J Morrison, DK Daar, IO AF Cho, Hee Jun Hwang, Yoo-Seok Mood, Kathleen Ji, Yon Ju Lim, Junghwa Morrison, Deborah K. Daar, Ira O. TI EphrinB1 Interacts with CNK1 and Promotes Cell Migration through c-Jun N-terminal Kinase (JNK) Activation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TYROSINE PHOSPHORYLATION; EPH-RECEPTOR; TRANSMEMBRANE LIGANDS; SCAFFOLD PROTEIN; GASTRIC-CANCER; MORPHOGENESIS; SIGNALS; RHO; ANGIOGENESIS; MAINTENANCE AB The Eph receptors and their membrane-bound ligands, ephrins, play important roles in various biological processes such as cell adhesion and movement. The transmembrane ephrinBs transduce reverse signaling in a tyrosine phosphorylation-dependent or -independent, as well as PDZ-dependent manner. Here, we show that ephrinB1 interacts with Connector Enhancer of KSR1 (CNK1) in an EphB receptor-independent manner. In cultured cells, cotransfection of ephrinB1 with CNK1 increases JNK phosphorylation. EphrinB1/CNK1-mediated JNK activation is reduced by overexpression of dominant-negative RhoA. Overexpression of CNK1 alone is sufficient for activation of RhoA; however, both ephrinB1 and CNK1 are required for JNK phosphorylation. Co-immunoprecipitation data showed that ephrinB1 and CNK1 act as scaffold proteins that connect RhoA and JNK signaling components, such as p115RhoGEF and MKK4. Furthermore, adhesion to fibronectin or active Src overexpression increases ephrinB1/CNK1 binding, whereas blocking Src activity by a pharmacological inhibitor decreases not only ephrinB1/CNK1 binding, but also JNK activation. EphrinB1 overexpression increases cell motility, however, CNK1 depletion by siRNA abrogates ephrinB1-mediated cell migration and JNK activation. Moreover, Rho kinase inhibitor or JNK inhibitor treatment suppresses ephrinB1-mediated cell migration. Taken together, our findings suggest that CNK1 is required for ephrinB1-induced JNK activation and cell migration. C1 [Cho, Hee Jun; Hwang, Yoo-Seok; Mood, Kathleen; Ji, Yon Ju; Lim, Junghwa; Morrison, Deborah K.; Daar, Ira O.] NCI, Lab Cell & Dev Signaling, NIH, Frederick, MD 21702 USA. RP Daar, IO (reprint author), NCI, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. EM daar@ncifcrf.gov OI Daar, Ira/0000-0003-2657-526X FU Intramural Research Program of the National Institutes of Health, NCI FX This research was supported by the Intramural Research Program of the National Institutes of Health, NCI. NR 52 TC 8 Z9 8 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 27 PY 2014 VL 289 IS 26 BP 18556 EP 18568 DI 10.1074/jbc.M114.558809 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AJ9OM UT WOS:000338042000052 PM 24825906 ER PT J AU Dalla Rosa, I Huang, SYN Agama, K Khiati, S Zhang, HL Pommier, Y AF Dalla Rosa, Ilaria Huang, Shar-yin N. Agama, Keli Khiati, Salim Zhang, Hongliang Pommier, Yves TI Mapping Topoisomerase Sites in Mitochondrial DNA with a Poisonous Mitochondrial Topoisomerase I (Top1mt) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INITIATION SEQUENCE; ACTIVE-SITE; TRANSCRIPTION; CAMPTOTHECIN; REPLICATION; MECHANISM; CLEAVAGE; TEMPLATE; DAMAGE; ELONGATION AB Mitochondrial topoisomerase I (Top1mt) is a type IB topoisomerase present in vertebrates and exclusively targeted to mitochondria. Top1mt relaxes mitochondrial DNA (mtDNA) supercoiling by introducing transient cleavage complexes wherein the broken DNA strand swivels around the intact strand. Top1mt cleavage complexes (Top1mtcc) can be stabilized in vitro by camptothecin (CPT). However, CPT does not trap Top1mtcc efficiently in cells and is highly cytotoxic due to nuclear Top1 targeting. To map Top1mtcc on mtDNA in vivo and to overcome the limitations of CPT, we designed two substitutions (T546A and N550H) in Top1mt to stabilize Top1mtcc. We refer to the double-mutant enzyme as Top1mt*. Using retroviral transduction and ChIP-on-chip assays with Top1mt* in Top1mt knock-out murine embryonic fibroblasts, we demonstrate that Top1mt* forms high levels of cleavage complexes preferentially in the noncoding regulatory region of mtDNA, accumulating especially at the heavy strand replication origin O-H, in the ribosomal genes (12S and 16S) and at the light strand replication origin O-L. Expression of Top1mt* also caused rapid mtDNA depletion without affecting mitochondria mass, suggesting the existence of specific mitochondrial pathways for the removal of damaged mtDNA. C1 [Dalla Rosa, Ilaria; Huang, Shar-yin N.; Agama, Keli; Khiati, Salim; Zhang, Hongliang; Pommier, Yves] NCI, Mol Pharmacol Lab, Dev Therapeut Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Dev Therapeut Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM pommier@nih.gov FU Intramural Program of the NCI, National Institutes of Health, Department of Health and Human Services Grant [Z01 BC 006161] FX This work was supported, in whole or in part, by the Intramural Program of the NCI, National Institutes of Health, Department of Health and Human Services Grant Z01 BC 006161. NR 47 TC 2 Z9 2 U1 2 U2 12 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 JUN 27 PY 2014 VL 289 IS 26 BP 18595 EP 18602 DI 10.1074/jbc.M114.555367 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AJ9OM UT WOS:000338042000057 PM 24798329 ER PT J AU Golla, JP Zhao, JF Mann, IK Sayeed, SK Mandal, A Rose, RB Vinson, C AF Golla, Jaya Prakash Zhao, Jianfei Mann, Ishminder K. Sayeed, Syed K. Mandal, Ajeet Rose, Robert B. Vinson, Charles TI Carboxylation of cytosine (5caC) in the CG dinucleotide in the E-box motif (CGCAG vertical bar GTG) increases binding of the Tcf3 vertical bar Ascl1 helix-loop-helix heterodimer 10-fold SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Carboxylation; E-Box motif; CG dinucleotide; Basic-helix-loop-helix; DNA binding; Tcf3 vertical bar Ascl1 heterodimer ID DIMERIZATION SPECIFICITY; CPG METHYLATION; DNA-BINDING; CRYSTAL-STRUCTURE; TET PROTEINS; TRANSCRIPTION; RECOGNITION; SEQUENCE; GENOME; 5-FORMYLCYTOSINE AB Three oxidative products of 5-methylcytosine (5mC) occur in mammalian genomes. We evaluated if these cytosine modifications in a CG dinucleotide altered DNA binding of four B-HLH homodimers and three heterodimers to the E-Box motif CGCAG vertical bar GTG. We examined 25 DNA probes containing all combinations of cytosine in a CG dinucleotide and none changed binding except for carboxylation of cytosine (5caC) in the strand CGCAG vertical bar GTG. 5caC enhanced binding of all examined B-HLH homodimers and heterodimers, particularly the Tcf3 vertical bar Ascl1 heterodimer which increased binding similar to 10-fold. These results highlight a potential function of the oxidative products of 5mC, changing the DNA binding of sequence-specific transcription factors. C1 [Golla, Jaya Prakash; Zhao, Jianfei; Mann, Ishminder K.; Sayeed, Syed K.; Mandal, Ajeet; Vinson, Charles] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Rose, Robert B.] N Carolina State Univ, Dept Biochem, Raleigh, NC 27695 USA. RP Vinson, C (reprint author), NCI, Lab Metab, NIH, Room 3128,Bldg 37, Bethesda, MD 20892 USA. EM vinsonc@mail.nih.gov OI Zhao, Jianfei/0000-0003-4746-6804 FU National Cancer Institute, NIH, Bethesda, USA FX This work is supported by the intramural research project of National Cancer Institute, NIH, Bethesda, USA. NR 31 TC 8 Z9 8 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUN 27 PY 2014 VL 449 IS 2 BP 248 EP 255 DI 10.1016/j.bbrc.2014.05.018 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AJ4RY UT WOS:000337664700011 PM 24835951 ER PT J AU Pigott, DM Bhatt, S Golding, N Duda, KA Battle, KE Brady, OJ Messina, JP Balard, Y Bastien, P Pratlong, F Brownstein, JS Freifeld, C Mekaru, SR Gething, PW George, DB Myers, MF Reithinger, R Hay, SI AF Pigott, David M. Bhatt, Samir Golding, Nick Duda, Kirsten A. Battle, Katherine E. Brady, Oliver J. Messina, Jane P. Balard, Yves Bastien, Patrick Pratlong, Francine Brownstein, John S. Freifeld, Clark Mekaru, Sumiko R. Gething, Peter W. George, Dylan B. Myers, Monica F. Reithinger, Richard Hay, Simon I. TI Global Distribution Maps of the Leishmaniases SO ELIFE LA English DT Article DE cutaneous leishmaniasis; visceral leishmaniasis; niche based modelling; boosted regression trees; species distribution modelling; disease mapping ID PHLEBOTOMINE SAND FLIES; PSEUDO-ABSENCE DATA; VISCERAL LEISHMANIASIS; KALA-AZAR; ENVIRONMENTAL VARIABLES; CUTANEOUS LEISHMANIASIS; ZOONOTIC LEISHMANIASIS; POTENTIAL DISTRIBUTION; SEASONAL DISTRIBUTION; DISTRIBUTION MODELS AB The leishmaniases are vector-borne diseases that have a broad global distribution throughout much of the Americas, Africa and Asia. Despite representing a significant public health burden, our understanding of the global distribution of the leishmaniases remains vague, reliant upon expert opinion and limited to poor spatial resolution. A global assessment of the consensus of evidence for leishmaniasis was performed at a sub-national level by aggregating information from a variety of sources. A database of records of cutaneous and visceral leishmaniasis occurrence was compiled from published literature, online reports, strain archives and GenBank accessions. These, with a suite of biologically relevant environmental covariates, were used in a boosted regression tree modelling framework to generate global environmental risk maps for the leishmaniases. These high-resolution evidence-based maps can help direct future surveillance activities, identify areas to target for disease control and inform future burden estimation efforts. C1 [Pigott, David M.; Bhatt, Samir; Golding, Nick; Duda, Kirsten A.; Battle, Katherine E.; Brady, Oliver J.; Messina, Jane P.; Gething, Peter W.; Myers, Monica F.; Hay, Simon I.] Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Oxford OX1 3PS, England. [Balard, Yves; Bastien, Patrick; Pratlong, Francine] Univ Montpellier 1 UFR Med, Montpellier, France. [Balard, Yves; Bastien, Patrick; Pratlong, Francine] CNRS 5290 IRD 224 UMR MiVEGEC, Lab Parasitol Mycol, Montpellier, France. [Bastien, Patrick; Pratlong, Francine] CHRU, Ctr Natl Reference Leishmanioses, Dept Parasitol Mycol, Montpellier, France. [Brownstein, John S.; Freifeld, Clark; Mekaru, Sumiko R.] Boston Childrens Hosp, Childrens Hosp Informat Program, Boston, MA USA. [Brownstein, John S.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Freifeld, Clark] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [George, Dylan B.; Hay, Simon I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Reithinger, Richard] RTI Int, Washington, DC USA. RP Pigott, DM (reprint author), Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Tinbergen Bldg,S Parks Rd, Oxford OX1 3PS, England. RI Hay, Simon/F-8967-2015; OI Hay, Simon/0000-0002-0611-7272; Pigott, David/0000-0002-6731-4034; Golding, Nick/0000-0001-8916-5570; Gething, Peter/0000-0001-6759-5449; Brady, Oliver/0000-0002-3235-2129; Battle, Katherine/0000-0003-2401-2615 FU Richard Southwood Graduate Scholarship from the Department of Zoology at the University of Oxford; Senior Research Fellowship from the Wellcome Trust [095066]; Bill & Melinda Gates Foundation [OPP1053338, OPP1068048]; Medical Research Council (UK) Career Development [K00669X]; BBSRC studentship; International Research Consortium on Dengue Risk Assessment Management and Surveillance (IDAMS, European Commission 7th Framework Programme) [21803]; NIH National Library of Medicine [R01LM010812] FX DMP is funded by a Sir Richard Southwood Graduate Scholarship from the Department of Zoology at the University of Oxford. SIH is funded by a Senior Research Fellowship from the Wellcome Trust (095066) which also supports KAD and KEB. NG is funded by a grant from the Bill & Melinda Gates Foundation (#OPP1053338). PWG is a Medical Research Council (UK) Career Development Fellow (#K00669X) and receives support from the Bill and Melinda Gates Foundation (#OPP1068048) which also supports SB. OJB is funded by a BBSRC studentship. JPM is funded by, and SIH and OJB acknowledge the support of, the International Research Consortium on Dengue Risk Assessment Management and Surveillance (IDAMS, European Commission 7th Framework Programme (#21803) http://www.idams.eu). JSB, CF and SRM acknowledge funding from NIH National Library of Medicine (R01LM010812). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 83 TC 29 Z9 30 U1 4 U2 6 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD JUN 27 PY 2014 VL 3 AR e02851 DI 10.7554/eLife.02851 PG 33 WC Biology SC Life Sciences & Biomedicine - Other Topics GA AK9GE UT WOS:000338734800001 ER PT J AU Wagoner, KM Lehmann, T Huestis, DL Ehrmann, BM Cech, NB Wasserberg, G AF Wagoner, Kaira M. Lehmann, Tovi Huestis, Diana L. Ehrmann, Brandie M. Cech, Nadja B. Wasserberg, Gideon TI Identification of morphological and chemical markers of dry- and wet-season conditions in female Anopheles gambiae mosquitoes SO PARASITES & VECTORS LA English DT Article DE Aestivation; Cuticular hydrocarbon; Photoperiod; Spiracle; Wing length; Malaria ID CUTICULAR HYDROCARBONS; DESICCATION RESISTANCE; METABOLIC-RATE; WESTERN KENYA; CULEX-PIPIENS; WING LENGTH; MALARIA; DIAPAUSE; DROSOPHILA; CULICIDAE AB Background: Increased understanding of the dry-season survival mechanisms of Anopheles gambiae in semi-arid regions could benefit vector control efforts by identifying weak links in the transmission cycle of malaria. In this study, we examined the effect of photoperiod and relative humidity on morphologic and chemical traits known to control water loss in mosquitoes. Methods: Anopheles gambiae body size (indexed by wing length), mesothoracic spiracle size, and cuticular hydrocarbon composition (both standardized by body size) were examined in mosquitoes raised from eggs exposed to short photoperiod and low relative humidity, simulating the dry season, or long photoperiod and high relative humidity, simulating the wet-season. Results: Mosquitoes exposed to short photoperiod exhibited larger body size and larger mesothoracic spiracle length than mosquitoes exposed to long photoperiod. Mosquitoes exposed to short photoperiod and low relative humidity exhibited greater total cuticular hydrocarbon amount than mosquitoes exposed to long photoperiod and high relative humidity. In addition, total cuticular hydrocarbon amount increased with age and was higher in mated females. Mean n-alkane retention time (a measure of cuticular hydrocarbon chain length) was lower in mosquitoes exposed to short photoperiod and low relative humidity, and increased with age. Individual cuticular hydrocarbon peaks were examined, and several cuticular hydrocarbons were identified as potential biomarkers of dry- and wet-season conditions, age, and insemination status. Conclusions: Results from this study indicate that morphological and chemical changes underlie aestivation of Anopheles gambiae and may serve as biomarkers of aestivation. C1 [Wagoner, Kaira M.; Wasserberg, Gideon] Univ N Carolina, Dept Biol, Greensboro, NC 27402 USA. [Lehmann, Tovi; Huestis, Diana L.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Ehrmann, Brandie M.; Cech, Nadja B.] Univ N Carolina, Dept Chem & Biochem, Greensboro, NC 27402 USA. RP Wasserberg, G (reprint author), Univ N Carolina, Dept Biol, 235 Eberhart Bldg, Greensboro, NC 27402 USA. EM g_wasser@uncg.edu FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX Many thanks to Kathryne Dieter, Aleah Bowie, Jen Hume, and Kevin Lee for their assistance in the insectary and with early laboratory work. Thanks also to Bruce Kirchoff and Bruce Harrison for guidance with morphometric analysis, and to Scott Richter for assistance with statistical analysis. We thank Dennis LaJeunesse for the SEM photo of the spiracle. This study was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. This work is dedicated to the late Ron Rivera, a leader in the fight against waterborne disease who died from malaria in 2008. NR 60 TC 7 Z9 7 U1 3 U2 18 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-3305 J9 PARASITE VECTOR JI Parasites Vectors PD JUN 26 PY 2014 VL 7 AR 294 DI 10.1186/1756-3305-7-294 PG 13 WC Parasitology SC Parasitology GA AL4AO UT WOS:000339075300001 PM 24970701 ER PT J AU Kawabata, S Mercado-Matos, JR Hollander, MC Donahue, D Wilson, W Regales, L Butaney, M Pao, W Wong, KK Jaenne, PA Dennis, PA AF Kawabata, Shigeru Mercado-Matos, Jose R. Hollander, M. Christine Donahue, Danielle Wilson, Willie, III Regales, Lucia Butaney, Mohit Pao, William Wong, Kwok-Kin Jaenne, Pasi A. Dennis, Phillip A. TI Rapamycin Prevents the Development and Progression of Mutant Epidermal Growth Factor Receptor Lung Tumors with the Acquired Resistance Mutation T790M SO CELL REPORTS LA English DT Article ID TYROSINE KINASE INHIBITOR; EGFR T790M; CANCER; DISEASE; GEFITINIB; ADENOCARCINOMAS; DIFFERENTIATION; ERLOTINIB; MURINE; MICE AB Lung cancer in never-smokers is an important disease often characterized by mutations in epidermal growth factor receptor (EGFR), yet risk reduction measures and effective chemopreventive strategies have not been established. We identify mammalian target of rapamycin (mTOR) as potentially valuable target for EGFR mutant lung cancer. mTOR is activated in human lung cancers with EGFR mutations, and this increases with acquisition of T790M mutation. In a mouse model of EGFR mutant lung cancer, mTOR activation is an early event. As a single agent, the mTOR inhibitor rapamycin prevents tumor development, prolongs overall survival, and improves outcomes after treatment with an irreversible EGFR tyrosine kinase inhibitor (TKI). These studies support clinical testing of mTOR inhibitors in order to prevent the development and progression of EGFR mutant lung cancers. C1 [Kawabata, Shigeru; Dennis, Phillip A.] Johns Hopkins Bayview Med Ctr, Dept Oncol, Baltimore, MD 21224 USA. [Mercado-Matos, Jose R.; Hollander, M. Christine; Wilson, Willie, III] NCI, Ctr Canc Res, Med Oncol Branch, Bethesda, MD 20892 USA. [Donahue, Danielle] Natl Inst Neurol Disorders & Stroke, Mouse Imaging Facil, NIH, Bethesda, MD 20892 USA. [Regales, Lucia] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Butaney, Mohit; Wong, Kwok-Kin; Jaenne, Pasi A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Pao, William] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Dept Med, Div Hematol Oncol, Nashville, TN 37232 USA. RP Dennis, PA (reprint author), Johns Hopkins Bayview Med Ctr, Dept Oncol, Baltimore, MD 21224 USA. EM pdennis@jhmi.edu FU NIH [R01CA135257]; NCI; CCR; Open Access Promotion Fund of the Johns Hopkins University Libraries FX The authors would like to thank Maiga Emmanuel (Office of the Director, NCI) for assistance with genotyping; Morales-Contreras Juan, Dumas Tarra, and Dr. John U. Dennis (Laboratory Animal Medicine, NCI) for veterinary services; Dr. Jeffrey A. Whitsett (University of Cincinnati College of Medicine) for providing CCSP-rtTA transgenic mice; Dr. Nathanael S. Gray (Harvard Medical School) for providing WZ4002 compound; and the NIH Fellows Editorial Board for editorial assistance. This research was supported by the Intramural Research Program of the NIH, NCI, and CCR (P.A.D.) and NIH R01CA135257 (P.A.J.). 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. Publication of this article was funded in part by the Open Access Promotion Fund of the Johns Hopkins University Libraries. NR 21 TC 6 Z9 6 U1 0 U2 1 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 JUN 26 PY 2014 VL 7 IS 6 BP 1824 EP 1832 DI 10.1016/j.celrep.2014.05.039 PG 9 WC Cell Biology SC Cell Biology GA AK3LL UT WOS:000338325400009 PM 24931608 ER PT J AU Ryu, H Gygi, SP Azuma, Y Arnaoutov, A Dasso, M AF Ryu, Hyunju Gygi, Steven P. Azuma, Yoshiaki Arnaoutov, Alexei Dasso, Mary TI SUMOylation of Psmd1 Controls Adrm1 Interaction with the Proteasome SO CELL REPORTS LA English DT Article ID XENOPUS EGG EXTRACTS; MEDIATED PROTEOLYSIS; TOPOISOMERASE-II; SUMO PROTEASES; SPINDLE; BINDING; RECOGNITION; CHROMOSOMES; SPECIFICITY; CONJUGATION AB SUMOylation is the covalent conjugation of SUMO polypeptides to cellular target proteins. Psmd1 is a subunit of the proteasomal 19S regulatory particle that acts as a docking site for Adrm1, another proteasome subunit that recruits ubiquitinated substrates for proteolysis. Here, we show that the SUMO deconjugating enzyme xSENP1 specifically interacts with Psmd1 and that disruption of xSENP1 targeting delays mitotic exit. Psmd1 becomes SUMOylated through the action of the SUMO E3 enzyme PIASy. We mapped SUMOylation sites within Psmd1 and found that SUMOylation of a critical lysine immediately adjacent to the Adrm1-binding domain regulates the association of Adrm1 with Psmd1. Together, our findings suggest that the interaction of Psmd1 with Adrm1 is controlled by SUMOylation in a manner that may alter proteasome composition and function. These findings demonstrate a mechanism for regulation of ubiquitin-mediated protein degradation by ubiquitin-like proteins of the SUMO family. C1 [Ryu, Hyunju; Arnaoutov, Alexei; Dasso, Mary] NICHHD, NIH, Bethesda, MD 20892 USA. [Gygi, Steven P.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Azuma, Yoshiaki] Univ Kansas, Dept Mol Biosci, Lawrence, KS 66045 USA. RP Dasso, M (reprint author), NICHHD, NIH, Bethesda, MD 20892 USA. EM dassom@mail.nih.gov OI Dasso, Mary/0000-0002-5410-1371 FU NICHD [HD001902]; NIH/NIGMS [GM80278] FX We thank Kara Lukasiewicz for critical reading of this manuscript and Woong Kim for the mass spectrometry analysis of Psmd1 SUMOylation sites. H.R., A. A., and M. D. were supported by NICHD project no. HD001902. Y.A. was supported by NIH/NIGMS grant RO1 no. GM80278. NR 25 TC 4 Z9 4 U1 2 U2 10 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 JUN 26 PY 2014 VL 7 IS 6 BP 1842 EP 1848 DI 10.1016/j.celrep.2014.05.009 PG 7 WC Cell Biology SC Cell Biology GA AK3LL UT WOS:000338325400011 PM 24910440 ER PT J AU Goktuna, SI Canli, O Bollrath, J Fingerle, AA Horst, D Diamanti, MA Pallangyo, C Bennecke, M Nebelsiek, T Mankan, AK Lang, R Artis, D Hu, YL Patzelt, T Ruland, J Kirchner, T Taketo, MM Chariot, A Arkan, MC Greten, FR AF Goektuna, Serkan I. Canli, Ozge Bollrath, Julia Fingerle, Alexander A. Horst, David Diamanti, Michaela A. Pallangyo, Charles Bennecke, Moritz Nebelsiek, Tim Mankan, Arun K. Lang, Roland Artis, David Hu, Yinling Patzelt, Thomas Ruland, Juergen Kirchner, Thomas Taketo, M. Mark Chariot, Alain Arkan, Melek C. Greten, Florian R. TI IKK alpha Promotes Intestinal Tumorigenesis by Limiting Recruitment of M1-like Polarized Myeloid Cells SO CELL REPORTS LA English DT Article ID NF-KAPPA-B; TUMOR-INITIATING CELLS; COLORECTAL-CANCER; INFLAMMATION; METASTASIS; ACTIVATION; EXPRESSION; GENE; MICROENVIRONMENT; PROGRESSION AB The recruitment of immune cells into solid tumors is an essential prerequisite of tumor development. Depending on the prevailing polarization profile of these infiltrating leucocytes, tumorigenesis is either promoted or blocked. Here, we identify I kappa B kinase alpha (IKK alpha) as a central regulator of a tumoricidal microenvironment during intestinal carcinogenesis. Mice deficient in IKK alpha kinase activity are largely protected from intestinal tumor development that is dependent on the enhanced recruitment of interferon gamma (IFN gamma)-expressing M1-like myeloid cells. In IKK alpha mutant mice, M1-like polarization is not controlled in a cell-autonomous manner but, rather, depends on the interplay of both IKK alpha mutant tumor epithelia and immune cells. Because therapies aiming at the tumor microenvironment rather than directly at the mutated cancer cell may circumvent resistance development, we suggest IKK alpha as a promising target for colorectal cancer (CRC) therapy. C1 [Goektuna, Serkan I.; Canli, Ozge; Bollrath, Julia; Diamanti, Michaela A.; Pallangyo, Charles; Bennecke, Moritz; Nebelsiek, Tim; Mankan, Arun K.; Arkan, Melek C.; Greten, Florian R.] Tech Univ Munich, Klinikum Rechts Isar, Inst Mol Immunol, D-81675 Munich, Germany. [Goektuna, Serkan I.; Chariot, Alain] Univ Liege, GIGA R, Unit Signal Transduct GIGA ST, B-4000 Liege, Belgium. [Canli, Ozge; Diamanti, Michaela A.; Pallangyo, Charles; Greten, Florian R.] CHU, WELBIO, B-4000 Liege, Belgium. [Canli, Ozge; Diamanti, Michaela A.; Pallangyo, Charles; Greten, Florian R.] Inst Tumor Biol & Expt Therapy, D-60596 Frankfurt, Germany. [Fingerle, Alexander A.] Tech Univ Munich, Klinikum Rechts Isar, Dept Radiol, D-81675 Munich, Germany. [Horst, David; Kirchner, Thomas] Univ Munich, Inst Pathol, D-80337 Munich, Germany. [Lang, Roland] Univ Hosp Erlangen, Inst Clin Microbiol Immunol & Hyg, D-91054 Erlangen, Germany. [Artis, David] Univ Penn, Perelman Sch Med, Dept Microbiol, Philadelphia, PA 19104 USA. [Artis, David] Univ Penn, Perelman Sch Med, Inst Immunol, Philadelphia, PA 19104 USA. [Hu, Yinling] NCI, Ctr Canc Res, Canc & Inflammat Program, Lab Expt Immunol, Frederick, MD 21701 USA. [Patzelt, Thomas; Ruland, Juergen] Tech Univ Munich, Klinikum Rechts Isar, Dept Clin Chem, D-81675 Munich, Germany. [Ruland, Juergen; Kirchner, Thomas; Greten, Florian R.] German Canc Consortium DKTK, D-69120 Heidelberg, Germany. [Ruland, Juergen; Kirchner, Thomas; Greten, Florian R.] German Canc Res Ctr, D-69120 Heidelberg, Germany. [Taketo, M. Mark] Kyoto Univ, Grad Sch Med, Dept Pharmacol, Kyoto 6068501, Japan. RP Greten, FR (reprint author), Tech Univ Munich, Klinikum Rechts Isar, Inst Mol Immunol, D-81675 Munich, Germany. EM greten@gsh.uni-frankfurt.de OI Goktuna, Serkan/0000-0001-6169-768X FU Deutsche Krebshilfe [108872]; Deutsche Forschungsgemeinschaft [GR 1916/3-1]; European Research Council [ERC 281967]; LOEWE Center for Cell and Gene Therapy Frankfurt - Hessian Ministry of Higher Education, Research and the Arts [III L 4- 518/17.004] FX We thank Kerstin Burmeister, Saskia Ettl, Kristin Retzlaff, Birgit Wittig, and Andrea Sendlhofert for technical assistance. We are grateful to Michael Karin for generously providing Ikk alphaAA/AA and Ikk betaF/F mice as well as Frank Schmitz and Roland M. Schmid for providing Ifnar-/- and Nfkb2-/- mice, respectively. We thank Jorg Mages for performing microarray experiments. This work was supported by grants from the Deutsche Krebshilfe (108872), Deutsche Forschungsgemeinschaft (GR 1916/3-1), and the European Research Council (ERC 281967) to F.R.G. Further support was provided by the LOEWE Center for Cell and Gene Therapy Frankfurt (funded by the Hessian Ministry of Higher Education, Research and the Arts; III L 4- 518/17.004). NR 40 TC 5 Z9 6 U1 0 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 JUN 26 PY 2014 VL 7 IS 6 BP 1914 EP 1925 DI 10.1016/j.celrep.2014.05.006 PG 12 WC Cell Biology SC Cell Biology GA AK3LL UT WOS:000338325400018 PM 24882009 ER PT J AU Zhao, XZ Smith, SJ Metifiot, M Marchand, C Boyer, PL Pommier, Y Hughes, SH Burke, TR AF Zhao, Xue Zhi Smith, Steven J. Metifiot, Mathieu Marchand, Christophe Boyer, Paul L. Pommier, Yves Hughes, Stephen H. Burke, Terrence R., Jr. TI 4-Amino-1-hydroxy-2-oxo-1,8-naphthyridine-Containing Compounds Having High Potency against Raltegravir-Resistant Integrase Mutants of HIV-1 SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PHARMACOKINETIC PROFILES; REVERSE-TRANSCRIPTASE; RIBONUCLEASE H; INHIBITORS; 4,5-DIHYDROXYPYRIMIDINE; DOLUTEGRAVIR; DERIVATIVES; POLYMERASE; DESIGN; ACIDS AB There are currently three HIV-1 integrase (IN) strand transfer inhibitors (INSTIs) approved by the FDA for the treatment of AIDS. However, the emergence of drug-resistant mutants emphasizes the need to develop additional agents that have improved efficacies against the existent resistant mutants. As reported herein, we modified our recently disclosed 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides IN inhibitors to develop compounds that have improved efficacies against recombinant IN in biochemical assays. These new compounds show single-digit nanomolar antiviral potencies against HIV vectors that carry wild-type (WT) IN in a single round replication assay and have improved potency against vectors harboring the major forms of drug resistant IN mutants. These compounds also have low toxicity for cultured cells, which in several cases, results in selectivity indices (CC50/EC50) of greater than 10000. The compounds have the potential, with additional structural modifications, to yield clinical agents that are effective against the known strains of resistant viruses. C1 [Zhao, Xue Zhi; Burke, Terrence R., Jr.] NCI, Biol Chem Lab, NIH, Frederick, MD 21702 USA. [Smith, Steven J.; Boyer, Paul L.; Hughes, Stephen H.] NCI, HIV Drug Resistance Program, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Metifiot, Mathieu; Marchand, Christophe; Pommier, Yves] NCI, Mol Pharmacol Lab, Dev Therapeut Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Burke, TR (reprint author), NCI, Biol Chem Lab, NIH, Bldg 376,Boyles St,POB B, Frederick, MD 21702 USA. EM burkete@helix.nih.gov RI Zhao, Xue Zhi/N-9594-2014; Burke, Terrence/N-2601-2014 OI Zhao, Xue Zhi/0000-0003-1006-6364; FU NIH, Center for Cancer Research, National Institutes of Health, NCI at Frederick; Joint Science and Technology Office of the Department of Defense; Intramural AIDS Targeted Antiviral Program FX This work was supported in part by the Intramural Research Program of the NIH, Center for Cancer Research, National Institutes of Health, NCI at Frederick, and the Joint Science and Technology Office of the Department of Defense and funds from the Intramural AIDS Targeted Antiviral Program. 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 30 TC 6 Z9 6 U1 0 U2 7 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 JUN 26 PY 2014 VL 57 IS 12 BP 5190 EP 5202 DI 10.1021/jm5001908 PG 13 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA AK1OJ UT WOS:000338184100016 PM 24901667 ER PT J AU Kedei, N Chen, JQ Herrmann, MA Telek, A Goldsmith, PK Petersen, ME Keck, GE Blumberg, PM AF Kedei, Noemi Chen, Jin-Qiu Herrmann, Michelle A. Telek, Andrea Goldsmith, Paul K. Petersen, Mark E. Keck, Gary E. Blumberg, Peter M. TI Molecular Systems Pharmacology: Isoelectric Focusing Signature of Protein Kinase C delta Provides an Integrated Measure of Its Modulation in Response to Ligands SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PROSTATE-CANCER CELLS; ESTER-INDUCED APOPTOSIS; PHORBOL ESTER; TYROSINE PHOSPHORYLATION; ACTIVATION MECHANISMS; CRYSTAL-STRUCTURE; GENE-EXPRESSION; BRYOSTATIN 1; PKC-DELTA; TRANSLOCATION AB Protein kinase C (PKC), a validated therapeutic target for cancer chemotherapy, provides a paradigm for assessing structure activity relations, where ligand binding has multiple consequences for a target. For PKC, ligand binding controls not only PKC activation and multiple phosphorylations but also subcellular localization, affecting subsequent signaling. Using a capillary isoelectric focusing immunoassay system, we could visualize a high resolution isoelectric focusing signature of PKC delta upon stimulation by ligands of the phorbol ester and bryostatin classes. Derivatives that possessed different physicochemical characteristics and induced different patterns of biological response generated different signatures. Consistent with different patterns of PKC delta localization as one factor linked to these different signatures, we found different signatures for activated PKC delta from the nuclear and non-nuclear fractions. We conclude that the capillary isoelectric focusing immunoassay system may provide a window into the integrated consequences of ligand binding and thus afford a powerful platform for compound development. C1 [Kedei, Noemi; Telek, Andrea; Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. [Chen, Jin-Qiu; Herrmann, Michelle A.] NCI, Collaborat Prot Technol Resource, Cell Biol Lab, Bethesda, MD 20892 USA. [Goldsmith, Paul K.] NCI, Off Sci & Technol Partnerships, Ctr Canc Res, Bethesda, MD 20892 USA. [Petersen, Mark E.; Keck, Gary E.] Univ Utah, Dept Chem, Salt Lake City, UT 84112 USA. RP Blumberg, PM (reprint author), NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. EM blumberp@dc37a.nci.nih.gov FU Intramural Research Program, National Institutes of Health, Center for Cancer Research, National Cancer Institute [ZIA BC 005270]; [GM28961] FX This research was supported in part by the Intramural Research Program, National Institutes of Health, Center for Cancer Research, National Cancer Institute (Grant ZIA BC 005270) and in part by Grant GM28961 to G.E.K. NR 55 TC 1 Z9 1 U1 0 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 JUN 26 PY 2014 VL 57 IS 12 BP 5356 EP 5369 DI 10.1021/jm500417b PG 14 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA AK1OJ UT WOS:000338184100029 PM 24906106 ER PT J AU Cousins, MM Konikoff, J Sabin, D Khaki, L Longosz, AF Laeyendecker, O Celum, C Buchbinder, SP Seage, GR Kirk, GD Moore, RD Mehta, SH Margolick, JB Brown, J Mayer, KH Kobin, BA Wheeler, D Justman, JE Hodder, SL Quinn, TC Brookmeyer, R Eshleman, SH AF Cousins, Matthew M. Konikoff, Jacob Sabin, Devin Khaki, Leila Longosz, Andrew F. Laeyendecker, Oliver Celum, Connie Buchbinder, Susan P. Seage, George R., III Kirk, Gregory D. Moore, Richard D. Mehta, Shruti H. Margolick, Joseph B. Brown, Joelle Mayer, Kenneth H. Kobin, Beryl A. Wheeler, Darrell Justman, Jessica E. Hodder, Sally L. Quinn, Thomas C. Brookmeyer, Ron Eshleman, Susan H. TI A Comparison of Two Measures of HIV Diversity in Multi-Assay Algorithms for HIV Incidence Estimation SO PLOS ONE LA English DT Article ID RESOLUTION MELTING ASSAY; UNITED-STATES; VACCINE PREPAREDNESS; GENETIC DIVERSITY; INCIDENCE RATES; INFECTION; COHORT; SEQUENCE; TRIALS; BED AB Background: Multi-assay algorithms (MAAs) can be used to estimate HIV incidence in cross-sectional surveys. We compared the performance of two MAAs that use HIV diversity as one of four biomarkers for analysis of HIV incidence. Methods: Both MAAs included two serologic assays (LAg-Avidity assay and BioRad-Avidity assay), HIV viral load, and an HIV diversity assay. HIV diversity was quantified using either a high resolution melting (HRM) diversity assay that does not require HIV sequencing (HRM score for a 239 base pair env region) or sequence ambiguity (the percentage of ambiguous bases in a 1,302 base pair pol region). Samples were classified as MAA positive (likely from individuals with recent HIV infection) if they met the criteria for all of the assays in the MAA. The following performance characteristics were assessed: (1) the proportion of samples classified as MAA positive as a function of duration of infection, (2) the mean window period, (3) the shadow (the time period before sample collection that is being assessed by the MAA), and (4) the accuracy of cross-sectional incidence estimates for three cohort studies. Results: The proportion of samples classified as MAA positive as a function of duration of infection was nearly identical for the two MAAs. The mean window period was 141 days for the HRM-based MAA and 131 days for the sequence ambiguity-based MAA. The shadows for both MAAs were,1 year. Both MAAs provided cross-sectional HIV incidence estimates that were very similar to longitudinal incidence estimates based on HIV seroconversion. Conclusions: MAAs that include the LAg-Avidity assay, the BioRad-Avidity assay, HIV viral load, and HIV diversity can provide accurate HIV incidence estimates. Sequence ambiguity measures obtained using a commercially-available HIV genotyping system can be used as an alternative to HRM scores in MAAs for cross-sectional HIV incidence estimation. C1 [Cousins, Matthew M.; Sabin, Devin; Khaki, Leila; Eshleman, Susan H.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Konikoff, Jacob; Brookmeyer, Ron] Univ Calif Los Angeles, Sch Publ Hlth, Dept Biostat, Los Angeles, CA 90024 USA. [Longosz, Andrew F.; Laeyendecker, Oliver; Quinn, Thomas C.] NIAID, NIH, Bethesda, MD 20892 USA. [Laeyendecker, Oliver; Moore, Richard D.; Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Celum, Connie] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Celum, Connie] Univ Washington, Dept Med, Seattle, WA USA. [Buchbinder, Susan P.] San Francisco Dept Hlth, Bridge HIV, San Francisco, CA USA. [Buchbinder, Susan P.] Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94143 USA. [Buchbinder, Susan P.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Seage, George R., III] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Kirk, Gregory D.; Mehta, Shruti H.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Margolick, Joseph B.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA. [Brown, Joelle] Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA 90024 USA. [Brown, Joelle] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Mayer, Kenneth H.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Fenway Inst, Boston, MA 02215 USA. [Kobin, Beryl A.] New York Blood Ctr, Lab Infect Dis Prevent, New York, NY 10021 USA. [Wheeler, Darrell] Loyola Univ Chicago, Grad Sch Social Work, Chicago, IL USA. [Justman, Jessica E.] Columbia Univ, Dept Epidemiol, New York, NY USA. [Justman, Jessica E.] Columbia Univ, Dept Med, New York, NY USA. [Hodder, Sally L.] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Med, Div Infect Dis, Newark, NJ 07103 USA. RP Eshleman, SH (reprint author), Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. EM seshlem@jhmi.edu OI Laeyendecker, Oliver/0000-0002-6429-4760 FU HIV Prevention Trials Network (HPTN) - National Institute of Allergy and Infectious Diseases (NIAID), National Institute on Drug Abuse (NIDA) [UM1-AI068613]; Division of Intramural Research, NIAID, NIH; National Institute of Mental Health (NIMH), and the Office of AIDS Research of the National Institutes of Health (NIH), Department of Health and Human Services; [R01-AI095068] FX This work was supported by: (1) the HIV Prevention Trials Network (HPTN) sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), National Institute on Drug Abuse (NIDA), National Institute of Mental Health (NIMH), and the Office of AIDS Research of the National Institutes of Health (NIH), Department of Health and Human Services (UM1-AI068613 to SE); (2) R01-AI095068 (to SE and RB); and (3) the Division of Intramural Research, NIAID, NIH. Support for the studies that provided samples for this project was as follows: HIVNET 001/001.1: N01-AI35176, N01-AI-45200, and AI-45202; ALIVE: R01-DA-04334 and R01-DA12568; MACS: U01-AI35042, U01-AI35043, U01-AI35039, U01-AI35040, U01-AI35041, and UL1-RR025005; JHHCC: R01-DA011602 to RDM and R01-AA016893 to RDM; HPTN 061 and HPTN 064: UM1-AI068619, UM1-AI068617, and UM1-AI068613. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 5 Z9 5 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 26 PY 2014 VL 9 IS 6 AR e101043 DI 10.1371/journal.pone.0101043 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK2WP UT WOS:000338280800100 PM 24968135 ER PT J AU Woldehawariat, G Martinez, PE Hauser, P Hoover, DM Drevets, WWC McMahon, FJ AF Woldehawariat, Girma Martinez, Pedro E. Hauser, Peter Hoover, David M. Drevets, Wayne W. C. McMahon, Francis J. TI Corpus Callosum Size Is Highly Heritable in Humans, and May Reflect Distinct Genetic Influences on Ventral and Rostral Regions SO PLOS ONE LA English DT Article ID WHITE-MATTER ABNORMALITIES; BIPOLAR AFFECTIVE-DISORDER; HUMAN BRAIN; MOOD DISORDERS; INTERHEMISPHERIC COMMUNICATION; SCHIZOPHRENIA; TWINS; SPECIALIZATION; PERSPECTIVES; NEUROANATOMY AB Anatomical differences in the corpus callosum have been found in various psychiatric disorders, but data on the genetic contributions to these differences have been limited. The current study used morphometric MRI data to assess the heritability of corpus callosum size and the genetic correlations among anatomical sub-regions of the corpus callosum among individuals with and without mood disorders. The corpus callosum (CC) was manually segmented at the mid-sagittal plane in 42 women (healthy, n = 14; major depressive disorder, n = 15; bipolar disorder, n = 13) and their 86 child or adolescent offspring. Four anatomical sub-regions (CC-genu, CC2, CC3 and CC-splenium) and total CC were measured and analyzed. Heritability and genetic correlations were estimated using a variance components method, with adjustment for age, sex, diagnosis, and diagnosis x age, where appropriate. Significant heritability was found for several CC sub-regions (P < 0.01), with estimated values ranging from 48% (splenium) to 67% (total CC). There were strong and significant genetic correlations among most sub regions. Correlations between the genu and mid-body, between the genu and total corpus callosum, and between anterior and mid body were all > 90%, but no significant genetic correlations were detected between ventral and rostral regions in this sample. Genetic factors play an important role in corpus callosum size among individuals. Distinct genetic factors seem to be involved in caudal and rostral regions, consistent with the divergent functional specialization of these brain areas. C1 [Woldehawariat, Girma; McMahon, Francis J.] NIMH, Genet Basis Mood & Anxiety Disorders Sect, Human Genet Branch, NIH,DHHS, Bethesda, MD 20892 USA. [Martinez, Pedro E.] NIMH, Sect Behav Endocrinol, NIH, DHHS, Bethesda, MD 20892 USA. [Hauser, Peter] VISN 22 Network Off, Long Beach, CA USA. [Hoover, David M.] NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. [Drevets, Wayne W. C.] Laureate Inst Brain Res, Tulsa, OK USA. [Drevets, Wayne W. C.] Univ Oklahoma, Coll Med, Tulsa, OK USA. RP Woldehawariat, G (reprint author), NIMH, Genet Basis Mood & Anxiety Disorders Sect, Human Genet Branch, NIH,DHHS, Bethesda, MD 20892 USA. EM hawariag@mail.nih.gov OI McMahon, Francis/0000-0002-9469-305X FU National Institutes of Mental Health (NIMH) of the US government FX This research is funded by National Institutes of Mental Health (NIMH) of the US government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 58 TC 0 Z9 0 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 26 PY 2014 VL 9 IS 6 AR e99980 DI 10.1371/journal.pone.0099980 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK2WP UT WOS:000338280800022 PM 24968245 ER PT J AU Hovestadt, V Jones, DTW Picelli, S Wang, W Kool, M Northcott, PA Sultan, M Stachurski, K Ryzhova, M Warnatz, HJ Ralser, M Brun, S Bunt, J Jager, N Kleinheinz, K Erkek, S Weber, UD Bartholomae, CC von Kalle, C Lawerenz, C Eils, J Koster, J Versteeg, R Milde, T Witt, O Schmidt, S Wolf, S Pietsch, T Rutkowski, S Scheurlen, W Taylor, MD Brors, B Felsberg, J Reifenberger, G Borkhardt, A Lehrach, H Wechsler-Reya, RJ Eils, R Yaspo, ML Landgraf, P Korshunov, A Zapatka, M Radlwimmer, B Pfister, SM Lichter, P AF Hovestadt, Volker Jones, David T. W. Picelli, Simone Wang, Wei Kool, Marcel Northcott, Paul A. Sultan, Marc Stachurski, Katharina Ryzhova, Marina Warnatz, Hans-Joerg Ralser, Meryem Brun, Sonja Bunt, Jens Jaeger, Natalie Kleinheinz, Kortine Erkek, Scrap Weber, Ursula D. Bartholomae, Cynthia C. von Kalle, Christof Lawerenz, Chris Eils, Jurgen Koster, Jan Versteeg, Rogier Milde, Till Witt, Olaf Schmidt, Sabine Wolf, Stephan Pietsch, Torsten Rutkowski, Stefan Scheurlen, Wolfram Taylor, Michael D. Brors, Benedikt Felsberg, Joerg Reifenberger, Guido Borkhardt, Arndt Lehrach, Hans Wechsler-Reya, Robert J. Eils, Roland Yaspo, Marie-Laure Landgraf, Pablo Korshunov, Andrey Zapatka, Marc Radlwimmer, Bernhard Pfister, Stefan M. Lichter, Peter TI Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing SO NATURE LA English DT Article ID EMBRYONIC STEM-CELLS; CPG ISLAND SHORES; CANCER GENOME; GENE; DIFFERENTIATION; HYPERMETHYLATION; IDENTIFICATION; SUPPRESSOR; EXPRESSION; METHYLOME AB Epigenetic alterations, that is, disruption of DNA methylation and chromatin architecture, are now acknowledged as a universal feature of tumorigenesis(1). Medulloblastoma, a clinically challenging, malignant childhood brain tumour, is no exception. Despite much progress from recent genomics studies, with recurrent changes identified in each of the four distinct tumour subgroups(WNT-pathway-activated, SHH-pathway-activated, and the less-well-characterized Group 3 and Group 4)(2-4), many cases still lack an obvious genetic driver. Here we present whole-genome bisulphite-sequencing data from thirty-four human and five murine tumours plus eight human and three murine normal controls, augmented with matched whole-genome, RNA and chromatin immunoprecipitation sequencing data. This comprehensive data set allowed us to decipher several features underlying the interplay between the genome, epigenome and transcriptome, and its effects on medulloblastoma pathophysiology. Most notable were highly prevalent regions of hypomethylation correlating with increased gene expression, extending tens of kilobases downstream of transcription start sites. Focal regions of low methylation linked to transcription-factor-binding sites shed light on differential transcriptional networks between subgroups, whereas increased methylation due to re-normalization of repressed chromatin in DNA methylation valleys was positively correlated with gene expression. Large, partially methylated domains affecting up to one-third of the genome showed increased mutation rates and gene silencing in a subgroup-specific fashion. Epigenetic alterations also affected novel medulloblastoma candidate genes (for example, LIN28B), resulting in alternative promoter usage and/or differential messenger RNA/microRNA expression. Analysis of mouse medulloblastoma and precursor-cell methylation demonstrated a somatic origin for many alterations. Our data provide insights into the epigenetic regulation of transcription and genome organization in medulloblastoma pathogenesis, which are probably also of importance in a wider developmental and disease context. C1 [Hovestadt, Volker; Picelli, Simone; Wang, Wei; Kleinheinz, Kortine; Weber, Ursula D.; Zapatka, Marc; Radlwimmer, Bernhard; Lichter, Peter] German Canc Res Ctr, Div Mol Genet, D-69120 Heidelberg, Germany. [Jones, David T. W.; Kool, Marcel; Northcott, Paul A.; Erkek, Scrap; Pfister, Stefan M.] German Canc Res Ctr, Div Pediat Neurooncol, D-69120 Heidelberg, Germany. [Sultan, Marc; Warnatz, Hans-Joerg; Ralser, Meryem; Lehrach, Hans; Yaspo, Marie-Laure] Max Planck Inst Mol Genet, D-14195 Berlin, Germany. [Stachurski, Katharina; Borkhardt, Arndt; Landgraf, Pablo] Univ Dusseldorf, Dept Pediat Oncol Hematol & Clin Immunol, D-40225 Dusseldorf, Germany. [Ryzhova, Marina] NN Burdenko Inst Neurosurg, Dept Neuropathol, Moscow 125047, Russia. [Brun, Sonja; Wechsler-Reya, Robert J.] Sanford Burnham Med Res Inst, Designated Canc Ctr, NCI, Tumor Initiat & Maintenance Program, La Jolla, CA 92037 USA. [Bunt, Jens] Univ Queensland, Queensland Brain Inst, St Lucia, Qld 4072, Australia. [Bunt, Jens; Koster, Jan; Versteeg, Rogier] Univ Amsterdam, AMC, Dept Oncogen, NL-1105 AZ Amsterdam, Netherlands. [Jaeger, Natalie; Kleinheinz, Kortine; Brors, Benedikt; Eils, Roland] German Canc Res Ctr, Div Theoret Bioinformat, D-69120 Heidelberg, Germany. [Erkek, Scrap] EMBL, D-69117 Heidelberg, Germany. [Bartholomae, Cynthia C.; von Kalle, Christof] German Canc Res Ctr, Div Translat Oncol, D-69120 Heidelberg, Germany. [Bartholomae, Cynthia C.; von Kalle, Christof] Natl Ctr Tumor Dis NCT, D-69120 Heidelberg, Germany. [Lawerenz, Chris; Eils, Jurgen] German Canc Res Ctr, Data Management Facil, D-69120 Heidelberg, Germany. [Milde, Till; Witt, Olaf; Pfister, Stefan M.] Univ Heidelberg Hosp, Dept Pediat Oncol Hematol & Immunol, D-69120 Heidelberg, Germany. [Milde, Till; Witt, Olaf] German Canc Res Ctr, Clin Cooperat Unit Pediat Oncol, D-69120 Heidelberg, Germany. [Schmidt, Sabine; Wolf, Stephan] German Canc Res Ctr, Genom & Prote Core Facil, D-69120 Heidelberg, Germany. [Pietsch, Torsten] Univ Bonn, Med Ctr, Dept Neuropathol, D-53105 Bonn, Germany. [Rutkowski, Stefan] Univ Med Ctr Hamburg Eppendorf, Dept Paediat Haematol & Oncol, D-20246 Hamburg, Germany. [Scheurlen, Wolfram] Nurnberg Childrens Hosp, Cnopfsche Kinderklin, D-90419 Nurnberg, Germany. [Taylor, Michael D.] Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Program Dev & Stem Cell Biol, Toronto, ON M5G 1X8, Canada. [Taylor, Michael D.] Hosp Sick Children, Div Neurosurg, Toronto, ON M5G 1X8, Canada. [Taylor, Michael D.] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5S 1A8, Canada. [Felsberg, Joerg; Reifenberger, Guido] Univ Dusseldorf, Dept Neuropathol, D-40225 Dusseldorf, Germany. [Felsberg, Joerg; Reifenberger, Guido] German Canc Res Ctr, German Consortium Translat Canc Res DKTK, D-69120 Heidelberg, Germany. [Eils, Roland] Heidelberg Univ, IPMB, D-69120 Heidelberg, Germany. [Eils, Roland] Heidelberg Univ, Bioquant Ctr, D-69120 Heidelberg, Germany. [Eils, Roland; Lichter, Peter] Heidelberg Ctr Personalised Oncol DKFZ HIPO, D-69120 Heidelberg, Germany. [Korshunov, Andrey] Heidelberg Univ, Dept Neuropathol, D-69120 Heidelberg, Germany. [Korshunov, Andrey] German Canc Res Ctr, Clin Cooperat Unit Neuropathol, D-69120 Heidelberg, Germany. RP Hovestadt, V (reprint author), German Canc Res Ctr, Div Mol Genet, Neuenheimer Feld 280, D-69120 Heidelberg, Germany. RI Kool, Marcel/H-2541-2013; Brors, Benedikt/E-5620-2013; Milde, Till/L-7755-2015; Bunt, Jens/C-4775-2014; Radlwimmer, Bernhard/I-3229-2013; Eils, Roland/B-6121-2009; Pfister, Stefan/F-6860-2013; OI Hovestadt, Volker/0000-0002-3480-6649; Kleinheinz, Kortine/0000-0002-1859-2281; Brors, Benedikt/0000-0001-5940-3101; Bunt, Jens/0000-0003-0397-2019; Radlwimmer, Bernhard/0000-0002-4553-7800; Eils, Roland/0000-0002-0034-4036; Pfister, Stefan/0000-0002-5447-5322; Jaeger, Natalie/0000-0002-9589-7580; Warnatz, Hans-Jorg/0000-0002-0327-9209 FU German Cancer Aid [109252]; German Federal Ministry of Education and Research (BMBF) [01KU1201A]; German Federal Ministry of Education and Research (MedSys) [0315416C]; German Federal Ministry of Education and Research (NGFNplus) [01GS0883]; DKFZ-Heidelberg Center for Personalized Oncology (DKFZ-HIPO); Dutch Cancer Foundations KWF [2010-4713]; KIKA; German Research Foundation (DFG) [LA2983/2-1] FX We thank the members of the ICGC PedBrain Tumor Project, the German Cancer Research Center (DKFZ) Genomics and Proteomics Core Facility, the European Molecular Biology Laboratory (EMBL) Genomics Core Facility, M. Schick, R. Fischer, M. Bewerunge-Hudler, M. Knopf, R. Kabbe, A. Benner, R. Volckman and P. van Sluis for technical support and helpful discussion. Active Motif, Inc. is acknowledged for ChIP and library preparation. We also thank C. Plass for critical reading of the manuscript. This work was principally supported by the PedBrain Tumor Project contributing to the International Cancer Genome Consortium, funded by German Cancer Aid (109252) and the German Federal Ministry of Education and Research (BMBF, grants #01KU1201A, MedSys #0315416C and NGFNplus #01GS0883). Additional support came from the DKFZ-Heidelberg Center for Personalized Oncology (DKFZ-HIPO), the Dutch Cancer Foundations KWF (2010-4713) and KIKA (M.Ko.), and the German Research Foundation (DFG; grant LA2983/2-1 to P.La.). NR 48 TC 90 Z9 92 U1 3 U2 56 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 JUN 26 PY 2014 VL 510 IS 7506 BP 537 EP + DI 10.1038/nature13268 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AJ6LK UT WOS:000337806300047 PM 24847876 ER PT J AU Willis, NA Chandramouly, G Huang, B Kwok, A Follonier, C Deng, CX Scully, R AF Willis, Nicholas A. Chandramouly, Gurushankar Huang, Bin Kwok, Amy Follonier, Cindy Deng, Chuxia Scully, Ralph TI BRCA1 controls homologous recombination at Tus/Ter-stalled mammalian replication forks SO NATURE LA English DT Article ID STRAND BREAK REPAIR; EPSTEIN-BARR-VIRUS; SISTER-CHROMATID RECOMBINATION; TRACT GENE CONVERSION; DNA-DAMAGE RESPONSE; ESCHERICHIA-COLI; IN-VITRO; CELLS; PROTEIN; ORIP AB Replication fork stalling can promote genomic instability, predisposing to cancer and other diseases(1-3). Stalled replication forks may be processed by sister chromatid recombination (SCR), generating error-free or error-prone homologous recombination (HR) outcomes(4-8). In mammalian cells, a long-standing hypothesis proposes that the major hereditary breast/ovarian cancer predisposition gene products, BRCA1 and BRCA2, control HR/SCR at stalled replication forks(9). Although BRCA1 and BRCA2 affect replication fork processing(10-12), direct evidence that BRCA gene products regulate homologous recombination at stalled chromosomal replication forks is lacking, due to a dearth of tools for studying this process. Here we report that the Escherichia coli Tus/Ter complex(13-16) can be engineered to induce site-specific replication fork stalling and chromosomal HR/SCR in mouse cells. Tus/Ter-induced homologous recombination entails processing of bidirectionally arrested forks. We find that the Brca1 carboxy (C)-terminal tandem BRCT repeat and regions of Brca1 encoded by exon 11-two Brca1 elements implicated in tumour suppression-control Tus/Ter-induced homologous recombination. Inactivation of either Brca1 or Brca2 increases the absolute frequency of 'long-tract' gene conversions at Tus/Ter-stalled forks, an outcome not observed in response to a site-specific endonuclease-mediated chromosomal double-strand break. Therefore, homologous recombination at stalled forks is regulated differently from homologous recombination at double-strand breaks arising independently of a replication fork. We propose that aberrant long-tract homologous recombination at stalled replication forks contributes to genomic instability and breast/ovarian cancer predisposition in BRCA mutant cells. C1 [Willis, Nicholas A.; Chandramouly, Gurushankar; Huang, Bin; Kwok, Amy; Scully, Ralph] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Willis, Nicholas A.; Chandramouly, Gurushankar; Huang, Bin; Kwok, Amy; Scully, Ralph] Harvard Univ, Sch Med, Boston, MA 02215 USA. [Follonier, Cindy] Princeton Univ, Lewis Thomas Lab 101, Princeton, NJ 08544 USA. [Deng, Chuxia] NIDDK, NIH, Bethesda, MD 20814 USA. RP Scully, R (reprint author), Beth Israel Deaconess Med Ctr, 330 Brookline Ave, Boston, MA 02215 USA. EM rscully@bidmc.harvard.edu RI Scully, Ralph/F-5008-2013; deng, chuxia/N-6713-2016 FU NIH [R01CA095175, R01GM073894, R21CA144017, R37GM26938]; NIH/NCI [5T32CA081156]; ACS [PF-12-248-01-DMC] FX We thank B. Michel for reagents and advice; D. Livingston, K. Marians, J. Walter, I. Hickson, S. Powell, V. Zakian and members of the Scully laboratory for helpful discussions; I. Hickson and S. Powell for sharing their unpublished data on Tus/Ter replication blocks in eukaryotes; R. Baer for antibodies and A. Ashworth for Brca1 conditional ES cell line 11C0/47T. This work was supported by NIH grants R01CA095175, R01GM073894 and R21CA144017 (to R.S.). N.A.W. was supported by an NIH/NCI postdoctoral fellowship (5T32CA081156) and an ACS postdoctoral research fellowship (PF-12-248-01-DMC). C.F. was supported by NIH grant R37GM26938 (to V.A.Z.). NR 33 TC 30 Z9 32 U1 1 U2 23 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 JUN 26 PY 2014 VL 510 IS 7506 BP 556 EP + DI 10.1038/nature13295 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AJ6LK UT WOS:000337806300051 PM 24776801 ER PT J AU Koroshetz, WJ AF Koroshetz, Walter J. TI PERSPECTIVE Time to tackle blood pressure SO NATURE LA English DT Editorial Material ID PREVALENCE; DEMENTIA C1 US Natl Inst Neurol Disorders & Stroke, Bethesda, MD 20892 USA. RP Koroshetz, WJ (reprint author), US Natl Inst Neurol Disorders & Stroke, Bethesda, MD 20892 USA. EM koroshetzw@ninds.nih.gov NR 10 TC 1 Z9 1 U1 0 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 JUN 26 PY 2014 VL 510 IS 7506 BP S4 EP S4 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AJ6LK UT WOS:000337806300003 PM 24964024 ER PT J AU Liu, X Gu, QH Duan, KZ Li, Z AF Liu, Xing Gu, Qin-Hua Duan, Kaizheng Li, Zheng TI NMDA Receptor-Dependent LTD Is Required for Consolidation But Not Acquisition of Fear Memory SO JOURNAL OF NEUROSCIENCE LA English DT Article DE Bax; NMDA receptor; LTD; memory consolidation; fear memory; depressive behavior ID LONG-TERM DEPRESSION; SYNAPTIC PLASTICITY; SPATIAL MEMORY; BEHAVIORAL FLEXIBILITY; ANIMAL-MODEL; BAX; HIPPOCAMPUS; STRESS; BRAIN; MICE AB NMDA receptor-dependent long-term depression (NMDAR-LTD) is a form of synaptic plasticity leading to long-lasting decreases in synaptic strength. NMDAR-LTD is essential for spatial and working memory, but its role in hippocampus-dependent fear memory has yet to be determined. Induction of NMDAR-LTD requires the activation of caspase-3 by cytochrome c. Cytochrome c normally resides in mitochondria and during NMDAR-LTD is released from mitochondria, a process promoted by Bax (Bcl-2-associated X protein). Bax induces cell death in apoptosis, but it plays a nonapoptotic role in NMDAR-LTD. Here, we investigated the role of NMDAR-LTD in fear memory in CA1-specific Bax knock-out mice. In hippocampal slices from these knock-out mice, while long-term potentiation of synaptic transmission, basal synaptic transmission, and paired-pulse ratio are intact, LTD in both young and fear-conditioned adult mice is obliterated. Interestingly, in CA1-specific Bax knock-out mice, long-term contextual fear memory is impaired, but the acquisition of fear memory and innate fear are normal. Moreover, these conditional Bax knock-out mice exhibit less behavioral despair. These findings indicate that NMDAR-LTD is required for consolidation, but not the acquisition of fear memory. Our study also shows that Bax plays an important role in depressive behavior. C1 [Liu, Xing; Gu, Qin-Hua; Duan, Kaizheng; Li, Zheng] NIMH, Unit Synapse Dev & Plast, NIH, Bethesda, MD 20892 USA. [Liu, Xing] Fudan Univ, Shanghai Med Coll, Res Ctr, State Key Lab Med Neurobiol & Pharmacol, Shanghai 200032, Peoples R China. [Liu, Xing] Fudan Univ, Inst Brain Sci, Shanghai 200032, Peoples R China. Shanghai Univ, Shanghai, Peoples R China. RP Li, Z (reprint author), NIMH, NIH, 35 Convent Dr,Room 2C1010, Bethesda, MD 20892 USA. EM lizheng2@mail.nih.gov RI Li, Zheng/I-8016-2014 OI Li, Zheng/0000-0002-2978-2531 FU National Institute of Mental Health, Division of Intramural Research Programs, National Institutes of Health FX This work was supported by the National Institute of Mental Health, Division of Intramural Research Programs, National Institutes of Health. NR 43 TC 8 Z9 8 U1 2 U2 9 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 JUN 25 PY 2014 VL 34 IS 26 BP 8741 EP 8748 DI 10.1523/JNEUROSCI.2752-13.2014 PG 8 WC Neurosciences SC Neurosciences & Neurology GA AK9HI UT WOS:000338737800009 PM 24966374 ER PT J AU Breton, CV Siegmund, KD Joubert, BR Wang, XH Qui, WL Carey, V Nystad, W Haberg, SE Ober, C Nicolae, D Barnes, KC Martinez, F Liu, A Lemanske, R Strunk, R Weiss, S London, S Gilliland, F Raby, B AF Breton, Carrie V. Siegmund, Kimberly D. Joubert, Bonnie R. Wang, Xinhui Qui, Weiliang Carey, Vincent Nystad, Wenche Haberg, Siri E. Ober, Carole Nicolae, Dan Barnes, Kathleen C. Martinez, Fernando Liu, Andy Lemanske, Robert Strunk, Robert Weiss, Scott London, Stephanie Gilliland, Frank Raby, Benjamin CA Asthma BRIDGE Consortium TI Prenatal Tobacco Smoke Exposure Is Associated with Childhood DNA CpG Methylation SO PLOS ONE LA English DT Article ID MATERNAL SMOKING; NICOTINE DEPENDENCE; AMINOPEPTIDASE-P; SMOOTH-MUSCLE; LUNG-FUNCTION; ASTHMA; PREGNANCY; CHILDREN; COHORT; FRMD4A AB Background: Smoking while pregnant is associated with a myriad of negative health outcomes in the child. Some of the detrimental effects may be due to epigenetic modifications, although few studies have investigated this hypothesis in detail. Objectives: To characterize site-specific epigenetic modifications conferred by prenatal smoking exposure within asthmatic children. Methods: Using Illumina HumanMethylation27 microarrays, we estimated the degree of methylation at 27,578 distinct DNA sequences located primarily in gene promoters using whole blood DNA samples from the Childhood Asthma Management Program (CAMP) subset of Asthma BRIDGE childhood asthmatics (n = 527) ages 5-12 with prenatal smoking exposure data available. Using beta-regression, we screened loci for differential methylation related to prenatal smoke exposure, adjusting for gender, age and clinical site, and accounting for multiple comparisons by FDR. Results: Of 27,578 loci evaluated, 22,131 (80%) passed quality control assessment and were analyzed. Sixty-five children (12%) had a history of prenatal smoke exposure. At an FDR of 0.05, we identified 19 CpG loci significantly associated with prenatal smoke, of which two replicated in two independent populations. Exposure was associated with a 2% increase in mean CpG methylation in FRMD4A (p = 0.01) and Cllorf52 (p = 0.001) compared to no exposure. Four additional genes, XPNPEP1, PPEF2, SMPD3 and CRYGN, were nominally associated in at least one replication group. Conclusions: These data suggest that prenatal exposure to tobacco smoke is associated with reproducible epigenetic changes that persist well into childhood. However, the biological significance of these altered loci remains unknown. C1 [Breton, Carrie V.; Siegmund, Kimberly D.; Wang, Xinhui; Gilliland, Frank] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Joubert, Bonnie R.; London, Stephanie] NIEHS, Div Intramural Res, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Qui, Weiliang; Carey, Vincent; Weiss, Scott; Raby, Benjamin] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med,Dept Med, Boston, MA 02115 USA. [Nystad, Wenche; Haberg, Siri E.] Norwegian Inst Publ Hlth, Oslo, Norway. [Ober, Carole; Nicolae, Dan] Univ Chicago, Chicago, IL 60637 USA. [Barnes, Kathleen C.] Johns Hopkins Univ, Baltimore, MD USA. [Martinez, Fernando] Univ Arizona, Arizona Resp Ctr, Tucson, AZ 85721 USA. [Liu, Andy] Natl Jewish Hlth, Denver, CO USA. [Lemanske, Robert] Univ Wisconsin, Madison, WI USA. [Strunk, Robert] Washington Univ, Sch Med, St Louis, MT USA. RP Breton, CV (reprint author), Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. EM Breton@usc.edu OI London, Stephanie/0000-0003-4911-5290 FU National Heart, Lung and Blood Institute, National Institutes of Health [U01 HL075419, U01 HL65899, P01 HL083069 R01 HL 086601]; NIEHS [5P30ES007048, 1K01ES017801]; Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Dept of Health and Human Services, US; Norwegian Ministry of Health; Ministry of Education and Research; NIH/NIEHS [NO-ES-75558]; NIH/NINDS [1 UO1 NS 047537-01]; Norwegian Research Council/FUGE [151918/S10]; Mary Beryl Patch Turnbull Scholar Program; [5RC2HL101543-02] FX The CAMP Genetics Ancillary Study is supported by U01 HL075419, U01 HL65899, P01 HL083069 R01 HL 086601, from the National Heart, Lung and Blood Institute, National Institutes of Health. The methylation data described here was funded by 5RC2HL101543-02 and NIEHS grants 5P30ES007048 and 1K01ES017801. Also supported in part by the Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Dept of Health and Human Services, US. The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health and the Ministry of Education and Research, NIH/NIEHS (contract no NO-ES-75558), NIH/NINDS (grant no. 1 UO1 NS 047537-01), and the Norwegian Research Council/FUGE (grant no. 151918/S10). KCB was supported in part by the Mary Beryl Patch Turnbull Scholar Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 33 Z9 33 U1 1 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 25 PY 2014 VL 9 IS 6 AR e99716 DI 10.1371/journal.pone.0099716 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK8WO UT WOS:000338709500015 PM 24964093 ER PT J AU Ryan, VH Primiani, CT Rao, JS Ahn, K Rapoport, SI Blanchard, H AF Ryan, Veronica H. Primiani, Christopher T. Rao, Jagadeesh S. Ahn, Kwangmi Rapoport, Stanley I. Blanchard, Helene TI Coordination of Gene Expression of Arachidonic and Docosahexaenoic Acid Cascade Enzymes during Human Brain Development and Aging SO PLOS ONE LA English DT Article ID CYTOSOLIC PHOSPHOLIPASE A(2); ALZHEIMERS-DISEASE BRAIN; HUMAN PREFRONTAL CORTEX; MICROARRAY DATA; SYNAPTIC MARKERS; CEREBRAL-CORTEX; STEM-CELLS; RAT-BRAIN; N-3 PUFA; METABOLISM AB Background: The polyunsaturated arachidonic and docosahexaenoic acids (AA and DHA) participate in cell membrane synthesis during neurodevelopment, neuroplasticity, and neurotransmission throughout life. Each is metabolized via coupled enzymatic reactions within separate but interacting metabolic cascades. Hypothesis: AA and DHA pathway genes are coordinately expressed and underlie cascade interactions during human brain development and aging. Methods: The BrainCloud database for human non-pathological prefrontal cortex gene expression was used to quantify postnatal age changes in mRNA expression of 34 genes involved in AA and DHA metabolism. Results: Expression patterns were split into Development (0 to 20 years) and Aging (21 to 78 years) intervals. Expression of genes for cytosolic phospholipases A(2) (cPLA(2)), cyclooxygenases (COX)-1 and -2, and other AA cascade enzymes, correlated closely with age during Development, less so during Aging. Expression of DHA cascade enzymes was less inter-correlated in each period, but often changed in the opposite direction to expression of AA cascade genes. Except for the PLA2G4A (cPLA(2) IVA) and PTGS2 (COX-2) genes at 1q25, highly inter-correlated genes were at distant chromosomal loci. Conclusions: Coordinated age-related gene expression during the brain Development and Aging intervals likely underlies coupled changes in enzymes of the AA and DHA cascades and largely occur through distant transcriptional regulation. Healthy brain aging does not show upregulation of PLA2G4 or PTGS2 expression, which was found in Alzheimer's disease. C1 [Ryan, Veronica H.; Primiani, Christopher T.; Rao, Jagadeesh S.; Rapoport, Stanley I.; Blanchard, Helene] NIA, Brain Physiol & Metab Sect, Lab Neurosci, NIH, Bethesda, MD 20892 USA. [Ahn, Kwangmi] NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. RP Ryan, VH (reprint author), NIA, Brain Physiol & Metab Sect, Lab Neurosci, NIH, Bethesda, MD 20892 USA. EM veronica.ryan@nih.gov FU Intramural Research Programs of the National Institute on Aging at the National Institutes of Health FX This work was supported by the Intramural Research Programs of the National Institute on Aging at the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 88 TC 8 Z9 8 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 25 PY 2014 VL 9 IS 6 AR e100858 DI 10.1371/journal.pone.0100858 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK8WO UT WOS:000338709500090 PM 24963629 ER PT J AU Geisbert, TW Mire, CE Geisbert, JB Chan, YP Agans, KN Feldmann, F Fenton, KA Zhu, ZY Dimitrov, DS Scott, DP Bossart, KN Feldmann, H Broder, CC AF Geisbert, Thomas W. Mire, Chad E. Geisbert, Joan B. Chan, Yee-Peng Agans, Krystle N. Feldmann, Friederike Fenton, Karla A. Zhu, Zhongyu Dimitrov, Dimiter S. Scott, Dana P. Bossart, Katharine N. Feldmann, Heinz Broder, Christopher C. TI Therapeutic Treatment of Nipah Virus Infection in Nonhuman Primates with a Neutralizing Human Monoclonal Antibody SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID HAMSTER MODEL; PIG-FARMERS; ENCEPHALITIS; TRANSMISSION; PATHOGENESIS; PROTECTION; RIBAVIRIN; MALAYSIA; DISEASE AB Nipah virus (NiV) is an emerging zoonotic paramyxovirus that causes severe and often fatal disease in pigs and humans. There are currently no vaccines or treatments approved for human use. Studies in small-animal models of NiV infection suggest that antibody therapy may be a promising treatment. However, most studies have assessed treatment at times shortly after virus exposure before animals show signs of disease. We assessed the efficacy of a fully human monoclonal antibody, m102.4, at several time points after virus exposure including at the onset of clinical illness in a uniformly lethal nonhuman primate model of NiV disease. Sixteen African green monkeys (AGMs) were challenged intratracheally with a lethal dose of NiV, and 12 animals were infused twice with m102.4 (15 mg/kg) beginning at either 1, 3, or 5 days after virus challenge and again about 2 days later. The presence of viral RNA, infectious virus, and/or NiV-specific immune responses demonstrated that all subjects were infected after challenge. All 12 AGMs that received m102.4 survived infection, whereas the untreated control subjects succumbed to disease between days 8 and 10 after infection. AGMs in the day 5 treatment group exhibited clinical signs of disease, but all animals recovered by day 16. These results represent the successful therapeutic in vivo efficacy by an investigational drug against NiV in a nonhuman primate and highlight the potential impact that a monoclonal antibody can have on a highly pathogenic zoonotic human disease. C1 [Geisbert, Thomas W.; Mire, Chad E.; Geisbert, Joan B.; Agans, Krystle N.; Fenton, Karla A.] Univ Texas Med Branch, Galveston Natl Lab, Galveston, TX 77550 USA. [Geisbert, Thomas W.; Mire, Chad E.; Geisbert, Joan B.; Agans, Krystle N.; Fenton, Karla A.] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77550 USA. [Chan, Yee-Peng; Broder, Christopher C.] Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. [Feldmann, Friederike; Scott, Dana P.] NIH, Rocky Mt Vet Branch, Hamilton, MT 59840 USA. [Zhu, Zhongyu; Dimitrov, Dimiter S.] NCI, Lab Expt Immunol, Canc & Inflammat Program, NIH, Frederick, MD 21702 USA. [Bossart, Katharine N.] Univ Texas Med Branch, Dept Pathol, Galveston, TX 77550 USA. [Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT 59840 USA. RP Geisbert, TW (reprint author), Univ Texas Med Branch, Galveston Natl Lab, Galveston, TX 77550 USA. EM twgeisbe@utmb.edu; christopher.broder@usuhs.edu FU Department of Health and Human Services; NIH [AI082121, AI054715, AI077995]; National Institute of Allergy and Infectious Diseases (NIAID) FX This study was supported by the Department of Health and Human Services, NIH, grants AI082121 (to T. W. G.) and AI054715 and AI077995 (to C. C. B.) and in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), NIH. NR 27 TC 17 Z9 17 U1 0 U2 14 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 JUN 25 PY 2014 VL 6 IS 242 AR 242ra82 DI 10.1126/scitranslmed.3008929 PG 8 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA AK8XL UT WOS:000338711900004 PM 24964990 ER PT J AU Xu, LH Stevens, J Hilton, MB Seaman, S Conrads, TP Veenstra, TD Logsdon, D Morris, H Swing, DA Patel, NL Kalen, J Haines, DC Zudaire, E Croix, BS AF Xu, Lihong Stevens, Janine Hilton, Mary Beth Seaman, Steven Conrads, Thomas P. Veenstra, Timothy D. Logsdon, Daniel Morris, Holly Swing, Deborah A. Patel, Nimit L. Kalen, Joseph Haines, Diana C. Zudaire, Enrique Croix, Brad St. TI COX-2 Inhibition Potentiates Antiangiogenic Cancer Therapy and Prevents Metastasis in Preclinical Models SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID COLON-CANCER; TUMOR ANGIOGENESIS; CYCLOOXYGENASE-2 EXPRESSION; ANTIINFLAMMATORY DRUGS; COLORECTAL-CANCER; GENE-EXPRESSION; SAFETY ANALYSIS; GROWTH; CELLS; TRIAL AB Antiangiogenic agents that block vascular endothelial growth factor (VEGF) signaling are important components of current cancer treatment modalities but are limited by alternative ill-defined angiogenesis mechanisms that allow persistent tumor vascularization in the face of continued VEGF pathway blockade. We identified prostaglandin E-2 (PGE(2)) as a soluble tumor-derived angiogenic factor associated with VEGF-independent angiogenesis. PGE2 production in preclinical breast and colon cancer models was tightly controlled by cyclooxygenase-2 (COX-2) expression, and COX-2 inhibition augmented VEGF pathway blockade to suppress angiogenesis and tumor growth, prevent metastasis, and increase overall survival. These results demonstrate the importance of the COX-2/PGE2 pathway in mediating resistance to VEGF pathway blockade and could aid in the rapid development of more efficacious anticancer therapies. C1 [Xu, Lihong; Stevens, Janine; Hilton, Mary Beth; Seaman, Steven; Zudaire, Enrique; Croix, Brad St.] NCI, Tumor Angiogenesis Sect, MCGP, NIH, Frederick, MD 21702 USA. [Hilton, Mary Beth; Logsdon, Daniel] Frederick Natl Lab Canc Res, Basic Res Program, Frederick, MD 21702 USA. [Conrads, Thomas P.; Veenstra, Timothy D.] Frederick Natl Lab Canc Res, Lab Prote & Analyt Technol, Frederick, MD 21702 USA. [Morris, Holly; Swing, Deborah A.] NCI, Transgen Core Facil, MCGP, Frederick, MD 21702 USA. [Patel, Nimit L.; Kalen, Joseph] Frederick Natl Lab Canc Res, Small Anim Imaging Program LASP, Frederick, MD 21702 USA. [Haines, Diana C.] Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, Pathol Histotechnol Lab, Frederick, MD 21702 USA. RP Croix, BS (reprint author), NCI, Tumor Angiogenesis Sect, MCGP, NIH, Frederick, MD 21702 USA. EM stcroix@ncifcrf.gov FU Center for Cancer Research Intramural Program; NCI [HHSN261200800001E]; NIH [HL34788]; U.S. Department of Health and Human Services (DHHS) FX Supported by the Center for Cancer Research Intramural Program, NCI, NIH, a part of the U.S. Department of Health and Human Services (DHHS), and with federal funds from the NCI under contract no. HHSN261200800001E and NIH HL34788. The content of this publication does not necessarily reflect the views or policies of the DHHS. NR 40 TC 19 Z9 20 U1 1 U2 12 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 JUN 25 PY 2014 VL 6 IS 242 AR 242ra84 DI 10.1126/scitranslmed.3008455 PG 12 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA AK8XL UT WOS:000338711900006 PM 24964992 ER PT J AU Sah, P Singh, LO Clauset, A Bansal, S AF Sah, Pratha Singh, Lisa O. Clauset, Aaron Bansal, Shweta TI Exploring community structure in biological networks with random graphs SO BMC BIOINFORMATICS LA English DT Article DE Biological networks; Community structure; Random graphs; Modularity; Benchmark graphs ID PROTEIN-INTERACTION NETWORK; FOOD-WEB STRUCTURE; METABOLIC NETWORKS; SMALL-WORLD; MODULARITY; ORGANIZATION; COMPARTMENTALIZATION; MODELS AB Background: Community structure is ubiquitous in biological networks. There has been an increased interest in unraveling the community structure of biological systems as it may provide important insights into a system's functional components and the impact of local structures on dynamics at a global scale. Choosing an appropriate community detection algorithm to identify the community structure in an empirical network can be difficult, however, as the many algorithms available are based on a variety of cost functions and are difficult to validate. Even when community structure is identified in an empirical system, disentangling the effect of community structure from other network properties such as clustering coefficient and assortativity can be a challenge. Results: Here, we develop a generative model to produce undirected, simple, connected graphs with a specified degrees and pattern of communities, while maintaining a graph structure that is as random as possible. Additionally, we demonstrate two important applications of our model: (a) to generate networks that can be used to benchmark existing and new algorithms for detecting communities in biological networks; and (b) to generate null models to serve as random controls when investigating the impact of complex network features beyond the byproduct of degree and modularity in empirical biological networks. Conclusion: Our model allows for the systematic study of the presence of community structure and its impact on network function and dynamics. This process is a crucial step in unraveling the functional consequences of the structural properties of biological systems and uncovering the mechanisms that drive these systems. C1 [Sah, Pratha; Bansal, Shweta] Georgetown Univ, Dept Biol, Washington, DC 20057 USA. [Singh, Lisa O.] Georgetown Univ, Dept Comp Sci, Washington, DC 20057 USA. [Clauset, Aaron] Univ Colorado, Dept Comp Sci, Boulder, CO 80309 USA. [Clauset, Aaron] Univ Colorado, BioFrontiers Inst, Boulder, CO 80303 USA. [Clauset, Aaron] Santa Fe Inst, Santa Fe, NM 87501 USA. [Bansal, Shweta] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Bansal, S (reprint author), Georgetown Univ, Dept Biol, Washington, DC 20057 USA. EM sb753@georgetown.edu OI Sah, Pratha/0000-0001-8936-5871; Bansal, Shweta/0000-0002-1740-5421 FU NSF [DEB-1216054] FX This work was supported by NSF award DEB-1216054. NR 75 TC 13 Z9 13 U1 1 U2 16 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 JUN 25 PY 2014 VL 15 AR 220 DI 10.1186/1471-2105-15-220 PG 14 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA AK9FO UT WOS:000338733200001 PM 24965130 ER PT J AU Kondo, Y Iwao, T Nakamura, K Sasaki, T Takahashi, S Kamada, N Matsubara, T Gonzalez, FJ Akutsu, H Miyagawa, Y Okita, H Kiyokawa, N Toyoda, M Umezawa, A Nagata, K Matsunaga, T Ohmori, S AF Kondo, Yuki Iwao, Takahiro Nakamura, Katsunori Sasaki, Takamitsu Takahashi, Shogo Kamada, Noboru Matsubara, Tsutomu Gonzalez, Frank J. Akutsu, Hidenori Miyagawa, Yoshitaka Okita, Hajime Kiyokawa, Nobutaka Toyoda, Masashi Umezawa, Akihiro Nagata, Kiyoshi Matsunaga, Tamihide Ohmori, Shigeru TI An Efficient Method for Differentiation of Human Induced Pluripotent Stem Cells into Hepatocyte-like Cells Retaining Drug Metabolizing Activity SO DRUG METABOLISM AND PHARMACOKINETICS LA English DT Article DE iPS; differentiation; hepatocyte; drug-metabolizing enzyme; CYP ID MESSENGER-RNA EXPRESSION; EXTRACELLULAR-MATRIX; LIVER DEVELOPMENT; GENE-EXPRESSION; ONCOSTATIN-M; IN-VITRO; TRANSCRIPTIONAL ACTIVATION; FUNCTIONAL HEPATOCYTES; HEPATIC MATURATION; PRIMARY CULTURES AB The use of human induced pluripotent stem (iPS) cells would be of great value for a variety of applications involving drug development studies. Several reports have been published on the differentiation of human iPS cells into hepatocyte-like cells; however, the cells were insufficient for application in drug metabolism studies. In this study, we aimed to establish effective methods for differentiation of human iPS cells into hepatocytes. Two human iPS cell lines were differentiated by addition of activin A, dimethyl sulfoxide, hepatocyte growth factor, oncostatin M, and dexamethasone. The differentiated cells expressed hepatocyte markers and drug-metabolizing enzymes, revealing that the human iPS cells were differentiated into hepatocyte-like cells. Expression of CYP3A4 and UGT1A1 mRNAs increased with treatment with typical inducers of the enzymes, and the response of the cells against the inducers was similar to that of human hepatocytes. Furthermore, the drug-metabolizing activity of CYP3A4, as monitored by testosterone 6 beta-hydroxylase activity, was elevated by these inducers. In conclusion, we established methods for differentiation of hepatocyte-like cells expressing drug metabolizing activity from human iPS cells. The hepatocyte-like cells derived from human iPS cells will be useful for drug metabolism studies. C1 [Kondo, Yuki; Iwao, Takahiro; Nakamura, Katsunori; Matsunaga, Tamihide] Nagoya City Univ, Grad Sch Pharmaceut Sci, Dept Clin Pharm, Nagoya, Aichi 4678603, Japan. [Sasaki, Takamitsu; Takahashi, Shogo; Nagata, Kiyoshi] Tohoku Pharmaceut Univ, Dept Environm Hlth Sci, Sendai, Miyagi, Japan. [Kamada, Noboru] Kissei Pharmaceut Co Ltd, Matsumoto, Nagano, Japan. [Matsubara, Tsutomu; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD USA. [Matsubara, Tsutomu] Osaka City Univ, Grad Sch Med, Dept Anat & Regenerat Biol, Osaka 558, Japan. [Akutsu, Hidenori; Toyoda, Masashi; Umezawa, Akihiro] Natl Inst Child Hlth & Dev, Dept Reprod Biol, Tokyo, Japan. [Miyagawa, Yoshitaka; Okita, Hajime; Kiyokawa, Nobutaka] Natl Inst Child Hlth & Dev, Dept Dev Biol, Tokyo, Japan. [Ohmori, Shigeru] Shinshu Univ Hosp, Div Pharm, Matsumoto, Nagano, Japan. RP Matsunaga, T (reprint author), Nagoya City Univ, Grad Sch Pharmaceut Sci, Dept Clin Pharm, Mizuho Ku, 3-1 Tanabe Dori, Nagoya, Aichi 4678603, Japan. EM tmatsu@phar.nagoya-cu.ac.jp FU Japan Society for the Promotion of Science [23390036]; Research on Publicly Essential Drugs and Medical Devices from Japan Health Sciences Foundation [KHB1011, KHB1208]; Japanese Ministry of Health, Labour and Welfare [H22-003] FX This work was supported, in part, by Grants-in-Aid from the Japan Society for the Promotion of Science (23390036), by Research on Publicly Essential Drugs and Medical Devices from Japan Health Sciences Foundation (KHB1011 and KHB1208), and by a National Grant-in-Aid from Japanese Ministry of Health, Labour and Welfare (H22-003). NR 46 TC 11 Z9 11 U1 2 U2 15 PU JAPANESE SOC STUDY XENOBIOTICS PI TOKYO PA INT MED INF CENTER SHINANOMACHI RENGAKAN, 35 SHINANO-MACHI SHINJUKU-KU, TOKYO, 160-0016, JAPAN SN 1347-4367 EI 1880-0920 J9 DRUG METAB PHARMACOK JI Drug Metab. Pharmacokinet. PD JUN 25 PY 2014 VL 29 IS 3 BP 237 EP 243 DI 10.2133/dmpk.DMPK-13-RG-104 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AJ4JI UT WOS:000337641200003 PM 24334537 ER PT J AU Barua, B Nagy, A Sellers, JR Hitchcock-DeGregori, SE AF Barua, Bipasha Nagy, Attila Sellers, James R. Hitchcock-DeGregori, Sarah E. TI Regulation of Nonmuscle Myosin II by Tropomyosin SO BIOCHEMISTRY LA English DT Article ID ACTOMYOSIN SUBFRAGMENT-1 ATPASE; SKELETAL-MUSCLE; ACTIN-BINDING; ALPHA-TROPOMYOSIN; MIGRATING CELLS; MOTOR DOMAIN; F-ACTIN; ADENOSINE-TRIPHOSPHATASE; KINETIC CHARACTERIZATION; MONOCLONAL-ANTIBODIES AB The actin cytoskeleton carries out cellular functions, including division, migration, adhesion, and intra-cellular transport, that require a variety of actin binding proteins, including myosins. Our focus here is on class II nonmuscle myosin isoforms, NMIIA, NMIIB, and NMIIC, and their regulation by the actin binding protein, tropomyosin. NMII myosins are localized to different populations of stress fibers and the contractile ring, structures involved in force generation required for cell migration, adhesion, and cytokinesis. The stress fibers and contractile ring that contain NMII myosins also contain tropomyosin. Four mammalian genes encode more than 40 tropomyosins. Tropomyosins inhibit or activate actomyosin MgATPase and motility depending on the myosin and tropomyosin isoform. In vivo, tropomyosins play a role in cell migration, adhesion, cytokinesis, and NMII isoform localization in an isoform-specific manner. We postulate that the isoform-specific tropomyosin localization and effect on NMII isoform localization reflect modulation of NMII actomyosin kinetics and motile function. In this study, we compare the ability of different tropomyosin isoforms to support actin filament motility with NMIIA, NMIIB, and NMIIC as well as skeletal muscle myosin. Tropomyosins activated, inhibited, or had no effect on motility depending on the myosin, indicating that the myosin isoform is the primary determinant of the isoform-specific effect of tropomyosin on actomyosin regulation. Activation of motility of nonmuscle tropomyosin actin filaments by NMII myosin correlates with an increased V-max of the myosin MgATPase, implying a direct effect on the myosin MgATPase, in contrast to the skeletal tropomyosin actin filament that has no effect on the V-max, or maximal filament velocity. C1 [Barua, Bipasha; Hitchcock-DeGregori, Sarah E.] Rutgers State Univ, Dept Pathol & Lab Med, Robert Wood Johnson Med Sch, Piscataway, NJ 08854 USA. [Nagy, Attila; Sellers, James R.] NHLBI, Lab Mol Physiol, NIH, Bethesda, MD 20824 USA. RP Barua, B (reprint author), Rutgers State Univ, Dept Pathol & Lab Med, Robert Wood Johnson Med Sch, 675 Hoes Ln, Piscataway, NJ 08854 USA. EM baruabi@rwjms.rutgers.edu FU National Institutes of Health (NIH) [GM093065]; NIH Intramural Project [HL001786] FX This work was supported by National Institutes of Health (NIH) Grant GM093065 to S.E.H.-D. and NIH Intramural Project HL001786 (J.RS.). NR 74 TC 12 Z9 12 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 24 PY 2014 VL 53 IS 24 BP 4015 EP 4024 DI 10.1021/bi500162z PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AO3LA UT WOS:000341229500016 PM 24873380 ER PT J AU Beydoun, MA Beydoun, HA Gamaldo, AA Teel, A Zonderman, AB Wang, YF AF Beydoun, May A. Beydoun, Hind A. Gamaldo, Alyssa A. Teel, Alison Zonderman, Alan B. Wang, Youfa TI Epidemiologic studies of modifiable factors associated with cognition and dementia: systematic review and meta-analysis SO BMC PUBLIC HEALTH LA English DT Review DE Cognition; Dementia; Alzheimer's disease; Risk factor; Nutrition; Meta-analysis ID INCIDENT ALZHEIMER-DISEASE; N-3 FATTY-ACIDS; VASCULAR RISK-FACTORS; PLASMA HOMOCYSTEINE LEVELS; SACRAMENTO AREA LATINO; COMMUNITY-BASED SAMPLE; MIDDLE-AGED ADULTS; MODERATE ALCOHOL-CONSUMPTION; HEALTHY ELDERLY INDIVIDUALS; APOLIPOPROTEIN E4 ALLELE AB Background: Cognitive impairment, including dementia, is a major health concern with the increasing aging population. Preventive measures to delay cognitive decline are of utmost importance. Alzheimer's disease (AD) is the most frequent cause of dementia, increasing in prevalence from <1% below the age of 60 years to >40% above 85 years of age. Methods: We systematically reviewed selected modifiable factors such as education, smoking, alcohol, physical activity, caffeine, antioxidants, homocysteine (Hcy), n-3 fatty acids that were studied in relation to various cognitive health outcomes, including incident AD. We searched MEDLINE for published literature (January 1990 through October 2012), including cross-sectional and cohort studies (sample sizes > 300). Analyses compared study finding consistency across factors, study designs and study-level characteristics. Selecting studies of incident AD, our meta-analysis estimated pooled risk ratios (RR), population attributable risk percent (PAR%) and assessed publication bias. Results: In total, 247 studies were retrieved for systematic review. Consistency analysis for each risk factor suggested positive findings ranging from similar to 38.9% for caffeine to similar to 89% for physical activity. Education also had a significantly higher propensity for "a positive finding" compared to caffeine, smoking and antioxidant-related studies. Meta-analysis of 31 studies with incident AD yielded pooled RR for low education (RR = 1.99; 95% CI: 1.30-3.04), high Hcy (RR = 1.93; 95% CI: 1.50-2.49), and current/ever smoking status (RR = 1.37; 95% CI: 1.23-1.52) while indicating protective effects of higher physical activity and n-3 fatty acids. Estimated PAR% were particularly high for physical activity (PAR% = 31.9; 95% CI: 22.7-41.2) and smoking (PAR%= 31.09%; 95% CI: 17.9-44.3). Overall, no significant publication bias was found. Conclusions: Higher Hcy levels, lower educational attainment, and decreased physical activity were particularly strong predictors of incident AD. Further studies are needed to support other potential modifiable protective factors, such as caffeine. C1 [Beydoun, May A.; Gamaldo, Alyssa A.; Zonderman, Alan B.] NIA, Lab Epidemiol & Populat Sci, NIH, IRP, Baltimore, MD 21224 USA. [Beydoun, Hind A.; Teel, Alison] Eastern Virginia Med Sch, Grad Program Publ Hlth, Norfolk, VA USA. [Wang, Youfa] SUNY Buffalo, Sch Publ Hlth & Hlth Profess, Dept Epidemiol & Environm Hlth, New York, NY USA. [Wang, Youfa] John Hopkins Global Ctr Childhood Obes, Baltimore, MD USA. RP Beydoun, MA (reprint author), NIA, Lab Epidemiol & Populat Sci, NIH, IRP, 251 Bayview Blvd,Suite 100,Room 04B118, Baltimore, MD 21224 USA. EM baydounm@mail.nih.gov OI Zonderman, Alan B/0000-0002-6523-4778 FU Intramural Research Program of the National Institute on Aging; NIA/NIH/IRP FX This study was supported by the Intramural Research Program of the National Institute on Aging, NIA/NIH/IRP. The authors would like to thank Mr. James Byrnes, NIA/NIH/IRP, for help with literature search and retrieval. Special thanks also go to Drs. Lori L. Beason-Held and Madhav Thambisetty, NIA/NIH/IRP, for their review and comments on the manuscript. NR 306 TC 73 Z9 73 U1 20 U2 76 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD JUN 24 PY 2014 VL 14 AR 643 DI 10.1186/1471-2458-14-643 PG 33 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AL2JI UT WOS:000338951500002 PM 24962204 ER PT J AU Pletnev, S Shcherbakova, DM Subach, OM Pletneva, NV Malashkevich, VN Almo, SC Dauter, Z Verkhusha, VV AF Pletnev, Sergei Shcherbakova, Daria M. Subach, Oksana M. Pletneva, Nadya V. Malashkevich, Vladimir N. Almo, Steven C. Dauter, Zbigniew Verkhusha, Vladislav V. TI Orange Fluorescent Proteins: Structural Studies of LSSmOrange, PSmOrange and PSmOrange2 SO PLOS ONE LA English DT Article ID LARGE STOKES SHIFT; MONOMERIC RED; CHROMOPHORE; FRET; ZOANTHUS; VARIANT; PHOTOCONVERSION; REFINEMENT; PATHWAYS; DYNAMICS AB A structural analysis of the recently developed orange fluorescent proteins with novel phenotypes, LSSmOrange (lambda(ex)/lambda(em) at 437/572 nm), PSmOrange (lambda(ex)/lambda(em) at 548/565 nm and for photoconverted form at 636/662 nm) and PSmOrange2 (lambda(ex)/lambda(em) at 546/561 nm and for photoconverted form at 619/651 nm), is presented. The obtained crystallographic structures provide an understanding of how the ensemble of a few key mutations enabled special properties of the orange FPs. While only a single Ile161Asp mutation, enabling excited state proton transfer, is critical for LSSmOrange, other substitutions provide refinement of its special properties and an exceptional 120 nm large Stokes shift. Similarly, a single Gln64Leu mutation was sufficient to cause structural changes resulting in photoswitchability of PSmOrange, and only one additional substitution (Phe65Ile), yielding PSmOrange2, was enough to greatly decrease the energy of photoconversion and increase its efficiency of photoswitching. Fluorescence of photoconverted PSmOrange and PSmOrange2 demonstrated an unexpected bathochromic shift relative to the fluorescence of classic red FPs, such as DsRed, eqFP578 and zFP574. The structural changes associated with this fluorescence shift are of considerable value for the design of advanced far-red FPs. For this reason the chromophore transformations accompanying photoconversion of the orange FPs are discussed. C1 [Pletnev, Sergei] Leidos Biomed Res Inc, Basic Res Program, Argonne, IL 60439 USA. [Pletnev, Sergei; Dauter, Zbigniew] NCI, Macromol Crystallog Lab, Argonne, IL USA. [Shcherbakova, Daria M.; Subach, Oksana M.; Verkhusha, Vladislav V.] Albert Einstein Coll Med, Dept Anat & Struct Biol, Bronx, NY 10467 USA. [Malashkevich, Vladimir N.; Almo, Steven C.] Albert Einstein Coll Med, Dept Biochem, Bronx, NY 10467 USA. [Pletneva, Nadya V.] Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, Moscow, Russia. [Subach, Oksana M.] Moscow Inst Phys & Technol, Dept Nano Bio Informat & Cognit Technol, Moscow, Russia. RP Pletnev, S (reprint author), Leidos Biomed Res Inc, Basic Res Program, Argonne, IL 60439 USA. EM pletnevs@mail.nih.gov; vladislav.verkhusha@einstein.yu.edu RI Subach, Oksana (Gritsenko)/K-7086-2014; Pletneva, Nadya/F-7839-2014; OI Zucker-Scharff, Thomas/0000-0002-1790-7405 FU US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; National Cancer Institute, NIH [HHSN261200800001E]; NIH [GM073913, CA164468]; Albert Einstein Cancer Center [CA013330]; New York Structural Genomics Research Center; Russian Science Foundation [14-14-00281] FX Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. W-31-109-Eng-38. The authors thank Rafael Toro for help with the crystallization screening and X29 beamline staff at NSLS for help with data collection. This work was supported in part with Federal funds from the National Cancer Institute, NIH, under contract HHSN261200800001E, the Intramural Research Program of the NIH, the NIH grants GM073913 and CA164468 (to VVV), the Albert Einstein Cancer Center grant CA013330, the New York Structural Genomics Research Center (to SCA), and by a grant from the Russian Science Foundation 14-14-00281. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products or organizations imply endorsement by the US Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 6 Z9 6 U1 2 U2 17 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 24 PY 2014 VL 9 IS 6 AR e99136 DI 10.1371/journal.pone.0099136 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK7UT UT WOS:000338633900003 PM 24960050 ER PT J AU Hansen, MS Olivieri, LJ O'Brien, K Cross, RR Inati, SJ Kellman, P AF Hansen, Michael S. Olivieri, Laura J. O'Brien, Kendall Cross, Russell R. Inati, Souheil J. Kellman, Peter TI Method for calculating confidence intervals for phase contrast flow measurements SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE Phase contrast; Flow; Confidence intervals; Standard deviation; Region of interest ID CARDIOVASCULAR MAGNETIC-RESONANCE; CONGENITAL HEART-DISEASE; BLOOD-FLOW; OFFSET ERRORS; MR; QUANTIFICATION; RECONSTRUCTION; ACCURACY; NOISE AB Background: Phase contrast (PC) measurements play an important role in several cardiovascular magnetic resonance (CMR) protocols but considerable variation is observed in such measurements. Part of this variation stems from the propagation of thermal noise from the measurement data through the image reconstruction to the region of interest analysis used in flow measurement, which limits the precision. The purpose of this study was to develop a method for direct estimation of the variation caused by thermal noise and to validate this method in phantom and in vivo data. Methods: The estimation of confidence intervals in flow measurements is complicated by noise correlation among the image pixels and cardiac phases. This correlation is caused by sequence and reconstruction parameters. A method for the calculation of the standard deviation of region of interest measurements was adapted and expanded to accommodate typical clinical PC measurements and the region-of-interest analysis used for such measurements. This included the dependency between cardiac phases that arises due to retrospective cardiac gating used in such studies. The proposed method enables calculation of standard deviations of flow measurements without the need for repeated experiments or repeated reconstructions. The method was compared to repeated trials in phantom measurements and pseudo replica reconstructions of in vivo data. Three different flow protocols (free breathing and breath hold with various accelerations) were compared in terms of the confidence interval ranges caused by thermal noise in the measurement data. Results: Using the proposed method it was possible to accurately predict confidence intervals for flow measurements. The method was in good agreement with repeated measurements in phantom experiments and there was also good agreement with confidence intervals predicted by pseudo replica reconstructions in both phantom and in vivo data. The proposed method was used to demonstrate that the variation in cardiac output caused by thermal noise is on the order of 1% in clinically used free breathing protocols, and on the order of 3-5% in breath-hold protocols with higher parallel imaging factors. Conclusions: It is possible to calculate confidence intervals for Cartesian PC contrast flow measurements directly without the need for time consuming pseudo replica reconstructions. C1 [Hansen, Michael S.; Olivieri, Laura J.; O'Brien, Kendall; Cross, Russell R.; Kellman, Peter] NHLBI, NIH, Bethesda, MD 20814 USA. [Olivieri, Laura J.; O'Brien, Kendall; Cross, Russell R.] Childrens Natl Med Ctr, Div Cardiol, Washington, DC 20010 USA. [Inati, Souheil J.] NIMH, NIH, Bethesda, MD 20814 USA. RP Hansen, MS (reprint author), NHLBI, NIH, 9000 Rockville Pike, Bethesda, MD 20814 USA. EM michael.hansen@nih.gov RI Hansen, Michael/J-5391-2015 OI Hansen, Michael/0000-0002-8087-8731 FU Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute and National Institute of Mental Health FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute and National Institute of Mental Health. NR 19 TC 4 Z9 4 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 EI 1532-429X J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD JUN 24 PY 2014 VL 16 AR 46 DI 10.1186/1532-429X-16-46 PG 12 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA AK7FR UT WOS:000338592500001 PM 24962371 ER PT J AU Gregory, MT Park, GY Johnstone, TC Lee, YS Yang, W Lippard, SJ AF Gregory, Mark T. Park, Ga Young Johnstone, Timothy C. Lee, Young-Sam Yang, Wei Lippard, Stephen J. TI Structural and mechanistic studies of polymerase eta bypass of phenanthriplatin DNA damage SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cancer therapy; monofunctional platinum drug candidates; pol eta; X-ray crystallography ID PLATINUM ANTICANCER DRUGS; LESION-BYPASS; CISPLATIN; CHEMOTHERAPY; RESISTANCE; FIDELITY; BINDING; AGENTS; ADDUCT; ZETA AB Platinum drugs are a mainstay of anticancer chemotherapy. Nevertheless, tumors often display inherent or acquired resistance to platinum-based treatments, prompting the search for new compounds that do not exhibit cross-resistance with current therapies. Phenanthriplatin, cis-diamminephenanthridinechloroplatinum(II), is a potent monofunctional platinum complex that displays a spectrum of activity distinct from those of the clinically approved platinum drugs. Inhibition of RNA polymerases by phenanthriplatin lesions has been implicated in its mechanism of action. The present study evaluates the ability of phenanthriplatin lesions to inhibit DNA replication, a function disrupted by traditional platinum drugs. Phenanthriplatin lesions effectively inhibit DNA polymerases nu, zeta and k and the Klenow fragment. In contrast to results obtained with DNA damaged by cisplatin, all of these polymerases were capable of inserting a base opposite a phenanthriplatin lesion, but only Pol eta, an enzyme efficient in translesion synthesis, was able to fully bypass the adduct, albeit with low efficiency. X-ray structural characterization of Pol eta complexed with site-specifically platinated DNA at both the insertion and + 1 extension steps reveals that phenanthriplatin on DNA interacts with and inhibits Pol eta in a manner distinct from that of cisplatin- DNA adducts. Unlike cisplatin and oxaliplatin, the efficacies of which are influenced by Pol eta expression, phenanthriplatin is highly toxic to both Pol eta+ and Pol eta-cells. Given that increased expression of Pol eta is a known mechanism by which cells resist cisplatin treatment, phenanthriplatin may be valuable in the treatment of cancers that are, or can easily become, resistant to cisplatin. C1 [Gregory, Mark T.; Lee, Young-Sam; Yang, Wei] NIDDK, Mol Biol Lab, Bethesda, MD 20892 USA. [Gregory, Mark T.] Johns Hopkins Univ, NIH, Grad Partnership Program, Bethesda, MD 20892 USA. [Park, Ga Young; Johnstone, Timothy C.; Lippard, Stephen J.] MIT, Dept Chem, Cambridge, MA 02139 USA. RP Lippard, SJ (reprint author), MIT, Dept Chem, Cambridge, MA 02139 USA. EM lippard@mit.edu RI Yang, Wei/D-4926-2011 OI Yang, Wei/0000-0002-3591-2195 FU National Cancer Institute [CA034992]; Misrock Fellowship FX This work is supported by National Cancer Institute Grant CA034992 (to S.J.L). G.Y.P. received support from a Misrock Fellowship. NR 31 TC 12 Z9 12 U1 0 U2 25 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 JUN 24 PY 2014 VL 111 IS 25 BP 9133 EP 9138 DI 10.1073/pnas.1405739111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AJ5WJ UT WOS:000337760600040 PM 24927576 ER PT J AU Tanaka, T Tahara-Hanaoka, S Nabekura, T Ikeda, K Jiang, S Tsutsumi, S Inagaki, T Magoori, K Higurashi, T Takahashi, H Tachibana, K Tsurutani, Y Raza, S Anai, M Minami, T Wada, Y Yokote, K Doi, T Hamakubo, T Auwerx, J Gonzalez, FJ Nakajima, A Aburatani, H Naito, M Shibuya, A Kodama, T Sakai, J AF Tanaka, Toshiya Tahara-Hanaoka, Satoko Nabekura, Tsukasa Ikeda, Kaori Jiang, Shuying Tsutsumi, Shuichi Inagaki, Takeshi Magoori, Kenta Higurashi, Takuma Takahashi, Hirokazu Tachibana, Keisuke Tsurutani, Yuya Raza, Sana Anai, Motonobu Minami, Takashi Wada, Youichiro Yokote, Koutaro Doi, Takefumi Hamakubo, Takao Auwerx, Johan Gonzalez, Frank J. Nakajima, Atsushi Aburatani, Hiroyuki Naito, Makoto Shibuya, Akira Kodama, Tatsuhiko Sakai, Juro TI PPAR beta/delta activation of CD300a controls intestinal immunity SO SCIENTIFIC REPORTS LA English DT Article ID METABOLIC SYNDROME; MACROPHAGE ACTIVATION; INNATE IMMUNITY; MAST-CELL; DELTA; INFLAMMATION; EXPRESSION; RECEPTORS; MICE; GENE AB Macrophages are important for maintaining intestinal immune homeostasis. Here, we show that PPAR beta/delta (peroxisome proliferator-activated receptor beta/delta) directly regulates CD300a in macrophages that express the immunoreceptor tyrosine based-inhibitory motif (ITIM)-containing receptor. In mice lacking CD300a, high-fat diet (HFD) causes chronic intestinal inflammation with low numbers of intestinal lymph capillaries and dramatically expanded mesenteric lymph nodes. As a result, these mice exhibit triglyceride malabsorption and reduced body weight gain on HFD. Peritoneal macrophages from Cd300a(-/-) mice on HFD are classically M1 activated. Activation of toll-like receptor 4 (TLR4)/MyD88 signaling by lipopolysaccharide (LPS) results in prolonged IL-6 secretion in Cd300a(-/-) macrophages. Bone marrow transplantation confirmed that the phenotype originates from CD300a deficiency in leucocytes. These results identify CD300a-mediated inhibitory signaling in macrophages as a critical regulator of intestinal immune homeostasis. C1 [Tanaka, Toshiya; Ikeda, Kaori; Raza, Sana; Anai, Motonobu; Wada, Youichiro; Kodama, Tatsuhiko] Univ Tokyo, RCAST, LSBM, Tokyo 1538904, Japan. [Tahara-Hanaoka, Satoko; Nabekura, Tsukasa; Shibuya, Akira] Univ Tsukuba, Fac Med, Ctr TARA, Dept Immunol, Tsukuba, Ibaraki 3058575, Japan. [Tahara-Hanaoka, Satoko; Nabekura, Tsukasa; Shibuya, Akira] Univ Tsukuba, Japan Sci & Technol Agcy, CREST, Tsukuba, Ibaraki 3058575, Japan. [Jiang, Shuying; Naito, Makoto] Niigata Univ, Grad Sch Med & Dent Sci, Div Cellular & Mol Pathol, Niigata 9518510, Japan. [Jiang, Shuying] Peruseus Prote, Tokyo 1530041, Japan. [Tsutsumi, Shuichi; Aburatani, Hiroyuki] Univ Tokyo, RCAST, Genome Sci Div, Tokyo 1538904, Japan. [Inagaki, Takeshi; Magoori, Kenta; Tsurutani, Yuya; Sakai, Juro] Univ Tokyo, RCAST, Div Metab Med, Tokyo 1538904, Japan. [Higurashi, Takuma; Takahashi, Hirokazu; Nakajima, Atsushi] Yokohama City Univ, Sch Med, Div Gastroenterol, Yokohama, Kanagawa 2360004, Japan. [Tachibana, Keisuke; Doi, Takefumi] Osaka Univ, Grad Sch Pharmaceut Sci, Osaka 5650871, Japan. [Tsurutani, Yuya; Yokote, Koutaro] Chiba Univ, Grad Sch Med, Dept Clin Cell Biol & Med, Chiba 2608670, Japan. [Minami, Takashi] Univ Tokyo, RCAST, Lab Vasc Biol, Tokyo 1538904, Japan. [Hamakubo, Takao] Univ Tokyo, RCAST, Dept Quantitat Biol & Med, Tokyo 1538904, Japan. [Auwerx, Johan] Ecole Polytech Fed Lausanne, Lab Integrat & Syst Physiol, CH-1015 Lausanne, Switzerland. [Gonzalez, Frank J.] NCI, Ctr Canc Res, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Shibuya, A (reprint author), Univ Tsukuba, Fac Med, Ctr TARA, Dept Immunol, Tsukuba, Ibaraki 3058575, Japan. EM ashibuya@md.tsukuba.ac.jp; kodama@lsbm.org; jmsakai-tky@umin.ac.jp FU Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program; Project for Developing Innovation Systems; Special Coordination Fund for Science and Technology from the Ministry of Education, Culture, Sports, Science, and Technology; Takeda Science Foundation FX This work was supported through Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program, Project for Developing Innovation Systems and by the Special Coordination Fund for Science and Technology from the Ministry of Education, Culture, Sports, Science, and Technology. This work was also supported, in part, by Takeda Science Foundation. All animal care was in accordance with the University of Tokyo and Tsukuba University guidelines. NR 38 TC 10 Z9 10 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUN 24 PY 2014 VL 4 AR 5412 DI 10.1038/srep05412 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AJ7PT UT WOS:000337889300002 PM 24958459 ER PT J AU Liu, X Yang, N Tang, J Liu, S Luo, DY Duan, Q Wang, XL AF Liu, Xin Yang, Ning Tang, Jun Liu, Song Luo, Deyan Duan, Qing Wang, Xiliang TI Downregulation of angiotensin-converting enzyme 2 by the neuraminidase protein of influenza A (H1N1) virus SO VIRUS RESEARCH LA English DT Article DE Influenza; ACE2; Downregulation; Neuraminidase ID RESPIRATORY-SYNDROME-CORONAVIRUS; ACUTE LUNG INJURY; SARS-CORONAVIRUS; FUNCTIONAL RECEPTOR; ACE2; CELLS; ANGIOTENSIN-CONVERTING-ENZYME-2; REPLICATION; ACID; COV AB Influenza A (H1N1) virus, a high-risk infectious pathogen, can cause severe acute lung injury leading to significant morbidity and mortality. Angiotensin-converting enzyme 2 (ACE2), a negative regulator of the renin-angiotensin system (RAS), plays a protective role in pathogenesis of acute lung injury. Here, we showed that ACE2 protein levels were significantly downregulated after infection with H1N1 viruses but was dispensable for viral replication. ACE2 protein downregulation was most likely related to ACE2 protein degradation by proteasome pathway rather than ACE2 shedding. Finally, we found that ACE2 cleavage could be regulated by influenza neuraminidase (NA), which was fundamentally different from the classically sheddase-induced proteolytic cleavage of ACE2. (C) 2014 Elsevier B.V. All rights reserved. C1 [Liu, Xin; Luo, Deyan; Duan, Qing; Wang, Xiliang] Beijing Inst Microbiol & Epidemiol, State Key Lab Pathogen & Biosecur, Beijing 100071, Peoples R China. [Yang, Ning] NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. [Tang, Jun; Liu, Song] Peking Union Med Coll, Inst Basic Med Sci, Beijing 100005, Peoples R China. RP Liu, X (reprint author), Beijing Inst Microbiol & Epidemiol, State Key Lab Pathogen & Biosecur, 20 Dongda St, Beijing 100071, Peoples R China. EM merryliuzin@gmail.com NR 29 TC 5 Z9 6 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 EI 1872-7492 J9 VIRUS RES JI Virus Res. PD JUN 24 PY 2014 VL 185 BP 64 EP 71 DI 10.1016/j.virusres.2014.03.010 PG 8 WC Virology SC Virology GA AG7XA UT WOS:000335630900008 PM 24662240 ER PT J AU Wang, R Ross, CA Cai, H Cong, WN Daimon, CM Carlson, OD Egan, JM Siddiqui, S Maudsley, S Martin, B AF Wang, Rui Ross, Christopher A. Cai, Huan Cong, Wei-Na Daimon, Caitlin M. Carlson, Olga D. Egan, Josephine M. Siddiqui, Sana Maudsley, Stuart Martin, Bronwen TI Metabolic and hormonal signatures in pre-manifest and manifest Huntington's disease patients SO FRONTIERS IN PHYSIOLOGY LA English DT Article DE Huntington's disease; pre-manifest; metabolic hormones; lipids; peripheral energy metabolism ID CENTRAL-NERVOUS-SYSTEM; EXPANDED CAG REPEAT; ALZHEIMERS-DISEASE; INSULIN-RESISTANCE; DIABETES-MELLITUS; CHOLESTEROL-METABOLISM; NEUROTROPHIC SIGNALS; PITUITARY-HORMONES; OXIDATIVE STRESS; MOUSE MODELS AB Huntington's disease (HD) is an inherited neurodegenerative disorder typified by involuntary body movements, and psychiatric and cognitive abnormalities. Many HD patients also exhibit metabolic changes including progressive weight loss and appetite dysfunction. Here we have investigated metabolic function in pre-manifest and manifest HD subjects to establish an HD subject metabolic hormonal plasma signature. Individuals at risk for HD who have had predictive genetic testing showing the cytosine-adenine-guanine (CAG) expansion causative of HD, but who do not yet present signs and symptoms sufficient for the diagnosis of manifest HD are said to be "pre-manifest." Pre-manifest and manifest HD patients, as well as both familial and non-familial controls, were evaluated for multiple peripheral metabolism signals including circulating levels of hormones, growth factors, lipids, and cytokines. Both pre-manifest and manifest HD subjects exhibited significantly reduced levels of circulating growth factors, including growth hormone and prolactin. HD-related changes in the levels of metabolic hormones such as ghrelin, glucagon, and amylin were also observed. Total cholesterol, HDL-C, and LDL-C were significantly decreased in HD subjects. C-reactive protein was significantly elevated in pre-manifest HD subjects. The observation of metabolic alterations, even in subjects considered to be in the pre-manifest stage of HD, suggests that in addition, and prior, to overt neuronal damage, HD affects metabolic hormone secretion and energy regulation, which may shed light on pathogenesis, and provide opportunities for biomarker development. C1 [Wang, Rui; Cai, Huan; Cong, Wei-Na; Daimon, Caitlin M.; Martin, Bronwen] NIA, Metab Unit, NIH, Baltimore, MD 21224 USA. [Ross, Christopher A.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Div Neurobiol, Baltimore, MD 21205 USA. [Ross, Christopher A.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Ross, Christopher A.] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. [Carlson, Olga D.; Egan, Josephine M.] NIA, Diabet Sect, NIH, Baltimore, MD 21224 USA. [Siddiqui, Sana] NIA, Receptor Pharmacol Unit, NIH, Baltimore, MD 21224 USA. [Maudsley, Stuart] Univ Antwerp VIB, Dept Mol Genet, B-2610 Antwerp, Belgium. RP Martin, B (reprint author), NIA, Metab Unit, NIH, 251 Bayview Blvd,Suite 100 Room 08C009, Baltimore, MD 21224 USA. EM bronwenmartin@gmail.com RI Cai, Huan/B-6578-2016 OI Cai, Huan/0000-0001-7731-8891 FU Intramural Research Program of the National Institute on Aging, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. We thank the Hopkins and BLSA participants for contributing to this study. We also thank Dr. Luigi Ferrucci (NIA) for kindly providing us with BLSA samples. NR 71 TC 18 Z9 18 U1 0 U2 3 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-042X J9 FRONT PHYSIOL JI Front. Physiol. PD JUN 23 PY 2014 VL 5 AR 231 DI 10.3389/fphys.2014.00231 PG 10 WC Physiology SC Physiology GA AX6XX UT WOS:000347062500001 PM 25002850 ER PT J AU Chen, J Pan, HN Chen, C Wu, W Iskandar, K He, J Piermartiri, T Jacobowitz, DM Yu, QS McDonough, JH Greig, NH Marini, AM AF Chen, Jun Pan, Hongna Chen, Cynthia Wu, Wei Iskandar, Kevin He, Jeffrey Piermartiri, Tetsade Jacobowitz, David M. Yu, Qian-Sheng McDonough, John H. Greig, Nigel H. Marini, Ann M. TI (-)-Phenserine Attenuates Soman-Induced Neuropathology SO PLOS ONE LA English DT Article ID AMYLOID PRECURSOR PROTEIN; SUBWAY SARIN ATTACK; POSTTRAUMATIC-STRESS-DISORDER; ORGANOPHOSPHORUS NERVE AGENTS; ALZHEIMERS-DISEASE; INDUCED SEIZURES; ACETYLCHOLINESTERASE INHIBITION; CHOLINESTERASE-INHIBITORS; TRANSCRIPTION FACTOR; NEURONAL SURVIVAL AB Organophosphorus (OP) nerve agents are deadly chemical weapons that pose an alarming threat to military and civilian populations. The irreversible inhibition of the critical cholinergic degradative enzyme acetylcholinesterase (AChE) by OP nerve agents leads to cholinergic crisis. Resulting excessive synaptic acetylcholine levels leads to status epilepticus that, in turn, results in brain damage. Current countermeasures are only modestly effective in protecting against OP-induced brain damage, supporting interest for evaluation of new ones. (-)-Phenserine is a reversible AChE inhibitor possessing neuroprotective and amyloid precursor protein lowering actions that reached Phase III clinical trials for Alzheimer's Disease where it exhibited a wide safety margin. This compound preferentially enters the CNS and has potential to impede soman binding to the active site of AChE to, thereby, serve in a protective capacity. Herein, we demonstrate that (-)-phenserine protects neurons against soman-induced neuronal cell death in rats when administered either as a pretreatment or post-treatment paradigm, improves motoric movement in soman-exposed animals and reduces mortality when given as a pretreatment. Gene expression analysis, undertaken to elucidate mechanism, showed that (-)-phenserine pretreatment increased select neuroprotective genes and reversed a Homer1expression elevation induced by soman exposure. These studies suggest that (-)-phenserine warrants further evaluation as an OP nerve agent protective strategy. C1 [Chen, Jun; Pan, Hongna; Chen, Cynthia; Wu, Wei; Iskandar, Kevin; He, Jeffrey; Piermartiri, Tetsade; Marini, Ann M.] Uniformed Serv Univ Hlth Sci, Dept Neurol, Bethesda, MD 20814 USA. [Jacobowitz, David M.] Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. [Yu, Qian-Sheng; Greig, Nigel H.] NIA, Drug Design & Dev Sect, Translat Gerontol Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [McDonough, John H.] US Army Med Res Inst Chem Def, Pharmacol Branch, Div Res, Aberdeen Proving Ground, MD USA. RP Marini, AM (reprint author), Uniformed Serv Univ Hlth Sci, Dept Neurol, Bethesda, MD 20814 USA. EM ann.marini@usuhs.edu OI Piermartiri, Tetsade/0000-0002-9773-6983 FU Defense Threat Reduction Agency-Joint Science and Technology Office, Medical ST Division [CBM.NEURO.01.10.US.012, CBM.NEURO.01.10.US.019]; Intramural Research Program, National Institute on Aging, National Institutes of Health FX This work was supported by Defense Threat Reduction Agency-Joint Science and Technology Office, Medical S&T Division [Grant Numbers CBM.NEURO.01.10.US.012 and CBM.NEURO.01.10.US.019] (AMM); Intramural Research Program, National Institute on Aging, National Institutes of Health (NHG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 88 TC 3 Z9 4 U1 0 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 23 PY 2014 VL 9 IS 6 AR e99818 DI 10.1371/journal.pone.0099818 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AL1WV UT WOS:000338917900019 PM 24955574 ER PT J AU Giebeler, A Streetz, KL Soehnlein, O Neumann, U Wang, JM Brandenburg, LO AF Giebeler, Arne Streetz, Konrad L. Soehnlein, Oliver Neumann, Ulf Wang, Ji Ming Brandenburg, Lars-Ove TI Deficiency of Formyl Peptide Receptor 1 and 2 Is Associated with Increased Inflammation and Enhanced Liver Injury after LPS-Stimulation SO PLOS ONE LA English DT Article ID N-FORMYLPEPTIDE RECEPTOR; BILE-DUCT LIGATION; 1-42-INDUCED SIGNAL-TRANSDUCTION; HEPATIC-FIBROSIS; GLIAL-CELLS; TRANSCRIPTIONAL REGULATION; HUMAN NEUTROPHILS; GENE-CLUSTER; C-MET; EXPRESSION AB Introduction: Formyl peptide-receptor 1 and 2 (FPR1 and FPR2) in mice were identified as receptors with contrary affinity for the PAMP fMLF. Formyl-methionyl-leucyl-phenylalanine is either part of the bacterial membrane and is secreted by the mitochondria of eukaryotic ceslls during apoptosis. Furthermore FPR1 and 2 are described as highly relevant factors for the chemotaxis of immune cells. Their role during the acute liver injury has not been investigated yet. Materials and Methods: Constitutive knockout mice for FPR1 (mFPR1(-/-)), FPR2 (mFPR2(-/-)) and wild type (WT) mice were challenged with LPS i.p. for 3 h and 6 h. Liver and serum were sampled for further analysis. Results: Liver transaminases were elevated in all mice 3 h and 6 h post LPS stimulation. Gene expression analysis displayed a reduced expression of the pro-inflammatory cytokines IL-6 and CXCL1 after 3 h in the mFPR1(-/-) compared to wild type and mFPR2(-/-) mice. After 6 h, IL-6, TNF-alpha and CXCL1 were significantly higher in mice lacking mFPR1 or 2. Consistent to these findings the numbers of CD11b(+) and Ly6G(+) immune cells were altered in the livers. The analysis of TLR2 and TLR4 revealed time and genotype specific changes in theirs gene expression. Additionally, the liver in mFPR1- and mFPR2-deficient mice seem to be more susceptible to apoptosis by showing a significant higher number of TUNEL+-cells in the liver than WT-mice and displayed less Ki67-positive nuclei in the liver. Conclusion: The results suggest a prominent role of FPRs in the regulation of the hepatic inflammatory response after LPS induced liver injury. Deletion of mFPR1 or mFPR2 leads to deregulation of the inflammatory response compared to WT mice, associated with more severe liver injury represented by higher levels of transaminases, apoptotic cells and a reduced regenerative capacity. C1 [Giebeler, Arne; Neumann, Ulf] Rhein Westfal TH Aachen, Dept Surg, Univ Hosp, Aachen, Germany. [Brandenburg, Lars-Ove] Rhein Westfal TH Aachen, Dept Anat & Cell Biol, Aachen, Germany. [Streetz, Konrad L.] Rhein Westfal TH Aachen, Dept Med 3, Univ Hosp, Aachen, Germany. [Soehnlein, Oliver] Ludwig Maximilians Univ Munchen, Inst Cardiovasc Prevent IPEK, Munich, Germany. [Wang, Ji Ming] NCI, Mol Immunoregulat Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. RP Giebeler, A (reprint author), Rhein Westfal TH Aachen, Dept Surg, Univ Hosp, Aachen, Germany. EM agiebeler@ukaachen.de FU Department of Surgery, University Hospital Aachen, RWTH Aachen FX This work was supported by the Department of Surgery, University Hospital Aachen, RWTH Aachen. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 5 Z9 5 U1 0 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 23 PY 2014 VL 9 IS 6 AR e100522 DI 10.1371/journal.pone.0100522 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AL1WV UT WOS:000338917900063 PM 24956481 ER PT J AU Liu, WL Dogan, RI Kwon, D Marques, H Rinaldi, F Wilbur, WJ Comeau, DC AF Liu, Wanli Dogan, Rezarta Islamaj Kwon, Dongseop Marques, Hernani Rinaldi, Fabio Wilbur, W. John Comeau, Donald C. TI BioC implementations in Go, Perl, Python and Ruby SO DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION LA English DT Article ID BIOINFORMATICS; SOFTWARE AB As part of a communitywide effort for evaluating text mining and information extraction systems applied to the biomedical domain, BioC is focused on the goal of interoperability, currently a major barrier to wide-scale adoption of text mining tools. BioC is a simple XML format, specified by DTD, for exchanging data for biomedical natural language processing. With initial implementations in C++ and Java, BioC provides libraries of code for reading and writing BioC text documents and annotations. We extend BioC to Perl, Python, Go and Ruby. We used SWIG to extend the C++ implementation for Perl and one Python implementation. A second Python implementation and the Ruby implementation use native data structures and libraries. BioC is also implemented in the Google language Go. BioC modules are functional in all of these languages, which can facilitate text mining tasks. BioC implementations are freely available through the BioC site: http://bioc.sourceforge.net. Database URL: http://bioc.sourceforge.net/ C1 [Liu, Wanli; Dogan, Rezarta Islamaj; Wilbur, W. John; Comeau, Donald C.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Kwon, Dongseop] Myongji Univ, Dept Comp Engn, Yongin, South Korea. [Marques, Hernani; Rinaldi, Fabio] Univ Zurich, Inst Computat Linguist, CH-8050 Zurich, Switzerland. RP Comeau, DC (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM comeau@ncbi.nlm.nih.gov OI Rinaldi, Fabio/0000-0001-5718-5462 FU National Institutes of Health, National Library of Medicine; Swiss National Science Foundation [100014-118396/1, 105315-130558/1]; National Research Foundation of Korea (NRF) - Ministry of Education [2012R1A1A2044389, 2011-0022437] FX The research at NCBI was supported by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. The OntoGene group at the University of Zurich is partially supported by the Swiss National Science Foundation (grants 100014-118396/1 and 105315-130558/1). D.K. was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2012R1A1A2044389 and 2011-0022437). NR 8 TC 0 Z9 0 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1758-0463 J9 DATABASE-OXFORD JI Database PD JUN 23 PY 2014 AR bau059 DI 10.1093/database/bau059 PG 9 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA AK7AR UT WOS:000338578900001 ER PT J AU Patel, VN Lombaert, IMA Cowherd, SN Shworak, NW Xu, YM Liu, J Hoffman, MP AF Patel, Vaishali N. Lombaert, Isabelle M. A. Cowherd, Samuel N. Shworak, Nicholas W. Xu, Yongmei Liu, Jian Hoffman, Matthew P. TI Hs3st3-Modified Heparan Sulfate Controls KIT plus Progenitor Expansion by Regulating 3-O-Sulfotransferases SO DEVELOPMENTAL CELL LA English DT Article ID GLAND EPITHELIAL MORPHOGENESIS; EMBRYONIC STEM-CELLS; GROWTH-FACTOR FAMILY; BRANCHING MORPHOGENESIS; RECEPTOR SPECIFICITY; PRECURSOR POOL; DIFFERENTIATION; FGF; SULFOTRANSFERASE; ORGANOGENESIS AB The exquisite control of growth factor function by heparan sulfate (HS) is dictated by tremendous structural heterogeneity of sulfated modifications. How specific HS structures control growth factor-dependent progenitor expansion during organogenesis is unknown. We isolated KIT+ progenitors from fetal salivary glands during a stage of rapid progenitor expansion and profiled HS biosynthetic enzyme expression. Enzymes generating a specific type of 3-O-sulfated-HS (3-O-HS) are enriched, and fibroblast growth factor 10 (FGF10)/FGF receptor 2b (FGFR2b) signaling directly regulates their expression. Bioengineered 3-O-HS binds FGFR2b and stabilizes FGF10/FGFR2b complexes in a receptor- and growth factor-specific manner. Rapid autocrine feedback increases 3-O-HS, KIT, and progenitor expansion. Knockdown of multiple Hs3st isoforms limits fetal progenitor expansion but is rescued with bioengineered 3-O-HS, which also increases adult progenitor expansion. Altering specific 3-O-sulfated epitopes provides a mechanism to rapidly respond to FGFR2b signaling and control progenitor expansion. 3-O-HS may expand KIT+ progenitors in vitro for regenerative therapy. C1 [Patel, Vaishali N.; Lombaert, Isabelle M. A.; Cowherd, Samuel N.; Hoffman, Matthew P.] Natl Inst Dent & Craniofacial Res, Matrix & Morphogenesis Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. [Shworak, Nicholas W.] Geisel Sch Med Dartmouth, Dept Med, Sect Cardiol, Hanover, NH 03756 USA. [Xu, Yongmei; Liu, Jian] Univ N Carolina, Sch Pharm, Div Med Chem & Nat Prod, Chapel Hill, NC 27599 USA. RP Hoffman, MP (reprint author), Natl Inst Dent & Craniofacial Res, Matrix & Morphogenesis Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. EM mhoffman@mail.nih.gov FU NIH National Institute of Dental and Craniofacial Research Intramural Research Program; [R01 HL079104] FX We thank Drs. S.M. Knox and I.T. Rebustini for helpful discussions; Drs. G.H. Cohen and R.J. Eisenberg (University of Pennsylvania) for the HSV-gD1 protein; and Dr. D.M. Ornitz (Washington University) for the BaF3 cell lines. The research was supported by the NIH National Institute of Dental and Craniofacial Research Intramural Research Program and R01 HL079104 to N.W.S. NR 44 TC 17 Z9 17 U1 2 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 EI 1878-1551 J9 DEV CELL JI Dev. Cell PD JUN 23 PY 2014 VL 29 IS 6 BP 662 EP 673 DI 10.1016/j.devcel.2014.04.024 PG 12 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA AK1KS UT WOS:000338174600005 PM 24960693 ER PT J AU Romagnoli, R Baraldi, PG Salvador, MK Chayah, M Camacho, ME Prencipe, F Hamel, E Consolaro, F Basso, G Viola, G AF Romagnoli, Romeo Baraldi, Pier Giovanni Salvador, Maria Kimatrai Chayah, Mariem Camacho, M. Encarnacion Prencipe, Filippo Hamel, Ernest Consolaro, Francesca Basso, Giuseppe Viola, Giampietro TI Design, synthesis and biological evaluation of arylcinnamide hybrid derivatives as novel anticancer agents SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article DE Apoptosis; Phenylcinnamides; Michael acceptor; In vitro antiproliferative activity; GSH depletion; Oxidative stress ID ALPHA-HALOGENOACRYLIC DERIVATIVES; DNA-DAMAGE RESPONSE; ANTIPROLIFERATIVE ACTIVITY; MULTIDRUG-RESISTANCE; GLUTATHIONE CONTENT; ACID-DERIVATIVES; ANTITUMOR AGENTS; FLOW-CYTOMETRY; DRUG DESIGN; APOPTOSIS AB The combination of two pharmacophores into a single molecule represents one of the methods that can be adopted for the synthesis of new anticancer molecules. A series of novel antiproliferative agents designed by a pharmacophore hybridization approach, combining the arylcinnamide skeleton and an alpha-bromoacryloyl moiety, was synthesized and evaluated for its antiproliferative activity against a panel of seven human cancer cell lines. In addition, the new derivatives were also active on multidrug-resistant cell lines over-expressing P-glycoprotein. The biological effects of various substituents on the N-phenyl ring of the benzamide portion were also described. In order to study the possible mechanism of action, we observed that 4p slightly increased the Reactive Oxygen Species (ROS) production in HeLa cells, but, more importantly, a remarkable decrease of intracellular reduced glutathione content was detected in treated cells compared with controls. These results were confirmed by the observation that only thiol-containing antioxidants were able to significantly protect the cells from induced cell death. Altogether our results indicate that the new derivatives are endowed with good anticancer activity in vitro, and their properties may result in the development of new cancer therapeutic strategies. (C) 2014 Elsevier Masson SAS. All rights reserved. C1 [Romagnoli, Romeo; Baraldi, Pier Giovanni; Salvador, Maria Kimatrai; Chayah, Mariem; Camacho, M. Encarnacion; Prencipe, Filippo] Univ Ferrara, Dipartimento Sci Chim & Farmaceut, I-44121 Ferrara, Italy. [Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program,NIH, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA. [Consolaro, Francesca; Basso, Giuseppe; Viola, Giampietro] Univ Padua, Lab Oncoematol, Dipartimento Salute Donna & Bambino, I-35131 Padua, Italy. RP Romagnoli, R (reprint author), Univ Ferrara, Dipartimento Sci Chim & Farmaceut, Via Fossato di Mortara 17, I-44121 Ferrara, Italy. EM rmr@unife.it; pgb@unife.it; giampietro.viola1@unipd.it RI Viola, Giampietro/I-4095-2012; Camacho, M. Encarnacion/G-7916-2015; Romagnoli, Romeo/G-9887-2015; Baraldi, Pier Giovanni/B-7933-2017; OI Viola, Giampietro/0000-0001-9329-165X; Camacho, M. Encarnacion/0000-0003-1214-5103; BASSO, GIUSEPPE/0000-0002-2634-9302 FU Intramural NIH HHS [Z99 CA999999] NR 51 TC 4 Z9 4 U1 2 U2 17 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 JUN 23 PY 2014 VL 81 BP 394 EP 407 DI 10.1016/j.ejmech.2014.05.028 PG 14 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA AK7HD UT WOS:000338598400037 PM 24858544 ER PT J AU Prinz, WA AF Prinz, William A. TI Bridging the gap: Membrane contact sites in signaling, metabolism, and organelle dynamics SO JOURNAL OF CELL BIOLOGY LA English DT Review ID OXYSTEROL-BINDING PROTEINS; STROMAL INTERACTION MOLECULE-1; LIPID-TRANSFER PROTEINS; ESTER TRANSFER PROTEIN; CA2+ STORE DEPLETION; ENDOPLASMIC-RETICULUM; PLASMA-MEMBRANE; SKELETAL-MUSCLE; SARCOPLASMIC-RETICULUM; PHOSPHATIDYLSERINE TRANSPORT AB Regions of close apposition between two organelles, often referred to as membrane contact sites (MCSs), mostly form between the endoplasmic reticulum and a second organelle, although contacts between mitochondria and other organelles have also begun to be characterized. Although these contact sites have been noted since cells first began to be visualized with electron microscopy, the functions of most of these domains long remained unclear. The last few years have witnessed a dramatic increase in our understanding of MCSs, revealing the critical roles they play in intracellular signaling, metabolism, the trafficking of metabolites, and organelle inheritance, division, and transport. C1 NIDDK, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Prinz, WA (reprint author), NIDDK, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. EM prinzw@helix.nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 113 TC 77 Z9 77 U1 5 U2 42 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD JUN 23 PY 2014 VL 205 IS 6 BP 759 EP 769 DI 10.1083/jcb.201401126 PG 11 WC Cell Biology SC Cell Biology GA AJ9AJ UT WOS:000337998900003 PM 24958771 ER PT J AU Avella, MA Baibakov, B Dean, J AF Avella, Matte A. Baibakov, Boris Dean, Jurrien TI A single domain of the ZP2 zona pellucida protein mediates gamete recognition in mice and humans SO JOURNAL OF CELL BIOLOGY LA English DT Article ID SPERM RECEPTOR-ACTIVITY; O-LINKED OLIGOSACCHARIDES; TRANSGENIC MICE; MONOCLONAL-ANTIBODIES; ARTIFICIAL-INSEMINATION; GLYCOPROTEIN ZP3; EGG INTERACTION; MOUSE SPERM; BINDING; FERTILIZATION AB The extracellular zona pellucida surrounds ovulated eggs and mediates gamete recognition that is essential for mammalian fertilization. Zonae matrices contain three (mouse) or four (human) glycoproteins (ZP1-4), but which protein binds sperm remains controversial. A defining characteristic of an essential zona ligand is sterility after genetic ablation. We have established transgenic mice expressing human ZP4 that form zonae pellucidae in the absence of mouse or human ZP2. Neither mouse nor human sperm bound to these ovulated eggs, and these female mice were sterile after in vivo insemination or natural mating. The same phenotype was observed with truncated ZP2 that lacks a restricted domain within ZP2(51-149). Chimeric human/mouse ZP2 isoforms expressed in transgenic mice and recombinant peptide bead assays confirmed that this region accounts for the taxon specified), observed in human mouse gamete recognition. These observations in transgenic mice document that the ZP2(51-149) sperm-binding domain is necessary for human and mouse gamete recognition and penetration through the zona pellucida. C1 [Avella, Matte A.; Baibakov, Boris; Dean, Jurrien] NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Dean, J (reprint author), NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. EM jurriend@helix.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases [ZIA-DK015603] FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (ZIA-DK015603). NR 43 TC 24 Z9 24 U1 2 U2 44 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD JUN 23 PY 2014 VL 205 IS 6 BP 801 EP 809 DI 10.1083/jcb.201404025 PG 9 WC Cell Biology SC Cell Biology GA AJ9AJ UT WOS:000337998900007 PM 24934154 ER PT J AU Longo, DM Louie, B Ptacek, J Friedland, G Evensen, E Putta, S Atallah, M Spellmeyer, D Wang, E Pos, Z Marincola, FM Schaeffer, A Lukac, S Railkar, R Beals, CR Cesano, A Carayannopoulos, LN Hawtin, RE AF Longo, Diane M. Louie, Brent Ptacek, Jason Friedland, Greg Evensen, Erik Putta, Santosh Atallah, Michelle Spellmeyer, David Wang, Ena Pos, Zoltan Marincola, Francesco M. Schaeffer, Andrea Lukac, Suzanne Railkar, Radha Beals, Chan R. Cesano, Alessandra Carayannopoulos, Leonidas N. Hawtin, Rachael E. TI High-dimensional analysis of the aging immune system: Verification of age-associated differences in immune signaling responses in healthy donors SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article DE Multi-parameter flow cytometry; Systems immunology; Aging; Immune signaling ID PATHWAY ACTIVATION; FLOW-CYTOMETRY; T-CELLS; RECEPTOR; INTERLEUKIN-2; LYMPHOCYTES; EXPRESSION; DECREASE; HUMANS AB Background: Single-cell network profiling (SCNP) is a multiparametric flow cytometry-based approach that simultaneously measures evoked signaling in multiple cell subsets. Previously, using the SCNP approach, age-associated immune signaling responses were identified in a cohort of 60 healthy donors. Methods: In the current study, a high-dimensional analysis of intracellular signaling was performed by measuring 24 signaling nodes in 7 distinct immune cell subsets within PBMCs in an independent cohort of 174 healthy donors [144 elderly (>65 yrs); 30 young (25-40 yrs)]. Results: Associations between age and 9 immune signaling responses identified in the previously published 60 donor cohort were confirmed in the current study. Furthermore, within the current study cohort, 48 additional immune signaling responses differed significantly between young and elderly donors. These associations spanned all profiled modulators and immune cell subsets. Conclusions: These results demonstrate that SCNP, a systems-based approach, can capture the complexity of the cellular mechanisms underlying immunological aging. Further, the confirmation of age associations in an independent donor cohort supports the use of SCNP as a tool for identifying reproducible predictive biomarkers in areas such as vaccine response and response to cancer immunotherapies. C1 [Longo, Diane M.; Louie, Brent; Ptacek, Jason; Friedland, Greg; Evensen, Erik; Putta, Santosh; Atallah, Michelle; Spellmeyer, David; Cesano, Alessandra; Hawtin, Rachael E.] Nodality, San Francisco, CA 94080 USA. [Wang, Ena; Marincola, Francesco M.] Sidra Med & Res Ctr, Res Branch, Doha, Qatar. [Wang, Ena; Marincola, Francesco M.] NIH, Infect Dis & Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Wang, Ena; Marincola, Francesco M.] NIH, Ctr Human Immunol, Bethesda, MD 20892 USA. [Pos, Zoltan] MTA SE Lendulet Expt & Translat Immun Res Grp, H-1089 Budapest, Hungary. [Schaeffer, Andrea; Lukac, Suzanne; Railkar, Radha; Beals, Chan R.; Carayannopoulos, Leonidas N.] Merck & Co Inc, Rahway, NJ 07065 USA. RP Hawtin, RE (reprint author), Nodality, San Francisco, CA 94080 USA. EM rachael.hawtin@nodality.com OI Pos, Zoltan/0000-0002-2574-7616 NR 23 TC 3 Z9 3 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD JUN 21 PY 2014 VL 12 AR 178 DI 10.1186/1479-5876-12-178 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AK5OS UT WOS:000338475000001 PM 24952610 ER PT J AU Bhandari, N Rongsen-Chandola, T Bavdekar, A John, J Antony, K Taneja, S Goyal, N Kawade, A Kang, G Rathore, SS Juvekar, S Muliyil, J Arya, A Shaikh, H Abraham, V Vrati, S Proschan, M Kohberger, R Thiry, G Glass, R Greenberg, HB Curlin, G Mohan, K Harshavardhan, GVJA Prasad, S Rao, TS Boslego, J Bhan, MK AF Bhandari, Nita Rongsen-Chandola, Temsunaro Bavdekar, Ashish John, Jacob Antony, Kalpana Taneja, Sunita Goyal, Nidhi Kawade, Anand Kang, Gagandeep Rathore, Sudeep Singh Juvekar, Sanjay Muliyil, Jayaprakash Arya, Alok Shaikh, Hanif Abraham, Vinod Vrati, Sudhanshu Proschan, Michael Kohberger, Robert Thiry, Georges Glass, Roger Greenberg, Harry B. Curlin, George Mohan, Krishna Harshavardhan, G. V. J. A. Prasad, Sai Rao, T. S. Boslego, John Bhan, Maharaj Kishan CA India Rotavirus Vaccine Grp TI Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian infants: a randomised, double-blind, placebo-controlled trial SO LANCET LA English DT Article ID 1ST 2 YEARS; AFRICAN INFANTS; RRV-TV; SAFETY; IMMUNOGENICITY; CHILDREN; GASTROENTERITIS; DIARRHEA; POLIO; CONFIDENCE AB Background Rotavirus is the most common cause of severe dehydrating gastroenteritis in developing countries. Safe, effective, and affordable rotavirus vaccines are needed in these countries. We aimed to assess the efficacy and tolerability of a monovalent human-bovine rotavirus vaccine for severe rotavirus gastroenteritis in low-resource urban and rural settings in India. Methods We did a randomised double-blind, placebo-controlled, multicentre trial at three sites in Delhi (urban), Pune (rural), and Vellore (urban and rural) between March 11, 2011, and Nov 5, 2012. Infants aged 6-7 weeks were randomly assigned (2: 1), via a central interactive voice or web response system with a block size of 12, to receive either three doses of oral human-bovine natural reassortant vaccine (116E) or placebo at ages 6-7 weeks, 10 weeks, and 14 weeks. Infants' families, study investigators, paediatricians in referral hospitals, laboratory staff, and committee members were all masked to treatment allocation. The primary outcome was incidence of severe rotavirus gastroenteritis (>= 11 on the Vesikari scale). Efficacy outcomes and adverse events were ascertained through active surveillance. Analysis was by intention to treat and per protocol. The trial is registered with Clinical Trial Registry-India (CTRI/2010/091/000102) and ClinicalTrials. gov (NCT01305109). Findings 4532 infants were assigned to receive the 116E vaccine and 2267 to receive placebo, of whom 4354 (96%) and 2187 (96%) infants, respectively, were included in the primary per-protocol efficacy analysis. 71 events of severe rotavirus gastroenteritis were reported in 4752 person-years in infants in the vaccine group compared with 76 events in 2360 person-years in those in the placebo group; vaccine efficacy against severe rotavirus gastroenteritis was 53 . 6% (95% CI 35 . 0-66 . 9; p= 0.0013) and 56 . 4% (36 . 6-70.1; p< 0.0001) in the first year of life. The number of infants needed to be immunised to prevent one severe rotavirus gastroenteritis episode was 55 (95% CI 37-97). The incidence of severe rotavirus gastroenteritis per 100 person-years was 1 . 5 in the vaccine group and 3 . 2 in the placebo group, with an incidence rate ratio of 0.46 (95% CI 0.33-0.65). Prevalence of immediate, solicited, and serious adverse events was similar in both groups. One case of urticaria in the vaccine group and one each of acute gastroenteritis and suspected sepsis in the placebo group were regarded as related to the study product. We recorded six cases of intussusception in the vaccine group and two in the placebo group, all of which happened after the third dose. 25 (< 1%) infants in the vaccine group and 17 (< 1%) in the placebo group died; no death was regarded as related to the study product. Interpretation Monovalent human-bovine (116E) rotavirus vaccine is effective and well tolerated in Indian infants. C1 [Bhandari, Nita; Rongsen-Chandola, Temsunaro; Taneja, Sunita; Goyal, Nidhi; Rathore, Sudeep Singh; Arya, Alok] Soc Appl Studies, Ctr Hlth Res & Dev, New Delhi, India. [Bavdekar, Ashish; Kawade, Anand; Juvekar, Sanjay; Shaikh, Hanif] KEM Hosp, Res Ctr, Pune, Maharashtra, India. [John, Jacob; Kang, Gagandeep; Muliyil, Jayaprakash; Abraham, Vinod] Christian Med Coll & Hosp, Vellore, Tamil Nadu, India. [Antony, Kalpana] PATH, New Delhi, India. [Vrati, Sudhanshu] Translat Hlth Sci & Technol Inst, Gurgaon, Haryana, India. [Proschan, Michael; Glass, Roger; Curlin, George] NIH, Bethesda, MD 20892 USA. [Kohberger, Robert] Blair & Co, Greenwich, CT USA. [Thiry, Georges] PATH, Adv Rotavirus Vaccines Dev Project, Ferney Voltaire, France. [Greenberg, Harry B.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Mohan, Krishna; Harshavardhan, G. V. J. A.; Prasad, Sai] Bharat Biotech Int, Genome Valley, Andhra Pradesh, India. [Rao, T. S.] Govt India, Dept Biotechnol, New Delhi 110017, India. [Bhan, Maharaj Kishan] Govt India, Minist Sci & Technol, New Delhi 110017, India. [Boslego, John] PATH, Vaccine Dev Global Program, Seattle, WA USA. RP Bhan, MK (reprint author), Govt India, Minist Sci & Technol, New Delhi 110017, India. EM rajkbhan@gmail.com RI Strand, Tor/D-9836-2016; OI Strand, Tor/0000-0002-4038-151X; John, Jacob/0000-0003-3654-5099; Kang, Gagandeep/0000-0002-3656-564X FU Department of Biotechnology; Bill & Melinda Gates Foundation; Research Council of Norway; UK Department for International Development; National Institutes of Health, Bethesda, USA; Bharat Biotech International, Hyderabad, India; Biotechnology Industry Research Assistance Council, Government of India FX Department of Biotechnology and the Biotechnology Industry Research Assistance Council, Government of India; Bill & Melinda Gates Foundation to PATH, USA; Research Council of Norway; UK Department for International Development; National Institutes of Health, Bethesda, USA; and Bharat Biotech International, Hyderabad, India. NR 37 TC 45 Z9 47 U1 4 U2 26 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 JUN 21 PY 2014 VL 383 IS 9935 BP 2136 EP 2143 DI 10.1016/S0140-6736(13)62630-6 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA AJ7VG UT WOS:000337906600028 PM 24629994 ER PT J AU Bhan, MK Glass, RI Ella, KM Bhandari, N Boslego, J Greenberg, HB Mohan, K Curlin, G Rao, TS AF Bhan, Maharaj K. Glass, Roger I. Ella, Krishna M. Bhandari, Nita Boslego, John Greenberg, Harry B. Mohan, Krishna Curlin, George Rao, T. S. TI Team science and the creation of a novel rotavirus vaccine in India: a new framework for vaccine development SO LANCET LA English DT Editorial Material C1 [Bhan, Maharaj K.] Govt India, Minist Sci & Technol, New Delhi 110017, India. [Rao, T. S.] Govt India, Dept Biotechnol, New Delhi 110017, India. [Glass, Roger I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Curlin, George] NIAID, NIH, Bethesda, MD 20892 USA. [Ella, Krishna M.; Mohan, Krishna] Bharat Biotech Int, Hyderabad, Andhra Pradesh, India. [Bhandari, Nita] Soc Appl Studies, New Delhi, India. [Boslego, John] PATH, Vaccine Dev Global Program, Seattle, WA USA. [Greenberg, Harry B.] Stanford Univ, Sch Med, Stanford, CA USA. RP Bhan, MK (reprint author), Govt India, Minist Sci & Technol, New Delhi 110017, India. EM rajkbhan@gmail.com NR 6 TC 5 Z9 5 U1 0 U2 7 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 JUN 21 PY 2014 VL 383 IS 9935 BP 2180 EP 2183 DI 10.1016/S0140-6736(14)60191-4 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA AJ7VG UT WOS:000337906600032 PM 24629993 ER PT J AU Harel, A Kravitz, DJ Baker, CI AF Harel, Assaf Kravitz, Dwight J. Baker, Chris I. TI Holding a stick at both ends: on faces and expertise SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Editorial Material DE expertise; perceptual expertise; object recognition; visual perception; fMRI; review; visual cortex ID AREA C1 [Harel, Assaf; Baker, Chris I.] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Kravitz, Dwight J.] George Washington Univ, Dept Psychol, Washington, DC 20052 USA. RP Harel, A (reprint author), NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. EM assaf.harel@nih.gov OI Baker, Chris/0000-0001-6861-8964; Harel, Assaf/0000-0002-4899-6156 NR 15 TC 2 Z9 2 U1 2 U2 9 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD JUN 20 PY 2014 VL 8 AR 442 DI 10.3389/fnhum.2014.00442 PG 2 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA AM5ZF UT WOS:000339939000001 PM 24999321 ER PT J AU Chen, KQ Xiang, Y Huang, JQ Gong, WH Yoshimura, T Jiang, Q Tessarollo, L Le, YY Wang, JM AF Chen, Keqiang Xiang, Yi Huang, Jiaqiang Gong, Wanghua Yoshimura, Teizo Jiang, Qun Tessarollo, Lino Le, Yingying Wang, Ji Ming TI The Formylpeptide Receptor 2 (Fpr2) and Its Endogenous Ligand Cathelin-related Antimicrobial Peptide (CRAMP) Promote Dendritic Cell Maturation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HOST-DEFENSE; CHEMOTACTIC AGONIST; LIPOXIN A(4); INFLAMMATION; IDENTIFICATION; RESPONSES; POLARIZATION; ACTIVATION; MECHANISMS; EXPRESSION AB Mouse formylpeptide receptor 2 (Fpr2) is a homologue of the human G-protein coupled chemoattractant receptor FPR2, which interacts with pathogen and host-derived chemotactic agonists. Our previous studies revealed reduced allergic airway inflammation and immune responses in Fpr2-deficient (Fpr2(-/-)) mice in association with diminished dendritic cell (DC) recruitment into the airway and draining lymph nodes. These defects prompted us to investigate the potential changes in the differentiation and maturation of DCs caused by Fpr2 deficiency. Bone marrow monocytes from Fpr2(-/-) mouse mice incubated with GM-CSF and IL-4 in vitro showed normal expression of markers of immature DCs. However, upon stimulation with the TLR4 agonist LPS, Fpr2(-/-) mouse DCs failed to express normal levels of maturation markers with reduced production of IL-12 and diminished chemotaxis in response to the DC homing chemokine CCL21. Fpr2(-/-) DCs also failed to induce allogeneic T-cell proliferation in vitro, and their recruitment into the T-cell zones of the spleen was reduced after antigen immunization. The capacity of Fpr2 to sustain normal DC maturation was dependent on its interaction with an endogenous ligand CRAMP expressed by DCs, because neutralization of either Fpr2 or CRAMP inhibited DC maturation in response to LPS. We additionally observed that the presence of exogenous CRAMP in culture increased the sensitivity of WT mouse DCs to LPS stimulation. The importance of CRAMP for DC maturation was further demonstrated by the observations that DCs from CRAMP(-/-) mice expressed lower levels of costimulatory molecules and MHC II and exhibited poor chemotaxis in response to CCL21 after LPS stimulation. Our observations indicate a nonredundant role for Fpr2 and its agonist CRAMP in DC maturation in immune responses. C1 [Chen, Keqiang; Xiang, Yi; Huang, Jiaqiang; Yoshimura, Teizo; Wang, Ji Ming] NCI, Lab Mol Immunoregulat, Canc & Inflammat Program, Frederick, MD 21702 USA. [Jiang, Qun] NCI, Lab Expt Immunol, Canc & Inflammat Program, Frederick, MD 21702 USA. [Tessarollo, Lino] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. [Xiang, Yi] Shanghai Jiao Tong Univ, Dept Pulm Med, Rui Jin Hosp, Sch Med, Shanghai 200025, Peoples R China. [Huang, Jiaqiang] Beijing Jiaotong Univ, Sch Sci, Coll Life Sci & Bioengn, Beijing 100044, Peoples R China. [Gong, Wanghua] SAIC Frederick, Leidos Biomed Res Inc, Frederick, MD 21702 USA. [Le, Yingying] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Nutr Sci, Shanghai 200031, Peoples R China. RP Wang, JM (reprint author), NCI, Mol Immunoregulat Lab, Canc & Inflammat Program, Ctr Canc Res, Bldg 560,Rm 31-76, Frederick, MD 21702 USA. EM wangji@mail.nih.gov FU National Institutes of Health [HHSN261200800001E]; NCI, National Institutes of Health FX This work was supported, in whole or in part, by National Institutes of Health Grant HHSN261200800001E. This work was also supported by the Intramural Research Program of the NCI, National Institutes of Health. NR 36 TC 5 Z9 7 U1 0 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 20 PY 2014 VL 289 IS 25 BP 17553 EP 17563 DI 10.1074/jbc.M113.535674 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AJ9HE UT WOS:000338018100021 PM 24808174 ER PT J AU Chrousos, G AF Chrousos, George TI Video Q & A: The impact of stress. An interview with George Chrousos SO BMC MEDICINE LA English DT Editorial Material ID INFLAMMATION; DISORDER AB In this video Q & A, we talk to George Chrousos about stress and its impact on chronic non-communicable disorders (NCDs) and early life development. Professor Chrousos also discusses the effects of psychological and economical stressors on health, and suggests ways in which we can learn to cope with stress. C1 [Chrousos, George] Univ Athens, Sch Med, Aghia Sophia Childrens Hosp, Div Endocrinol Metab & Diabet, Athens 11527, Greece. [Chrousos, George] Natl Inst Child Hlth & Human Dev NICHD, NIH Bethesda, Bethesda, MD 20892 USA. RP Chrousos, G (reprint author), Univ Athens, Sch Med, Aghia Sophia Childrens Hosp, Div Endocrinol Metab & Diabet, Athens 11527, Greece. EM chrousog@mail.nih.gov NR 12 TC 0 Z9 0 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7015 J9 BMC MED JI BMC Med. PD JUN 20 PY 2014 VL 12 AR 102 DI 10.1186/1741-7015-12-102 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA AK2LV UT WOS:000338251700001 PM 24950967 ER PT J AU Sternberg, CN Apolo, AB AF Sternberg, Cora N. Apolo, Andrea B. TI Everything Old Is New Again ! Neoadjuvant Chemotherapy in the Treatment of Muscle-Invasive Bladder Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID TRANSITIONAL-CELL-CARCINOMA; COLONY-STIMULATING FACTOR; UROTHELIAL TRACT TUMORS; M-VAC METHOTREXATE; PHASE-III TRIAL; ACCELERATED METHOTREXATE; VINBLASTINE; CISPLATIN; DOXORUBICIN; CYSTECTOMY C1 [Sternberg, Cora N.] Hosp San Camillo Forlanini, Rome, Italy. [Apolo, Andrea B.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Sternberg, CN (reprint author), Hosp San Camillo Forlanini, Rome, Italy. NR 21 TC 3 Z9 3 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2014 VL 32 IS 18 BP 1868 EP 1870 DI 10.1200/JCO.2014.55.4055 PG 3 WC Oncology SC Oncology GA AJ7TT UT WOS:000337901200003 PM 24821880 ER PT J AU Aoude, LG Xu, M Zhao, ZZ Kovacs, M Palmer, JM Johansson, P Symmons, J Trent, JM Martin, NG Montgomery, GW Brown, KM Hayward, NK AF Aoude, Lauren G. Xu, Mai Zhao, Zhen Zhen Kovacs, Michael Palmer, Jane M. Johansson, Peter Symmons, Judith Trent, Jeffrey M. Martin, Nicholas G. Montgomery, Grant W. Brown, Kevin M. Hayward, Nicholas K. TI Assessment of PALB2 as a Candidate Melanoma Susceptibility Gene SO PLOS ONE LA English DT Article ID ONSET BREAST-CANCER; BRCA2-INTERACTING PROTEIN PALB2; FRENCH-CANADIAN WOMEN; PANCREATIC-CANCER; GERMLINE MUTATIONS; FANCONI-ANEMIA; FAMILIES; PREVALENCE; PARTNER AB Partner and localizer of BRCA2 (PALB2) interacts with BRCA2 to enable double strand break repair through homologous recombination. Similar to BRCA2, germline mutations in PALB2 have been shown to predispose to Fanconi anaemia as well as pancreatic and breast cancer. The PALB2/BRCA2 protein interaction, as well as the increased melanoma risk observed in families harbouring BRCA2 mutations, makes PALB2 a candidate for melanoma susceptibility. In order to assess PALB2 as a melanoma predisposition gene, we sequenced the entire protein-coding sequence of PALB2 in probands from 182 melanoma families lacking pathogenic mutations in known high penetrance melanoma susceptibility genes: CDKN2A, CDK4, and BAP1. In addition, we interrogated whole-genome and exome data from another 19 kindreds with a strong family history of melanoma for deleterious mutations in PALB2. Here we report a rare known deleterious PALB2 mutation (rs118203998) causing a premature truncation of the protein (p. Y1183X) in an individual who had developed four different cancer types, including melanoma. Three other family members affected with melanoma did not carry the variant. Overall our data do not support a case for PALB2 being associated with melanoma predisposition. C1 [Aoude, Lauren G.; Zhao, Zhen Zhen; Palmer, Jane M.; Johansson, Peter; Symmons, Judith; Martin, Nicholas G.; Montgomery, Grant W.; Hayward, Nicholas K.] QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia. [Aoude, Lauren G.] Univ Queensland, Brisbane, Qld, Australia. [Xu, Mai; Kovacs, Michael; Brown, Kevin M.] NCI, Bethesda, MD 20892 USA. [Trent, Jeffrey M.; Brown, Kevin M.] Translat Genom Res Inst, Phoenix, AZ USA. RP Aoude, LG (reprint author), QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia. EM Lauren.Aoude@qimrberghofer.edu.au RI Aoude, Lauren/C-7484-2014; Johansson, Peter/K-1053-2014; hayward, nicholas/C-1367-2015; Montgomery, Grant/B-7148-2008; OI Aoude, Lauren/0000-0003-1448-3923; Johansson, Peter/0000-0001-7015-5452; hayward, nicholas/0000-0003-4760-1033; Montgomery, Grant/0000-0002-4140-8139; Martin, Nicholas/0000-0003-4069-8020 FU Melanoma Research Alliance; National Health and Medical Research Council (NHMRC) of Australia; NHMRC; Australia and New Zealand Banking Group Limited Trustees PhD scholarship; Division of Cancer Epidemiology and Genetics, National Cancer Institute, USA FX This work was supported by the Melanoma Research Alliance and the National Health and Medical Research Council (NHMRC) of Australia. NKH and GWM receive salary support through a NHMRC Senior Principal Research Fellowship. LGA receives salary support by the Australia and New Zealand Banking Group Limited Trustees PhD scholarship. KMB is supported by the Division of Cancer Epidemiology and Genetics, National Cancer Institute, USA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 3 Z9 3 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 20 PY 2014 VL 9 IS 6 AR e100683 DI 10.1371/journal.pone.0100683 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK2UZ UT WOS:000338276300107 PM 24949998 ER PT J AU Yoshizaki, K Hu, LZ Nguyen, T Sakai, K He, B Fong, C Yamada, Y Bikle, DD Oda, Y AF Yoshizaki, Keigo Hu, Lizhi Thai Nguyen Sakai, Kiyoshi He, Bing Fong, Chak Yamada, Yoshihiko Bikle, Daniel D. Oda, Yuko TI Ablation of Coactivator Med1 Switches the Cell Fate of Dental Epithelia to That Generating Hair SO PLOS ONE LA English DT Article ID MAMMARY-GLAND DEVELOPMENT; MEDIATOR SUBUNIT MED1; FOLLICLE STEM-CELLS; AMELOBLAST-LINEAGE; GENE-EXPRESSION; DIFFERENTIATION; TRANSCRIPTION; NOTCH; COMPLEX; PROTEIN AB Cell fates are determined by specific transcriptional programs. Here we provide evidence that the transcriptional coactivator, Mediator 1 (Med1), is essential for the cell fate determination of ectodermal epithelia. Conditional deletion of Med1 in vivo converted dental epithelia into epidermal epithelia, causing defects in enamel organ development while promoting hair formation in the incisors. We identified multiple processes by which hairs are generated in Med1 deficient incisors: 1) dental epithelial stem cells lacking Med 1 fail to commit to the dental lineage, 2) Sox2-expressing stem cells extend into the differentiation zone and remain multi-potent due to reduced Notch1 signaling, and 3) epidermal fate is induced by calcium as demonstrated in dental epithelial cell cultures. These results demonstrate that Med1 is a master regulator in adult stem cells to govern epithelial cell fate. C1 [Hu, Lizhi; Thai Nguyen; Fong, Chak; Bikle, Daniel D.; Oda, Yuko] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Hu, Lizhi; Thai Nguyen; Fong, Chak; Bikle, Daniel D.; Oda, Yuko] Univ Calif San Francisco, Dept Endocrinol, San Francisco, CA 94143 USA. [Hu, Lizhi; Thai Nguyen; Fong, Chak; Bikle, Daniel D.; Oda, Yuko] Vet Affairs Med Ctr San Francisco, San Francisco, CA USA. [Yoshizaki, Keigo; Sakai, Kiyoshi; He, Bing; Yamada, Yoshihiko] Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD USA. RP Oda, Y (reprint author), Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. EM yuko.oda@ucsf.edu OI Nguyen, Tuan V./0000-0002-3246-6281 FU National Institutes of Health [R01 AR050023]; DOD [CA110338]; VA Merit Review; Intramural Research Program of the National Institutes of Dental and Craniofacial Research, NIH; Japanese Research Fellowship of Japan Society for the Promotion of Science; Chinese Research grant NSFC [81301360] FX This work was supported by the National Institutes of Health grant R01 AR050023 (DDB), DOD grant CA110338 (DDB), a VA Merit Review (DDB), the Intramural Research Program of the National Institutes of Dental and Craniofacial Research, NIH (YY), and Chinese Research grant NSFC 81301360 (LH). KY was supported in part by the Japanese Research Fellowship of Japan Society for the Promotion of Science. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 2 Z9 2 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 20 PY 2014 VL 9 IS 6 AR e99991 DI 10.1371/journal.pone.0099991 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK2UZ UT WOS:000338276300027 PM 24949995 ER PT J AU Zhang, J Hsieh, JH Zhu, H AF Zhang, Jun Hsieh, Jui-Hua Zhu, Hao TI Profiling Animal Toxicants by Automatically Mining Public Bioassay Data: A Big Data Approach for Computational Toxicology SO PLOS ONE LA English DT Article ID PUBCHEM; MANAGEMENT; CHEMICALS; TOXICITY; ASSAYS AB In vitro bioassays have been developed and are currently being evaluated as potential alternatives to traditional animal toxicity models. Already, the progress of high throughput screening techniques has resulted in an enormous amount of publicly available bioassay data having been generated for a large collection of compounds. When a compound is tested using a collection of various bioassays, all the testing results can be considered as providing a unique bio-profile for this compound, which records the responses induced when the compound interacts with different cellular systems or biological targets. Profiling compounds of environmental or pharmaceutical interest using useful toxicity bioassay data is a promising method to study complex animal toxicity. In this study, we developed an automatic virtual profiling tool to evaluate potential animal toxicants. First, we automatically acquired all PubChem bioassay data for a set of 4,841 compounds with publicly available rat acute toxicity results. Next, we developed a scoring system to evaluate the relevance between these extracted bioassays and animal acute toxicity. Finally, the top ranked bioassays were selected to profile the compounds of interest. The resulting response profiles proved to be useful to prioritize untested compounds for their animal toxicity potentials and form a potential in vitro toxicity testing panel. The protocol developed in this study could be combined with structure-activity approaches and used to explore additional publicly available bioassay datasets for modeling a broader range of animal toxicities. C1 [Zhang, Jun; Zhu, Hao] Rutgers State Univ, Dept Chem, Camden, NJ 08102 USA. [Zhang, Jun; Zhu, Hao] Rutgers Ctr Computat & Integrat Biol, Camden, NJ USA. [Hsieh, Jui-Hua] Natl Inst Environm Hlth Sci, Div Natl Toxicol Program, Biomol Screening Branch, Res Triangle Pk, NC USA. RP Zhu, H (reprint author), Rutgers State Univ, Dept Chem, Camden, NJ 08102 USA. EM hao.zhu99@rutgers.edu FU National Institute of Environmental Health Sciences of the National Institutes of Health [R15ES023148]; Colgate-Palmolive Grant for Alternative Research FX This work was supported, in part, by the National Institute of Environmental Health Sciences of the National Institutes of Health under Award Number [R15ES023148] and the Colgate-Palmolive Grant for Alternative Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. https://www.niehs.nih.gov/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 6 Z9 6 U1 3 U2 35 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 JUN 20 PY 2014 VL 9 IS 6 AR e99863 DI 10.1371/journal.pone.0099863 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK2UZ UT WOS:000338276300021 PM 24950175 ER PT J AU Pallotto, M Deprez, F AF Pallotto, Marta Deprez, Francine TI Regulation of adult neurogenesis by GABAergic transmission: signaling beyond GABA(A)-receptors SO FRONTIERS IN CELLULAR NEUROSCIENCE LA English DT Review DE adult neurogenesis; olfactory bulb; dentate gyrus; GABA(A) receptor; plasticity ID NEWLY GENERATED NEURONS; POSTNATAL SUBVENTRICULAR ZONE; GABA(A) RECEPTOR SUBUNITS; NEURAL STEM-CELLS; OLFACTORY-BULB INTERNEURONS; BORN NEURONS; DENTATE GYRUS; GRANULE CELLS; SYNAPTIC PLASTICITY; NEWBORN NEURONS AB In the adult mammalian brain, neurogenesis occurs in the olfactory bulb (OB) and in the dentate gyrus (DG) of the hippocampus. Several studies have shown that multiple stages of neurogenesis are regulated by GABAergic transmission with precise spatio-temporal selectivity, and involving mechanisms common to both systems or specific only to one. In the subgranular zone (SGZ) of the DG, GABA neurotransmitter, released by a specific population of interneurons, regulates stem cell quiescence and neuronal cell fate decisions. Similarly, in the subventricular zone (SVZ), OB neuroblast production is modulated by ambient GABA. Ambient GABA, acting on extrasynaptic GABA(A) receptors (GABAAR), is also crucial for proper adult-born granule cell (GC) maturation and synaptic integration in the OB as well as in the DG. Throughout adult-born neuron development, various GABA receptors and receptor subunits play specific roles. Previous work has demonstrated that adult-born GCs in both the OB and the DG show a time window of increased plasticity in which adult-born cells are more prone to modification by external stimuli. One mechanism that controls this "critical period" is GABAergic modulation. Indeed, depleting the main phasic GABAergic inputs in adult-born neurons results in dramatic effects, such as reduction of spine density and dendritic branching in adult-born OB GCs. In this review, we systematically compare the role of GABAergic transmission in the regulation of adult neurogenesis between the OB and the hippocampus, focusing on the role of GABA in modulating plasticity and critical periods of adult-born neuron development. Finally, we discuss signaling pathways that might mediate some of the deficits observed upon targeted deletion of postsynaptic GABA(A)Rs in adult-born neurons. C1 [Pallotto, Marta] NINDS, Circuit Dynam & Connect Unit, NIH, Bethesda, MD 20892 USA. [Deprez, Francine] Univ Zurich, Neurosci Ctr Zurich, Inst Pharmacol & Toxicol, Zurich, Switzerland. RP Pallotto, M (reprint author), NINDS, Circuit Dynam & Connect Unit, NIH, Bldg 37,Room 1016,37 Convent Dr, Bethesda, MD 20892 USA. EM marta.pallotto@nih.gov OI Pallotto, Marta/0000-0001-7694-0398 FU Intramural research program of the NIH; NINDS; Swiss National Science Foundation FX We would like to thank Dr. Jean-Marc Fritschy (University of Zurich) for discussion and comments on the manuscript. This research was supported by the Intramural research program of the NIH, NINDS and the Swiss National Science Foundation. We are also grateful to Dr. Paul Watkins and Dr. Christopher Harris for corrections to the English. NR 108 TC 22 Z9 23 U1 1 U2 14 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5102 J9 FRONT CELL NEUROSCI JI Front. Cell. Neurosci. PD JUN 20 PY 2014 VL 8 AR 166 DI 10.3389/fncel.2014.00166 PG 13 WC Neurosciences SC Neurosciences & Neurology GA AJ5ML UT WOS:000337727300001 PM 24999317 ER PT J AU Rotimi, C AF Rotimi, Charles CA H3Africa Consortium TI Enabling the genomic revolution in Africa SO SCIENCE LA English DT Editorial Material ID CHRONIC KIDNEY-DISEASE; APOL1 RISK VARIANTS; HIV-ASSOCIATED NEPHROPATHY; POPULATION C1 [Rotimi, Charles] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. RP Rotimi, C (reprint author), NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. EM rotimic@mail.nih.gov RI Mayige, Mary/L-5342-2016; OI Masiga, Daniel/0000-0001-7513-0887; Nicol, Mark/0000-0002-1366-4805; Kassim, Samar/0000-0002-4359-6620; McCurdy, Sheryl/0000-0003-0526-1608; Patterton, Hugh-George/0000-0003-2550-0493; Mayige, Mary/0000-0003-4861-7870; Amodu, Olukemi/0000-0003-1477-4229; Bethke, Lara/0000-0002-1316-4704; Rasooly, Rebekah/0000-0002-6357-5528; lawlor, Rita/0000-0003-3160-0634; christoffels, alan/0000-0002-0420-2916; Owen, Andrew/0000-0002-9819-7651; McIlleron, Helen/0000-0002-0982-6226; Tastan Bishop, Ozlem/0000-0001-6861-7849 NR 11 TC 42 Z9 42 U1 0 U2 7 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 JUN 20 PY 2014 VL 344 IS 6190 BP 1346 EP 1348 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AJ2YQ UT WOS:000337531700022 ER PT J AU Hatziioannou, T Del Prete, GQ Keele, BF Estes, JD McNatt, MW Bitzegeio, J Raymond, A Rodriguez, A Schmidt, F Mac Trubey, C Smedley, J Piatak, M KewalRamani, VN Lifson, JD Bieniasz, PD AF Hatziioannou, Theodora Del Prete, Gregory Q. Keele, Brandon F. Estes, Jacob D. McNatt, Matthew W. Bitzegeio, Julia Raymond, Alice Rodriguez, Anthony Schmidt, Fabian Mac Trubey, C. Smedley, Jeremy Piatak, Michael, Jr. KewalRamani, Vineet N. Lifson, Jeffrey D. Bieniasz, Paul D. TI HIV-1-induced AIDS in monkeys SO SCIENCE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; HIV-1 INFECTION; ANIMAL-MODEL; HIV/AIDS; PROTEINS; MACAQUES; VIF AB Primate lentiviruses exhibit narrow host tropism, reducing the occurrence of zoonoses but also impairing the development of optimal animal models of AIDS. To delineate the factors limiting cross-species HIV-1 transmission, we passaged a modified HIV-1 in pigtailed macaques that were transiently depleted of CD8(+) cells during acute infection. During adaptation over four passages in macaques, HIV-1 acquired the ability to antagonize the macaque restriction factor tetherin, replicated at progressively higher levels, and ultimately caused marked CD4(+) T cell depletion and AIDS-defining conditions. Transient treatment with an antibody to CD8 during acute HIV-1 infection caused rapid progression to AIDS, whereas untreated animals exhibited an elite controller phenotype. Thus, an adapted HIV-1 can cause AIDS in macaques, and stark differences in outcome can be determined by immunological perturbations during early infection. C1 [Hatziioannou, Theodora; McNatt, Matthew W.; Bitzegeio, Julia; Raymond, Alice; Rodriguez, Anthony; Schmidt, Fabian; Bieniasz, Paul D.] Aaron Diamond AIDS Res Ctr, New York, NY 10016 USA. [Del Prete, Gregory Q.; Keele, Brandon F.; Estes, Jacob D.; Mac Trubey, C.; Piatak, Michael, Jr.; Lifson, Jeffrey D.] Frederick Natl Lab, AIDS & Canc Virus Program, Leidos Biomed Res, Frederick, MD 21702 USA. [McNatt, Matthew W.; Bitzegeio, Julia; Schmidt, Fabian; Bieniasz, Paul D.] Rockefeller Univ, Lab Retrovirol, New York, NY 10016 USA. [Smedley, Jeremy] Frederick Natl Lab, Lab Anim Sci Program, Leidos Biomed Res, Frederick, MD 21702 USA. [KewalRamani, Vineet N.] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Bieniasz, Paul D.] Howard Hughes Med Inst, New York, NY 10016 USA. RP Hatziioannou, T (reprint author), Aaron Diamond AIDS Res Ctr, 455 First Ave, New York, NY 10016 USA. EM thatziio@adarc.org; vineet.kewalramani@nih.gov; lifsonj@mail.nih.gov; pbienias@adarc.org OI Smedley, Jeremy/0000-0003-3369-4662 FU NIH [R37AI64003, R01AI50111, R01AI078788]; Deutsche Forschungsgemeinschaft [BI1540/1-1]; Howard Hughes Medical Institute; National Cancer Institute, NIH [HHSN261200800001E] FX The data presented in this paper are tabulated in the main paper and in the supplementary materials. HIV-1 Env sequences used in Fig. 3 have been deposited in GenBank (accession numbers KJ201545 through KJ201764). Sequences encompassing the full-length viral genome for P5 and P6 have also been deposited in GenBank (accession numbers KJ767573 through KJ767592). This work was supported by NIH grants R37AI64003 and R01AI50111 (to P. D. B.) and R01AI078788 (to T. H.); Deutsche Forschungsgemeinschaft fellowship BI1540/1-1 (to J.B.); the Howard Hughes Medical Institute; and in part with federal funds from the National Cancer Institute, NIH, under contract no. HHSN261200800001E. We thank V. Coalter, A. Wiles, R. Wiles, and D. Johnson for assistance with study coordination and sample processing. Histology support was provided by the Pathology/Histotechnology Laboratory core service located at the Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Frederick, MD. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. NR 24 TC 33 Z9 34 U1 3 U2 23 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 JUN 20 PY 2014 VL 344 IS 6190 BP 1401 EP 1405 DI 10.1126/science.1250761 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AJ2YQ UT WOS:000337531700041 PM 24948736 ER PT J AU Hinrichs, CS Stevanovic, S Draper, L Somerville, R Wunderlich, J Restifo, NP Sherry, R Giao, PQ Kammula, US Yang, JC Rosenberg, SA AF Hinrichs, Christian S. Stevanovic, Sanja Draper, Lindsey Somerville, Robert Wunderlich, John Restifo, Nicholas P. Sherry, Richard Giao, Phan Q. Kammula, Udai S. Yang, James C. Rosenberg, Steven A. TI HPV-targeted tumor-infiltrating lymphocytes for cervical cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. NCI, Surg Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2014 VL 32 IS 18 SU S MA LBA3008 PG 1 WC Oncology SC Oncology GA CN2IS UT WOS:000358244900007 ER PT J AU Liu, J Barry, WT Birrer, MJ Lee, JM Buckanovich, RJ Fleming, GF Rime, B Buss, MK Natiam, SR Hurteau, J Luo, WX Quy, P Obermayer, E Whalen, C Lee, H Winer, EP Kohn, EC Ivy, SP Matulonis, U AF Liu, Joyce Barry, William Thomas Birrer, Michael J. Lee, Jung-Min Buckanovich, Ronald J. Fleming, Gini F. Rime, Bj Buss, Mary K. Natiam, Sreenivasa R. Hurteau, Jean Luo, Weixiu Quy, Philippa Obermayer, Elizabeth Whalen, Christin Lee, Hang Winer, Eric P. Kohn, Elise C. Ivy, S. Percy Matulonis, Ursula TI A randomized phase 2 trial comparing efficacy of the combination of the PARP inhibitor olaparib and the antiangiogenic cediranib against olaparib alone in recurrent platinum-sensitive ovarian cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NCI, NIH, Bethesda, MD 20892 USA. Univ Michigan, Ann Arbor, MI 48109 USA. Univ Chicago, Med Ctr, Chicago, IL 60637 USA. Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Ft Wayne Med Oncol & Hematol, Ft Wayne, IN USA. Univ Chicago, Northshore Univ Hlth Syst, Evanston, IL USA. Dana Farber Canc Inst, IBCSG Stat Ctr, Boston, MA 02115 USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2014 VL 32 IS 18 SU S MA LBA5500 PG 1 WC Oncology SC Oncology GA CN2IS UT WOS:000358244900008 ER PT J AU Moore, HCF Unger, JM Phillips, KA Boyle, FM Hitre, E Porter, DJ Francis, PA Minasian, LM Gelber, RD Goldstein, LJ Gomez, HL Vallejos, C Partridge, AH Dakhil, SR Martino, S Barlow, WE Fabian, CJ Meyskens, FL Hortobagyi, GN Albain, KS AF Moore, Halle C. F. Unger, Joseph M. Phillips, Kelly-Anne Boyle, Frances M. Hitre, Erika Porter, David James Francis, Prudence A. Minasian, Lori M. Gelber, Richard D. Goldstein, Lori J. Gomez, Henry Leonidas Vallejos, Carlos Partridge, Ann H. Dakhil, Shaker R. Martino, Silvana Barlow, William E. Fabian, Carol J. Meyskens, Frank L. Hortobagyi, Gabriel N. Albain, Kathy S. TI Phase III trial (Prevention of Early Menopause Study [POEMS]-SWOG S0230) of LHRH analog during chemotherapy (CT) to reduce ovarian failure in early-stage, hormone receptor-negative breast cancer: An international Intergroup trial of SWOG, IBCSG, ECOG, and CALGB (Alliance). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Cleveland Clin, Cleveland, OH 44106 USA. SWOG Stat Ctr, Seattle, WA USA. Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. Mater Hosp, Sydney, NSW, Australia. Natl Inst Oncol, Budapest, Hungary. Auckland City Hosp, Dept Oncol, Auckland, New Zealand. Peter MacCallum Canc Ctr, East Melbourne, Australia. NCI, Bethesda, MD 20892 USA. Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Inst Nacl Enfermedades Neoplas, Lima, Peru. ONCOSALUD, Lima, Peru. Dana Farber Canc Inst, Boston, MA 02115 USA. Wichita Community Clin Oncol Program, Wichita, KS USA. Angeles Clin & Res Inst, Santa Monica, CA USA. Canc Res & Biostat, Seattle, WA USA. Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. Chao Family Comprehens Canc Ctr, Orange, CA USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Loyola Univ, Med Ctr, Maywood, IL 60153 USA. NR 0 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 JUN 20 PY 2014 VL 32 IS 18 SU S MA LBA505 PG 1 WC Oncology SC Oncology GA CN2IS UT WOS:000358244900006 ER PT J AU Piccart-Gebhart, MJ Holmes, AP Baselga, J De Azambuja, E Dueck, AC Viale, G Zujewski, JA Goldhirsch, A Santillana, S Pritchard, KI Wolff, AC Jackisch, C Lang, I Untch, M Smith, LE Boyle, F Xu, BH Gomez, HL Gelber, RD Perez, EA AF Piccart-Gebhart, Martine J. Holmes, Andrew Peter Baselga, Jose De Azambuja, Evandro Dueck, Amylou C. Viale, Giuseppe Zujewski, Jo Anne Goldhirsch, Aron Santillana, Sergio Pritchard, Kathleen I. Wolff, Antonio C. Jackisch, Christian Lang, Istvan Untch, Michael Smith, Lan E. Boyle, Frances Xu, Binghe Gomez, Henry Leonidas Gelber, Richard D. Perez, Edith A. TI First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T -> L), or their combination (T plus L) in the adjuvant treatment of HER2-positive early breast cancer (EBC). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Inst Jules Bordet, Breast Int Grp, B-1000 Brussels, Belgium. Frontier Sci Scotland Ltd, Kincraig, England. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Libre Bruxelles, Inst Jules Bordet, Brussels, Belgium. Mayo Clin, Scottsdale, AZ USA. European Inst Oncol, Div Pathol, Milan, Italy. NCI, Bethesda, MD 20892 USA. European Inst Oncol, Div Med Oncol, Milan, Italy. GlaxoSmithKline, Malvern, PA USA. Sunnybrook Odette Canc Ctr, Toronto, ON, Canada. Univ Toronto, Toronto, ON, Canada. Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. Sana Kliniken Offenbach, Offenbach, Germany. Orszagos Onkol Int, Budapest, Hungary. Helios Klinikum Berlin Buch, Berlin, Germany. Royal Marsden NHS Fdn Trust, London, England. Univ Sydney, Patricia Ritchie Ctr Canc Care & Res, Mater Hosp, Sydney, NSW 2006, Australia. Chinese Acad Med Sci, Canc Hosp, Beijing 100730, Peoples R China. Inst Natl Enfermedades Neoplas, Lima, Peru. Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. Mayo Clin, Jacksonville, FL 32224 USA. NR 0 TC 4 Z9 4 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2014 VL 32 IS 18 SU S MA LBA4 PG 1 WC Oncology SC Oncology GA CN2IS UT WOS:000358244900005 ER PT J AU Ballard, ED Ionescu, DF Vande Voort, JL Slonena, EE Franco-Chaves, JA Zarate, CA Grillon, C AF Ballard, Elizabeth D. Ionescu, Dawn F. Vande Voort, Jennifer L. Slonena, Elizabeth E. Franco-Chaves, Jose A. Zarate, Carlos A., Jr. Grillon, Christian TI Increased fear-potentiated startle in major depressive disorder patients with lifetime history of suicide attempt SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Suicide; Major depressive disorder; Fear-potentiated startle ID ANXIETY; EVENTS; CAPABILITY; EXPRESSION; TOLERANCE; IDEATION; RECEPTOR; AMYGDALA; VICTIMS; HUMANS AB Background: Suicide is a common reason for psychiatric emergency and morbidity, with few effective treatments. Anxiety symptoms have emerged as potential modifiable risk factors in the time before a suicide attempt, but few studies have been conducted using laboratory measures of fear and anxiety. We operationally defined fear and anxiety as increased startle reactivity during anticipation of predictable (fear-potentiated startle) and unpredictable (anxiety-potentiated startle) shock. We hypothesized that a lifetime history of suicide attempt (as compared to history of no suicide attempt) would be associated with increased fear-potentiated startle. Methods: A post-hoc analysis of fear- and anxiety-potentiated startle was conducted in 28 medication-free patients with Major Depressive Disorder (MDD) divided according to suicide attempt history. Results: The magnitude of fear-potentiated startle was increased in depressed patients with lifetime suicide attempts compared to those without a lifetime history of suicide attempt (F(1,26)=5.629, p=.025). There was no difference in anxiety-potentiated startle by suicide attempt history. Limitations: This is a post-hoc analysis of previously analyzed patient data from a study of depressed inpatients. Further replication of the finding with a larger patient sample is indicated. Conclusions: Increased fear-potentiated startle in suicide attempters suggests the role of amygdala in depressed patients with a suicide attempt history. Findings highlight the importance of anxiety symptoms in the treatment of patients at increased suicide risk, Published by Elsevier B.V. C1 [Ballard, Elizabeth D.; Ionescu, Dawn F.; Vande Voort, Jennifer L.; Slonena, Elizabeth E.; Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Grillon, Christian] NIMH, Sect Neurobiol Fear & Anxiety, NIH, Bethesda, MD 20892 USA. [Franco-Chaves, Jose A.] Vet Hlth Adm, Dept Psychiat, VA Caribbean Hlth Network, San Juan, PR USA. RP Ballard, ED (reprint author), NIMH, NIH, Bldg 10-CRC,7-5541, Bethesda, MD 20892 USA. EM Elizabeth.Ballard@nih.gov RI Ionescu, Dawn/K-5675-2015 FU Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH); NARSAD Independent Investigator Award; 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), by a NARSAD Independent Investigator Award to CAZ, and by the Brain & Behavior Mood Disorders Research Award to CAZ. NR 30 TC 6 Z9 6 U1 1 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 EI 1573-2517 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD JUN 20 PY 2014 VL 162 BP 34 EP 38 DI 10.1016/j.jad.2014.03.027 PG 5 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AG4JO UT WOS:000335386000007 PM 24767002 ER PT J AU Ellis, JS Zarate, CA Luckenbaugh, DA Furey, ML AF Ellis, Jessica S. Zarate, Carlos A., Jr. Luckenbaugh, David A. Furey, Maura L. TI Antidepressant treatment history as a predictor of response to scopolamine: clinical implications SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Treatment history; Treatment resistant; Scopolamine; Depression; Antidepressant ID ASTERISK-D REPORT; TREATMENT-RESISTANT DEPRESSION; TRIALS AB Background: The intravenous administration of scopolamine produces rapid antidepressant effects. Generally, tailing multiple previous antidepressant trials is associated with a poor prognosis for response to future medications. This study evaluated whether treatment history predicts antidepressant response to scopolamine. Methods: Treatment resistant patients (2 failed medication trials) (n=31) and treatment naive patients (no exposure to psychotropic medication) (n=31) with recurrent major depressive or bipolar disorder participated in a double-blind, placebo-controlled, crossover clinical trial. Following a placebo lead-in, participants randomly received P/S or S/P (P=3 placebo; S=3 scopolamine (4 ug/kg) sessions 3 to 5 clays apart). The Montgomery-Asberg Depression Rating Scale (MADRS) was the primary outcome measure. A linear mixed model was used to examine the interaction between clinical response and treatment history, adjusting for baseline MADRS. Results: Treatment resistant and treatment naive subjects combined responded significantly to scopolamine compared to placebo (F=15.06, p < 0.001). Reduction in depressive symptoms was significant by the first post-scopolamine session (F=42.75, p < 0.001). A treatment history by scopolamine session interaction (F=3.37, p=0.04) indicated treatment naive subjects had lower MADRS scores than treatment resistant patients; this was significant after the second scopolamine infusion (t=2.15, p=0.03). Limitations: Post-hoc analysis: Also, we used a single regimen to administer scopolamine, and smokers were excluded from the sample, limiting generalizability. Conclusions: Treatment naive and treatment resistant patients showed improved clinical symptoms following scopolamine, while those who were treatment naive showed greater improvement. Scopolamine rapidly reduces symptoms in both treatment history groups, and demonstrates sustained improvement even in treatment resistant patients. Published by Elsevier B.V. C1 [Ellis, Jessica S.; Zarate, Carlos A., Jr.; Luckenbaugh, David A.; Furey, Maura L.] NIMH, NIH, Expt Therapeut & Pathophysiol Branch, Bethesda, MD 20814 USA. RP Ellis, JS (reprint author), NIMH, NIH, Expt Therapeut & Pathophysiol Branch, 10 Ctr Dr,Bldg 10-CRC,Room 7-5561, Bethesda, MD 20814 USA. EM brockmeyerjs@mail.nih.gov FU Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH); NARSAD Independent Investigator Award; 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), by a NARSAD Independent Investigator Award to CAZ, and by the Brain & Behavior Mood Disorders Research Award to CAZ. NR 15 TC 5 Z9 6 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 EI 1573-2517 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD JUN 20 PY 2014 VL 162 BP 39 EP 42 DI 10.1016/j.jad.2014.03.010 PG 4 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AG4JO UT WOS:000335386000008 PM 24767003 ER PT J AU Escobar, TM Kanellopoulou, C Kugler, DG Kilaru, G Nguyen, CK Nagarajan, V Bhairavabhotla, RK Northrup, D Zahr, R Burr, P Liu, XH Zhao, KJ Sher, A Jankovic, D Zhu, JF Muljo, SA AF Escobar, Thelma M. Kanellopoulou, Chrysi Kugler, David G. Kilaru, Gokhul Nguyen, Cuong K. Nagarajan, Vijayaraj Bhairavabhotla, Ravikiran K. Northrup, Daniel Zahr, Rami Burr, Patrick Liu, Xiuhuai Zhao, Keji Sher, Alan Jankovic, Dragana Zhu, Jinfang Muljo, Stefan A. TI miR-155 Activates Cytokine Gene Expression in Th17 Cells by Regulating the DNA-Binding Protein Jarid2 to Relieve Polycomb-Mediated Repression SO IMMUNITY LA English DT Article ID T-CELLS; T(H)17 CELLS; STEM-CELLS; TGF-BETA; DIFFERENTIATION; TARGET; MICRORNA-155; PRC2; MICE; INFLAMMATION AB Specification of the T helper 17 (Th17) cell lineage requires a well-defined set of transcription factors, but how these integrate with posttranscriptional and epigenetic programs to regulate gene expression is poorly understood. Here we found defective Th17 cell cytokine expression in miR-155-deficient CD4(+) T cells in vitro and in vivo. Mir155 was bound by Th17 cell transcription factors and was highly expressed during Th17 cell differentiation. miR-155-deficient Th17 and T regulatory (Treg) cells expressed increased amounts of Jarid2, a DNA-binding protein that recruits the Polycomb Repressive Complex 2 (PRC2) to chromatin. PRC2 binding to chromatin and H3K27 histone methylation was increased in miR-155-deficient cells, coinciding with failure to express Il22, Il10, Il9, and Atf3. Defects in Th17 cell cytokine expression and Treg cell homeostasis in the absence of Mir155 could be partially suppressed by Jarid2 deletion. Thus, miR-155 contributes to Th17 cell function by suppressing the inhibitory effects of Jarid2. C1 [Escobar, Thelma M.; Kanellopoulou, Chrysi; Kilaru, Gokhul; Nguyen, Cuong K.; Bhairavabhotla, Ravikiran K.; Zahr, Rami; Burr, Patrick; Liu, Xiuhuai; Zhu, Jinfang; Muljo, Stefan A.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Kugler, David G.; Sher, Alan; Jankovic, Dragana] NIAID, Lab Parasit Dis, NIH, Bethesda, MD 20892 USA. [Nagarajan, Vijayaraj] NIAID, Bioinformat & Computat Biosci Branch, NIH, Bethesda, MD 20892 USA. [Northrup, Daniel; Zhao, Keji] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. RP Muljo, SA (reprint author), NIAID, Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM stefan.muljo@nih.gov RI Muljo, Stefan/F-5671-2015; Nguyen, Cuong/D-7567-2013; Zhu, Jinfang/B-7574-2012 OI Muljo, Stefan/0000-0003-1013-446X; Nguyen, Cuong/0000-0002-1741-669X; FU Intramural Research Program of the NIAID, NIH FX We thank W.E. Paul for his generou support and advice throughout; Y.S. Chang and T. Hai (Ohio State University) for providing Atf3-deficient mice; B.J. Abraham for help with ChIP-seq analyses; E. Shevach for facilitating human T cell studies; B. Kelsall for BM chimera protocol; L. Barron, J. Hu-Li, and S. Sharma for technical advice and assistance; J. Edwards for cell sorting; the Biowulf Linux cluster (http://biowulf.nih.gov/) and NIAID Office of Cyber Infrastructure and Computational Biology for providing high performance computing; the NIH Tetramer Core Facility at Emory University for MHC tetramers; W. Ouyang (Genentech) for IL-22 antibody; and B. Brady, M. Crank, R. Germain, W. Leonard, A. Oler, J. O'Shea, and anonymous reviewers for constructive criticisms of the manuscript. T.M.E. was in the NIH-Johns Hopkins University Graduate Partnership Program and received valuable guidance from K. Beemon and S. Gottesman. This work was supported by the Intramural Research Program of the NIAID, NIH. NR 58 TC 41 Z9 46 U1 1 U2 16 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 JUN 19 PY 2014 VL 40 IS 6 BP 865 EP 879 DI 10.1016/j.immuni.2014.03.014 PG 15 WC Immunology SC Immunology GA AO6DT UT WOS:000341440200010 PM 24856900 ER PT J AU Hong, CW Luckey, MA Ligons, DL Waickman, AT Park, JY Kim, GY Keller, HR Etzensperger, R Tai, XG Lazarevic, V Feigenbaum, L Catalfamo, M Walsh, STR Park, JH AF Hong, Changwan Luckey, Megan A. Ligons, Davinna L. Waickman, Adam T. Park, Joo-Young Kim, Grace Y. Keller, Hilary R. Etzensperger, Ruth Tai, Xuguang Lazarevic, Vanja Feigenbaum, Lionel Catalfamo, Marta Walsh, Scott T. R. Park, Jung-Hyun TI Activated T Cells Secrete an Alternatively Spliced Form of Common gamma-Chain that Inhibits Cytokine Signaling and Exacerbates Inflammation SO IMMUNITY LA English DT Article ID IN-VIVO; INTERLEUKIN-7 RECEPTOR; SOLUBLE FORM; DEFICIENT MICE; IL-7; LINEAGE; GENERATION; MECHANISM; DISTINCT; DIFFERENTIATION AB The common gamma-chain (gamma c) plays a central role in signaling by IL-2 and other gamma c-dependent cytokines. Here we report that activated T cells produce an alternatively spliced form of gc mRNA that results in protein expression and secretion of the gamma c extracellular domain. The soluble form of gamma c (s gamma c) is present in serum and directly binds to IL-2R beta and IL-7R alpha proteins on T cells to inhibit cytokine signaling and promote inflammation. s gamma c suppressed IL-7 signaling to impair naive T cell survival during homeostasis and exacerbated Th17-cell-mediated inflammation by inhibiting IL-2 signaling upon T cell activation. Reciprocally, the severity of Th17-cell-mediated inflammatory diseases was markedly diminished in mice lacking s gamma c. Thus, s gamma c expression is a naturally occurring immunomodulator that regulates gamma c cytokine signaling and controls T cell activation and differentiation. C1 [Hong, Changwan; Luckey, Megan A.; Ligons, Davinna L.; Waickman, Adam T.; Park, Joo-Young; Kim, Grace Y.; Keller, Hilary R.; Etzensperger, Ruth; Tai, Xuguang; Lazarevic, Vanja; Park, Jung-Hyun] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Feigenbaum, Lionel] Leidos Biomedical Res Inc, Frederick Natl Lab Canc Res, Ft Detrick, MD 21702 USA. [Catalfamo, Marta] NIAID, Clin & Mol Retrovirol Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Walsh, Scott T. R.] Univ Maryland, WM Keck Lab Struct Biol, Inst Biosci & Biotechnol Res, Dept Cell Biol & Mol Genet, Rockville, MD 20850 USA. RP Park, JH (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM parkhy@mail.nih.gov RI Park, Jung Hyun /B-5712-2015; Davis, Megan/F-5339-2015 OI Park, Jung Hyun /0000-0002-9547-9055; FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; NIH [AI072142] FX We thank A. Singer, C. Mackall, and M. Kimura for critical review of this manuscript. This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; and the NIH (AI072142 to S.T.R.W.). NR 43 TC 14 Z9 14 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD JUN 19 PY 2014 VL 40 IS 6 BP 910 EP 923 DI 10.1016/j.immuni.2014.04.020 PG 14 WC Immunology SC Immunology GA AO6DT UT WOS:000341440200013 PM 24909888 ER PT J AU Tejeda, HA Bonci, A AF Tejeda, Hugo A. Bonci, Antonello TI Shedding "UV" Light on Endogenous Opioid Dependence SO CELL LA English DT Editorial Material ID SYSTEM; DRUGS AB Excessive sun tanning can result in addictive behavior. In this issue of Cell, Fell et al. utilize a combination of behavioral pharmacology and transgenic mice to demonstrate that chronic UV light exposure recruits p53 signaling in keratinocytes, subsequently increasing beta-endorphin signaling at opioid receptors, and produces an endogenous opioid-dependent state. C1 [Tejeda, Hugo A.; Bonci, Antonello] Natl Inst Drug Abuse, Cellular Neurobiol Res Branch, Synapt Plast Sect, Baltimore, MD 21224 USA. RP Bonci, A (reprint author), Natl Inst Drug Abuse, Cellular Neurobiol Res Branch, Synapt Plast Sect, Baltimore, MD 21224 USA. EM antonello.bonci@nih.gov NR 8 TC 1 Z9 1 U1 3 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 JUN 19 PY 2014 VL 157 IS 7 BP 1500 EP 1501 DI 10.1016/j.cell.2014.06.009 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN9QG UT WOS:000340941900003 PM 24949960 ER PT J AU de Cabo, R Carmona-Gutierrez, D Bernier, M Hall, MN Madeo, F AF de Cabo, Rafael Carmona-Gutierrez, Didac Bernier, Michel Hall, Michael N. Madeo, Frank TI The Search for Antiaging Interventions: From Elixirs to Fasting Regimens SO CELL LA English DT Review ID EXTENDS LIFE-SPAN; ALL-CAUSE MORTALITY; CALORIC RESTRICTION; SACCHAROMYCES-CEREVISIAE; OXIDATIVE-STRESS; CAENORHABDITIS-ELEGANS; INSULIN-RESISTANCE; PHYSICAL-ACTIVITY; RHESUS-MONKEYS; C-ELEGANS AB The phenomenon of aging is an intrinsic feature of life. Accordingly, the possibility to manipulate it has fascinated humans likely since time immemorial. Recent evidence is shaping a picture where low caloric regimes and exercise may improve healthy senescence, and several pharmacological strategies have been suggested to counteract aging. Surprisingly, the most effective interventions proposed to date converge on only a few cellular processes, in particular nutrient signaling, mitochondrial efficiency, proteostasis, and autophagy. Here, we critically examine drugs and behaviors to which life- or healthspan-extending properties have been ascribed and discuss the underlying molecular mechanisms. C1 [de Cabo, Rafael; Bernier, Michel] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Hall, Michael N.] Univ Basel, CH-4056 Basel, Switzerland. [Carmona-Gutierrez, Didac; Madeo, Frank] Graz Univ, Inst Mol Biosci, A-8010 Graz, Austria. RP de Cabo, R (reprint author), NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. EM decabora@mail.nih.gov; frank.madeo@uni-graz.at RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; Bernier, Michel/0000-0002-5948-368X; , rafael/0000-0003-2830-5693 FU Austrian Science Fund FWF [SFB-LIPO-TOX F3007, F3012, P23490-B12, P24381-B20, W1226-B18]; European Commission for project APOSYS; Intramural Research Program of the National Institute on Aging; National Institutes of Health; Swiss National Science Foundation FX F.M. and D.C.-G. are grateful to the Austrian Science Fund FWF (SFB-LIPO-TOX F3007, F3012, P23490-B12, P24381-B20, W1226-B18) and the European Commission for project APOSYS. R.d.C. and M.B. were funded by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. M.N.H. acknowledges the Swiss National Science Foundation. We are thankful to Luigi Ferrucci, Donald K. Ingram, Mark Mattson, and Steven Sollott for their insightful comments and suggestions for this Review. We apologize to those authors whose work could not be included due to space limitations. NR 115 TC 62 Z9 62 U1 6 U2 48 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 JUN 19 PY 2014 VL 157 IS 7 BP 1515 EP 1526 DI 10.1016/j.cell.2014.05.031 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN9QG UT WOS:000340941900008 PM 24949965 ER PT J AU Wang, HL Li, YJ Truong, LN Shi, LDZ Hwang, PYH He, J Do, J Cho, MJ Li, HZ Negrete, A Shiloach, J Berns, MW Shen, BH Chen, LC Wu, XH AF Wang, Hailong Li, Yongjiang Truong, Lan N. Shi, Linda Z. Hwang, Patty Yi-Hwa He, Jing Do, Johnny Cho, Michael Jeffrey Li, Hongzhi Negrete, Alejandro Shiloach, Joseph Berns, Michael W. Shen, Binghui Chen, Longchuan Wu, Xiaohua TI CtIP Maintains Stability at Common Fragile Sites and Inverted Repeats by End Resection-Independent Endonuclease Activity SO MOLECULAR CELL LA English DT Article ID DOUBLE-STRAND BREAKS; CHROMOSOME REARRANGEMENTS; SACCHAROMYCES-CEREVISIAE; GENE AMPLIFICATION; SUPERCOILED DNA; MRE11 COMPLEX; CANCER-CELLS; REPAIR; REPLICATION; INSTABILITY AB Chromosomal rearrangements often occur at genomic loci with DNA secondary structures, such as common fragile sites (CFSs) and palindromic repeats. We developed assays in mammalian cells that revealed CFS-derived AT-rich sequences and inverted Alu repeats (Alu-IRs) are mitotic recombination hotspots, requiring the repair functions of carboxy-terminal binding protein (CtBP)-interacting protein (CtIP) and the Mre11/Rad50/Nbs1 complex (MRN). We also identified an endonuclease activity of CtIP that is dispensable for end resection and homologous recombination (HR) at I-SceI-generated "clean'' double-strand breaks (DSBs) but is required for repair of DSBs occurring at CFS-derived AT-rich sequences. In addition, CtIP nuclease-defective mutants are impaired in Alu-IRs-induced mitotic recombination. These studies suggest that an end resection-independent CtIP function is important for processing DSB ends with secondary structures to promote HR. Furthermore, our studies uncover an important role of MRN, CtIP, and their associated nuclease activities in protecting CFSs in mammalian cells. C1 [Wang, Hailong; Li, Yongjiang; Truong, Lan N.; Hwang, Patty Yi-Hwa; He, Jing; Do, Johnny; Cho, Michael Jeffrey; Wu, Xiaohua] Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA. [Shi, Linda Z.; Berns, Michael W.] Univ Calif San Diego, Inst Engn Med, La Jolla, CA 92093 USA. [Berns, Michael W.] Univ Calif Irvine, Beckman Laser Inst, Dept Biomed Engn, Irvine, CA 92612 USA. [Li, Hongzhi] City Hope Natl Med Ctr, Beckman Res Inst, Dept Mol Med, Duarte, CA 91010 USA. [Negrete, Alejandro; Shiloach, Joseph] Natl Inst Diabet & Digest & Kidney Dis NIDDK, Biotechnol Core Lab, NIH, Bethesda, MD 20892 USA. [Shen, Binghui] City Hope Natl Med Ctr, Beckman Res Inst, Dept Radiat Biol, Duarte, CA 91010 USA. [Chen, Longchuan] Vet Affairs Med Ctr, Dept Pathol, Long Beach, CA 90822 USA. RP Wu, XH (reprint author), Scripps Res Inst, Dept Mol & Expt Med, 10666 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM xiaohwu@scripps.edu OI Cho, Michael Jeffrey/0000-0002-4628-303X FU NIH [CA102361, GM080677, CA140972, CA102361-07S1, CA140972-03S1, R01CA073764]; Beckman Laser Institute Foundation FX We thank Drs. Catherine Freudenreich (Tufts University), Kirill Lobachev (Georgia Tech), Sang Eun Lee (University of Texas Health Science Center at San Antonio), Tanya Paull (University of Texas at Austin), Andras Nagy (University of Toronto), Michele Calos (Stanford University School of Medicine), Thomas W. Glover (University of Michigan Medical School), Bing Xia (Rutgers University), and Eros Lazzerini Denchi (The Scripps Research Institute) for kindly providing valuable reagents. This work was supported by NIH grants CA102361, GM080677, CA140972, CA102361-07S1, and CA140972-03S1 to X. W.; NIH grant R01CA073764 to B. S.; and the Beckman Laser Institute Foundation to M. W. B. The authors declare no conflicts of interest. NR 43 TC 35 Z9 36 U1 0 U2 6 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 JUN 19 PY 2014 VL 54 IS 6 BP 1012 EP 1021 DI 10.1016/j.molcel.2014.04.012 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN5JY UT WOS:000340628000011 PM 24837675 ER PT J AU Law, SHW Sargent, TD AF Law, Sheran H. W. Sargent, Thomas D. TI The Serine-Threonine Protein Kinase PAK4 Is Dispensable in Zebrafish: Identification of a Morpholino-Generated Pseudophenotype SO PLOS ONE LA English DT Article ID ENDODERM FORMATION; RECEPTOR; ACTIVATION; PATHWAYS; SURVIVAL; CASANOVA; EMBRYOS; GENES; PLAYS; ALPHA AB TALEN-based inactivation of the zebrafish pak4 gene resulted in embryos and adult fish that appear normal and fertile. This is in contrast to our previously published studies which were based on the use of antisense morpholino oligonucleotides (MOs). We have excluded potential explanations such as gene duplication, alternate splicing, cryptic initiation of translation, and translation-independent RNA function. Our conclusion is that pak4 is dispensable in zebrafish, and that even when corroborated by robust controls, such as RNA rescue, MOs may elicit misleading pseudophenotypes that do not correspond to results obtained by genetic mutations, and should thus be used with caution. C1 [Law, Sheran H. W.; Sargent, Thomas D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Vertebrate Dev, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. RP Sargent, TD (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Vertebrate Dev, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. EM tsargent@nih.gov FU Intramural Research Program, National Institute of Child Health and Human Development FX Funding provided by Intramural Research Program, National Institute of Child Health and Human Development. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 16 Z9 16 U1 1 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 19 PY 2014 VL 9 IS 6 AR e100268 DI 10.1371/journal.pone.0100268 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN6QP UT WOS:000340721500055 PM 24945275 ER PT J AU May, SL Zhou, Q Lewellen, M Carter, CM Coffey, D Highfill, SL Bucher, CM Matise, I Morse, HC O'Sullivan, MG Schutten, M Johnson, C Bellgrau, D Blazar, BR Modiano, JF AF May, Sarah L. Zhou, Qing Lewellen, Mitzi Carter, Cristan M. Coffey, David Highfill, Steven L. Bucher, Christoph M. Matise, Ilze Morse, Herbert C., III O'Sullivan, M. Gerard Schutten, Melissa Johnson, Charles Bellgrau, Donald Blazar, Bruce R. Modiano, Jaime F. TI Nfatc2 and Tob1 Have Non-Overlapping Function in T Cell Negative Regulation and Tumorigenesis SO PLOS ONE LA English DT Article ID TRANSCRIPTION FACTOR; NUCLEAR FACTOR; CYCLOSPORINE-A; IN-VITRO; MICE; ACTIVATION; FOXP3; HOMEOSTASIS; EXPRESSION; TOLERANCE AB Nfatc2 and Tob1 are intrinsic negative regulators of T cell activation. Nfatc2-deficient and Tob1-deficient T cells show reduced thresholds of activation; however, whether these factors have independent or overlapping roles in negative regulation of T cell responses has not been previously examined. Here, we show that Nfatc2 knockout (KO) but not Tob1 KO mice have age-associated accumulation of persistently activated T cells in vivo and expansion of the CD44(+) memory cell compartment and age-associated lymphocytic infiltrates in visceral organs, without significant changes in numbers of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg). In vitro, CD4(+)CD25(-) "conventional'' T cells (Tconvs) from both KO strains showed greater proliferation than wild type (WT) Tconvs. However, while Tregs from Nfatc2 KO mice retained normal suppressive function, Tregs from Tob1 KOs had enhanced suppressive activity. Nfatc2 KO Tconvs expanded somewhat more rapidly than WT Tconvs under conditions of homeostatic proliferation, but their accelerated growth capacity was negated, at least acutely, in a lymphoreplete environment. Finally, Nfatc2 KO mice developed a previously uncharacterized increase in B-cell malignancies, which was not accelerated by the absence of Tob1. The data thus support the prevailing hypothesis that Nfatc2 and Tob1 are non-redundant regulators of lymphocyte homeostasis. C1 [May, Sarah L.; Zhou, Qing; Lewellen, Mitzi; Highfill, Steven L.; Bucher, Christoph M.; Matise, Ilze; O'Sullivan, M. Gerard; Schutten, Melissa; Johnson, Charles; Blazar, Bruce R.; Modiano, Jaime F.] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55455 USA. [May, Sarah L.; Lewellen, Mitzi; Modiano, Jaime F.] Univ Minnesota, Coll Vet Med, Dept Vet Clin Sci, St Paul, MN 55108 USA. [Zhou, Qing; Highfill, Steven L.; Bucher, Christoph M.; Blazar, Bruce R.] Univ Minnesota, Sch Med, Dept Pediat, Minneapolis, MN 55455 USA. [Carter, Cristan M.; Coffey, David; Bellgrau, Donald; Modiano, Jaime F.] Univ Colorado, Sch Med, Integrated Dept Immunol, Denver, CO USA. [Carter, Cristan M.; Coffey, David; Bellgrau, Donald; Modiano, Jaime F.] Univ Colorado, Ctr Canc, Aurora, CO USA. [Matise, Ilze; O'Sullivan, M. Gerard; Schutten, Melissa; Johnson, Charles] Univ Minnesota, Coll Vet Med, Dept Vet Populat Med, St Paul, MN 55108 USA. [Morse, Herbert C., III] NIAID, NIH, Rockville, MD USA. RP Modiano, JF (reprint author), Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55455 USA. EM modiano@umn.edu RI bucher, christoph/A-2520-2008; OI Morse, Herbert/0000-0002-9331-3705; Modiano, Jaime/0000-0001-6398-7648 FU National Institute of Diabetes and Digestive and Kidney Diseases [R21DK63410]; National Institutes of Health National Heart Lung and Blood Institute [R01HL56067]; National Institutes of Health National Cancer Institute [R01CA72669, P01CA065493, P30CA077598]; National Institutes of Health National Institute of Allergy and Infectious Diseases [R01AI081918]; National Institutes of Health (Cancer Center Support Grant, Masonic Cancer Center, University of Minnesota, Douglas Yee) Intramural Research Program of the National Institutes of Health; National Institute of Allergy and Infectious Diseases University of Minnesota Animal Cancer Care and Research Program Alvin S. and June Perlman Chair in Animal Oncology at the University of Minnesota FX R21DK63410 National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (JFM DB) R01HL56067 National Heart Lung and Blood Institute, National Institutes of Health (BRB) R01CA72669 National Cancer Institute, National Institutes of Health (BRB) R01AI081918 National Institute of Allergy and Infectious Diseases, National Institutes of Health (BRB) P01CA065493 National Cancer Institute, National Institutes of Health (BRB) P30CA077598 National Cancer Institute, National Institutes of Health (Cancer Center Support Grant, Masonic Cancer Center, University of Minnesota, Douglas Yee) Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases (HRM) University of Minnesota Animal Cancer Care and Research Program (JFM) Alvin S. and June Perlman Chair in Animal Oncology at the University of Minnesota (JFM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 2 Z9 2 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 19 PY 2014 VL 9 IS 6 AR e100629 DI 10.1371/journal.pone.0100629 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN6QP UT WOS:000340721500099 PM 24945807 ER PT J AU Wong, MM Byun, JS Sacta, M Jin, QH Baek, S Gardner, K AF Wong, Madeline M. Byun, Jung S. Sacta, Maria Jin, Qihuang Baek, SongJoon Gardner, Kevin TI Promoter-Bound p300 Complexes Facilitate Post-Mitotic Transmission of Transcriptional Memory SO PLOS ONE LA English DT Article ID RNA-POLYMERASE-II; BROMODOMAIN PROTEIN BRD4; LONG-TERM-MEMORY; MITOTIC BOOKMARKING; GENE-EXPRESSION; HISTONE ACETYLTRANSFERASES; DEPENDENT TRANSCRIPTION; EPIGENETIC CONTROL; COACTIVATOR P300; BINDING PROTEIN AB A central hallmark of epigenetic inheritance is the parental transmission of changes in patterns of gene expression to progeny without modification of DNA sequence. Although, the trans-generational conveyance of this molecular memory has been traditionally linked to covalent modification of histone and/or DNA, recent studies suggest a role for proteins that persist or remain bound within chromatin to "bookmark" specific loci for enhanced or potentiated responses in daughter cells immediately following cell division. In this report we describe a role for p300 in enabling gene bookmarking by pre-initiation complexes (PICs) containing RNA polymerase II (pol II), Mediator and TBP. Once formed these complexes require p300 to facilitate reacquisition of protein complex assemblies, chromatin modifications and long range chromatin interactions that enable post-mitotic transmission of transcriptional memory of prior environmental stimuli. C1 [Wong, Madeline M.; Byun, Jung S.; Sacta, Maria; Gardner, Kevin] NCI, Genet Branch, Bethesda, MD 20892 USA. [Jin, Qihuang] Natl Inst Diabet & Digest & Kidney Dis, Lab Endocrinol & Receptor Biol, Bethesda, MD USA. [Baek, SongJoon] NCI, Lab Receptor Biol & Gene Express, Bethesda, MD 20892 USA. RP Gardner, K (reprint author), NCI, Genet Branch, Bethesda, MD 20892 USA. EM gardnerk@mail.nih.gov FU Intramural Research Program of the US National Institutes of Health; US National Cancer Institute; US National Institute on Minority Health and Health Disparities FX This research was supported by the Intramural Research Program of the US National Institutes of Health, the US National Cancer Institute, and the US National Institute on Minority Health and Health Disparities. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 83 TC 6 Z9 6 U1 2 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 19 PY 2014 VL 9 IS 6 AR e99989 DI 10.1371/journal.pone.0099989 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN6QP UT WOS:000340721500038 PM 24945803 ER PT J AU Kasar, S Underbayev, C Yuan, Y Hanlon, M Aly, S Khan, H Chang, V Batish, M Gavrilova, T Badiane, F Degheidy, H Marti, G Raveche, E AF Kasar, S. Underbayev, C. Yuan, Y. Hanlon, M. Aly, S. Khan, H. Chang, V. Batish, M. Gavrilova, T. Badiane, F. Degheidy, H. Marti, G. Raveche, E. TI Therapeutic implications of activation of the host gene (Dleu2) promoter for miR-15a/16-1 in chronic lymphocytic leukemia SO ONCOGENE LA English DT Article DE miR-15a/16-1; BSAP; HDAC inhibitor; CLL; NZB ID MALIGNANT B-1 CELLS; HISTONE DEACETYLASE INHIBITOR; ZEALAND BLACK MOUSE; B-CELLS; TRANSCRIPTION FACTOR; MULTIPLE-MYELOMA; MANTLE CELL; IN-SITU; CANCER; PAX5 AB Genetic lesions and other regulatory events lead to silencing of the 13q14 locus in a majority of chronic lymphocytic leukemia (CLL) patients. This locus encodes a pair of critical proapoptotic microRNAs, miR-15a/16-1. Decreased levels of miR-15a/16-1 are critical for the increased survival exhibited by CLL cells. Similarly, in a de novo murine model of CLL, the NZB strain, germline-encoded regulation of the syntenic region resulted in decreased miR-15a/16-1. In this paper, we have identified additional molecular mechanisms regulating miR-15a/16-1 levels and have shown that the transcription factor BSAP (B-cell-specific activator protein) directly interacts with Dleu2, the host gene containing the miR-15a/16-1 loci, and by negative regulation of the Dleu2 promoter, results in repression of miR-15a/16-1 expression. CLL patient B-cell expression levels of BSAP were increased compared with control sources of B cells. With the use of small interfering RNA-mediated repression, the levels of BSAP were decreased in vitro in the NZB-derived malignant B-1 cell line, LNC, and in ex vivo CLL patient peripheral blood mononuclear cells (PBMCs). BSAP knockdown led to an increase in the expression of miR-15a/16-1 and an increase in apoptosis, and a cell cycle arrest in both the cell line and patient PBMCs. Moreover, using Dleu2 promoter analysis by chromatin immunoprecipitation assay, we have shown that BSAP directly interacts with the Dleu2 promoter. Derepression of the Dleu2 promoter via inhibition of histone deacetylation combined with BSAP knockdown increased miR-15a/16-1 expression, and also increased malignant B-cell death. In summary, therapy targeting enhanced host gene Dleu2 transcription may augment CLL therapy. C1 [Kasar, S.; Underbayev, C.; Hanlon, M.; Aly, S.; Khan, H.; Chang, V.; Batish, M.; Gavrilova, T.; Badiane, F.; Raveche, E.] Univ Med & Dent New Jersey, New Jersey Med Sch, Newark, NJ 07103 USA. [Yuan, Y.] NIH, Bethesda, MD 20892 USA. [Chang, V.] Vet Affairs New Jersey Hlth Care Syst, E Orange, NJ USA. [Degheidy, H.; Marti, G.] OSEL CDRH FDA, White Oak, MD USA. RP Raveche, E (reprint author), Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Pathol, 185S Orange Ave,MSB C-512, Newark, NJ 07103 USA. EM batishmo@njms.rutgers.edu; raveches@njms.rutgers.edu FU NSF/FDA/SIR [1238375]; NIH [R01CA12926]; Early Independence Award [1DP5OD012160-01]; UMDNJ-NJMS Flow Cytometry Core FX This work was supported by NSF/FDA/SIR No. 1238375 and NIH R01CA12926 (ESR). Early Independence Award # 1DP5OD012160-01 (MB). We thank the UMDNJ-NJMS Flow Cytometry Core for their support. NR 66 TC 5 Z9 6 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD JUN 19 PY 2014 VL 33 IS 25 BP 3307 EP 3315 DI 10.1038/onc.2013.291 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA AK5DA UT WOS:000338443400010 PM 23995789 ER PT J AU Guerra, CA Reiner, RC Perkins, TA Lindsay, SW Midega, JT Brady, OJ Barker, CM Reisen, WK Harrington, LC Takken, W Kitron, U Lloyd, AL Hay, SI Scott, TW Smith, DL AF Guerra, Carlos A. Reiner, Robert C., Jr. Perkins, T. Alex Lindsay, Steve W. Midega, Janet T. Brady, Oliver J. Barker, Christopher M. Reisen, William K. Harrington, Laura C. Takken, Willem Kitron, Uriel Lloyd, Alun L. Hay, Simon I. Scott, Thomas W. Smith, David L. TI A global assembly of adult female mosquito mark-release-recapture data to inform the control of mosquito-borne pathogens SO PARASITES & VECTORS LA English DT Article DE Mosquito; Vector; Mark-release-recapture; Database; Pathogen transmission models ID DOMINANT ANOPHELES VECTORS; PLASMODIUM-FALCIPARUM TRANSMISSION; DISTRIBUTION MAPS; BIONOMIC PRECIS; HUMAN MALARIA; SENSITIVITY-ANALYSIS; POPULATION-DYNAMICS; MATHEMATICAL-MODEL; AEDES-AEGYPTI; CULICIDAE AB Background: Pathogen transmission by mosquitos is known to be highly sensitive to mosquito bionomic parameters. Mosquito mark-release-recapture (MMRR) experiments are a standard method for estimating such parameters including dispersal, population size and density, survival, blood feeding frequency and blood meal host preferences. Methods: We assembled a comprehensive database describing adult female MMRR experiments. Bibliographic searches were used to build a digital library of MMRR studies and selected data describing the reported outcomes were extracted. Results: The resulting database contained 774 unique adult female MMRR experiments involving 58 vector mosquito species from the three main genera of importance to human health: Aedes, Anopheles and Culex. Crude examination of these data revealed patterns associated with geography as well as mosquito genus, consistent with bionomics varying by species-specific life history and ecological context. Recapture success varied considerably and was significantly different amongst genera, with 8, 4 and 1% of adult females recaptured for Aedes, Anopheles and Culex species, respectively. A large proportion of experiments (59%) investigated dispersal and survival and many allowed disaggregation of the release and recapture data. Geographic coverage was limited to just 143 localities around the world. Conclusions: This MMRR database is a substantial contribution to the compilation of global data that can be used to better inform basic research and public health interventions, to identify and fill knowledge gaps and to enrich theory and evidence-based ecological and epidemiological studies of mosquito vectors, pathogen transmission and disease prevention. The database revealed limited geographic coverage and a relative scarcity of information for vector species of substantial public health relevance. It represents, however, a wealth of entomological information not previously compiled and of particular interest for mosquito-borne pathogen transmission models. C1 [Guerra, Carlos A.; Reiner, Robert C., Jr.; Perkins, T. Alex; Lindsay, Steve W.; Barker, Christopher M.; Reisen, William K.; Kitron, Uriel; Lloyd, Alun L.; Hay, Simon I.; Scott, Thomas W.; Smith, David L.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Guerra, Carlos A.; Smith, David L.] Ctr Dis Dynam Econ & Policy, Washington, DC USA. [Reiner, Robert C., Jr.; Perkins, T. Alex; Scott, Thomas W.] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. [Lindsay, Steve W.] London Sch Hyg & Trop Med, Dept Dis Control, London WC1, England. [Lindsay, Steve W.] Univ Durham, Sch Biol & Biomed Sci, Durham, England. [Midega, Janet T.] KEMRI Univ Oxford Wellcome Trust Res Programme, Pathogen Vector & Human Biol Unit, Kilifi, Kenya. [Midega, Janet T.] Univ London Imperial Coll Sci Technol & Med, Dept Life Sci, London, England. [Brady, Oliver J.; Hay, Simon I.] Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Oxford OX1 3PS, England. [Barker, Christopher M.; Reisen, William K.] Univ Calif Davis, Sch Vet Med, Dept Pathol Microbiol & Immunol, Ctr Vectorborne Dis, Davis, CA 95616 USA. [Harrington, Laura C.] Cornell Univ, Dept Entomol, Ithaca, NY 14853 USA. [Takken, Willem] Wageningen Univ, Entomol Lab, NL-6700 AP Wageningen, Netherlands. [Kitron, Uriel] Emory Univ, Dept Environm Sci, Atlanta, GA 30322 USA. [Lloyd, Alun L.] N Carolina State Univ, Dept Math, Raleigh, NC 27695 USA. [Lloyd, Alun L.] N Carolina State Univ, Biomath Grad Program, Raleigh, NC 27695 USA. [Smith, David L.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. RP Guerra, CA (reprint author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM carlos.guerraloaiza@gmail.com RI Hay, Simon/F-8967-2015; Smith, David/L-8850-2013; OI Hay, Simon/0000-0002-0611-7272; Smith, David/0000-0003-4367-3849; Perkins, Alex/0000-0002-7518-4014; Brady, Oliver/0000-0002-3235-2129 FU Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directory, Department of Homeland Security; Fogarty International Center, National Institutes of Health (NIH); Wellcome Trust [095066]; [NIH R01AI091980]; [NSF DMS 1246991] FX This work was supported by the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directory, Department of Homeland Security and Fogarty International Center, National Institutes of Health (NIH), including funding for data assembly and workshops that led to the writing of this manuscript. ALL acknowledges support from the following grants: NIH R01AI091980 and NSF DMS 1246991. SIH is funded by a Senior Research Fellowship from the Wellcome Trust (#095066). NR 54 TC 14 Z9 14 U1 6 U2 46 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-3305 J9 PARASITE VECTOR JI Parasites Vectors PD JUN 19 PY 2014 VL 7 AR 276 DI 10.1186/1756-3305-7-276 PG 15 WC Parasitology SC Parasitology GA AK4BS UT WOS:000338369600001 PM 24946878 ER PT J AU Ueda, Y Calado, RT Norberg, A Kajigaya, S Roos, G Hellstrom-Lindberg, E Young, NS AF Ueda, Yasutaka Calado, Rodrigo T. Norberg, Anna Kajigaya, Sachiko Roos, Goran Hellstrom-Lindberg, Eva Young, Neal S. TI A mutation in the H/ACA box of telomerase RNA component gene (TERC) in a young patient with myelodysplastic syndrome SO BMC MEDICAL GENETICS LA English DT Article DE Myelodysplastic syndrome (MDS); Telomerase RNA component (TERC); H/ACA box; Southern blotting; Single Telomere Elongation Length Analysis (STELA); RNA fluorescence in situ hybridization (RNA FISH) ID IDIOPATHIC PULMONARY-FIBROSIS; DYSKERATOSIS-CONGENITA; APLASTIC-ANEMIA; HUMAN FIBROBLASTS; MALE GERMLINE; CAJAL BODIES; LENGTH; CELLS; DOMAIN; AGE AB Background: Telomeres are repeated sequences (the hexanucleotide TTAGGG in vertebrates) located at chromosome ends of eukaryotes, protecting DNA from end joining or degradation. Telomeres become shorter with each cell cycle, but telomerase, a ribonucleoprotein complex, alleviates this attrition. The telomerase RNA component (TERC) is an essential element of telomerase, serving as a template for telomere elongation. The H/ACA domain of TERC is indispensable for telomere biogenesis. Mutations in the telomerase components allow accelerated telomere loss, resulting in various disease manifestations, including bone marrow failure. To date, this is the first detailed report of an H-box mutation in TERC that is related to human disease. Case presentation: A 26-year-old man with myelodysplastic syndrome (MDS) had very short telomeres. Sequencing identified a single heterozygous mutation in the H box of the patient's TERC gene. The same mutation was also present in his father and his son, demonstrating that it was germline in origin. The telomere length in the father's blood was shorter compared to age-matched healthy controls, while it was normal in the son and also in the sperm cells of the patient. In vitro experiments suggested that the mutation was responsible for the telomere shortening in the patient's leukocytes and contributed to the pathogenesis of bone marrow failure in our patient. Conclusion: We analyzed a mutation (A377G) in the H box of TERC in a young MDS patient who had significantly short-for-age telomeres. As telomeres protect chromosomes from instability, it is highly plausible that this genetic lesion was responsible for the patient's hematological manifestations, including marrow failure and aneuploidy in the hematopoietic stem cell compartment. C1 [Ueda, Yasutaka; Kajigaya, Sachiko; Young, Neal S.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Calado, Rodrigo T.] Univ Sao Paulo, Sch Med, Dept Internal Med, BR-14049 Ribeirao Preto, SP, Brazil. [Norberg, Anna] Umea Univ, Dept Med Biosci Med & Clin Genet, Umea, Sweden. [Roos, Goran] Umea Univ, Dept Med Biosci, Umea, Sweden. [Hellstrom-Lindberg, Eva] Karolinska Univ Hosp, Stockholm, Sweden. [Hellstrom-Lindberg, Eva] Karolinska Inst, Stockholm, Sweden. RP Ueda, Y (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10-CRC,Rm 3E-5216,9000 Rockville Pike, Bethesda, MD 20892 USA. EM yueda.maro@gmail.com RI Calado, Rodrigo/G-2619-2011 FU Intramural Research Program of the NIH; NHLBI; Swedish Cancer Research Foundation FX We are grateful to the patient and his parents for their participation in this research. We also thank Dr. Daniela Malide at the Light Microscopy Core of NHLBI for technical help. This research was supported by the Intramural Research Program of the NIH, the NHLBI, and by the Swedish Cancer Research Foundation. NR 47 TC 4 Z9 4 U1 2 U2 16 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2350 J9 BMC MED GENET JI BMC Med. Genet. PD JUN 19 PY 2014 VL 15 AR 68 DI 10.1186/1471-2350-15-68 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA AK2QU UT WOS:000338265000001 PM 24948335 ER PT J AU Hoberman, A Greenfield, SP Mattoo, TK Keren, R Mathews, R Pohl, HG Kropp, BP Skoog, SJ Nelson, CP Moxey-Mims, M Chesney, RW Carpenter, MA AF Hoberman, Alejandro Greenfield, Saul P. Mattoo, Tej K. Keren, Ron Mathews, Ranjiv Pohl, Hans G. Kropp, Bradley P. Skoog, Steven J. Nelson, Caleb P. Moxey-Mims, Marva Chesney, Russell W. Carpenter, Myra A. CA RIVUR Trial Investigators TI Antimicrobial Prophylaxis for Children with Vesicoureteral Reflux SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID URINARY-TRACT-INFECTION; ANTIBIOTIC-PROPHYLAXIS; SURGICAL-TREATMENT; TRIAL; PYELONEPHRITIS; MULTICENTER; MANAGEMENT; INFANTS AB Background Children with febrile urinary tract infection commonly have vesicoureteral reflux. Because trial results have been limited and inconsistent, the use of antimicrobial prophylaxis to prevent recurrences in children with reflux remains controversial. Methods In this 2-year, multisite, randomized, placebo-controlled trial involving 607 children with vesicoureteral reflux that was diagnosed after a first or second febrile or symptomatic urinary tract infection, we evaluated the efficacy of trimethoprimsulfamethoxazole prophylaxis in preventing recurrences (primary outcome). Secondary outcomes were renal scarring, treatment failure (a composite of recurrences and scarring), and antimicrobial resistance. Results Recurrent urinary tract infection developed in 39 of 302 children who received prophylaxis as compared with 72 of 305 children who received placebo (relative risk, 0.55; 95% confidence interval [CI], 0.38 to 0.78). Prophylaxis reduced the risk of recurrences by 50% (hazard ratio, 0.50; 95% CI, 0.34 to 0.74) and was particularly effective in children whose index infection was febrile (hazard ratio, 0.41; 95% CI, 0.26 to 0.64) and in those with baseline bladder and bowel dysfunction (hazard ratio, 0.21; 95% CI, 0.08 to 0.58). The occurrence of renal scarring did not differ significantly between the prophylaxis and placebo groups (11.9% and 10.2%, respectively). Among 87 children with a first recurrence caused by Escherichia coli, the proportion of isolates that were resistant to trimethoprim-sulfamethoxazole was 63% in the prophylaxis group and 19% in the placebo group. Conclusions Among children with vesicoureteral reflux after urinary tract infection, antimicrobial prophylaxis was associated with a substantially reduced risk of recurrence but not of renal scarring. C1 [Hoberman, Alejandro] Univ Pittsburgh, Childrens Hosp Pittsburgh, Med Ctr, Pittsburgh, PA 15213 USA. [Greenfield, Saul P.] Women & Childrens Hosp Buffalo, Buffalo, NY USA. [Mattoo, Tej K.] Wayne State Univ, Sch Med, Detroit, MI USA. [Hoberman, Alejandro; Keren, Ron] Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA. [Mathews, Ranjiv] Johns Hopkins Sch Med, Baltimore, MD USA. [Pohl, Hans G.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Kropp, Bradley P.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Skoog, Steven J.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Nelson, Caleb P.] Boston Childrens Hosp, Boston, MA USA. [Moxey-Mims, Marva] NIDDK, Bethesda, MD 20892 USA. [Chesney, Russell W.] Le Bonheur Childrens Hosp, Memphis, TN USA. [Carpenter, Myra A.] Univ N Carolina, Chapel Hill, NC USA. RP Hoberman, A (reprint author), Childrens Hosp Pittsburgh, 3414 Fifth Ave,CHOB 3rd Fl,Rm 321, Pittsburgh, PA 15213 USA. EM hoberman@chp.edu FU National Institute of Diabetes and Digestive and Kidney Diseases FX Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; RIVUR ClinicalTrials.gov number, NCT00405704. NR 22 TC 81 Z9 86 U1 1 U2 6 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 JUN 19 PY 2014 VL 370 IS 25 BP 2367 EP 2376 DI 10.1056/NEJMoa1401811 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA AJ0OA UT WOS:000337353000005 ER PT J AU Wilson, MR Naccache, SN Samayoa, E Biagtan, M Bashir, H Yu, GX Salamat, SM Somasekar, S Federman, S Miller, S Sokolic, R Garabedian, E Candotti, F Buckley, RH Reed, KD Meyer, TL Seroogy, CM Galloway, R Henderson, SL Gern, JE DeRisi, JL Chiu, CY AF Wilson, Michael R. Naccache, Samia N. Samayoa, Erik Biagtan, Mark Bashir, Hiba Yu, Guixia Salamat, Shahriar M. Somasekar, Sneha Federman, Scot Miller, Steve Sokolic, Robert Garabedian, Elizabeth Candotti, Fabio Buckley, Rebecca H. Reed, Kurt D. Meyer, Teresa L. Seroogy, Christine M. Galloway, Renee Henderson, Sheryl L. Gern, James E. DeRisi, Joseph L. Chiu, Charles Y. TI Actionable Diagnosis of Neuroleptospirosis by Next-Generation Sequencing SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID TRIATHLON PARTICIPANTS; PATHOGEN DISCOVERY; LEPTOSPIROSIS; ENCEPHALITIS; OUTBREAK; GENOME; ETIOLOGIES; EXPERIENCE; CHALLENGE; PCR AB A 14-year-old boy with severe combined immunodeficiency presented three times to a medical facility over a period of 4 months with fever and headache that progressed to hydrocephalus and status epilepticus necessitating a medically induced coma. Diagnostic workup including brain biopsy was unrevealing. Unbiased next-generation sequencing of the cerebrospinal fluid identified 475 of 3,063,784 sequence reads (0.016%) corresponding to leptospira infection. Clinical assays for leptospirosis were negative. Targeted antimicrobial agents were administered, and the patient was discharged home 32 days later with a status close to his premorbid condition. Polymerase-chain-reaction (PCR) and serologic testing at the Centers for Disease Control and Prevention (CDC) subsequently confirmed evidence of Leptospira santarosai infection. C1 [Wilson, Michael R.; DeRisi, Joseph L.] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94107 USA. [Wilson, Michael R.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94107 USA. [Naccache, Samia N.; Samayoa, Erik; Yu, Guixia; Somasekar, Sneha; Federman, Scot; Miller, Steve; Chiu, Charles Y.] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94107 USA. [Chiu, Charles Y.] Univ Calif San Francisco, Dept Med, Div Infect Dis, San Francisco, CA 94107 USA. [Naccache, Samia N.; Samayoa, Erik; Yu, Guixia; Somasekar, Sneha; Federman, Scot; Miller, Steve; Chiu, Charles Y.] Univ Calif San Francisco, Abbott Viral Diagnost & Discovery Ctr, San Francisco, CA 94107 USA. [Biagtan, Mark; Bashir, Hiba; Gern, James E.] Univ Wisconsin, Dept Med, Div Allergy & Immunol, Madison, WI 53706 USA. [Salamat, Shahriar M.; Reed, Kurt D.] Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI 53706 USA. [Meyer, Teresa L.; Seroogy, Christine M.; Henderson, Sheryl L.; Gern, James E.] Univ Wisconsin, Dept Pediat, Madison, WI 53706 USA. [Sokolic, Robert; Garabedian, Elizabeth; Candotti, Fabio] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Buckley, Rebecca H.] Duke Univ, Dept Pediat, Div Allergy & Immunol, Durham, NC 27706 USA. [Buckley, Rebecca H.] Duke Univ, Dept Immunol, Div Allergy & Immunol, Durham, NC USA. [Galloway, Renee] Ctr Dis Control & Prevent, Atlanta, GA USA. RP Chiu, CY (reprint author), Univ Calif San Francisco, Dept Lab Med, 185 Berry St,Box 134, San Francisco, CA 94107 USA. EM charles.chiu@ucsf.edu OI Chiu, Charles/0000-0003-2915-2094 FU American Brain Foundation; National Human Genome Research Institute; Howard Hughes Medical Institute; National Institutes of Health [R01-HL105704]; University of California; Amazon Web Services in Education Research Grant; Abbott Viral Discovery Award FX Supported by the American Brain Foundation Clinical Research Training Fellowship (to Dr. Wilson), a National Human Genome Research Institute Intramural Research Program appointment (to Dr. Sokolic, Ms. Garabedian, and Dr. Candotti), a Howard Hughes Medical Institute appointment (to Dr. DeRisi), a grant from the National Institutes of Health (R01-HL105704, to Dr. Chiu), a University of California Discovery Grant (to Dr. Chiu), an Amazon Web Services in Education Research Grant (to Dr. Chiu), and an Abbott Viral Discovery Award (to Dr. Chiu). NR 38 TC 114 Z9 116 U1 6 U2 22 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 JUN 19 PY 2014 VL 370 IS 25 BP 2408 EP 2417 DI 10.1056/NEJMoa1401268 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA AJ0OA UT WOS:000337353000009 PM 24896819 ER PT J AU Biesecker, LG Green, RC AF Biesecker, Leslie G. Green, Robert C. TI Diagnostic Clinical Genome and Exome Sequencing SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID INCIDENTAL FINDINGS; VARIANTS; DISEASE; IMPACT C1 [Biesecker, Leslie G.] NHGRI, NIH, Bethesda, MD 20892 USA. [Green, Robert C.] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA. [Green, Robert C.] Harvard Univ, Sch Med, Boston, MA USA. [Green, Robert C.] Partners Healthcare Personalized Med, Boston, MA USA. RP Biesecker, LG (reprint author), 49 Convent Dr,Rm 4A56, Bethesda, MD 20892 USA. EM lesb@mail.nih.gov NR 23 TC 156 Z9 158 U1 5 U2 38 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 JUN 19 PY 2014 VL 370 IS 25 BP 2418 EP 2425 DI 10.1056/NEJMra1312543 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA AJ0OA UT WOS:000337353000010 PM 24941179 ER PT J AU Esmail, H Barry, CE Young, DB Wilkinson, RJ AF Esmail, H. Barry, C. E., III Young, D. B. Wilkinson, R. J. TI The ongoing challenge of latent tuberculosis SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Review DE latent tuberculosis; Mycobacterium tuberculosis; elimination; diagnosis; treatment; natural history ID HIV-INFECTED PATIENTS; VITAMIN-D DEFICIENCY; MYCOBACTERIUM-TUBERCULOSIS; PULMONARY TUBERCULOSIS; NATURAL-HISTORY; SUBCLINICAL TUBERCULOSIS; ACTIVE TUBERCULOSIS; APICAL LOCALIZATION; TUBERCLE-BACILLI; HIGH-PREVALENCE AB The global health community has set itself the task of eliminating tuberculosis (TB) as a public health problem by 2050. Although progress has been made in global TB control, the current decline in incidence of 2% yr(-1) is far from the rate needed to achieve this. If we are to succeed in this endeavour, new strategies to reduce the reservoir of latently infected persons (from which new cases arise) would be advantageous. However, ascertainment of the extent and risk posed by this group is poor. The current diagnostics tests (tuberculin skin test and interferon-gamma release assays) poorly predict who will develop active disease and the therapeutic options available are not optimal for the scale of the intervention that may be required. In this article, we outline a basis for our current understanding of latent TB and highlight areas where innovation leading to development of novel diagnostic tests, drug regimens and vaccines may assist progress. We argue that the pool of individuals at high risk of progression may be significantly smaller than the 2.33 billion thought to be immune sensitized by Mycobacterium tuberculosis and that identifying and targeting this group will be an important strategy in the road to elimination. C1 [Esmail, H.; Young, D. B.; Wilkinson, R. J.] Univ London Imperial Coll Sci Technol & Med, Dept Med, London W2 1PG, England. [Esmail, H.; Wilkinson, R. J.] Univ Cape Town, Inst Infect Dis & Mol Med, Clin Infect Dis Res Initiat, ZA-7925 Observatory, South Africa. [Barry, C. E., III] NIAID, TB Res Sect, NIH, Bethesda, MD 20892 USA. [Young, D. B.; Wilkinson, R. J.] MRC Natl Inst Med Res, London NW7 1AA, England. RP Esmail, H (reprint author), Univ London Imperial Coll Sci Technol & Med, Dept Med, London W2 1PG, England. EM h.esmail@imperial.ac.uk RI Barry, III, Clifton/H-3839-2012; OI Wilkinson, Robert/0000-0002-2753-1800; Esmail, Hanif/0000-0002-4278-9316 FU Medical Research Council [MC_U117581288, MC_U117588499]; Wellcome Trust [084323, 088316] NR 129 TC 36 Z9 36 U1 2 U2 30 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 JUN 19 PY 2014 VL 369 IS 1645 SI SI AR 20130437 DI 10.1098/rstb.2013.0437 PG 14 WC Biology SC Life Sciences & Biomedicine - Other Topics GA AH4KA UT WOS:000336094600011 PM 24821923 ER PT J AU Cheng, H Devadoss, SL Li, B Risteski, A AF Cheng, Howard Devadoss, Satyan L. Li, Brian Risteski, Andrej TI Skeletal configurations of ribbon trees SO DISCRETE APPLIED MATHEMATICS LA English DT Article DE Ribbon trees; Straight skeleton; Rigidity ID GEOMETRY; SPACE AB The straight skeleton construction creates a straight-line tree from a polygon. Motivated by moduli spaces from algebraic geometry, we consider the inverse problem of constructing a polygon whose straight skeleton is a given tree. We prove there exists only a finite set of planar embeddings of a tree appearing as straight skeletons of convex polygons. The heavy lifting of this result is performed by using an analogous version of Cauchy's arm lemma. Computational issues are also considered, uncovering ties to a much older angle bisector problem. (C) 2014 Elsevier B.V. All rights reserved. C1 [Cheng, Howard] NYU, Courant Inst Math Sci, New York, NY 10012 USA. [Devadoss, Satyan L.] Williams Coll, Dept Math & Stat, Williamstown, MA 01267 USA. [Li, Brian] NIH, Bethesda, MD 20892 USA. [Risteski, Andrej] Princeton Univ, Dept Comp Sci, Princeton, NJ 08544 USA. RP Devadoss, SL (reprint author), Williams Coll, 18 Hoxsey St, Williamstown, MA 01267 USA. EM howardc@cims.nyu.edu; satyan.devadoss@williams.edu; brian.li@nih.gov; risteski@princeton.edu OI /0000-0001-7321-776X FU Williams College; NSF [DMS-0850577] FX We thank Oswin Aichholzer, Erik Demaine, Thomas Hackl, Stefan Huber, Robert Lang, Stefan Langerman, and Joe O'Rourke for helpful conversations and clarifications, and especially Lior Pachter for motivating this question. The comments by the referees were exemplary, refining and tightening this paper. We are also grateful to Williams College and the NSF for partially supporting this work with grant DMS-0850577. NR 13 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-218X EI 1872-6771 J9 DISCRETE APPL MATH JI Discret Appl. Math. PD JUN 19 PY 2014 VL 170 BP 46 EP 54 DI 10.1016/j.dam.2014.01.013 PG 9 WC Mathematics, Applied SC Mathematics GA AE6GB UT WOS:000334087500005 ER PT J AU Casanova, R Saldana, S Chew, EY Danis, RP Greven, CM Ambrosius, WT AF Casanova, Ramon Saldana, Santiago Chew, Emily Y. Danis, Ronald P. Greven, Craig M. Ambrosius, Walter T. TI Application of Random Forests Methods to Diabetic Retinopathy Classification Analyses SO PLOS ONE LA English DT Article ID AUTOMATED DETECTION; FUNDUS PHOTOGRAPHS; RISK-FACTORS; FRAMEWORK; IMAGES; HEALTH; EYE AB Background: Diabetic retinopathy (DR) is one of the leading causes of blindness in the United States and world-wide. DR is a silent disease that may go unnoticed until it is too late for effective treatment. Therefore, early detection could improve the chances of therapeutic interventions that would alleviate its effects. Methodology: Graded fundus photography and systemic data from 3443 ACCORD-Eye Study participants were used to estimate Random Forest (RF) and logistic regression classifiers. We studied the impact of sample size on classifier performance and the possibility of using RF generated class conditional probabilities as metrics describing DR risk. RF measures of variable importance are used to detect factors that affect classification performance. Principal Findings: Both types of data were informative when discriminating participants with or without DR. RF based models produced much higher classification accuracy than those based on logistic regression. Combining both types of data did not increase accuracy but did increase statistical discrimination of healthy participants who subsequently did or did not have DR events during four years of follow-up. RF variable importance criteria revealed that microaneurysms counts in both eyes seemed to play the most important role in discrimination among the graded fundus variables, while the number of medicines and diabetes duration were the most relevant among the systemic variables. Conclusions and Significance: We have introduced RF methods to DR classification analyses based on fundus photography data. In addition, we propose an approach to DR risk assessment based on metrics derived from graded fundus photography and systemic data. Our results suggest that RF methods could be a valuable tool to diagnose DR diagnosis and evaluate its progression. C1 [Casanova, Ramon; Saldana, Santiago; Ambrosius, Walter T.] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC 27157 USA. [Chew, Emily Y.] NEI, NIH, Bethesda, MD 20892 USA. [Danis, Ronald P.] Univ Wisconsin, Fundus Photograph Reading Ctr, Madison, WI USA. [Greven, Craig M.] Wake Forest Sch Med, Winston Salem, NC USA. RP Casanova, R (reprint author), Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC 27157 USA. EM Casanova@wakehealth.edu FU National Heart, Lung, and Blood Institute [N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA-Y1-HC-9035, IAA-Y1-HC-1010] FX This study was supported by contracts (N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA-Y1-HC-9035, and IAA-Y1-HC-1010) from the National Heart, Lung, and Blood Institute; by other components of the National Institutes of Health, including the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Eye Institute; by the Centers for Disease Control and Prevention; and by General Clinical Research Centers. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 9 Z9 9 U1 1 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 18 PY 2014 VL 9 IS 6 AR e98587 DI 10.1371/journal.pone.0098587 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK6AC UT WOS:000338508200009 PM 24940623 ER PT J AU Kohn, KW Zeeberg, BM Reinhold, WC Pommier, Y AF Kohn, Kurt W. Zeeberg, Barry M. Reinhold, William C. Pommier, Yves TI Gene Expression Correlations in Human Cancer Cell Lines Define Molecular Interaction Networks for Epithelial Phenotype SO PLOS ONE LA English DT Article ID E3 UBIQUITIN LIGASE; TIGHT JUNCTION PROTEIN; COLORECTAL-CANCER; BREAST-CANCER; MESENCHYMAL TRANSITION; SODIUM-CHANNEL; INTERACTION MAPS; MATRIPTASE; GROWTH; DIFFERENTIATION AB Using gene expression data to enhance our knowledge of control networks relevant to cancer biology and therapy is a challenging but urgent task. Based on the premise that genes that are expressed together in a variety of cell types are likely to functions together, we derived mutually correlated genes that function together in various processes in epithelial-like tumor cells. Expression-correlated genes were derived from data for the NCI-60 human tumor cell lines, as well as data from the Broad Institute's CCLE cell lines. NCI-60 cell lines that selectively expressed a mutually correlated subset of tight junction genes served as a signature for epithelial-like cancer cells. Those signature cell lines served as a seed to derive other correlated genes, many of which had various other epithelial-related functions. Literature survey yielded molecular interaction and function information about those genes, from which molecular interaction maps were assembled. Many of the genes had epithelial functions unrelated to tight junctions, demonstrating that new function categories were elicited. The most highly correlated genes were implicated in the following epithelial functions: interactions at tight junctions (CLDN7, CLDN4, CLDN3, MARVELD3, MARVELD2, TJP3, CGN, CRB3, LLGL2, EPCAM, LNX1); interactions at adherens junctions (CDH1, ADAP1, CAMSAP3); interactions at desmosomes (PPL, PKP3, JUP); transcription regulation of cell-cell junction complexes (GRHL1 and 2); epithelial RNA splicing regulators (ESRP1 and 2); epithelial vesicle traffic (RAB25, EPN3, GRHL2, EHF, ADAP1, MYO5B); epithelial Ca(+2) signaling (ATP2C2, S100A14, BSPRY); terminal differentiation of epithelial cells (OVOL1 and 2, ST14, PRSS8, SPINT1 and 2); maintenance of apico-basal polarity (RAB25, LLGL2, EPN3). The findings provide a foundation for future studies to elucidate the functions of regulatory networks specific to epithelial-like cancer cells and to probe for anti-cancer drug targets. C1 [Kohn, Kurt W.; Zeeberg, Barry M.; Reinhold, William C.; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Kohn, KW (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. EM kohnk@dc37a.nci.nih.gov FU budget of the Laboratory of Molecular Pharmacology allocated from the National Cancer Institute FX Funded by the budget of the Laboratory of Molecular Pharmacology allocated from the National Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 117 TC 20 Z9 20 U1 1 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 18 PY 2014 VL 9 IS 6 AR e99269 DI 10.1371/journal.pone.0099269 PG 29 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK6AC UT WOS:000338508200017 PM 24940735 ER PT J AU Liang, Y Tang, WZ Huang, TQ Gao, Y Tan, AH Yang, XB Zhang, HY Hu, YL Qin, X Li, S Zhang, SJ Mo, LJ Liang, ZJ Shi, DY Huang, Z Guan, YY Zhou, JC Winkler, C O'Brien, SJ Xu, JF Mo, ZN Peng, T AF Liang, Yu Tang, Weizhong Huang, Tiqiang Gao, Yong Tan, Aihua Yang, Xiaobo Zhang, Haiying Hu, Yanling Qin, Xue Li, Shan Zhang, Shijun Mo, Linjian Liang, Zhenjia Shi, Deyi Huang, Zhang Guan, Yingyong Zhou, Jicheng Winkler, Cheryl O'Brien, Stephen J. Xu, Jianfeng Mo, Zengnan Peng, Tao TI Genetic Variations Affecting Serum Carcinoembryonic Antigen Levels and Status of Regional Lymph Nodes in Patients with Sporadic Colorectal Cancer from Southern China SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; III COLON-CANCER; BODY-MASS INDEX; BLOOD-GROUP; ADJUVANT CHEMOTHERAPY; PANCREATIC-CANCER; TUMOR-MARKERS; CEA LEVELS; CIGARETTE-SMOKING; FREE SURVIVAL AB Background: Serum carcinoembryonic antigen (sCEA) level might be an indicator of disease. Indeed, an elevated sCEA level is a prognostic factor in colorectal cancer (CRC) patients. However, the genetic determinants of sCEA level in healthy and CRC population remains unclear. Thus we investigated the genetic markers associated with elevated serum sCEA level in these two populations and its clinical implications. Methods and Findings: Genome-wide association study (GWAS) was conducted in a cohort study with 4,346 healthy male adults using the Illumina Omni 1 M chip. Candidate SNPs associated with elevated sCEA levels were validated in 194 CRC patients on ABI Taqman platform. Eight candidate SNPs were validated in CRC patients. The rs1047781 (chr19-FUT2) (A/T) was associated with elevated sCEA levels, and rs8176746 (chr9-ABO) was associated with the regional lymph metastasis in the CRC patients. The preoperative sCEA level was a risk factor for tumor recurrence in 5 years after operation (OR = 1.427, 95% CI: 1.005& 1.843, P = 0.006). It was also one of the risk factors for regional lymph node metastasis (OR = 2.266, 95% CI: 1.196& 4.293, P = 0.012). The sCEA level in rs1047781-T carriers was higher than that in the A carriers in CRC patients without lymph node metastasis (P = 0.006). The regional lymph node metastasis in patients with homozygote AA of rs8176746 was more common than that in the heterozygote AG carriers (P = 0.022). In addition, rs1047781-AT and TT CRC patients exhibited a worse disease-free survival than AA genotype carriers (P = 0.023). Conclusions: We found candidate SNPs associated with elevated sCEA levels in both healthy males and CRC population. Rs1047781 (chr19-FUT2) may be the susceptible locus for recurrence of CRC in a population from Southern China. C1 [Liang, Yu; Peng, Tao] Guangxi Med Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Nanning, Guangxi, Peoples R China. [Tang, Weizhong; Huang, Tiqiang] Guangxi Med Univ, Affiliated Hosp 1, Dept Anal & Colorectal Surg, Nanning, Guangxi, Peoples R China. [Huang, Tiqiang; Gao, Yong; Zhang, Shijun; Mo, Linjian; Xu, Jianfeng; Mo, Zengnan] Guangxi Med Univ, Ctr Genom & Personalized Med, Nanning, Guangxi, Peoples R China. [Yang, Xiaobo; Zhang, Haiying] Guangxi Med Univ, Sch Publ Hlth, Dept Occupat Hlth & Environm Hlth, Nanning, Guangxi, Peoples R China. [Hu, Yanling] Guangxi Med Univ, Med Sci Res Ctr, Nanning, Guangxi, Peoples R China. [Qin, Xue; Li, Shan] Guangxi Med Univ, Affiliated Hosp 1, Dept Clin Lab, Nanning, Guangxi, Peoples R China. [Mo, Linjian; Mo, Zengnan] Guangxi Med Univ, Affiliated Hosp 1, Inst Urol & Nephrol, Nanning, Guangxi, Peoples R China. [Liang, Zhenjia; Shi, Deyi] Fangchenggang First Peoples Hosp, Med Examinat Ctr, Fangchenggang, Guangxi, Peoples R China. [Huang, Zhang] Guigang First Peoples Hosp, Med Examinat Ctr, Guigang, Guangxi, Peoples R China. [Guan, Yingyong] Yulin First Peoples Hosp, Med Examinat Ctr, Yulin, Guangxi, Peoples R China. [Zhou, Jicheng] Guangxi Med Univ, Affiliated Hosp 1, Dept Hematol, Nanning, Guangxi, Peoples R China. [Winkler, Cheryl] NCI, Mol Genet Epidemiol Sec, Frederick Nat Lab Canc Res, NIH, Frederick, MD USA. [O'Brien, Stephen J.; Peng, Tao] NCI, Lab Genom Divers, NIH, Frederick, MD USA. [O'Brien, Stephen J.] St Petersburg State Univ, Theodosius Dobzhansky Ctr Genome Bioinformat, St Petersburg 199034, Russia. [O'Brien, Stephen J.] Nova SE Univ, Oceanog Ctr, Ft Lauderdale, FL 33314 USA. [Xu, Jianfeng] Wake Forest Univ, Bowman Gray Sch Med, Ctr Canc Genom, Winston Salem, NC USA. RP Mo, ZN (reprint author), Guangxi Med Univ, Ctr Genom & Personalized Med, Nanning, Guangxi, Peoples R China. EM zengnanmo@hotmail.com; pengtaocn@hotmail.com RI Yang, Xiaobo/G-3854-2016; OI O'Brien, Stephen J./0000-0001-7353-8301 FU General Program of National Natural Science Foundation of China [30945204, 81072321, 81272853, 81360378, 81360099, 81370857, 30760243, 30460143, 30560133]; Ministry of Education, China; Key Program and University Talents Highland Innovation Team of Guangxi [2012012D003, GJR201147-09]; Chairman Science and Technology Fund and Tackle Program of Guangxi [1116-03, GKG1298003-07-01]; Guangxi Natural Science Foundation [2011 GXNSFB018100, 2012GXNSFAA053152, 2013GXNSFFA 019002]; Guangxi Nature Sciences Grant [GuiKeGong 1104003A-7]; Guangxi Provincial Department of Finance and Education [2009GJCJ150]; Guangxi Health Ministry Medicine Grant [Z201018]; Russian Ministry of Science Mega-grant [11.G34.31.0068] FX This work was funded by the General Program of National Natural Science Foundation of China (30945204, 81072321, 81272853, 81360378, 81360099, 81370857, 30760243, 30460143 and 30560133), Ministry of Education, China (Program for New Century Excellent Talents in University, NCET2009), Key Program and University Talents Highland Innovation Team of Guangxi (2012012D003, GJR201147-09), Chairman Science and Technology Fund and Tackle Program of Guangxi (1116-03, GKG1298003-07-01), Guangxi Natural Science Foundation (2011 GXNSFB018100, 2012GXNSFAA053152, 2013GXNSFFA 019002), Guangxi Nature Sciences Grant (GuiKeGong 1104003A-7), the Guangxi Provincial Department of Finance and Education (2009GJCJ150) and Guangxi Health Ministry Medicine Grant (Z201018). This research was supported in part by Russian Ministry of Science Mega-grant no. 11.G34.31.0068; SJ O'Brien Principal Investigator, No funding body had any influence or input into the study design, data collection, analysis, data interpretation, or writing of the report. NR 66 TC 5 Z9 5 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 18 PY 2014 VL 9 IS 6 AR e97923 DI 10.1371/journal.pone.0097923 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK6AC UT WOS:000338508200007 PM 24941225 ER PT J AU Kasagi, S Zhang, P Che, L Abbatiello, B Maruyama, T Nakatsukasa, H Zanvit, P Jin, WW Konkel, JE Chen, WJ AF Kasagi, Shimpei Zhang, Pin Che, Li Abbatiello, Brittany Maruyama, Takashi Nakatsukasa, Hiroko Zanvit, Peter Jin, Wenwen Konkel, Joanne E. Chen, WanJun TI In Vivo-Generated Antigen-Specific Regulatory T Cells Treat Autoimmunity Without Compromising Antibacterial Immune Response SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID GROWTH-FACTOR-BETA; GLUTAMIC-ACID DECARBOXYLASE; TGF-BETA; SELF-TOLERANCE; MONOCLONAL-ANTIBODY; IN-VIVO; DISEASE; FOXP3; MICE; MECHANISMS AB Harnessing regulatory T (T-reg) cells is a promising approach for treating autoimmune disease. However, inducing antigen-specific T-reg cells that target inflammatory immune cells without compromising beneficial immune responses has remained an unmet challenge. We developed a pathway to generate autoantigen-specific T-reg cells in vivo, which showed therapeutic effects on experimental autoimmune encephalomyelitis and nonobese diabetes in mice. Specifically, we induced apoptosis of immune cells by systemic sublethal irradiation or depleted B and CD8(+) T cells with specific antibodies and then administered autoantigenic peptides in mice with established autoimmune diseases. We demonstrated mechanistically that apoptotic cells triggered professional phagocytes to produce transforming growth factor-beta, under which the autoantigenic peptides directed naive CD4(+) T cells to differentiate into Foxp3(+) T-reg cells instead of into T effector cells in vivo. These antigen-specific Treg cells specifically ameliorated autoimmunity without compromising immune responses to bacterial antigen. We have thus successfully generated antigen-specific T-reg cells with therapeutic activity toward autoimmunity. The findings may lead to the development of antigen-specific T-reg cell-mediated immunotherapy for multiple sclerosis and type 1 diabetes and also other autoimmune diseases. C1 [Kasagi, Shimpei; Zhang, Pin; Che, Li; Abbatiello, Brittany; Maruyama, Takashi; Nakatsukasa, Hiroko; Zanvit, Peter; Jin, Wenwen; Konkel, Joanne E.; Chen, WanJun] Natl Inst Dent & Craniofacial Res, Mucosal Immunol Sect, Oral Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Chen, WJ (reprint author), Natl Inst Dent & Craniofacial Res, Mucosal Immunol Sect, Oral Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. EM wchen@mail.nih.gov RI MaruYama, Takashi/N-5994-2014 FU Intramural Research Program of the NIH, NIDCR; Japan Society for the Promotion of Science FX This research was supported by the Intramural Research Program of the NIH, NIDCR. S.K. and H.N. are supported in part by Japan Society for the Promotion of Science research fellowship. NR 38 TC 14 Z9 14 U1 1 U2 10 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 JUN 18 PY 2014 VL 6 IS 241 AR 241ra78 DI 10.1126/scitranslmed.3008895 PG 12 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA AK8XJ UT WOS:000338711700004 PM 24944193 ER PT J AU Vermund, SH Narayan, KMV Glass, RI AF Vermund, Sten H. Narayan, K. M. Venkat Glass, Roger I. TI Chronic Diseases in HIV Survivors SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Editorial Material C1 [Vermund, Sten H.] Vanderbilt Univ, Sch Med, Vanderbilt Inst Global Hlth, Nashville, TN 37203 USA. [Vermund, Sten H.] Vanderbilt Univ, Sch Med, Dept Pediat, Nashville, TN 37203 USA. [Narayan, K. M. Venkat] Emory Univ, Sch Publ Hlth, Dept Global Hlth, Atlanta, GA 30322 USA. [Narayan, K. M. Venkat] Emory Univ, Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. [Glass, Roger I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Vermund, SH (reprint author), Vanderbilt Univ, Sch Med, Vanderbilt Inst Global Hlth, Nashville, TN 37203 USA. EM sten.vermund@vanderbilt.edu RI Narayan, K.M. Venkat /J-9819-2012 OI Narayan, K.M. Venkat /0000-0001-8621-5405 NR 5 TC 3 Z9 3 U1 0 U2 2 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 JUN 18 PY 2014 VL 6 IS 241 AR 241ed14 DI 10.1126/scitranslmed.3008684 PG 2 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA AK8XJ UT WOS:000338711700001 PM 24944191 ER PT J AU Wang, XQ Campos, CR Peart, JC Smith, LK Boni, JL Cannon, RE Miller, DS AF Wang, Xueqian Campos, Christopher R. Peart, John C. Smith, Lindsay K. Boni, Jessica L. Cannon, Ronald E. Miller, David S. TI Nrf2 Upregulates ATP Binding Cassette Transporter Expression and Activity at the Blood-Brain and Blood-Spinal Cord Barriers SO JOURNAL OF NEUROSCIENCE LA English DT Article DE ABC transporters; blood-brain barrier; drug delivery; NF-kappa B; P-glycoprotein; p53 ID P-GLYCOPROTEIN EXPRESSION; XENOBIOTIC EFFLUX TRANSPORTERS; PLACEBO-CONTROLLED PHASE-3; MULTIPLE-SCLEROSIS; ENDOTHELIAL-CELLS; DEFENSE PATHWAY; ORAL BG-12; INJURY; ACTIVATION; MICE AB Activation of nuclear factor E2-related factor-2 (Nrf2), a sensor of oxidative stress, is neuroprotective in animal models of cerebral ischemia, traumatic brain injury, subarachnoid hemorrhage, and spinal cord injury. We show here that Nrf2 activation with sulforaphane (SFN) in vivo or in vitro increases expression and transport activity of three ATP-driven drug efflux pumps at the blood-brain barrier [P-glycoprotein, ATP binding cassette b1 (Abcb1); multidrug resistance-associated protein-2 (Mrp2), Abcc2; and breast cancer resistance protein (Bcrp), Abcg2]. Dosing rats with SFN increased protein expression of all three transporters in brain capillaries and decreased by 50% brain accumulation of the P-glycoprotein substrate verapamil. Exposing rat or mouse brain capillaries to SFN increased P-glycoprotein, Bcrp, and Mrp2 transport activity and protein expression; SFN increased P-glycoprotein activity in mouse spinal cord capillaries. Inhibiting transcription or translation abolished upregulation of P-glycoprotein activity. No such effects were seen in brain capillaries from Nrf2-null mice, indicating Nrf2 dependence. Nrf2 signaled indirectly to increase transporter activity/expression. The p53 inhibitor pifithrin abolished the SFN-induced increase in transporter activity/expression, and the p53-activator nutlin-3 increased P-glycoprotein activity. SFN did not alter P-glycoprotein transport activity in brain and spinal cord capillaries from p53-null mice. Inhibitors of p38 MAPK and nuclear factor kappa B (NF-kappa B) blocked the effects of SFN and nutlin-3 on P-glycoprotein activity. These results implicate Nrf2, p53, and NF-kappa B in the upregulation of P-glycoprotein, Bcrp, and Mrp2 at blood-CNS barriers. They imply that the barriers are tightened selectively (efflux transporter upregulation) by oxidative stress, providing increased neuroprotection, but also reduced penetration of many therapeutic drugs. C1 [Wang, Xueqian; Campos, Christopher R.; Peart, John C.; Smith, Lindsay K.; Boni, Jessica L.; Cannon, Ronald E.; Miller, David S.] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. RP Miller, DS (reprint author), NIEHS, Lab Toxicol & Pharmacol, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM miller@niehs.nih.gov FU Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health. NR 43 TC 28 Z9 28 U1 2 U2 12 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUN 18 PY 2014 VL 34 IS 25 BP 8585 EP 8593 DI 10.1523/JNEUROSCI.2935-13.2014 PG 9 WC Neurosciences SC Neurosciences & Neurology GA AK5FD UT WOS:000338449200019 PM 24948812 ER PT J AU Krupovic, M Koonin, EV AF Krupovic, Mart Koonin, Eugene V. TI Evolution of eukaryotic single-stranded DNA viruses of the Bidnaviridae family from genes of four other groups of widely different viruses SO SCIENTIFIC REPORTS LA English DT Article ID RICE DWARF PHYTOREOVIRUS; BOMBYX-MORI-BIDENSOVIRUS; DENSOVIRUS CHINA ISOLATE; STRUCTURAL PROTEIN; CELL ENTRY; HOST-RANGE; REPLICATION; GENOME; RNA; RECOMBINATION AB Single-stranded (ss)DNA viruses are extremely widespread, infect diverse hosts from all three domains of life and include important pathogens. Most ssDNA viruses possess small genomes that replicate by the rolling-circle-like mechanism initiated by a distinct virus-encoded endonuclease. However, viruses of the family Bidnaviridae, instead of the endonuclease, encode a protein-primed type B DNA polymerase (PolB) and hence break this pattern. We investigated the provenance of all bidnavirus genes and uncover an unexpected turbulent evolutionary history of these unique viruses. Our analysis strongly suggests that bidnaviruses evolved from a parvovirus ancestor from which they inherit a jelly-roll capsid protein and a superfamily 3 helicase. The radiation of bidnaviruses from parvoviruses was probably triggered by integration of the ancestral parvovirus genome into a large virus-derived DNA transposon of the Polinton (polintovirus) family resulting in the acquisition of the polintovirus PolB gene along with terminal inverted repeats. Bidnavirus genes for a receptor-binding protein and a potential novel antiviral defense modulator are derived from dsRNA viruses (Reoviridae) and dsDNA viruses (Baculoviridae), respectively. The unusual evolutionary history of bidnaviruses emphasizes the key role of horizontal gene transfer, sometimes between viruses with completely different genomes but occupying the same niche, in the emergence of new viral types. C1 [Krupovic, Mart] Inst Pasteur, Dept Microbiol, Unite Biol Mol Gene Chez Extremophiles, F-75015 Paris, France. [Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Krupovic, M (reprint author), Inst Pasteur, Dept Microbiol, Unite Biol Mol Gene Chez Extremophiles, F-75015 Paris, France. EM krupovic@pasteur.fr RI Krupovic, Mart/I-4209-2012 OI Krupovic, Mart/0000-0001-5486-0098 FU European Molecular Biology Organization [ASTF 82-2014]; intramural funds of the US Department of Health and Human Services FX M.K. was partly supported by the European Molecular Biology Organization (ASTF 82-2014). E.V.K. is supported by intramural funds of the US Department of Health and Human Services (to the National Library of Medicine). NR 60 TC 19 Z9 21 U1 0 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUN 18 PY 2014 VL 4 AR 5347 DI 10.1038/srep05347 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AJ2PC UT WOS:000337499100012 PM 24939392 ER PT J AU Montgomery, DC Sorum, AW Meier, JL AF Montgomery, David C. Sorum, Alexander W. Meier, Jordan L. TI Chemoproteomic Profiling of Lysine Acetyltransferases Highlights an Expanded Landscape of Catalytic Acetylation SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID ACTIVITY-BASED PROBES; ATP-CITRATE LYASE; HISTONE ACETYLTRANSFERASE; CELLULAR-METABOLISM; COENZYME-A; IN-VIVO; INHIBITORS; COMPLEXES; IDENTIFICATION; PROTEOMICS AB Lysine acetyltransferases (KATs) play a critical role in the regulation of gene expression, metabolism, and other key cellular functions. One shortcoming of traditional KAT assays is their inability to study KAT activity in complex settings, a limitation that hinders efforts at KAT discovery, characterization, and inhibitor development. To address this challenge, here we describe a suite of cofactor-based affinity probes capable of profiling KAT activity in biological contexts. Conversion of KAT bisubstrate inhibitors to clickable photoaffinity probes enables the selective covalent labeling of three phylogenetically distinct families of KAT enzymes. Cofactor-based affinity probes report on KAT activity in cell lysates, where KATs exist as multiprotein complexes. Chemical affinity purification and unbiased LC-MS/MS profiling highlights an expanded landscape of orphan lysine acetyltransferases present in the human genome and provides insight into the global selectivity and sensitivity of CoA-based proteomic probes that will guide future applications. Chemoproteomic profiling provides a powerful method to study the molecular interactions of KATs in native contexts and will aid investigations into the role of ICATs in cell state and disease. C1 [Montgomery, David C.; Sorum, Alexander W.; Meier, Jordan L.] NCI, Biol Chem Lab, Frederick, MD 21702 USA. RP Meier, JL (reprint author), NCI, Biol Chem Lab, Frederick, MD 21702 USA. EM jordan.meier@nih.gov RI Meier, Jordan/N-2608-2014 FU NIH, National Cancer Institute, Center for Cancer Research [ZIA BC011488-01] FX The authors thank Dr. Ming Zhou (Laboratory of Proteomics and Analytical Technology) for LC-MS/MS analyses, Dr. Hans Luecke (NIDDK) for the pCAF overexpression plasmid, Dr. Brian Lewis (NCI) for helpful discussions, and Dr. Michael Giano of the Schneider lab for assistance with peptide synthesis. This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (ZIA BC011488-01). NR 55 TC 16 Z9 16 U1 5 U2 34 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD JUN 18 PY 2014 VL 136 IS 24 BP 8669 EP 8676 DI 10.1021/ja502372j PG 8 WC Chemistry, Multidisciplinary SC Chemistry GA AJ5KD UT WOS:000337720200030 PM 24836640 ER PT J AU Pahor, M Guralnik, JM Ambrosius, WT Blair, S Bonds, DE Church, TS Espeland, MA Fielding, RA Gill, TM Groessl, EJ King, AC Kritchevsky, SB Manini, TM McDermott, MM Miller, ME Newman, AB Rejeski, WJ Sink, KM Williamson, JD AF Pahor, Marco Guralnik, Jack M. Ambrosius, Walter T. Blair, Steven Bonds, Denise E. Church, Timothy S. Espeland, Mark A. Fielding, Roger A. Gill, Thomas M. Groessl, Erik J. King, Abby C. Kritchevsky, Stephen B. Manini, Todd M. McDermott, Mary M. Miller, Michael E. Newman, Anne B. Rejeski, W. Jack Sink, Kaycee M. Williamson, Jeff D. CA LIFE Study Investigators TI Effect of Structured Physical Activity on Prevention of Major Mobility Disability in Older Adults The LIFE Study Randomized Clinical Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID LOWER-EXTREMITY FUNCTION; STYLE INTERVENTIONS; SUBSEQUENT DISABILITY; KNEE OSTEOARTHRITIS; GAIT SPEED; INDEPENDENCE; PERFORMANCE; PREDICTORS; MORTALITY; ELDERS AB IMPORTANCE In older adults reduced mobility is common and is an independent risk factor for morbidity, hospitalization, disability, and mortality. Limited evidence suggests that physical activity may help prevent mobility disability; however, there are no definitive clinical trials examining whether physical activity prevents or delays mobility disability. OBJECTIVE To test the hypothesis that a long-term structured physical activity program is more effective than a health education program (also referred to as a successful aging program) in reducing the risk of major mobility disability. DESIGN, SETTING, AND PARTICIPANTS The Lifestyle Interventions and Independence for Elders (LIFE) study was a multicenter, randomized trial that enrolled participants between February 2010 and December 2011, who participated for an average of 2.6 years. Follow-up ended in December 2013. Outcome assessors were blinded to the intervention assignment. Participants were recruited from urban, suburban, and rural communities at 8 centers throughout the United States. We randomized a volunteer sample of 1635 sedentary men and women aged 70 to 89 years who had physical limitations, defined as a score on the Short Physical Performance Battery of 9 or below, but were able to walk 400 m. INTERVENTIONS Participants were randomized to a structured, moderate-intensity physical activity program (n = 818) conducted in a center (twice/wk) and at home (3-4 times/wk) that included aerobic, resistance, and flexibility training activities or to a health education program (n = 817) consisting of workshops on topics relevant to older adults and upper extremity stretching exercises. MAIN OUTCOMES AND MEASURES The primary outcome was major mobility disability objectively defined by loss of ability to walk 400 m. RESULTS Incident major mobility disability occurred in 30.1%(246 participants) of the physical activity group and 35.5%(290 participants) of the health education group (hazard ratio [HR], 0.82 [95% CI, 0.69-0.98], P = .03). Persistent mobility disability was experienced by 120 participants (14.7%) in the physical activity group and 162 participants (19.8%) in the health education group (HR, 0.72 [95% CI, 0.57-0.91]; P = .006). Serious adverse events were reported by 404 participants (49.4%) in the physical activity group and 373 participants (45.7%) in the health education group (risk ratio, 1.08 [95% CI, 0.98-1.20]). CONCLUSIONS AND RELEVANCE A structured, moderate-intensity physical activity program compared with a health education program reduced major mobility disability over 2.6 years among older adults at risk for disability. These findings suggest mobility benefit from such a program in vulnerable older adults. C1 [Pahor, Marco; Guralnik, Jack M.; Manini, Todd M.] Univ Florida, Dept Aging & Geriatr Res, Gainesville, FL 32610 USA. [Guralnik, Jack M.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Ambrosius, Walter T.; Espeland, Mark A.; Kritchevsky, Stephen B.; Miller, Michael E.; Rejeski, W. Jack; Sink, Kaycee M.; Williamson, Jeff D.] Wake Forest Univ, Dept Internal Med, Winston Salem, NC 27109 USA. [Ambrosius, Walter T.; Espeland, Mark A.; Kritchevsky, Stephen B.; Miller, Michael E.; Rejeski, W. Jack; Sink, Kaycee M.; Williamson, Jeff D.] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. [Blair, Steven] Univ S Carolina, Dept Exercise Sci, Arnold Sch Publ Hlth, Columbia, SC 29208 USA. [Bonds, Denise E.] NHLBI, Div Cardiac Sci, Bethesda, MD 20892 USA. [Church, Timothy S.] Pennington Biomed Res Ctr, Dept Preventat Med, Baton Rouge, LA USA. [Fielding, Roger A.] Tufts Univ, Jean Mayer US Dept, Agr Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Gill, Thomas M.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. [Groessl, Erik J.] Vet Affairs San Diego Healthcare Syst, San Diego, CA USA. [Groessl, Erik J.] Univ Calif San Diego, Dept Family & Prevent Med, San Diego, CA 92103 USA. [King, Abby C.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [King, Abby C.] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA. [McDermott, Mary M.] Northwestern Univ, Dept Med & Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. RP Pahor, M (reprint author), Univ Florida, Dept Aging & Geriatr Res, POB 100107, Gainesville, FL 32610 USA. EM mpahor@ufl.edu RI Buford, Thomas /B-1111-2011; Beavers, Daniel/G-5338-2016; Newman, Anne B./C-6408-2013 OI Buford, Thomas /0000-0002-9541-4358; Marsiske, Michael/0000-0001-5973-2116; Newman, Anne B./0000-0002-0106-1150 FU National Institutes of Health (NIH) [UO1AG22376]; National Institute on Aging; National Heart, Lung, and Blood Institute [3U01AG022376-05A2S]; Intramural Research Program; Claude D. Pepper Older Americans Independence Centers at the University of Florida [1 P30 AG028740]; Wake Forest University [1 P30 AG21332]; Tufts University [1P30AG031679]; University of Pittsburgh [P30 AG024827]; Yale University [P30AG021342]; NIH/NCRR CTSA at Stanford University [UL1 RR025744]; NIH/NCRR CTSA at University of Florida [U54RR025208]; NIH/NCRR CTSA at Yale University [UL1 TR000142]; Boston Rehabilitation Outcomes Center [1R24HD065688-01A1]; National Institute on Aging [K07AG3587]; Department of Veterans Affairs; US Department of Agriculture [58-1950-0-014] FX The Lifestyle Interventions and Independence for Elders Study is funded by cooperative agreement UO1AG22376 from the National Institutes of Health (NIH) and National Institute on Aging; supplement 3U01AG022376-05A2S from the National Heart, Lung, and Blood Institute; and was sponsored in part by the Intramural Research Program. The research is partially supported by the Claude D. Pepper Older Americans Independence Centers at the University of Florida (1 P30 AG028740), Wake Forest University (1 P30 AG21332), Tufts University (1P30AG031679), University of Pittsburgh (P30 AG024827), and Yale University (P30AG021342) and the NIH/NCRR CTSA at Stanford University (UL1 RR025744), at University of Florida (U54RR025208) and at Yale University (UL1 TR000142). Tufts University is also supported by the Boston Rehabilitation Outcomes Center (1R24HD065688-01A1). LIFE investigators are also partially supported by the following: Dr Thomas Gill (Yale University) is the recipient of an Academic Leadership Award (K07AG3587) from the National Institute on Aging. Dr Carlos Fragoso (Spirometry Reading Center, Yale University) is the recipient of a Career Development Award from the Department of Veterans Affairs. Dr Roger Fielding (Tufts University) is partially supported by the US Department of Agriculture, under agreement 58-1950-0-014. NR 33 TC 199 Z9 202 U1 11 U2 66 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 JUN 18 PY 2014 VL 311 IS 23 BP 2387 EP 2396 DI 10.1001/jama.2014.5616 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA AI9XV UT WOS:000337301500019 PM 24866862 ER PT J AU Carvajal, RD Sosman, JA Quevedo, JF Milhem, MM Joshua, AM Kudchadkar, RR Linette, GP Gajewski, TF Lutzky, J Lawson, DH Lao, CD Flynn, PJ Albertini, MR Sato, T Lewis, K Doyle, A Ancell, K Panageas, KS Bluth, M Hedvat, C Erinjeri, J Ambrosini, G Marr, B Abramson, DH Dickson, MA Wolchok, JD Chapman, PB Schwartz, GK AF Carvajal, Richard D. Sosman, Jeffrey A. Quevedo, Jorge Fernando Milhem, Mohammed M. Joshua, Anthony M. Kudchadkar, Ragini R. Linette, Gerald P. Gajewski, Thomas F. Lutzky, Jose Lawson, David H. Lao, Christopher D. Flynn, Patrick J. Albertini, Mark R. Sato, Takami Lewis, Karl Doyle, Austin Ancell, Kristin Panageas, Katherine S. Bluth, Mark Hedvat, Cyrus Erinjeri, Joseph Ambrosini, Grazia Marr, Brian Abramson, David H. Dickson, Mark Andrew Wolchok, Jedd D. Chapman, Paul B. Schwartz, Gary K. TI Effect of Selumetinib vs Chemotherapy on Progression-Free Survival in Uveal Melanoma A Randomized Clinical Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID COLLABORATIVE OCULAR MELANOMA; CHOROIDAL MELANOMA; METASTATIC-DISEASE; MEK INHIBITOR; GROWTH-FACTOR; SOLID TUMORS; LUNG-CANCER; MUTANT GNAQ; CELL-DEATH; MUTATIONS AB IMPORTANCE Uveal melanoma is characterized by mutations in GNAQ and GNA11, resulting in mitogen-activated protein kinase pathway activation. OBJECTIVE To assess the efficacy of selumetinib, a selective, non-adenosine triphosphate competitive inhibitor of MEK1 and MEK2, in uveal melanoma. DESIGN, SETTING, AND PARTICIPANTS Randomized, open-label, phase 2 clinical trial comparing selumetinib vs chemotherapy conducted from August 2010 through December 2013 among 120 patients with metastatic uveal melanoma at 15 academic oncology centers in the United States and Canada. INTERVENTIONS One hundred one patients were randomized in a 1:1 ratio to receive selumetinib, 75mg orally twice daily on a continual basis (n = 50), or chemotherapy (temozolomide, 150mg/m(2) orally daily for 5 of every 28 days, or dacarbazine, 1000mg/m(2) intravenously every 21 days [investigator choice]; n = 51) until disease progression, death, intolerable adverse effects, or withdrawal of consent. After primary outcome analysis, 19 patients were registered and 18 treated with selumetinib without randomization to complete the planned 120-patient enrollment. Patients in the chemotherapy group could receive selumetinib at the time of radiographic progression. MAIN OUTCOMES AND MEASURES Progression-free survival, the primary end point, was assessed as of April 22, 2013. Additional end points, including overall survival, response rate, and safety/toxicity, were assessed as of December 31, 2013. RESULTS Median progression-free survival among patients randomized to chemotherapy was 7 weeks (95% CI, 4.3-8.4weeks; median treatment duration, 8weeks; interquartile range [IQR], 4.3-16weeks) and among those randomized to selumetinib was 15.9 weeks (95% CI, 8.4-21.1 weeks; median treatment duration, 16.1 weeks; IQR, 8.1-25.3weeks) (hazard ratio, 0.46; 95% CI, 0.30-0.71; P < .001). Median overall survival time was 9.1 months (95% CI, 6.1-11.1 months) with chemotherapy and 11.8 months (95% CI, 9.8-15.7 months) with selumetinib (hazard ratio, 0.66; 95% CI, 0.41-1.06; P = .09). No objective responses were observed with chemotherapy. Forty-nine percent of patients treated with selumetinib achieved tumor regression, with 14% achieving an objective radiographic response to therapy. Treatment-related adverse events were observed in 97% of patients treated with selumetinib, with 37% requiring at least 1 dose reduction. CONCLUSIONS AND RELEVANCE In this hypothesis-generating study of patients with advanced uveal melanoma, selumetinib compared with chemotherapy resulted in a modestly improved progression-free survival and response rate; however, no improvement in overall survivalwas observed. Improvement in clinical outcomeswas accompanied by a high rate of adverse events. C1 [Carvajal, Richard D.; Panageas, Katherine S.; Bluth, Mark; Hedvat, Cyrus; Erinjeri, Joseph; Ambrosini, Grazia; Marr, Brian; Abramson, David H.; Dickson, Mark Andrew; Wolchok, Jedd D.; Chapman, Paul B.; Schwartz, Gary K.] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Carvajal, Richard D.; Abramson, David H.; Dickson, Mark Andrew; Wolchok, Jedd D.; Chapman, Paul B.; Schwartz, Gary K.] Cornell Univ, Weill Med Coll, New York, NY 10021 USA. [Sosman, Jeffrey A.; Ancell, Kristin] Vanderbilt Univ, Med Ctr, Dept Hematol Oncol, Nashville, TN USA. [Quevedo, Jorge Fernando] Mayo Clin, Rochester, MN USA. [Milhem, Mohammed M.] Univ Iowa Hosp & Clin, Iowa City, IA 52242 USA. [Joshua, Anthony M.] Princess Margaret Canc Ctr, Div Med Oncol & Hematol, Toronto, ON, Canada. [Kudchadkar, Ragini R.] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Linette, Gerald P.] Washington Univ, St Louis, MO USA. [Gajewski, Thomas F.] Univ Chicago, Chicago, IL 60637 USA. [Lutzky, Jose] Mt Sinai Comprehens Canc Ctr, Miami Beach, FL USA. [Lawson, David H.] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Lao, Christopher D.] Univ Michigan, Ann Arbor, MI 48109 USA. [Flynn, Patrick J.] Metro Minnesota Community Clin Oncol Program, St Louis Pk, MN USA. [Albertini, Mark R.] Univ Wisconsin, Madison, WI 53706 USA. [Sato, Takami] Thomas Jefferson Univ, Jefferson Med Coll, Philadelphia, PA 19107 USA. [Lewis, Karl] Univ Colorado, Aurora, CO USA. [Doyle, Austin] NCI, Invest Drug Branch, Rockville, MD USA. RP Carvajal, RD (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, 300 E 66th St, New York, NY 10065 USA. EM carvajar@mskcc.org OI Erinjeri, Joseph/0000-0003-1876-727X; HEDVAT, CYRUS/0000-0003-0045-3491 FU Cancer Therapy Evaluation Program; National Cancer Institute; Conquer Cancer Foundation; Cycle for Survival; Fund for Ophthalmic Knowledge FX This study was sponsored by the Cancer Therapy Evaluation Program. Financial support for this trial was provided by the National Cancer Institute, the Conquer Cancer Foundation, Cycle for Survival, and the Fund for Ophthalmic Knowledge. The Division of Cancer Treatment and Diagnosis at the National Cancer Institute provided selumetinib for this clinical trial. NR 26 TC 102 Z9 104 U1 2 U2 11 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 JUN 18 PY 2014 VL 311 IS 23 BP 2397 EP 2405 DI 10.1001/jama.2014.6096 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA AI9XV UT WOS:000337301500020 PM 24938562 ER PT J AU Kreimer, AR Safaeian, M Hildesheim, A AF Kreimer, Aimee R. Safaeian, Mahboobeh Hildesheim, Allan TI Number of Human Papillomavirus Vaccine Doses and Condyloma SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID PARTICLE VACCINE; YOUNG-WOMEN; TRIAL C1 [Kreimer, Aimee R.; Safaeian, Mahboobeh; Hildesheim, Allan] NCI, Bethesda, MD 20892 USA. RP Kreimer, AR (reprint author), NCI, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM kreimera@mail.nih.gov RI Hildesheim, Allan/B-9760-2015; Kreimer, Aimee/H-1687-2015 OI Hildesheim, Allan/0000-0003-0257-2363; NR 5 TC 2 Z9 2 U1 0 U2 2 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 JUN 18 PY 2014 VL 311 IS 23 BP 2439 EP 2439 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA AI9XV UT WOS:000337301500027 PM 24938569 ER PT J AU Ameli, R Luckenbaugh, DA Gould, NF Holmes, MK Lally, N Ballard, ED Zarate, CA AF Ameli, Rezvan Luckenbaugh, David A. Gould, Neda F. Holmes, M. Kathleen Lally, Niall Ballard, Elizabeth D. Zarate, Carlos A., Jr. TI SHAPS-C: the Snaith-Hamilton pleasure scale modified for clinician administration SO PEERJ LA English DT Article DE Self-assessment; Anhedonia; Depression; Clinician administered ID MAJOR DEPRESSIVE DISORDER; MENTAL-HEALTH SURVEY; SELF-REPORT; PSYCHOMETRIC EVALUATION; GENERAL-POPULATION; ANHEDONIA; SYMPTOMATOLOGY; NEUROSCIENCE; CONCORDANCE; INVENTORY AB Anhedonia, a diminished or lack of ability to experience and anticipate pleasure represents a core psychiatric symptom in depression. Current clinician assessment of anhedonia is generally limited to one or two all-purpose questions and most well-known psychometric scales of anhedonia are relatively long, self-administered, typically not state sensitive, and are unsuitable for use in clinical settings. A user-friendly tool for a more in-depth clinician assessment of hedonic capacity is needed. The present study assessed the validity and reliability of a clinician administered version of the Snaith-Hamilton Pleasure Scale, the SHAPS-C, in 34 depressed subjects. We compared total and specific item scores on the SHAPS-C, SHAPS (self-report version), Montgomery-Asberg Depression Rating Scale (MADRS), and the Inventory of Depressive Symptomatology-Self Rating version (IDS-SR). We also examined construct, content, concurrent, convergent, and discriminant validity, internal consistency, and split-half reliability of the SHAPS-C. The SHAPS-C was found to be valid and reliable. The SHAPS and the SHAPS-C were positively correlated with one another, with levels of depression severity, as measured by the MADRS, and the IDS-SR total scores, and with specific items of the MADRS and IDS-SR sensitive to measuring hedonic capacity. Our investigation indicates that the SHAPS-C is a user friendly, reliable, and valid tool for clinician assessment of hedonic capacity in depressed bipolar and unipolar patients. C1 [Ameli, Rezvan; Luckenbaugh, David A.; Lally, Niall; Ballard, Elizabeth D.; Zarate, Carlos A., Jr.] NIMH, ETPB, NIH, DHHS, Bethesda, MD 20892 USA. [Gould, Neda F.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Holmes, M. Kathleen] St Johns Univ, Dept Clin Psychol, Jamaica, NY 11439 USA. [Lally, Niall] UCL, Inst Cognit Neurosci, London, England. RP Ameli, R (reprint author), NIMH, ETPB, NIH, DHHS, Bethesda, MD 20892 USA. EM Rezvan.Ameli@NIH.GOV FU National Institute of Mental Health, National Institutes of Health (NIMH-NIH); 7SE research unit of the NIMH-NIH FX The authors gratefully acknowledge the support of the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (NIMH-NIH) and thank the 7SE research unit of the NIMH-NIH for their support. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 4 Z9 4 U1 2 U2 3 PU PEERJ INC PI LONDON PA 341-345 OLD ST, THIRD FLR, LONDON, EC1V 9LL, ENGLAND SN 2167-8359 J9 PEERJ JI PeerJ PD JUN 17 PY 2014 VL 2 AR e429 DI 10.7717/peerj.429 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AY5KG UT WOS:000347610300004 PM 25024906 ER PT J AU Dugan, VG Emrich, SJ Giraldo-Calderon, GI Harb, OS Newman, RM Pickett, BE Schriml, LM Stockwell, TB Stoeckert, CJ Sullivan, DE Singh, I Ward, DV Yao, A Zheng, J Barrett, T Birren, B Brinkac, L Bruno, VM Caler, E Chapman, S Collins, FH Cuomo, CA Di Francesco, V Durkin, S Eppinger, M Feldgarden, M Fraser, C Fricke, WF Giovanni, M Henn, MR Hine, E Hotopp, JD Karsch-Mizrachi, I Kissinger, JC Lee, EM Mathur, P Mongodin, EF Murphy, CI Myers, G Neafsey, DE Nelson, KE Nierman, WC Puzak, J Rasko, D Roos, DS Sadzewicz, L Silva, JC Sobral, B Squires, RB Stevens, RL Tallon, L Tettelin, H Wentworth, D White, O Will, R Wortman, J Zhang, Y Scheuermann, RH AF Dugan, Vivien G. Emrich, Scott J. Giraldo-Calderon, Gloria I. Harb, Omar S. Newman, Ruchi M. Pickett, Brett E. Schriml, Lynn M. Stockwell, Timothy B. Stoeckert, Christian J., Jr. Sullivan, Dan E. Singh, Indresh Ward, Doyle V. Yao, Alison Zheng, Jie Barrett, Tanya Birren, Bruce Brinkac, Lauren Bruno, Vincent M. Caler, Elizabet Chapman, Sinead Collins, Frank H. Cuomo, Christina A. Di Francesco, Valentina Durkin, Scott Eppinger, Mark Feldgarden, Michael Fraser, Claire Fricke, W. Florian Giovanni, Maria Henn, Matthew R. Hine, Erin Hotopp, Julie Dunning Karsch-Mizrachi, Ilene Kissinger, Jessica C. Lee, Eun Mi Mathur, Punam Mongodin, Emmanuel F. Murphy, Cheryl I. Myers, Garry Neafsey, Daniel E. Nelson, Karen E. Nierman, William C. Puzak, Julia Rasko, David Roos, David S. Sadzewicz, Lisa Silva, Joana C. Sobral, Bruno Squires, R. Burke Stevens, Rick L. Tallon, Luke Tettelin, Herve Wentworth, David White, Owen Will, Rebecca Wortman, Jennifer Zhang, Yun Scheuermann, Richard H. TI Standardized Metadata for Human Pathogen/Vector Genomic Sequences SO PLOS ONE LA English DT Article ID BIOINFORMATICS RESOURCE; METAGENOMIC PROJECTS; MINIMUM INFORMATION; DATABASE GOLD; ONTOLOGIES AB High throughput sequencing has accelerated the determination of genome sequences for thousands of human infectious disease pathogens and dozens of their vectors. The scale and scope of these data are enabling genotype-phenotype association studies to identify genetic determinants of pathogen virulence and drug/insecticide resistance, and phylogenetic studies to track the origin and spread of disease outbreaks. To maximize the utility of genomic sequences for these purposes, it is essential that metadata about the pathogen/vector isolate characteristics be collected and made available in organized, clear, and consistent formats. Here we report the development of the GSCID/BRC Project and Sample Application Standard, developed by representatives of the Genome Sequencing Centers for Infectious Diseases (GSCIDs), the Bioinformatics Resource Centers (BRCs) for Infectious Diseases, and the U. S. National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), informed by interactions with numerous collaborating scientists. It includes mapping to terms from other data standards initiatives, including the Genomic Standards Consortium's minimal information (MIxS) and NCBI's BioSample/BioProjects checklists and the Ontology for Biomedical Investigations (OBI). The standard includes data fields about characteristics of the organism or environmental source of the specimen, spatial-temporal information about the specimen isolation event, phenotypic characteristics of the pathogen/vector isolated, and project leadership and support. By modeling metadata fields into an ontology-based semantic framework and reusing existing ontologies and minimum information checklists, the application standard can be extended to support additional project-specific data fields and integrated with other data represented with comparable standards. The use of this metadata standard by all ongoing and future GSCID sequencing projects will provide a consistent representation of these data in the BRC resources and other repositories that leverage these data, allowing investigators to identify relevant genomic sequences and perform comparative genomics analyses that are both statistically meaningful and biologically relevant. C1 [Dugan, Vivien G.; Pickett, Brett E.; Stockwell, Timothy B.; Singh, Indresh; Brinkac, Lauren; Caler, Elizabet; Durkin, Scott; Nelson, Karen E.; Nierman, William C.; Wentworth, David; Zhang, Yun; Scheuermann, Richard H.] J Craig Venter Inst, Rockville, MD 20850 USA. [Dugan, Vivien G.; Pickett, Brett E.; Stockwell, Timothy B.; Singh, Indresh; Brinkac, Lauren; Caler, Elizabet; Durkin, Scott; Nelson, Karen E.; Nierman, William C.; Wentworth, David; Zhang, Yun; Scheuermann, Richard H.] J Craig Venter Inst, La Jolla, CA USA. [Dugan, Vivien G.; Yao, Alison; Di Francesco, Valentina; Giovanni, Maria; Lee, Eun Mi; Mathur, Punam; Squires, R. Burke] NIAID, Rockville, MD USA. [Emrich, Scott J.; Giraldo-Calderon, Gloria I.; Collins, Frank H.] Univ Notre Dame, Notre Dame, IN 46556 USA. [Harb, Omar S.; Stoeckert, Christian J., Jr.; Zheng, Jie; Roos, David S.] Univ Penn, Philadelphia, PA 19104 USA. [Newman, Ruchi M.; Ward, Doyle V.; Birren, Bruce; Chapman, Sinead; Cuomo, Christina A.; Feldgarden, Michael; Henn, Matthew R.; Murphy, Cheryl I.; Neafsey, Daniel E.; Wortman, Jennifer] Broad Inst, Cambridge, MA USA. [Schriml, Lynn M.; Bruno, Vincent M.; Eppinger, Mark; Fraser, Claire; Fricke, W. Florian; Hine, Erin; Hotopp, Julie Dunning; Mongodin, Emmanuel F.; Myers, Garry; Rasko, David; Sadzewicz, Lisa; Silva, Joana C.; Tallon, Luke; Tettelin, Herve; White, Owen] Univ Maryland, Sch Med, Inst Genome Sci, Baltimore, MD 21201 USA. [Sullivan, Dan E.; Sobral, Bruno; Will, Rebecca] Virginia Bioinformat Inst, Cyberinfrastruct Div, Blacksburg, VA USA. [Barrett, Tanya; Karsch-Mizrachi, Ilene] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Kissinger, Jessica C.] Univ Georgia, Athens, GA 30602 USA. [Puzak, Julia] Kelly Govt Solut, Rockville, MD USA. [Stevens, Rick L.] Argonne Natl Lab, Lemont, IL USA. [Scheuermann, Richard H.] Univ Calif San Diego, Dept Pathol, San Diego, CA 92103 USA. RP Scheuermann, RH (reprint author), J Craig Venter Inst, Rockville, MD 20850 USA. EM rscheuermann@jcvi.org RI Zheng, Jie/M-1191-2015; OI Zheng, Jie/0000-0002-2999-0103; Cuomo, Christina/0000-0002-5778-960X; Wortman, Jennifer/0000-0002-8713-1227; Harb, Omar/0000-0003-4446-6200; David, Rasko/0000-0002-7337-7154; Fraser, Claire/0000-0003-1462-2428; Schriml, Lynn/0000-0001-8910-9851; Wentworth, David/0000-0002-5190-980X; Kissinger, Jessica/0000-0002-6413-1101; Squires, R Burke/0000-0001-9666-6285 FU U.S. National Institute of Allergy and Infectious Diseases [HHSN272200900018C, HHSN272200900009C, HHSN272200900007C]; Institute for Genome Sciences Genome at the University of Maryland; J. Craig Venter Institute; Bioinformatics Resource Centers [HHSN272200900038C, HHSN266200400041C, HHSN272200900040C, HHSN272200900039C, HHSN272200900041C]; EuPathDB; IRD; PATRIC; VectorBase; ViPR; NIH, National Library of Medicine; [R01GM093132] FX This work was made possible by the generous financial and philosophical support from the U.S. National Institute of Allergy and Infectious Diseases to the Genome Sequencing Centers for Infectious Diseases located at the Broad Institute of MIT and Harvard, the Institute for Genome Sciences Genome at the University of Maryland, and the J. Craig Venter Institute (Contract Numbers HHSN272200900018C, HHSN272200900009C, and HHSN272200900007C, respectively), and the Bioinformatics Resource Centers, including EuPathDB, IRD, PATRIC, VectorBase, and ViPR (Contract Numbers HHSN272200900038C, HHSN266200400041C, HHSN272200900040C, HHSN272200900039C, and HHSN272200900041C, respectively). This work was also supported in part by R01GM093132 and the Intramural Research Program of the NIH, National Library of Medicine. Although the funders were involved in manuscript editing and coordination, they had no direct role in study design, data collection and analysis, or the decision to publish. NR 29 TC 10 Z9 10 U1 2 U2 13 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 JUN 17 PY 2014 VL 9 IS 6 AR e99979 DI 10.1371/journal.pone.0099979 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK5YM UT WOS:000338503400061 PM 24936976 ER PT J AU Jin, J Hu, C Yu, MX Chen, FF Ye, L Yin, XF Zhuang, ZP Tong, HY AF Jin, Jie Hu, Chao Yu, Mengxia Chen, Feifei Ye, Li Yin, Xiufeng Zhuang, Zhengping Tong, Hongyan TI Prognostic Value of Isocitrate Dehydrogenase Mutations in Myelodysplastic Syndromes: A Retrospective Cohort Study and Meta-Analysis SO PLOS ONE LA English DT Article ID ACUTE MYELOID-LEUKEMIA; WORLD-HEALTH-ORGANIZATION; SCORING SYSTEM; IDH2 MUTATIONS; CLASSIFICATION; NEOPLASMS; GENES; TET2; 2-HYDROXYGLUTARATE; PATHOGENESIS AB Background: Recent genomic sequencing efforts have identified a number of recurrent mutations in myelodysplastic syndromes (MDS) that may contribute to disease progression and overall survival, including mutations in isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2). Methods: Pretreatment bone marrow (BM) samples were acquired from mononuclear cells in 146 adult patients with de novo MDS from January 2006 to June 2013. Polymerase chain reaction (PCR) and direct sequencing were performed on exon 4 of IDH1/2 genes and mutation status was correlated with overall survival (OS) and leukemia-free survival (LFS). We then performed a meta-analysis combining previously published and current studies to explore the effect of IDH mutations on OS and LFS in MDS. Results: In our study, somatic mutations of either IDH gene were discovered in 11 MDS patients (7.53%) and were significantly correlated with poorer OS (P = 0.007). IDH mutations were specifically associated with a poorer OS in the intermediate-1 risk group by the International Prognostic Scoring System (IPSS) (P = 0.039). In addition, we discovered decitabine achieved a better therapeutic effect compared to other treatments in IDH mutation-positive patients (P = 0.023). We identified six previous studies of IDH mutations in MDS. A meta-analysis of these studies included 111 MDS patients IDH mutations and 1671 MDS patients with wild-type IDH1/2. The hazard ratios (HRs) of OS and LFS for patients with IDH mutations were 1.62 (95% CI, 1.27-2.09) and 2.21 (95% CI, 1.48-3.30), respectively. Conclusion: The results from our study and the meta-analysis provide firm evidence that IDH mutations are significantly associated with poorer clinical outcomes in MDS. Identification of IDH mutations may be pivotal for better risk stratification in MDS patients and improving IPSS score. Additionally, hypomethylating agents may be an effective treatment option for MDS patients with IDH mutations. C1 [Jin, Jie; Hu, Chao; Yu, Mengxia; Chen, Feifei; Ye, Li; Yin, Xiufeng; Tong, Hongyan] Zhejiang Univ, Dept Hematol, Affiliated Hosp 1, Hangzhou 310003, Zhejiang, Peoples R China. [Jin, Jie; Hu, Chao; Yu, Mengxia; Chen, Feifei; Ye, Li; Yin, Xiufeng; Tong, Hongyan] Zhejiang Univ, Sch Med, Inst Hematol, Hangzhou 310003, Zhejiang, Peoples R China. [Zhuang, Zhengping] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Tong, HY (reprint author), Zhejiang Univ, Dept Hematol, Affiliated Hosp 1, Hangzhou 310003, Zhejiang, Peoples R China. EM zjuhongyantong@163.com FU Zhejiang Province Fund for Distinguished Young Scholars [LR12H08001]; Foundation of Key Innovation Team of Zhejiang Province [2011R50015]; National Public Health Grand Research Foundation [201202017]; Science Technology Department of Zhejiang Province [2013c03043-2]; National Natural Science Foundation of China [30870914, 81270582] FX This study was supported by grants from Zhejiang Province Fund for Distinguished Young Scholars (LR12H08001), the Foundation of Key Innovation Team of Zhejiang Province (2011R50015), National Public Health Grand Research Foundation (201202017), major program of Science Technology Department of Zhejiang Province fund (2013c03043-2) and the National Natural Science Foundation of China (No. 30870914, No. 81270582). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 13 Z9 14 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 17 PY 2014 VL 9 IS 6 AR e100206 DI 10.1371/journal.pone.0100206 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK5YM UT WOS:000338503400092 PM 24936872 ER PT J AU Myles, IA AF Myles, Ian A. TI Fast food fever: reviewing the impacts of the Western diet on immunity SO NUTRITION JOURNAL LA English DT Review ID SATURATED FATTY-ACIDS; INFLAMMATORY-BOWEL-DISEASE; TOLL-LIKE RECEPTOR-4; C-REACTIVE PROTEIN; INDUCED INSULIN-RESISTANCE; PATHOGENIC T(H)17 CELLS; HUMAN GUT MICROBIOTA; CANCER PREVENTION; CELIAC-DISEASE; BREAST-CANCER AB While numerous changes in human lifestyle constitute modern life, our diet has been gaining attention as a potential contributor to the increase in immune-mediated diseases. The Western diet is characterized by an over consumption and reduced variety of refined sugars, salt, and saturated fat. Herein our objective is to detail the mechanisms for the Western diet's impact on immune function. The manuscript reviews the impacts and mechanisms of harm for our over-indulgence in sugar, salt, and fat, as well as the data outlining the impacts of artificial sweeteners, gluten, and genetically modified foods; attention is given to revealing where the literature on the immune impacts of macronutrients is limited to either animal or in vitro models versus where human trials exist. Detailed attention is given to the dietary impact on the gut microbiome and the mechanisms by which our poor dietary choices are encoded into our gut, our genes, and are passed to our offspring. While today's modern diet may provide beneficial protection from micro-and macronutrient deficiencies, our over abundance of calories and the macronutrients that compose our diet may all lead to increased inflammation, reduced control of infection, increased rates of cancer, and increased risk for allergic and auto-inflammatory disease. C1 NIAID, Bacterial Pathogenesis Unit, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Myles, IA (reprint author), NIAID, Bacterial Pathogenesis Unit, Lab Clin Infect Dis, NIH, 9000 Rockville Pike Bldg 33,Room 2W10A, Bethesda, MD 20892 USA. EM mylesi@niaid.nih.gov FU Intramural Research Program of The National Institutes of Health; National Institute of Allergy and Infectious Disease FX This work was supported by the Intramural Research Program of The National Institutes of Health and The National Institute of Allergy and Infectious Disease. I.M. was responsible for all contributions related to this manuscript. The author would like to thank Nathan Pincus for assisting in the literature search, his friend William Howard for providing lively topical discussions, and above all Jennifer Myles for the inspiration. NR 250 TC 22 Z9 22 U1 11 U2 101 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2891 J9 NUTR J JI Nutr. J. PD JUN 17 PY 2014 VL 13 AR 61 DI 10.1186/1475-2891-13-61 PG 17 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AK3EK UT WOS:000338305700002 PM 24939238 ER PT J AU Liu, DB Yang, J Wang, HF Wang, ZL Huang, XL Wang, ZT Niu, G Walker, ARH Chen, XY AF Liu, Dingbin Yang, Jie Wang, He-Fang Wang, Zhongliang Huang, Xinglu Wang, Zhantong Niu, Gang Walker, A. R. Hight Chen, Xiaoyuan TI Glucose Oxidase-Catalyzed Growth of Gold Nanoparticles Enables Quantitative Detection of Attomolar Cancer Biomarkers SO ANALYTICAL CHEMISTRY LA English DT Article ID NAKED EYE; ULTRASENSITIVE DETECTION; COLORIMETRIC DETECTION; ROOM-TEMPERATURE; PLASMONIC ELISA; PROTEIN; SERUM; READOUT; SYSTEM AB Ultrasensitive and quantitative detection of cancer biomarkers is an unmet challenge because of their ultralow concentrations in clinical samples. Although gold nanoparticle (AuNP)-based immunoassays offer high sensitivity, they were unable to quantitatively detect targets of interest most likely due to their very narrow linear ranges. This article describes a quantitative colorimetric immunoassay based on glucose oxidase (GOx)-catalyzed growth of 5 nm AuNPs that can detect cancer biomarkers from attomolar to picomolar levels. In addition, the limit of detection (LOD) of prostate-specific antigen (PSA) of this approach (93 aM) exceeds that of commercial enzyme-linked immunosorbent assay (ELISA) (6.3 pM) by more than 4 orders of magnitude. The emergence of red or purple color based on enzyme-catalyzed growth of 5 nm AuNPs in the presence of target antigen is particularly suitable for point-of-care (POC) diagnostics in both resource-rich and resource-limited settings. C1 [Liu, Dingbin; Yang, Jie; Wang, He-Fang] Nankai Univ, Coll Chem, Collaborat Innovat Ctr Chem Sci & Engn, State Key Lab Med Chem Biol, Tianjin 300071, Peoples R China. [Liu, Dingbin; Yang, Jie; Wang, He-Fang] Nankai Univ, Coll Chem, Res Ctr Analyt Sci, Tianjin 300071, Peoples R China. [Wang, Zhongliang; Huang, Xinglu; Niu, Gang; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. [Wang, Zhantong] Xiamen Univ, Sch Publ Hlth, State Key Lab Mol Vaccinol & Mol Diagnost, Xiamen 361005, Peoples R China. [Wang, Zhongliang] Xiamen Univ, Sch Publ Hlth, Ctr Mol Imaging & Translat Med, Xiamen 361005, Peoples R China. [Walker, A. R. Hight] NIST, Opt Technol Div, Phys Lab, Gaithersburg, MD 20899 USA. RP Liu, DB (reprint author), Nankai Univ, Coll Chem, Collaborat Innovat Ctr Chem Sci & Engn, State Key Lab Med Chem Biol, Tianjin 300071, Peoples R China. EM liudb@nankai.edu.cn; zhongliang.wang@nih.gov; shawn.chen@nih.gov RI Wang, He-Fang/D-7842-2011; Hight Walker, Angela/C-3373-2009 OI Wang, He-Fang/0000-0003-4127-5038; Hight Walker, Angela/0000-0003-1385-0672 FU Fundamental Research Funds for Central Universities (China); Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health FX This work was supported in part, by the Fundamental Research Funds for Central Universities (China) and the Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health. NR 33 TC 38 Z9 38 U1 29 U2 233 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 JUN 17 PY 2014 VL 86 IS 12 BP 5800 EP 5806 DI 10.1021/ac500478g PG 7 WC Chemistry, Analytical SC Chemistry GA AJ4JX UT WOS:000337643500032 PM 24896231 ER PT J AU Muller, M Sigurdsson, S Kjartansson, O Aspelund, T Lopez, OL Jonnson, PV Harris, TB van Buchem, M Gudnason, V Launer, LJ AF Muller, Majon Sigurdsson, Sigurdur Kjartansson, Olafur Aspelund, Thor Lopez, Oscar L. Jonnson, Palmi V. Harris, Tamara B. van Buchem, Mark Gudnason, Vilmundur Launer, Lenore J. CA Age Gene Environm Susceptibility-R TI Joint effect of mid- and late-life blood pressure on the brain The AGES-Reykjavik Study SO NEUROLOGY LA English DT Article ID WHITE-MATTER HYPERINTENSITIES; COGNITIVE FUNCTION; SMART-MR; GENE/ENVIRONMENT SUSCEPTIBILITY; INCIDENT DEMENTIA; ALZHEIMER-DISEASE; LEIDEN 85-PLUS; ROTTERDAM SCAN; HEART-FAILURE; RISK-FACTORS AB Objective:We hypothesized that in participants with a history of hypertension, lower late-life blood pressure (BP) will be associated with more brain pathology.Methods:Participants are 4,057 older men and women without dementia with midlife (mean age 50 6 years) and late-life (mean age 76 5 years) vascular screening, cognitive function, and brain structures on MRI ascertained as part of the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study.Results:The association of late-life BP to brain measures depended on midlife hypertension history. Higher late-life systolic and diastolic BP (DBP) was associated with an increased risk of white matter lesions and cerebral microbleeds, and this was most pronounced in participants without a history of midlife hypertension. In contrast, in participants with a history of midlife hypertension, lower late-life DBP was associated with smaller total brain and gray matter volumes. This finding was reflected back in cognitive performance; in participants with midlife hypertension, lower DBP was associated with lower memory scores.Conclusion:In this large population-based cohort, late-life BP differentially affects brain pathology and cognitive performance, depending on the history of midlife hypertension. Our study suggests history of hypertension is critical to understand how late-life BP affects brain structure and function. C1 [Muller, Majon; Harris, Tamara B.; Launer, Lenore J.] NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, Bethesda, MD 20892 USA. [Muller, Majon] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, NL-2300 RA Leiden, Netherlands. [van Buchem, Mark] Leiden Univ, Med Ctr, Dept Radiol, NL-2300 RA Leiden, Netherlands. [Sigurdsson, Sigurdur; Kjartansson, Olafur; Aspelund, Thor; Gudnason, Vilmundur] Iceland Heart Assoc, Kopovagur, Iceland. [Kjartansson, Olafur] Landspitali Natl Univ Hosp, Dept Neurol & Radiol, Reykjavik, Iceland. [Jonnson, Palmi V.] Landspitali Natl Univ Hosp, Dept Geriatr, Reykjavik, Iceland. [Lopez, Oscar L.] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA. [Jonnson, Palmi V.] Univ Iceland, Fac Med, Reykjavik, Iceland. RP Launer, LJ (reprint author), NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, Bethesda, MD 20892 USA. EM LaunerL@nia.nih.gov RI Gudnason, Vilmundur/K-6885-2015; Aspelund, Thor/C-5983-2008 OI Gudnason, Vilmundur/0000-0001-5696-0084; Aspelund, Thor/0000-0002-7998-5433 FU NIH [N01-AG-1-2100]; National Institute on Aging Intramural Research Program; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); Alzheimer Nederland [WE.15-2011-02] FX Supported by a grant from the NIH (N01-AG-1-2100), National Institute on Aging Intramural Research Program, the Hjartavernd (the Icelandic Heart Association), the Althingi (the Icelandic Parliament), and Alzheimer Nederland (M. M.; WE.15-2011-02). NR 33 TC 16 Z9 17 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD JUN 17 PY 2014 VL 82 IS 24 BP 2187 EP 2195 DI 10.1212/WNL.0000000000000517 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA AJ5FA UT WOS:000337706700013 PM 24898928 ER PT J AU Prasad, V AF Prasad, Vinay TI Statins, Primary Prevention, and Overall Mortality SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID LOW-RISK; DISEASE; MEN; PEOPLE C1 NCI, NIH, Bethesda, MD 20892 USA. RP Prasad, V (reprint author), NCI, NIH, 10 Ctr Dr,Bldg 10,Room 12N226, Bethesda, MD 20892 USA. EM vinayak.prasad@nih.gov OI Prasad, Vinay/0000-0002-6110-8221 NR 11 TC 4 Z9 4 U1 0 U2 4 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 JUN 17 PY 2014 VL 160 IS 12 BP 867 EP U105 DI 10.7326/M13-2974 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA AJ0VR UT WOS:000337374900025 PM 24935491 ER PT J AU Ombrello, MJ Kirino, Y de Bakker, PIW Gul, A Kastner, DL Remmers, EF AF Ombrello, Michael J. Kirino, Yohei de Bakker, Paul I. W. Gul, Ahmet Kastner, Daniel L. Remmers, Elaine F. TI Behcet disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE HLA imputation; autoinflammation; antigen presentation; killer immunoglobulin-like receptors; natural killer cells ID GENOME-WIDE ASSOCIATION; MAJOR HISTOCOMPATIBILITY COMPLEX; IMMUNOGLOBULIN-LIKE RECEPTOR; SEQUENCE-DERIVED PEPTIDES; SUSCEPTIBILITY LOCI; HLA-B; RECOGNITION; REGION; GENE; HLA-B-ASTERISK-5101 AB The HLA protein, HLA-B*51, encoded by HLA-B in MHC, is the strongest known genetic risk factor for Behcet disease (BD). Associations between BD and other factors within the MHC have been reported also, although strong regional linkage disequilibrium complicates their confident disentanglement from HLA-B*51. In the current study, we examined a combination of directly obtained and imputed MHC-region SNPs, directly obtained HLA-B locus types, and imputed classical HLA types with their corresponding polymorphic amino acid residues for association with BD in 1,190 cases and 1,257 controls. SNP mapping with logistic regression of the MHC identified the HLA-B/MICA region and the region between HLA-F and HLA-A as independently associated with BD (P < 1.7 x 10(-8)). HLA-B*51, -A*03, -B*15, -B*27, -B*49, -B*57, and -A*26 each contributed independently to BD risk. We directly examined rs116799036, a noncoding SNP upstream of HLA-B that was recently suggested to underlie the association of HLA-B*51 with BD, but we were unable to replicate that finding in our collection. Instead, we mapped the BD association to seven MHC class I (MHC-I) amino acid residues, including anchor residues that critically define the selection and binding of peptides to MHC-I molecules, residues known to influence MHC-I-killer immunoglobulin-like receptor interactions, and a residue located in the signal peptide of HLA-B. The locations of these variants collectively implicate MHC-I peptide binding in the pathophysiology of BD. Furthermore, several lines of evidence suggest a role for altered regulation of cellular cytotoxicity in BD pathogenesis. C1 [Ombrello, Michael J.] NIAMSD, Translat Genet & Genom Unit, NIH, Bethesda, MD 20892 USA. [Ombrello, Michael J.; Kirino, Yohei; Kastner, Daniel L.; Remmers, Elaine F.] NHGRI, Inflammatory Dis Sect, NIH, Bethesda, MD 20892 USA. [Kirino, Yohei] Yokohama City Univ, Grad Sch Med, Dept Internal Med & Clin Immunol, Yokohama, Kanagawa 2360004, Japan. [Kirino, Yohei] Fac Med, Yokohama, Kanagawa 2360004, Japan. [de Bakker, Paul I. W.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Genet, Boston, MA 02115 USA. [de Bakker, Paul I. W.] Broad Inst & Harvard, Program Med & Populat Genet, Cambridge, MA 02141 USA. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Dept Med Genet, NL-3584 CX Utrecht, Netherlands. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Dept Epidemiol, NL-3584 CX Utrecht, Netherlands. [Gul, Ahmet] Istanbul Univ, Istanbul Fac Med, Dept Internal Med, Div Rheumatol, TR-34093 Istanbul, Turkey. RP Ombrello, MJ (reprint author), NIAMSD, Translat Genet & Genom Unit, NIH, Bethesda, MD 20892 USA. EM ombrellomj@mail.nih.gov; kastnerd@mail.nih.gov RI de Bakker, Paul/B-8730-2009; zhang, jun/D-7782-2015 OI de Bakker, Paul/0000-0001-7735-7858; FU National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Human Genome Research Institute of the National Institutes of Health (NIH); Istanbul University Research fund; NIH [N1R01AR062886-01]; Netherlands Organization for Scientific Research [016.126.354] FX This work was supported by the Intramural Research Programs of the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Human Genome Research Institute of the National Institutes of Health (NIH) and the Istanbul University Research fund. P.I.W.d.B. received support from NIH Grant N1R01AR062886-01 and from the Netherlands Organization for Scientific Research Project Number 016.126.354. NR 41 TC 21 Z9 21 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 17 PY 2014 VL 111 IS 24 BP 8867 EP 8872 DI 10.1073/pnas.1406575111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AI9XO UT WOS:000337300100044 PM 24821759 ER PT J AU Payne, F Lim, K Girousse, A Brown, RJ Kory, N Robbins, A Xue, YL Sleigh, A Cochran, E Adams, C Borman, AD Russel-Jones, BD Gorden, P Semple, RK Saudek, V O'Rahilly, S Walther, TC Barroso, I Savage, DB AF Payne, Felicity Lim, Koini Girousse, Amandine Brown, Rebecca J. Kory, Nora Robbins, Ann Xue, Yali Sleigh, Alison Cochran, Elaine Adams, Claire Borman, Arundhati Dev Russel-Jones, Bormanf David Gorden, Phillip Semple, Robert K. Saudek, Vladimir O'Rahilly, Stephen Walther, Tobias C. Barroso, Ines Savage, David B. TI Mutations disrupting the Kennedy phosphatidylcholine pathway in humans with congenital lipodystrophy and fatty liver disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID PHOSPHOCHOLINE CYTIDYLYLTRANSFERASE-ALPHA; CAUSE SPONDYLOMETAPHYSEAL DYSPLASIA; CONE-ROD DYSTROPHY; INSULIN-RESISTANCE; TARGETED DELETION; CHOLINE; PCYT1A; CTP; PHOSPHATIDYLETHANOLAMINE; METABOLISM AB Phosphatidylcholine (PC) is the major glycerophospholipid in eukaryotic cells and is an essential component in all cellular membranes. The biochemistry of de novo PC synthesis by the Kennedy pathway is well established, but less is known about the physiological functions of PC. We identified two unrelated patients with defects in the Kennedy pathway due to biallellic loss-of-function mutations in phosphate cytidylyltransferase 1 alpha (PCYT1A), the rate-limiting enzyme in this pathway. The mutations lead to a marked reduction in PCYT1A expression and PC synthesis. The phenotypic consequences include some features, such as severe fatty liver and low HDL cholesterol levels, that are predicted by the results of previously reported liver-specific deletion of murine Pcyt1a. Both patients also had lipodystrophy, severe insulin resistance, and diabetes, providing evidence for an additional and essential role for PCYT1A-generated PC in the normal function of white adipose tissue and insulin action. C1 [Payne, Felicity; Xue, Yali; Barroso, Ines] Wellcome Trust Sanger Inst, Metabol Dis Grp, Cambridge CB10 1SA, England. [Lim, Koini; Girousse, Amandine; Robbins, Ann; Adams, Claire; Semple, Robert K.; Saudek, Vladimir; O'Rahilly, Stephen; Barroso, Ines; Savage, David B.] Univ Cambridge, Metab Res Labs, Wellcome Trust Med Res Council Inst Metab Sci, Cambridge CB2 0QQ, England. [Brown, Rebecca J.; Cochran, Elaine; Gorden, Phillip] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Kory, Nora; Walther, Tobias C.] Yale Univ, Sch Med, Dept Cell Biol, New Haven, CT 06520 USA. [Sleigh, Alison] Univ Cambridge, Wolfson Brain Imaging Ctr, Cambridge CB2 0QQ, England. [Borman, Arundhati Dev] Moorfields Eye Hosp Natl Hlth Serv Trust, London EC1V 2PD, England. [Russel-Jones, Bormanf David] Royal Surrey Cty Hosp, Ctr Endocrinol Diabet & Res, Guildford GU2 7XX, Surrey, England. RP O'Rahilly, S (reprint author), Univ Cambridge, Metab Res Labs, Wellcome Trust Med Res Council Inst Metab Sci, Cambridge CB2 0QQ, England. EM so104@medschl.cam.ac.uk; ib1@sanger.ac.uk; dbs23@medschl.cam.ac.uk OI Semple, Robert/0000-0001-6539-3069; Payne, Felicity/0000-0003-4228-581X FU Wellcome Trust [WT098498, WT095515, WT098051, WT091551, WT091310]; Medical Research Council Metabolic Diseases Unit; United Kingdom National Institute for Health Research Cambridge Biomedical Research Centre; European Union/European Federation of Pharmaceutical Industries and Associations Innovative Medicines Initiative (European Medical Information Framework) [115372]; National Institute of General Medical Sciences [R01 GM09719] FX We are very grateful to the patients who consented and facilitated detailed studies of themselves, as well as to Dr. Ben Challis, Julie Harris, and the staff of the Wellcome Trust Clinical Research Facility in Cambridge for assistance with metabolic studies of P1. We thank Prof. Paul Lehner, Prof. David Ron, Dr. Heather Harding, Prof. Sadaf Farooqi, and Dr. Eleanor Wheeler for technical advice. We are grateful for access to exome sequence data from the CoLaus cohort, which was sequenced as part of a partnership between the Wellcome Trust Sanger Institute, the CoLaus principal investigators, and the Quantitative Sciences Department of GlaxoSmithKline. We thank the NHLBI GO Exome Sequencing Project and its ongoing studies, which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the Women's Health Initiative Sequencing Project (HL-102926), and the Heart GO Sequencing Project (HL-103010). This study makes use of data generated by the UK10K Consortium, derived from samples from TwinsUK and Avon Longitudinal Study of Parents and Children. A full list of the investigators who contributed to the generation of the data is available from www.UK10K.org. We also thank Emma Gray, David Jones (Sample Management), Danielle Walker (Sequencing Pipeline), Carol Scott and Jillian Durham (Variation Informatics), and the staff of the Wellcome Trust Sanger Institute. Clinical studies of P2 were supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases. R.K.S., S.O., I.B., and D.B.S. were supported by the Wellcome Trust (Grants WT098498, WT095515, WT098051, and WT091551, respectively), the Medical Research Council Metabolic Diseases Unit, and the United Kingdom National Institute for Health Research Cambridge Biomedical Research Centre. S.O. was supported by the European Union/European Federation of Pharmaceutical Industries and Associations Innovative Medicines Initiative Joint Undertaking (European Medical Information Framework Grant 115372). N.K. and T.C.W. were supported by National Institute of General Medical Sciences Grant R01 GM09719. Funding for UK10K was provided by the Wellcome Trust under Award WT091310. NR 26 TC 18 Z9 18 U1 1 U2 16 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 17 PY 2014 VL 111 IS 24 BP 8901 EP 8906 DI 10.1073/pnas.1408523111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AI9XO UT WOS:000337300100050 PM 24889630 ER PT J AU Pariyadath, V Stein, EA Ross, TJ AF Pariyadath, Vani Stein, Elliot A. Ross, Thomas J. TI Machine learning classification of resting state functional connectivity predicts smoking status SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE biomarkers; fMRI; machine learning; nicotine addiction; support vector machines ID DRUG-ADDICTION; BRAIN NETWORKS; FRONTAL-CORTEX; FMRI; NICOTINE; DISEASE; SCHIZOPHRENIA; IMPULSIVITY; DYSFUNCTION; ACTIVATION AB Machine learning-based approaches are now able to examine functional magnetic resonance imaging data in a multivariate manner and extract features predictive of group membership. We applied support vector machine (SVM)-based classification to resting state functional connectivity (rsFC) data from nicotine-dependent smokers and healthy controls to identify brain-based features predictive of nicotine dependence. By employing a network-centered approach, we observed that within-network functional connectivity measures offered maximal information for predicting smoking status, as opposed to between-network connectivity, or the representativeness of each individual node with respect to its parent network. Further, our analysis suggests that connectivity measures within the executive control and frontoparietal networks are particularly informative in predicting smoking status. Our findings suggest that machine learning-based approaches to classifying rsFC data offer a valuable alternative technique to understanding large-scale differences in addiction-related neurobiology. C1 [Pariyadath, Vani; Stein, Elliot A.; Ross, Thomas J.] NIDA, Neuroimaging Res Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Pariyadath, V (reprint author), NIDA, Neuroimaging Res Branch, Intramural Res Program, NIH, 251 Bayview Blvd,Suite 200,Rm 07A505-08, Baltimore, MD 21224 USA. EM vani.pariyadath@nih.gov OI Pariyadath, Vani/0000-0001-6340-0771; Ross, Thomas/0000-0002-7745-3572 FU National Institute on Drug Abuse, Intramural Research Program, NIH/DHHS FX We thank Steve Smith of the FMRIB Analysis Group at the University of Oxford for the use of the resting state network maps originally published in Smith et al. (2009). This work was supported by the National Institute on Drug Abuse, Intramural Research Program, NIH/DHHS. NR 52 TC 10 Z9 10 U1 3 U2 6 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD JUN 16 PY 2014 VL 8 AR 425 DI 10.3389/fnhum.2014.00425 PG 10 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA AM5XW UT WOS:000339935400001 PM 24982629 ER PT J AU Cheng, HC Angermann, BR Zhang, FK Meier-Schellersheim, M AF Cheng, Hsueh-Chien Angermann, Bastian R. Zhang, Fengkai Meier-Schellersheim, Martin TI NetworkViewer: visualizing biochemical reaction networks with embedded rendering of molecular interaction rules SO BMC SYSTEMS BIOLOGY LA English DT Article DE Visualization; User interface; Protein reaction networks; Cellular signaling; Rule-based modeling ID SYSTEMS; MODELS; TOOLS; MAPS AB Background: Network representations of cell-biological signaling processes frequently contain large numbers of interacting molecular and multi-molecular components that can exist in, and switch between, multiple biochemical and/or structural states. In addition, the interaction categories (associations, dissociations and transformations) in such networks cannot satisfactorily be mapped onto simple arrows connecting pairs of components since their specifications involve information such as reaction rates and conditions with regard to the states of the interacting components. This leads to the challenge of having to reconcile competing objectives: providing a high-level overview without omitting relevant information, and showing interaction specifics while not overwhelming users with too much detail displayed simultaneously. This problem is typically addressed by splitting the information required to understand a reaction network model into several categories that are rendered separately through combinations of visualizations and/or textual and tabular elements, requiring modelers to consult several sources to obtain comprehensive insights into the underlying assumptions of the model. Results: We report the development of an application, the Simmune NetworkViewer, that visualizes biochemical reaction networks using iconographic representations of protein interactions and the conditions under which the interactions take place using the same symbols that were used to specify the underlying model with the Simmune Modeler. This approach not only provides a coherent model representation but, moreover, following the principle of "overview first, zoom and filter, then details-on-demand," can generate an overview visualization of the global network and, upon user request, presents more detailed views of local sub-networks and the underlying reaction rules for selected interactions. This visual integration of information would be difficult to achieve with static network representations or approaches that use scripted model specifications without offering simple but detailed symbolic representations of molecular interactions, their conditions and consequences in terms of biochemical modifications. Conclusions: The Simmune NetworkViewer provides concise, yet comprehensive visualizations of reaction networks created in the Simmune framework. In the near future, by adopting the upcoming SBML standard for encoding multi-component, multi-state molecular complexes and their interactions as input, the NetworkViewer will, moreover, be able to offer such visualization for any rule-based model that can be exported to that standard. C1 [Cheng, Hsueh-Chien; Angermann, Bastian R.; Zhang, Fengkai; Meier-Schellersheim, Martin] NIAID, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Cheng, Hsueh-Chien] Univ Maryland, Dept Comp Sci, College Pk, MD 20742 USA. RP Cheng, HC (reprint author), NIAID, Lab Syst Biol, NIH, Bldg 4,4 Mem Dr, Bethesda, MD 20892 USA. EM cheng@cs.umd.edu FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases FX We are grateful for discussions with the other members of the Laboratory of Systems Biology. This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases. NR 23 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 1752-0509 J9 BMC SYST BIOL JI BMC Syst. Biol. PD JUN 16 PY 2014 VL 8 AR 70 DI 10.1186/1752-0509-8-70 PG 16 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA AL1MT UT WOS:000338890200001 PM 24934175 ER PT J AU Comeau, DC Liu, HB Dogan, RI Wilbur, WJ AF Comeau, Donald C. Liu, Haibin Dogan, Rezarta Islamaj Wilbur, W. John TI Natural language processing pipelines to annotate BioC collections with an application to the NCBI disease corpus SO DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION LA English DT Article ID OF-SPEECH TAGGER; BIOMEDICAL TEXT; NORMALIZATION; EXTRACTION; PARSERS; TOOL AB BioC is a new format and associated code libraries for sharing text and annotations. We have implemented BioC natural language preprocessing pipelines in two popular programming languages: C++ and Java. The current implementations interface with the well-known MedPost and Stanford natural language processing tool sets. The pipeline functionality includes sentence segmentation, tokenization, part-of-speech tagging, lemmatization and sentence parsing. These pipelines can be easily integrated along with other BioC programs into any BioC compliant text mining systems. As an application, we converted the NCBI disease corpus to BioC format, and the pipelines have successfully run on this corpus to demonstrate their functionality. Code and data can be downloaded from http://bioc.sourceforge.net. C1 [Comeau, Donald C.; Liu, Haibin; Dogan, Rezarta Islamaj; Wilbur, W. John] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Comeau, DC (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM comeau@ncbi.nlm.nih.gov FU NIH, National Library of Medicine FX This research was supported by the Intramural Research Program of the NIH, National Library of Medicine. Funding for open access charge: Intramural Research Program of the NIH, National Library of Medicine. NR 33 TC 2 Z9 2 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1758-0463 J9 DATABASE-OXFORD JI Database PD JUN 16 PY 2014 AR bau056 DI 10.1093/database/bau056 PG 7 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA AK6ZK UT WOS:000338575600001 ER PT J AU Feng, XD Degese, MS Iglesias-Bartolome, R Vaque, JP Molinolo, AA Rodrigues, M Zaidi, MR Ksander, BR Merlino, G Sodhi, A Chen, QM Gutkind, JS AF Feng, Xiaodong Degese, Maria Sol Iglesias-Bartolome, Ramiro Vaque, Jose P. Molinolo, Alfredo A. Rodrigues, Murilo Zaidi, M. Raza Ksander, Bruce R. Merlino, Glenn Sodhi, Akrit Chen, Qianming Gutkind, J. Silvio TI Hippo-Independent Activation of YAP by the GNAQ Uveal Melanoma Oncogene through a Trio-Regulated Rho GTPase Signaling Circuitry SO CANCER CELL LA English DT Article ID PROTEIN-COUPLED RECEPTORS; CELL-PROLIFERATION; PHOTODYNAMIC THERAPY; CHOROIDAL MELANOMA; SOMATIC MUTATION; TUMOR-SUPPRESSOR; ACTIN-BINDING; SIZE-CONTROL; ORGAN SIZE; PATHWAY AB Mutually exclusive activating mutations in the GNAQ and GNA11 oncogenes, encoding heterotrimeric G alpha q family members, have been identified in 83% and similar to 6% of uveal and skin melanomas, respectively. However, the molecular events underlying these GNAQ-driven malignancies are not yet defined, thus limiting the ability to develop cancer-targeted therapies. Here, we focused on the transcriptional coactivator YAP, a critical component of the Hippo signaling pathway that controls organ size. We found that Gag stimulates YAP through a Trio-Rho/Rac signaling circuitry promoting actin polymerization, independently of phospholipase C beta and the canonical Hippo pathway. Furthermore, we show that Goal promotes the YAP-dependent growth of uveal melanoma cells, thereby identifying YAP as a suitable therapeutic target in uveal melanoma, a GNAQ/GNA11-initiated human malignancy. C1 [Feng, Xiaodong; Degese, Maria Sol; Iglesias-Bartolome, Ramiro; Vaque, Jose P.; Molinolo, Alfredo A.; Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Feng, Xiaodong; Chen, Qianming] Sichuan Univ, West China Hosp Stomatol, State Key Lab Oral Dis, Chengdu 610041, Sichuan, Peoples R China. [Rodrigues, Murilo; Sodhi, Akrit] Johns Hopkins Sch Med, Wilmer Eye Inst, Baltimore, MD 21287 USA. [Zaidi, M. Raza] Temple Univ, Sch Med, Fels Inst Canc Res & Mol Biol, Philadelphia, PA 19140 USA. [Ksander, Bruce R.] Harvard Univ, Sch Med, Schepens Eye Res Inst, Boston, MA 02114 USA. [Merlino, Glenn] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. RP Chen, QM (reprint author), Sichuan Univ, West China Hosp Stomatol, State Key Lab Oral Dis, Chengdu 610041, Sichuan, Peoples R China. EM qmchen@scu.edu.cn; sg39v@nih.gov RI Vaque, Jose/H-8413-2015; Zaidi, M. Raza/H-1386-2016; Iglesias-Bartolome, Ramiro/H-4460-2014 OI Vaque, Jose/0000-0002-3913-2495; Zaidi, M. Raza/0000-0003-0480-3188; Iglesias-Bartolome, Ramiro/0000-0002-0792-1254 FU NIH, National Institute of Dental and Craniofacial Research FX We acknowledge the extensive support, guidance, and help from all members of the J.S.G. laboratory and the Oral Cancer Branch for their generous contributions and thoughtful suggestions throughout these studies. We thank Dr. Thomas Bugge and Dr. Marius Sudol for insightful advice and critically reading our manuscript. We thank Dr. James T. Hands and Dr. Shannath Merbs, Wilmer Eye Institute, Johns Hopkins School of Medicine, for generously providing snap-frozen uveal melanoma tissue. This research was partially supported by the Intramural Research Program of NIH, National Institute of Dental and Craniofacial Research. We apologize to all of our colleagues for not citing some of their original studies because of space limitations. NR 56 TC 107 Z9 108 U1 4 U2 25 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 JUN 16 PY 2014 VL 25 IS 6 BP 831 EP 845 DI 10.1016/j.ccr.2014.04.016 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AJ5GB UT WOS:000337709600013 PM 24882515 ER PT J AU Jacques, J Hotton, D De la Dure-Molla, M Petit, S Asselin, A Kulkarni, AB Gibson, CW Brookes, SJ Berdal, A Isaac, J AF Jacques, Jaime Hotton, Dominique De la Dure-Molla, Muriel Petit, Stephane Asselin, Audrey Kulkarni, Ashok B. Gibson, Carolyn Winters Brookes, Steven Joseph Berdal, Ariane Isaac, Juliane TI Tracking Endogenous Amelogenin and Ameloblastin In Vivo SO PLOS ONE LA English DT Article ID PERIODONTAL-LIGAMENT CELLS; ENAMEL MATRIX PROTEINS; PRIMARY RNA TRANSCRIPT; RAT INCISOR; SUPRAMOLECULAR STRUCTURES; RECOMBINANT AMELOGENIN; PROGENITOR CELLS; BONE-FORMATION; ALVEOLAR BONE; STEM-CELLS AB Research on enamel matrix proteins (EMPs) is centered on understanding their role in enamel biomineralization and their bioactivity for tissue engineering. While therapeutic application of EMPs has been widely documented, their expression and biological function in non-enamel tissues is unclear. Our first aim was to screen for amelogenin (AMELX) and ameloblastin (AMBN) gene expression in mandibular bones and soft tissues isolated from adult mice (15 weeks old). Using RT-PCR, we showed mRNA expression of AMELX and AMBN in mandibular alveolar and basal bones and, at low levels, in several soft tissues; eyes and ovaries were RNA-positive for AMELX and eyes, tongues and testicles for AMBN. Moreover, in mandibular tissues AMELX and AMBN mRNA levels varied according to two parameters: 1) ontogenic stage (decreasing with age), and 2) tissue-type (e. g. higher level in dental epithelial cells and alveolar bone when compared to basal bone and dental mesenchymal cells in 1 week old mice). In situ hybridization and immunohistodetection were performed in mandibular tissues using AMELX KO mice as controls. We identified AMELX-producing (RNA-positive) cells lining the adjacent alveolar bone and AMBN and AMELX proteins in the microenvironment surrounding EMPs-producing cells. Western blotting of proteins extracted by non-dissociative means revealed that AMELX and AMBN are not exclusive to mineralized matrix; they are present to some degree in a solubilized state in mandibular bone and presumably have some capacity to diffuse. Our data support the notion that AMELX and AMBN may function as growth factor-like molecules solubilized in the aqueous microenvironment. In jaws, they might play some role in bone physiology through autocrine/paracrine pathways, particularly during development and stress-induced remodeling. C1 [Jacques, Jaime; Hotton, Dominique; De la Dure-Molla, Muriel; Petit, Stephane; Asselin, Audrey; Berdal, Ariane; Isaac, Juliane] Univ Paris 05, Univ Paris 06, INSERM UMRS 1138, Lab Mol Oral Pathophysiol,Team Berdal,Cordeliers, Paris, France. [Jacques, Jaime; De la Dure-Molla, Muriel; Berdal, Ariane] Univ Paris 07, UFR Odontol, Paris, France. [Jacques, Jaime] Univ Talca, Dept Stomatol, Unit Periodontol, Talca, Chile. [De la Dure-Molla, Muriel; Berdal, Ariane] Hosp Rothschild, AP HP, Ctr Rare Malformat Face & Oral Cav MAFACE, Paris, France. [Kulkarni, Ashok B.] Natl Inst Dent & Craniofacial Res, Funct Genom Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD USA. [Gibson, Carolyn Winters] Univ Penn, Sch Dent Med, Dept Anat & Cell Biol, Philadelphia, PA 19104 USA. [Brookes, Steven Joseph] Univ Leeds, Sch Dent, Dept Oral Biol, Leeds LS2 9JT, W Yorkshire, England. [Isaac, Juliane] CNRS URA 2578, Inst Pasteur, Dept Dev & Stem Cells Biol, Lab Morphogenesis Mol Genet, Paris, France. RP Isaac, J (reprint author), Univ Paris 05, Univ Paris 06, INSERM UMRS 1138, Lab Mol Oral Pathophysiol,Team Berdal,Cordeliers, Paris, France. EM isaacjuliane@yahoo.fr OI BROOKES, STEVEN/0000-0002-9097-7311 FU French National Research Agency [ANR-12-BSV1-0018]; National Commission for Scientific and Technological Research of Chile CONICYT; IDEX Sorbonne Paris - Cite; The Wellcome Trust [093113] FX This research was supported by the French National Research Agency (Osteodiversity project: ANR-12-BSV1-0018) and the National Commission for Scientific and Technological Research of Chile CONICYT grant. Financial support (Once upon a tooth) was obtained from IDEX Sorbonne Paris - Cite. S.J. Brookes was supported by The Wellcome Trust (grant no. 093113). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. NR 70 TC 6 Z9 6 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 16 PY 2014 VL 9 IS 6 AR e99626 DI 10.1371/journal.pone.0099626 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AJ5PV UT WOS:000337738600050 PM 24933156 ER PT J AU Vattikuti, S Lee, JJ Chang, CC Hsu, SDH Chow, CC AF Vattikuti, Shashaank Lee, James J. Chang, Christopher C. Hsu, Stephen D. H. Chow, Carson C. TI Applying compressed sensing to genome-wide association studies SO GIGASCIENCE LA English DT Article DE GWAS; Genomic selection; Compressed sensing; Lasso; Underdetermined system; Sparsity; Phase transition ID PHASE-TRANSITIONS; MODEL SELECTION; PREDICTION; REGRESSION; LASSO; GWAS; SNPS; HERITABILITY; PERFORMANCE; VARIANTS AB Background: The aim of a genome-wide association study (GWAS) is to isolate DNA markers for variants affecting phenotypes of interest. This is constrained by the fact that the number of markers often far exceeds the number of samples. Compressed sensing (CS) is a body of theory regarding signal recovery when the number of predictor variables (i.e., genotyped markers) exceeds the sample size. Its applicability to GWAS has not been investigated. Results: Using CS theory, we show that all markers with nonzero coefficients can be identified (selected) using an efficient algorithm, provided that they are sufficiently few in number (sparse) relative to sample size. For heritability equal to one (h(2) = 1), there is a sharp phase transition from poor performance to complete selection as the sample size is increased. For heritability below one, complete selection still occurs, but the transition is smoothed. We find for h(2) similar to 0.5 that a sample size of approximately thirty times the number of markers with nonzero coefficients is sufficient for full selection. This boundary is only weakly dependent on the number of genotyped markers. Conclusion: Practical measures of signal recovery are robust to linkage disequilibrium between a true causal variant and markers residing in the same genomic region. Given a limited sample size, it is possible to discover a phase transition by increasing the penalization; in this case a subset of the support may be recovered. Applying this approach to the GWAS analysis of height, we show that 70-100% of the selected markers are strongly correlated with height-associated markers identified by the GIANT Consortium. C1 [Vattikuti, Shashaank; Lee, James J.; Chow, Carson C.] NIDDK, Math Biol Sect, Lab Biol Modeling, NIH, Bethesda, MD 20814 USA. [Lee, James J.] Univ Minnesota Twin Cities, Dept Psychol, Minneapolis, MN 55455 USA. [Chang, Christopher C.] BGI Hong Kong, Tai Po, Hong Kong, Peoples R China. [Hsu, Stephen D. H.] Michigan State Univ, Dept Phys, E Lansing, MI 48824 USA. [Hsu, Stephen D. H.] Michigan State Univ, Res & Grad Studies, E Lansing, MI 48824 USA. [Lee, James J.; Chang, Christopher C.; Hsu, Stephen D. H.] BGI Shenzhen, Cognit Genom Lab, Shenzhen, Peoples R China. RP Hsu, SDH (reprint author), Michigan State Univ, Dept Phys, 426 Auditorium Rd, E Lansing, MI 48824 USA. EM hsu@msu.edu; carsonc@mail.nih.gov FU Intramural Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C]; National Human Genome Research Institute [U01HG004402] FX We thank Nick Patterson for comments on earlier versions of this work and Phil Schniter for input on the EM-GM-AMP algorithm [52]. This work was supported by the Intramural Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).; The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). The authors thank the staff and participants of the ARIC study for their important contributions. Funding for GENEVA was provided by National Human Genome Research Institute grant U01HG004402 (E. Boerwinkle). NR 55 TC 8 Z9 8 U1 1 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND EI 2047-217X J9 GIGASCIENCE JI GigaScience PD JUN 16 PY 2014 VL 3 AR 10 DI 10.1186/2047-217X-3-10 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CX4FF UT WOS:000365653700001 PM 25002967 ER PT J AU Tokumasu, F Crivat, G Ackerman, H Hwang, J Wellems, TE AF Tokumasu, Fuyuki Crivat, Georgeta Ackerman, Hans Hwang, Jeeseong Wellems, Thomas E. TI Inward cholesterol gradient of the membrane system in P. falciparum-infected erythrocytes involves a dilution effect from parasite-produced lipids SO BIOLOGY OPEN LA English DT Article DE Malaria; Plasmodium falciparum; Fluorescence lifetime imaging microscopy; Parasitophorous vacuole membrane; Maurer's cleft; Detergent-resistant membrane domain; Membrane rafts ID PARASITOPHOROUS VACUOLE MEMBRANE; LIFETIME IMAGING MICROSCOPY; ATOMIC-FORCE MICROSCOPY; GPI-ANCHORED PROTEINS; HOST IMMUNE-SYSTEM; RED-CELL MEMBRANE; PLASMODIUM-FALCIPARUM; MALARIA PARASITE; MAURERS CLEFTS; SICKLE HEMOGLOBIN AB Plasmodium falciparum (Pf) infection remodels the human erythrocyte with new membrane systems, including a modified host erythrocyte membrane (EM), a parasitophorous vacuole membrane (PVM), a tubulovesicular network (TVN), and Maurer's clefts (MC). Here we report on the relative cholesterol contents of these membranes in parasitized normal (HbAA) and hemoglobin Scontaining (HbAS, HbAS) erythrocytes. Results from fluorescence lifetime imaging microscopy (FLIM) experiments with a cholesterolsensitive fluorophore show that membrane cholesterol levels in parasitized erythrocytes (pRBC) decrease inwardly from the EM, to the MC/TVN, to the PVM, and finally to the parasite membrane (PM). Cholesterol depletion of pRBC by methyl-beta-cyclodextrin treatment caused a collapse of this gradient. Lipid and cholesterol exchange data suggest that the cholesterol gradient involves a dilution effect from non-sterol lipids produced by the parasite. FLIM signals from the PVM or PM showed little or no difference between parasitized HbAA vs HbS-containing erythrocytes that differed in lipid content, suggesting that malaria parasites may regulate the cholesterol contents of the PVM and PM independently of levels in the host cell membrane. Cholesterol levels may affect raft structures and the membrane trafficking and sorting functions that support Pf survival in HbAA, HbAS and HbSS erythrocytes. C1 [Tokumasu, Fuyuki; Crivat, Georgeta; Ackerman, Hans; Wellems, Thomas E.] NIAID, Malaria Genet Sect, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Crivat, Georgeta; Hwang, Jeeseong] NIST, Quantum Elect & Photon Div, Phys Measurement Lab, Boulder, CO 80305 USA. RP Tokumasu, F (reprint author), Univ Tokyo, Dept Lipid, Fac Med, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan. EM ftokumasu@m.u-tokyo.ac.jp OI Tokumasu, Fuyuki/0000-0003-2790-1071 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Institute of Standards and Technology (NIST) FX This research was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, and by the National Institute of Standards and Technology (NIST). Certain commercial equipment, instruments, or materials identified in this manuscript are to foster understanding. Such identification does not imply recommendation or endorsement by the NIST, nor does it imply that the materials or equipment identified are necessarily the best available for the purpose. Because all authors are government employees and this is a government work, the work is in the public domain in the United States. Notwithstanding any other agreements, the National Institutes of Health reserves the right to provide the work to Central for display and use by the public, and Central may tag or modify the work consistent with its customary practices. Rights outside of the USA can be established subject to a government use license. Biology Open NR 103 TC 8 Z9 8 U1 0 U2 6 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 2046-6390 J9 BIOL OPEN JI Biol. Open PD JUN 15 PY 2014 VL 3 IS 6 BP 529 EP 541 DI 10.1242/bio.20147732 PG 13 WC Biology SC Life Sciences & Biomedicine - Other Topics GA AZ2NC UT WOS:000348069200014 PM 24876390 ER PT J AU Mathe, EA Patterson, AD Haznadar, M Manna, SK Krausz, KW Bowman, ED Shields, PG Idle, JR Smith, PB Anami, K Kazandjian, DG Hatzakis, E Gonzalez, FJ Harris, CC AF Mathe, Ewy A. Patterson, Andrew D. Haznadar, Majda Manna, Soumen K. Krausz, Kristopher W. Bowman, Elise D. Shields, Peter G. Idle, Jeffrey R. Smith, Philip B. Anami, Katsuhiro Kazandjian, Dickran G. Hatzakis, Emmanuel Gonzalez, Frank J. Harris, Curtis C. TI Noninvasive Urinary Metabolomic Profiling Identifies Diagnostic and Prognostic Markers in Lung Cancer SO CANCER RESEARCH LA English DT Article ID TANDEM MASS-SPECTROMETRY; BREAST-CANCER; PROSTATE-CANCER; TUMOR-MARKERS; SMOKERS; NUCLEOSIDES; METABOLITES; BIOMARKERS; MUTATIONS; GEFITINIB AB Lung cancer remains the most common cause of cancer deaths worldwide, yet there is currently a lack of diagnostic noninvasive biomarkers that could guide treatment decisions. Small molecules (<1,500 Da) were measured in urine collected from 469 patients with lung cancer and 536 population controls using unbiased liquid chromatography/mass spectrometry. Clinical putative diagnostic and prognostic biomarkers were validated by quantitation and normalized to creatinine levels at two different time points and further confirmed in an independent sample set, which comprises 80 cases and 78 population controls, with similar demographic and clinical characteristics when compared with the training set. Creatine riboside (IUPAC name: 2-{2-[(2R,3R,4S,5R)-3,4- dihydroxy-5-(hydroxymethyl)-oxolan-2-yl]-1-methylcarbamimidamido}acetic acid), a novel molecule identified in this study, and N-acetylneuraminic acid (NANA) were each significantly (P < 0.00001) elevated in non-small cell lung cancer and associated with worse prognosis [HR = 1.81 (P = 0.0002), and 1.54 (P = 0.025), respectively]. Creatine riboside was the strongest classifier of lung cancer status in all and stage I-II cases, important for early detection, and also associated with worse prognosis in stage I-II lung cancer (HR = 1.71, P = 0.048). All measurements were highly reproducible with intraclass correlation coefficients ranging from 0.82 to 0.99. Both metabolites were significantly (P < 0.03) enriched in tumor tissue compared with adjacent nontumor tissue (N = 48), thus revealing their direct association with tumor metabolism. Creatine riboside and NANA may be robust urinary clinical metabolomic markers that are elevated in tumor tissue and associated with early lung cancer diagnosis and worse prognosis. (C)2014 AACR. C1 [Mathe, Ewy A.] NIAMS, Lab Mol Immunogen, Genom & Immun Sect, NIH, Bethesda, MD USA. [Mathe, Ewy A.; Haznadar, Majda; Bowman, Elise D.; Anami, Katsuhiro; Kazandjian, Dickran G.; Harris, Curtis C.] NCI, Lab Human Carcinogenesis, NIH, Bethesda, MD 20892 USA. [Manna, Soumen K.; Krausz, Kristopher W.; Gonzalez, Frank J.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Patterson, Andrew D.] Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. [Patterson, Andrew D.] Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, University Pk, PA 16802 USA. [Smith, Philip B.] Penn State Univ, Metabol Core Facil, University Pk, PA 16802 USA. [Hatzakis, Emmanuel] Penn State Univ, University Pk, PA 16802 USA. [Shields, Peter G.] Ohio State Univ, Ctr Canc, Columbus, OH 43210 USA. [Idle, Jeffrey R.] Univ Bern, Dept Clin Res, Bern, Switzerland. RP Harris, CC (reprint author), NCI, 37 Convent Dr,Room 3068A, Bethesda, MD 20892 USA. EM Curtis_Harris@nih.gov RI Patterson, Andrew/G-3852-2012; OI Patterson, Andrew/0000-0003-2073-0070; Idle, Jeff/0000-0002-6143-1520 FU NIH [ES022186] FX This work was partially funded by the NIH grant # ES022186. NR 56 TC 23 Z9 23 U1 6 U2 22 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 JUN 15 PY 2014 VL 74 IS 12 BP 3259 EP 3270 DI 10.1158/0008-5472.CAN-14-0109 PG 12 WC Oncology SC Oncology GA AL1IA UT WOS:000338877900007 PM 24736543 ER PT J AU Deyo, RA Dworkin, SF Amtmann, D Andersson, G Borenstein, D Carragee, E Carrino, J Chou, R Cook, K DeLitto, A Goertz, C Khalsa, P Loeser, J Mackey, S Panagis, J Rainville, J Tosteson, T Turk, D Von Korff, M Weiner, DK AF Deyo, Richard A. Dworkin, Samuel F. Amtmann, Dagmar Andersson, Gunnar Borenstein, David Carragee, Eugene Carrino, John Chou, Roger Cook, Karon DeLitto, Anthony Goertz, Christine Khalsa, Partap Loeser, John Mackey, Sean Panagis, James Rainville, James Tosteson, Tor Turk, Dennis Von Korff, Michael Weiner, Debra K. TI Report of the NIH Task Force on Research Standards for Chronic Low Back Pain SO SPINE LA English DT Article DE low back pain; chronic low back pain; research standards; minimum data set; NIH Task Force ID CLINICAL-PRACTICE GUIDELINE; DEFINING CHRONIC PAIN; INFORMATION-SYSTEM PROMIS; FUNCTION ITEM BANK; QUALITY-OF-LIFE; PRIMARY-CARE; PROGNOSTIC APPROACH; SCREENING TOOL; START BACK; OUTCOME MEASURES AB Despite rapidly increasing intervention, functional disability due to chronic low back pain (cLBP) has increased in recent decades. We often cannot identify mechanisms to explain the major negative impact cLBP has on patients' lives. Such cLBP is often termed nonspecific and may be due to multiple biologic and behavioral etiologies. Researchers use varied inclusion criteria, definitions, baseline assessments, and outcome measures, which impede comparisons and consensus. Therefore, NIH Pain Consortium charged a research task force to draft standards for research on cLBP. The resulting multidisciplinary panel recommended using 2 questions to define cLBP; classifying cLBP by its impact (defined by pain intensity, pain interference, and physical function); use of a minimum data set to describe research participants (drawing heavily on the Patient Reported Outcomes Measurement Information System methodology); reporting "responder analyses" in addition to mean outcome scores; and suggestions for future research and dissemination. The Pain Consortium has approved the recommendations, which investigators should incorporate into NIH grant proposals. The research task force believes that these recommendations will advance the field, help resolve controversies, and facilitate future research addressing the genomic, neurological, and other mechanistic substrates of cLBP. We expect that the research task force recommendations will become a dynamic document and undergo continual improvement. Perspective: A task force was convened by the NIH Pain Consortium with the goal of developing research standards for cLBP. The results included recommendations for definitions, a minimum data set, reporting outcomes, and future research. Greater consistency in reporting should facilitate comparisons among studies and the development of phenotypes. C1 [Deyo, Richard A.; Chou, Roger] Oregon Hlth & Sci Univ, Portland, OR 97239 USA. [Dworkin, Samuel F.; Amtmann, Dagmar; Loeser, John; Turk, Dennis] Univ Washington, Seattle, WA 98195 USA. [Andersson, Gunnar] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Borenstein, David] George Washington Univ, Washington, DC USA. [Carragee, Eugene; Mackey, Sean] Stanford Univ, Stanford, CA 94305 USA. [Carrino, John] Johns Hopkins Univ, Baltimore, MD USA. [Cook, Karon] Northwestern Univ, Evanston, IL USA. [DeLitto, Anthony; Weiner, Debra K.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [DeLitto, Anthony; Weiner, Debra K.] Univ Pittsburgh, Pittsburgh, PA USA. [Goertz, Christine] Palmer Coll Chiropract, Davenport, IA USA. [Khalsa, Partap] Natl Ctr Complementary & Alternat Med, Bethesda, MD USA. [Panagis, James] NIAMSD, Bethesda, MD 20892 USA. [Rainville, James] New England Baptist Hosp, Roxbury Crossing, MA USA. [Tosteson, Tor] Dartmouth Coll, Hanover, NH USA. [Von Korff, Michael] Grp Hlth Res Inst, Seattle, WA USA. RP Deyo, RA (reprint author), Oregon Hlth & Sci Univ, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM deyor@ohsu.edu FU National Center for Complementary and Alternative Medicine; National Institute for Arthritis and Musculoskeletal and Skin Diseases FX Supported by the National Center for Complementary and Alternative Medicine and the National Institute for Arthritis and Musculoskeletal and Skin Diseases. NR 127 TC 13 Z9 13 U1 9 U2 19 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-2436 EI 1528-1159 J9 SPINE JI SPINE PD JUN 15 PY 2014 VL 39 IS 14 BP 1128 EP 1143 DI 10.1097/BRS.0000000000000434 PG 16 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA AL5HL UT WOS:000339164300014 PM 24887571 ER PT J AU Fondell, E O'Reilly, EJ Fitzgerald, KC Falcone, GJ Kolonel, LN Park, Y McCullough, ML Ascherio, A AF Fondell, Elinor O'Reilly, Eilis J. Fitzgerald, Kathryn C. Falcone, Guido J. Kolonel, Laurence N. Park, Yikyung McCullough, Marjorie L. Ascherio, Alberto TI Dietary Fiber and Amyotrophic Lateral Sclerosis: Results From 5 Large Cohort Studies SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE amyotrophic lateral sclerosis; fiber; longitudinal cohort studies; motor neuron disease ID FOOD FREQUENCY QUESTIONNAIRE; C-REACTIVE PROTEIN; SOCIETY CANCER PREVENTION; BASE-LINE CHARACTERISTICS; GLYCEMIC LOAD; SYSTEMIC INFLAMMATION; ALCOHOL-CONSUMPTION; MULTIETHNIC COHORT; CIGARETTE-SMOKING; NUTRITION COHORT AB Amyotrophic lateral sclerosis (ALS) is a fast-progressing neurodegenerative disease with a median survival time from diagnosis of 1.5-3 years. The cause of ALS is unknown, but inflammation may play a role. Fiber has been shown to lower inflammatory markers, and a high fiber intake was associated with a lower risk of ALS in a case-control study; however, prospective studies are lacking. We explored the relation between dietary intake of fiber and the risk of ALS in 5 large prospective cohort studies comprising over 1,050,000 US citizens who contributed 1,133 ALS cases during a mean of 15 years of follow-up (1980-2008). Cox proportional hazards models were used within each cohort, and cohort-specific estimates were subsequently pooled using a random-effects model. We found that intakes of total fiber, cereal fiber, vegetable fiber, and fruit fiber were not associated with ALS risk when comparing the highest quintile of intake with the lowest (for total fiber, pooled multivariable relative risk (RR) = 0.99, 95% confidence interval (CI): 0.80, 1.24; for cereal fiber, RR = 1.13, 95% CI: 0.94, 1.37; for vegetable fiber, RR = 0.97, 95% CI: 0.77, 1.23; and for fruit fiber, RR = 1.05, 95% CI: 0.86, 1.29). These findings do not support the hypothesis that fiber intake is a major determinant of ALS risk. C1 [Fondell, Elinor; O'Reilly, Eilis J.; Fitzgerald, Kathryn C.; Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Falcone, Guido J.; Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Falcone, Guido J.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Kolonel, Laurence N.] Univ Hawaii, Program Epidemiol, Ctr Canc, Honolulu, HI 96822 USA. [Park, Yikyung] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol, Bethesda, MD 20892 USA. [McCullough, Marjorie L.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Ascherio, Alberto] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Ascherio, Alberto] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Fondell, E (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 655 Huntington Ave, Boston, MA 02115 USA. EM efondell@hsph.harvard.edu RI Falcone, Guido/L-2287-2016; OI Falcone, Guido/0000-0002-6407-0302; Park, Yikyung/0000-0002-6281-489X FU National Institute of Neurological Diseases and Stroke [R01 NS045893]; National Cancer Institute [P01 CA87969, P01 CA055075] FX This work was supported by grant R01 NS045893 from the National Institute of Neurological Diseases and Stroke and grants P01 CA87969 and P01 CA055075 from the National Cancer Institute. NR 40 TC 0 Z9 0 U1 1 U2 6 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 JUN 15 PY 2014 VL 179 IS 12 BP 1442 EP 1449 DI 10.1093/aje/kwu089 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AK0MC UT WOS:000338106100008 PM 24816788 ER PT J AU Lin, CHS Chen, J Ziman, B Marshall, S Maizel, J Goligorsky, MS AF Lin, Chi Hua Sarah Chen, Jun Ziman, Bruce Marshall, Shannon Maizel, Julien Goligorsky, Michael S. TI Endostatin and kidney fibrosis in aging: a case for antagonistic pleiotropy? SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE endostatin; dormant tumors; aging; antiangiogenesis ID COLLAGEN XVIII; GROWTH-FACTOR; TUMOR-GROWTH; SIRTUIN 1; ANGIOGENESIS; CELLS; SENESCENCE; DISEASE; MICE; TELOMERES AB A recurring theme of a host of gerontologic studies conducted in either experimental animals or in humans is related to documenting the functional decline with age. We hypothesize that elevated circulating levels of a powerful antiangiogenic peptide, endostatin, represent one of the potent systemic causes for multiorgan microvascular rarefaction and functional decline due to fibrosis. It is possible that during the life span of an organism there is an accumulation of dormant transformed cells producing antiangiogenic substances (endostatin) that maintain the dormancy of such scattered malignant cells. The proof of this postulate cannot be obtained by physically documenting these scattered cells, and it rests exclusively on the detection of sequelae of shifted pro- and antiangiogenic balance toward the latter. Here we compared circulating levels of endostatin in young and aging mice of two different strains and showed that endostatin levels are elevated in the latter. Renal expression of endostatin increased similar to 5.6-fold in aging animals. This was associated with microvascular rarefaction and progressive tubulointerstitial fibrosis. In parallel, the levels of sirtuins 1 and 3 were significantly suppressed in aging mice in conjunction with the expression of markers of senescence. Treating young mice with endostatin for 28 days showed delayed recovery of circulation after femoral artery ligation and reduced patency of renal microvasculature but no fibrosis. In conclusion, the findings are consistent with the hypothesis on elevation of endostatin levels and parallel microvascular rarefaction and induction of renal fibrosis in aging mice. C1 [Lin, Chi Hua Sarah; Chen, Jun; Goligorsky, Michael S.] New York Med Coll, Dept Med, Valhalla, NY 10595 USA. [Lin, Chi Hua Sarah; Chen, Jun; Goligorsky, Michael S.] New York Med Coll, Dept Physiol & Pharmacol, Valhalla, NY 10595 USA. [Ziman, Bruce; Marshall, Shannon] NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. [Maizel, Julien] Univ Amiens, Dept Intens Care Med, Amiens, France. RP Goligorsky, MS (reprint author), NYMC, Basic Sci Bldg,15 Dana Rd, Valhalla, NY 10595 USA. EM michael_goligorsky@nymc.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [DK-54602, DK-052783, DK-45462]; Westchester Artificial Kidney Foundation FX This study was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-54602, DK-052783, and DK-45462 and Westchester Artificial Kidney Foundation. NR 50 TC 11 Z9 11 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 EI 1522-1539 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD JUN 15 PY 2014 VL 306 IS 12 BP H1692 EP H1699 DI 10.1152/ajpheart.00064.2014 PG 8 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA AK3WD UT WOS:000338354900010 PM 24727495 ER PT J AU Leslie, R O'Donnell, CJ Johnson, AD AF Leslie, Richard O'Donnell, Christopher J. Johnson, Andrew D. TI GRASP: analysis of genotype-phenotype results from 1390 genome-wide association studies and corresponding open access database SO BIOINFORMATICS LA English DT Article; Proceedings Paper CT 10th Student Council Symposium of the International-Society-for-Computational-Biology (ISCB) held in conjunction with the 22nd Annual Meeting of Intelligent Systems for Molecular Biology (ISMB) CY JUL 11, 2014 CL Boston, MA SP Int Soc Computat Biol ID PROSTATE-CANCER SUSCEPTIBILITY; EUROPEAN POPULATIONS; GENETIC ASSOCIATION; PARKINSONS-DISEASE; COMMON VARIANTS; LOCI; MULTIPLE; TRAITS; RISK; IDENTIFICATION AB We created a deeply extracted and annotated database of genome-wide association studies (GWAS) results. GRASP v1.0 contains 46.2 million SNP-phenotype association from among 1390 GWAS studies. We re-annotated GWAS results with 16 annotation sources including some rarely compared to GWAS results (e.g. RNAediting sites, lincRNAs, PTMs). Motivation: To create a high-quality resource to facilitate further use and interpretation of human GWAS results in order to address important scientific questions. Results: GWAS have grown exponentially, with increases in sample sizes and markers tested, and continuing bias toward European ancestry samples. GRASP contains > 100 000 phenotypes, roughly: eQTLs (71.5%), metabolite QTLs (21.2%), methylation QTLs (4.4%) and diseases, biomarkers and other traits (2.8%). c/s-eQTLs, meQTLs, mQTLs and MHC region SNPs are highly enriched among significant results. After removing these categories, GRASP still contains a greater proportion of studies and results than comparable GWAS catalogs. Cardiovascular disease and related risk factors pre-dominate remaining GWAS results, followed by immunological, neurological and cancer traits. Significant results in GWAS display a highly gene-centric tendency. Sex chromosome X (OR= 0.18[0.16-0.20]) and Y (OR= 0.003[0.001-0.01]) genes are depleted for GWAS results. Gene length is correlated with GWAS results at nominal significance (P <= 0.05) levels. We show this gene-length correlation decays at increasingly more stringent P-value thresholds. Potential pleotropic genes and SNPs enriched for multi-phenotype association in GWAS are identified. However, we note possible population stratification at some of these loci. Finally, via re-annotation we identify compelling functional hypotheses at GWAS loci, in some cases unrealized in studies to date. Conclusion: Pooling summary-level GWAS results and re-annotating with bioinformatics predictions and molecular features provides a good platform for new insights. C1 [Leslie, Richard; O'Donnell, Christopher J.; Johnson, Andrew D.] NHLBI, Cardiovasc Epidemiol & Human Genom Branch, Framingham Heart Study, Framingham, MA 01702 USA. [Leslie, Richard] Univ Massachusetts, Sch Med, Worcester, MA 01655 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP Johnson, AD (reprint author), NHLBI, Cardiovasc Epidemiol & Human Genom Branch, Framingham Heart Study, Framingham, MA 01702 USA. EM johnsonad2@nhlbi.nih.gov RI Johnson, Andrew/G-6520-2013 FU National Heart, Lung and Blood Institute intramural funds FX National Heart, Lung and Blood Institute intramural funds to R. L., C.J.O. and A.D.J. NR 58 TC 30 Z9 30 U1 3 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD JUN 15 PY 2014 VL 30 IS 12 BP 185 EP 194 DI 10.1093/bioinformatics/btu273 PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA AK0NF UT WOS:000338109200022 PM 24931982 ER PT J AU Huang, L Li, FH Sheng, JT Xia, XF Ma, JW Zhan, M Wong, STC AF Huang, Lei Li, Fuhai Sheng, Jianting Xia, Xiaofeng Ma, Jinwen Zhan, Ming Wong, Stephen T. C. TI DrugComboRanker: drug combination discovery based on target network analysis SO BIOINFORMATICS LA English DT Article; Proceedings Paper CT 10th Student Council Symposium of the International-Society-for-Computational-Biology (ISCB) held in conjunction with the 22nd Annual Meeting of Intelligent Systems for Molecular Biology (ISMB) CY JUL 11, 2014 CL Boston, MA SP Int Soc Computat Biol ID SIGNALING NETWORK; CANCER; MOLECULES; HOTSPOTS; GENES; MAP AB Motivation: Currently there are no curative anticancer drugs, and drug resistance is often acquired after drug treatment. One of the reasons is that cancers are complex diseases, regulated by multiple signaling pathways and cross talks among the pathways. It is expected that drug combinations can reduce drug resistance and improve patients' outcomes. In clinical practice, the ideal and feasible drug combinations are combinations of existing Food and Drug Administration-approved drugs or bioactive compounds that are already used on patients or have entered clinical trials and passed safety tests. These drug combinations could directly be used on patients with less concern of toxic effects. However, there is so far no effective computational approach to search effective drug combinations from the enormous number of possibilities. Results: In this study, we propose a novel systematic computational tool DrugComboRanker to prioritize synergistic drug combinations and uncover their mechanisms of action. We first build a drug functional network based on their genomic profiles, and partition the network into numerous drug network communities by using a Bayesian non-negative matrix factorization approach. As drugs within overlapping community share common mechanisms of action, we next uncover potential targets of drugs by applying a recommendation system on drug communities. We meanwhile build disease-specific signaling networks based on patients' genomic profiles and interactome data. We then identify drug combinations by searching drugs whose targets are enriched in the complementary signaling modules of the disease signaling network. The novel method was evaluated on lung adenocarcinoma and endocrine receptor positive breast cancer, and compared with other drug combination approaches. These case studies discovered a set of effective drug combinations top ranked in our prediction list, and mapped the drug targets on the disease signaling network to highlight the mechanisms of action of the drug combinations. C1 [Huang, Lei; Ma, Jinwen] Peking Univ, Sch Math Sci, Dept Informat Sci, Beijing 100871, Peoples R China. [Huang, Lei; Ma, Jinwen] Peking Univ, LMAM, Beijing 100871, Peoples R China. [Huang, Lei; Li, Fuhai; Sheng, Jianting; Xia, Xiaofeng; Zhan, Ming; Wong, Stephen T. C.] NCI, Ctr Modeling Canc Dev, Dept Syst Med & Bioengn, Houston Methodist Hosp,Res Inst, Houston, TX 77030 USA. [Huang, Lei; Li, Fuhai; Sheng, Jianting; Xia, Xiaofeng; Zhan, Ming; Wong, Stephen T. C.] Cornell Univ, Weill Cornell Med Coll, Houston, TX 77030 USA. RP Wong, STC (reprint author), NCI, Ctr Modeling Canc Dev, Dept Syst Med & Bioengn, Houston Methodist Hosp,Res Inst, Houston, TX 77030 USA. EM stwong@tmhs.org FU CPRIT [RP110532]; NCI [U54 CA149196]; Ting Tsung and Wei Fong Chao Foundation; John S Dunn Foundation FX CPRIT (RP110532) and NCI (U54 CA149196). Ting Tsung and Wei Fong Chao Foundation and John S Dunn Foundation NR 30 TC 24 Z9 25 U1 0 U2 12 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD JUN 15 PY 2014 VL 30 IS 12 BP 228 EP 236 DI 10.1093/bioinformatics/btu278 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA AK0NF UT WOS:000338109200027 PM 24931988 ER PT J AU Arnaldez, FI Helman, LJ AF Arnaldez, Fernanda I. Helman, Lee J. TI New Strategies in Ewing Sarcoma: Lost in Translation? SO CLINICAL CANCER RESEARCH LA English DT Article ID CHILDRENS-ONCOLOGY-GROUP; FACTOR-I RECEPTOR; PEDIATRIC SOLID TUMORS; GENE-EXPRESSION; HISTONE DEACETYLASE; TARGET GENE; PHASE-II; TRANSCRIPTIONAL REPRESSION; MONOCLONAL-ANTIBODY; INHIBITS GROWTH AB Ewing sarcoma is the second most common pediatric malignant bone tumor. Aggressive multimodality therapy has led to an improvement in outcomes, particularly in patients with localized disease. However, therapy-related toxicities are not trivial, and the prognosis for patients with relapsed and/or metastatic disease continues to be poor. In this article, we outline some of the promising therapies that have the potential to change the Ewing sarcoma therapeutic paradigm in the not-too-distant future: insulin-like growth factor receptor inhibitors, targeting of the fusion protein, epigenetic manipulation, PARP inhibitors, and immunotherapy. (C) 2014 AACR. C1 [Arnaldez, Fernanda I.; Helman, Lee J.] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Arnaldez, FI (reprint author), NCI, 10 Ctr Dr,Bldg 10CRC,Room 13816, Bethesda, MD 20892 USA. EM arnaldezf@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999, ZIA BC011493-01] NR 71 TC 5 Z9 6 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN 15 PY 2014 VL 20 IS 12 BP 3050 EP 3056 DI 10.1158/1078-0432.CCR-13-0633 PG 7 WC Oncology SC Oncology GA AK3SG UT WOS:000338344400002 PM 24756371 ER PT J AU Nakaoku, T Tsuta, K Ichikawa, H Shiraishi, K Sakamoto, H Enari, M Furuta, K Shimada, Y Ogiwara, H Watanabe, S Nokihara, H Yasuda, K Hiramoto, M Nammo, T Ishigame, T Schetter, AJ Okayama, H Harris, CC Kim, YH Mishima, M Yokota, J Yoshida, T Kohno, T AF Nakaoku, Takashi Tsuta, Koji Ichikawa, Hitoshi Shiraishi, Kouya Sakamoto, Hiromi Enari, Masato Furuta, Koh Shimada, Yoko Ogiwara, Hideaki Watanabe, Shun-ichi Nokihara, Hiroshi Yasuda, Kazuki Hiramoto, Masaki Nammo, Takao Ishigame, Teruhide Schetter, Aaron J. Okayama, Hirokazu Harris, Curtis C. Kim, Young Hak Mishima, Michiaki Yokota, Jun Yoshida, Teruhiko Kohno, Takashi TI Druggable Oncogene Fusions in Invasive Mucinous Lung Adenocarcinoma SO CLINICAL CANCER RESEARCH LA English DT Article ID INTERNATIONAL ASSOCIATION; TARGETED THERAPIES; CANCER; RET; CLASSIFICATION; ALK; INHIBITOR; GENOME; RAF AB Purpose: To identify druggable oncogenic fusions in invasive mucinous adenocarcinoma (IMA) of the lung, a malignant type of lung adenocarcinoma in which KRAS mutations frequently occur. Experimental Design: From an IMA cohort of 90 cases, consisting of 56 cases (62%) with KRAS mutations and 34 cases without (38%), we conducted whole-transcriptome sequencing of 32 IMAs, including 27 cases without KRAS mutations. We used the sequencing data to identify gene fusions, and then performed functional analyses of the fusion gene products. Results: We identified oncogenic fusions that occurred mutually exclusively with KRAS mutations: CD74-NRG1, SLC3A2-NRG1, EZR-ERBB4, TRIM24-BRAF, and KIAA1468-RET. NRG1 fusions were present in 17.6% (6/34) of KRAS-negative IMAs. The CD74-NRG1 fusion activated HER2:HER3 signaling, whereas the EZR-ERBB4 and TRIM24-BRAF fusions constitutively activated the ERBB4 and BRAF kinases, respectively. Signaling pathway activation and fusion-induced anchorage-independent growth/tumorigenicity of NIH3T3 cells expressing these fusions were suppressed by tyrosine kinase inhibitors approved for clinical use. Conclusions: Oncogenic fusions act as driver mutations in IMAs without KRAS mutations, and thus represent promising therapeutic targets for the treatment of such IMAs. (C) 2014 AACR. C1 [Nakaoku, Takashi; Shiraishi, Kouya; Shimada, Yoko; Ogiwara, Hideaki; Yokota, Jun; Kohno, Takashi] Natl Canc Ctr, Div Genome Biol, Tokyo 1040045, Japan. [Ichikawa, Hitoshi; Sakamoto, Hiromi] Natl Canc Ctr, Div Genet, Tokyo 1040045, Japan. [Enari, Masato] Natl Canc Ctr, Div Refractory Canc Res, Tokyo 1040045, Japan. [Tsuta, Koji; Furuta, Koh] Natl Canc Ctr, Div Pathol & Clin Labs, Chuo Ku, Tokyo, Japan. [Watanabe, Shun-ichi] Natl Canc Ctr, Div Thorac Surg, Chuo Ku, Tokyo, Japan. [Nokihara, Hiroshi] Natl Canc Ctr, Div Thorac Oncol, Chuo Ku, Tokyo, Japan. [Yasuda, Kazuki; Hiramoto, Masaki; Nammo, Takao] Natl Ctr Global Hlth & Med, Res Inst, Diabet Res Ctr, Dept Metab Disorder,Shinjuku Ku, Tokyo, Japan. [Kim, Young Hak; Mishima, Michiaki] Kyoto Univ, Grad Sch Med, Dept Resp Med, Sakyo Ku, Kyoto, Japan. [Ishigame, Teruhide; Schetter, Aaron J.; Okayama, Hirokazu; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Yokota, Jun] Inst Predict & Personalized Med Canc IMPPC, Barcelona, Spain. RP Kohno, T (reprint author), Natl Canc Ctr, Div Genome Biol, Chuo Ku, 5-1-1 Tsukiji, Tokyo 1040045, Japan. EM tkkohno@ncc.go.jp FU Advanced Research for Medical Products Mining Program of the National Institute of Biomedical Innovation (NIBIO); Ministry of Health, Labor, and Welfare; Princess Takamatsu Cancer Research Fund FX This work was supported, in part, by the Advanced Research for Medical Products Mining Program of the National Institute of Biomedical Innovation (NIBIO), Grants-in-Aid from the Ministry of Health, Labor, and Welfare for the Third-term Comprehensive 10 year Strategy for Cancer Control and for Research for Promotion of Cancer Control Programs; and the Princess Takamatsu Cancer Research Fund. NR 27 TC 36 Z9 39 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN 15 PY 2014 VL 20 IS 12 BP 3087 EP 3093 DI 10.1158/1078-0432.CCR-14-0107 PG 7 WC Oncology SC Oncology GA AK3SG UT WOS:000338344400007 PM 24727320 ER PT J AU Cook, KL Warri, A Soto-Pantoja, DR Clarke, PAG Cruz, MI Zwart, A Clarke, R AF Cook, Katherine L. Waerri, Anni Soto-Pantoja, David R. Clarke, Pamela A. G. Cruz, M. Idalia Zwart, Alan Clarke, Robert TI Hydroxychloroquine Inhibits Autophagy to Potentiate Antiestrogen Responsiveness in ER+ Breast Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID CELL-LINE MCF-7; RESISTANCE; ESTROGEN; TAMOXIFEN; APOPTOSIS; CHLOROQUINE; ANGIOGENESIS; METASTASIS; SIGNATURE; CARCINOMA AB Purpose: Estrogen receptor-alpha (ER alpha)-targeted therapies including tamoxifen (TAM) or Faslodex (ICI) are used to treat ER+ breast cancers. Up to 50% of tumors will acquire resistance to these interventions. Autophagy has been implicated as a major driver of antiestrogen resistance. We have explored the ability of hydroxychloroquine (HCQ), which inhibits autophagy, to affect antiestrogen responsiveness. Experimental Design: TAM-resistant MCF7-RR and ICI-resistant/TAM cross-resistant LCC9 ER+ breast cancer cells were injected into mammary fat pads of female athymic mice and treated with TAM and/or ICI in combination with oral low-dose HCQ. Results: We show that HCQ can increase antiestrogen responsiveness in MCF7-RR and LCC9 cells and tumors, likely through the inhibition of autophagy. However, the combination of ICI+HCQ was less effective than HCQ alone in vivo, unlike the TAM+HCQ combination. Antiestrogen treatment stimulated angiogenesis in tumors but did not prevent HCQ effectiveness. The lower efficacy of ICI+HCQ was associated with ICI effects on cell-mediated immunity within the tumor microenvironment. The mouse chemokine KC (CXCL1) and IFN gamma were differentially regulated by both TAM and ICI treatments, suggesting a possible effect on macrophage development/activity. Consistent with these observations, TAM+HCQ treatment increased tumor CD68(+) cells infiltration, whereas ICI and ICI+HCQ reduced peripheral tumor macrophage content. Moreover, macrophage elimination of breast cancer target cells in vitro was reduced following exposure to ICI. Conclusion: HCQ restores antiestrogen sensitivity to resistant tumors. Moreover, the beneficial combination of TAM+HCQ suggests a positive outcome for ongoing neoadjuvant clinical trials using this combination for the treatment of ER+ ductal carcinoma in situ lesions. (C) 2014 AACR. C1 [Cook, Katherine L.; Waerri, Anni; Clarke, Pamela A. G.; Cruz, M. Idalia; Zwart, Alan; Clarke, Robert] Georgetown Univ, Med Ctr, Dept Oncol, Washington, DC 20057 USA. [Cook, Katherine L.; Waerri, Anni; Clarke, Pamela A. G.; Cruz, M. Idalia; Zwart, Alan; Clarke, Robert] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. [Soto-Pantoja, David R.] NCI, Dept Pathol, NIH, Bethesda, MD 20892 USA. RP Clarke, R (reprint author), Georgetown Univ, Med Ctr, W405A Res Bldg,3970 Reservoir Rd NW, Washington, DC 20057 USA. EM clarker@georgetown.edu RI Clarke, Robert/A-6485-2008; OI Clarke, Robert/0000-0002-9278-0854; Cook, Katherine/0000-0001-6241-0214 FU US Department of Health and Human Services [R01-CA131465, U54-CA149147]; DOD Breast Cancer Research Program Postdoctoral Fellowship [BC112023] FX This work was supported, in part, by awards from the US Department of Health and Human Services (R01-CA131465 and U54-CA149147; to R. Clarke) and a DOD Breast Cancer Research Program Postdoctoral Fellowship (BC112023; to K.L. Cook). NR 44 TC 18 Z9 20 U1 2 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN 15 PY 2014 VL 20 IS 12 BP 3222 EP 3232 DI 10.1158/1078-0432.CCR-13-3227 PG 11 WC Oncology SC Oncology GA AK3SG UT WOS:000338344400018 PM 24928945 ER PT J AU Afzal, MM Latour, LL Armstrong, RC Butman, JA Chan, L Cota, MR Dsurney, J Eisenberg, HM Fitzsimmons, SM Joshi, S Merchant, RE Pham, DL Roy, MJ Shenouda, CN Vandermerwe, AJ Diaz-Arrastia, RR AF Afzal, M. M. Latour, L. L. Armstrong, R. C. Butman, J. A. Chan, L. Cota, M. R. Dsurney, J. Eisenberg, H. M. Fitzsimmons, S. M. Joshi, S. Merchant, R. E. Pham, D. L. Roy, M. J. Shenouda, C. N. Vandermerwe, A. J. Diaz-Arrastia, R. R. TI RECRUITMENT, SCREENING, AND CLASSIFICATION OF ACUTE TBI: ADVANTAGES OF A MULTI-PATHWAY SCREENING PROTOCOL SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 32nd Annual National Neurotrauma Symposium CY JUN 29-JUL 02, 2014 CL San Francisco, CA DE classification; early MRI; multi-site; recruitment; screening C1 [Afzal, M. M.; Latour, L. L.; Armstrong, R. C.; Butman, J. A.; Chan, L.; Cota, M. R.; Dsurney, J.; Fitzsimmons, S. M.; Joshi, S.; Pham, D. L.; Roy, M. J.; Shenouda, C. N.; Vandermerwe, A. J.; Diaz-Arrastia, R. R.] Ctr Neurosci & Regenerat Med, Bethesda, MD USA. [Latour, L. L.] NINDS, Bethesda, MD 20892 USA. [Armstrong, R. C.; Roy, M. J.; Diaz-Arrastia, R. R.] USUHS, Bethesda, MD USA. [Butman, J. A.; Chan, L.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Eisenberg, H. M.] Univ Maryland, Med Ctr, Baltimore, MD 21201 USA. [Merchant, R. E.] Virginia Commonwealth Univ, Richmond, VA 23284 USA. NR 0 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 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2014 VL 31 IS 12 MA A2-13 BP A28 EP A29 PG 2 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA AK5DC UT WOS:000338443600074 ER PT J AU Curley, KC Greenspan, A Hicks, RA Hoffman, SW Miller, AC AF Curley, K. C. Greenspan, A. Hicks, R. A. Hoffman, S. W. Miller, A. C. TI FEDERAL COORDINATION FOR TRAUMATIC BRAIN INJURY RESEARCH: THE NATIONAL RESEARCH ACTION PLAN SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 32nd Annual National Neurotrauma Symposium CY JUN 29-JUL 02, 2014 CL San Francisco, CA DE federal funding agencies; research coordination; strategic planning C1 [Curley, K. C.] US Army MRMC, Ft Detrick, MD USA. [Greenspan, A.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Hicks, R. A.] NINDS, NIH, Rockville, MD USA. [Hoffman, S. W.] Dept Vet Affairs, Washington, DC USA. [Miller, A. C.] US DOE, Washington, DC 20585 USA. NR 0 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 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2014 VL 31 IS 12 MA B1-22 BP A51 EP A52 PG 2 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA AK5DC UT WOS:000338443600138 ER PT J AU Dempsey, AI Moses, AD Armstrong, RC Butman, JA Cota, MR Nair, G Perl, DP Chaudhury, AR Reich, DS Parikh, G Latour, LL AF Dempsey, A. I. Moses, A. D. Armstrong, R. C. Butman, J. A. Cota, M. R. Nair, G. Perl, D. P. Chaudhury, A. R. Reich, D. S. Parikh, G. Latour, L. L. TI MRI TARGETED PATHOLOGY OF ACUTE TBI SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 32nd Annual National Neurotrauma Symposium CY JUN 29-JUL 02, 2014 CL San Francisco, CA DE acute injury; histopathology; imaging; MRI; pathology C1 [Dempsey, A. I.; Moses, A. D.; Armstrong, R. C.; Cota, M. R.; Perl, D. P.] Ctr Neurosci & Regenerat Med, Bethesda, MD USA. [Butman, J. A.; Nair, G.; Chaudhury, A. R.; Reich, D. S.; Parikh, G.; Latour, L. L.] NIH, Bethesda, MD 20892 USA. [Armstrong, R. C.; Perl, D. P.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 0 TC 0 Z9 0 U1 0 U2 0 PU 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 JUN 15 PY 2014 VL 31 IS 12 MA A2-26 BP A33 EP A34 PG 2 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA AK5DC UT WOS:000338443600087 ER PT J AU Diaz-Arrastia, R Moore, CB Amyot, F Kenney, K Shenouda, C Gandjbakhche, A Wasserman, EM AF Diaz-Arrastia, R. Moore, C. B. Amyot, F. Kenney, K. Shenouda, C. Gandjbakhche, A. Wasserman, E. M. TI CEREBROVASCULAR DYSFUNCTION AFTER TRAUMATIC BRAIN INJURY: ASSESSMENT WITH MRI AND NIRS SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 32nd Annual National Neurotrauma Symposium CY JUN 29-JUL 02, 2014 CL San Francisco, CA DE BOLD-MRI; cerebrovascular reactivity; near-infrared C1 [Diaz-Arrastia, R.; Moore, C. B.; Amyot, F.; Kenney, K.; Shenouda, C.; Gandjbakhche, A.] Ctr Neurosci & Regenerat Med, Bethesda, MD USA. [Diaz-Arrastia, R.; Moore, C. B.; Amyot, F.; Kenney, K.; Wasserman, E. M.] USUHS, Bethesda, MD USA. [Diaz-Arrastia, R.; Moore, C. B.; Kenney, K.; Wasserman, E. M.] NINDS, Bethesda, MD 20892 USA. [Amyot, F.; Gandjbakhche, A.] NICHD, Bethesda, MD USA. [Shenouda, C.] NIH, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 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 JUN 15 PY 2014 VL 31 IS 12 MA A2-21 BP A32 EP A32 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA AK5DC UT WOS:000338443600082 ER PT J AU Magrath, ER Pham, DL Chou, YY Afzal, MM Rao, A Mongkolwat, P Latour, L Butman, JA AF Magrath, E. R. Pham, D. L. Chou, Y. Y. Afzal, M. M. Rao, A. Mongkolwat, P. Latour, L. Butman, J. A. TI CHARACTERIZING TBI RADIOLOGY READS USING THE ANNOTATION AND IMAGE MARKUP PLATFORM SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 32nd Annual National Neurotrauma Symposium CY JUN 29-JUL 02, 2014 CL San Francisco, CA DE CT; imaging; MRI; TBI C1 [Magrath, E. R.; Pham, D. L.; Chou, Y. Y.; Afzal, M. M.] HJF, CNRM, Bethesda, MD USA. [Rao, A.] UCSF, San Francisco, CA USA. [Mongkolwat, P.] Northwestern Univ, Chicago, IL 60611 USA. [Latour, L.] NINDS, Bethesda, MD 20892 USA. [Butman, J. A.] RAD&IS, Bethesda, MD USA. NR 0 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 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2014 VL 31 IS 12 MA A2-14 BP A29 EP A29 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA AK5DC UT WOS:000338443600075 ER PT J AU McEntee, JE Chou, YY McNally, SM Chan, L Butman, JA Pham, PL AF McEntee, J. E. Chou, Y. Y. McNally, S. M. Chan, L. Butman, J. A. Pham, P. L. TI CROSS-SECTIONAL VOLUMETRIC COMPARISON OF MILD AND MODERATE TRAUMATIC BRAIN INJURY SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 32nd Annual National Neurotrauma Symposium CY JUN 29-JUL 02, 2014 CL San Francisco, CA DE cross-sectional; segmentation; TBI; TBI classification; voxel based morphometry C1 [McEntee, J. E.; Chou, Y. Y.; McNally, S. M.; Chan, L.; Butman, J. A.; Pham, P. L.] CNRM, Bethesda, MD USA. [McEntee, J. E.; Chou, Y. Y.; Butman, J. A.; Pham, P. L.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [McNally, S. M.; Chan, L.] NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. NR 0 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 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2014 VL 31 IS 12 MA A2-27 BP A34 EP A34 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA AK5DC UT WOS:000338443600088 ER PT J AU Mierzwa, MJ Sullivan, GM Beer, LA Ahn, S Armstrong, RC AF Mierzwa, M. J. Sullivan, G. M. Beer, L. A. Ahn, S. Armstrong, R. C. TI HETEROGENEOUS TBI MODELS REVEAL DIVERGENT EFFECTS IN NEURONAL AND OLIGODENDROGLIAL PROGENITORS SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 32nd Annual National Neurotrauma Symposium CY JUN 29-JUL 02, 2014 CL San Francisco, CA DE neural stem cell; oligodendrocyte progenitor; sonic hedgehog; subventricular zone C1 [Mierzwa, M. J.; Sullivan, G. M.; Beer, L. A.; Armstrong, R. C.] Uniformed Serv Univ Hlth Sci, CNRM, Bethesda, MD 20814 USA. [Ahn, S.] NIH, Bethesda, MD 20892 USA. NR 0 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 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JUN 15 PY 2014 VL 31 IS 12 MA D2-01 BP A113 EP A113 PG 1 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA AK5DC UT WOS:000338443600308 ER PT J AU Tu, TW Turtzo, LC Lescher, JD Williams, R Frank, JA AF Tu, T. W. Turtzo, L. C. Lescher, J. D. Williams, R. Frank, J. A. TI CEST-MRI IS SENSITIVE IN NON-INVASIVE DETECTION OF GLUCOSE, LACTATE, AND GLUTAMATE plus GLUTAMINE INTERRELATION IN MILD CLOSE HEAD TBI SO JOURNAL OF NEUROTRAUMA LA English DT Meeting Abstract CT 32nd Annual National Neurotrauma Symposium CY JUN 29-JUL 02, 2014 CL San Francisco, CA DE CEST MRI; glucose; glutamate; lactate; non-invasive C1 [Tu, T. W.; Turtzo, L. C.; Lescher, J. D.; Williams, R.; Frank, J. A.] NIH, Frank Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 7 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 JUN 15 PY 2014 VL 31 IS 12 MA A2-18 BP A30 EP A31 PG 2 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA AK5DC UT WOS:000338443600079 ER PT J AU Krivega, I Dale, RK Dean, A AF Krivega, Ivan Dale, Ryan K. Dean, Ann TI Role of LDB1 in the transition from chromatin looping to transcription activation SO GENES & DEVELOPMENT LA English DT Article DE beta-globin genes; chromatin; looping; enhancers; transcription ID BETA-GLOBIN LOCUS; BINDING PROTEIN LDB1; ERYTHROID-DIFFERENTIATION; CONTROL REGION; GENE ACTIVATION; IN-VIVO; FACTOR COMPLEXES; STRUCTURAL BASIS; POSITIVE ROLE; FACTOR GATA-1 AB Many questions remain about how close association of genes and distant enhancers occurs and how this is linked to transcription activation. In erythroid cells, lim domain binding 1 (LDB1) protein is recruited to the beta-globin locus via LMO2 and is required for looping of the beta-globin locus control region (LCR) to the active beta-globin promoter. We show that the LDB1 dimerization domain (DD) is necessary and, when fused to LMO2, sufficient to completely restore LCR-promoter looping and transcription in LDB1-depleted cells. The looping function of the DD is unique and irreplaceable by heterologous DDs. Dissection of the DD revealed distinct functional properties of conserved subdomains. Notably, a conserved helical region (DD4/5) is dispensable for LDB1 dimerization and chromatin looping but essential for transcriptional activation. DD4/5 is required for the recruitment of the coregulators FOG1 and the nucleosome remodeling and deacetylating (NuRD) complex. Lack of DD4/5 alters histone acetylation and RNA polymerase II recruitment and results in failure of the locus to migrate to the nuclear interior, as normally occurs during erythroid maturation. These results uncouple enhancer-promoter looping from nuclear migration and transcription activation and reveal new roles for LDB1 in these processes. C1 [Krivega, Ivan; Dale, Ryan K.; Dean, Ann] NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Dean, A (reprint author), NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. EM anndean@helix.nih.gov RI Krivega, Ivan/G-9247-2015; OI Krivega, Ivan/0000-0002-3473-4198; Dale, Ryan/0000-0003-2664-3744 FU Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health [ZIA DK015508-25] FX We thank Dr. Elissa Lei, Dr. Gerd Blobel, Dr. Paul Love, and Dr. Liqi Li for helpful comments on the manuscript. We thank Dr. Paul Love and Dr. Liqi Li for supplying floxed Ldb1 animals. We thank Dr. Tom Misteli and Dr. Karen Meaburn for help with the FISH studies, and Francine Katz for help in MEL cell cloning. Work in the laboratory of A.D. is supported by the Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (ZIA DK015508-25). NR 73 TC 26 Z9 26 U1 1 U2 15 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 EI 1549-5477 J9 GENE DEV JI Genes Dev. PD JUN 15 PY 2014 VL 28 IS 12 BP 1278 EP 1290 DI 10.1101/gad.239749.114 PG 13 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA AJ8XI UT WOS:000337991000003 PM 24874989 ER PT J AU Wilker, EH Ljungman, PL Rice, MB Kloog, I Schwartz, J Gold, DR Koutrakis, P Vita, JA Mitchell, GF Vasan, RS Benjamin, EJ Hamburg, NM Mittleman, MA AF Wilker, Elissa H. Ljungman, Petter L. Rice, Mary B. Kloog, Itai Schwartz, Joel Gold, Diane R. Koutrakis, Petros Vita, Joseph A. Mitchell, Gary F. Vasan, Ramachandran S. Benjamin, Emelia J. Hamburg, Naomi M. Mittleman, Murray A. TI Relation of Long-Term Exposure to Air Pollution to Brachial Artery Flow-Mediated Dilation and Reactive Hyperemia SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CARDIOVASCULAR EVENTS; ENDOTHELIAL FUNCTION; VASCULAR REACTIVITY; HEALTHY-ADULTS; HEART; VASOCONSTRICTION; INHALATION; RESPONSES; DESIGN AB Long-term exposure to ambient air pollution has been associated with cardiovascular morbidity and mortality. Impaired vascular responses may, in part, explain these findings, but the association of such long-term exposure with measures of both conduit artery and microvascular function has not been widely reported. We evaluated the association between residential proximity to a major roadway (primary or secondary highway) and spatially resolved average fine particulate matter (PM2.5) and baseline brachial artery diameter and mean flow velocity, flow-mediated dilation%, and hyperemic flow velocity, in the Framingham Offspring and Third Generation Cohorts. We examined 5,112 participants (2,731 [53%] women, mean age 49 +/- 14 years). Spatially resolved average PM2.5 was associated with lower flow-mediated dilation% and hyperemic flow velocity. An inter-quartile range difference in PM2.5 (1.99 mu g/m(3)) was associated with -0.16% (95% confidence interval [CI] -0.27%, -0.05%) lower flow-mediated dilation% and -0.72 (95% CI -1.38, -0.06) cm/s lower hyperemic flow velocity%. Residential proximity to a major roadway was negatively associated with flow-mediated dilation%. Compared with living 400 m away, living <50 m from a major roadway was associated with 0.32% lower flow mediated dilation (95% CI -0.58%, -0.06%), but results for hyperemic flow velocity had wide confidence intervals -0.68 cm/s (95% CI -2.29, 0.93). In conclusion, residential proximity to a major roadway and higher levels of spatially resolved estimates of PM2.5 at participant residences are associated with impaired conduit artery and microvascular function in this large community-based cohort of middle-aged and elderly adults. (C) 2014 Elsevier Inc. All rights reserved. C1 [Wilker, Elissa H.; Ljungman, Petter L.; Rice, Mary B.; Mittleman, Murray A.] Beth Israel Deaconess Med Ctr, Dept Med, Cardiovasc Epidemiol Res Unit, Boston, MA 02215 USA. [Wilker, Elissa H.; Schwartz, Joel; Gold, Diane R.; Koutrakis, Petros; Mittleman, Murray A.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Ljungman, Petter L.] Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden. [Rice, Mary B.] Massachusetts Gen Hosp, Dept Med, Pulm & Crit Care Unit, Boston, MA 02114 USA. [Kloog, Itai] Ben Gurion Univ Negev, Dept Geog & Environm Dev, IL-84105 Beer Sheva, Israel. [Vita, Joseph A.; Vasan, Ramachandran S.; Benjamin, Emelia J.; Hamburg, Naomi M.] NHLBI, Framingham, MA USA. [Vita, Joseph A.; Vasan, Ramachandran S.; Benjamin, Emelia J.; Hamburg, Naomi M.] Boston Univ, Framingham Heart Study, Framingham, MA USA. [Vita, Joseph A.; Vasan, Ramachandran S.; Benjamin, Emelia J.; Hamburg, Naomi M.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Mitchell, Gary F.] Cardiovasc Engn Inc, Norwood, MA USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Prevent Med & Epidemiol Sect, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02118 USA. RP Wilker, EH (reprint author), Beth Israel Deaconess Med Ctr, Dept Med, Cardiovasc Epidemiol Res Unit, Boston, MA 02215 USA. EM ewilker@bidmc.harvard.edu RI Ljungman, Petter/C-6371-2014; OI Ljungman, Petter/0000-0002-7815-2632; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI [N01HC 25195, 1R01HL60040, 1R01HL70100]; USEPA [RD834798]; NIEHS [ES009825, ES022243, ES023352, ES000002]; Swedish Council for Working Life and Social Research; Marie Curie International Postdoctoral Fellowship Programme; Swedish Heart-Lung Foundation; Swedish Society of Cardiology; Swedish Society for Medical Research FX This work was supported by the NHLBI (N01HC 25195, 1R01HL60040, 1R01HL70100), the USEPA (RD834798), and NIEHS (ES009825, ES022243, ES023352, and ES000002), Swedish Council for Working Life and Social Research, Marie Curie International Postdoctoral Fellowship Programme, the Swedish Heart-Lung Foundation, the Swedish Society of Cardiology, and the Swedish Society for Medical Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the EPA. Further, the NTH and USEPA do not endorse the purchase of any commercial products or services mentioned in the publication. NR 25 TC 17 Z9 18 U1 0 U2 6 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUN 15 PY 2014 VL 113 IS 12 BP 2057 EP 2063 DI 10.1016/j.amjcard.2014.03.048 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AJ4KE UT WOS:000337644300020 PM 24793676 ER PT J AU Rosenberg, SA AF Rosenberg, Steven A. TI IL-2: The First Effective Immunotherapy for Human Cancer SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TUMOR-INFILTRATING LYMPHOCYTES; ACTIVATED KILLER-CELLS; IN-VITRO GROWTH; MURINE T-CELLS; DOSE RECOMBINANT INTERLEUKIN-2; CYTOTOXIC HUMAN-LYMPHOCYTES; PERIPHERAL-BLOOD LYMPHOCYTES; PURIFIED HUMAN INTERLEUKIN-2; PROSPECTIVE RANDOMIZED-TRIAL; LONG-TERM CULTURE AB The ability of IL-2 to expand T cells with maintenance of functional activity has been translated into the first reproducible effective human cancer immunotherapies. The administration of IL-2 can lead to durable, complete, and apparently curative regressions in patients with metastatic melanoma and renal cancer. The growth of large numbers of tumor-infiltrating lymphocytes with in vitro anti-cancer activity in IL-2 has led to the development of cell transfer therapies that are highly effective in patients with melanoma. The genetic modification of T cells with genes encoding alpha beta TCRs or chimeric Ag receptors and the administration of these cells after expansion in IL-2 have extended effective cell transfer therapy to other cancer types. C1 [Rosenberg, Steven A.] NCI, Surg Branch, Bethesda, MD 20892 USA. RP Rosenberg, SA (reprint author), NIH, 9000 Rockville Pike,CRC Bldg,Room 3W-3940, Bethesda, MD 20892 USA. EM sar@nih.gov NR 85 TC 115 Z9 118 U1 6 U2 38 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 JUN 15 PY 2014 VL 192 IS 12 BP 5451 EP 5458 DI 10.4049/jimmunol.1490019 PG 8 WC Immunology SC Immunology GA AI8MV UT WOS:000337172100003 PM 24907378 ER PT J AU Kwon, SJ Crespo-Barreto, J Zhang, W Wang, TH Kim, DS Krensky, A Clayberger, C AF Kwon, Seok Joo Crespo-Barreto, Juan Zhang, Wei Wang, Tianhong Kim, Dong Seok Krensky, Alan Clayberger, Carol TI KLF13 Cooperates with c-Maf To Regulate IL-4 Expression in CD4(+) T Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TRANSCRIPTION FACTOR GATA-3; GENE-EXPRESSION; TH2 CYTOKINES; DIFFERENTIATION; INTERLEUKIN-4; LYMPHOCYTES; RECEPTOR; RANTES; MECHANISMS; PROMOTER AB Kruppel-like factor (KLF) 13 is a transcription factor that positively regulates expression of the chemokine RANTES 3-5 d after activation of T cells. In this study, we document a key role for KLF13 in the expression of IL-4 in CD4(+) T cells. Gene expression analysis in activated T cells from Klf13(-/-) mice showed that IL-4, along with other Th2 cytokine genes, was downregulated when compared with cells from wild-type mice. The decreased levels of IL-4 were not associated with changes in expression of the Th2-inducing transcription factors GATA3 or c-Maf. Additional analysis revealed that KLF13 directly binds to IL-4 promoter regions and synergizes with c-Maf to positively regulate IL-4 expression. These results indicate that KLF13 is a positive regulator for differentiation of Th2 cells, as part of the transcriptional machinery that regulates IL-4 production in Th2 cells. C1 [Kwon, Seok Joo; Crespo-Barreto, Juan; Zhang, Wei; Wang, Tianhong; Kim, Dong Seok; Krensky, Alan; Clayberger, Carol] NCI, Lab Cellular & Mol Biol, NIH, Bethesda, MD 20892 USA. [Krensky, Alan; Clayberger, Carol] Northwestern Univ, Feinberg Sch Med, Dept Microbiol & Immunol, Chicago, IL 60611 USA. [Krensky, Alan] Northwestern Univ, Feinberg Sch Med, Dept Pediat, Chicago, IL 60611 USA. RP Clayberger, C (reprint author), Feinberg Sch Med, Dept Microbiol & Immunol, Tarry 6-735, Chicago, IL 60611 USA. EM Clayberger@northwestern.edu RI zhang, wei/A-7015-2011 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute; Center for Cancer Research FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and the Center for Cancer Research. NR 36 TC 2 Z9 3 U1 1 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2014 VL 192 IS 12 BP 5703 EP 5709 DI 10.4049/jimmunol.1302830 PG 7 WC Immunology SC Immunology GA AI8MV UT WOS:000337172100031 PM 24821970 ER PT J AU Weiss, JM Subleski, JJ Back, T Chen, X Watkins, SK Yagita, H Sayers, TJ Murphy, WJ Wiltrout, RH AF Weiss, Jonathan M. Subleski, Jeff J. Back, Tim Chen, Xin Watkins, Stephanie K. Yagita, Hideo Sayers, Thomas J. Murphy, William J. Wiltrout, Robert H. TI Regulatory T Cells and Myeloid-Derived Suppressor Cells in the Tumor Microenvironment Undergo Fas-Dependent Cell Death during IL-2/alpha CD40 Therapy SO JOURNAL OF IMMUNOLOGY LA English DT Article ID SIGNALING COMPLEX; LIGAND; EXPRESSION; APOPTOSIS; CARCINOMA; RECEPTOR; IMMUNOTHERAPY; INTERLEUKIN-2; LYMPHOCYTES; MODULATION AB Fas ligand expression in certain tumors has been proposed to contribute to immunosuppression and poor prognosis. However, immunotherapeutic approaches may elicit the Fas-mediated elimination of immunosuppressive regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) within tumors that represent major obstacles for cancer immunotherapy. Previously, we showed that IL-2 and agonistic CD40 Ab (alpha CD40) elicited synergistic antitumor responses coincident with the efficient removal of Tregs and MDSCs. We demonstrate in this study in two murine tumor models that Treg and MDSC loss within the tumor microenvironment after IL-2/alpha CD40 occurs through a Fas-dependent cell death pathway. Among tumor-infiltrating leukocytes, CD8(+) T cells, neutrophils, and immature myeloid cells expressed Fas ligand after treatment. Fas was expressed by tumor-associated Tregs and immature myeloid cells, including MDSCs. Tregs and MDSCs in the tumor microenvironment expressed active caspases after IL-2/alpha CD40 therapy and, in contrast with effector T cells, Tregs significantly down-regulated Bcl-2 expression. In contrast, Tregs and MDSCs proliferated and expanded in the spleen after treatment. Adoptive transfer of Fas-deficient Tregs or MDSCs into wild-type, Treg-, or MDSC-depleted hosts resulted in the persistence of Tregs or MDSCs and the loss of antitumor efficacy in response to IL-2/alpha CD40. These results demonstrate the importance of Fas-mediated Treg/MDSC removal for successful antitumor immunotherapy. Our results suggest that immunotherapeutic strategies that include exploiting Treg and MDSC susceptibility to Fas-mediated apoptosis hold promise for treatment of cancer. C1 [Weiss, Jonathan M.; Subleski, Jeff J.; Back, Tim; Sayers, Thomas J.; Wiltrout, Robert H.] NCI, Canc & Inflammat Program, Frederick, MD 21702 USA. [Chen, Xin] Leidos Biomed Res Inc, Basic Sci Program, Frederick, MD 21702 USA. [Watkins, Stephanie K.] Loyola Univ, Med Ctr, Dept Surg, Maywood, IL 60153 USA. [Yagita, Hideo] Juntendo Univ, Sch Med, Dept Immunol, Tokyo 1138421, Japan. [Murphy, William J.] Univ Calif Davis, Dept Dermatol, Sacramento, CA 95816 USA. RP Wiltrout, RH (reprint author), NCI, Canc & Inflammat Program, 1050 Boyles St,Bldg 428,Room 48A, Frederick, MD 21702 USA. EM wiltrour@mail.nih.gov RI Sayers, Thomas/G-4859-2015; Chen, Xin/I-6601-2015 OI Chen, Xin/0000-0002-2628-4027 FU Intramural NIH HHS [Z01 BC009262-25, Z99 CA999999] NR 34 TC 13 Z9 13 U1 0 U2 16 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 JUN 15 PY 2014 VL 192 IS 12 BP 5821 EP 5829 DI 10.4049/jimmunol.1400404 PG 9 WC Immunology SC Immunology GA AI8MV UT WOS:000337172100042 PM 24808361 ER PT J AU Boonnak, K Vogel, L Feldmann, F Feldmann, H Legge, KL Subbarao, K AF Boonnak, Kobporn Vogel, Leatrice Feldmann, Friederike Feldmann, Heinz Legge, Kevin L. Subbarao, Kanta TI Lymphopenia Associated with Highly Virulent H5N1 Virus Infection Due to Plasmacytoid Dendritic Cell-Mediated Apoptosis of T Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INFLUENZA-A VIRUS; HONG-KONG; IMMUNE-RESPONSES; DEATH APOPTOSIS; MOUSE MODEL; FAS LIGAND; H7N9 VIRUS; HUMANS; MICE; PATHOGENESIS AB Although lymphopenia is a hallmark of severe infection with highly pathogenic H5N1 and the newly emerged H7N9 influenza viruses in humans, the mechanism(s) by which lethal H5N1 viruses cause lymphopenia in mammalian hosts remains poorly understood. Because influenza-specific T cell responses are initiated in the lung draining lymph nodes (LNs), and lymphocytes subsequently traffic to the lungs or peripheral circulation, we compared the immune responses in the lung draining LNs postinfection with a lethal A/HK/483/97 or nonlethal A/HK/486/97 (H5N1) virus in a mouse model. We found that lethal H5N1, but not nonlethal H5N1, virus infection in mice enhances Fas ligand (FasL) expression on plasmacytoid dendritic cells (pDCs), resulting in apoptosis of influenza-specific CD8(+) T cells via a Fas-FasL-mediated pathway. We also found that pDCs, but not other DC subsets, preferentially accumulate in the lung draining LNs of lethal H5N1 virus-infected mice, and that the induction of FasL expression on pDCs correlates with high levels of IL-12p40 monomer/homodimer in the lung draining LNs. Our data suggest that one of the mechanisms of lymphopenia associated with lethal H5N1 virus infection involves a deleterious role for pDCs. C1 [Boonnak, Kobporn; Vogel, Leatrice; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Feldmann, Friederike] NIAID, Vet Branch, Rocky Mt Lab, NIH, Hamilton, MT 59840 USA. [Feldmann, Heinz] NIAID, Virol Lab, Rocky Mt Lab, NIH, Hamilton, MT 59840 USA. [Legge, Kevin L.] Univ Iowa, Dept Pathol, Iowa City, IA 52242 USA. RP Subbarao, K (reprint author), NIAID, Emerging Resp Viruses Sect, Infect Dis Lab, NIH, Bldg 33,Room 3E13C-1,33 North Dr,MSC 3203, Bethesda, MD 20892 USA. EM kevin-legge@uiowa.edu; KSUBBARAO@niaid.nih.gov OI Legge, Kevin/0000-0001-9800-6854 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases; National Institutes of Health; National Institutes of Health/National Institute of Allergy and Infectious Diseases Grant [AI071085]; Department of Pathology, University of Iowa FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, National Institutes of Health/National Institute of Allergy and Infectious Diseases Grant AI071085, and the Department of Pathology, University of Iowa. NR 36 TC 6 Z9 6 U1 0 U2 6 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 JUN 15 PY 2014 VL 192 IS 12 BP 5906 EP 5912 DI 10.4049/jimmunol.1302992 PG 7 WC Immunology SC Immunology GA AI8MV UT WOS:000337172100050 PM 24829418 ER PT J AU Abdi, K Singh, NJ Spooner, E Kessler, BM Radaev, S Lantz, L Xiao, TS Matzinger, P Sun, PD Ploegh, HL AF Abdi, Kaveh Singh, Nevil J. Spooner, Eric Kessler, Benedikt M. Radaev, Sergei Lantz, Larry Xiao, Tsan Sam Matzinger, Polly Sun, Peter D. Ploegh, Hidde L. TI Free IL-12p40 Monomer Is a Polyfunctional Adaptor for Generating Novel IL-12-like Heterodimers Extracellularly SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INTERLEUKIN-12 P40 HOMODIMER; INTERFERON-GAMMA; IMMUNE-RESPONSES; CYTOKINE; SUBUNITS; CELLS; MACROPHAGES; EXPRESSION; RESISTANCE; DISTINCT AB IL-12p40 partners with the p35 and p19 polypeptides to generate the heterodimeric cytokines IL-12 and IL-23, respectively. These cytokines play critical and distinct roles in host defense. The assembly of these heterodimers is thought to take place within the cell, resulting in the secretion of fully functional cytokines. Although the p40 subunit alone can also be rapidly secreted in response to inflammatory signals, its biological significance remains unclear. In this article, we show that the secreted p40 monomer can generate de novo IL-12-like activities by combining extracellularly with p35 released from other cells. Surprisingly, an unbiased proteomic analysis reveals multiple such extracellular binding partners for p40 in the serum of mice after an endotoxin challenge. We biochemically validate the binding of one of these novel partners, the CD5 Ag-like glycoprotein, to the p40 monomer. Nevertheless, the assembled p40-CD5L heterodimer does not recapitulate the biological activity of IL-12. These findings underscore the plasticity of secreted free p40 monomer, suggesting that p40 functions as an adaptor that is able to generate multiple de novo composites in combination with other locally available polypeptide partners after secretion. C1 [Abdi, Kaveh; Matzinger, Polly] NIAID, Lab Cellular & Mol Immunol, NIH, Rockville, MD 20852 USA. [Singh, Nevil J.] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. [Spooner, Eric; Ploegh, Hidde L.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Kessler, Benedikt M.] Univ Oxford, Target Discovery Inst, Nuffield Dept Clin Med, Oxford OX3 7FZ, England. [Radaev, Sergei] NCI, Resources & Training Review Branch, Bethesda, MD 20892 USA. [Lantz, Larry] NIAID, Res Technol Branch, NIH, Rockville, MD 20852 USA. [Xiao, Tsan Sam] NIAID, Struct Immunobiol Unit, Immunol Lab, NIH, Rockville, MD 20852 USA. [Sun, Peter D.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Abdi, K (reprint author), NIAID, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. EM kabdi@niaid.nih.gov RI Xiao, Tsan/A-8590-2010; OI Xiao, Tsan/0000-0001-9688-475X; Kessler, Benedikt/0000-0002-8160-2446 FU Intramural Research Program at the National Institutes of Health; National Institute of Allergy and Infectious Diseases; National Institutes of Health FX This work was supported by the Intramural Research Program at the National Institutes of Health, National Institute of Allergy and Infectious Diseases, and the National Institutes of Health. H.L.P. is funded by the National Institutes of Health. NR 37 TC 12 Z9 13 U1 0 U2 2 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 JUN 15 PY 2014 VL 192 IS 12 BP 6028 EP 6036 DI 10.4049/jimmunol.1400159 PG 9 WC Immunology SC Immunology GA AI8MV UT WOS:000337172100063 PM 24821971 ER PT J AU Chen, CTL Liu, CT Chen, GK Andrews, JS Arnold, AM Dreyfus, J Franceschini, N Garcia, ME Kerr, KF Li, G Lohman, KK Musani, SK Nalls, MA Raffel, LJ Smith, J Ambrosone, CB Bandera, EV Bernstein, L Britton, A Brzyski, RG Cappola, A Carlson, CS Couper, D Deming, SL Goodarzi, MO Heiss, G John, EM Lu, XN Le Marchand, L Marciante, K Mcknight, B Millikan, R Nock, NL Olshan, AF Press, MF Vaiyda, D Woods, NF Taylor, HA Zhao, W Zheng, W Evans, MK Harris, TB Henderson, BE Kardia, SLR Kooperberg, C Liu, YM Mosley, TH Psaty, B Wellons, M Windham, BG Zonderman, AB Cupples, LA Demerath, EW Haiman, C Murabito, JM Rajkovic, A AF Chen, Christina T. L. Liu, Ching-Ti Chen, Gary K. Andrews, Jeanette S. Arnold, Alice M. Dreyfus, Jill Franceschini, Nora Garcia, Melissa E. Kerr, Kathleen F. Li, Guo Lohman, Kurt K. Musani, Solomon K. Nalls, Michael A. Raffel, Leslie J. Smith, Jennifer Ambrosone, Christine B. Bandera, Elisa V. Bernstein, Leslie Britton, Angela Brzyski, Robert G. Cappola, Anne Carlson, Christopher S. Couper, David Deming, Sandra L. Goodarzi, Mark O. Heiss, Gerardo John, Esther M. Lu, Xiaoning Le Marchand, Loic Marciante, Kristin Mcknight, Barbara Millikan, Robert Nock, Nora L. Olshan, Andrew F. Press, Michael F. Vaiyda, Dhananjay Woods, Nancy F. Taylor, Herman A. Zhao, Wei Zheng, Wei Evans, Michele K. Harris, Tamara B. Henderson, Brian E. Kardia, Sharon L. R. Kooperberg, Charles Liu, Yongmei Mosley, Thomas H. Psaty, Bruce Wellons, Melissa Windham, Beverly G. Zonderman, Alan B. Cupples, L. Adrienne Demerath, Ellen W. Haiman, Christopher Murabito, Joanne M. Rajkovic, Aleksandar TI Meta-analysis of loci associated with age at natural menopause in African-American women SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; PREMATURE OVARIAN FAILURE; MULTILOCUS GENOTYPE DATA; CHINESE WOMEN; RECEPTOR GENE; INFERENCE; DESIGN; POLYMORPHISMS; RISK; IMPUTATION AB Age at menopause marks the end of a woman's reproductive life and its timing associates with risks for cancer, cardiovascular and bone disorders. GWAS and candidate gene studies conducted in women of European ancestry have identified 27 loci associated with age at menopause. The relevance of these loci to women of African ancestry has not been previously studied. We therefore sought to uncover additional menopause loci and investigate the relevance of European menopause loci by performing a GWAS meta-analysis in 6510 women with African ancestry derived from 11 studies across the USA. We did not identify any additional loci significantly associated with age at menopause in African Americans. We replicated the associations between six loci and age at menopause (P-value < 0.05): AMHR2, RHBLD2, PRIM1, HK3/UMC1, BRSK1/TMEM150B and MCM8. In addition, associations of 14 loci are directionally consistent with previous reports. We provide evidence that genetic variants influencing reproductive traits identified in European populations are also important in women of African ancestry residing in USA. C1 [Chen, Christina T. L.; Carlson, Christopher S.; Kooperberg, Charles] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Liu, Ching-Ti; Lu, Xiaoning; Cupples, L. Adrienne] Boston Univ, Dept Biostat, Sch Publ Hlth, Boston, MA 02118 USA. [Liu, Ching-Ti; Cupples, L. Adrienne; Murabito, Joanne M.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Chen, Gary K.; Henderson, Brian E.; Haiman, Christopher] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. [Press, Michael F.] Univ So Calif, Dept Pathol, Keck Sch Med, Los Angeles, CA 90089 USA. [Press, Michael F.] Univ So Calif, Norris Comprehens Canc Ctr, Los Angeles, CA 90089 USA. [Andrews, Jeanette S.; Lohman, Kurt K.] Wake Forest Sch Med, Div Publ Hlth Sci, Dept Biostat Sci, Winston Salem, NC 27157 USA. [Arnold, Alice M.; Kerr, Kathleen F.; Li, Guo; Marciante, Kristin; Mcknight, Barbara] Wake Forest Sch Med, Dept Med, Winston Salem, NC 27157 USA. [Dreyfus, Jill; Demerath, Ellen W.] Univ Minnesota, Div Epidemiol & Community Hlth, Sch Publ Hlth, Minneapolis, MN 55455 USA. [Franceschini, Nora; Heiss, Gerardo; Millikan, Robert; Olshan, Andrew F.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27514 USA. [Couper, David] Univ N Carolina, Dept Biostat, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27514 USA. [Millikan, Robert; Olshan, Andrew F.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27514 USA. [Garcia, Melissa E.; Harris, Tamara B.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20814 USA. [Musani, Solomon K.; Taylor, Herman A.] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [Mosley, Thomas H.; Windham, Beverly G.] Univ Mississippi, Med Ctr, Div Geriatr Med, Jackson, MS 39216 USA. [Nalls, Michael A.; Britton, Angela] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Raffel, Leslie J.] Cedars Sinai Med Ctr, Dept Pediat & Biomed Sci, Los Angeles, CA 90048 USA. [Goodarzi, Mark O.] Cedars Sinai Med Ctr, Div Endocrinol Diabet & Metab, Los Angeles, CA 90048 USA. [Smith, Jennifer; Zhao, Wei; Kardia, Sharon L. R.] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Ambrosone, Christine B.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Bandera, Elisa V.] Canc Inst New Jersey, New Brunswick, NJ 08903 USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Div Canc Etiol, Duarte, CA 91010 USA. [Brzyski, Robert G.] Univ Texas Hlth Sci Ctr San Antonio, Dept Obstet & Gynecol, San Antonio, TX 78229 USA. [Cappola, Anne] Univ Penn, Perelman Sch Med, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA. [Deming, Sandra L.; Zheng, Wei] Vanderbilt Univ, Sch Med, Dept Med, Div Epidemiol, Nashville, TN 37232 USA. [John, Esther M.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Div Epidemiol, Stanford, CA 94305 USA. [Lu, Xiaoning] Beth Israel Deaconess Med Ctr, Div Clin Informat, Boston, MA 02118 USA. [Le Marchand, Loic] Univ Hawaii, Program Epidemiol, Canc Res Ctr, Honolulu, HI 96813 USA. [Nock, Nora L.] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Vaiyda, Dhananjay] Johns Hopkins Univ, Dept Med, Baltimore, MD 21287 USA. [Woods, Nancy F.] Univ Washington, Seattle, WA 98109 USA. [Evans, Michele K.] NIA, Hlth Dispar Res Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA. [Zonderman, Alan B.] NIA, Lab Personal & Cognit, NIH, Baltimore, MD 21224 USA. [Liu, Yongmei] Wake Forest Univ, Dept Epidemiol & Prevent, Div Publ Hlth Sci, Sch Med, Winston Salem, NC 27157 USA. [Psaty, Bruce] Univ Washington, Dept Med, Seattle, WA USA. [Psaty, Bruce] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Wellons, Melissa] Vanderbilt Univ, Sch Med, Nashville, TN 37240 USA. [Murabito, Joanne M.] Boston Univ, Sch Med, Dept Med, Sect Gen Internal Med, Boston, MA 02118 USA. [Rajkovic, Aleksandar] Univ Pittsburgh, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA 15213 USA. RP Chen, CTL (reprint author), Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave N,M4-B402,POB 19024, Seattle, WA 98109 USA. EM ctchen@fhcrc.org; christopher.haiman@med.usc.edu; murabito@bu.edu; rajkovic@upmc.edu RI Bandera, Elisa/M-4169-2014; Kerr, Kathleen/A-2893-2013; OI Bandera, Elisa/0000-0002-8789-2755; Nock, Nora L./0000-0002-6476-6692; Zonderman, Alan B/0000-0002-6523-4778; Smith, Jennifer/0000-0002-3575-5468 FU National Institute of Health [N01-HC-65226]; NIH [HHSN268200900055C, 5215810-550000234]; National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221]; National Heart, Lung, and Blood Institute (NHLBI); CTSA [UL1-RR-024156]; National Center for Research Resources [UL1RR033176]; National Center for Advancing Translational Sciences [UL1TR000124]; NHLBI [N01-HC-65226, N02-HL-6-4278]; National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201200036C, N01-HC-85239, N01 HC-55222, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85086, HL080295]; National Institute of Neurological Disorders and Stroke (NINDS); National Institute on Aging (NIA) [AG-023629]; National Center of Advancing Translational Technologies CTSI [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; Cedars-Sinai Board of Governors' Chair in Medical Genetics; Intramural Research Program of the NIH, National Institute on Aging; National Center on Minority Health and Health Disparities [Z01-AG000513, 2009-149]; National Heart, Lung, and Blood Institute of the National Institutes of Health [HL54457, HL087660]; National Institutes of Health provided by the National Heart, Lung, and Blood Institute [N01-HC-95170, N01-HC-95171, N01-HC-95172]; National Center for Minority Health and Health Disparities (NCMHD); Department of Defense Breast Cancer Research Program Era of Hope Scholar Award [W81XWH-08-1-0383]; Norris Foundation; MEC (National Institutes of Health) [R01-CA63464, R37-CA54281]; CBCS (National Institutes of Health Specialized Program of Research Excellence in Breast Cancer) [P50-CA58223]; CBCS (Center for Environmental Health and Susceptibility, National Institute of Environmental Health Sciences, National Institutes of Health) [P30-ES10126]; NIA [N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1]; National Institutes of Health [HHSN268200782096C, HHSN268200625226C]; National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268 201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268 201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694]; National Human Genome Research Institute [U01HG004402]; component of the National Institutes of Health and NIH Roadmap for Medical Research [UL1RR025005]; [R21AG032598]; [N01-HC-95159]; [N01-HC-95169]; [R01-HL-071051]; [R01-HL-071205]; [R01-HL-071250]; [R01-HL-071251]; [R01-HL-071252]; [R01-HL-071258]; [R01-HL-071259]; [UL1-RR-025005] FX The National Institute of Health funded the CARe Consortium that contributed data and DNA to the Broad Institute (N01-HC-65226) to create the phenotype/genotype resource for wide dissemination to the biomedical community. NIH contract HHSN268200900055C and subcontract 5215810-550000234, provided statistical resources for the age at menopause genetic association analyses conducted in the CARe cohorts with additional support from R21AG032598.; The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. This manuscript was prepared in collaboration with investigators of theWHI, and has been approved by the WHI. WHI investigators are listed at http://www.whiscience.org/publications/WHI_ investigators_shortlist.pdf.; The MESA and MESA Family are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts N01-HC-95159 through N01-HC-95169 and CTSA UL1-RR-024156. Funding for MESA Family is provided by grants R01-HL-071051, R01-HL-071205, R01-HL-071250, R01-HL-071251, R01-HL-071252, R01-HL-071258, R01-HL-071259, UL1-RR-025005, by the National Center for Research Resources, Grant UL1RR033176, and is now at the National Center for Advancing Translational Sciences, Grant UL1TR000124. Funding for genotyping was provided by NHLBI Contract N02-HL-6-4278 and N01-HC-65226.; The Cardiovascular Health Study was supported by contracts HHSN268201200036C, N01-HC-85239, N01 HC-55222, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85086 and grant HL080295 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by AG-023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org. DNA handling and genotyping was supported in part by National Center of Advancing Translational Technologies CTSI grant UL1TR000124 and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center and Cedars-Sinai Board of Governors' Chair in Medical Genetics (JIR).; The HANDLS study was supported by the Intramural Research Program of the NIH, National Institute on Aging and the National Center on Minority Health and Health Disparities (contract # Z01-AG000513 and human subjects protocol # 2009-149). Data analyses for the HANDLS study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD, USA (http://biowulf.nih.gov).; The Genetic Epidemiology Network of Arteriopathy (GENOA) phenotyping and genome-wide genotyping was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health (HL54457 and HL087660). Genotyping was performed at the Mayo Clinic (Stephen T. Turner, Mariza de Andrade, Julie Cunningham) and was made possible by the University of Texas Health Sciences Center (Eric Boerwinkle, Megan L. Grove-Gaona). Wethank the families that participated in the GENOA study.; The Jackson Heart Study was supported by National Institutes of Health contracts (N01-HC-95170, N01-HC-95171 and N01-HC-95172) provided by the National Heart, Lung, and Blood Institute and the National Center for Minority Health and Health Disparities (NCMHD).; The African American Breast Cancer Consortium was supported by a Department of Defense Breast Cancer Research Program Era of Hope Scholar Award to C. A. H. (W81XWH-08-1-0383) and the Norris Foundation. Each of the participating studies was supported by the following grants: MEC (National Institutes of Health grants R01-CA63464 and R37-CA54281) and CBCS (National Institutes of Health Specialized Program of Research Excellence in Breast Cancer, grant number P50-CA58223, and Center for Environmental Health and Susceptibility, National Institute of Environmental Health Sciences, National Institutes of Health, grant number P30-ES10126).; The Health ABC Study was supported by NIA contracts N01AG62101, N01AG62103 and N01AG62106. The genomewide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C.; The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268 201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268 201100011C and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by grant number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. NR 77 TC 17 Z9 17 U1 3 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JUN 15 PY 2014 VL 23 IS 12 BP 3327 EP 3342 DI 10.1093/hmg/ddu041 PG 16 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA AI7CJ UT WOS:000337038600023 PM 24493794 ER PT J AU Cassetti, MC Thomas, SJ AF Cassetti, M. Cristina Thomas, Stephen J. TI Dengue Human Infection Model: Introduction SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID VACCINE DEVELOPMENT; ANIMAL-MODELS; VIRUS; CHALLENGE; ETIOLOGY; IMMUNITY; FEVER; PHASE C1 [Cassetti, M. Cristina] NIAID, Virol Branch, Bethesda, MD 20892 USA. [Thomas, Stephen J.] Walter Reed Army Inst Res, Viral Dis Branch, Silver Spring, MD 20910 USA. RP Thomas, SJ (reprint author), Walter Reed Army Inst Res, Viral Dis Branch, 503 Robert Grant Ave, Silver Spring, MD 20910 USA. EM stephen.j.thomas3.mil@mail.mil NR 27 TC 5 Z9 5 U1 0 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD JUN 15 PY 2014 VL 209 SU 2 BP 537 EP 539 DI 10.1093/infdis/jiu061 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AI7JG UT WOS:000337063800001 PM 24872393 ER PT J AU Talaat, KR Luke, CJ Khurana, S Manischewitz, J King, LR McMahon, BA Karron, RA Lewis, KDC Qin, J Follmann, DA Golding, H Neuzil, KM Subbarao, K AF Talaat, Kawsar R. Luke, Catherine J. Khurana, Surender Manischewitz, Jody King, Lisa R. McMahon, Bridget A. Karron, Ruth A. Lewis, Kristen D. C. Qin, Jing Follmann, Dean A. Golding, Hana Neuzil, Kathleen M. Subbarao, Kanta TI A Live Attenuated Influenza A(H5N1) Vaccine Induces Long-Term Immunity in the Absence of a Primary Antibody Response SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE H5N1; avian influenza; live attenuated; vaccine ID A H5N1 VACCINE; HEALTHY-ADULTS; VIRUS VACCINE; PHASE-I; A/DUCK/SINGAPORE/97 VACCINE; MF59-ADJUVANTED INFLUENZA; ANTIGENIC VARIANT; IMMUNOGENICITY; SAFETY; HUMANS AB Background. Highly pathogenic avian influenza A(H5N1) causes severe infections in humans. We generated 2 influenza A(H5N1) live attenuated influenza vaccines for pandemic use (pLAIVs), but they failed to elicit a primary immune response. Our objective was to determine whether the vaccines primed or established long-lasting immunity that could be detected by administration of inactivated subvirion influenza A(H5N1) vaccine (ISIV). Methods. The following groups were invited to participate in the study: persons who previously received influenza A(H5N1) pLAIV; persons who previously received an irrelevant influenza A(H7N3) pLAIV; and community members who were naive to influenza A(H5N1) and LAIV. LAIV-experienced subjects received a single 45-mu g dose of influenza A(H5N1) ISIV. Influenza A(H5N1)- and LAIV-naive subjects received either 1 or 2 doses of ISIV. Results. In subjects who had previously received antigenically matched influenza A(H5N1) pLAIV followed by 1 dose of ISIV compared with those who were naive to influenza A(H5N1) and LAIV and received 2 doses of ISIV, we observed an increased frequency of antibody response (82% vs 50%, by the hemagglutination inhibition assay) and a significantly higher antibody titer (112 vs 76; P =.04). The affinity of antibody and breadth of cross-clade neutralization was also enhanced in influenza A(H5N1) pLAIV-primed subjects. Conclusions. ISIV administration unmasked long-lasting immunity in influenza A(H5N1) pLAIV recipients, with a rapid, high-titer, high-quality antibody response that was broadly cross-reactive across several influenza A(H5N1) clades. C1 [Talaat, Kawsar R.; McMahon, Bridget A.; Karron, Ruth A.] Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Immunizat Res, Baltimore, MD USA. [Luke, Catherine J.; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Qin, Jing; Follmann, Dean A.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Khurana, Surender; Manischewitz, Jody; King, Lisa R.; Golding, Hana] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. [Lewis, Kristen D. C.; Neuzil, Kathleen M.] PATH, Seattle, WA USA. RP Subbarao, K (reprint author), NIAID, Infect Dis Lab, NIH, 33 North Dr,MSC 3203, Bethesda, MD 20892 USA. EM ksubbarao@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health; Influenza Vaccine Manufacturing Improvement Initiative of the Biomedical Advanced Research and Development Authority, US Department of Health and Human Services; PATH Vaccine Solutions; Center for Biologics Evaluation and Research, Food and Drug Administration FX This work was supported by the Intramural Research Program of National Institute of Allergy and Infectious Diseases, National Institutes of Health; the Influenza Vaccine Manufacturing Improvement Initiative of the Biomedical Advanced Research and Development Authority, US Department of Health and Human Services; PATH Vaccine Solutions; and Pandemic Flu Funding from the Center for Biologics Evaluation and Research, Food and Drug Administration. NR 35 TC 38 Z9 39 U1 1 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD JUN 15 PY 2014 VL 209 IS 12 BP 1860 EP 1869 DI 10.1093/infdis/jiu123 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AI7JB UT WOS:000337063100002 PM 24604819 ER PT J AU Zonios, D Yamazaki, H Murayama, N Natarajan, V Palmore, T Childs, R Skinner, J Bennett, JE AF Zonios, Dimitrios Yamazaki, Hiroshi Murayama, Norie Natarajan, Ven Palmore, Tara Childs, Richard Skinner, Jeff Bennett, John E. TI Voriconazole Metabolism, Toxicity, and the Effect of Cytochrome P450 2C19 Genotype SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE voriconazole; metabolites; CYP2C19; toxicity ID ANTIFUNGAL AGENT VORICONAZOLE; INVASIVE FUNGAL-INFECTIONS; CELL TRANSPLANT RECIPIENTS; CYP2C19 GENOTYPE; PHARMACOKINETICS; SAFETY; EFFICACY; THERAPY AB Background. Prospective evaluation of the antifungal drug, voriconazole, is needed to determine whether drug toxicity correlates with CYP2C19 genotype or serum concentrations of voriconazole or its metabolites. Methods. We conducted a prospective study of 95 patients to determine voriconazole toxicity and its relationship to genotype and serum levels of voriconazole and its two metabolites. Efficacy was not evaluated because, in most cases, the drug was given for empirical or prophylactic therapy. Results. Hallucinations occurred in 16 patients (16.8%), visual changes in 17 (17.9%), photosensitivity in 10 (10.5%), and hepatotoxicity in 6 (6.3%). There was no correlation between photosensitivity or hepatotoxicity and levels of voriconazole or metabolites. Patients with hallucinations had higher average voriconazole levels (4.5 vs 2.5 mu g/mL) but with extensive overlap. The recommended oral dose of 200 mg did not provide consistently detectable serum voriconazole levels in adults. CYP2C19 and CYP2C9 genotypes had a minor influence over levels, though the 4 patients homozygous for the 2C19*2 genotype had higher average levels for voriconazole (4.3 vs 2.5 mu g/mL) and lower N-oxide levels (1.6 vs 2.5 mu g/mL). Conclusions. CYP2C19 and 2C9 genotypes were not major determinants of voriconazole metabolism. No toxic serum level of voriconazole or its metabolites could be identified. C1 [Zonios, Dimitrios; Palmore, Tara; Skinner, Jeff; Bennett, John E.] NIAID, NIH, Bethesda, MD 20892 USA. [Yamazaki, Hiroshi; Murayama, Norie] Showa Pharmaceut Univ, Machida, Tokyo 1948543, Japan. [Natarajan, Ven] NCI, SAIC Frederick Inc, Frederick, MD 21701 USA. [Childs, Richard] NHLBI, NIH, Bethesda, MD 20892 USA. RP Bennett, JE (reprint author), NIH, Ctr Clin, Room 12C103b,9000 Rockville Pike, Bethesda, MD 20892 USA. EM jbennett@niaid.nih.gov OI Yamazaki, Hiroshi/0000-0002-1068-4261; Skinner, Jeff/0000-0001-5697-0442 FU Ministry of Education, Science, Sports and Culture of Japan; National Institute of Allergy and Infectious Diseases; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported in part by the Ministry of Education, Science, Sports and Culture of Japan and by the Intramural Program of the National Institute of Allergy and Infectious Diseases. This project also was funded in part by the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. NR 21 TC 19 Z9 22 U1 1 U2 15 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD JUN 15 PY 2014 VL 209 IS 12 BP 1941 EP 1948 DI 10.1093/infdis/jiu017 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AI7JB UT WOS:000337063100012 PM 24403552 ER PT J AU Nichols, L Freund, M Ng, C Kau, A Parisi, M Taylor, A Armstrong, D Avenilla, F Joseph, J Meinecke, D Wagner, A Little, AR AF Nichols, Lisa Freund, Michelle Ng, Cathy Kau, Alice Parisi, Melissa Taylor, Anna Armstrong, David Avenilla, Frank Joseph, Jeymohan Meinecke, Doug Wagner, Ann Little, A. Roger TI The National Institutes of Health Neurobiobank: A Federated National Network of Human Brain and Tissue Repositories SO BIOLOGICAL PSYCHIATRY LA English DT Letter C1 [Kau, Alice; Parisi, Melissa] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Taylor, Anna] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. [Nichols, Lisa; Freund, Michelle; Ng, Cathy; Armstrong, David; Avenilla, Frank; Joseph, Jeymohan; Meinecke, Doug; Wagner, Ann; Little, A. Roger] NIMH, Bethesda, MD 20892 USA. RP Little, AR (reprint author), NIMH, Bethesda, MD 20892 USA. EM alittle@mail.nih.gov RI Little, A/O-6191-2014; OI Little, A/0000-0001-6831-0177; Taylor, Anna/0000-0002-6501-3393 NR 2 TC 3 Z9 3 U1 0 U2 0 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 JUN 15 PY 2014 VL 75 IS 12 BP E21 EP E22 DI 10.1016/j.biopsych.2013.07.039 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AH8DV UT WOS:000336365200001 PM 24074636 ER PT J AU Andridge, RR Shoben, AB Muller, KE Murray, DM AF Andridge, Rebecca R. Shoben, Abigail B. Muller, Keith E. Murray, David M. TI Analytic methods for individually randomized group treatment trials and group-randomized trials when subjects belong to multiple groups SO STATISTICS IN MEDICINE LA English DT Article DE individually randomized group treatment trial; group-randomized trial; intraclass correlation; mixed models ID GENERALIZED ESTIMATING EQUATIONS; SMALL-SAMPLE ADJUSTMENTS; CLINICAL-TRIALS; INTRACLASS CORRELATION; DESIGN; INFERENCE; MODELS; INTERVENTIONS; ESTIMATOR; TESTS AB Participants in trials may be randomized either individually or in groups and may receive their treatment either entirely individually, entirely in groups, or partially individually and partially in groups. This paper concerns cases in which participants receive their treatment either entirely or partially in groups, regardless of how they were randomized. Participants in group-randomized trials are randomized in groups, and participants in individually randomized group treatment trials are individually randomized, but participants in both types of trials receive part or all of their treatment in groups or through common change agents. Participants who receive part or all of their treatment in a group are expected to have positively correlated outcome measurements. This paper addresses a situation that occurs in group-randomized trials and individually randomized group treatment trialsparticipants receive treatment through more than one group. As motivation, we consider trials in The Childhood Obesity Prevention and Treatment Research Consortium, in which each child participant receives treatment in at least two groups. In simulation studies, we considered several possible analytic approaches over a variety of possible group structures. A mixed model with random effects for both groups provided the only consistent protection against inflated type I error rates and did so at the cost of only moderate loss of power when intraclass correlations were not large. We recommend constraining variance estimates to be positive and using the Kenward-Roger adjustment for degrees of freedom; this combination provided additional power but maintained type I error rates at the nominal level. Copyright (c) 2014 John Wiley & Sons, Ltd. C1 [Andridge, Rebecca R.; Shoben, Abigail B.] Ohio State Univ, Div Biostat, Coll Publ Hlth, Columbus, OH 43210 USA. [Muller, Keith E.] Univ Florida, Dept Hlth Outcomes & Policy, Coll Med, Gainesville, FL 32610 USA. [Murray, David M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20892 USA. RP Andridge, RR (reprint author), Ohio State Univ, Div Biostat, 242 Cunz Hall,1841 Neil Ave, Columbus, OH 43210 USA. EM randridge@cph.osu.edu RI Andridge, Rebecca/C-8457-2012 OI Andridge, Rebecca/0000-0001-9991-9647 FU NIDCR [R01-DE020832, U54-DE019261]; NIDDK [R01-DK072398]; NCRR [K30-RR022258]; NIDA [R01-DA031017]; NICHD [P01-HD065647]; Texas Health and Human Services Commission [529-07-0093-00001G]; NHLBI [U01-HL-103561]; Research Coordinating Unit for COPTR FX Dr. Muller's support included NIDCR R01-DE020832, NIDDK R01-DK072398, NIDCR U54-DE019261, NCRR K30-RR022258, NIDA R01-DA031017, NICHD P01-HD065647, and Texas Health and Human Services Commission 529-07-0093-00001G. Dr. Murray's work on this project was supported in part by a grant from the NHLBI (U01-HL-103561), which supported the Research Coordinating Unit for COPTR. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 23 TC 0 Z9 0 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD JUN 15 PY 2014 VL 33 IS 13 BP 2178 EP 2190 DI 10.1002/sim.6083 PG 13 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA AG9XH UT WOS:000335772800002 PM 24399701 ER PT J AU Baytas, SN Inceler, N Yilmaz, A Olgac, A Menevse, S Banoglu, E Hamel, E Bortolozzi, R Viola, G AF Baytas, Sultan Nacak Inceler, Nazan Yilmaz, Akin Olgac, Abdurrahman Menevse, Sevda Banoglu, Erden Hamel, Ernest Bortolozzi, Roberta Viola, Giampietro TI Synthesis, biological evaluation and molecular docking studies of trans-indole-3-acrylamide derivatives, a new class of tubulin polymerization inhibitors SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Synthesis; Anticancer activity; Indole; Tubulin polymerization; Colchicine binding; Apoptosis; Cell cycle arrest; Molecular docking ID RAPID COLORIMETRIC ASSAY; ANTITUBULIN AGENTS; INDOLE-DERIVATIVES; ANTIMITOTIC AGENTS; COMBRETASTATIN A4; CHALCONES; ANALOGS; COLCHICINE; GROWTH; CELLS AB In this study, we synthesized a series of trans-indole-3-acrylamide derivatives (3a-k) and investigated their activity for inhibition of cell proliferation against five human cancer cell lines (HeLa, MCF7, MDA-MB-231, Raji and HL-60) by MTT assay. Compound 3e showed significant antiproliferative activity against both the Raji and HL-60 cell lines with IC50 values of 9.5 and 5.1 mu M, respectively. Compound 3e also exhibited moderate inhibitory activity on tubulin polymerization (IC50 = 17 mu M). Flow cytometric analysis of cultured cells treated with 3e also demonstrated that the compound caused cell cycle arrest at the G2/M phase in HL-60 and HeLa cells. Moreover, 3e, the most active compound, caused an apoptotic cell death through the activation of caspase-3. Docking simulations suggested that 3e binds to the colchicine site of tubulin. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Baytas, Sultan Nacak; Inceler, Nazan; Olgac, Abdurrahman; Banoglu, Erden] Gazi Univ, Div Pharmaceut Sci, Dept Pharmaceut Chem, Fac Pharm, TR-06330 Ankara, Turkey. [Yilmaz, Akin; Menevse, Sevda] Gazi Univ, Dept Med Biol & Genet, Fac Med, TR-06500 Ankara, Turkey. [Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program,NIH, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA. [Bortolozzi, Roberta; Viola, Giampietro] Univ Padua, Dept Womens & Childrens Hlth, Lab Oncohematol, I-35128 Padua, Italy. RP Baytas, SN (reprint author), Gazi Univ, Div Pharmaceut Sci, Dept Pharmaceut Chem, Fac Pharm, TR-06330 Ankara, Turkey. EM baytas@gazi.edu.tr RI YILMAZ, AKIN/G-1451-2011; Viola, Giampietro/I-4095-2012; Bortolozzi, Roberta/D-4950-2015; Olgac, Abdurrahman/B-3723-2017 OI YILMAZ, AKIN/0000-0002-4368-0777; Viola, Giampietro/0000-0001-9329-165X; Bortolozzi, Roberta/0000-0002-3357-4815; Olgac, Abdurrahman/0000-0001-8470-4942 FU Gazi University BAP [02/2011-09] FX This research was supported by Scientific Research Grant 02/2011-09, awarded by Gazi University BAP. NR 47 TC 7 Z9 7 U1 1 U2 36 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 EI 1464-3391 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD JUN 15 PY 2014 VL 22 IS 12 BP 3096 EP 3104 DI 10.1016/j.bmc.2014.04.027 PG 9 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA AH1WL UT WOS:000335912300004 PM 24816066 ER PT J AU Garcia, LC Donadio, LG Mann, E Kolusheva, S Kedei, N Lewin, NE Hill, CS Kelsey, JS Yang, J Esch, TE Santos, M Peach, ML Kelley, JA Blumberg, PM Jelinek, R Marquez, VE Comin, MJ AF Garcia, Lia C. Gandolfi Donadio, Lucia Mann, Ella Kolusheva, Sofiya Kedei, Noemi Lewin, Nancy E. Hill, Colin S. Kelsey, Jessica S. Yang, Jing Esch, Timothy E. Santos, Marina Peach, Megan L. Kelley, James A. Blumberg, Peter M. Jelinek, Raz Marquez, Victor E. Comin, Maria J. TI Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRP SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Indolo-lactones; C1 domain; RasGRP; Cancer ID PROTEIN-KINASE-C; CONFORMATIONALLY CONSTRAINED ANALOGS; PHORBOL ESTERS; LIPID INTERACTIONS; PK-C; DIACYLGLYCEROL-LACTONES; TRYPTOPHAN ANALOGS; SIGNALING SYSTEMS; BINDING-AFFINITY; BRYOSTATIN 1 AB The development of selective agents capable of discriminating between protein kinase C (PKC) isoforms and other diacylglycerol (DAG)-responsive C1 domain-containing proteins represents an important challenge. Recent studies have highlighted the role that Ras guanine nucleotide-releasing protein (RasGRP) isoforms play both in immune responses as well as in the development of prostate cancer and melanoma, suggesting that the discovery of selective ligands could have potential therapeutic value. Thus far, the N-methyl-substituted indololactone 1 is the agonist with the highest reported potency and selectivity for RasGRP relative to PKC. Here we present the synthesis, binding studies, cellular assays and biophysical analysis of interactions with model membranes of a family of regioisomers of 1 (compounds 2-5) that differ in the position of the linkage between the indole ring and the lactone moiety. These structural variations were studied to explore the interaction of the active complex (C1 domain-ligand) with cellular membranes, which is believed to be an important factor for selectivity in the activation of DAG-responsive C1 domain containing signaling proteins. All compounds were potent and selective activators of RasGRP when compared to PKC alpha with selectivities ranging from 6 to 65 fold. However, the parent compound 1 was appreciably more selective than any of the other isomers. In intact cells, modest differences in the patterns of translocation of the C1 domain targets were observed. Biophysical studies using giant vesicles as model membranes did show substantial differences in terms of molecular interactions impacting lipid organization, dynamics and membrane insertion. However, these differences did not yield correspondingly large changes in patterns of biological response, at least for the parameters examined. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Garcia, Lia C.; Gandolfi Donadio, Lucia; Santos, Marina; Comin, Maria J.] Natl Inst Ind Technol, Ctr Res & Dev Chem, Organ Synth Lab, Buenos Aires, DF, Argentina. [Kedei, Noemi; Lewin, Nancy E.; Hill, Colin S.; Kelsey, Jessica S.; Yang, Jing; Esch, Timothy E.; Blumberg, Peter M.] NCI, Ctr Canc Res, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. [Mann, Ella; Kolusheva, Sofiya; Jelinek, Raz] Ben Gurion Univ Negev, Dept Chem, IL-84105 Beer Sheva, Israel. [Peach, Megan L.] NIH, Basic Sci Program, Leidos Biomed Inc, Chem Biol Lab,Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Kelley, James A.; Marquez, Victor E.] NCI, Biol Chem Lab, Mol Discovery Program, Ctr Canc Res,NIH, Frederick, MD 21702 USA. RP Comin, MJ (reprint author), Natl Inst Ind Technol, Ctr Res & Dev Chem, Organ Synth Lab, Buenos Aires, DF, Argentina. EM jcomin@inti.gob.ar OI jelinek, raz/0000-0002-0336-1384 FU National Institute of Industrial Technology (INTI); Consejo Nacional de Investigacion Cientifica y Tecnologica (CONICET); Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute [Z1A BC 005720]; Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E] FX The research was supported in part by The National Institute of Industrial Technology (INTI) and Consejo Nacional de Investigacion Cientifica y Tecnologica (CONICET); in part by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute (Z1A BC 005720) and in part with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, 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 US Government. NR 69 TC 1 Z9 1 U1 1 U2 17 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 EI 1464-3391 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD JUN 15 PY 2014 VL 22 IS 12 BP 3123 EP 3140 DI 10.1016/j.bmc.2014.04.024 PG 18 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA AH1WL UT WOS:000335912300007 PM 24794745 ER PT J AU Kim, HS Jin, MK Kang, SU Lim, JO Tran, PT Hoang, VH Ann, J Ha, TH Pearce, LV Pavlyukovets, VA Blumberg, PM Lee, J AF Kim, Ho Shin Jin, Mi-Kyoung Kang, Sang-Uk Lim, Ju-Ok Phuong-Thao Tran Van-Hai Hoang Ann, Jihyae Ha, Tae-Hwan Pearce, Larry V. Pavlyukovets, Vladimir A. Blumberg, Peter M. Lee, Jeewoo TI alpha-Methylated simplified resiniferatoxin (sRTX) thiourea analogues as potent and stereospecific TRPV1 antagonists SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Vanilloid receptor 1; TRPV1 antagonist; Capsaicin; Resiniferatoxin ID VANILLOID RECEPTOR; ANALGESICS; CAPSAICIN; AGONISTS; REGION AB A series of alpha-methylated analogues of the potent sRTX thiourea antagonists were investigated as rTRPV1 ligands in order to examine the effect of alpha-methylation on receptor activity. The SAR analysis indicated that activity was stereospecific with the (R)-configuration of the newly formed chiral center providing high binding affinity and potent antagonism while the configuration of the C-region was not significant. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Kim, Ho Shin; Jin, Mi-Kyoung; Kang, Sang-Uk; Lim, Ju-Ok; Phuong-Thao Tran; Van-Hai Hoang; Ann, Jihyae; Ha, Tae-Hwan; Lee, Jeewoo] Seoul Natl Univ, Coll Pharm, Pharmaceut Sci Res Inst, Med Chem Lab, Seoul 151742, South Korea. [Pearce, Larry V.; Pavlyukovets, Vladimir A.; Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Lee, J (reprint author), Seoul Natl Univ, Coll Pharm, Pharmaceut Sci Res Inst, Med Chem Lab, Seoul 151742, South Korea. EM jeewoo@snu.ac.kr FU National Research Foundation of Korea (NRF) [R11-2007-107-02001-0]; Intramural Research Program of NIH; Center for Cancer Research, NCI [Z1A BC 005270] FX This research was supported by Grants from the National Research Foundation of Korea (NRF) (R11-2007-107-02001-0), and by the Intramural Research Program of NIH, Center for Cancer Research, NCI (Project Z1A BC 005270). NR 19 TC 2 Z9 2 U1 2 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X EI 1464-3405 J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD JUN 15 PY 2014 VL 24 IS 12 BP 2685 EP 2688 DI 10.1016/j.bmcl.2014.04.054 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA AH1ZT UT WOS:000335921200018 PM 24794110 ER PT J AU Swift, MR Pham, VN Castranova, D Bell, K Poole, RJ Weinstein, BM AF Swift, Matthew R. Pham, Van N. Castranova, Daniel Bell, Kameha Poole, Richard J. Weinstein, Brant M. TI SoxF factors and Notch regulate nr2f2 gene expression during venous differentiation in zebrafish SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Nr2f2; COUP-TFII; Zebrafish; Cardinal vein; Dorsal aorta ID EMBRYONIC VASCULAR DEVELOPMENT; COUP-TFII; LYMPHATIC DEVELOPMENT; TRANSGENIC ZEBRAFISH; REDUNDANT ROLES; SPECIFICATION; IDENTITY; VECTOR; CLOCHE; CELLS AB Initial embryonic determination of artery or vein identity is regulated by genetic factors that work in concert to specify the endothelial cell's (EC) fate, giving rise to two structurally unique components of the circulatory loop. The Shh/VEGF/Notch pathway is critical for arterial specification, while the orphan receptor nr2f2 (COUP-TFII) has been implicated in venous specification. Studies in mice have shown that nr2f2 is expressed in venous but not arterial ECs, and that it preferentially induces markers of venous cell fate. We have examined the role of nr2f2 during early arterial-venous development in the zebrafish trunk. We show that expression of a subset of markers of venous endothelial identity requires nr2f2, while the expression of nr2f2 itself requires sox7 and sax 18 gene function. However, while sox7 and sox18 are expressed in both the cardinal vein and the dorsal aorta during early trunk development, nr2f2 is expressed only in the cardinal vein. We show that Notch signaling activity present in the dorsal aorta suppresses expression of nr2f2, restricting nr2f2-dependent promotion of venous differentiation to the cardinal vein. Published by Elsevier Inc. C1 [Swift, Matthew R.; Pham, Van N.; Castranova, Daniel; Bell, Kameha; Weinstein, Brant M.] Natl Inst Child Hlth & Human Dev, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Poole, Richard J.] UCL, Dept Cell & Dev Biol, London WC1E 6BT, England. RP Weinstein, BM (reprint author), Natl Inst Child Hlth & Human Dev, Program Genom Differentiat, NIH, Bldg 6B,Room 413,6 Ctr Dr, Bethesda, MD 20892 USA. EM flyingfish2@nih.gov FU NICHD; NIH; Leducq Foundation FX We thank members of the Weinstein laboratory for critical comments on this manuscript. We thank Daniel Castranova, Andrew Davis, and Van Pham for technical support and reagents. We also thank Louis Dye of the NICHD Microscopy and Imaging Core for helpful advice and guidance on vibratome use. This research was supported by the intramural program of the NICHD, NIH and the Leducq Foundation. NR 37 TC 16 Z9 16 U1 1 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 EI 1095-564X J9 DEV BIOL JI Dev. Biol. PD JUN 15 PY 2014 VL 390 IS 2 BP 116 EP 125 DI 10.1016/j.ydbio.2014.03.018 PG 10 WC Developmental Biology SC Developmental Biology GA AG6PG UT WOS:000335540300003 PM 24699544 ER PT J AU Brusco, J Merlo, S Ikeda, ET Petralia, RS Kachar, B Rasia, AA Moreira, JE AF Brusco, Janaina Merlo, Suelen Ikeda, Erika T. Petralia, Ronald S. Kachar, Bechara Rasia-Filho, Alberto A. Moreira, Jorge E. TI Inhibitory and Multisynaptic Spines, and Hemispherical Synaptic Specialization in the Posterodorsal Medial Amygdala of Male and Female Rats SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE extended amygdala; 3D reconstruction; electron microscopy; laterality; inhibitory dendritic spines; multisynaptic dendritic spines ID DENDRITIC BRANCHING FEATURES; LONG-TERM POTENTIATION; SEXUAL-DIMORPHISM; ESTROUS-CYCLE; IN-VIVO; POSTSYNAPTIC DENSITIES; CIRCULATING ANDROGENS; STRUCTURAL-CHANGES; MATERNAL-BEHAVIOR; EXTENDED AMYGDALA AB The density of dendritic spines is sexually dimorphic and variable throughout the female estrous cycle in the rat posterodorsal medial amygdala (MePD), a relevant area for the modulation of reproductive behavior in rats. The local synaptic activity differs between hemispheres in prepubertal animals. Here we used serial section transmission electron microscopy to produce 3D reconstructions of dendritic shafts and spines to characterize synaptic contacts on MePD neurons of both hemispheres in adult males and in females along the estrous cycle. Pleomorphic spines and nonsynaptic filopodia occur in the MePD. On average, 8.6% of dendritic spines received inputs from symmetric gamma-aminobutyric acid (GABA)-immunoreactive terminals, whereas 3.6% received two synaptic contacts on the spine head, neck, or base. Presynaptic terminals in female right MePD had a higher density of synaptic vesicles and docked vesicles than the left MePD, suggesting a higher rate of synaptic vesicle release in the right MePD of female rats. In contrast, males did not show laterality in any of those parameters. The proportion of putative inhibitory synapses on dendritic shafts in the right MePD of females in proestrus was higher than in the left MePD, and higher than in the right MePD in males, or in females in diestrus or estrus. This work shows synaptic laterality depending on sex and estrous cycle phase in mature MePD neurons. Most likely, sexual hormone effects are lateralized in this brain region, leading to higher synaptic activity in the right than in the left hemisphere of females, mediating timely neuroendocrine and social/reproductive behavior. J. Comp. Neurol. 522:2075-2088, 2014. (c) 2013 Wiley Periodicals, Inc. C1 [Brusco, Janaina; Merlo, Suelen; Moreira, Jorge E.] Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Neurosci & Behav, BR-14049900 Ribeirao Preto, Brazil. [Brusco, Janaina; Petralia, Ronald S.; Kachar, Bechara] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA. [Ikeda, Erika T.; Moreira, Jorge E.] Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Cell & Mol Biol, BR-14049900 Ribeirao Preto, Brazil. [Rasia-Filho, Alberto A.] Fed Univ Hlth Sci Porto Alegre, Dept Basic Sci Physiol, BR-90050110 Porto Alegre, RS, Brazil. RP Moreira, JE (reprint author), Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Cell & Mol Biol, Av Bandeirantes 3900, BR-14049900 Ribeirao Preto, Brazil. EM cello@fmrp.usp.br FU CNPq (Brazil) [141534/2008-7, 201560/2010-0]; FAPESP [2009/01571-6, 2011/10753-0, 12/19011-0, CinAPCe 05/56447-7]; Intramural Research Program of the NIDCD/NIH, USA FX Grant sponsor: CNPq (Brazil); Grant numbers: 141534/2008-7 and 201560/2010-0 (to J.B.); Grant sponsor: FAPESP; Grant number: 2009/01571-6, 2011/10753-0, 12/19011-0 and CinAPCe 05/56447-7 (to J.E.M.); Grant sponsor: Intramural Research Program of the NIDCD/NIH, USA. NR 96 TC 11 Z9 13 U1 2 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9967 EI 1096-9861 J9 J COMP NEUROL JI J. Comp. Neurol. PD JUN 15 PY 2014 VL 522 IS 9 BP 2075 EP 2088 DI 10.1002/cne.23518 PG 14 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA AF1QS UT WOS:000334489000007 PM 24318545 ER PT J AU Chappell, G Kutanzi, K Uehara, T Tryndyak, V Hong, HH Hoenerhoff, M Beland, FA Rusyn, I Pogribny, IP AF Chappell, Grace Kutanzi, Kristy Uehara, Takeki Tryndyak, Volodymyr Hong, Hue-Hua Hoenerhoff, Mark Beland, Frederick A. Rusyn, Ivan Pogribny, Igor P. TI Genetic and epigenetic changes in fibrosis-associated hepatocarcinogenesis in mice SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE mouse; liver carcinogenesis; DNA methylation; genetics; epigenetics; histone lysine methylation ID TUMOR-SUPPRESSOR GENE; HEPATOCELLULAR-CARCINOMA; DNA METHYLATION; BETA-CATENIN; MOLECULAR-MECHANISMS; SOMATIC MUTATIONS; HUMAN CANCERS; LIVER-TUMORS; CPG ISLANDS; MOUSE AB Hepatocellular carcinoma (HCC) is one of the most prevalent cancers and is rising in incidence worldwide. The molecular mechanisms leading to the development of HCC are complex and include both genetic and epigenetic events. To determine the relative contribution of these alterations in liver tumorigenesis, we evaluated epigenetic modifications at both global and gene specific levels, as well as the mutational profile of genes commonly altered in liver tumors. A mouse model of fibrosis-associated liver cancer that was designed to emulate cirrhotic liver, a prevailing disease state observed in most humans with HCC, was used. Tumor and nontumor liver samples from B6C3F1 mice treated with N-nitrosodiethylamine (DEN; a single ip injection of 1 mg/kg at 14 days of age) and carbon tetrachloride (CCl4; 0.2 ml/kg, 2 times/week ip starting at 8 weeks of age for 14 weeks), as well as corresponding vehicle control animals, were analyzed for genetic and epigenetic alterations. H-ras, Ctnnb1 and Hnf1 alpha genes were not mutated in tumors in mice treated with DEN+CCl4. In contrast, the increased tumor incidence in mice treated with DEN+CCl4 was associated with marked epigenetic changes in liver tumors and nontumor liver tissue, including demethylation of genomic DNA and repetitive elements, a decrease in histone 3 lysine 9 trimethylation (H3K9me3) and promoter hypermethylation and functional downregulation of Riz1, a histone lysine methyltransferase tumor suppressor gene. Additionally, the reduction in H3K9me3 was accompanied by increased expression of long interspersed nucleotide elements 1 and short interspersed nucleotide elements B2, which is an indication of genomic instability. In summary, our results suggest that epigenetic events, rather than mutations in known cancer-related genes, play a prominent role in increased incidence of liver tumors in this mouse model of fibrosis-associated liver cancer. C1 [Chappell, Grace; Uehara, Takeki; Rusyn, Ivan] Univ N Carolina, Dept Environm Sci & Engn, Chapel Hill, NC USA. [Kutanzi, Kristy; Tryndyak, Volodymyr; Beland, Frederick A.; Pogribny, Igor P.] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Hong, Hue-Hua; Hoenerhoff, Mark] NIEHS, Cellular & Mol Pathol Branch, Res Triangle Pk, NC 27709 USA. [Hong, Hue-Hua; Hoenerhoff, Mark] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Pogribny, IP (reprint author), Natl Ctr Toxicol Res, Div Biochem Toxicol, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM iir@unc.edu; igor.pogribny@fda.hhs.gov RI Rusyn, Ivan/S-2426-2016 FU National Institutes of Health [R01 ES015241, P42 ES005948, R01 ES023195] FX Grant sponsor: National Institutes of Health; Grant numbers: R01 ES015241, P42 ES005948 and R01 ES023195 NR 49 TC 11 Z9 12 U1 0 U2 37 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 JUN 15 PY 2014 VL 134 IS 12 BP 2778 EP 2788 DI 10.1002/ijc.28610 PG 11 WC Oncology SC Oncology GA AE1SU UT WOS:000333751000004 PM 24242335 ER PT J AU DellaValle, CT Xiao, Q Yang, G Shu, XO Aschebrook-Kilfoy, B Zheng, W Li, HL Ji, BT Rothman, N Chow, WH Gao, YT Ward, MH AF DellaValle, Curt T. Xiao, Qian Yang, Gong Shu, Xiao-Ou Aschebrook-Kilfoy, Briseis Zheng, Wei Li, Hong Lan Ji, Bu-Tian Rothman, Nathaniel Chow, Wong-Ho Gao, Yu-Tang Ward, Mary H. TI Dietary nitrate and nitrite intake and risk of colorectal cancer in the Shanghai Women's Health Study SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE diet; vitamin C; colon cancer; N-nitroso compounds; nitrite; rectum cancer; nitrate ID N-NITROSO COMPOUNDS; NIH-AARP DIET; VITAMIN-C; ENDOGENOUS NITROSATION; DRINKING-WATER; THYROID-CANCER; RECTAL-CANCER; CHINA; COLON; EXPOSURE AB Nitrate and nitrite are precursors of endogenously formed N-nitroso compounds (NOC), known animal carcinogens. Nitrosation reactions forming NOCs can be inhibited by vitamin C and other antioxidants. We prospectively investigated the association between dietary nitrate and nitrite intake and risk of colorectal cancer in the Shanghai Women's Health Study, a cohort of 73,118 women ages 40-70 residing in Shanghai. We evaluated effect modification by factors that affect endogenous formation of NOCs: vitamin C (at or above/below median) and red meat intake (at or above/below median). Nitrate, nitrite and other dietary intakes were estimated from a 77-item food frequency questionnaire administered at baseline. Over a mean of 11 years of follow-up, we identified 619 colorectal cancer cases (n = 383, colon; n = 236, rectum). Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazard regression. Overall, nitrate intake was not associated with colorectal cancer risk (HR = 1.08; 95% CI: 0.73-1.59). However, among women with vitamin C intake below the median (83.9 mg day(-1)) and hence higher potential exposure to NOCs, risk of colorectal cancer increased with increasing quintiles of nitrate intake (highest vs. lowest quintile HR = 2.45; 95% CI: 1.15-5.18; p trend = 0.02). There was no association among women with higher vitamin C intake. We found no association between nitrite intake and risk of colorectal cancer overall or by intake level of vitamin C. Our findings suggest that high dietary nitrate intake among subgroups expected to have higher exposure to endogenously formed NOCs increases risk of colorectal cancer. C1 [DellaValle, Curt T.; Ji, Bu-Tian; Rothman, Nathaniel; Ward, Mary H.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Xiao, Qian] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Yang, Gong; Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Dept Med, Div Epidemiol, Nashville, TN USA. [Yang, Gong; Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Vanderbilt Epidemiol Ctr, Nashville, TN 37235 USA. [Yang, Gong; Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Dept Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37235 USA. [Aschebrook-Kilfoy, Briseis] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. [Li, Hong Lan; Gao, Yu-Tang] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Chow, Wong-Ho] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Div OVP Canc Prevent & Populat Sci, Houston, TX 77030 USA. RP Ward, MH (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room SG-6E138 MSC 9771, Bethesda, MD 20892 USA. EM wardm@mail.nih.gov FU National Institutes of Health [R37 CA70867]; Intramural Research Program of the National Institutes of Health, Division of Cancer Epidemiology and Genetics [N02 CP1101066] FX Grant sponsor: National Institutes of Health; Grant number: R37 CA70867; Grant sponsor: Intramural Research Program of the National Institutes of Health, Division of Cancer Epidemiology and Genetics; Grant number: N02 CP1101066 NR 50 TC 20 Z9 21 U1 3 U2 46 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 JUN 15 PY 2014 VL 134 IS 12 BP 2917 EP 2926 DI 10.1002/ijc.28612 PG 10 WC Oncology SC Oncology GA AE1SU UT WOS:000333751000017 PM 24242755 ER PT J AU Zhang, DL Ghosh, MC Rouault, TA AF Zhang, De-Liang Ghosh, Manik C. Rouault, Tracey A. TI The physiological functions of on regulatory proteins in iron homeostasis - an update SO FRONTIERS IN PHARMACOLOGY LA English DT Review DE iron regulatory protein; iron responsive element; erythropoiesis; polycythemia; pulmonary hypertension; iron metabolism ID HYPOXIA-INDUCIBLE FACTORS; RESPONSIVE ELEMENT; MESSENGER-RNA; PULMONARY-HYPERTENSION; CHUVASH POLYCYTHEMIA; HEREDITARY HEMOCHROMATOSIS; NEURODEGENERATIVE DISEASE; MITOCHONDRIAL ACONITASE; DROSOPHILA-MELANOGASTER; 5-UNTRANSLATED REGION AB Iron regulatory proteins (IRPs) regulate the expression of genes involved in iron metabolism by binding to RNA stem-loop structures known as iron responsive elements (IREs) in target mRNAs. IRP binding inhibits the translation of mRNAs that contain an IRE in the 5'untranslated region of the transcripts, and increases the stability of mRNAs that contain IREs in the 3'untranslated region of transcripts. By these mechanisms, IRPs increase cellular iron absorption and decrease storage and export of iron to maintain an optimal intracellular iron balance. There are two members of the mammalian IRP protein family, IRP1 and IRP2, and they have redundant functions as evidenced by the embryonic lethality of the mice that completely lack IRP expression (Irp1(-/-) /Irp2(-/-) mice), which contrasts with the fact that Irp1(-/-) and Irp2(-/-) mice are viable. In addition, Irp2(-/-) mice also display neurodegenerative symptoms and microcytic hypochromic anemia, suggesting that IRP2 function predominates in the nervous system and erythropoietic homeostasis. Though the physiological significance of IRP1 had been unclear since Irp1(-/-) animals were first assessed in the early 1990s, recent studies indicate that IRP1 plays an essential function in orchestrating the balance between erythropoiesis and bodily iron homeostasis. Additionally, Irp1(-/-) mice develop pulmonary hypertension, and they experience sudden death when maintained on an iron-deficient diet, indicating that IRP1 has a critical role in the pulmonary and cardiovascular systems. This review summarizes recent progress that has been made in understanding the physiological roles of IRP1 and IRP2, and further discusses the implications for clinical research on patients with idiopathic polycythemia, pulmonary hypertension, and neurodegeneration. C1 [Zhang, De-Liang; Ghosh, Manik C.; Rouault, Tracey A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Med Program, NIH, Bethesda, MD 20892 USA. RP Rouault, TA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Med Program, NIH, Bethesda, MD 20892 USA. EM rouault@mail.nih.gov FU NICHD FX This work was supported by the intramural programs of NICHD. NR 102 TC 24 Z9 25 U1 2 U2 12 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1663-9812 J9 FRONT PHARMACOL JI Front. Pharmacol. PD JUN 13 PY 2014 VL 5 AR 124 DI 10.3389/fphar.2014.00124 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AX7MG UT WOS:000347099400001 PM 24982634 ER PT J AU Yu, S Klaus, A Yang, HD Plenz, D AF Yu, Shan Klaus, Andreas Yang, Hongdian Plenz, Dietmar TI Scale-Invariant Neuronal Avalanche Dynamics and the Cut-Off in Size Distributions SO PLOS ONE LA English DT Article ID SELF-ORGANIZED CRITICALITY; POWER-LAW DISTRIBUTIONS; PROPAGATING WAVES; CORTICAL NETWORKS; VISUAL-CORTEX; RANGE; POPULATION; SYNCHRONY; PATTERNS; BRAIN AB Identification of cortical dynamics strongly benefits from the simultaneous recording of as many neurons as possible. Yet current technologies provide only incomplete access to the mammalian cortex from which adequate conclusions about dynamics need to be derived. Here, we identify constraints introduced by sub-sampling with a limited number of electrodes, i.e. spatial 'windowing', for well-characterized critical dynamics_neuronal avalanches. The local field potential (LFP) was recorded from premotor and prefrontal cortices in two awake macaque monkeys during rest using chronically implanted 96-microelectrode arrays. Negative deflections in the LFP (nLFP) were identified on the full as well as compact sub-regions of the array quantified by the number of electrodes N (10-95), i.e., the window size. Spatiotemporal nLFP clusters organized as neuronal avalanches, i.e., the probability in cluster size, p(s), invariably followed a power law with exponent -1.5 up to N, beyond which p(s) declined more steeply producing a 'cut-off' that varied with N and the LFP filter parameters. Clusters of size s <= N consisted mainly of nLFPs from unique, non-repeated cortical sites, emerged from local propagation between nearby sites, and carried spatial information about cluster organization. In contrast, clusters of size s>N were dominated by repeated site activations and carried little spatial information, reflecting greatly distorted sampling conditions. Our findings were confirmed in a neuron-electrode network model. Thus, avalanche analysis needs to be constrained to the size of the observation window to reveal the underlying scale-invariant organization produced by locally unfolding, predominantly feed-forward neuronal cascades. C1 [Yu, Shan; Klaus, Andreas; Yang, Hongdian; Plenz, Dietmar] NIMH, Sect Crit Brain Dynam, Bethesda, MD 20892 USA. [Klaus, Andreas] Karolinska Inst, Nobel Inst Neurophysiol, Dept Neurosci, S-10401 Stockholm, Sweden. RP Yu, S (reprint author), NIMH, Sect Crit Brain Dynam, Bethesda, MD 20892 USA. EM yushan.mail@gmail.com RI Yang, Hongdian/D-1450-2015; OI Klaus, Andreas/0000-0002-4133-351X FU Intramural Research Program of the National Institute of Mental Health; National Institutes of Health/Karolinska Institutet Doctoral Program FX This study was supported by the Intramural Research Program of the National Institute of Mental Health (http://intramural.nimh.nih.gov/). A.K. was in addition supported by the National Institutes of Health/Karolinska Institutet Doctoral Program (http://intramural.nimh.nih.gov/ ki-nih/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 5 Z9 5 U1 0 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 13 PY 2014 VL 9 IS 6 AR e99761 DI 10.1371/journal.pone.0099761 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK2VQ UT WOS:000338278100076 PM 24927158 ER PT J AU Dorweiler, JE Ni, T Zhu, J Munroe, SH Anderson, JT AF Dorweiler, Jane E. Ni, Ting Zhu, Jun Munroe, Stephen H. Anderson, James T. TI Certain Adenylated Non-Coding RNAs, Including 5' Leader Sequences of Primary MicroRNA Transcripts, Accumulate in Mouse Cells following Depletion of the RNA Helicase MTR4 SO PLOS ONE LA English DT Article ID SMALL NUCLEOLAR RNAS; RIBOSOMAL-RNA; SACCHAROMYCES-CEREVISIAE; NUCLEAR-RNA; QUALITY-CONTROL; MESSENGER-RNA; POLY(A) POLYMERASE; ALZHEIMERS-DISEASE; TRAMP COMPLEX; U3B RNA AB RNA surveillance plays an important role in posttranscriptional regulation. Seminal work in this field has largely focused on yeast as a model system, whereas exploration of RNA surveillance in mammals is only recently begun. The increased transcriptional complexity of mammalian systems provides a wider array of targets for RNA surveillance, and, while many questions remain unanswered, emerging data suggest the nuclear RNA surveillance machinery exhibits increased complexity as well. We have used a small interfering RNA in mouse N2A cells to target the homolog of a yeast protein that functions in RNA surveillance (Mtr4p). We used high-throughput sequencing of polyadenylated RNAs (PA-seq) to quantify the effects of the mMtr4 knockdown (KD) on RNA surveillance. We demonstrate that overall abundance of polyadenylated protein coding mRNAs is not affected, but several targets of RNA surveillance predicted from work in yeast accumulate as adenylated RNAs in the mMtr4KD. microRNAs are an added layer of transcriptional complexity not found in yeast. After Drosha cleavage separates the pre-miRNA from the microRNA's primary transcript, the byproducts of that transcript are generally thought to be degraded. We have identified the 59 leading segments of pri-miRNAs as novel targets of mMtr4 dependent RNA surveillance. C1 [Dorweiler, Jane E.; Munroe, Stephen H.; Anderson, James T.] Marquette Univ, Dept Biol Sci, Milwaukee, WI 53233 USA. [Ni, Ting; Zhu, Jun] NHLBI, DNA Sequencing & Genom Core, Genet & Dev Biol Ctr, NIH, Bethesda, MD 20892 USA. RP Munroe, SH (reprint author), Marquette Univ, Dept Biol Sci, Milwaukee, WI 53233 USA. EM Stephen.munroe@marquette.edu; james.anderson@marquette.edu FU Marquette University Way Klingler College of Arts and Sciences; Marquette University Department of Biological Sciences; National Heart Lung Blood Institute, National Institutes of Health; National Institutes of Health [1R15GM100445-01A1]; open access charge: Marquette University FX This work was supported by Marquette University Way Klingler College of Arts and Sciences to J.T.A.; by Marquette University Department of Biological Sciences to J.T.A. and S.H.M.; and by intramural research program at National Heart Lung Blood Institute, National Institutes of Health to J.Z.; and by National Institutes of Health grant number 1R15GM100445-01A1 to J.T.A. Funding for open access charge: Marquette University and National Institutes of Health grant number 1R15GM100445-01A1. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 103 TC 1 Z9 1 U1 0 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 13 PY 2014 VL 9 IS 6 AR e99430 DI 10.1371/journal.pone.0099430 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK2VQ UT WOS:000338278100040 PM 24926684 ER PT J AU Menafra, R Brinkman, AB Matarese, F Franci, G Bartels, SJJ Nguyen, L Shimbo, T Wade, PA Hubner, NC Stunnenberg, HG AF Menafra, Roberta Brinkman, Arie B. Matarese, Filomena Franci, Gianluigi Bartels, Stefanie J. J. Luan Nguyen Shimbo, Takashi Wade, Paul A. Hubner, Nina C. Stunnenberg, Hendrik G. TI Genome-Wide Binding of MBD2 Reveals Strong Preference for Highly Methylated Loci SO PLOS ONE LA English DT Article ID TUMOR-SUPPRESSOR GENE; HUMAN X-CHROMOSOME; DNA METHYLATION; BREAST-CANCER; CPG ISLANDS; XIST GENE; CHROMATIN; TRANSCRIPTION; CELLS; IDENTIFICATION AB MBD2 is a subunit of the NuRD complex that is postulated to mediate gene repression via recruitment of the complex to methylated DNA. In this study we adopted an MBD2 tagging-approach to study its genome wide binding characteristics. We show that in vivo MBD2 is mainly recruited to CpG island promoters that are highly methylated. Interestingly, MBD2 binds around 1 kb downstream of the transcription start site of a subset of similar to 400 CpG island promoters that are characterized by the presence of active histone marks, RNA polymerase II (Pol2) and low to medium gene expression levels and H3K36me3 deposition. These tagged-MBD2 binding sites in MCF-7 show increased methylation in a cohort of primary breast cancers but not in normal breast samples, suggesting a putative role for MBD2 in breast cancer. C1 [Menafra, Roberta; Brinkman, Arie B.; Matarese, Filomena; Franci, Gianluigi; Bartels, Stefanie J. J.; Luan Nguyen; Hubner, Nina C.; Stunnenberg, Hendrik G.] Radboud Univ Nijmegen, Dept Mol Biol, Nijmegen Ctr Mol Life Sci, NL-6525 ED Nijmegen, Netherlands. [Shimbo, Takashi; Wade, Paul A.] NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Stunnenberg, HG (reprint author), Radboud Univ Nijmegen, Dept Mol Biol, Nijmegen Ctr Mol Life Sci, NL-6525 ED Nijmegen, Netherlands. EM H.Stunnenberg@ncmls.ru.nl RI Stunnenberg, Hendrik/D-6875-2012; Hubner, Nina/C-4298-2008; OI Hubner, Nina/0000-0002-7864-2877; Franci, Gianluigi/0000-0003-3321-4331 FU Dutch Cancer Foundation (KWF) grant KUN [20135833]; ATLAS; EC-FP7 project BLUEPRINT [282510]; SYSCOL (EU FP7); Intramural Research Program of the National Institute of Environmental Health Sciences, NIH [ZO1ES101965] FX This work was supported by the Dutch Cancer Foundation (KWF) grant KUN 20135833, by ATLAS, by the EC-FP7 project BLUEPRINT (n degrees 282510) and by SYSCOL (EU FP7). This work was also supported, in part, by the Intramural Research Program of the National Institute of Environmental Health Sciences, NIH (Project number ZO1ES101965 to PAW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 12 Z9 12 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 13 PY 2014 VL 9 IS 6 AR e99603 DI 10.1371/journal.pone.0099603 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK2VQ UT WOS:000338278100055 PM 24927503 ER PT J AU Ekwueme, DU Yabroff, KR Guy, GP Banegas, MP de Moor, JS Li, CY Han, XS Zheng, ZY Soni, A Davidoff, A Rechis, R Virgo, KS AF Ekwueme, Donatus U. Yabroff, K. Robin Guy, Gery P., Jr. Banegas, Matthew P. de Moor, Janet S. Li, Chunyu Han, Xuesong Zheng, Zhiyuan Soni, Anita Davidoff, Amy Rechis, Ruth Virgo, Katherine S. TI Medical Costs and Productivity Losses of Cancer Survivors - United States, 2008-2011 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article ID CARE C1 [Ekwueme, Donatus U.; Guy, Gery P., Jr.; Li, Chunyu] CDC, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. [Yabroff, K. Robin; Banegas, Matthew P.; de Moor, Janet S.] NCI, Bethesda, MD 20892 USA. [Han, Xuesong; Zheng, Zhiyuan] Amer Canc Soc, Atlanta, GA 30329 USA. [Soni, Anita; Davidoff, Amy] Agcy Healthcare Res & Qual, Rockville, MD USA. [Rechis, Ruth] Livestrong Fdn, Austin, TX USA. [Virgo, Katherine S.] Emory Univ, Atlanta, GA 30322 USA. RP Ekwueme, DU (reprint author), CDC, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. EM dce3@cdc.gov NR 10 TC 20 Z9 20 U1 0 U2 9 PU CENTER DISEASE CONTROL & PREVENTION PI ATLANTA PA MAILSTOP E-90, ATLANTA, GA 30333 USA SN 0149-2195 EI 1545-861X J9 MMWR-MORBID MORTAL W JI MMWR-Morb. Mortal. Wkly. Rep. PD JUN 13 PY 2014 VL 63 IS 23 BP 505 EP 510 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AJ4KN UT WOS:000337645300001 PM 24918485 ER PT J AU Moreno-Estrada, A Gignoux, CR Fernandez-Lopez, JC Zakharia, F Sikora, M Contreras, AV Acuna-Alonzo, V Sandoval, K Eng, C Romero-Hidalgo, S Ortiz-Tello, P Robles, V Kenny, EE Nuno-Arana, I Barquera-Lozano, R Macin-Perez, G Granados-Arriola, J Huntsman, S Galanter, JM Via, M Ford, JG Chapela, R Rodriguez-Cintron, W Rodriguez-Santana, JR Romieu, I Sienra-Monge, JJ Navarro, BD London, SJ Ruiz-Linares, A Garcia-Herrera, R Estrada, K Hidalgo-Miranda, A Jimenez-Sanchez, G Carnevale, A Soberon, X Canizales-Quinteros, S Rangel-Villalobos, H Silva-Zolezzi, I Burchard, EG Bustamante, CD AF Moreno-Estrada, Andres Gignoux, Christopher R. Carlos Fernandez-Lopez, Juan Zakharia, Fouad Sikora, Martin Contreras, Alejandra V. Acuna-Alonzo, Victor Sandoval, Karla Eng, Celeste Romero-Hidalgo, Sandra Ortiz-Tello, Patricia Robles, Victoria Kenny, Eimear E. Nuno-Arana, Ismael Barquera-Lozano, Rodrigo Macin-Perez, Gaston Granados-Arriola, Julio Huntsman, Scott Galanter, Joshua M. Via, Marc Ford, Jean G. Chapela, Rocio Rodriguez-Cintron, William Rodriguez-Santana, Jose R. Romieu, Isabelle Jose Sienra-Monge, Juan del Rio Navarro, Blanca London, Stephanie J. Ruiz-Linares, Andres Garcia-Herrera, Rodrigo Estrada, Karol Hidalgo-Miranda, Alfredo Jimenez-Sanchez, Gerardo Carnevale, Alessandra Soberon, Xavier Canizales-Quinteros, Samuel Rangel-Villalobos, Hector Silva-Zolezzi, Irma Burchard, Esteban Gonzalez Bustamante, Carlos D. TI HUMAN GENETICS The genetics of Mexico recapitulates Native American substructure and affects biomedical traits SO SCIENCE LA English DT Article ID HUMAN-POPULATIONS; ANCESTRY; ADMIXTURE; INDIVIDUALS; CHROMOSOME; DIVERSITY; HISTORY; EUROPE; SAMPLE; GENES AB Mexico harbors great cultural and ethnic diversity, yet fine-scale patterns of human genome-wide variation from this region remain largely uncharacterized. We studied genomic variation within Mexico from over 1000 individuals representing 20 indigenous and 11 mestizo populations. We found striking genetic stratification among indigenous populations within Mexico at varying degrees of geographic isolation. Some groups were as differentiated as Europeans are from East Asians. Pre-Columbian genetic substructure is recapitulated in the indigenous ancestry of admixed mestizo individuals across the country. Furthermore, two independently phenotyped cohorts of Mexicans and Mexican Americans showed a significant association between subcontinental ancestry and lung function. Thus, accounting for fine-scale ancestry patterns is critical for medical and population genetic studies within Mexico, in Mexican-descent populations, and likely in many other populations worldwide. C1 [Moreno-Estrada, Andres; Zakharia, Fouad; Sikora, Martin; Sandoval, Karla; Ortiz-Tello, Patricia; Robles, Victoria; Kenny, Eimear E.; Rodriguez-Santana, Jose R.; Bustamante, Carlos D.] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA. [Gignoux, Christopher R.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. [Carlos Fernandez-Lopez, Juan; Contreras, Alejandra V.; Romero-Hidalgo, Sandra; Rodriguez-Santana, Jose R.; Garcia-Herrera, Rodrigo; Estrada, Karol; Hidalgo-Miranda, Alfredo; Jimenez-Sanchez, Gerardo; Carnevale, Alessandra; Soberon, Xavier; Canizales-Quinteros, Samuel; Silva-Zolezzi, Irma] Inst Nacl Med Genom INMEGEN, Mexico City, DF, Mexico. [Acuna-Alonzo, Victor; Barquera-Lozano, Rodrigo; Macin-Perez, Gaston] ENAH, Mexico City, DF, Mexico. [Acuna-Alonzo, Victor; Ruiz-Linares, Andres] UCL, Dept Genet Evolut & Environm, London, England. [Eng, Celeste; Huntsman, Scott; Galanter, Joshua M.; Via, Marc; Burchard, Esteban Gonzalez] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Nuno-Arana, Ismael; Rangel-Villalobos, Hector] Univ Guadalajara, Inst Invest Genet Mol, Ocotlan, Mexico. [Granados-Arriola, Julio] Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Mexico City, DF, Mexico. [Galanter, Joshua M.; Burchard, Esteban Gonzalez] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. [Ford, Jean G.] Brooklyn Hosp Ctr, Brooklyn, NY USA. [Chapela, Rocio; Romieu, Isabelle] INER, Mexico City, DF, Mexico. [Rodriguez-Cintron, William] Vet Caribbean Hlth Care Syst, San Juan, PR USA. Ctr Neumol Pediat, San Juan, PR USA. Int Agcy Res Canc, F-69372 Lyon, France. [Jose Sienra-Monge, Juan; del Rio Navarro, Blanca] Hosp Infantil Mexico Dr Federico Gomez, Mexico City, DF, Mexico. [London, Stephanie J.] NIEHS, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Canizales-Quinteros, Samuel] Univ Nacl Autonoma Mexico, Fac Quim, Mexico City 04510, DF, Mexico. RP Moreno-Estrada, A (reprint author), Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA. EM morenoe@stanford.edu; esteban.burchard@ucsf.edu; cdbustam@stanford.edu RI Hidalgo-Miranda, Alfredo/B-2123-2010; Via, Marc/L-6511-2014; Contreras, Alejandra/E-7815-2013; Fernandez, Juan Carlos/C-4976-2013; Sikora, Martin/C-8609-2015; OI Hidalgo-Miranda, Alfredo/0000-0003-2315-3977; Via, Marc/0000-0002-9966-9921; Contreras, Alejandra/0000-0003-3653-5958; Fernandez, Juan Carlos/0000-0003-3680-4193; Sikora, Martin/0000-0003-2818-8319; Garcia-Herrera, Rodrigo/0000-0002-7972-5746; London, Stephanie/0000-0003-4911-5290 FU Stanford University; Department of Genetics; Federal Government of Mexico; Ministry of Health; Mexican Health Foundation (FUNSALUD); Gonzalo Rio Arronte Foundation; George Rosenkranz Prize for Health Care Research in Developing Countries; University of California San Francisco (UCSF) Chancellor's Research Fellowship; Dissertation Year Fellowship; NIH Training Grants [T32GM007175, T32HG000044]; Robert Wood Johnson Foundation Amos Medical Faculty Development Award; Sandler Foundation; American Asthma Foundation; CONACYT [129693]; BBSRC grant [BB/I021213/1]; National Institutes of Health (NIH) [R01GM090087, R01HG003229, ES015794, GM007546, GM061390, HL004464, HL078885, HL088133, HL111636, RR000083, P60MD006902, ZIA ES49019]; National Science Foundation [DMS-1201234]; Intramural Research Program of NIH, National Institute of Environmental Health Sciences FX We thank all volunteers for generously donating DNA samples and participating in the study. This project was possible with the joint support from multiple Institutions in Mexico and the United States. Stanford University supported C.D.B. with funding from the Department of Genetics. INMEGEN received support from the Federal Government of Mexico, particularly the Ministry of Health, the Mexican Health Foundation (FUNSALUD), and the Gonzalo Rio Arronte Foundation. State governments and universities of Durango, Campeche, Guanajuato, Guerrero, Oaxaca, Sonora, Tamaulipas, Veracruz, Yucatan, and Zacatecas contributed significantly to this work. This research was also supported by the George Rosenkranz Prize for Health Care Research in Developing Countries awarded to A.M.-E.; University of California San Francisco (UCSF) Chancellor's Research Fellowship, Dissertation Year Fellowship, and NIH Training Grants T32GM007175 and T32HG000044 (to C. R. G.); the Robert Wood Johnson Foundation Amos Medical Faculty Development Award; the Sandler Foundation; the American Asthma Foundation (to E. G. B.); CONACYT grant 129693 (to H. R.-V.); BBSRC grant BB/I021213/1 (to A. R.-L.); the National Institutes of Health (NIH) (grants R01GM090087, R01HG003229, ES015794, GM007546, GM061390, HL004464, HL078885, HL088133, HL111636, RR000083, P60MD006902, and ZIA ES49019); and National Science Foundation award DMS-1201234. This work was supported in part by the Intramural Research Program of NIH, National Institute of Environmental Health Sciences (to S.J.L.). Some computations were performed using the UCSF Biostatistics High Performance Computing System. We also thank B. Henn, S. Gravel, and J. Byrnes for helpful discussions; C. Gunter and M. Carpenter for editing the manuscript; and M. Morales for informatics and programming support. C. D. B. is on the advisory board of a project at 23andMe; and on the scientific advisory boards of Personalis, Inc.; InVitae; Etalon, Inc.; and Ancestry.com. The collections and methods for the Population Reference Sample (POPRES) are described by Nelson et al. (2008). The POPRES data sets used for the analyses described here were obtained from dbGaP through accession number phs000145.v1.p1. Access to the MCCAS data set may be obtained under the terms of a data transfer agreement with the National Institute of Environmental Health Sciences; the contact is S.J.L.. Individual-level genotypes for new data presented in this study are available, through a data access agreement to respect the privacy of the participants for the transfer of genetic data, by contacting C.D.B., A.M.-E., and INMEGEN (http://www.inmegen.gob.mx/). NR 31 TC 70 Z9 72 U1 3 U2 33 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 JUN 13 PY 2014 VL 344 IS 6189 BP 1280 EP 1285 DI 10.1126/science.1251688 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AI7ND UT WOS:000337077500040 PM 24926019 ER PT J AU Hundal, S Levin, DM Keselman, A AF Hundal, Savreen Levin, Daniel M. Keselman, Alla TI Lessons of Researcher-Teacher Co-design of an Environmental Health Afterschool Club Curriculum SO INTERNATIONAL JOURNAL OF SCIENCE EDUCATION LA English DT Article DE Informal education; Co-design; Argumentation; Environmental health education; Teacher beliefs ID SCIENTIFIC ARGUMENTATION; SCIENCE; STUDENTS; CLASSROOM; SCHOOL; ATTITUDES; CURIOSITY; THINKING; SKILLS; IMPACT AB This paper addresses the impact of teachers' beliefs about argumentation and their community of practice framed views of teaching on co-designing an environmental health afterschool club curriculum with researchers. Our team collaborated with a group of four middle school teachers, asking them to co-design a club that would facilitate (1) students' understanding of environmental health, (2) use of electronic resources, and (3) argumentation skills. The process included researcher-led sessions emphasizing the importance of argumentation to science and teacher-led curriculum design sessions. The qualitative analysis of the meetings and teacher interview transcripts suggests that while teachers viewed argumentation as important, its practice was relegated to the background by the focus on student engagement and perceived logistical and systemic constraints. The paper concludes that in addition to stressing relevance of argumentation to science learning, researchers involved in co-design need to emphasize the potential of argumentation to engage students and to fit into science curriculum. The analysis also reveals teacher-participants' views of environmental health as an important area of middle school education, relevant to students' lives, linkable to the existing curriculum, essential for informed citizenship, and capable of inspiring interest in science. These findings underscore the importance of integrating environmental health into science education and advocating for its inclusion in informal and formal educational settings. C1 [Hundal, Savreen] Univ Maryland, Dept Commun, College Pk, MD 20742 USA. [Levin, Daniel M.] Univ Maryland, Coll Educ, Dept Teaching & Learning Policy & Leadership, College Pk, MD 20742 USA. [Keselman, Alla] Natl Lib Med, Div Specialized Informat Serv, Bethesda, MD 20892 USA. RP Keselman, A (reprint author), Natl Lib Med, Specialized Informat Serv, Two Democracy Plaza,Suite 510, Bethesda, MD 20892 USA. EM keselmana@mail.nih.gov NR 51 TC 2 Z9 2 U1 5 U2 30 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0950-0693 EI 1464-5289 J9 INT J SCI EDUC JI Int. J. Sci. Educ. PD JUN 13 PY 2014 VL 36 IS 9 SI SI BP 1510 EP 1530 DI 10.1080/09500693.2013.844377 PG 21 WC Education & Educational Research SC Education & Educational Research GA AH1EI UT WOS:000335862200007 ER PT J AU Zhao, XR Maric, I AF Zhao, Xiangrong Maric, Irina TI Chance identification of synchronous hairy cell leukemia and plasma cell myeloma in a potential HSC donor SO BLOOD LA English DT Editorial Material C1 [Zhao, Xiangrong; Maric, Irina] NIH, Bethesda, MD 20892 USA. RP Zhao, XR (reprint author), NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 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 JUN 12 PY 2014 VL 123 IS 24 BP 3694 EP 3694 DI 10.1182/blood-2014-02-558189 PG 1 WC Hematology SC Hematology GA AQ2LI UT WOS:000342617200009 PM 25054196 ER PT J AU Triot, A Jarvinen, PM Arostegui, JI Murugan, D Kohistani, N Diaz, JLD Racek, T Puchalka, J Gertz, EM Schaffer, AA Kotlarz, D Pfeifer, D Rubio, CDD Ozdemir, MA Patiroglu, T Karakukcu, M Codina, JSD Yague, J Touw, IP Unal, E Klein, C AF Triot, Alexa Jaervinen, Paeivi M. Arostegui, Juan I. Murugan, Dhaarini Kohistani, Naschla Dapena Diaz, Jose Luis Racek, Tomas Puchalka, Jacek Gertz, E. Michael Schaeffer, Alejandro A. Kotlarz, Daniel Pfeifer, Dietmar de Heredia Rubio, Cristina Diaz Ozdemir, Mehmet Akif Patiroglu, Turkan Karakukcu, Musa de Toledo Codina, Jose Sanchez Yaguee, Jordi Touw, Ivo P. Unal, Ekrem Klein, Christoph TI Inherited biallelic CSF3R mutations in severe congenital neutropenia SO BLOOD LA English DT Article ID COLONY-STIMULATING-FACTOR; ACUTE MYELOID-LEUKEMIA; FACTOR-RECEPTOR; PROLACTIN RECEPTOR; ERYTHROPOIETIN RECEPTOR; EXTRACELLULAR DOMAIN; ACTIVATING MUTATION; WSXWS MOTIF; IN-VIVO; GRANULOCYTE AB Severe congenital neutropenia (SCN) is characterized by low numbers of peripheral neutrophil granulocytes and a predisposition to life-threatening bacterial infections. We describe a novel genetic SCN type in 2 unrelated families associated with recessively inherited loss-of-function mutations in CSF3R, encoding the granulocyte colony-stimulating factor (G-CSF) receptor. Family A, with 3 affected children, carried a homozygous missense mutation (NM_000760.3:c.922C>T, NP_000751.1:p.Arg308Cys), which resulted in perturbed N-glycosylation and aberrant localization to the cell surface. Family B, with 1 affected infant, carried compound heterozygous deletions provoking frame shifts and premature stop codons(NM_000760.3:c.948_963del, NP_000751.1: p. Gly316fsTer322 and NM_000760.3:c.1245del, NP_000751.1:p.Gly415fsTer432). Despite peripheral SCN, all patients had morphologic evidence of full myeloid cell maturation in bone marrow. None of the patients responded to treatment with recombinant human G-CSF. Our study highlights the genetic and morphologic SCN variability and provides evidence both for functional importance and redundancy of G-CSF receptor-mediated signaling in human granulopoiesis. C1 [Triot, Alexa; Jaervinen, Paeivi M.; Murugan, Dhaarini; Kohistani, Naschla; Racek, Tomas; Puchalka, Jacek; Kotlarz, Daniel; Klein, Christoph] Univ Munich, Dr von Hauner Childrens Hosp, Div Pediat Hematol & Oncol, Dept Pediat, Munich, Germany. [Arostegui, Juan I.; Yaguee, Jordi] Hosp Clin Barcelona, Dept Immunol, Barcelona, Spain. [Dapena Diaz, Jose Luis; de Heredia Rubio, Cristina Diaz; de Toledo Codina, Jose Sanchez] Maternal Infant Hosp Vall dHebron, Dept Pediat Oncol Hematol, Barcelona, Spain. [Gertz, E. Michael; Schaeffer, Alejandro A.] NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. [Pfeifer, Dietmar] Univ Med Ctr, Dept Hematol Oncol & Stem Cell Transplantat, Freiburg, Germany. [Ozdemir, Mehmet Akif; Patiroglu, Turkan; Karakukcu, Musa; Unal, Ekrem] Erciyes Univ, Fac Med, Div Pediat Hematol & Oncol, Kayseri, Turkey. [Touw, Ivo P.] Erasmus MC, Dept Hematol, Rotterdam, Netherlands. RP Klein, C (reprint author), Dr von Hauner Childrens Hosp, Dept Pediat, Lindwurmstr 4, D-80337 Munich, Germany. EM christoph.klein@med.uni-muenchen.de RI Dapena Diaz, Jose Luis/E-6159-2016; OI Dapena Diaz, Jose Luis/0000-0002-6711-7479; Arostegui, Juan Ignacio/0000-0003-4757-504X; Yague Ribes, Jordi/0000-0002-1935-4488 FU European Research Council (ERC) [268608 Explore]; Bundministerium fur Bildung und Forschung (E-RARE); Care-for-Rare Foundation; German Center for Infection Research (DZIF); Spanish Ministry of Health [FIS PS09/01182]; Intramural Research Program of the National Institutes of Health (NIH), National Library of Medicine (NLM) [ZIA LM000097-13] FX This work was supported by the European Research Council (ERC Advanced Grant-268608 Explore), the Bundministerium fur Bildung und Forschung (E-RARE), the Care-for-Rare Foundation, the German Center for Infection Research (DZIF), and the Spanish Ministry of Health (FIS PS09/01182). This work was also supported by the Intramural Research Program of the National Institutes of Health (NIH), National Library of Medicine (NLM; ZIA LM000097-13). NR 38 TC 9 Z9 9 U1 0 U2 7 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 JUN 12 PY 2014 VL 123 IS 24 BP 3811 EP 3817 DI 10.1182/blood-2013-11-535419 PG 7 WC Hematology SC Hematology GA AQ2LI UT WOS:000342617200025 PM 24753537 ER PT J AU Yue, S Tang, LY Tang, Y Tang, Y Shen, QH Ding, J Chen, Y Zhang, ZD Yu, TT Zhang, YE Cheng, SY AF Yue, Shen Tang, Liu-Ya Tang, Ying Tang, Yi Shen, Qiu-Hong Ding, Jie Chen, Yan Zhang, Zengdi Yu, Ting-Ting Zhang, Ying E. Cheng, Steven Y. TI Requirement of Smurf-mediated endocytosis of Patched1 in sonic hedgehog signal reception SO ELIFE LA English DT Article ID STEROL-SENSING DOMAIN; EPITHELIAL STEM-CELLS; E3 UBIQUITIN LIGASE; TGF-BETA RECEPTOR; PRIMARY CILIUM; SUBCELLULAR-LOCALIZATION; VESICULAR TRAFFICKING; PATHWAY ACTIVATION; NEURAL-TUBE; PROTEIN AB Cell surface reception of Sonic hedgehog (Shh) must ensure that the graded morphogenic signal is interpreted accordingly in neighboring cells to specify tissue patterns during development. Here, we report endocytic sorting signals for the receptor Patched1 (Ptch1), comprising two 'PPXY' motifs, that direct it to degradation in lysosomes. These signals are recognized by two HECT-domain ubiquitin E3 ligases, Smurf1 and Smurf2, which are induced by Shh and become enriched in Caveolin-1 lipid rafts in association with Ptch1. Smurf-mediated endocytic turnover of Ptch1 is essential for its clearance from the primary cilium and pathway activation. Removal of both Smurfs completely abolishes the ability of Shh to sustain the proliferation of postnatal granule cell precursors in the cerebellum. These findings reveal a novel step in the Shh pathway activation as part of the Ptch1 negative feedback loop that precisely controls the signaling output in response to Shh gradient signal. C1 [Yue, Shen; Tang, Ying; Shen, Qiu-Hong; Ding, Jie; Chen, Yan; Zhang, Zengdi; Yu, Ting-Ting; Cheng, Steven Y.] Nanjing Med Univ, Sch Basic Med Sci, Dept Dev Genet, Nanjing, Jiangsu, Peoples R China. [Tang, Liu-Ya; Tang, Yi; Zhang, Ying E.] NCI, Cellular & Mol Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Cheng, SY (reprint author), Nanjing Med Univ, Sch Basic Med Sci, Dept Dev Genet, Nanjing, Jiangsu, Peoples R China. EM zhangyin@mail.nih.gov; sycheng@njmu.edu.cn RI Zhang, Ying/G-3657-2015 OI Zhang, Ying/0000-0003-2753-7601 FU US-China Biomedical Collaborative Research program; Chinese National Science foundation [81272238, 81261120386]; National Basic Research Program of China (973 Program) [2012CB945003, 2009CB918403]; National Institutes of Health, National Cancer Institute, Center for Cancer Research FX We wish to thank Rajat Rohatgi for the generous gift of the Smoothened antibody, and Tian Jin, Joseph Brzostowski and Valarie Barr for their assistance with confocal imaging. This work was supported by funding from the US-China Biomedical Collaborative Research program to SYC and YEZ; grants from the Chinese National Science foundation (81272238 and 81261120386) and the National Basic Research Program of China (973 Program) to SYC (2012CB945003 and 2009CB918403); and by funding from the intramural research program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research to YEZ. SY is supported by a young investigator grant from the Chinese National Science Foundation (81101497). NR 80 TC 16 Z9 17 U1 2 U2 10 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD JUN 12 PY 2014 VL 3 AR e02555 DI 10.7554/eLife.02555 PG 24 WC Biology SC Life Sciences & Biomedicine - Other Topics GA AK8ZP UT WOS:000338717600001 ER PT J AU Carson, JM Okamura, K Wakashin, H McFann, K Dobrinskikh, E Kopp, JB Blaine, J AF Carson, John M. Okamura, Kayo Wakashin, Hidefumi McFann, Kim Dobrinskikh, Evgenia Kopp, Jeffrey B. Blaine, Judith TI Podocytes Degrade Endocytosed Albumin Primarily in Lysosomes SO PLOS ONE LA English DT Article ID PROTEIN ACCUMULATION; OVERLOAD PROTEINURIA; GLOMERULAR PROTEIN; NEPHROTIC SYNDROME; FABRY-DISEASE; CELLS; AUTOPHAGY; KIDNEY; INJURY; GLOMERULOSCLEROSIS AB Albuminuria is a strong, independent predictor of chronic kidney disease progression. We hypothesize that podocyte processing of albumin via the lysosome may be an important determinant of podocyte injury and loss. A human urine derived podocyte-like epithelial cell (HUPEC) line was used for in vitro experiments. Albumin uptake was quantified by Western blot after loading HUPECs with fluorescein-labeled (FITC) albumin. Co-localization of albumin with lysosomes was determined by confocal microscopy. Albumin degradation was measured by quantifying FITC-albumin abundance in HUPEC lysates by Western blot. Degradation experiments were repeated using HUPECs treated with chloroquine, a lysosome inhibitor, or MG-132, a proteasome inhibitor. Lysosome activity was measured by fluorescence recovery after photo bleaching (FRAP). Cytokine production was measured by ELISA. Cell death was determined by trypan blue staining. In vivo, staining with lysosome-associated membrane protein-1 (LAMP-1) was performed on tissue from a Denys-Drash trangenic mouse model of nephrotic syndrome. HUPECs endocytosed albumin, which co-localized with lysosomes. Choloroquine, but not MG-132, inhibited albumin degradation, indicating that degradation occurs in lysosomes. Cathepsin B activity, measured by FRAP, significantly decreased in HUPECs exposed to albumin (12.5% of activity in controls) and chloroquine (12.8%), and declined further with exposure to albumin plus chloroquine (8.2%, p < 0.05). Cytokine production and cell death were significantly increased in HUPECs exposed to albumin and chloroquine alone, and these effects were potentiated by exposure to albumin plus chloroquine. Compared to wild-type mice, glomerular staining of LAMP-1 was significantly increased in Denys-Drash mice and appeared to be most prominent in podocytes. These data suggest lysosomes are involved in the processing of endocytosed albumin in podocytes, and lysosomal dysfunction may contribute to podocyte injury and glomerulosclerosis in albuminuric diseases. Modifiers of lysosomal activity may have therapeutic potential in slowing the progression of glomerulosclerosis by enhancing the ability of podocytes to process and degrade albumin. C1 [Carson, John M.; Okamura, Kayo; McFann, Kim; Dobrinskikh, Evgenia; Blaine, Judith] Univ Colorado, Hlth Sci Ctr, Aurora, CO 80045 USA. [Wakashin, Hidefumi; Kopp, Jeffrey B.] NIDDK, Kidney Dis Sect, NIH, Bethesda, MD USA. RP Carson, JM (reprint author), Univ Colorado, Hlth Sci Ctr, Aurora, CO 80045 USA. EM john.m.carson@ucdenver.edu OI Kopp, Jeffrey/0000-0001-9052-186X FU NIH [K08DK080989]; Intramural Research program, NIDDK, NIH FX This research was supported by NIH grant K08DK080989 to Judith Blaine and the Intramural Research program, NIDDK, NIH to Jeffrey B. Kopp. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 10 Z9 10 U1 2 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 12 PY 2014 VL 9 IS 6 AR e99771 DI 10.1371/journal.pone.0099771 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK8TP UT WOS:000338701300092 PM 24924335 ER PT J AU Escott-Price, V Bellenguez, C Wang, LS Choi, SH Harold, D Jones, L Holmans, P Gerrish, A Vedernikov, A Richards, A DeStefano, AL Lambert, JC Ibrahim-Verbaas, CA Naj, AC Sims, R Jun, G Bis, JC Beecham, GW Grenier-Boley, B Russo, G Thornton-Wells, TA Denning, N Smith, AV Chouraki, V Thomas, C Ikram, MA Zelenika, D Vardarajan, BN Kamatani, Y Lin, CF Schmidt, H Kunkle, B Dunstan, ML Vronskaya, M Johnson, AD Ruiz, A Bihoreau, MT Reitz, C Pasquier, F Hollingworth, P Hanon, O Fitzpatrick, AL Buxbaum, JD Campion, D Crane, PK Baldwin, C Becker, T Gudnason, V Cruchaga, C Craig, D Amin, N Berr, C Lopez, OL De Jager, PL Deramecourt, V Johnston, JA Evans, D Lovestone, S Letenneur, L Hernandez, I Rubinsztein, DC Eiriksdottir, G Sleegers, K Goate, AM Fievet, N Huentelman, MJ Gill, M Brown, K Kamboh, MI Keller, L Barberger-Gateau, P McGuinness, B Larson, EB Myers, AJ Dufouil, C Todd, S Wallon, D Love, S Rogaeva, E Gallacher, J St George-Hyslop, P Clarimon, J Lleo, A Bayer, A Tsuang, DW Yu, L Tsolaki, M Bossu, P Spalletta, G Proitsi, P Collinge, J Sorbi, S Garcia, FS Fox, NC Hardy, J Naranjo, MCD Bosco, P Clarke, R Brayne, C Galimberti, D Scarpini, E Bonuccelli, U Mancuso, M Siciliano, G Moebus, S Mecocci, P Del Zompo, M Maier, W Hampel, H Pilotto, A Frank-Garcia, A Panza, F Solfrizzi, V Caffarra, P Nacmias, B Perry, W Mayhaus, M Lannfelt, L Hakonarson, H Pichler, S Carrasquillo, MM Ingelsson, M Beekly, D Alvarez, V Zou, FG Valladares, O Younkin, SG Coto, E Hamilton-Nelson, KL Gu, W Razquin, C Pastor, P Mateo, I Owen, MJ Faber, KM Jonsson, PV Combarros, O O'Donovan, MC Cantwell, LB Soininen, H Blacker, D Mead, S Mosley, TH Bennett, DA Harris, TB Fratiglioni, L Holmes, C de Bruijn, RFAG Passmore, P Montine, TJ Bettens, K Rotter, JI Brice, A Morgan, K Foroud, TM Kukull, WA Hannequin, D Powell, JF Nalls, MA Ritchie, K Lunetta, KL Kauwe, JSK Boerwinkle, E Riemenschneider, M Boada, M Hiltunen, M Martin, ER Schmidt, R Rujescu, D Dartigues, JF Mayeux, R Tzourio, C Hofman, A Nothen, MM Graff, C Psaty, BM Haines, JL Lathrop, M Pericak-Vance, MA Launer, LJ Van Broeckhoven, C Farrer, LA van Duijn, CM Ramirez, A Seshadri, S Schellenberg, GD Amouyel, P Williams, J AF Escott-Price, Valentina Bellenguez, Celine Wang, Li-San Choi, Seung-Hoan Harold, Denise Jones, Lesley Holmans, Peter Gerrish, Amy Vedernikov, Alexey Richards, Alexander DeStefano, Anita L. Lambert, Jean-Charles Ibrahim-Verbaas, Carla A. Naj, Adam C. Sims, Rebecca Jun, Gyungah Bis, Joshua C. Beecham, Gary W. Grenier-Boley, Benjamin Russo, Giancarlo Thornton-Wells, Tricia A. Denning, Nicola Smith, Albert V. Chouraki, Vincent Thomas, Charlene Ikram, M. Arfan Zelenika, Diana Vardarajan, Badri N. Kamatani, Yoichiro Lin, Chiao-Feng Schmidt, Helena Kunkle, Brian Dunstan, Melanie L. Vronskaya, Maria Johnson, Andrew D. Ruiz, Agustin Bihoreau, Marie-Therese Reitz, Christiane Pasquier, Florence Hollingworth, Paul Hanon, Olivier Fitzpatrick, Annette L. Buxbaum, Joseph D. Campion, Dominique Crane, Paul K. Baldwin, Clinton Becker, Tim Gudnason, Vilmundur Cruchaga, Carlos Craig, David Amin, Najaf Berr, Claudine Lopez, Oscar L. De Jager, Philip L. Deramecourt, Vincent Johnston, Janet A. Evans, Denis Lovestone, Simon Letenneur, Luc Hernandez, Isabel Rubinsztein, David C. Eiriksdottir, Gudny Sleegers, Kristel Goate, Alison M. Fievet, Nathalie Huentelman, Matthew J. Gill, Michael Brown, Kristelle Kamboh, M. Ilyas Keller, Lina Barberger-Gateau, Pascale McGuinness, Bernadette Larson, Eric B. Myers, Amanda J. Dufouil, Carole Todd, Stephen Wallon, David Love, Seth Rogaeva, Ekaterina Gallacher, John St George-Hyslop, Peter Clarimon, Jordi Lleo, Alberto Bayer, Anthony Tsuang, Debby W. Yu, Lei Tsolaki, Magda Bossu, Paola Spalletta, Gianfranco Proitsi, Petra Collinge, John Sorbi, Sandro Garcia, Florentino Sanchez Fox, Nick C. Hardy, John Deniz Naranjo, Maria Candida Bosco, Paolo Clarke, Robert Brayne, Carol Galimberti, Daniela Scarpini, Elio Bonuccelli, Ubaldo Mancuso, Michelangelo Siciliano, Gabriele Moebus, Susanne Mecocci, Patrizia Del Zompo, Maria Maier, Wolfgang Hampel, Harald Pilotto, Alberto Frank-Garcia, Ana Panza, Francesco Solfrizzi, Vincenzo Caffarra, Paolo Nacmias, Benedetta Perry, William Mayhaus, Manuel Lannfelt, Lars Hakonarson, Hakon Pichler, Sabrina Carrasquillo, Minerva M. Ingelsson, Martin Beekly, Duane Alvarez, Victoria Zou, Fanggeng Valladares, Otto Younkin, Steven G. Coto, Eliecer Hamilton-Nelson, Kara L. Gu, Wei Razquin, Cristina Pastor, Pau Mateo, Ignacio Owen, Michael J. Faber, Kelley M. Jonsson, Palmi V. Combarros, Onofre O'Donovan, Michael C. Cantwell, Laura B. Soininen, Hilkka Blacker, Deborah Mead, Simon Mosley, Thomas H., Jr. Bennett, David A. Harris, Tamara B. Fratiglioni, Laura Holmes, Clive de Bruijn, Renee F. A. G. Passmore, Peter Montine, Thomas J. Bettens, Karolien Rotter, Jerome I. Brice, Alexis Morgan, Kevin Foroud, Tatiana M. Kukull, Walter A. Hannequin, Didier Powell, John F. Nalls, Michael A. Ritchie, Karen Lunetta, Kathryn L. Kauwe, John S. K. Boerwinkle, Eric Riemenschneider, Matthias Boada, Merce Hiltunen, Mikko Martin, Eden R. Schmidt, Reinhold Rujescu, Dan Dartigues, Jean-Francois Mayeux, Richard Tzourio, Christophe Hofman, Albert Noethen, Markus M. Graff, Caroline Psaty, Bruce M. Haines, Jonathan L. Lathrop, Mark Pericak-Vance, Margaret A. Launer, Lenore J. Van Broeckhoven, Christine Farrer, Lindsay A. van Duijn, Cornelia M. Ramirez, Alfredo Seshadri, Sudha Schellenberg, Gerard D. Amouyel, Philippe Williams, Julie CA United Kingdom Brain Expression TI Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease SO PLOS ONE LA English DT Article ID GENOME SCAN METAANALYSIS; IDENTIFIES VARIANTS; BIPOLAR DISORDER; COMMON VARIANTS; COMPLEX TRAITS; LEIGH-SYNDROME; ASSOCIATION; EXPRESSION; TP53INP1; CANCER AB Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4x10(-6)) and 14 (IGHV1-67 p = 7.9x10(-8)) which indexed novel susceptibility loci. Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease. 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[Wang, Li-San; Lin, Chiao-Feng; Valladares, Otto; Cantwell, Laura B.; Schellenberg, Gerard D.] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Choi, Seung-Hoan; DeStefano, Anita L.; Jun, Gyungah; Lunetta, Kathryn L.; Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Ibrahim-Verbaas, Carla A.] Erasmus MC Univ Med Ctr, Dept Epidemiol & Neurol, Rotterdam, Netherlands. [Naj, Adam C.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Naj, Adam C.] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Jun, Gyungah; Vardarajan, Badri N.; Baldwin, Clinton; Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Med Biomed Genet, Boston, MA 02118 USA. [Jun, Gyungah; Lathrop, Mark; Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Ophthalmol, Boston, MA 02118 USA. [Bis, Joshua C.; Fitzpatrick, Annette L.; Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Beecham, Gary W.; Kunkle, Brian; Perry, William; Hamilton-Nelson, Kara L.; Pericak-Vance, Margaret A.] Univ Miami, John P Hussman Inst Human Genom, Miami, FL USA. [Beecham, Gary W.; Perry, William; Pericak-Vance, Margaret A.] Univ Miami, Dr John T Macdonald Fdn, Dept Human Genet, Miami, FL USA. [Russo, Giancarlo] ETH Univ Zurich, Funct Genom Ctr Zurich, Zurich, Switzerland. [Thornton-Wells, Tricia A.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Smith, Albert V.; Gudnason, Vilmundur; Jonsson, Palmi V.] Univ Iceland, Fac Med, Reykjavik, Iceland. [Smith, Albert V.; Gudnason, Vilmundur; Eiriksdottir, Gudny] Iceland Heart Assoc, Kopavogur, Iceland. [Chouraki, Vincent; Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Ikram, M. 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[Carrasquillo, Minerva M.; Zou, Fanggeng; Younkin, Steven G.] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. [Beekly, Duane] Univ Washington, Natl Alzheimers Coordinating Ctr, Seattle, WA 98195 USA. [Alvarez, Victoria; Coto, Eliecer] Genet Mol Huca Oviedo, Oviedo, Spain. [Gu, Wei; Riemenschneider, Matthias] Univ Hosp, Dept Psychiat, Saarland, Germany. [Razquin, Cristina; Pastor, Pau] Univ Navarra, Sch Med, Ctr Appl Med Res, Neurogenet Lab,Div Neurosci, E-31080 Pamplona, Spain. [Pastor, Pau] Inst Salud Carlos III, Ctr Invest Biome Red Enfermedades Neurodegenerat, CIBERNED, Madrid, Spain. [Mateo, Ignacio; Combarros, Onofre] Univ Cantabria, Marques de Valdecilla Univ Hosp, Neurol Serv, E-39005 Santander, Spain. [Mateo, Ignacio; Combarros, Onofre] Univ Cantabria, Marques de Valdecilla Univ Hosp, CIBERNED, E-39005 Santander, Spain. [Mateo, Ignacio; Combarros, Onofre] IFIMAV, Santander, Spain. [Faber, Kelley M.; Foroud, Tatiana M.] Indiana Univ, Dept Med & Mol Genet, Indianapolis, IN 46204 USA. [Jonsson, Palmi V.] Landspitali Univ Hosp, Reykjavik, Iceland. [Soininen, Hilkka; Hiltunen, Mikko] Univ Eastern Finland, Inst Clin Med Neurol, Kuopio, Finland. [Soininen, Hilkka; Hiltunen, Mikko] Kuopio Univ Hosp, Dept Neurol, SF-70210 Kuopio, Finland. [Blacker, Deborah] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Blacker, Deborah] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Mosley, Thomas H., Jr.] Univ Mississippi, Med Ctr, Dept Geriatr Med, Jackson, MS 39216 USA. [Bennett, David A.] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA. [Harris, Tamara B.; Launer, Lenore J.] NIH, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Fratiglioni, Laura] Karolinska Inst, Care Sci & Soc, Dept Neurobiol, Aging Res Ctr, Stockholm, Sweden. [Fratiglioni, Laura; Graff, Caroline] Karolinska Univ Hosp Huddinge, Genet Unit, Dept Geriatr Med, Stockholm, Sweden. [Holmes, Clive] Univ Southampton, Sch Med, Div Clin Neurosci, Southampton, Hants, England. [de Bruijn, Renee F. A. G.] Erasmus MC Univ Med Ctr, Dept Neurol, Rotterdam, Netherlands. [de Bruijn, Renee F. A. G.] Erasmus MC Univ Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Montine, Thomas J.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA. [Brice, Alexis] Univ Paris 06, INSERM UMR S975 CNRS UMR 7225, Ctr Rech, Inst Cerveau & Moelle Epiniere CRICM,Hop Salpetri, Paris, France. [Brice, Alexis] Hop La Pitie Salpetriere, AP HP, Paris, France. [Kukull, Walter A.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Nalls, Michael A.] NIA, Neurogenet Lab, Intramural Res Program, Bethesda, MD 20892 USA. [Ritchie, Karen] Univ London Imperial Coll Sci Technol & Med, London, England. [Kauwe, John S. K.] Brigham Young Univ, Dept Biol, Provo, UT 84602 USA. [Boerwinkle, Eric] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Div Epidemiol, Houston, TX 77030 USA. [Boada, Merce] Univ Autonoma Barcelona VHIR UAB, Inst Recerca, Hosp Univ Vall d Hebron, Barcelona, Spain. [Schmidt, Reinhold] Med Univ Graz, Dept Neurol, Graz, Austria. [Dartigues, Jean-Francois] CHU Bordeaux, Ctr Memoire Ressources & Rech Bordeaux, Bordeaux, France. [Tzourio, Christophe] Victor Segalen Univ, INSERM, U708, Bordeaux, France. [Noethen, Markus M.] Univ Bonn, Life & Brain Ctr, Dept Genom, Inst Human Genet, Bonn, Germany. [Graff, Caroline] Karolinska Inst, Dept Neurobiol, Care Sci & Soc, KIADRC, Stockholm, Sweden. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Haines, Jonathan L.] Vanderbilt Univ, Vanderbilt Ctr Human Genet Res, Nashville, TN 37235 USA. [Haines, Jonathan L.] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Lathrop, Mark] McGill Univ, Montreal, PQ, Canada. [Lathrop, Mark] Genome Quebec Innovat Ctr, Montreal, PQ, Canada. [Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [van Duijn, Cornelia M.] Ctr Med Syst Biol, Leiden, Netherlands. [Ramirez, Alfredo] Univ Bonn, Dept Psychiat & Psychotherapy, Bonn, Germany. [Ramirez, Alfredo] Univ Bonn, Inst Human Genet, Bonn, Germany. [Seshadri, Sudha] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Amouyel, Philippe] CHRU Lille, F-59037 Lille, France. RP Schellenberg, GD (reprint author), Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. EM gerardsc@mail.med.upenn.edu; philippe.amouyel@pasteur-lille.fr; WilliamsJ@cf.ac.uk RI Lambert, jean-charles/A-9553-2014; Smith, Albert/K-5150-2015; Ritchie, Karen/G-3571-2013; Caffarra, Paolo/K-6567-2016; Bonuccelli, Ubaldo/K-8681-2016; berr, Claudine/D-5238-2014; Johnson, Andrew/G-6520-2013; Tsuang, Debby/L-7234-2016; graff, caroline/A-2545-2009; Hardy, John/C-2451-2009; Pastor, Pau/C-9834-2009; Tzourio, christophe/B-4015-2009; Fox, Nick/B-1319-2009; Powell, John/G-4412-2011; lambert, jean-charles/F-8787-2013; Holmans, Peter/F-4518-2015; Frank Garcia, Ana/I-5159-2015; Gudnason, Vilmundur/K-6885-2015; Bosso, Paola/E-4832-2014; Kamatani, Yoichiro/N-5513-2015 OI Harold, Denise/0000-0001-5195-0143; Buxbaum, Joseph/0000-0001-8898-8313; Panza, Francesco/0000-0002-7220-0656; Nothen, Markus/0000-0002-8770-2464; Todd, Stephen/0000-0002-2312-9195; Clarimon, Jordi/0000-0002-6824-6942; Bayer, Antony/0000-0002-7514-248X; Gill, Michael/0000-0003-0206-5337; Escott-Price, Valentina/0000-0003-1784-5483; mancuso, michelangelo/0000-0003-2738-8562; Seshadri, Sudha/0000-0001-6135-2622; galimberti, daniela/0000-0002-9284-5953; O'Donovan, Michael/0000-0001-7073-2379; Denning, Nicola/0000-0001-8467-7382; Kukull, Walter/0000-0001-8761-9014; Cruchaga, Carlos/0000-0002-0276-2899; sorbi, sandro/0000-0002-0380-6670; Kamboh, M. Ilyas/0000-0002-3453-1438; scarpini, elio/0000-0002-6395-2119; Lambert, jean-charles/0000-0003-0829-7817; Smith, Albert/0000-0003-1942-5845; Caffarra, Paolo/0000-0003-2246-5223; Bonuccelli, Ubaldo/0000-0001-6218-6312; berr, Claudine/0000-0001-5254-7655; Tsuang, Debby/0000-0002-4716-1894; Crane, Paul/0000-0003-4278-7465; NACMIAS, Benedetta/0000-0001-9338-9040; Chouraki, Vincent/0000-0002-4698-1794; Farrer, Lindsay/0000-0001-5533-4225; Pastor, Pau/0000-0002-7493-8777; Tzourio, christophe/0000-0002-6517-2984; Fox, Nick/0000-0002-6660-657X; Powell, John/0000-0001-6124-439X; Holmans, Peter/0000-0003-0870-9412; Frank Garcia, Ana/0000-0003-3858-9116; Gudnason, Vilmundur/0000-0001-5696-0084; Bosso, Paola/0000-0002-1432-0078; FU French National Foundation; Institut Pasteur de Lille, Inserm, FRC (fondation pour la recherche sur le cerveau) and Rotary; LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease); LABEX GENMED grant (Medical Genomics); IGAP; National Foundation for Alzheimer's disease and related disorders, the Institut Pasteur de Lille and the Centre National de Genotypage; The Fondation pour la Recherche Medicale; Caisse Nationale Maladie des Travailleurs Salaries, Direction Generale de la Sante, MGEN, Institut de la Longevite, Agence Francaise, de Securite Sanitaire des Produits de Sante; ANR; Eisai; Belgian Science Policy Office Interuniversity Attraction Poles program; Foundation Alzheimer Research (SAO-FRA); Flemish Government initiated Methusalem Excellence Program; Research Foundation Flanders (FWO); University of Antwerp Research Fund, Belgium; Health Research Council of the Academy of Finland; Kuopio University Hospital [5772708]; Nordic Centre of Excellence in Neurodegeneration; Cassa di Risparmio di Pistoia e Pescia [2012]; Cassa di Risparmio di Firenze [2012]; Stichting MS Research; Brain Net Europe; Hersenstichting Nederland Breinbrekend Werk; International Parkinson Fonds, Internationale Stiching Alzheimer Onderzoek; Institut de Neuropatologia, Servei Anatomia Patologica, Universitat de Barcelona; ADNI; Abbott; AstraZeneca AB; Bayer Schering Pharma AG; Bristol-Myers Squibb; Eisai Global Clinical Development; Elan Corporation; Genentech; GE Healthcare; Glaxo-SmithKline; Innogenetics; Johnson and Johnson; Eli Lilly and Co; Medpace, Inc; Merck and Co., Inc.; Novartis AG; Pfizer Inc; F. Hoffman-La Roche; Schering-Plough; Synarc, Inc.; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Dana Foundation; National Institute of Biomedical Imaging and Bioengineering; NIA [U01 AG024904, RC2 AG036535, K01 AG030514]; ADNI (National Institutes of Health) [U01 AG024904]; National Institute on Aging; The Canadian Institutes of Health Research; NIH [K01 AG030514, P30 AG010129]; Alzheimer Association (LAF) [IIRG-08-89720]; Alzheimer Association (MP-V) [IIRG-05-14147]; United States Department of Veterans Affairs Administration, Office of Research and Development, Biomedical Laboratory Research Program; Wellcome Trust; Howard Hughes Medical Institute; Canadian Institute of Health; LABEX; CNG; EADI; Aquitaine and Bourgogne Regional Councils, Agence Nationale de la Recherche; [RF-2010-2319722] FX The i-Select chips was funded by the French National Foundation on Alzheimer's disease and related disorders. The French National Fondation on Alzheimer's disease and related disorders supported several I-GAP meetings and communications. Data management involved the Centre National de Genotypage, and was supported by the Institut Pasteur de Lille, Inserm, FRC (fondation pour la recherche sur le cerveau) and Rotary. This work has been developed and supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease) and by the LABEX GENMED grant (Medical Genomics). The French National Foundation on Alzheimer's disease and related disorders and the Alzheimer's Association (Chicago, Illinois) grant supported IGAP in-person meetings, communication and the Alzheimer's Association (Chicago, Illinois) grant provided some funds to each consortium for analyses. EADI The authors thank Dr. Anne Boland (CNG) for her technical help in preparing the DNA samples for analyses. This work was supported by the National Foundation for Alzheimer's disease and related disorders, the Institut Pasteur de Lille and the Centre National de Genotypage. The Three-City Study was performed as part of a collaboration between the Institut National de la Sante et de la Recherche Medicale (Inserm), the Victor Segalen Bordeaux II University and Sanofi-Synthelabo. The Fondation pour la Recherche Medicale funded the preparation and initiation of the study. The 3C Study was also funded by the Caisse Nationale Maladie des Travailleurs Salaries, Direction Generale de la Sante, MGEN, Institut de la Longevite, Agence Francaise, de Securite Sanitaire des Produits de Sante, the Aquitaine and Bourgogne Regional Councils, Agence Nationale de la Recherche, ANR supported the COGINUT and COVADIS projects. Fondation de France and the joint French Ministry of Research/INSERM << Cohortes et collections de donnees biologiques >> programme. Lille Genopole received an unconditional grant from Eisai. The Three-city biological bank was developed and maintained by the laboratory for genomic analysis LAG-BRC - Institut Pasteur de Lille. Belgium sample collection: The patients were clinically and pathological characterized by the neurologists Sebastiaan Engelborghs, Rik Vandenberghe and Peter P. De Deyn, and in part genetically by Caroline Van Cauwenberghe, Karolien Bettens and Kristel Sleegers. Research at the Antwerp site is funded in part by the Belgian Science Policy Office Interuniversity Attraction Poles program, the Foundation Alzheimer Research (SAO-FRA), the Flemish Government initiated Methusalem Excellence Program, the Research Foundation Flanders (FWO) and the University of Antwerp Research Fund, Belgium. Karolien Bettens is a postdoctoral fellow of the FWO. The Antwerp site authors thank the personnel of the VIB Genetic Service Facility, the Biobank of the Institute Born-Bunge and the Departments of Neurology and Memory Clinics at the Hospital Network Antwerp and the University Hospitals Leuven. Finish sample collection: Financial support for this project was provided by the Health Research Council of the Academy of Finland, EVO grant 5772708 of Kuopio University Hospital, and the Nordic Centre of Excellence in Neurodegeneration. Italian sample collections: the Bologna site (FL) obtained funds from the Italian Ministry of research and University as well as Carimonte Foundation.; The Florence site was supported by grant RF-2010-2319722, grant from the the Cassa di Risparmio di Pistoia e Pescia (Grant 2012) and the Cassa di Risparmio di Firenze (Grant 2012). The Milan site was supported by a grant from the (funding via numerous sources including Stichting MS Research, Brain Net Europe, Hersenstichting Nederland Breinbrekend Werk, International Parkinson Fonds, Internationale Stiching Alzheimer Onderzoek), Institut de Neuropatologia, Servei Anatomia Patologica, Universitat de Barcelona. Marcelle Morrison-Bogorad, PhD., Tony Phelps, PhD and Walter Kukull PhD are thanked for helping to co-ordinate this collection. ADNI Funding for ADNI is through the Northern California Institute for Research and Education by grants from Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, Glaxo-SmithKline, Innogenetics, Johnson and Johnson, Eli Lilly and Co., Medpace, Inc., Merck and Co., Inc., Novartis AG, Pfizer Inc, F. Hoffman-La Roche, Schering-Plough, Synarc, Inc., Alzheimer's Association, Alzheimer's Drug Discovery Foundation, the Dana Foundation, and by the National Institute of Biomedical Imaging and Bioengineering and NIA grants U01 AG024904, RC2 AG036535, K01 AG030514. Data collection and sharing for this project was funded by the ADNI (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Alzheimer's Association; Alzheimer's Drug Discovery Foundation; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129 and K01 AG030514. The authors thank Drs. D. Stephen Snyder and Marilyn Miller from NIA who are ex-o_cio ADGC members. Support was also from the Alzheimer's Association (LAF, IIRG-08-89720; MP-V, IIRG-05-14147) and the United States Department of Veterans Affairs Administration, Office of Research and Development, Biomedical Laboratory Research Program. Peter St George-Hyslop is supported by Wellcome Trust, Howard Hughes Medical Institute, and the Canadian Institute of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 27 Z9 28 U1 3 U2 36 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 JUN 12 PY 2014 VL 9 IS 6 AR e94661 DI 10.1371/journal.pone.0094661 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK8TP UT WOS:000338701300002 PM 24922517 ER PT J AU Schluter, EW Mitz, AR Cheer, JF Averbeck, BB AF Schluter, Erik W. Mitz, Andrew R. Cheer, Joseph F. Averbeck, Bruno B. TI Real-Time Dopamine Measurement in Awake Monkeys SO PLOS ONE LA English DT Article ID SCAN CYCLIC VOLTAMMETRY; DEEP BRAIN-STIMULATION; VENTRAL TEGMENTAL AREA; IN-VIVO; PREMOTOR CORTEX; REWARD; STRIATUM; RELEASE; NEURONS; MICROELECTRODES AB Fast-scan cyclic voltammetry (FSCV) is often used to measure real-time dopamine (DA) concentrations in awake, behaving rodents. Extending this technique to work in monkeys would provide a platform for advanced behavioral studies and a primate model for preclinical research. The present study demonstrates the feasibility of DA recordings in two awake monkeys (Macaca mulatta) using a mixture of techniques adapted from rodent, primate and brain slice work. We developed a long carbon fiber electrode to operate in the larger primate brain. This electrode was lowered into the striatum each day using a recording chamber and a detachable micromanipulator system. A manipulator also moved one or more tungsten stimulating electrodes into either the nearby striatum or the ventral tegmental area/substantia nigra pars compacta (VTA/SNc). We developed an electrical stimulation controller to reduce artifacts during electrical stimulation. We also introduce a stimulation-based methodology for estimating distances between electrodes in the brain. Dopamine responses within the striatum were evoked by either stimulation of the striatum near the FSCV electrode, or stimulation within the VTA/SNc. Unexpected juice rewards also evoked dopamine responses in the ventral striatum. Thus, we demonstrate that robust dopamine responses can be recorded from awake, behaving primates with FSCV. In addition, we describe how a stimulation technique borrowed from the neuroprosthetics field can activate the distributed monkey midbrain dopamine system in a way that mimics rodent VTA stimulation. C1 [Schluter, Erik W.; Mitz, Andrew R.; Averbeck, Bruno B.] NIMH, Neuropsychol Lab, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Cheer, Joseph F.] Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. RP Averbeck, BB (reprint author), NIMH, Neuropsychol Lab, Div Intramural Res, NIH, Bldg 9, Bethesda, MD 20892 USA. EM bruno.averbeck@nih.gov FU US National Institute of Mental Health FX This work was supported by the Intramural Research Program of the US National Institute of Mental Health (http://www.nimh.nih.gov). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 5 Z9 5 U1 2 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 12 PY 2014 VL 9 IS 6 AR e98692 DI 10.1371/journal.pone.0098692 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK8TP UT WOS:000338701300013 PM 24921937 ER PT J AU Kalnin, K Tibbitts, T Yan, YH Stegalkina, S Shen, LH Costa, V Sabharwal, R Anderson, SF Day, PM Christensen, N Schiller, JT Jagu, S Roden, RBS Almond, J Kleanthous, H AF Kalnin, Kirin Tibbitts, Timothy Yan, Yanhua Stegalkina, Svetlana Shen, Lihua Costa, Victor Sabharwal, Robert Anderson, Stephen F. Day, Patricia M. Christensen, Neil Schiller, John T. Jagu, Subhashini Roden, Richard B. S. Almond, Jeffrey Kleanthous, Harold TI Low doses of flagellin-L2 multimer vaccines protect against challenge with diverse papillomavirus genotypes SO VACCINE LA English DT Article DE Human papillomavirus; Vaginal challenge; Cutaneous challenge; L2; HPV; Prophylactic vaccine; Neutralizing antibody; Protective efficacy ID CROSS-NEUTRALIZING EPITOPE; VIRUS TYPE-16 DNA; INFLUENZA VACCINE; IMMUNE-RESPONSE; HPV TYPES; AS04-ADJUVANTED VACCINE; SALMONELLA FLAGELLIN; PHAGOSOME MATURATION; SENSITIVE MEASURE; PARTICLE VACCINE AB Genetically modified bacterial flagellin (Fla), a Toll-like receptor-5 (TLR5) ligand, was evaluated as a fusion partner for human papillomavirus (HPV) L2-based immunogens in two animal challenge models; either cutaneous inoculation of rabbits with HPV 'quasivirions' containing cottontail rabbit papillomavirus (CRPV) genomes that induce warts, or intra-vaginal inoculation of mice with HPV 'pseudovirions' encapsidating a luciferase reporter plasmid and measurement of bioluminescence to determine infectivity. An Escherichia coli production system was developed for flagellin-L2 (Fla-L2) fusions containing either monomeric HPV-16 L2 a.a. 11( x 11-200) or oligomeric L2 comprising a fusion of the a.a. 11-88 peptides of five (Fla similar to 5 x 11-88) or eight (Fla similar to 8 x 11-88) genital HPV types. Immunogenicity and bioactivity of Fla-L2 constructs were assessed using an in vitro neutralization and cell-based TLR-5 binding assay, respectively. Efficacy was evaluated following active immunization of rabbits or mice administered 3 intramuscular doses of Fla-L2 recombinants without exogenous adjuvant, followed by challenge. In addition, passive immunization studies of naive rabbits with serial dilutions of pooled immune sera were used to determine End-Point Protection Titers (EPPT) for each formulation against a broader spectrum of HPV quasivirions. Efficacy was assessed for up to 10 weeks on the basis of wart volume induced following challenge and results compared to licensed L1-VLP vaccines (Gardasil and Cervarix). Following active immunization at doses as low as 1 mu g, Fla-L2 fusions afforded complete protection against infection (mice) and disease (rabbits) following either homologous or heterologous HPV challenge. Passive immunization with anti-L2 immune sera discriminated between the different vaccine candidates under evaluation, demonstrated the protective role of antibody and suggested the superiority of this oligomeric L2-TLR5 agonist fusion approach compared to L1-based vaccines in its ability to cross-protect against non-vaccine HPV types. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Kalnin, Kirin; Tibbitts, Timothy; Yan, Yanhua; Stegalkina, Svetlana; Shen, Lihua; Costa, Victor; Sabharwal, Robert; Anderson, Stephen F.; Almond, Jeffrey; Kleanthous, Harold] Sanofi Pasteur, Discovery, Cambridge, MA 02139 USA. [Christensen, Neil] Penn State Univ, Coll Med, Dept Pathol, Hershey, PA USA. [Jagu, Subhashini; Roden, Richard B. S.] Johns Hopkins Univ, Dept Pathol, Baltimore, MD USA. [Day, Patricia M.; Schiller, John T.] NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. RP Kalnin, K (reprint author), Sanofi Pasteur, Dept Mol Biol, 38 Sydney St, Cambridge, MA 02139 USA. EM kirill.kalnin@sanofipasteur.com FU Sanofi Pasteur FX This study was funded by Sanofi Pasteur. NR 47 TC 12 Z9 13 U1 1 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD JUN 12 PY 2014 VL 32 IS 28 BP 3540 EP 3547 DI 10.1016/j.vaccine.2014.04.032 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AL0NC UT WOS:000338822600011 PM 24780250 ER PT J AU Johnson, DB Quinn, E Sitaker, M Ammerman, A Byker, C Dean, W Fleischhacker, S Kolodinsky, J Pinard, C Pitts, SBJ Sharkey, J AF Johnson, Donna B. Quinn, Emilee Sitaker, Marilyn Ammerman, Alice Byker, Carmen Dean, Wesley Fleischhacker, Sheila Kolodinsky, Jane Pinard, Courtney Pitts, Stephanie B. Jilcott Sharkey, Joseph TI Developing an agenda for research about policies to improve access to healthy foods in rural communities: a concept mapping study SO BMC PUBLIC HEALTH LA English DT Article DE Rural populations; Nutrition; Food systems; Food access; Policy ID EASTERN NORTH-CAROLINA; TEXAS BORDER COLONIAS; UNITED-STATES; NEIGHBORHOOD CHARACTERISTICS; PHYSICAL-ACTIVITY; NUTRITION ENVIRONMENTS; POPULATION HEALTH; VEGETABLE INTAKE; SERVICE PLACES; SPATIAL ACCESS AB Background: Policies that improve access to healthy, affordable foods may improve population health and reduce health disparities. In the United States most food access policy research focuses on urban communities even though residents of rural communities face disproportionately higher risk for nutrition-related chronic diseases compared to residents of urban communities. The purpose of this study was to (1) identify the factors associated with access to healthy, affordable food in rural communities in the United States; and (2) prioritize a meaningful and feasible rural food policy research agenda. Methods: This study was conducted by the Rural Food Access Workgroup (RFAWG), a workgroup facilitated by the Nutrition and Obesity Policy Research and Evaluation Network. A national sample of academic and non-academic researchers, public health and cooperative extension practitioners, and other experts who focus on rural food access and economic development was invited to complete a concept mapping process that included brainstorming the factors that are associated with rural food access, sorting and organizing the factors into similar domains, and rating the importance of policies and research to address these factors. As a last step, RFAWG members convened to interpret the data and establish research recommendations. Results: Seventy-five participants in the brainstorming exercise represented the following sectors: non-extension research (n = 27), non-extension program administration (n = 18), "other" (n = 14), policy advocacy (n = 10), and cooperative extension service (n = 6). The brainstorming exercise generated 90 distinct statements about factors associated with rural food access in the United States; these were sorted into 5 clusters. Go Zones were established for the factors that were rated highly as both a priority policy target and a priority for research. The highest ranked policy and research priorities include strategies designed to build economic viability in rural communities, improve access to federal food and nutrition assistance programs, improve food retail systems, and increase the personal food production capacity of rural residents. Respondents also prioritized the development of valid and reliable research methodologies to measure variables associated with rural food access. Conclusions: This collaborative, trans-disciplinary, participatory process, created a map to guide and prioritize research about polices to improve healthy, affordable food access in rural communities. C1 [Johnson, Donna B.] Univ Washington, Seattle, WA 98195 USA. [Quinn, Emilee] Univ Washington, Ctr Publ Hlth Nutr, Seattle, WA 98195 USA. [Sitaker, Marilyn] Battelle Hlth & Analyt, Seattle, WA 98109 USA. [Ammerman, Alice] Univ N Carolina, Ctr Hlth Promot & Dis Prevent, Dept Nutr, Chapel Hill, NC 27599 USA. [Byker, Carmen] Montana State Univ, Dept Hlth & Human Dev, Bozeman, MT 59717 USA. [Dean, Wesley] Food & Nutr Serv, USDA, Off Policy Support, Food Nutr & Consumer Serv Headquarters, Alexandria, VA 22302 USA. [Fleischhacker, Sheila] NIH, Div Nutr Res Coordinat, Bethesda, MD 20892 USA. [Kolodinsky, Jane] Univ Vermont, Dept Community Dev & Appl Econ, Burlington, VT 05405 USA. [Pinard, Courtney] Gretchen Swanson Ctr Nutr, Omaha, NE 68114 USA. [Pitts, Stephanie B. Jilcott] E Carolina Univ, Dept Publ Hlth, Greenville, NC 27834 USA. [Sharkey, Joseph] Texas A&M Hlth Sci Ctr, Sch Publ Hlth, Dept Hlth Promot & Community Hlth Sci, College Stn, TX 77843 USA. RP Johnson, DB (reprint author), Univ Washington, Box 353410, Seattle, WA 98195 USA. EM djohn@uw.edu OI Byker Shanks, Carmen/0000-0002-9030-9938 FU Nutrition and Obesity Policy Research and Evaluation Network (NOPREN) from the Centers for Disease Control and Prevention [5U48-DP001911] FX The authors would like to acknowledge Dr. Heidi Blanck, Chief, Obesity Prevention and Control Branch at the Centers for Disease Control and Prevention, and Demia Wright, Health Education Specialist in Division of Nutrition, Physical Activity, and Obesity, Centers for Disease Control and Prevention, for their support of this project and their participation in the data interpretation session. The project would not have been possible without the generous donation of time and expertise of all of the experts who participated in the stages of the concept mapping process. This project is supported through the Nutrition and Obesity Policy Research and Evaluation Network (NOPREN) by Cooperative Agreement Number 5U48-DP001911 from the Centers for Disease Control and Prevention. The findings and conclusions are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention, or the National Institutes of Health, or the United States Department of Agriculture Food and Nutrition Service. NR 66 TC 7 Z9 7 U1 9 U2 27 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD JUN 12 PY 2014 VL 14 AR 592 DI 10.1186/1471-2458-14-592 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AL2PE UT WOS:000338966700001 PM 24919425 ER PT J AU Choi, H Shung, KK AF Choi, Hojong Shung, K. Kirk TI Crossed SMPS MOSFET-based protection circuit for high frequency ultrasound transceivers and transducers SO BIOMEDICAL ENGINEERING ONLINE LA English DT Article DE Protection circuit; SMPS MOSFET; Ultrasound system; Ultrasonic transducer ID ARRAY AB Background: The ultrasonic transducer is one of the core components of ultrasound systems, and the transducer's sensitivity is significantly related the loss of electronic components such as the transmitter, receiver, and protection circuit. In an ultrasonic device, protection circuits are commonly used to isolate the electrical noise between an ultrasound transmitter and transducer and to minimize unwanted discharged pulses in order to protect the ultrasound receiver. However, the performance of the protection circuit and transceiver obviously degrade as the operating frequency or voltage increases. We therefore developed a crossed SMPS (Switching Mode Power Supply) MOSFET-based protection circuit in order to maximize the sensitivity of high frequency transducers in ultrasound systems. The high frequency pulse signals need to trigger the transducer, and high frequency pulse signals must be received by the transducer. We therefore selected the SMPS MOSFET, which is the main component of the protection circuit, to minimize the loss in high frequency operation. The crossed configuration of the protection circuit can drive balanced bipolar high voltage signals from the pulser and transfer the balanced low voltage echo signals from the transducer. Methods: The equivalent circuit models of the SMPS MOSFET-based protection circuit are shown in order to select the proper device components. The schematic diagram and operation mechanism of the protection circuit is provided to show how the protection circuit is constructed. The P-Spice circuit simulation was also performed in order to estimate the performance of the crossed MOSFET-based protection circuit. Results: We compared the performance of our crossed SMPS MOSFET-based protection circuit with a commercial diode-based protection circuit. At 60 MHz, our expander and limiter circuits have lower insertion loss than the commercial diode-based circuits. The pulse-echo test is typical method to evaluate the sensitivity of ultrasonic transducers. Therefore, we performed a pulse-echo test using a single element transducer in order to utilize the crossed SMPS MOSFET-based protection circuit in an ultrasound system. Conclusions: The SMPS-based protection circuit could be a viable alternative that provides better sensitivity, especially for high frequency ultrasound applications. C1 [Choi, Hojong] Univ So Calif, NIH, Transducer Resource Ctr, Los Angeles, CA 90089 USA. Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. RP Choi, H (reprint author), Univ So Calif, NIH, Transducer Resource Ctr, Los Angeles, CA 90089 USA. EM hojongch@usc.edu FU National Institutes of Health [P41-EB002182] FX The authors thank Dr. Andrew Weitz for editing this manuscript, editor-in-chief, Dr. Foster, and the reviewers for valuable advices about the manuscript. This research was supported by National Institutes of Health Grant #P41-EB002182. NR 18 TC 0 Z9 0 U1 0 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-925X J9 BIOMED ENG ONLINE JI Biomed. Eng. Online PD JUN 12 PY 2014 VL 13 AR 76 DI 10.1186/1475-925X-13-76 PG 10 WC Engineering, Biomedical SC Engineering GA AK0XK UT WOS:000338139400001 PM 24924595 ER PT J AU Kang, MJ Abdelmohsen, K Hutchison, ER Mitchell, SJ Grammatikakis, I Guo, R Noh, JH Martindale, JL Yang, XL Lee, EK Faghihi, MA Wahlestedt, C Troncoso, JC Pletnikova, O Perrone-Bizzozero, N Resnick, SM De Cabo, R Mattson, MP Gorospe, M AF Kang, Min-Ju Abdelmohsen, Kotb Hutchison, Emmette R. Mitchell, Sarah J. Grammatikakis, Ioannis Guo, Rong Noh, Ji Heon Martindale, Jennifer L. Yang, Xiaoling Lee, Eun Kyung Faghihi, Mohammad A. Wahlestedt, Claes Troncoso, Juan C. Pletnikova, Olga Perrone-Bizzozero, Nora Resnick, Susan M. De Cabo, Rafael Mattson, Mark P. Gorospe, Myriam TI HuD Regulates Coding and Noncoding RNA to Induce APP -> A beta Processing SO CELL REPORTS LA English DT Article ID BINDING PROTEIN HUD; POSTTRANSCRIPTIONAL GENE-REGULATION; NEURONAL DIFFERENTIATION; TRANSLATION; EXPRESSION; CELLS AB The primarily neuronal RNA-binding protein HuD is implicated in learning and memory. Here, we report the identification of several HuD target transcripts linked to Alzheimer's disease (AD) pathogenesis. HuD interacted with the 3' UTRs of APP mRNA (encoding amyloid precursor protein) and BACE1 mRNA (encoding beta-site APP-cleaving enzyme 1) and increased the half-lives of these mRNAs. HuD also associated with and stabilized the long noncoding (lnc) RNA BACE1AS, which partly complements BACE1 mRNA and enhances BACE1 expression. Consistent with HuD promoting production of APP and APP-cleaving enzyme, the levels of APP, BACE1, BACE1AS, and A beta were higher in the brain of HuD-overexpressing mice. Importantly, cortex (superior temporal gyrus) from patients with AD displayed significantly higher levels of HuD and, accordingly, elevated APP, BACE1, BACE1AS, and A beta than did cortical tissue from healthy age-matched individuals. We propose that HuD jointly promotes the production of APP and the cleavage of its amyloidogenic fragment, A beta. C1 [Kang, Min-Ju; Abdelmohsen, Kotb; Grammatikakis, Ioannis; Guo, Rong; Noh, Ji Heon; Martindale, Jennifer L.; Yang, Xiaoling; Lee, Eun Kyung; Gorospe, Myriam] Natl Inst Aging Intramural Res Program, Genet Lab, NIH, Baltimore, MD 21224 USA. [Hutchison, Emmette R.; Mattson, Mark P.] Natl Inst Aging Intramural Res Program, Lab Neurosci, NIH, Baltimore, MD 21224 USA. [Mitchell, Sarah J.; De Cabo, Rafael] Natl Inst Aging Intramural Res Program, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Resnick, Susan M.] Natl Inst Aging Intramural Res Program, Lab Behav Neurosci, NIH, Baltimore, MD 21224 USA. [Faghihi, Mohammad A.; Wahlestedt, Claes] Univ Miami, Miller Sch Med, Ctr Therapeut Innovat, Miami, FL 33136 USA. [Troncoso, Juan C.; Pletnikova, Olga] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Perrone-Bizzozero, Nora] Univ New Mexico, Sch Med, Dept Neurosci, Albuquerque, NM 87131 USA. RP Gorospe, M (reprint author), Natl Inst Aging Intramural Res Program, Genet Lab, NIH, Baltimore, MD 21224 USA. EM myriam-gorospe@nih.gov RI de Cabo, Rafael/J-5230-2016 OI de Cabo, Rafael/0000-0002-3354-2442 FU Johns Hopkins University Alzheimer's Disease Research Center; NIA-IRP, NIH; NIA [P50AG05146]; NIDA [R01DA034097] FX We thank H. Cai for providing reagents and information, J.H. Yoon for advice, and D. Phillips-Boyer, D. Nines, and J. Lucas for exceptional animal care. We appreciate the support of The Johns Hopkins University Alzheimer's Disease Research Center. This work was funded by the NIA-IRP, NIH, by NIA P50AG05146 to J. C. T., and by NIDA R01DA034097 to N.P.-B. NR 23 TC 14 Z9 14 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD JUN 12 PY 2014 VL 7 IS 5 BP 1401 EP 1409 DI 10.1016/j.celrep.2014.04.050 PG 9 WC Cell Biology SC Cell Biology GA AK3LA UT WOS:000338324200008 PM 24857657 ER PT J AU Siersbaek, R Baek, S Rabiee, A Nielsen, R Traynor, S Clark, N Sandelin, A Jensen, ON Sung, MH Hager, GL Mandrup, S AF Siersbaek, Rasmus Baek, Songjoon Rabiee, Atefeh Nielsen, Ronni Traynor, Sofie Clark, Nicholas Sandelin, Albin Jensen, Ole N. Sung, Myong-Hee Hager, Gordon L. Mandrup, Susanne TI Molecular Architecture of Transcription Factor Hotspots in Early Adipogenesis SO CELL REPORTS LA English DT Article ID FACTOR-BINDING PROFILES; OPEN-ACCESS DATABASE; DNA-BINDING; GLUCOCORTICOID-RECEPTOR; REGULATORY ELEMENTS; C/EBP-ALPHA; PPAR-GAMMA; IN-VIVO; OCCUPANCY; SEQUENCES AB Transcription factors have recently been shown to colocalize in hotspot regions of the genome, which are further clustered into super-enhancers. However, the detailed molecular organization of transcription factors at hotspot regions is poorly defined. Here, we have used digital genomic footprinting to precisely define factor localization at a genome-wide level during the early phase of 3T3-L1 adipocyte differentiation, which allows us to obtain detailed molecular insight into how transcription factors target hotspots. We demonstrate the formation of ATF-C/EBP heterodimers at a composite motif on chromatin, and we suggest that this may be a general mechanism for integrating external signals on chromatin. Furthermore, we find evidence of extensive recruitment of transcription factors to hotspots through alternative mechanisms not involving their known motifs and demonstrate that these alternative binding events are functionally important for hotspot formation and activity. Taken together, these findings provide a framework for understanding transcription factor cooperativity in hotspots. C1 [Siersbaek, Rasmus; Rabiee, Atefeh; Nielsen, Ronni; Traynor, Sofie; Jensen, Ole N.; Mandrup, Susanne] Univ Southern Denmark, Dept Biochem & Mol Biol, DK-5230 Odense M, Denmark. [Baek, Songjoon; Sung, Myong-Hee; Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Clark, Nicholas; Sandelin, Albin] Univ Copenhagen, Dept Biol, Bioinformat Ctr, DK-2200 Copenhagen, Denmark. [Clark, Nicholas; Sandelin, Albin] Univ Copenhagen, Biotech Res & Innovat Ctr, DK-2200 Copenhagen, Denmark. RP Mandrup, S (reprint author), Univ Southern Denmark, Dept Biochem & Mol Biol, DK-5230 Odense M, Denmark. EM s.mandrup@bmb.sdu.dk RI Sandelin, Albin/G-2881-2011; OI Sandelin, Albin/0000-0002-7109-7378; Mandrup, Susanne/0000-0002-0961-5787; Jensen, Ole Norregaard/0000-0003-1862-8528 FU Villum Foundation; Danish Independent Research Council\Natural Sciences; Novo Nordisk Foundation; Danish National Research Foundation [DNRF82]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; Lundbeck foundation FX We thank members of the Mandrup and Hager groups for valuable discussions. In particular, we thank Bjork D. Larsen for experimental assistance. The work was in part carried out at the Villum Center for Bioanalytical Sciences, Department of Biochemistry and Molecular Biology, SDU, supported by the Villum Foundation. Work in the Mandrup laboratory was supported by grants from the Danish Independent Research Council vertical bar Natural Sciences and the Novo Nordisk Foundation; work in the Jensen laboratory was financed by the Danish National Research Foundation grant number DNRF82 to the Center for Epigenetics; work in the Hager laboratory was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; and work in the Sandelin group was supported by the Lundbeck foundation and Novo Nordisk Foundation. NR 32 TC 19 Z9 19 U1 3 U2 10 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 JUN 12 PY 2014 VL 7 IS 5 BP 1434 EP 1442 DI 10.1016/j.celrep.2014.04.043 PG 9 WC Cell Biology SC Cell Biology GA AK3LA UT WOS:000338324200012 PM 24857666 ER PT J AU Sakofsky, CJ Roberts, SA Malc, E Mieczkowski, PA Resnick, MA Gordenin, DA Malkova, A AF Sakofsky, Cynthia J. Roberts, Steven A. Malc, Ewa Mieczkowski, Piotr A. Resnick, Michael A. Gordenin, Dmitry A. Malkova, Anna TI Break-Induced Replication Is a Source of Mutation Clusters Underlying Kataegis SO CELL REPORTS LA English DT Article ID CONSERVATIVE DNA-SYNTHESIS; HALF-CROSSOVERS; HUMAN CANCERS; REPAIR; MUTAGENESIS; BUBBLE AB Clusters of simultaneousmultiple mutations can be a source of rapid change during carcinogenesis and evolution. Such mutation clusters have been recently shown to originate from DNA damage within long single-stranded DNA (ssDNA) formed at resected double-strand breaks and dysfunctional replication forks. Here, we identify double-strand break (DSB)-induced replication (BIR) as another powerful source of mutation clusters that formed in nearly half of wild-type yeast cells undergoing BIR in the presence of alkylating damage. Clustered mutations were primarily formed along the track of DNA synthesis and were frequently associated with additional breakage and rearrangements. Moreover, the base specificity, strand coordination, and strand bias of the mutation spectrum were consistent with mutations arising from damage in persistent ssDNA stretches within unconventional replication intermediates. Altogether, these features closely resemble kataegic events in cancers, suggesting that replication intermediates during BIR may be the most prominent source of mutation clusters across species. C1 [Sakofsky, Cynthia J.; Malkova, Anna] Univ Iowa, Coll Liberal Arts & Sci, Dept Biol, Iowa City, IA 52242 USA. [Roberts, Steven A.; Resnick, Michael A.; Gordenin, Dmitry A.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. [Malc, Ewa; Mieczkowski, Piotr A.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Genet, Chapel Hill, NC 27599 USA. [Malc, Ewa; Mieczkowski, Piotr A.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA. [Sakofsky, Cynthia J.; Malkova, Anna] IUPUI, Sch Sci, Dept Biol, Indianapolis, IN 46202 USA. RP Gordenin, DA (reprint author), Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. EM gordenin@niehs.nih.gov; anna-malkova@uiowa.edu OI Gordenin, Dmitry/0000-0002-8399-1836 FU NIH [GM084242, 5R01GM052319-17]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [ES065073]; NIH Pathway to Independence [K99ES022633-01]; Department of Biology at IUPUI FX This work was funded by NIH grants GM084242 (to A.M.) and 5R01GM052319-17 (to P.A.M.) and by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (project ES065073, to M.A.R). S.A.R. was supported by NIH Pathway to Independence Award K99ES022633-01. C.J.S. was supported in part by the Department of Biology at IUPUI. NR 27 TC 34 Z9 34 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD JUN 12 PY 2014 VL 7 IS 5 BP 1640 EP 1648 DI 10.1016/j.celrep.2014.04.053 PG 9 WC Cell Biology SC Cell Biology GA AK3LA UT WOS:000338324200028 PM 24882007 ER PT J AU Mullen, AR Hu, Z Shi, X Jiang, L Boroughs, LK Kovacs, Z Boriack, R Rakheja, D Sullivan, LB Linehan, WM Chandel, NS DeBerardinis, RJ AF Mullen, Andrew R. Hu, Zeping Shi, Xiaolei Jiang, Lei Boroughs, Lindsey K. Kovacs, Zoltan Boriack, Richard Rakheja, Dinesh Sullivan, Lucas B. Linehan, W. Marston Chandel, Navdeep S. DeBerardinis, Ralph J. TI Oxidation of Alpha-Ketoglutarate Is Required for Reductive Carboxylation in Cancer Cells with Mitochondrial Defects SO CELL REPORTS LA English DT Article ID FUMARATE HYDRATASE; GLUTAMINE-METABOLISM; DEFICIENT CELLS; TUMOR-CELLS; IN-VIVO; MUTATIONS; HYPOXIA; CITRATE; GROWTH; CYCLE AB Mammalian cells generate citrate by decarboxylating pyruvate in the mitochondria to supply the tricarboxylic acid (TCA) cycle. In contrast, hypoxia and other impairments of mitochondrial function induce an alternative pathway that produces citrate by reductively carboxylating alpha-ketoglutarate (AKG) via NADPH-dependent isocitrate dehydrogenase (IDH). It is unknown how cells generate reducing equivalents necessary to supply reductive carboxylation in the setting of mitochondrial impairment. Here, we identified shared metabolic features in cells using reductive carboxylation. Paradoxically, reductive carboxylation was accompanied by concomitant AKG oxidation in the TCA cycle. Inhibiting AKG oxidation decreased reducing equivalent availability and suppressed reductive carboxylation. Interrupting transfer of reducing equivalents from NADH to NADPH by nicotinamide nucleotide transhydrogenase increased NADH abundance and decreased NADPH abundance while suppressing reductive carboxylation. The data demonstrate that reductive carboxylation requires bidirectional AKG metabolism along oxidative and reductive pathways, with the oxidative pathway producing reducing equivalents used to operate IDH in reverse. C1 [Mullen, Andrew R.; Hu, Zeping; Shi, Xiaolei; Jiang, Lei; Boroughs, Lindsey K.; DeBerardinis, Ralph J.] Univ Texas SW Med Ctr Dallas, Childrens Med Ctr Res Inst, Dallas, TX 75390 USA. [Kovacs, Zoltan] Univ Texas SW Med Ctr Dallas, Adv Imaging Res Ctr, Dallas, TX 75390 USA. [Boriack, Richard; Rakheja, Dinesh] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA. [DeBerardinis, Ralph J.] Univ Texas SW Med Ctr Dallas, McDermott Ctr Human Growth & Dev, Dallas, TX 75390 USA. [Sullivan, Lucas B.; Chandel, Navdeep S.] Northwestern Univ, Dept Med, Chicago, IL 60611 USA. [Sullivan, Lucas B.; Chandel, Navdeep S.] Northwestern Univ, Dept Cell & Mol Biol, Chicago, IL 60611 USA. [Linehan, W. Marston] NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP DeBerardinis, RJ (reprint author), Univ Texas SW Med Ctr Dallas, Childrens Med Ctr Res Inst, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM ralph.deberardinis@utsouthwestern.edu RI Hu, Zeping/F-6205-2010 FU NIH [R01 CA157996, 5T32GM083831]; Welch Foundation [I-1733] FX We thank Hien Nguyen for measurements of AKG, the Live Cell Imaging Core at UT Southwestern for microscopy, and Robert Harris for experimental assistance. Patrick Pollard provided the FH Delta MTS construct, and Othon Iliopoulos provided advice on western blots for NNT. The 143B cybrids were supplied by I.F.M. de Coo and Carlos Moraes. R.J.D. was supported by grants from the NIH (R01 CA157996) and the Welch Foundation (I-1733). A. R. M. was supported by an NIH Training Grant (5T32GM083831). R.J.D. is a member of the scientific advisory boards of Agios Pharmaceuticals and Peloton Therapeutics. NR 38 TC 55 Z9 56 U1 5 U2 25 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 JUN 12 PY 2014 VL 7 IS 5 BP 1679 EP 1690 DI 10.1016/j.celrep.2014.04.037 PG 12 WC Cell Biology SC Cell Biology GA AK3LA UT WOS:000338324200031 PM 24857658 ER PT J AU Li, KF Hu, C Mei, C Ren, ZG Vera, JC Zhuang, ZP Jin, J Tong, HY AF Li, Kongfei Hu, Chao Mei, Chen Ren, Zhigang Vera, Juan Carlos Zhuang, Zhengping Jin, Jie Tong, Hongyan TI Sequential combination of decitabine and idarubicin synergistically enhances anti-leukemia effect followed by demethylating Wnt pathway inhibitor promoters and downregulating Wnt pathway nuclear target SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article DE ZOOM PROBLEM ID ACUTE MYELOID-LEUKEMIA; CELL-LINE; DNA METHYLTRANSFERASE; SIGNALING PATHWAY; VALPROIC ACID; 5-AZA-2'-DEOXYCYTIDINE; DIFFERENTIATION; METHYLATION; CANCER; HYPERMETHYLATION C1 [Li, Kongfei; Hu, Chao; Jin, Jie; Tong, Hongyan] Zhejiang Univ, Dept Hematol, Affiliated Hosp 1, Hangzhou 310003, Zhejiang, Peoples R China. [Li, Kongfei] Yin Zhou People Hosp, Dept Hematol, Ningbo 315040, Zhejiang, Peoples R China. [Li, Kongfei; Hu, Chao; Jin, Jie; Tong, Hongyan] Zhejiang Univ, Sch Med, Inst Hematol, Hangzhou 310009, Zhejiang, Peoples R China. [Ren, Zhigang] Zhejiang Univ, Dept Hepatobiliary & Pancreat Surg, Affiliated Hosp 1, Hangzhou 310003, Zhejiang, Peoples R China. [Vera, Juan Carlos; Zhuang, Zhengping] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Mei, Chen] Zhejiang Univ, Sir Run Run Shaw Hosp, Dept Hematol, Hangzhou 310016, Zhejiang, Peoples R China. RP Tong, HY (reprint author), Zhejiang Univ, Dept Hematol, Affiliated Hosp 1, Hangzhou 310003, Zhejiang, Peoples R China. EM hongyantong@aliyun.com NR 38 TC 0 Z9 0 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD JUN 12 PY 2014 VL 12 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AK5OC UT WOS:000338473300004 ER PT J AU Fu, Q Liu, P Lu, QS Wang, F Wang, H Shen, W Xu, F Liu, L Sergeev, YV Sui, RF AF Fu, Qing Liu, Peng Lu, Qingsheng Wang, Feng Wang, Hui Shen, Wei Xu, Fei Liu, Lin Sergeev, Yuri V. Sui, Ruifang TI Novel mutation in FBN1 causes ectopia lentis and varicose great saphenous vein in one Chinese autosomal dominant family SO MOLECULAR VISION LA English DT Article ID MARFAN-SYNDROME; FIBRILLIN-1 GENE; IDENTIFICATION; PHENOTYPE; GENOTYPE; PROBANDS; DOMAINS; SMART AB Purpose: To identify genetic defects in a Chinese family with ectopia lentis (EL) and varicose great saphenous vein (GSV) and to analyze the correlations between phenotype and genotype. Methods: Twenty-two (12 affected subjects and ten unaffected subjects) among 53 members of a Chinese family underwent complete physical, ophthalmic, and cardiovascular examinations. Genomic DNA was extracted from the leukocytes in the subjects' peripheral blood. A minimum interval was achieved with linkage study and haplotype analysis. All 65 exons and the flanking intronic regions of fibrillin-1 (FBN1) were amplified with PCR and screened for mutations with direct Sanger sequencing. Molecular modeling was analyzed in an in silico study. Results: The linkage study showed a strong cosegregation signal on chromosome 15. The non-parametric linkage analysis yielded a maximum score of 29.1(p<0.00001), and the parametric logarithm of the odds (LOD) score was 3.6. The minimum interval of the shared haplotype was rs1565863-rs877228. The best candidate gene in this region was FBN1. A novel mutation, c.3928G>A, p.1310G>S in exon 31, was identified in FBN1 and cosegregated well in the family. We applied molecular modeling to show the effect of this mutation on the fibrillin-1 structure. The mutation significantly distorts the calcium coordination, decreases the binding of the calcium ion in that motif, and affects the local calcium-binding epidermal growth factor (cbEGF) interface that depends on Ca binding. Conclusions: FBN1-associated fibrillinopathies are a group of diseases with dynamic phenotype changes. Novel mutation p.1310G>S was first reported to cause Marfan syndrome (MFS). Our results expand the mutation spectrum in FBN1 and enhance our knowledge of genotype-phenotype correlations underlying FBN1 mutations. C1 [Fu, Qing; Xu, Fei; Sui, Ruifang] Peking Union Med Coll, Peking Union Med Coll Hosp, Dept Ophthalmol, Beijing 100021, Peoples R China. [Liu, Peng] Second Mil Med Univ, Changhai Hosp, Dept Surg, Shanghai, Peoples R China. [Lu, Qingsheng] Second Mil Med Univ, Changhai Hosp, Dept Vasc Surg, Shanghai, Peoples R China. [Wang, Feng; Wang, Hui] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Shen, Wei] Second Mil Med Univ, Changhai Hosp, Dept Ophthalmol, Shanghai, Peoples R China. [Liu, Lin] Shanghai Jiao Tong Univ, Renji Hosp, Dept Ophthalmol, Shanghai 200030, Peoples R China. [Fu, Qing] Fudan Univ, North Huashan Hosp, Dept Ophthalmol, Shanghai 200433, Peoples R China. [Sergeev, Yuri V.] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. RP Sui, RF (reprint author), Peking Union Med, Coll Hosp, Dept Ophthalmol, 1 Shuai Fu Yuan, Beijing 100730, Peoples R China. EM hrfsui@163.com RI Wang, Feng/G-4847-2015 FU Ministry of Human Resource; Social Security of the People's Republic of China; Foundation Fighting Blindness USA [CD-CL-0808-0470-PUMCH] FX We are very grateful to all participating patients and their relatives. The research leading to these results received funding from the Ministry of Human Resource and Social Security of the People's Republic of China (2009) and the Foundation Fighting Blindness USA (CD-CL-0808-0470-PUMCH) to R.S. Author Contributions The authors declare no conflict of interest. Ruifang Sui conceived the project, designed the experiments and prepared the manuscript. Fei Xu performed the genetic experiments. Qing Fu analyzed the data and wrote the paper. Peng Liu was involved in clinical evaluations of patients and prepared the Figures and Tables. Feng Wang and Hui Wang were involved in the linkage analysis. Wei Shen and Lin Liu were involved in ophthalmic examinations. Yuri V. Sergeev did the structural modeling. NR 27 TC 1 Z9 2 U1 0 U2 2 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD JUN 12 PY 2014 VL 20 BP 812 EP 821 PG 10 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA AK3KB UT WOS:000338321000004 PM 24940037 ER PT J AU Kulemzina, AI Perelman, PL Grafodatskaya, DA Nguyen, TT Thompson, M Roelke-Parker, ME Graphodatsky, AS AF Kulemzina, Anastasia I. Perelman, Polina L. Grafodatskaya, Darya A. Nguyen, Trung T. Thompson, Mary Roelke-Parker, Melody E. Graphodatsky, Alexander S. TI Comparative chromosome painting of pronghorn (Antilocapra americana) and saola (Pseudoryx nghetinhensis) karyotypes with human and dromedary camel probes SO BMC GENETICS LA English DT Article DE Pronghorn; Antilocapra americana; Saola; Pseudoryx nghetinhensis; Comparative cytogenetics; Pecora; Phylogeny; Chromosome evolution ID MUNTJAC MUNTIACUS-REEVESI; PHYLOGENETIC-RELATIONSHIPS; GIRAFFA-CAMELOPARDALIS; ANCESTRAL KARYOTYPE; CYTOCHROME-B; CETARTIODACTYLA; EVOLUTION; RUMINANTIA; SEQUENCES; INSIGHTS AB Background: Pronghorn (Antilocapridae, 2n = 58) and saola (Bovidae, 2n = 50) are members of Pecora, a highly diversified group of even-toed hoofed mammals. Karyotypes of these species were not involved in chromosome painting studies despite their intriguing phylogenetic positions in Pecora. Results: To trace the chromosome evolution during very fast radiation of main families from the common Pecoran ancestor, high-resolution comparative chromosome maps of pronghorn and saola with human (HSA) and dromedary camel (CDR) painting probes were established. The human and dromedary camel painting probes revealed 50 and 64 conserved segments respectively in the pronghorn genome, while 51 and 63 conserved segments respectively in the saola genome. Integrative analysis with published comparative maps showed that inversions in chromosomes homologous to CDR19/35/19 (HSA 10/20/10), CDR12/34/12 (HSA 12/22/12/22), CDR10/33/10 (HSA 11) are present in representatives of all five living Pecoran families. The pronghorn karyotype could have formed from a putative 2n = 58 Pecoran ancestral karyotype by one fission and one fusion and that the saola karyotype differs from the presumed 2n = 60 bovid ancestral karyotype (2n = 60) by five fusions. Conclusion: The establishment of high-resolution comparative maps for pronghorn and saola has shed some new insights into the putative ancestral karyotype, chromosomal evolution and phylogenic relationships in Pecora. No cytogenetic signature rearrangements were found that could unite the Antilocapridae with Giraffidae or with any other Pecoran families. Our data on the saola support a separate position of Pseudorigyna subtribe rather than its affinity to either Bovina or Bubalina, but the saola phylogenetic position within Bovidae remains unresolved. C1 [Kulemzina, Anastasia I.; Perelman, Polina L.; Graphodatsky, Alexander S.] SB RAS, Inst Mol & Cellular Biol, Novosibirsk, Russia. [Kulemzina, Anastasia I.; Perelman, Polina L.; Graphodatsky, Alexander S.] Novosibirsk State Univ, Novosibirsk 630090, Russia. [Grafodatskaya, Darya A.] Hosp Sick Children, Genet & Genome Biol Program, Toronto, ON M5G 1X8, Canada. [Nguyen, Trung T.] Vietnam Acad Sci & Technol, Lab Embryo Technol, Inst Biotechnol, Hanoi, Vietnam. [Nguyen, Trung T.] ETH, Swiss Fed Inst Technol, Inst Anim Sci, CH-8092 Zurich, Switzerland. [Thompson, Mary] Ctr Canc Res, BSP CCR Genet Core, Frederick, MD 21702 USA. [Roelke-Parker, Melody E.] Leidos Biomed Res Inc, Frederick Natl Lab, Lab Anim Sci Program, Frederick, MD 21702 USA. [Perelman, Polina L.; Roelke-Parker, Melody E.] NCI, Lab Genom Div, Frederick, MD 21702 USA. RP Kulemzina, AI (reprint author), SB RAS, Inst Mol & Cellular Biol, Novosibirsk, Russia. EM zakal@mcb.nsc.ru RI Graphodatsky, Alexander/B-4922-2010; Perelman, Polina/N-8088-2015; Kulemzina, Anastasia/N-8554-2015 OI Graphodatsky, Alexander/0000-0002-8282-1085; Perelman, Polina/0000-0002-0982-5100; FU Russian Fund for Basic Research; MCB program of the Russian Academy of Science; Integration program of the Siberian Branch of the Russian Academy of Science; National Cancer Institute, National Institutes of Health [HHSN26120080001E] FX The work was supported by research grants of the Russian Fund for Basic Research, MCB program of the Russian Academy of Science and Integration program of the Siberian Branch of the Russian Academy of Science (ASG). We would like to sincerely thank Malcolm A Ferguson-Smith, Fengtang Yang and Patricia CM O'Brien for kindly providing the sets of human and dromedary camel chromosome-specific painting probes. We would like to sincerely thank Hank Edwards and WGFD Wildlife Disease Laboratory, Wyoming Game and Fish Department, Laramie, Wyoming, USA for kindly providing the ear sample of the pronghorn. MT and MER-P research was supported in part by the Intramural Research Program and federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E. MT, MER-P and PP acknowledge the head of Laboratory of Genomic Diversity Stephen J. O'Brien. The content of this publication does not 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 32 TC 0 Z9 0 U1 3 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2156 J9 BMC GENET JI BMC Genet. PD JUN 12 PY 2014 VL 15 AR 68 DI 10.1186/1471-2156-15-68 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA AK1HV UT WOS:000338167100001 PM 24923361 ER PT J AU Marzaro, G Coluccia, A Ferrarese, A Brun, P Castagliuolo, I Conconi, MT La Regina, G Bai, RL Silvestri, R Hamel, E Chilin, A AF Marzaro, Giovanni Coluccia, Antonio Ferrarese, Alessandro Brun, Paola Castagliuolo, Ignazio Conconi, Maria Teresa La Regina, Giuseppe Bai, Ruoli Silvestri, Romano Hamel, Ernest Chilin, Adriana TI Discovery of Biarylaminoquinazolines as Novel Tubulin Polymerization Inhibitors SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID KINASE INHIBITORS; COLCHICINE; CANCER; GROWTH; CONFORMATION; DOMAIN; APOPTOSIS; STATHMIN; TYROSINE; COMPLEX AB Cell cycle experiments with our previously reported 4-biphenylaminoquinazoline (1-3) multityrosine kinase inhibitors revealed an activity profile resembling that of known tubulin polymerization inhibitors. Novel 4-biarylaminoquinazoline analogues of compound 2 were synthesized and evaluated as inhibitors of several tyrosine kinases and of tubulin. Although compounds 1-3 acted as dual inhibitors, the heterobiaryl analogues possessed only anti-tubulin properties and targeted the colchicine site. Furthermore, molecular modeling studies allowed the rationalization of the pharmacodynamic properties of the compounds. C1 [Marzaro, Giovanni; Ferrarese, Alessandro; Conconi, Maria Teresa; Chilin, Adriana] Univ Padua, Dipartimento Sci Farmaco, I-35131 Padua, Italy. [Coluccia, Antonio; La Regina, Giuseppe; Silvestri, Romano] Univ Roma La Sapienza, Dipartimento Chim & Tecnol Farmaco, Ist Pasteur, Fdn Cenci Bolognetti, I-00185 Rome, Italy. [Brun, Paola; Castagliuolo, Ignazio] Univ Padua, Dept Mol Med, I-35121 Padua, Italy. [Bai, Ruoli; Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program,NIH, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Ft Detrick, MD 21702 USA. RP Chilin, A (reprint author), Univ Padua, Dipartimento Sci Farmaco, Via Marzolo 5, I-35131 Padua, Italy. EM adriana.chilin@unipd.it RI La Regina, Giuseppe/I-2161-2012; CASTAGLIUOLO, IGNAZIO/K-9963-2016; OI La Regina, Giuseppe/0000-0003-3252-1161; CASTAGLIUOLO, IGNAZIO/0000-0001-9888-7030; marzaro, giovanni/0000-0002-5892-5992; Chilin, Adriana/0000-0002-2038-1299; Silvestri, Romano/0000-0003-2489-0178; /0000-0002-7940-8206 FU University of Padova [CPDA084954/08] FX The present work was carried out with financial support from the University of Padova, "Progetto di Ricerca di Ateneo 2008" CPDA084954/08 to A. Chilin. A. Coluccia thanks Dr. A. Brancale for his support and helpful suggestions. NR 33 TC 8 Z9 8 U1 2 U2 15 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 JUN 12 PY 2014 VL 57 IS 11 BP 4598 EP 4605 DI 10.1021/jm500034j PG 8 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA AJ0JK UT WOS:000337336600014 PM 24801610 ER PT J AU Chen, JY Levant, B Jiang, C Keck, TM Newman, AH Wang, SM AF Chen, Jianyong Levant, Beth Jiang, Cheng Keck, Thomas M. Newman, Amy Hauck Wang, Shaomeng TI Tranylcypromine Substituted cis-Hydroxycyclobutylnaphthamides as Potent and Selective Dopamine D-3 Receptor Antagonists SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID FUNCTIONALIZED LINKING CHAINS; COCAINE-SEEKING BEHAVIOR; ABUSE THERAPEUTIC AGENTS; D3 RECEPTOR; HIGH-AFFINITY; RAT-BRAIN; PARTIAL AGONISTS; LIGANDS; BINDING; INHIBITION AB We report a class of potent and selective dopamine D-3 receptor antagonists based upon tranylcypromine. Although tranylcypromine has a low affinity for the rat D-3 receptor (K-i = 12.8 mu M), our efforts have yielded (1R,2S)-11 (CJ-1882), which has K-i values of 2.7 and 2.8 nM at the rat and human dopamine D-3 receptors, respectively, and displays respective selectivities of >10000-fold and 223-fold over the rat and human D-2 receptors. Evaluation in a beta-arrestin functional assay showed that (1R,2S)-11 is a potent and competitive antagonist at the human D-3 receptor. C1 [Chen, Jianyong; Jiang, Cheng; Wang, Shaomeng] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Chen, Jianyong; Jiang, Cheng; Wang, Shaomeng] Univ Michigan, Dept Pharmacol, Ann Arbor, MI 48109 USA. [Chen, Jianyong; Jiang, Cheng; Wang, Shaomeng] Univ Michigan, Dept Med Chem, Ann Arbor, MI 48109 USA. [Levant, Beth] Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, Kansas City, KS 66160 USA. [Keck, Thomas M.; Newman, Amy Hauck] NIDA, Med Chem Sect, Mol Targets & Medicat Discovery Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP Wang, SM (reprint author), Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. EM Shaomeng@umich.edu RI Keck, Thomas/G-9798-2012 OI Keck, Thomas/0000-0003-1845-9373 FU National Institute on Drug Abuse, National Institutes of Health [R01 DA032943]; NIDA-Intramural Research Program FX This work was supported by a grant from the National Institute on Drug Abuse, National Institutes of Health (R01 DA032943 to S.W.) and the NIDA-Intramural Research Program (A.H.N, T.M.K). We thank Dr. David R. Sibley at NINDS/NIH for providing HEK293 cells stably expressing human dopamine D2 and D3 receptors, Heather Spaulding at the University of Kansas Medical Center, and Catherine Schweppe and Caitlin Burzynski at NIDA/NIH for their technical assistance. NR 34 TC 20 Z9 20 U1 2 U2 12 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 JUN 12 PY 2014 VL 57 IS 11 BP 4962 EP 4968 DI 10.1021/jm401798r PG 7 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA AJ0JK UT WOS:000337336600040 PM 24848155 ER PT J AU Krzewski, K Bryceson, YT AF Krzewski, Konrad Bryceson, Yenan T. TI Molecular mechanisms regulating cytotoxic lymphocyte development and function, and their associations to human diseases SO FRONTIERS IN IMMUNOLOGY LA English DT Editorial Material DE cytotoxicity; lytic granules; secretory lysosomes; perforin; granzyme; immunological synapse; hemophagocytic histiocytosis; immune therapy C1 [Krzewski, Konrad] NIAID, Receptor Cell Biol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Bryceson, Yenan T.] Karolinska Univ Hosp Huddinge, Karolinska Inst, Dept Med, Ctr Infect Dis, Stockholm, Sweden. RP Krzewski, K (reprint author), NIAID, Receptor Cell Biol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM krzewskikj@niaid.nih.gov; yenan.bryceson@ki.se OI Bryceson, Yenan/0000-0002-7783-9934 NR 16 TC 1 Z9 1 U1 1 U2 1 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD JUN 11 PY 2014 VL 5 AR 279 DI 10.3389/fimmu.2014.00279 PG 2 WC Immunology SC Immunology GA CH8IP UT WOS:000354280200001 PM 24966858 ER PT J AU Gonzalez-Castillo, J Handwerker, DA Robinson, ME Hoy, CW Buchanan, LC Saad, ZS Bandettini, PA AF Gonzalez-Castillo, Javier Handwerker, Daniel A. Robinson, Meghan E. Hoy, Colin Weir Buchanan, Laura C. Saad, Ziad S. Bandettini, Peter A. TI The spatial structure of resting state connectivity stability on the scale of minutes SO FRONTIERS IN NEUROSCIENCE LA English DT Article DE fMRI; connectivity dynamics; stability; rest; sliding window analysis ID SPONTANEOUS BRAIN ACTIVITY; DEFAULT MODE NETWORK; INTRINSIC FUNCTIONAL CONNECTIVITY; FMRI CONNECTIVITY; CORPUS-CALLOSUM; MRI; ARCHITECTURE; CORTEX; ORGANIZATION; CONNECTOME AB Resting state functional M RI (rsfMRI) connectivity patterns are not temporally stable, but fluctuate in time at scales shorter than most common rest scan durations (5-10 min). Consequently, connectivity patterns for two different portions of the same scan can differ drastically. To better characterize this temporal variability and understand how it is spatially distributed across the brain, we scanned subjects continuously for 60 min, at a temporal resolution of 1 s, while they rested inside the scanner. We then computed connectivity matrices between functionally-defined regions of interest for non-overlapping 1 min windows, and classified connections according to their strength, polarity, and variability. We found that the most stable connections correspond primarily to inter-hemispheric connections between left/right homologous ROls. However, only 32% of all within-network connections were classified as most stable. This shows that resting state networks have some long-term stability, but confirms the flexible configuration of these networks, particularly those related to higher order cognitive functions. The most variable connections correspond primarily to inter-hemispheric, across-network connections between non-homologous regions in occipital and frontal cortex. Finally we found a series of connections with negative average correlation, but further analyses revealed that such average negative correlations may be related to the removal of CSF signals during pre-processing. Using the same dataset, we also evaluated how similarity of within-subject whole-brain connectivity matrices changes as a function of window duration (used here as a proxy for scan duration). Our results suggest scanning for a minimum of 10 min to optimize within-subject reproducibility of connectivity patterns across the entire brain, rather than a few predefined networks. C1 [Gonzalez-Castillo, Javier; Handwerker, Daniel A.; Robinson, Meghan E.; Hoy, Colin Weir; Buchanan, Laura C.; Bandettini, Peter A.] NIMH, Lab Brain & Cognit, Sect Funct Imaging Methods, NIH, Bethesda, MD 20892 USA. [Robinson, Meghan E.] VA Boston Healthcare Syst, Translat Res Ctr TBI & Stress Disorder TRACTS, Boston, MA USA. [Saad, Ziad S.] NIMH, Sci & Stat Comput Core, NIH, Bethesda, MD 20892 USA. RP Gonzalez-Castillo, J (reprint author), NIMH, Sect Funct Imaging Methods, NIH, Building 10,Room 1D80,10 Ctr Dr, Bethesda, MD 20892 USA. EM javier.gonzalez-castillo@nih.gov OI Gonzalez-Castillo, Javier/0000-0002-6520-5125 FU NIMHIRP FX This research was possible thanks to the support of the NIMHIRP. Portions of this study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf. nih.gov). Also, we would like to acknowledge Dr. Gang Chen from the Statistical and Scientific Computing Core for his valuable input. NR 57 TC 21 Z9 21 U1 0 U2 6 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-453X J9 FRONT NEUROSCI-SWITZ JI Front. Neurosci. PD JUN 11 PY 2014 VL 8 AR 138 DI 10.3389/fnins.2014.00138 PG 19 WC Neurosciences SC Neurosciences & Neurology GA AW8CM UT WOS:000346488200001 PM 24999315 ER PT J AU Karst, SM Wobus, CE Goodfellow, IG Green, KY Virgin, HW AF Karst, Stephanie M. Wobus, Christiane E. Goodfellow, Ian G. Green, Kim Y. Virgin, Herbert W. TI Advances in Norovirus Biology SO CELL HOST & MICROBE LA English DT Review ID INFECTIOUS NONBACTERIAL GASTROENTERITIS; BLOOD GROUP ANTIGENS; INTESTINAL EPITHELIAL-CELLS; NORWALK VIRUS-INFECTION; MURINE NOROVIRUS; IN-VIVO; IMMUNE-RESPONSES; RNA-POLYMERASE; MURINE-NOROVIRUS-1 INFECTION; VIRAL GASTROENTERITIS AB Human noroviruses are a major cause of epidemic and sporadic gastroenteritis worldwide and can chronically infect immunocompromised patients. Efforts to develop effective vaccines and antivirals have been hindered by the uncultivable nature and extreme genetic diversity of human noroviruses. Although they remain a particularly challenging pathogen to study, recent advances in norovirus animal models and in vitro cultivation systems have led to an increased understanding of norovirus molecular biology and replication, pathogenesis, cell tropism, and innate and adaptive immunity. Furthermore, clinical trials of vaccines consisting of nonreplicating virus-like particles have shown promise. In this review, we summarize these recent advances and discuss controversies in the field, which is rapidly progressing toward generation of antiviral agents and increasingly effective vaccines. C1 [Karst, Stephanie M.] Univ Florida, Emerging Pathogens Inst, Dept Mol Genet & Microbiol, Coll Med, Gainesville, FL 32610 USA. [Wobus, Christiane E.] Univ Michigan, Sch Med, Dept Microbiol & Immunol, Ann Arbor, MI 48109 USA. [Goodfellow, Ian G.] Addenbrookes Hosp, Dept Pathol, Div Virol, Cambridge CB2 2QQ, England. [Green, Kim Y.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Virgin, Herbert W.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. RP Virgin, HW (reprint author), Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. EM virgin@wustl.edu OI Goodfellow, Ian/0000-0002-9483-510X FU NIAID NIH HHS [R01 AI084887, R21 AI103961, R01 AI054483, U19 AI109725, R01 AI080611]; Wellcome Trust [097997] NR 123 TC 43 Z9 44 U1 6 U2 33 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 EI 1934-6069 J9 CELL HOST MICROBE JI Cell Host Microbe PD JUN 11 PY 2014 VL 15 IS 6 BP 668 EP 680 DI 10.1016/j.chom.2014.05.015 PG 13 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AM6BA UT WOS:000339944300006 PM 24922570 ER PT J AU Santana-Quintero, L Dingerdissen, H Thierry-Mieg, J Mazumder, R Simonyan, V AF Santana-Quintero, Luis Dingerdissen, Hayley Thierry-Mieg, Jean Mazumder, Raja Simonyan, Vahan TI HIVE-Hexagon: High-Performance, Parallelized Sequence Alignment for Next-Generation Sequencing Data Analysis SO PLOS ONE LA English DT Article ID GENOME; ALGORITHMS; PROTEINS; SEARCH; SITES; TOOL AB Due to the size of Next-Generation Sequencing data, the computational challenge of sequence alignment has been vast. Inexact alignments can take up to 90% of total CPU time in bioinformatics pipelines. High-performance Integrated Virtual Environment (HIVE), a cloud-based environment optimized for storage and analysis of extra-large data, presents an algorithmic solution: the HIVE-hexagon DNA sequence aligner. HIVE-hexagon implements novel approaches to exploit both characteristics of sequence space and CPU, RAM and Input/Output (I/O) architecture to quickly compute accurate alignments. Key components of HIVE-hexagon include non-redundification and sorting of sequences; floating diagonals of linearized dynamic programming matrices; and consideration of cross-similarity to minimize computations. C1 [Santana-Quintero, Luis; Dingerdissen, Hayley; Simonyan, Vahan] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. [Dingerdissen, Hayley; Mazumder, Raja] George Washington Univ, Med Ctr, Dept Biochem & Mol Biol, Washington, DC 20037 USA. [Thierry-Mieg, Jean] NIH, Natl Ctr Biotechnol Informat, US Natl Lib Med, Bethesda, MD 20892 USA. RP Mazumder, R (reprint author), George Washington Univ, Med Ctr, Dept Biochem & Mol Biol, Washington, DC 20037 USA. EM mazumder@gwu.edu; Vahan.Simonyan@fda.hhs.gov RI THIERRY-MIEG, Jean/F-1975-2017 OI THIERRY-MIEG, Jean/0000-0002-0396-6789 FU Food and Drug Administration Medical Countermeasures Initiative; Intramural Research Program of the NIH, National Library of Medicine FX This research was supported in part by the Food and Drug Administration Medical Countermeasures Initiative and in part by 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 35 TC 8 Z9 8 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 11 PY 2014 VL 9 IS 6 AR e99033 DI 10.1371/journal.pone.0099033 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK7TQ UT WOS:000338631000043 PM 24918764 ER PT J AU Graydon, CW Cho, S Diamond, JS Kachar, B von Gersdorff, H Grimes, WN AF Graydon, Cole W. Cho, Soyoun Diamond, Jeffrey S. Kachar, Bechara von Gersdorff, Henrique Grimes, William N. TI Specialized Postsynaptic Morphology Enhances Neurotransmitter Dilution and High-Frequency Signaling at an Auditory Synapse SO JOURNAL OF NEUROSCIENCE LA English DT Article DE auditory; diffusion; glutamate; hair cell; ribbon synapse; synapse ID CELL RIBBON SYNAPSE; AMPA RECEPTOR DESENSITIZATION; VESTIBULAR HAIR-CELLS; HIPPOCAMPAL SYNAPSES; TRANSMITTER RELEASE; GLUTAMATE DIFFUSION; ELECTRON-MICROSCOPY; CALCIUM-DEPENDENCE; AFFERENT SYNAPSES; BASILAR P