FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Bulashev, AK Borovikov, SN Serikova, SS Suranshiev, ZA Kiyan, VS Eskendirova, SZ AF Bulashev, Aitbay K. Borovikov, Sergey N. Serikova, Shynar S. Suranshiev, Zhanbolat A. Kiyan, Vladimir S. Eskendirova, Saule Z. TI Development of an ELISA using anti-idiotypic antibody for diagnosis of opisthorchiasis SO FOLIA PARASITOLOGICA LA English DT Article DE Opisthorchis felineus; excretory-secretory antigen; antigenicity; immunogenicity; monoclonal antibody; polyclonal antibody ID ENZYME-IMMUNOASSAY; VIVERRINI; INFECTIONS; RESPONSES; PROTEINS; FELINEUS; ANTIGENS; SYSTEM; CELLS; LIVER AB Monoclonal antibody specific for an epitope of cretory-secretory antigen protein of Opisthorchis felineus (Rivolta, 1884) (Trematoda: Opisthorchiidae) with a molecular weight of 28 kDa was used in a sandwich enzyme-linked immunosorbent assay (ELISA) for immobilisation of liver fluke specific antigen to the solid phase. Examination of human sera by this ELISA compared with commercial assays demonstrated that the monoclonal antibody epitope is located within this significant parasite protein. Anti-idiotypic antibody specific for the paratope of this monoclonal antibody was obtained by a hybridoma technique. Mimicking an epitope of excretory-secretory antigen of O. felineus, it had the capacity to bind specific antibody and elicit an antibody response. The value of anti-idiotypic antibody as a substitute for the liver fluke antigen was tested by ELISA using serum samples of infected dogs. Anti-idiotypic antibody proved to be of value in both an indirect-ELISA and a competitive-ELISA for diagnosis of opisthorchiasis. Mature trematodes were isolated from all infected animals. The faecal egg counts were negative in dogs with a relatively small number of parasites, despite finding antibodies in serum by ELISA. Substitution of parasite antigen with anti-idiotype avoids the use of experimental animals and also reduces time-consuming steps of antigen preparation. C1 [Bulashev, Aitbay K.; Borovikov, Sergey N.; Serikova, Shynar S.; Suranshiev, Zhanbolat A.; Kiyan, Vladimir S.] S Seifullin Kazakh Agrotech Univ, Fac Vet & Livestock Technol, Prospect Pobedy 62, Astana 010011, Kazakhstan. [Eskendirova, Saule Z.] Natl Ctr Biotechnol Republ Kazakhstan, Cell Engn Lab, Astana, Kazakhstan. RP Bulashev, AK (reprint author), S Seifullin Kazakh Agrotech Univ, Fac Vet & Livestock Technol, Prospect Pobedy 62, Astana 010011, Kazakhstan. EM aytbay57@mail.ru FU Ministry of Education and Science of the Republic of Kazakhstan [0109RK00476, 0112 RK01353] FX The authors are grateful to S.K. Atygaeva (Astana Infectious Diseases Hospital, Astana, Kazakhstan) who provided serum samples from patients suspected of contracting infectious diseases and Orken S. Akibekov, Lyudmila A. Lider (S. Seifullin Kazakh Agro-Technical University, Astana, Kazakhstan), Sadibek S. Tokpan (National Veterinary Laboratory, Astana, Kazakhstan) for their technical support to test fish for the presence of metacercariae and infect dogs. We are also indebted to Sara O. Kitaibekova for the revision of the manuscript. This investigation was financially supported by the Ministry of Education and Science of the Republic of Kazakhstan within the framework of the projects Nos. 0109RK00476 and 0112 RK01353 for 2009-2011 and 2012-2014, respectively. NR 36 TC 1 Z9 1 U1 8 U2 8 PU FOLIA PARASITOLOGICA PI CESKE BUDEJOVICE PA BRANISOVSKA 31,, CESKE BUDEJOVICE 370 05, CZECH REPUBLIC SN 0015-5683 EI 1803-6465 J9 FOLIA PARASIT JI Folia Parasitol. PD JUL 14 PY 2016 VL 63 AR 025 DI 10.14411/fp.2016.025 PG 8 WC Parasitology SC Parasitology GA DV0LJ UT WOS:000382608700001 ER PT J AU Courneya, KS McNeely, ML Culos-Reed, SN Vallance, JK Bell, GJ Mackey, JR Matthews, CE Morielli, AR Cook, D MacLaughlin, S Farris, MS Voaklander, S O'Reilly, R Friedenreich, CM AF Courneya, Kerry S. McNeely, Margaret L. Culos-Reed, S. Nicole Vallance, Jeff K. Bell, Gordon J. Mackey, John R. Matthews, Charles E. Morielli, Andria R. Cook, Diane MacLaughlin, Sarah Farris, Megan S. Voaklander, Stephanie O'Reilly, Rachel Friedenreich, Christine M. TI The Alberta Moving Beyond Breast Cancer (AMBER) Cohort Study: Recruitment, Baseline Assessment, and Description of the First 500 Participants SO BMC CANCER LA English DT Article DE Body composition; Breast cancer; Exercise; Health-related fitness; Lymphedema; Physical activity; Quality of life; Sedentary behavior; Survivorship ID PHYSICAL-ACTIVITY; UNITED-STATES; SURVIVORS; HEALTH; QUESTIONNAIRE; METAANALYSIS; VALIDITY; LIFE AB Background: To our knowledge, the Alberta Moving Beyond Breast Cancer (AMBER) Study is the first and only prospective cohort study of breast cancer survivors that includes objectively-measured physical activity (PA), sedentary behavior, health-related fitness (HRF), and biologic mechanisms focused on understanding breast cancer outcomes. The purpose of the present study was to report on the feasibility of recruitment, baseline measurement completion, and the representativeness of the first 500 participants. Methods: AMBER is enrolling newly diagnosed stage I (>= T1c) to IIIc breast cancer survivors in Alberta, Canada. Baseline assessments are completed soon after diagnosis and include cardiorespiratory fitness, musculoskeletal fitness, body composition, objective and self-reported PA and sedentary behavior, lymphedema, and blood collection. Results: Between July 2012 and November 2014, AMBER recruited its first 500 participants from a pool of 1,447 (35 %) eligible breast cancer survivors. Baseline HRF assessments were completed on >= 85 % of participants with the exception of upper body strength. Collection of >= 4 days/week of monitoring for the Actigraph GT3X (R) and ActivPAL (R) were obtained from 90 % of participants. Completion rates were also high for blood (99 %), lymphedema (98 %), and questionnaires (95 %) including patient-reported outcomes and correlates of exercise. The first 500 participants in AMBER are an average age of 56 years, 60 % are overweight or obese, and 58 % have disease stage II or III. Conclusion: Despite the modest recruitment rate and younger age, AMBER has demonstrated that many newly diagnosed breast cancer survivors are willing and able to complete a wide array of sophisticated and physically demanding HRF and PA assessments soon after diagnosis. AMBER is a unique breast cancer survivor cohort that may inform future randomized controlled trials on lifestyle and breast cancer outcomes as well as PA behavior change in breast cancer survivors. Moreover, AMBER may also inform guidelines on PA, sedentary behavior, and HRF for improving breast cancer outcomes and survivorship. C1 [Courneya, Kerry S.; Bell, Gordon J.; Morielli, Andria R.; Cook, Diane; Voaklander, Stephanie] Univ Alberta, Fac Phys Educ & Recreat, 1-113 Univ Hall, Edmonton, AB T6G 2H9, Canada. [McNeely, Margaret L.] Univ Alberta, Fac Rehabil Med, Edmonton, AB, Canada. [Culos-Reed, S. Nicole] Univ Calgary, Fac Kinesiol, Calgary, AB, Canada. [Vallance, Jeff K.] Athabasca Univ, Fac Hlth Disciplines, Athabasca, AB, Canada. [Mackey, John R.] Univ Alberta, Fac Med & Dent, Edmonton, AB, Canada. [Matthews, Charles E.] US Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD USA. [MacLaughlin, Sarah; Farris, Megan S.; O'Reilly, Rachel; Friedenreich, Christine M.] Alberta Hlth Serv, Dept Canc Epidemiol & Prevent Res, Calgary, AB, Canada. RP Courneya, KS (reprint author), Univ Alberta, Fac Phys Educ & Recreat, 1-113 Univ Hall, Edmonton, AB T6G 2H9, Canada. EM Kerry.courneya@ualberta.ca FU Canadian Institutes of Health Research; Canada Research Chairs Program; Alberta Innovates-Health Solutions Population Health Investigator Award; AIHS Health Senior Scholar Award; Alberta Cancer Foundation FX This study is funded by a Team Grant from the Canadian Institutes of Health Research. KSC and JKV are supported by the Canada Research Chairs Program. JKV is also supported by an Alberta Innovates-Health Solutions Population Health Investigator Award. CMF is supported by an AIHS Health Senior Scholar Award and by the Alberta Cancer Foundation Weekend to End Women's Cancers Breast Cancer Chair. NR 17 TC 1 Z9 1 U1 5 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD JUL 14 PY 2016 VL 16 AR 481 DI 10.1186/s12885-016-2534-4 PG 9 WC Oncology SC Oncology GA DR7PQ UT WOS:000380092600001 PM 27416835 ER PT J AU Vandenberg, LN Agerstrand, M Beronius, A Beausoleil, C Bergman, A Bero, LA Bornehag, CG Boyer, CS Cooper, GS Cotgreave, I Gee, D Grandjean, P Guyton, KZ Hass, U Heindel, JJ Jobling, S Kidd, KA Kortenkamp, A Macleod, MR Martin, OV Norinder, U Scheringer, M Thayer, KA Toppari, J Whaley, P Woodruff, TJ Ruden, C AF Vandenberg, Laura N. Agerstrand, Marlene Beronius, Anna Beausoleil, Claire Bergman, Ake Bero, Lisa A. Bornehag, Carl-Gustaf Boyer, C. Scott Cooper, Glinda S. Cotgreave, Ian Gee, David Grandjean, Philippe Guyton, Kathryn Z. Hass, Ulla Heindel, Jerrold J. Jobling, Susan Kidd, Karen A. Kortenkamp, Andreas Macleod, Malcolm R. Martin, Olwenn V. Norinder, Ulf Scheringer, Martin Thayer, Kristina A. Toppari, Jorma Whaley, Paul Woodruff, Tracey J. Ruden, Christina TI A proposed framework for the systematic review and integrated assessment (SYRINA) of endocrine disrupting chemicals SO ENVIRONMENTAL HEALTH LA English DT Article DE Endocrine disrupting chemicals; Systematic review; Study evaluation; Strength of evidence; Weight of evidence; Adverse effect; Endocrine disrupting activity; Evidence integration; Epidemiology; In vivo ID EVIDENCE-BASED MEDICINE; ENVIRONMENTAL-HEALTH SCIENCE; RISK-ASSESSMENT; PUBLIC-HEALTH; FETAL-GROWTH; DEVELOPMENTAL ORIGINS; SCIENTIFIC STATEMENT; EVALUATION CRITERIA; DISEASE; GUIDE AB Background: The issue of endocrine disrupting chemicals (EDCs) is receiving wide attention from both the scientific and regulatory communities. Recent analyses of the EDC literature have been criticized for failing to use transparent and objective approaches to draw conclusions about the strength of evidence linking EDC exposures to adverse health or environmental outcomes. Systematic review methodologies are ideal for addressing this issue as they provide transparent and consistent approaches to study selection and evaluation. Objective methods are needed for integrating the multiple streams of evidence (epidemiology, wildlife, laboratory animal, in vitro, and in silico data) that are relevant in assessing EDCs. Methods: We have developed a framework for the systematic review and integrated assessment (SYRINA) of EDC studies. The framework was designed for use with the International Program on Chemical Safety (IPCS) and World Health Organization (WHO) definition of an EDC, which requires appraisal of evidence regarding 1) association between exposure and an adverse effect, 2) association between exposure and endocrine disrupting activity, and 3) a plausible link between the adverse effect and the endocrine disrupting activity. Results: Building from existing methodologies for evaluating and synthesizing evidence, the SYRINA framework includes seven steps: 1) Formulate the problem; 2) Develop the review protocol; 3) Identify relevant evidence; 4) Evaluate evidence from individual studies; 5) Summarize and evaluate each stream of evidence; 6) Integrate evidence across all streams; 7) Draw conclusions, make recommendations, and evaluate uncertainties. The proposed method is tailored to the IPCS/WHO definition of an EDC but offers flexibility for use in the context of other definitions of EDCs. Conclusions: When using the SYRINA framework, the overall objective is to provide the evidence base needed to support decision making, including any action to avoid/minimise potential adverse effects of exposures. This framework allows for the evaluation and synthesis of evidence from multiple evidence streams. Finally, a decision regarding regulatory action is not only dependent on the strength of evidence, but also the consequences of action/inaction, e.g. limited or weak evidence may be sufficient to justify action if consequences are serious or irreversible. C1 [Agerstrand, Marlene; Bergman, Ake; Ruden, Christina] Stockholm Univ, Dept Environm Sci & Analyt Chem, Stockholm, Sweden. [Vandenberg, Laura N.] Univ Massachusetts, Amherst Sch Publ Hlth & Hlth Sci, Dept Environm Hlth Sci, Amherst, MA USA. [Beronius, Anna] Karolinska Inst, Inst Environm Med, Stockholm, Sweden. [Beausoleil, Claire] ANSES French Agcy Food Environm & Occupat Hlth Sa, Maisons Alfort, France. [Bergman, Ake; Boyer, C. Scott; Norinder, Ulf] Swedish Toxicol Sci Res Ctr, Sodertalje, Sweden. [Bero, Lisa A.] Univ Sydney, Charles Perkins Ctr, Sydney, NSW, Australia. [Bornehag, Carl-Gustaf] Karlstad Univ, Dept Hlth Sci, Karlstad, Sweden. [Bornehag, Carl-Gustaf] Icahn Sch Med Mt Sinai, New York, NY USA. [Cooper, Glinda S.] US EPA, Washington, DC USA. [Cotgreave, Ian] Karolinska Inst, Swedish Toxicol Sci Res Ctr Swetox, Sodertalje, Sweden. [Gee, David; Jobling, Susan; Kortenkamp, Andreas; Martin, Olwenn V.] Brunel Univ London, Inst Environm Hlth & Societies, Uxbridge, Middx, England. [Grandjean, Philippe] Univ Southern Denmark, Dept Environm Med, Odense, Denmark. Int Agcy Res Canc, Lyon, France. Tech Univ Denmark, Natl Food Inst, Soborg, Denmark. [Heindel, Jerrold J.] Natl Inst Environm Hlth Sci, Div Extramural Res & Training, Res Triangle Pk, NC USA. [Kidd, Karen A.] Univ New Brunswick, Dept Biol, St John, NB, Canada. [Kidd, Karen A.] Univ New Brunswick, Canadian Rivers Inst, St John, NB, Canada. [Macleod, Malcolm R.] Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland. [Scheringer, Martin] ETH, Inst Chem & Bioengn, Zurich, Switzerland. [Thayer, Kristina A.] Natl Inst Environm Hlth Sci, Dept Hlth & Human Serv, Div Natl Toxicol Program, NIH, Res Triangle Pk, NC USA. [Toppari, Jorma] Univ Turku, Turku Univ Hosp, Turku, Finland. [Whaley, Paul] Univ Lancaster, Lancaster Environm Ctr, Lancaster, England. [Woodruff, Tracey J.] Univ Calif San Francisco, Sch Med, Program Reprod Hlth & Environm, Oakland, CA USA. RP Ruden, C (reprint author), Stockholm Univ, Dept Environm Sci & Analyt Chem, Stockholm, Sweden. EM christina.ruden@aces.su.se RI jobling, susan/N-9316-2016; OI Whaley, Paul/0000-0003-4021-0785; Macleod, Malcolm Robert/0000-0001-9187-9839; Grandjean, Philippe/0000-0003-4046-9658 FU Swedish Foundation for Strategic Environmental Research "Mistra"; National Institute of Environmental Health Sciences of the National Institutes of Health [K22ES025811]; Clarence Heller Foundation [A123547]; Passport Foundation; Forsythia Foundation; National Institute of Environmental Health Sciences [ES018135, ESO22841]; U.S. EPA STAR grants [RD83467801, RD83543301]; Academy of Finland; Sigrid Juselius; Danish EPA; Canada Research Chairs program [950-230607] FX The workshops that supported the writing of this manuscript were funded by the Swedish Foundation for Strategic Environmental Research "Mistra". LNV was funded by Award Number K22ES025811 from the National Institute of Environmental Health Sciences of the National Institutes of Health. TJW was funded by The Clarence Heller Foundation (A123547), the Passport Foundation, the Forsythia Foundation, the National Institute of Environmental Health Sciences (grants ES018135 and ESO22841), and U.S. EPA STAR grants (RD83467801 and RD83543301). JT was funded by the Academy of Finland and Sigrid Juselius. UH was funded by the Danish EPA. KAK was funded by the Canada Research Chairs program grant number 950-230607. NR 96 TC 1 Z9 1 U1 10 U2 27 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-069X J9 ENVIRON HEALTH-GLOB JI Environ. Health PD JUL 14 PY 2016 VL 15 AR 74 DI 10.1186/s12940-016-0156-6 PG 19 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA DR6EG UT WOS:000379994300001 PM 27412149 ER PT J AU Junker, A Balasubramanian, R Ciancetta, A Uliassi, E Kiselev, E Martiriggiano, C Trujillo, K Mtchedlidze, G Birdwell, L Brown, KA Harden, TK Jacobson, KA AF Junker, Anna Balasubramanian, Ramachandran Ciancetta, Antonella Uliassi, Elisa Kiselev, Evgeny Martiriggiano, Chiara Trujillo, Kevin Mtchedlidze, Giorgi Birdwell, Leah Brown, Kyle A. Harden, T. Kendall Jacobson, Kenneth A. TI Structure-Based Design of 3-(4-Aryl-1H-1,2,3-triazol-1-yl)-Biphenyl Derivatives as P2Y(14) Receptor Antagonists SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID GENERAL FORCE-FIELD; MOLECULAR-DYNAMICS; HUMAN NEUTROPHILS; CHEMOTAXIS; INHIBITION; AUTOMATION; CHEMISTRY; TEMPLATE; LIGANDS; ESTERS AB UDP and UDP-glucose activate the P2Y(14) receptor (P2Y(14)R) to modulate processes related to inflammation, diabetes, and asthma. A computational pipeline suggested alternatives to naphthalene of a previously reported P2Y14R antagonist (3, PPTN) using docking and molecular dynamics simulations on a hP2Y(14)R homology model based on P2Y(12)R structures. By reevaluating the binding of 3 to P2Y(14)R computationally, two alternatives, i.e., alkynyl and triazolyl derivatives, were identified. Improved synthesis of fluorescent antagonist 4 enabled affinity quantification (IC(50)s, nM) using flow cytometry of P2Y(14)R-expressing CHO cells. p-F3C-phenyl-triazole 65 (32) was more potent than a corresponding alkyne 11. Thus, additional triazolyl derivatives were prepared, as guided by docking simulations, with nonpolar aryl substituents favored. Although triazoles were less potent than 3 (6), simpler synthesis facilitated further structural optimization. Additionally, relative P2Y(14)R affinities agreed with predicted binding of alkynyl and triazole analogues. These triazoles, designed through a structure-based approach, can be assessed in disease models. C1 [Junker, Anna; Balasubramanian, Ramachandran; Ciancetta, Antonella; Uliassi, Elisa; Kiselev, Evgeny; Martiriggiano, Chiara; Trujillo, Kevin; Mtchedlidze, Giorgi; Birdwell, Leah; Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Brown, Kyle A.; Harden, T. Kendall] Univ N Carolina, Dept Pharmacol, Sch Med, Chapel Hill, NC 27599 USA. RP Jacobson, KA (reprint author), NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM kennethj@niddk.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU NIDDK Intramural Research Program [ZIA DK031116-28]; Deutsche Forschungsgemeinschaft (German Research Foundation); National Institute of Mental Health's Psychoactive Drug Screening Program [HHSN-271-2008-00025-C] FX We acknowledge support from the NIDDK Intramural Research Program (ZIA DK031116-28) and technical assistance of Ryan Surujdin and Jinha Yu (NIDDK). Financial support of Anna Junker by the Deutsche Forschungsgemeinschaft (German Research Foundation) is gratefully acknowledged. We thank Bryan L. Roth (University of North Carolina at Chapel Hill) and National Institute of Mental Health's Psychoactive Drug Screening Program (contract no. HHSN-271-2008-00025-C) for screening data. We thank Rolf Swenson and Zhen-Dan Shi (Imaging Probe Development Center, NHLBI) for reagents 115 and 116. NR 46 TC 0 Z9 0 U1 5 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 JUL 14 PY 2016 VL 59 IS 13 BP 6149 EP 6168 DI 10.1021/acs.jmedchem.6b00044 PG 20 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA DR6CN UT WOS:000379989800014 PM 27331270 ER PT J AU Ashinsky, BG Fishbein, KW Carter, EM Lin, PC Pleshko, N Raggio, CL Spencer, RG AF Ashinsky, Beth G. Fishbein, Kenneth W. Carter, Erin M. Lin, Ping-Chang Pleshko, Nancy Raggio, Cathleen L. Spencer, Richard G. TI Multiparametric Classification of Skin from Osteogenesis Imperfecta Patients and Controls by Quantitative Magnetic Resonance Microimaging SO PLOS ONE LA English DT Article ID COLLAGEN MUTATION DATABASE; CONNECTIVE-TISSUE; RELAXATION-TIMES; CARTILAGE; MRI; AGE; DISEASE; TESLA; T2 AB The purpose of this study is to evaluate the ability of quantitative magnetic resonance imaging (MRI) to discriminate between skin biopsies from individuals with osteogenesis imperfecta (OI) and skin biopsies from individuals without OI. Skin biopsies from nine controls (unaffected) and nine OI patients were imaged to generate maps of five separate MR parameters, T-1, T-2, k(m), MTR and ADC. Parameter values were calculated over the dermal region and used for univariate and multiparametric classification analysis. A substantial degree of overlap of individual MR parameters was observed between control and OI groups, which limited the sensitivity and specificity of univariate classification. Classification accuracies ranging between 39% and 67% were found depending on the variable of investigation, with T-2 yielding the best accuracy of 67%. When several MR parameters were considered simultaneously in a multivariate analysis, the classification accuracies improved up to 89% for specific combinations, including the combination of T-2 and k(m). These results indicate that multiparametric classification by quantitative MRI is able to detect differences between the skin of OI patients and of unaffected individuals, which motivates further study of quantitative MRI for the clinical diagnosis of OI. C1 [Ashinsky, Beth G.; Fishbein, Kenneth W.; Spencer, Richard G.] NIA, Lab Clin Invest, Magnet Resonance Imaging & Spect Sect, NIH, Baltimore, MD 21224 USA. [Carter, Erin M.; Raggio, Cathleen L.] Hosp Special Surg, Kathryn O & Alan C Greenberg Ctr Skeletal Dysplas, 535 E 70th St, New York, NY 10021 USA. [Lin, Ping-Chang] Augusta Univ, GRU Canc Ctr, Core Imaging Facil Small Anim, Augusta, GA USA. [Pleshko, Nancy] Temple Univ, Coll Engn, Dept Bioengn, Philadelphia, PA 19122 USA. [Raggio, Cathleen L.] Hosp Special Surg, Dept Orthopaed, 535 E 70th St, New York, NY 10021 USA. RP Spencer, RG (reprint author), NIA, Lab Clin Invest, Magnet Resonance Imaging & Spect Sect, NIH, Baltimore, MD 21224 USA. EM spencer@helix.nih.gov OI Fishbein, Kenneth/0000-0002-6353-4603 FU Pediatric Society of North America; National Institute on Aging, National Institutes of Health, Intramural Research Program FX This work was supported by a Pediatric Society of North America (https://posna.org/) Grant to CLR, "Identification of Skin Abnormalities in OI Patients by MR Imaging" and the National Institute on Aging, National Institutes of Health, Intramural Research Program (RGS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 0 Z9 0 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 14 PY 2016 VL 11 IS 7 AR e0157891 DI 10.1371/journal.pone.0157891 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR0DZ UT WOS:000379579500014 PM 27416032 ER PT J AU De Vries, RG Tomlinson, T Kim, HM Krenz, C Haggerty, D Ryan, KA Kim, SYH AF De Vries, Raymond Gene Tomlinson, Tom Kim, Hyungjin Myra Krenz, Chris Haggerty, Diana Ryan, Kerry A. Kim, Scott Y. H. TI Understanding the Public's Reservations about Broad Consent and Study-By-Study Consent for Donations to a Biobank: Results of a National Survey SO PLOS ONE LA English DT Article ID INFORMED-CONSENT; WILLINGNESS; CANCER; RISK AB Researchers and policymakers do not agree about the most appropriate way to get consent for the use of donations to a biobank. The most commonly used method is blanket-or broad-consent where donors allow their donation to be used for any future research approved by the biobank. This approach does not account for the fact that some donors may have moral concerns about the uses of their biospecimens. This problem can be avoided using "real-time"-or study-by-study-consent, but this policy places a significant burden on biobanks. In order to better understand the public's preferences regarding biobank consent policy, we surveyed a sample that was representative of the population of the United States. Respondents were presented with 5 biobank consent policies and were asked to indicate which policies were acceptable/unacceptable and to identify the best/worst policies. They were also given 7 research scenarios that could create moral concern (e.g. research intending to make abortions safer and more effective) and asked how likely they would be to provide broad consent knowing that their donation might be used in that research. Substantial minorities found both broad and study-by-study consent to be unacceptable and identified those two options as the worst policies. Furthermore, while the type of moral concern (e.g., regarding abortion, the commercial use of donations, or stem cell research) had no effect on policy preferences, an increase in the number of research scenarios generating moral concerns was related to an increased likelihood of finding broad consent to be the worst policy. The rejection of these ethically problematic and costly extremes is good news for biobanks. The challenge now is to design a policy that combines consent with access to information in a way that assures potential donors that their interests and moral concerns are being respected. C1 [De Vries, Raymond Gene; Krenz, Chris; Ryan, Kerry A.] Univ Michigan, Ctr Bioeth & Social Sci Med, Ann Arbor, MI 48109 USA. [Tomlinson, Tom] Michigan State Univ, Ctr Eth & Humanities Life Sci, E Lansing, MI 48824 USA. [Kim, Hyungjin Myra] Univ Michigan, Ctr Stat Consultat & Res, Ann Arbor, MI 48109 USA. [Haggerty, Diana] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Kim, Scott Y. H.] NIH, Ctr Clin, Dept Bioeth, Bldg 10, Bethesda, MD 20892 USA. [Kim, Scott Y. H.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. RP De Vries, RG (reprint author), Univ Michigan, Ctr Bioeth & Social Sci Med, Ann Arbor, MI 48109 USA. EM rdevries@med.umich.edu OI Krenz, Chris/0000-0002-0514-4586; De Vries, Raymond/0000-0003-3087-3040 FU National Human Genome Research Institute (NHGRI) [5R01HG007172] FX This research was funded by the National Human Genome Research Institute (NHGRI), grant number 5R01HG007172. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 0 Z9 0 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 14 PY 2016 VL 11 IS 7 AR e0159113 DI 10.1371/journal.pone.0159113 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR0DZ UT WOS:000379579500079 PM 27415017 ER PT J AU Wang, TY Santos, JH Feng, J Fargo, DC Shen, L Riadi, G Keeley, E Rosh, ZS Nestler, EJ Woychik, RP AF Wang, Tianyuan Santos, Janine H. Feng, Jian Fargo, David C. Shen, Li Riadi, Gonzalo Keeley, Elizabeth Rosh, Zachary S. Nestler, Eric J. Woychik, Richard P. TI A Novel Analytical Strategy to Identify Fusion Transcripts between Repetitive Elements and Protein Coding-Exons Using RNA-Seq SO PLOS ONE LA English DT Article ID TRANSPOSABLE ELEMENTS; NUCLEUS-ACCUMBENS; GENE-EXPRESSION; CELLS; METHYLATION; ISOFORM; TOPHAT; BRAIN AB Repetitive elements (REs) comprise 40-60% of the mammalian genome and have been shown to epigenetically influence the expression of genes through the formation of fusion transcript (FTs). We previously showed that an intracisternal A particle forms an FT with the agouti gene in mice, causing obesity/type 2 diabetes. To determine the frequency of FTs genome-wide, we developed a TopHat-Fusion-based analytical pipeline to identify FTs with high specificity. We applied it to an RNA-seq dataset from the nucleus accumbens (NAc) of mice repeatedly exposed to cocaine. Cocaine was previously shown to increase the expression of certain REs in this brain region. Using this pipeline that can be applied to single- or paired-end reads, we identified 438 genes expressing 813 different FTs in the NAc. Although all types of studied repeats were present in FTs, simple sequence repeats were underrepresented. Most importantly, reverse-transcription and quantitative PCR validated the expression of selected FTs in an independent cohort of animals, which also revealed that some FTs are the prominent isoforms expressed in the NAc by some genes. In other RNA-seq datasets, developmental expression as well as tissue specificity of some FTs differed from their corresponding non-fusion counterparts. Finally, in silico analysis predicted changes in the structure of proteins encoded by some FTs, potentially resulting in gain or loss of function. Collectively, these results indicate the robustness of our pipeline in detecting these new isoforms of genes, which we believe provides a valuable tool to aid in better understanding the broad role of REs in mammalian cellular biology. C1 [Wang, Tianyuan; Santos, Janine H.; Fargo, David C.; Woychik, Richard P.] NIEHS, 111 TW Alexander Dr,Bldg 101, Res Triangle Pk, NC 27709 USA. [Feng, Jian; Shen, Li; Keeley, Elizabeth; Rosh, Zachary S.; Nestler, Eric J.] Icahn Sch Med Mt Sinai, Fishberg Dept Neurosci, One Gustave L Levy Pl,Box 1065, New York, NY 10029 USA. [Feng, Jian; Shen, Li; Keeley, Elizabeth; Rosh, Zachary S.; Nestler, Eric J.] Icahn Sch Med Mt Sinai, Friedman Brain Inst, One Gustave L Levy Pl,Box 1065, New York, NY 10029 USA. [Riadi, Gonzalo] Univ Talca, Fac Ingn, Dept Bioinformat, CBSM, Av 2 Norte 685, Talca 3465548, Chile. RP Woychik, RP (reprint author), NIEHS, 111 TW Alexander Dr,Bldg 101, Res Triangle Pk, NC 27709 USA.; Nestler, EJ (reprint author), Icahn Sch Med Mt Sinai, Fishberg Dept Neurosci, One Gustave L Levy Pl,Box 1065, New York, NY 10029 USA.; Nestler, EJ (reprint author), Icahn Sch Med Mt Sinai, Friedman Brain Inst, One Gustave L Levy Pl,Box 1065, New York, NY 10029 USA. EM eric.nestler@mssm.edu; rick.woychik@nih.gov FU Intramural Research Program of the NIH; [P01DA008227]; [Fondecyt 11140869] FX This research was supported by the Intramural Research Program of the NIH (RPW) and by grants P01DA008227 (EJN) and Fondecyt 11140869 (GR). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 1 Z9 1 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 14 PY 2016 VL 11 IS 7 AR e0159028 DI 10.1371/journal.pone.0159028 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR0DZ UT WOS:000379579500059 PM 27415830 ER PT J AU Davids, MS Kim, HT Bachireddy, P Costello, C Liguori, R Savell, A Lukez, AP Avigan, D Chen, YB McSweeney, P LeBoeuf, NR Rooney, MS Bowden, M Zhou, CSW Granter, SR Hornick, JL Rodig, SJ Hirakawa, M Severgnini, M Hodi, FS Wu, CJ Ho, VT Cutler, C Koreth, J Alyea, EP Antin, JH Armand, P Streicher, H Ball, ED Ritz, J Bashey, A Soiffer, RJ AF Davids, Matthew S. Kim, Haesook T. Bachireddy, Pavan Costello, Caitlin Liguori, Rebecca Savell, Alexandra Lukez, Alexander P. Avigan, David Chen, Yi-Bin McSweeney, Peter LeBoeuf, Nicole R. Rooney, Michael S. Bowden, Michaela Zhou, Chensheng W. Granter, Scott R. Hornick, Jason L. Rodig, Scott J. Hirakawa, Masahiro Severgnini, Mariano Hodi, F. Stephen Wu, Catherine J. Ho, Vincent T. Cutler, Corey Koreth, John Alyea, Edwin P. Antin, Joseph H. Armand, Philippe Streicher, Howard Ball, Edward D. Ritz, Jerome Bashey, Asad Soiffer, Robert J. CA Leukemia Lymphoma Soc Blood Canc R TI Ipilimumab for Patients with Relapse after Allogeneic Transplantation SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID STEM-CELL TRANSPLANTATION; ACUTE MYELOID-LEUKEMIA; VERSUS-HOST-DISEASE; HEMATOLOGIC MALIGNANCIES; T-CELLS; BLOCKADE; CTLA-4; PATTERN; HLA AB BACKGROUND Loss of donor-mediated immune antitumor activity after allogeneic hematopoietic stem-cell transplantation (HSCT) permits relapse of hematologic cancers. We hypothesized that immune checkpoint blockade established by targeting cytotoxic T-lymphocyte-associated protein 4 with ipilimumab could restore antitumor reactivity through a graft-versus-tumor effect. METHODS We conducted a phase 1/1b multicenter, investigator-initiated study to determine the safety and efficacy of ipilimumab in patients with relapsed hematologic cancer after allogeneic HSCT. Patients received induction therapy with ipilimumab at a dose of 3 or 10 mg per kilogram of body weight every 3 weeks for a total of 4 doses, with additional doses every 12 weeks for up to 60 weeks in patients who had a clinical benefit. RESULTS A total of 28 patients were enrolled. Immune-related adverse events, including one death, were observed in 6 patients (21%), and graft-versus-host disease (GVHD) that precluded further administration of ipilimumab was observed in 4 patients (14%). No responses that met formal response criteria occurred in patients who received a dose of 3 mg per kilogram. Among 22 patients who received a dose of 10 mg per kilogram, 5 (23%) had a complete response, 2 (9%) had a partial response, and 6 (27%) had decreased tumor burden. Complete responses occurred in 4 patients with extramedullary acute myeloid leukemia and 1 patient with the myelodysplastic syndrome developing into acute myeloid leukemia. Four patients had a durable response for more than 1 year. Responses were associated with in situ infiltration of cytotoxic CD8+ T cells, decreased activation of regulatory T cells, and expansion of subpopulations of effector T cells in the blood. CONCLUSIONS Our early-phase data showed that administration of ipilimumab was feasible in patients with recurrent hematologic cancers after allogeneic HSCT, although immune-mediated toxic effects and GVHD occurred. Durable responses were observed in association with several histologic subtypes of these cancers, including extramedullary acute myeloid leukemia. C1 [Davids, Matthew S.; Kim, Haesook T.; Bachireddy, Pavan; Liguori, Rebecca; Savell, Alexandra; Lukez, Alexander P.; Hirakawa, Masahiro; Severgnini, Mariano; Hodi, F. Stephen; Wu, Catherine J.; Ho, Vincent T.; Cutler, Corey; Koreth, John; Alyea, Edwin P.; Antin, Joseph H.; Armand, Philippe; Ritz, Jerome; Soiffer, Robert J.] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02115 USA. [Davids, Matthew S.; Kim, Haesook T.; Bachireddy, Pavan; Liguori, Rebecca; Savell, Alexandra; Lukez, Alexander P.; Avigan, David; Chen, Yi-Bin; Hirakawa, Masahiro; Severgnini, Mariano; Hodi, F. Stephen; Wu, Catherine J.; Ho, Vincent T.; Cutler, Corey; Koreth, John; Alyea, Edwin P.; Antin, Joseph H.; Armand, Philippe; Ritz, Jerome; Soiffer, Robert J.] Harvard Med Sch, Boston, MA USA. [Avigan, David] Beth Israel Deaconess Med Ctr, Bone Marrow Transplant Program, Boston, MA 02215 USA. [Chen, Yi-Bin] Massachusetts Gen Hosp, Ctr Canc, Bone Marrow Transplant Program, Boston, MA USA. [LeBoeuf, Nicole R.] Dana Farber & Brigham & Womens Canc Ctr, Dept Dermatol, Boston, MA USA. [Granter, Scott R.; Hornick, Jason L.; Rodig, Scott J.] Dana Farber & Brigham & Womens Canc Ctr, Dept Pathol, Boston, MA USA. [Bowden, Michaela; Zhou, Chensheng W.] Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02115 USA. [Bachireddy, Pavan; Wu, Catherine J.] Broad Inst Massachusetts Inst Technol & Harvard, Cambridge, MA USA. [Rooney, Michael S.] Neon Therapeut, Cambridge, MA USA. [Costello, Caitlin; Ball, Edward D.] Univ Calif San Diego, Blood & Marrow Transplant Program, Moores Canc Ctr, La Jolla, CA 92093 USA. [McSweeney, Peter] Colorado Blood Canc Inst, Denver, CO USA. [Streicher, Howard] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Bashey, Asad] Northside Hosp, Blood & Marrow Transplant Grp Georgia, Atlanta, GA USA. RP Davids, MS (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02115 USA. EM matthew_davids@dfci.harvard.edu FU National Institutes of Health FX Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01822509. NR 22 TC 17 Z9 17 U1 3 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 JUL 14 PY 2016 VL 375 IS 2 BP 143 EP 153 DI 10.1056/NEJMoa1601202 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA DQ9KY UT WOS:000379530000007 PM 27410923 ER PT J AU Panackal, AA Marr, KA Williamson, PR AF Panackal, Anil A. Marr, Kieren A. Williamson, Peter R. TI Dexamethasone in Cryptococcal Meningitis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID GATTII C1 [Panackal, Anil A.; Williamson, Peter R.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Marr, Kieren A.] Johns Hopkins Med, Baltimore, MD USA. RP Panackal, AA (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM anil.panackal@nih.gov NR 4 TC 0 Z9 0 U1 0 U2 1 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 JUL 14 PY 2016 VL 375 IS 2 BP 188 EP 188 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA DQ9KY UT WOS:000379530000022 PM 27410935 ER PT J AU Perkins, TA Paz-Soldan, VA Stoddard, ST Morrison, AC Forshey, BM Long, KC Halsey, ES Kochel, TJ Elder, JP Kitron, U Scott, TW Vazquez-Prokopec, GM AF Perkins, T. Alex Paz-Soldan, Valerie A. Stoddard, Steven T. Morrison, Amy C. Forshey, Brett M. Long, Kanya C. Halsey, Eric S. Kochel, Tadeusz J. Elder, John P. Kitron, Uriel Scott, Thomas W. Vazquez-Prokopec, Gonzalo M. TI Calling in sick: impacts of fever on infra-urban human mobility SO PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE activity space; contact; dengue; infection; movement; network ID DENGUE VIRUS TRANSMISSION; HUMAN MOVEMENT; HUMAN-BEHAVIOR; INFECTIONS; IQUITOS; PERU; HYPOTHESIS; INFLUENZA; PATTERNS; MALARIA AB Pathogens inflict a wide variety of disease manifestations on their hosts, yet the impacts of disease on the behaviour of infected hosts are rarely studied empirically and are seldom accounted for in mathematical models of transmission dynamics. We explored the potential impacts of one of the most common disease manifestations, fever, on a key determinant of pathogen transmission, host mobility, in residents of the Amazonian city of Iquitos, Peru. We did so by comparing two groups of febrile individuals (dengue positive and dengue-negative) with an afebrile control group. A retrospective, semi-structured interview allowed us to quantify multiple aspects of mobility during the two-week period preceding each interview. We fitted nested models of each aspect of mobility to data from interviews and compared models using likelihood ratio tests to determine whether there were statistically distinguishable differences in mobility attributable to fever or its aetiology. Compared with afebrile individuals, febrile study participants spent more time at home, visited fewer locations, and, in some cases, visited locations closer to home and spent less time at certain types of locations. These multifaceted impacts are consistent with the possibility that disease mediated changes in host mobility generate dynamic and complex changes in host contact network structure. C1 [Perkins, T. Alex] Univ Notre Dame, Dept Biol Sci, Notre Dame, IN 46556 USA. [Perkins, T. Alex] Univ Notre Dame, Eck Inst Global Hlth, Notre Dame, IN 46556 USA. [Perkins, T. Alex; Stoddard, Steven T.; Morrison, Amy C.; Long, Kanya C.; Scott, Thomas W.] Univ Calif Davis, Dept Entomol & Nematol, Davis, CA 95616 USA. [Perkins, T. Alex; Kitron, Uriel; Scott, Thomas W.; Vazquez-Prokopec, Gonzalo M.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Paz-Soldan, Valerie A.] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Global Hlth Syst & Dev, New Orleans, LA USA. [Paz-Soldan, Valerie A.] Univ Peruana Cayetano Heredia, Fac Salud Publ & Adm, Lima, Peru. [Morrison, Amy C.; Forshey, Brett M.; Halsey, Eric S.; Kochel, Tadeusz J.] US Naval Med Res Unit No 6, Lima, Peru. [Long, Kanya C.] Andrews Univ, Dept Biol, Berrien Springs, MI 49104 USA. [Elder, John P.] San Diego State Univ, Grad Sch Publ Hlth, Inst Behav & Community Hlth, San Diego, CA 92182 USA. [Kitron, Uriel; Vazquez-Prokopec, Gonzalo M.] Emory Univ, Dept Environm Sci, Atlanta, GA 30322 USA. RP Perkins, TA (reprint author), Univ Notre Dame, Dept Biol Sci, Notre Dame, IN 46556 USA.; Perkins, TA (reprint author), Univ Notre Dame, Eck Inst Global Hlth, Notre Dame, IN 46556 USA.; Perkins, TA (reprint author), Univ Calif Davis, Dept Entomol & Nematol, Davis, CA 95616 USA.; Perkins, TA (reprint author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM taperkins@nd.edu FU US National Institutes of Health-National Institute of Allergy and Infectious Diseases (NIFI/NIAID) [R01 AI069341-01, 1P01AI098670-01A1]; 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 FX This research was supported by grants from the US National Institutes of Health-National Institute of Allergy and Infectious Diseases (NIFI/NIAID) awards R01 AI069341-01 and 1P01AI098670-01A1 (to T.W.S.) and 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. Authors E.S.H. and T.J.K. were US Military service members. 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 military service members or employees of the US Government as part of those persons' official duties. NR 46 TC 0 Z9 0 U1 7 U2 7 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8452 EI 1471-2954 J9 P ROY SOC B-BIOL SCI JI Proc. R. Soc. B-Biol. Sci. PD JUL 13 PY 2016 VL 283 IS 1834 AR 20160390 DI 10.1098/rspb.2016.0390 PG 9 WC Biology; Ecology; Evolutionary Biology SC Life Sciences & Biomedicine - Other Topics; Environmental Sciences & Ecology; Evolutionary Biology GA DT7FI UT WOS:000381652100009 ER PT J AU Sheeler, CA AF Sheeler, Carrie A. TI The Influence of Systemic Immune Response and Sleep Modulation on the Secondary Effects of Traumatic Brain Injury in the Rodent Model SO JOURNAL OF NEUROSCIENCE LA English DT Editorial Material ID BARRIER; INFLAMMATION; HUMANS; REFLEX C1 [Sheeler, Carrie A.] NIMH, Sect Neuroadaptat & Prot Metab, Bldg 10,Room 2D54,10 Ctr Dr, Bethesda, MD 20892 USA. RP Sheeler, CA (reprint author), NIMH, Sect Neuroadaptat & Prot Metab, Bldg 10,Room 2D54,10 Ctr Dr, Bethesda, MD 20892 USA. EM carrie.sheeler@nih.gov NR 16 TC 1 Z9 1 U1 3 U2 3 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 JUL 13 PY 2016 VL 36 IS 28 BP 7341 EP 7342 DI 10.1523/JNEUROSCI.1418-16.2016 PG 2 WC Neurosciences SC Neurosciences & Neurology GA DS1ST UT WOS:000380380500001 PM 27413144 ER PT J AU Aflaki, E Borger, DK Moaven, N Stubblefield, BK Rogers, SA Patnaik, S Schoenen, FJ Westbroek, W Zheng, W Sullivan, P Fujiwara, H Sidhu, R Khaliq, ZM Lopez, GJ Goldstein, DS Ory, DS Marugan, J Sidransky, E AF Aflaki, Elma Borger, Daniel K. Moaven, Nima Stubblefield, Barbara K. Rogers, Steven A. Patnaik, Samarjit Schoenen, Frank J. Westbroek, Wendy Zheng, Wei Sullivan, Patricia Fujiwara, Hideji Sidhu, Rohini Khaliq, Zayd M. Lopez, Grisel J. Goldstein, David S. Ory, Daniel S. Marugan, Juan Sidransky, Ellen TI A New Glucocerebrosidase Chaperone Reduces alpha-Synuclein and Glycolipid Levels in iPSC-Derived Dopaminergic Neurons from Patients with Gaucher Disease and Parkinsonism SO JOURNAL OF NEUROSCIENCE LA English DT Article DE alpha-synuclein; dopaminergic neurons; glucocerebrosidase; induced pluripotent stem cells; parkinsonism; pharmacological chaperone ID ENZYME REPLACEMENT THERAPY; MUTATIONS; CELLS; MANIFESTATIONS; MULTICENTER; DEFICIENCY; CARRIERS AB Among the known genetic risk factors for Parkinson disease, mutations in GBA1, the gene responsible for the lysosomal disorder Gaucher disease, are the most common. This genetic link has directed attention to the role of the lysosome in the pathogenesis of parkinsonism. To study how glucocerebrosidase impacts parkinsonism and to evaluate new therapeutics, we generated induced human pluripotent stem cells from four patients with Type 1 (non-neuronopathic) Gaucher disease, two with and two without parkinsonism, and one patient with Type 2 (acute neuronopathic) Gaucher disease, and differentiated them into macrophages and dopaminergic neurons. These cells exhibited decreased glucocerebrosidase activity and stored the glycolipid substrates glucosylceramide and glucosylsphingosine, demonstrating their similarity to patients with Gaucher disease. Dopaminergic neurons from patients with Type 2 and Type 1 Gaucher disease with parkinsonism had reduced dopamine storage and dopamine transporter reuptake. Levels of alpha-synuclein, a protein present as aggregates in Parkinson disease and related synucleinopathies, were selectively elevated in neurons from the patients with parkinsonism or Type 2 Gaucher disease. The cells were then treated with NCGC607, a small-molecule noninhibitory chaperone of glucocerebrosidase identified by high-throughput screening and medicinal chemistry structure optimization. This compound successfully chaperoned the mutant enzyme, restored glucocerebrosidase activity and protein levels, and reduced glycolipid storage in both iPSC-derived macrophages and dopaminergic neurons, indicating its potential for treating neuronopathic Gaucher disease. In addition, NCGC607 reduced alpha-synuclein levels in dopaminergic neurons from the patients with parkinsonism, suggesting that noninhibitory small-molecule chaperones of glucocerebrosidase may prove useful for the treatment of Parkinson disease. C1 [Aflaki, Elma; Borger, Daniel K.; Moaven, Nima; Stubblefield, Barbara K.; Westbroek, Wendy; Lopez, Grisel J.; Sidransky, Ellen] NHGRI, Sect Mol Neurogenet, NIH, Bethesda, MD 20892 USA. [Patnaik, Samarjit; Zheng, Wei; Marugan, Juan] NINDS, Natl Ctr Adv Translat Sci, NIH, Bethesda, MD 20892 USA. [Sullivan, Patricia; Goldstein, David S.] NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. [Khaliq, Zayd M.] NINDS, Cellular Neurophysiol Unit, NIH, Bethesda, MD 20892 USA. [Rogers, Steven A.; Schoenen, Frank J.] Univ Kansas, Specialized Chem Ctr, Lawrence, KS 66047 USA. [Fujiwara, Hideji; Sidhu, Rohini; Ory, Daniel S.] Washington Univ, Sch Med, Diabet Cardiovasc Dis Ctr, St Louis, MO 63110 USA. [Fujiwara, Hideji; Sidhu, Rohini; Ory, Daniel S.] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. RP Sidransky, E (reprint author), NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bldg 35,Room 1E623,35 Convent Dr,MSC 3708, Bethesda, MD 20892 USA. EM sidranse@mail.nih.gov RI Sidhu, Rohini/G-3547-2012; Zheng, Wei/J-8889-2014 OI Zheng, Wei/0000-0003-1034-0757 FU Intramural Research Programs of National Human Genome Research Institute, National Center for Advancing Translational Sciences, National Institute of Neurological Disorders and Stroke,; National Human Genome Research Institute [U54HG005031]; National Institutes of Health FX This work was supported by the Intramural Research Programs of the National Human Genome Research Institute, National Center for Advancing Translational Sciences, National Institute of Neurological Disorders and Stroke, and National Institutes of Health and in part by National Human Genome Research Institute Grant U54HG005031. NR 34 TC 9 Z9 9 U1 9 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 JUL 13 PY 2016 VL 36 IS 28 BP 7441 EP 7452 DI 10.1523/JNEUROSCI.0636-16.2016 PG 12 WC Neurosciences SC Neurosciences & Neurology GA DS1ST UT WOS:000380380500011 PM 27413154 ER PT J AU Smith, AA Navasa, N Yang, XL Wilder, CN Buyuktanir, O Marques, A Anguita, J Pal, U AF Smith, Alexis A. Navasa, Nicolas Yang, Xiuli Wilder, Cara N. Buyuktanir, Ozlem Marques, Adriana Anguita, Juan Pal, Utpal TI Cross-Species Interferon Signaling Boosts Microbicidal Activity within the Tick Vector SO CELL HOST & MICROBE LA English DT Article ID LYME-DISEASE SPIROCHETE; IXODES-SCAPULARIS; BORRELIA-BURGDORFERI; ANTIMICROBIAL PEPTIDES; STAT PROTEINS; IMMUNITY; DROSOPHILA; JAK; PATHWAY; GENES AB Evolution of hematophagy in blood-sucking parasites likely involves communication with their hosts. We find that Ixodes ticks are responsive to IFNg acquired in a blood meal from mice infected with the Lyme disease-causing bacteria Borrelia burgdorferi, leading to induction of antimicrobial responses. Ixodes ticks parasitizing B. burgdorferi-infected mice upregulated an I. scapularis Rho-like GTPase (IGTPase). IGTPase knockdown enhanced B. burgdorferi levels in postfed ticks, suggesting this protein controls spirochete survival. Notably, IGTPase was only induced during pathogen acquisition from mice and not upon transmission to naive hosts. Microinjection of ticks with IFNg induced IGTPase, and ticks parasitizing IFNg knockout mice, failed to upregulate IGTPase. Additionally, ticks lacking the transcription factor STAT, which signals downstream of IFNg, did not induce IGTPase. IGTPase expression induced antimicrobial peptides, including Dae2, previously shown to inhibit B. burgdorferi. These results identify an interspecies signaling cascade allowing ticks to detect invading bacteria and mount microbicidal responses. C1 [Smith, Alexis A.; Yang, Xiuli; Wilder, Cara N.; Pal, Utpal] Univ Maryland, Dept Vet Med, College Pk, MD 20742 USA. [Navasa, Nicolas; Anguita, Juan] CIC BioGUNE, Derio 48160, Bizkaia, Spain. [Buyuktanir, Ozlem] Ondokuz Mayis Univ, Dept Microbiol, Fac Vet Med, TR-55139 Samsun, Turkey. [Marques, Adriana] NIAID, Lab Clin Infect Dis, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Anguita, Juan] Basque Fdn Sci, Ikerbasque, Bilbao 48011, Spain. [Pal, Utpal] Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. RP Pal, U (reprint author), Univ Maryland, Dept Vet Med, College Pk, MD 20742 USA.; Pal, U (reprint author), Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. EM upal@umd.edu RI Anguita, Juan/D-5432-2011 OI Anguita, Juan/0000-0003-2061-7182 FU University of Maryland, College Park; National Institute of Allergy and Infectious Diseases [AI080615, AI116620]; Ondokuz Mayis University; Turkish Higher Education Council; Intramural Research Program of the National Institute of Allergy and Infectious Disease; European Union [602272] FX We thank John Anderson, Toru Kariu, Faith Kung, Kavita Sharma, Brian Backstedt, Juraj Koci, and Meghna Thakur for their assistance with this study. We would like to thank Ulrike Munderloh, University of Minnesota, for providing the IDE12 cell line. This work was supported by funding from University of Maryland, College Park, and the National Institute of Allergy and Infectious Diseases Award Number AI080615 and AI116620 (to U.P.). O.B. is supported by funding from Ondokuz Mayis University and Turkish Higher Education Council. A.M. is supported by the Intramural Research Program of the National Institute of Allergy and Infectious Disease. J.A. is funded by the European Union (Grant Agreement number 602272). NR 27 TC 6 Z9 6 U1 2 U2 7 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 JUL 13 PY 2016 VL 20 IS 1 BP 91 EP 98 DI 10.1016/j.chom.2016.06.001 PG 8 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA DS3UC UT WOS:000380707200013 PM 27374407 ER PT J AU Cho, YE Latour, LL Kim, H Turtzo, LC Olivera, A Livingston, WS Wang, D Martin, C Lai, C Cashion, A Gill, J AF Cho, Young-Eun Latour, Lawrence L. Kim, Hyungsuk Turtzo, L. Christine Olivera, Anlys Livingston, Whitney S. Wang, Dan Martin, Christiana Lai, Chen Cashion, Ann Gill, Jessica TI Older Age Results in Differential Gene Expression after Mild Traumatic Brain Injury and Is Linked to Imaging Differences at Acute Follow-up SO FRONTIERS IN AGING NEUROSCIENCE LA English DT Article DE traumatic brain injury; aging; inflammation; gene expression; imaging ID ACTIVATION; DISEASE; CELLS; TRANSCRIPTOME; INFLAMMATION; METAANALYSIS; MICROARRAY; PREDICTION; RECOVERY; CORTEX AB Older age consistently relates to a lesser ability to fully recover from a traumatic brain injury (TBI); however, there is limited data to explicate the nature of age-related risks. This study was undertaken to determine the relationship of age on gene-activity following a TBI, and how this biomarker relates to changes in neuroimaging findings. A young group (between the ages of 19 and 35 years), and an old group (between the ages of 60 and 89 years) were compared on global gene-activity within 48 h following a TBI, and then at follow-up within 1-week. At each time-point, gene expression profiles, and imaging findings from both magnetic resonance imaging (MRI) and computed tomography were obtained and compared. The young group was found to have greater gene expression of inflammatory regulatory genes at 48 h and 1-week in genes such as basic leucine zipper transcription factor 2 (BACH2), leucine-rich repeat neuronal 3 (LRRN3), and lymphoid enhancer-binding factor 1 (LEF1) compared to the old group. In the old group, there was increased activity in genes within S100 family, including calcium binding protein P (S100P) and S100 calcium binding protein A8 (S100A8), which previous studies have linked to poor recovery from TBI. The old group also had reduced activity of the noggin (NOG) gene, which is a member of the transforming growth factorT supertamily and is linked to neurorecovery and neuroregeneration compared to the young group. We link these gene expression findings that were validated to neuroimaging, reporting that in the old group with a MRI finding of TBI-related damage, there was a lesser likelihood to then have a negative MRI finding at follow-up compared to the young group. Together, these data indicate that age impacts gene activity following a TBI, and suggest that this differential activity related to immune regulation and neurorecovery contributes to a lesser likelihood of neuronal recovery in older patients as indicated through neuroimaging. C1 [Cho, Young-Eun; Kim, Hyungsuk; Olivera, Anlys; Livingston, Whitney S.; Wang, Dan; Martin, Christiana; Lai, Chen; Cashion, Ann; Gill, Jessica] NINR, NIH, Bethesda, MD 20892 USA. [Latour, Lawrence L.; Turtzo, L. Christine] Natl Inst Neurol Disorders, NIH, Bethesda, MD USA. RP Cashion, A; Gill, J (reprint author), NINR, NIH, Bethesda, MD 20892 USA. EM ann.cashion@nih.gov; gillj@mail.nih.gov OI Martin, Christiana/0000-0002-4484-6134 FU Intramural Research Program of National Institute of Nursing Research in NIH; Center for Neuroscience and Regenerative Medicine FX This research was supported by the Intramural Research Program of National Institute of Nursing Research in NIH. This research was also supported by the Center for Neuroscience and Regenerative Medicine. NR 66 TC 0 Z9 0 U1 2 U2 2 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1663-4365 J9 FRONT AGING NEUROSCI JI Front. Aging Neurosci. PD JUL 13 PY 2016 VL 8 AR 168 DI 10.3389/fnagi.2016.00168 PG 11 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA DR6XH UT WOS:000380044100001 PM 27468266 ER PT J AU Fenwick, RB Schwieters, CD Vogeli, B AF Fenwick, R. Bryn Schwieters, Charles D. Vogeli, Beat TI Direct Investigation of Slow Correlated Dynamics in Proteins via Dipolar Interactions SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID SMALL ALPHA/BETA PROTEIN; RESIDUAL DIPOLAR; CROSS-CORRELATION; NMR-SPECTROSCOPY; SUCCESSIVE RESIDUES; MOLECULAR-DYNAMICS; BACKBONE DYNAMICS; RELAXATION RATES; SCALAR COUPLINGS; SPIN RELAXATION AB The synchronization of native state motions as they transition between microstates influences catalysis kinetics, mediates allosteric interactions, and reduces the conformational entropy of proteins. However, it has proven difficult to describe native microstates because they are usually minimally frustrated and may interconvert on the micro- to millisecond time scale. Direct observation of concerted equilibrium fluctuations would therefore be an important tool for describing protein native states. Here we propose a strategy that relates NMR cross-correlated relaxation (CCR) rates between dipolar interactions to residual dipolar couplings (RDCs) of individual consecutive H-N-N and H-alpha-C-alpha bonds, which act as a proxy for the peptide planes and the side chains, respectively. Using Xplor-NIH ensemble structure calculations restrained with the RDC and CCR data, we observe collective motions on time scales slower than nanoseconds in the backbone for GB3. To directly access the correlations from CCR, we develop a structure-free data analysis. The resulting dynamic correlation map is consistent with the ensemble-restrained simulations and reveals a complex network. In general, we find that the bond motions are on average slightly correlated and that the local environment dominates many observations. Despite this, some patterns are typical over entire secondary structure elements. In the beta-sheet, nearly all bonds are weakly correlated, and there is an approximately binary alternation in correlation intensity corresponding to the solvent exposure/shielding alternation of the side chains. For alpha-helices, there is also a weak correlation in the H-N-N bonds. The degree of correlation involving H-alpha-C-alpha bonds is directly affected by side-chain fluctuations, whereas loops show complex and nonuniform behavior. C1 [Fenwick, R. Bryn] Inst Res Biomed IRB Barcelona, Parc Cient Barcelona,C Baldiri Reixac 10, Barcelona 08028, Spain. [Fenwick, R. Bryn] Scripps Res Inst TSRI, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA. [Schwieters, Charles D.] NIH, Div Computat Biosci, Ctr Informat Technol, Bldg 12A, Bethesda, MD 20892 USA. [Vogeli, Beat] ETH Honggerberg, Swiss Fed Inst Technol, Phys Chem Lab, Vladimir Prelog Weg 2, CH-8093 Zurich, Switzerland. RP Fenwick, RB (reprint author), Inst Res Biomed IRB Barcelona, Parc Cient Barcelona,C Baldiri Reixac 10, Barcelona 08028, Spain.; Fenwick, RB (reprint author), Scripps Res Inst TSRI, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA.; Vogeli, B (reprint author), ETH Honggerberg, Swiss Fed Inst Technol, Phys Chem Lab, Vladimir Prelog Weg 2, CH-8093 Zurich, Switzerland. EM fenwick@scripps.edu; beat.voegeli@phys.chem.ethz.ch OI Fenwick, Robert/0000-0002-0925-7422 FU Swiss National Science Foundation [140214]; Intramural Research Program of C.I.T, National Institutes of Health FX We thank Prof. Roland Riek, Dr. Jason Greenwald, Dr. Michael Sabo, and Dr. Donghan Lee for valuable discussion. We note that a similar correlation factor Fcorr has been presented by Dr. Donghan Lee at the Swiss Federal Institute of Technology and Dr. Michael Sabo at the 54th ENC conference 2013 in Asilomar. This work was supported by the Swiss National Science Foundation with Grant 140214 to B.V. and by the Intramural Research Program of C.I.T, National Institutes of Health, to C.D.S. NR 72 TC 0 Z9 0 U1 17 U2 17 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 JUL 13 PY 2016 VL 138 IS 27 BP 8412 EP 8421 DI 10.1021/jacs.6b01447 PG 10 WC Chemistry, Multidisciplinary SC Chemistry GA DR3HN UT WOS:000379794400024 PM 27331619 ER PT J AU Bayro, MJ Tycko, R AF Bayro, Marvin J. Tycko, Robert TI Structure of the Dimerization Interface in the Mature HIV-1 Capsid Protein Lattice from Solid State NMR of Tubular Assemblies SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; NUCLEAR-MAGNETIC-RESONANCE; CRYSTAL-STRUCTURE; MAS NMR; SPECTROSCOPY; DOMAIN; DYNAMICS; CONFORMATIONS; SIMULATION; FRAGMENT AB The HIV-1 capsid protein (CA) forms the capsid shell that encloses RNA within a mature HIV-1 virion. Previous studies by electron microscopy have shown that the capsid shell is primarily a triangular lattice of CA hexamers, with variable curvature that destroys the ideal symmetry of a planar lattice. The mature CA lattice depends on CA dimerization, which occurs through interactions between helix 9 segments of the C-terminal domain (CTD) of CA. Several high-resolution structures of the CTD-CTD dimerization interface have been reported, based on X-ray crystallography and multidimensional solution nuclear magnetic resonance (NMR), with significant differences in amino acid side chain conformations and helix 9-helix 9 orientations. In a structural model for tubular CA assemblies based on cryogenic electron microscopy (cryoEM) [Zhao et al. Nature, 2013, 497, 643-646], the dimerization interface is substantially disordered. The dimerization interface structure in noncrystalline CA assemblies and the extent to which this interface is structurally ordered within a curved lattice have therefore been unclear. Here we describe solid state NMR measurements on the dimerization interface in tubular CA assemblies, which contain the curved triangular lattice of a mature virion, including quantitative measurements of intermolecular and intramolecular distances using dipolar recoupling techniques, solid state NMR chemical shifts, and long-range side chain-side chain contacts. When combined with restraints on the distance and orientation between helix 9 segments from the cryoEM study, the solid state NMR data lead to a unique high-resolution structure for the dimerization interface in the noncrystalline lattice of CA tubes. These results demonstrate that CA lattice curvature is not dependent on disorder or variability in the dimerization interface. This work also demonstrates the feasibility of local structure determination within large noncrystalline assemblies formed by high-molecular weight proteins, using modern solid state NMR methods. C1 [Bayro, Marvin J.; Tycko, Robert] Natl Inst Diabet & Digest & Kidney Dis, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), Natl Inst Diabet & Digest & Kidney Dis, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM robertty@mail.nih.gov RI Bayro, Marvin/Q-4643-2016 OI Bayro, Marvin/0000-0003-1482-9381 FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health; NIH Intramural AIDS Targeted Antiviral Program FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, and by the NIH Intramural AIDS Targeted Antiviral Program. We thank Dr. Eric Moore for assistance with simulations of NMR data and Drs. Charles Schwieters and Guillermo Bermejo for assistance with Xplor-NIH calculations. NR 46 TC 2 Z9 2 U1 11 U2 23 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 JUL 13 PY 2016 VL 138 IS 27 BP 8538 EP 8546 DI 10.1021/jacs.6b03983 PG 9 WC Chemistry, Multidisciplinary SC Chemistry GA DR3HN UT WOS:000379794400038 PM 27298207 ER PT J AU Darbinyan, A Major, EO Morgello, S Holland, S Ryschkewitsch, C Monaco, MC Naidich, TP Bederson, J Malaczynska, J Ye, F Gordon, R Cunningham-Rundles, C Fowkes, M Tsankova, NM AF Darbinyan, Armine Major, Eugene O. Morgello, Susan Holland, Steven Ryschkewitsch, Caroline Monaco, Maria Chiara Naidich, Thomas P. Bederson, Joshua Malaczynska, Joanna Ye, Fei Gordon, Ronald Cunningham-Rundles, Charlotte Fowkes, Mary Tsankova, Nadejda M. TI BK virus encephalopathy and sclerosing vasculopathy in a patient with hypohidrotic ectodermal dysplasia and immunodeficiency SO ACTA NEUROPATHOLOGICA COMMUNICATIONS LA English DT Article DE Polyomavirus; BK virus; IKK-gamma; NF-kappa-B essential modulator (NEMO); Ectodermal dysplasia; HED-ID; Encephalopathy; Fibrosing vasculopathy ID PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; NONCODING CONTROL REGION; CENTRAL-NERVOUS-SYSTEM; INCONTINENTIA PIGMENTI; JC VIRUS; POLYOMAVIRUS BK; TRANSPLANT RECIPIENTS; PRODUCTIVE INFECTION; CEREBROSPINAL-FLUID; FUNCTIONAL-ANALYSIS AB Human BK polyomavirus (BKV) is reactivated under conditions of immunosuppression leading most commonly to nephropathy or cystitis; its tropism for the brain is rare and poorly understood. We present a unique case of BKV-associated encephalopathy in a man with hypohidrotic ectodermal dysplasia and immunodeficiency (HED-ID) due to IKK-gamma (NEMO) mutation, who developed progressive neurological symptoms. Brain biopsy demonstrated polyomavirus infection of gray and white matter, with predominant involvement of cortex and distinct neuronal tropism, in addition to limited demyelination and oligodendroglial inclusions. Immunohistochemistry demonstrated polyoma T-antigen in neurons and glia, but expression of VP1 capsid protein only in glia. PCR analysis on both brain biopsy tissue and cerebrospinal fluid detected high levels of BKV DNA. Sequencing studies further identified novel BKV variant and disclosed unique rearrangements in the noncoding control region of the viral DNA (BKVN NCCR). Neuropathological analysis also demonstrated an unusual form of obliterative fibrosing vasculopathy in the subcortical white matter with abnormal lysosomal accumulations, possibly related to the patient's underlying ectodermal dysplasia. Our report provides the first neuropathological description of HED-ID due to NEMO mutation, and expands the diversity of neurological presentations of BKV infection in brain, underscoring the importance of its consideration in immunodeficient patients with unexplained encephalopathy. We also document novel BKVN NCCR rearrangements that may be associated with the unique neuronal tropism in this patient. C1 [Darbinyan, Armine; Morgello, Susan; Malaczynska, Joanna; Ye, Fei; Gordon, Ronald; Fowkes, Mary; Tsankova, Nadejda M.] Icahn Sch Med Mt Sinai, Dept Pathol, New York, NY 10029 USA. [Major, Eugene O.; Ryschkewitsch, Caroline; Monaco, Maria Chiara] NINDS, Lab Mol Med & Neurosci, NIH, Bethesda, MD 20892 USA. [Morgello, Susan] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA. [Morgello, Susan; Tsankova, Nadejda M.] Icahn Sch Med Mt Sinai, Dept Neurosci, 1425 Madison Ave,Icahn 9-20E, New York, NY 10029 USA. [Morgello, Susan; Tsankova, Nadejda M.] Icahn Sch Med Mt Sinai, Friedman Brain Inst, 1425 Madison Ave,Icahn 9-20E, New York, NY 10029 USA. [Holland, Steven] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Naidich, Thomas P.] Icahn Sch Med Mt Sinai, Dept Radiol, New York, NY 10029 USA. [Bederson, Joshua] Icahn Sch Med Mt Sinai, Dept Neurosurg, New York, NY 10029 USA. [Cunningham-Rundles, Charlotte] Icahn Sch Med Mt Sinai, Dept Med Allergy & Immunol, New York, NY 10029 USA. RP Tsankova, NM (reprint author), Icahn Sch Med Mt Sinai, Dept Pathol, New York, NY 10029 USA.; Tsankova, NM (reprint author), Icahn Sch Med Mt Sinai, Dept Neurosci, 1425 Madison Ave,Icahn 9-20E, New York, NY 10029 USA.; Tsankova, NM (reprint author), Icahn Sch Med Mt Sinai, Friedman Brain Inst, 1425 Madison Ave,Icahn 9-20E, New York, NY 10029 USA. EM nadejda.tsankova@mssm.edu NR 59 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2051-5960 J9 ACTA NEUROPATHOL COM JI Acta Neuropathol. Commun. PD JUL 13 PY 2016 VL 4 AR 73 DI 10.1186/s40478-016-0342-3 PG 11 WC Neurosciences SC Neurosciences & Neurology GA DQ9IU UT WOS:000379524400001 PM 27411570 ER PT J AU Xu, BB Luo, ZP Wilson, AJ Chen, K Gao, WX Yuan, GL Chopra, HD Chen, X Willets, KA Dauter, Z Ren, SQ AF Xu, Beibei Luo, Zhipu Wilson, Andrew J. Chen, Ke Gao, Wenxiu Yuan, Guoliang Chopra, Harsh Deep Chen, Xing Willets, Katherine A. Dauter, Zbigniew Ren, Shenqiang TI Multifunctional Charge-Transfer Single Crystals through Supramolecular Assembly SO ADVANCED MATERIALS LA English DT Article ID TETRACYANOQUINODIMETHANE TTF-TCNQ; TRANSFER COMPLEXES; TRANSFER INTERFACES; ELECTRON-TRANSFER; TRANSFER SALT; MULTIFERROICITY; FERROELECTRICITY; SEMICONDUCTOR; CONDUCTIVITY; MAGNETISM AB Centimeter-sized segregated stacking TTF-C-60 single crystals are crystallized by a mass-transport approach combined with solvent-vapor evaporation for the first time. The intermolecular charge-transfer interaction in the long-range ordered superstructure enables the crystals to demonstrate external stimuli-controlled multifunctionalities and angle/electrical-potential-dependent luminescence. C1 [Xu, Beibei; Chopra, Harsh Deep; Ren, Shenqiang] Temple Univ, Dept Mech Engn, Temple Mat Inst, Philadelphia, PA 19122 USA. [Luo, Zhipu; Dauter, Zbigniew] Argonne Natl Lab, Synchrotron Radiat Res Sect, Macromol Crystallog Lab, Natl Canc Inst, 9700 S Cass Ave, Argonne, IL 60439 USA. [Wilson, Andrew J.; Willets, Katherine A.] Temple Univ, Dept Chem, Philadelphia, PA 19122 USA. [Chen, Ke] Temple Univ, Dept Phys, Temple Mat Inst, Philadelphia, PA 19122 USA. [Gao, Wenxiu; Yuan, Guoliang] Nanjing Univ Sci Technol, Sch Mat Sci & Engn, Nanjing 210094, Jiangsu, Peoples R China. [Chen, Xing] Argonne Natl Lab, Div Energy Syst, 9700 S Cass Ave, Argonne, IL 60439 USA. RP Ren, SQ (reprint author), Temple Univ, Dept Mech Engn, Temple Mat Inst, Philadelphia, PA 19122 USA. EM shenqiang.ren@temple.edu OI Wilson, Andrew/0000-0003-3427-810X FU Army Research Office, Young Investigator Program [W911NF-15-1-0610]; U.S. Department of Energy, Basic Energy Sciences Award [DE-FG02-13ER46937]; Department of Energy (DOE), Office of Science, Basic Energy Science (BES) [DE-SC0010307]; National Science Foundation DMR , Condensed Matter Physics [1541236]; Temple University's OVPR's Infrastructure Grant; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX Work at Temple University (S.R.) was supported by the Army Research Office, Young Investigator Program (W911NF-15-1-0610, material design/self-assembly of carbon photovoltaics), and the U.S. Department of Energy, Basic Energy Sciences Award No. DE-FG02-13ER46937 (organic synthesis and physical property measurement). Work at Temple University (A.J.W. and K.A.W.) was supported by the Department of Energy (DOE), Office of Science, Basic Energy Science (BES) under Award No. DE-SC0010307. H.D.C. gratefully acknowledges support from the National Science Foundation DMR, Condensed Matter Physics under Grant No. 1541236 (previously Grant No. 1309712) and Temple University's OVPR's Infrastructure Grant. Diffraction data were collected at the SER-CAT beamline 22BM at the Advanced Photon Source, Argonne National Laboratory. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. W-31-109-Eng-38. The authors also thank Temple Materials Institute and Dr. X. Xi for the AFM measurements. NR 48 TC 0 Z9 0 U1 24 U2 61 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 0935-9648 EI 1521-4095 J9 ADV MATER JI Adv. Mater. PD JUL 13 PY 2016 VL 28 IS 26 BP 5322 EP + DI 10.1002/adma.201600383 PG 9 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA DR5JH UT WOS:000379938800024 PM 27146726 ER PT J AU Auslander, N Yizhak, K Weinstock, A Budhu, A Tang, W Wang, XW Ambs, S Ruppin, E AF Auslander, Noam Yizhak, Keren Weinstock, Adam Budhu, Anuradha Tang, Wei Wang, Xin Wei Ambs, Stefan Ruppin, Eytan TI A joint analysis of transcriptomic and metabolomic data uncovers enhanced enzyme-metabolite coupling in breast cancer SO SCIENTIFIC REPORTS LA English DT Article ID HEPATOCELLULAR-CARCINOMA; LIPID-METABOLISM; PROSTATE-CANCER; EXPRESSION; INTEGRATION; TUMORS; CLASSIFICATION; DYSREGULATION; ACCUMULATION; PROGRESSION AB Disrupted regulation of cellular processes is considered one of the hallmarks of cancer. We analyze metabolomic and transcriptomic profiles jointly collected from breast cancer and hepatocellular carcinoma patients to explore the associations between the expression of metabolic enzymes and the levels of the metabolites participating in the reactions they catalyze. Surprisingly, both breast cancer and hepatocellular tumors exhibit an increase in their gene-metabolites associations compared to noncancerous adjacent tissues. Following, we build predictors of metabolite levels from the expression of the enzyme genes catalyzing them. Applying these predictors to a large cohort of breast cancer samples we find that depleted levels of key cancer-related metabolites including glucose, glycine, serine and acetate are significantly associated with improved patient survival. Thus, we show that the levels of a wide range of metabolites in breast cancer can be successfully predicted from the transcriptome, going beyond the limited set of those measured. C1 [Auslander, Noam; Ruppin, Eytan] Univ Maryland, Ctr Bioinformat & Computat Biol, College Pk, MD 20742 USA. [Auslander, Noam; Ruppin, Eytan] Univ Maryland, Dept Comp Sci, College Pk, MD 20742 USA. [Yizhak, Keren; Weinstock, Adam; Ruppin, Eytan] Tel Aviv Univ, Blavatnik Sch Comp Sci, IL-69978 Tel Aviv, Israel. [Budhu, Anuradha; Wang, Xin Wei] NCI, Liver Carcinogenesis Sect, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Tang, Wei; Ambs, Stefan] NCI, Mol Epidemiol Sect, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. [Ruppin, Eytan] Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel. RP Auslander, N; Ruppin, E (reprint author), Univ Maryland, Ctr Bioinformat & Computat Biol, College Pk, MD 20742 USA.; Auslander, N; Ruppin, E (reprint author), Univ Maryland, Dept Comp Sci, College Pk, MD 20742 USA.; Yizhak, K; Ruppin, E (reprint author), Tel Aviv Univ, Blavatnik Sch Comp Sci, IL-69978 Tel Aviv, Israel.; Ruppin, E (reprint author), Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel. EM noamaus@gmail.com; kerenyiz@post.tau.ac.il; eyruppin@gmail.com RI Wang, Xin/B-6162-2009 NR 43 TC 0 Z9 0 U1 7 U2 8 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 JUL 13 PY 2016 VL 6 AR 29662 DI 10.1038/srep29662 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR0EB UT WOS:000379579700001 PM 27406679 ER PT J AU Ganapathi, KA Jobanputra, V Iwamoto, F Jain, P Chen, JL Cascione, L Nahum, O Levy, B Xie, Y Khattar, P Hoehn, D Bertoni, F Murty, VV Pittaluga, S Jaffe, ES Alobeid, B Mansukhani, MM Bhagat, G AF Ganapathi, Karthik A. Jobanputra, Vaidehi Iwamoto, Fabio Jain, Preti Chen, Jinli Cascione, Luciano Nahum, Odelia Levy, Brynn Xie, Yi Khattar, Pallavi Hoehn, Daniela Bertoni, Francesco Murty, Vundavalli V. Pittaluga, Stefania Jaffe, Elaine S. Alobeid, Bachir Mansukhani, Mahesh M. Bhagat, Govind TI The genetic landscape of dural marginal zone lymphomas SO ONCOTARGET LA English DT Article DE dural marginal zone lymphoma; genome; mutations; TNFAIP3; NOTCH2 ID B-CELL LYMPHOMA; NF-KAPPA-B; RECURRENT MUTATIONS; CODING GENOME; NOTCH2; A20; ACTIVATION; PATHWAY; MALT AB The dura is a rare site of involvement by marginal zone lymphoma (MZL) and the biology of dural MZL is not well understood. We performed genome-wide DNA copy number and targeted mutational analysis of 14 dural MZL to determine the genetic landscape of this entity. Monoallelic and biallelic inactivation of TNFAIP3 by mutation (n=5) or loss (n=1) was observed in 6/9 (67%) dural MZL exhibiting plasmacytic differentiation, including 3 IgG4+ cases. In contrast, activating NOTCH2 mutations were detected in 4/5 (80%) dural MZL displaying variable monocytoid morphology. Inactivating TBL1XR1 mutations were identified in all NOTCH2 mutated cases. Recurrent mutations in KLHL6 (n=2) and MLL2 (n=2) were also detected. Gains at 6p25.3 (n=2) and losses at 1p36.32 (n=3) were common chromosomal imbalances, with loss of heterozygosity (LOH) of these loci observed in a subset of cases. Translocations involving the IGH or MALT1 genes were not identified. Our results indicate genetic similarities between dural MZL and other MZL subtypes. However, recurrent and mutually exclusive genetic alterations of TNFAIP3 and NOTCH2 appear to be associated with distinct disease phenotypes in dural MZL. C1 [Ganapathi, Karthik A.; Jobanputra, Vaidehi; Jain, Preti; Chen, Jinli; Nahum, Odelia; Levy, Brynn; Hoehn, Daniela; Murty, Vundavalli V.; Alobeid, Bachir; Mansukhani, Mahesh M.; Bhagat, Govind] Columbia Univ, Dept Pathol & Cell Biol, Med Ctr, New York, NY 10027 USA. [Iwamoto, Fabio] Columbia Univ, Dept Neurol, Med Ctr, New York, NY USA. [Cascione, Luciano; Bertoni, Francesco] Oncol Res Inst, Bellinzona, Switzerland. [Cascione, Luciano; Bertoni, Francesco] Oncol Inst Southern Switzerland, Bellinzona, Switzerland. [Xie, Yi; Pittaluga, Stefania; Jaffe, Elaine S.] NCI, Hematopathol Sect, Pathol Lab, Bethesda, MD 20892 USA. [Khattar, Pallavi] New York Med Coll, Dept Pathol, Valhalla, NY 10595 USA. RP Mansukhani, MM; Bhagat, G (reprint author), Columbia Univ, Dept Pathol & Cell Biol, Med Ctr, New York, NY 10027 USA. EM mm322@cumc.columbia.edu; gb96@cumc.columbia.edu OI Bhagat, Govind/0000-0001-6250-048X NR 35 TC 0 Z9 0 U1 1 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD JUL 12 PY 2016 VL 7 IS 28 BP 43052 EP 43061 DI 10.18632/oncotarget.9678 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DY8QU UT WOS:000385395700017 PM 27248180 ER PT J AU Mocsar, G Volko, J Ronnlund, D Widengren, J Nagy, P Szollosi, J Toth, K Goldman, CK Damjanovich, S Waldmann, TA Bodnar, A Vamosi, G AF Mocsar, Gabor Volko, Julianna Ronnlund, Daniel Widengren, Jerker Nagy, Peter Szollosi, Janos Toth, Katalin Goldman, Carolyn K. Damjanovich, Sandor Waldmann, Thomas A. Bodnar, Andrea Vamosi, Gyorgy TI MHC I Expression Regulates Co-clustering and Mobility of Interleukin-2 and-15 Receptors in T Cells SO BIOPHYSICAL JOURNAL LA English DT Article ID RESONANCE ENERGY-TRANSFER; HLA CLASS-I; FLUORESCENCE CORRELATION SPECTROSCOPY; HUMAN LYMPHOBLASTOID-CELLS; PLASMA-MEMBRANE; MONOCLONAL-ANTIBODY; IL-2 RECEPTOR; INSULIN-RECEPTORS; LYMPHOMA-CELLS; LIPID RAFTS AB MHC glycoproteins form supramolecular clusters with interleukin-2 and -15 receptors in lipid rafts of T cells. The role of highly expressed MHC I in maintaining these clusters is unknown. We knocked down MHC I in FT7.10 human T cells, and studied protein clustering at two hierarchic levels: molecular aggregations and mobility by Forster resonance energy transfer and fluorescence correlation spectroscopy; and segregation into larger domains or superclusters by superresolution stimulated emission depletion microscopy. Fluorescence correlation spectroscopy-based molecular brightness analysis revealed that the studied molecules diffused as tight aggregates of several proteins of a kind. Knockdown reduced the number of MHC I containing molecular aggregates and their average MHC I content, and decreased the heteroassociation of MHC I with IL-2R alpha/IL-15R alpha. The mobility of not only MHC I but also that of IL-2R alpha/IL-15R alpha increased, corroborating the general size decrease of tight aggregates. A multifaceted analysis of stimulated emission depletion images revealed that the diameter of MHC I superclusters diminished from 400-600 to 200-300 nm, whereas those of IL-2R alpha/IL-15R alpha hardly changed. MHC I and IL-2R alpha/IL-15R alpha colocalized with GM1 ganglioside-rich lipid rafts, but MHC I clusters retracted to smaller subsets of GM1-and IL-2R alpha/IL-15R alpha-rich areas upon knockdown. Our results prove that changes in expression level may significantly alter the organization and mobility of interacting membrane proteins. C1 [Mocsar, Gabor; Volko, Julianna; Nagy, Peter; Szollosi, Janos; Damjanovich, Sandor; Bodnar, Andrea; Vamosi, Gyorgy] Univ Debrecen, Fac Med, Dept Biophys & Cell Biol, Debrecen, Hungary. [Ronnlund, Daniel; Widengren, Jerker] Albanova Univ Ctr, Royal Inst Technol, Dept Appl Phys Expt Biomol Phys, Stockholm, Sweden. [Szollosi, Janos] Hungarian Acad Sci, Cell Biol & Signaling Res Grp, Debrecen, Hungary. [Szollosi, Janos] Univ Debrecen, Debrecen, Hungary. [Toth, Katalin] German Canc Res Ctr, Biophys Macromol, Heidelberg, Germany. [Goldman, Carolyn K.; Waldmann, Thomas A.] NCI, Lymphoid Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Vamosi, G (reprint author), Univ Debrecen, Fac Med, Dept Biophys & Cell Biol, Debrecen, Hungary. EM vamosig@med.unideb.hu RI Nagy, Peter/D-2188-2013; OI Nagy, Peter/0000-0002-7466-805X; Widengren, Jerker/0000-0003-3200-0374 FU Hungarian Scientific Research Fund [K103965, K103906, NK101337]; Intramural Research Program of the National Cancer Institute, National Institutes of Health; TAMOP grant [4.2.2.-08/1-2008-0019]; "MOLMEDREX'' FP7-REGPOT-1 grant [229920]; Tempus Public Foundation Hungary [73163]; Internal Research Program of the University of Debrecen grant [RH/885/2013]; Jedlik Anyos Fellowship grant [A2-JADJ-13-0170]; New Hungary Development Plan - European Social Fund [TAMOP-4.2.2.A-11/1/KONV-2012-0023 VED-ELEM, TAMOP-4.2.2.D-15/1/KONV-2015-0016]; European Regional Development Fund; European Union; State of Hungary; German Academic Exchange Service; European Social Fund [TAMOP-4.2.4.A/2-11/1-20120001] FX This work was supported by Hungarian Scientific Research Fund grant No. K103965 to G.V., grant No. K103906 to P.N., and grant No. NK101337 to J.S.; the Intramural Research Program of the National Cancer Institute, National Institutes of Health to T.A.W.; TAMOP grant No. 4.2.2.-08/1-2008-0019 to G.V.; "MOLMEDREX'' FP7-REGPOT-2008-1 grant No. 229920 to G.V.; German Academic Exchange Service and Tempus Public Foundation Hungary grant No. 73163 to G.V. and K.T.; Internal Research Program of the University of Debrecen grant No. RH/885/2013 to A.B.; Jedlik Anyos Fellowship grant No. A2-JADJ-13-0170 to G.M.; TAMOP-4.2.2.A-11/1/KONV-2012-0023 VED-ELEM and TAMOP-4.2.2.D-15/1/KONV-2015-0016 grants implemented through the New Hungary Development Plan cofinanced by the European Social Fund and the European Regional Development Fund to G.V. and J.S.; and the European Union and the State of Hungary, cofinanced by the European Social Fund in the framework of TAMOP-4.2.4.A/2-11/1-20120001 National Excellence Program to G.V. NR 77 TC 1 Z9 1 U1 3 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD JUL 12 PY 2016 VL 111 IS 1 BP 100 EP 112 DI 10.1016/j.bpj.2016.05.044 PG 13 WC Biophysics SC Biophysics GA DS1QN UT WOS:000380371400013 PM 27410738 ER PT J AU Collins, FS AF Collins, Francis S. TI Seeking a Cure for One of the Rarest Diseases: Progeria SO CIRCULATION LA English DT Editorial Material DE Editorials; everolimus; lamin type A; lonafarnib; morpholinos; progeria; rare diseases; translational medical research ID HUTCHINSON-GILFORD-PROGERIA C1 [Collins, Francis S.] NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA. RP Collins, FS (reprint author), NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA. EM francis.collins3@nih.gov NR 19 TC 1 Z9 1 U1 9 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD JUL 12 PY 2016 VL 134 IS 2 BP 126 EP 129 DI 10.1161/CIRCULATIONAHA.116.022965 PG 4 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DR8EA UT WOS:000380130000010 PM 27400897 ER PT J AU Amar, MJA Kaler, M Courville, AB Shamburek, R Sampson, M Remaley, AT AF Amar, Marcelo J. A. Kaler, Maryann Courville, Amber B. Shamburek, Robert Sampson, Maureen Remaley, Alan T. TI Randomized double blind clinical trial on the effect of oral alpha-cyclodextrin on serum lipids SO LIPIDS IN HEALTH AND DISEASE LA English DT Article DE alpha-cyclodextrin; TC; Total cholesterol; TG; Triglycerides; LIRI; Lipoprotein Insulin Resistance Index; LDL-C; Low density lipoprotein cholesterol; HDL-C; High density lipoprotein cholesterol; BAS; Bile acid sequestrants ID DENSITY-LIPOPROTEIN PARTICLES; TO-RETENTION HYPOTHESIS; BILE-ACID SEQUESTRANTS; INSULIN-RESISTANCE; DIETARY FIBER; CHOLESTEROL; DISEASE; RATS; ATHEROGENESIS; TRIGLYCERIDE AB Background: This single center, double-blinded, cross-over, placebo controlled clinical trial investigated the effect of oral a-cyclodextrin (alpha-CD), a soluble dietary fiber, on blood lipid and lipoprotein levels in healthy human subjects. alpha-CD, a cyclical polymer containing 6 glucose subunits, is currently sold as an over the counter food supplement and is also a common additive in many foods. alpha-CD forms a hydrophobic central cavity that binds lipids and has been shown in animal studies and in previous clinical trials to alter plasma lipid levels. Methods: We screened for healthy subjects, males and females, between ages 18 to 75. Out of total 103 subjects interviewed, 75 subjects completed the study. Qualified individuals in each gender group were randomized into two groups in terms of which treatment arm they received first (placebo vs. alpha-CD, receiving 6 grams P.O. a day, for 12-14 weeks with a 7 day wash out between arms). The primary outcome variable, plasma total cholesterol, as well as other tests related to lipids and lipoprotein and glucose metabolism, were measured at baseline and at the end of each arm of the study. Results: alpha-CD was well tolerated; no serious adverse events related to alpha-CD were observed. Approximately 8 % of the subjects on alpha-CD complained of minor gastrointestinal symptoms versus 3 % on placebo (p = 0.2). Small-LDL particle number decreased 10 % (p < 0.045) for subjects on alpha-CD versus placebo. Fasting plasma glucose (1.6 %, p < 0.05) and Insulin resistance index (11 %, p < 0.04) were also decreased when on alpha-CD versus placebo. Conclusion: alpha-CD treatment appears to be safe and well tolerated in healthy individuals and showed a modest reduction in small LDL particles, and an improvement in glucose related parameters. C1 [Amar, Marcelo J. A.; Kaler, Maryann; Courville, Amber B.; Shamburek, Robert; Sampson, Maureen; Remaley, Alan T.] NHLBI, Lipoprot Metab Sect, Cardiopulm Branch, NIH, Bldg 10,Room 8 N-228,10 Ctr Dr MSC 1666, Bethesda, MD 20892 USA. RP Amar, MJA (reprint author), NHLBI, Lipoprot Metab Sect, Cardiopulm Branch, NIH, Bldg 10,Room 8 N-228,10 Ctr Dr MSC 1666, Bethesda, MD 20892 USA. EM ma90x@nih.gov FU Intramural Research Program of the National Institutes of Health [National Heart, Lung, and Blood Institute] FX This research was supported by Intramural Research Program of the National Institutes of Health [National Heart, Lung, and Blood Institute]. NR 34 TC 2 Z9 2 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-511X J9 LIPIDS HEALTH DIS JI Lipids Health Dis. PD JUL 12 PY 2016 VL 15 AR 115 DI 10.1186/s12944-016-0284-6 PG 8 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA DR6FE UT WOS:000379996800001 PM 27405337 ER PT J AU Watters, SA Mlcochova, P Maldarelli, F Goonetilleke, N Pillay, D Gupta, RK AF Watters, Sarah A. Mlcochova, Petra Maldarelli, Frank Goonetilleke, Nilu Pillay, Deenan Gupta, Ravindra K. TI Sequential CCR5-Tropic HIV-1 Reactivation from Distinct Cellular Reservoirs following Perturbation of Elite Control SO PLOS ONE LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; T-CELLS; CORECEPTOR USAGE; PHYLOGENIES; DISCONTINUATION; IDENTIFICATION; REPLICATION; MACROPHAGES; PREDICTION AB Background HIV Elite Controllers may reveal insights into virus persistence given they harbour small reservoir sizes, akin to HIV non-controllers treated early with combination antiretroviral therapy. Both groups of patients represent the most promising candidates for interventions aimed at sustained remission or 'cure'. Analytic treatment interruption (ATI) in the latter group leads to stochastic rebound of virus, though it is unclear whether loss of elite control is also associated with similar rebound characteristics. Methods We studied three discrete periods of virus rebound during myeloma related immune disruption over 2.5 years in an elite controller who previously underwent autologous stem cell transplantation (ASCT) in the absence of any antiretroviral therapy. Single genome sequencing of the V1-V4 region of env in PBMC and plasma was performed and phylogenies reconstructed. Average pairwise distance (APD) was calculated and non-parametric methods used to assess compartmentalisation. Coreceptor usage was predicted based on genotypic algorithms. Results 122 single genome sequences were obtained (median 26 sequences per rebound). The initial rebounding plasma env sequences following ASCT represented two distinct lineages, and clustered with proviral DNA sequences isolated prior to ASCT. One of the lineages was monophyletic, possibly indicating reactivation from clonally expanded cells. The second rebound occurred 470 days after spontaneous control of the first rebound and was phylogenetically distinct from the first, confirmed by compartmentalisation analysis, with a different cellular origin rather than ongoing replication. By contrast, third rebound viruses clustered with second rebound viruses, with evidence for ongoing evolution that was associated with lymphopenia and myeloma progression. Following ASCT a shift in tropism from CXCR4-tropic viruses to a CCR5-tropic population was observed to persist through to the third rebound. Conclusions Our data highlight similarities in the viral reservoir between elite and non-controllers undergoing ATI following allogeneic transplantation. The lack of propagation of CXCR4 using viruses following transplantation warrants further study. C1 [Watters, Sarah A.; Mlcochova, Petra; Pillay, Deenan; Gupta, Ravindra K.] UCL, Div Infect & Immun, London, England. [Watters, Sarah A.; Maldarelli, Frank] NCI, HIV Dynam & Replicat Program, Frederick, MD USA. [Goonetilleke, Nilu] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC USA. [Pillay, Deenan] Africa Ctr Hlth & Populat Studies, Durban, Kwazulu Natal, South Africa. RP Gupta, RK (reprint author), UCL, Div Infect & Immun, London, England. EM Ravindra.gupta@ucl.ac.uk FU Wellcome Trust [WT098251AIA]; National Institutes for Health Research University College London Hospitals Biomedical Research Centre FX This work was supported by Wellcome Trust (SAW) WT098251AIA; National Institutes for Health Research University College London Hospitals Biomedical Research Centre. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 0 Z9 0 U1 4 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 12 PY 2016 VL 11 IS 7 AR e0158854 DI 10.1371/journal.pone.0158854 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ9CO UT WOS:000379508200017 PM 27403738 ER PT J AU Liu, SH Liu, J Ma, Q Cao, L Fattah, RJ Yu, ZX Bugge, TH Finkel, T Leppla, SH AF Liu, Shihui Liu, Jie Ma, Qian Cao, Liu Fattah, Rasem J. Yu, Zuxi Bugge, Thomas H. Finkel, Toren Leppla, Stephen H. TI Solid tumor therapy by selectively targeting stromal endothelial cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE anthrax toxin; tumor targeting; angiogenesis; CMG2; TEM8 ID ANTHRAX LETHAL FACTOR; CAPILLARY MORPHOGENESIS PROTEIN-2; CHRONIC LYMPHOCYTIC-LEUKEMIA; PROTECTIVE ANTIGEN; TOXIN VARIANTS; KINASE-KINASE; CANCER; ANGIOGENESIS; RECEPTOR; MATRIX AB Engineered tumor-targeted anthrax lethal toxin proteins have been shown to strongly suppress growth of solid tumors in mice. These toxins work through the native toxin receptors tumor endothelium marker-8 and capillary morphogenesis protein-2 (CMG2), which, in other contexts, have been described as markers of tumor endothelium. We found that neither receptor is required for tumor growth. We further demonstrate that tumor cells, which are resistant to the toxin when grown in vitro, become highly sensitive when implanted in mice. Using a range of tissue-specific loss-of-function and gain-of-function genetic models, we determined that this in vivo toxin sensitivity requires CMG2 expression on host-derived tumor endothelial cells. Notably, engineered toxins were shown to suppress the proliferation of isolated tumor endothelial cells. Finally, we demonstrate that administering an immunosuppressive regimen allows animals to receive multiple toxin dosages and thereby produces a strong and durable antitumor effect. The ability to give repeated doses of toxins, coupled with the specific targeting of tumor endothelial cells, suggests that our strategy should be efficacious for a wide range of solid tumors. C1 [Liu, Shihui; Ma, Qian; Fattah, Rasem J.; Leppla, Stephen H.] NIAID, Microbial Pathogenesis Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Liu, Shihui; Bugge, Thomas H.] Natl Inst Dent & Craniofacial Res, Proteases & Tissue Remodeling Sect, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Liu, Jie; Cao, Liu; Finkel, Toren] NHLBI, Ctr Mol Med, NIH, Bldg 10, Bethesda, MD 20892 USA. [Yu, Zuxi] NHLBI, Pathol Core Facil, NIH, Bldg 10, Bethesda, MD 20892 USA. [Cao, Liu] China Med Univ, Minist Educ, Key Lab Med Cell Biol, Shenyang 110001, Peoples R China. RP Liu, SH; Leppla, SH (reprint author), NIAID, Microbial Pathogenesis Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.; Liu, SH (reprint author), Natl Inst Dent & Craniofacial Res, Proteases & Tissue Remodeling Sect, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. EM shihui.liu@nih.gov; sleppla@niaid.nih.gov FU Divisions of Intramural Research of the National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute; National Institute of Dental and Craniofacial Research, National Institutes of Health FX We thank Mahtab Moayeri for helpful discussions. This research was supported with funds from the Divisions of Intramural Research of the National Institute of Allergy and Infectious Diseases, the National Heart, Lung, and Blood Institute, and the National Institute of Dental and Craniofacial Research, National Institutes of Health. NR 54 TC 1 Z9 1 U1 7 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 12 PY 2016 VL 113 IS 28 BP E4079 EP E4087 DI 10.1073/pnas.1600982113 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR1VX UT WOS:000379694100014 PM 27357689 ER PT J AU Fauci, AS AF Fauci, Anthony S. TI An HIV Vaccine Mapping Uncharted Territory SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID INFECTION C1 [Fauci, Anthony S.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Fauci, AS (reprint author), NIAID, Immunoregulat Lab, Bldg 31,Room 7A-03,31 Ctr Dr,MSC 2520, Bethesda, MD 20892 USA. EM afauci@niaid.nih.gov NR 7 TC 1 Z9 1 U1 1 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 JUL 12 PY 2016 VL 316 IS 2 BP 143 EP 144 DI 10.1001/jama.2016.7538 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DQ9CW UT WOS:000379509000006 PM 27404178 ER PT J AU Metsch, LR Feaster, DJ Gooden, L Matheson, T Stitzer, M Das, M Jain, MK Rodriguez, AE Armstrong, WS Lucas, GM Nijhawan, AE Drainoni, ML Herrera, P Vergara-Rodriguez, P Jacobson, JM Mugavero, MJ Sullivan, M Daar, ES McMahon, DK Ferris, DC Lindblad, R VanVeldhuisen, P Oden, N Castellon, PC Tross, S Haynes, LF Douaihy, A Sorensen, JL Metzger, DS Mandler, RN Colfax, GN del Rio, C AF Metsch, Lisa R. Feaster, Daniel J. Gooden, Lauren Matheson, Tim Stitzer, Maxine Das, Moupali Jain, Mamta K. Rodriguez, Allan E. Armstrong, Wendy S. Lucas, Gregory M. Nijhawan, Ank E. Drainoni, Mari-Lynn Herrera, Patricia Vergara-Rodriguez, Pamela Jacobson, Jeffrey M. Mugavero, Michael J. Sullivan, Meg Daar, Eric S. McMahon, Deborah K. Ferris, David C. Lindblad, Robert VanVeldhuisen, Paul Oden, Neal Castellon, Pedro C. Tross, Susan Haynes, Louise F. Douaihy, Antoine Sorensen, James L. Metzger, David S. Mandler, Raul N. Colfax, Grant N. del Rio, Carlos TI Effect of Patient Navigation With or Without Financial Incentives on Viral Suppression Among Hospitalized Patients With HIV Infection and Substance Use A Randomized Clinical Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID ADDICTION SEVERITY INDEX; CRACK COCAINE USERS; DRUG-USERS; CASE-MANAGEMENT; SCREENING-TEST; CARE; RETENTION; ADHERENCE; STATES; PROGRESSION AB IMPORTANCE Substance use is a major driver of the HIV epidemic and is associated with poor HIV care outcomes. Patient navigation (care coordination with case management) and the use of financial incentives for achieving predetermined outcomes are interventions increasingly promoted to engage patients in substance use disorders treatment and HIV care, but there is little evidence for their efficacy in improving HIV-1 viral suppression rates. OBJECTIVE To assess the effect of a structured patient navigation intervention with or without financial incentives to improve HIV-1 viral suppression rates among patients with elevated HIV-1 viral loads and substance use recruited as hospital inpatients. DESIGN, SETTING, AND PARTICIPANTS From July 2012 through January 2014, 801 patients with HIV infection and substance use from 11 hospitals across the United States were randomly assigned to receive patient navigation alone (n = 266), patient navigation plus financial incentives (n = 271), or treatment as usual (n = 264). HIV-1 plasma viral load was measured at baseline and at 6 and 12 months. INTERVENTIONS Patient navigation included up to 11 sessions of care coordination with case management and motivational interviewing techniques over 6 months. Financial incentives (up to $1160) were provided for achieving targeted behaviors aimed at reducing substance use, increasing engagement in HIV care, and improving HIV outcomes. Treatment as usual was the standard practice at each hospital for linking hospitalized patients to outpatient HIV care and substance use disorders treatment. MAIN OUTCOMES AND MEASURES The primary outcome was HIV viral suppression (<= 200 copies/mL) relative to viral nonsuppression or death at the 12-month follow-up. RESULTS Of 801 patients randomized, 261 (32.6%) were women (mean [SD] age, 44.6 years [10.0 years]). There were no differences in rates of HIV viral suppression versus nonsuppression or death among the 3 groups at 12 months. Eighty-five of 249 patients (34.1%) in the usual-treatment group experienced treatment success compared with 89 of 249 patients (35.7%) in the navigation-only group for a treatment difference of 1.6% (95% CI, -6.8% to 10.0%; P = .80) and compared with 98 of 254 patients (38.6%) in the navigation-plus-incentives group for a treatment difference of 4.5%(95% CI -4.0% to 12.8%; P = .68). The treatment difference between the navigation-only and the navigation-plus-incentives group was -2.8%(95% CI, -11.3% to 5.6%; P = .68). CONCLUSIONS AND RELEVANCE Among hospitalized patients with HIV infection and substance use, patient navigation with or without financial incentives did not have a beneficial effect on HIV viral suppression relative to nonsuppression or death at 12 months vs treatment as usual. These findings do not support these interventions in this setting. C1 [Metsch, Lisa R.; Gooden, Lauren; Castellon, Pedro C.] Columbia Univ, Dept Sociomed Sci, Mailman Sch Publ Hlth, 722 W168th St,Room 918, New York, NY 10032 USA. [Feaster, Daniel J.] Univ Miami, Miller Sch Med, Dept Publ Hlth Sci, Miami, FL 33136 USA. [Matheson, Tim; Das, Moupali; Colfax, Grant N.] San Francisco Dept Publ Hlth, San Francisco, CA USA. [Stitzer, Maxine] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Das, Moupali] San Francisco Gen Hosp, San Francisco, CA 94110 USA. [Das, Moupali] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Jain, Mamta K.; Nijhawan, Ank E.] Univ Texas Southwestern Med Ctr Dallas, Div Infect Dis, Dept Internal Med, Dallas, TX USA. [Jain, Mamta K.] Parkland Hlth & Hosp Syst, Dallas, TX USA. [Rodriguez, Allan E.] Univ Miami, Miller Sch Med, Div Infect Dis, Dept Med, Miami, FL 33136 USA. [Armstrong, Wendy S.; del Rio, Carlos] Emory Univ, Sch Med, Dept Med, Div Infect Dis, Atlanta, GA USA. [Lucas, Gregory M.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Drainoni, Mari-Lynn] Boston Univ, Sch Publ Hlth, Dept Hlth Law Policy & Management, Boston, MA USA. [Drainoni, Mari-Lynn; Sullivan, Meg] Boston Univ, Sch Med, Dept Med, Infect Dis Sect, Boston, MA 02118 USA. [Herrera, Patricia; Vergara-Rodriguez, Pamela] John H Stroger Jr Hosp Cook Cty, Ruth M Rothstein CORE Ctr, Chicago, IL USA. [Jacobson, Jeffrey M.] Drexel Univ, Div Infect Dis, Coll Med, Philadelphia, PA 19104 USA. [Jacobson, Jeffrey M.] Temple Univ, Lewis Katz Sch Med, Dept Med, Philadelphia, PA 19122 USA. [Jacobson, Jeffrey M.] Temple Univ, Lewis Katz Sch Med, Dept Neurosci, Philadelphia, PA 19122 USA. [Jacobson, Jeffrey M.] Temple Univ, Lewis Katz Sch Med, Inst Translat AIDS Res, Philadelphia, PA 19122 USA. [Mugavero, Michael J.] Univ Alabama Birmingham, Dept Med, Div Infect Dis, Birmingham, AL 35294 USA. [Daar, Eric S.] Univ Calif Los Angeles, Med Ctr, Los Angeles Biomed Res Inst Harbor, Torrance, CA 90509 USA. [McMahon, Deborah K.] Univ Pittsburgh, Pittsburgh, PA USA. [Ferris, David C.] Mt Sinai St Lukes & Mt Sinai West Hosp, New York, NY USA. [Ferris, David C.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Lindblad, Robert; VanVeldhuisen, Paul; Oden, Neal] Emmes Corp, Rockville, MD USA. [Tross, Susan] Columbia Univ, HIV Ctr Clin & Behav Studies, Div Gender Sexual & Hlth, Dept Psychiat, New York, NY USA. [Tross, Susan] Columbia Univ, Greater New York Node, Natl Drug Abuse Treatment Clin Trials Network, Substance Use Res Ctr,Dept Psychiat, New York, NY USA. [Haynes, Louise F.] Med Univ South Carolina, Div Addict Sci, Dept Psychiat & Behav Sci, Charleston, SC 29425 USA. [Douaihy, Antoine] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Sorensen, James L.] Univ Calif San Francisco, Dept Psychiat, Western States Node, Natl Drug Abuse Treatment Clin Trials Network, San Francisco, CA USA. [Metzger, David S.] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Metzger, David S.] Treatment Res Inst, Philadelphia, PA USA. [Mandler, Raul N.] NIDA, Ctr Clin Trials Network, NIH, Bethesda, MD 20892 USA. [del Rio, Carlos] Emory Univ, Hubert Dept Global Hlth, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. RP Metsch, LR (reprint author), Columbia Univ, Dept Sociomed Sci, Mailman Sch Publ Hlth, 722 W168th St,Room 918, New York, NY 10032 USA. EM lm2892@columbia.edu RI del Rio, Carlos/B-3763-2012 OI del Rio, Carlos/0000-0002-0153-3517 FU National Institute on Drug Abuse [U10DA013720, UG1DA013720, U10DA013035, UG1DA013035, U10DA013034, UG1DA013034]; University of Miami Center for AIDS Research (CFAR) [P30AI073961]; Emory University CFAR [P30AI050409]; Atlanta Clinical and Translational Science Institute [UL1TR000454]; HIV Center for Clinical and Behavioral Studies at the New York State Psychiatric Institute/Columbia University Medical Center [P30MH043520]; The National Institute on Drug Abuse [U10DA013727, UG1DA013727, U10DA020024, UG1DA020024, U10DA013732, UG1DA013732, U10DA015831, UG1DA015831, U10DA015815, UG1DA015815, U10DA020036, U10DA013043, U10DA013045, HHSN271200900034C/N01DA92217, HHSN271201400028C/N01DA142237, HHSN271201000024C/N01DA102221] FX Funding for this study and analysis was provided for the study's principal investigators by the National Institute on Drug Abuse under the following awards: U10DA013720 and UG1DA013720 (Drs Jose Szapocznik and Lisa R. Metsch); U10DA013035 and UG1DA013035 (Drs John Rotrosen and Edward V. Nunes, Jr); U10DA013034 and UG1DA013034 (Drs Maxine Stitzer and Robert Schwartz); U10DA013727 and UG1DA013727 (Drs. Kathleen T. Brady and Matthew Carpenter); U10DA020024 and UG1DA020024 (Dr Madhukar H. Trivedi); U10DA013732 and UG1DA013732 (Dr Theresa Winhusen); U10DA015831 and UG1DA015831 (Drs. Roger D. Weiss and Kathleen Carroll); U10DA015815 and UG1DA015815 (Drs James L. Sorensen and Dennis McCarty); U10DA020036 (Dr Dennis Daley); U10DA013043 (Dr George Woody); U10DA013045 (Dr Walter Ling); HHSN271200900034C/N01DA92217 and HHSN271201400028C/N01DA142237 (Dr Paul Van Veldhuisen); and HHSN271201000024C/N01DA102221 (Dr Robert Lindblad). Support from the University of Miami Center for AIDS Research (CFAR) (P30AI073961; Dr Savita Pahwa), the Emory University CFAR (P30AI050409; Drs Carlos del Rio, James W. Curran, and Eric Hunter), the Atlanta Clinical and Translational Science Institute (UL1TR000454; Dr David Stephens), and the HIV Center for Clinical and Behavioral Studies at the New York State Psychiatric Institute/Columbia University Medical Center (P30MH043520; Dr Robert Remien) is also acknowledged. NR 36 TC 7 Z9 7 U1 3 U2 6 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 JUL 12 PY 2016 VL 316 IS 2 BP 156 EP 170 DI 10.1001/jama.2016.8914 PG 15 WC Medicine, General & Internal SC General & Internal Medicine GA DQ9CW UT WOS:000379509000012 PM 27404184 ER PT J AU Kong, XR Kigozi, G Ssekasanvu, J Nalugoda, F Nakigozi, G Ndyanabo, A Lutalo, T Reynolds, SJ Ssekubugu, R Kagaayi, J Bugos, E Chang, LW Nanlesta, P Mary, G Berman, A Quinn, TC Serwadda, D Wawer, MJ Gray, RH AF Kong, Xiangrong Kigozi, Godfrey Ssekasanvu, Joseph Nalugoda, Fred Nakigozi, Gertrude Ndyanabo, Anthony Lutalo, Tom Reynolds, Steven J. Ssekubugu, Robert Kagaayi, Joseph Bugos, Eva Chang, Larry W. Nanlesta, Pilgrim Mary, Grabowski Berman, Amanda Quinn, Thomas C. Serwadda, David Wawer, Maria J. Gray, Ronald H. TI Association of Medical Male Circumcision and Antiretroviral Therapy Scale-up With Community HIV Incidence in Rakai, Uganda SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID PREVENTION; TRIAL; MEN; ACQUISITION; INFECTIONS; COVERAGE; RISK AB IMPORTANCE Medical male circumcision (MMC) and antiretroviral therapy (ART) are proven HIV prevention interventions, but there are limited data on the population-level effect of scale-up of these interventions in sub-Saharan Africa. Such evaluation is important for planning and resource allocation. OBJECTIVE To examine whether increasing community MMC and ART coverage was associated with reduced community HIV incidence in Rakai District, Uganda. DESIGN, SETTING, AND PARTICIPANTS Using person-level data from population-based surveys conducted from 1999 through 2013 in 45 rural Rakai communities, community-level ART and MMC coverage, sociodemographics, sexual behaviors, and HIV prevalence and incidence were estimated in 3 periods: prior to the availability of ART and MMC (1999-2004), during early availability of ART and MMC (2004-2007), and during mature program scale-up (2007-2013). EXPOSURES Community MMC coverage in males and ART coverage in HIV-positive persons of the opposite sex based on self-reported MMC status and ART use. MAIN OUTCOMES AND MEASURES Adjusted incidence rate ratios (IRRs) for sex-specific community HIV incidence estimated using multivariable Poisson regression with generalized estimating equations. RESULTS From 1999 through 2013, 44 688 persons participated in 1 or more surveys (mean age at the first survey, 24.6 years [range, 15-49]; female, 56.5%; mean survey participation rate, 92.6%[95% CI, 92.4%-92.7%]). Median community MMC coverage increased from 19% to 39%, and median community ART coverage rose from 0% to 21% in males and from 0% to 26% in females. Median community HIV incidence declined from 1.25 to 0.84 per 100 person-years in males, and from 1.25 to 0.99 per 100 person-years in females. Among males, each 10% increase in community MMC coverage was associated with an adjusted IRR of 0.87 (95% CI, 0.82-0.93). Comparing communities with MMC coverage more than 40% (mean male community incidence, 1.03 per 100 person-years) with communities with coverage of 10% or less (mean male incidence, 1.69 per 100 person-years), the adjusted IRR was 0.61 (95% CI, 0.43-0.88). For each 10% increase in female self-reported ART coverage, there was no significant reduction in male HIV incidence (adjusted IRR, 0.95 [95% CI, 0.81-1.13]). Comparing communities with female ART coverage more than 20%(mean male incidence, 0.87 per 100 person-years) to communities with female ART coverage of 20% or less (mean male incidence, 1.17 per 100 person-years), the adjusted IRR was 0.77 (95% CI, 0.61-0.98). Neither MMC nor male ART coverage was associated with lower female community HIV incidence. CONCLUSIONS AND RELEVANCE In Rakai, Uganda, increasing community MMC and female ART coverage was associated with lower community HIV incidence in males. If similar associations are found elsewhere, this would support further scale-up of MMC and ART for HIV prevention in sub-Saharan Africa. C1 [Kong, Xiangrong; Ssekasanvu, Joseph; Bugos, Eva; Chang, Larry W.; Mary, Grabowski; Wawer, Maria J.; Gray, Ronald H.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Kong, Xiangrong] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Kigozi, Godfrey; Ssekasanvu, Joseph; Nalugoda, Fred; Nakigozi, Gertrude; Ndyanabo, Anthony; Lutalo, Tom; Ssekubugu, Robert; Kagaayi, Joseph; Serwadda, David; Wawer, Maria J.; Gray, Ronald H.] Rakai Hlth Sci Program, Entebbe, Uganda. [Reynolds, Steven J.; Chang, Larry W.; Quinn, Thomas C.] Johns Hopkins Sch Med, Baltimore, MD USA. [Reynolds, Steven J.; Quinn, Thomas C.] NIAID, Div Intramural Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Nanlesta, Pilgrim] Populat Council, Washington, DC USA. [Berman, Amanda] Johns Hopkins, Ctr Commun Programs, Baltimore, MD USA. [Serwadda, David] Makerere Univ, Sch Publ Hlth, Kampala, Uganda. RP Kong, XR (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, 627 N Washington St, Baltimore, MD 21205 USA. EM xkong4@jhu.edu FU National Institutes of Health (NIH) [K25AI114461, U01AI100031, R01HD050180, U01AI075115, R01 HD070769]; Division of Intramural Research at the National Institute of Allergy and Infectious Diseases; Bill and Melinda Gates Foundation [081113, 22006.03]; Johns Hopkins Center for AIDS Research [JHU CFAR P30AI094189] FX This study was supported by grants from the National Institutes of Health (NIH, K25AI114461, U01AI100031, R01HD050180, U01AI075115, R01 HD070769), the Division of Intramural Research at the National Institute of Allergy and Infectious Diseases, the Bill and Melinda Gates Foundation (#081113, 22006.03), and the Johns Hopkins Center for AIDS Research (JHU CFAR P30AI094189). NR 24 TC 2 Z9 2 U1 3 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 12 PY 2016 VL 316 IS 2 BP 182 EP 190 DI 10.1001/jama.2016.7292 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA DQ9CW UT WOS:000379509000014 PM 27404186 ER PT J AU Chen, Y Singh, S Matsumoto, A Manna, SK Abdelmegeed, MA Golla, S Murphy, RC Dong, HB Song, BJ Gonzalez, FJ Thompson, DC Vasiliou, V AF Chen, Ying Singh, Surendra Matsumoto, Akiko Manna, Soumen K. Abdelmegeed, Mohamed A. Golla, Srujana Murphy, Robert C. Dong, Hongbin Song, Byoung-Joon Gonzalez, Frank J. Thompson, David C. Vasiliou, Vasilis TI Chronic Glutathione Depletion Confers Protection against Alcohol-induced Steatosis: Implication for Redox Activation of AMP-activated Protein Kinase Pathway SO SCIENTIFIC REPORTS LA English DT Article ID INDUCED LIVER-INJURY; POLYUNSATURATED FATTY-ACIDS; OXIDATIVE STRESS; DEFICIENT MICE; GENE-EXPRESSION; KNOCKOUT MICE; ALDEHYDE DEHYDROGENASES; MOLECULAR-MECHANISMS; SUPEROXIDE-DISMUTASE; METABOLIZING ENZYME AB The pathogenesis of alcoholic liver disease (ALD) is not well established. However, oxidative stress and associated decreases in levels of glutathione (GSH) are known to play a central role in ALD. The present study examines the effect of GSH deficiency on alcohol-induced liver steatosis in Gclm knockout (KO) mice that constitutively have approximate to 15% normal hepatic levels of GSH. Following chronic (6 week) feeding with an ethanol-containing liquid diet, the Gclm KO mice were unexpectedly found to be protected against steatosis despite showing increased oxidative stress (as reflected in elevated levels of CYP2E1 and protein carbonyls). Gclm KO mice also exhibit constitutive activation of liver AMP-activated protein kinase (AMPK) pathway and nuclear factor-erythroid 2-related factor 2 target genes, and show enhanced ethanol clearance, altered hepatic lipid profiles in favor of increased levels of polyunsaturated fatty acids and concordant changes in expression of genes associated with lipogenesis and fatty acid oxidation. In summary, our data implicate a novel mechanism protecting against liver steatosis via an oxidative stress adaptive response that activates the AMPK pathway. We propose redox activation of the AMPK may represent a new therapeutic strategy for preventing ALD. C1 [Chen, Ying; Singh, Surendra; Dong, Hongbin; Vasiliou, Vasilis] Yale Univ, Dept Environm Hlth Sci, New Haven, CT 06520 USA. [Matsumoto, Akiko] Saga Univ, Sch Med, Dept Social Med, Saga 8498501, Japan. [Manna, Soumen K.; Golla, Srujana; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, Bethesda, MD 20852 USA. [Abdelmegeed, Mohamed A.; Song, Byoung-Joon] NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. [Murphy, Robert C.] Univ Colorado AMC, Dept Pharmacol, Aurora, CO 80045 USA. [Thompson, David C.] Univ Colorado AMC, Dept Clin Pharm, Aurora, CO 80045 USA. RP Vasiliou, V (reprint author), Yale Univ, Dept Environm Hlth Sci, New Haven, CT 06520 USA. EM vasilis.vasiliou@yale.edu FU NIH [AA022057, AA021724]; NIAAA [T32 AA007464] FX This work is supported in part by NIH grants AA022057 (VV), AA021724 (VV). HD was supported by the NIAAA T32 AA007464. NR 63 TC 1 Z9 1 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUL 12 PY 2016 VL 6 AR 29743 DI 10.1038/srep29743 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ7MW UT WOS:000379392600001 PM 27403993 ER PT J AU Steemers, B Vicente-Grabovetsky, A Barry, C Smulders, P Schroder, TN Burgess, N Doeller, CF AF Steemers, Ben Vicente-Grabovetsky, Alejandro Barry, Caswell Smulders, Peter Schroder, Tobias Navarro Burgess, Neil Doeller, Christian F. TI Hippocampal Attractor Dynamics Predict Memory-Based Decision Making SO CURRENT BIOLOGY LA English DT Article ID MEDIAL TEMPORAL-LOBE; COMPLEMENTARY-LEARNING-SYSTEMS; VOXEL PATTERN-ANALYSIS; SPATIAL NAVIGATION; RECOGNITION MEMORY; REAL-WORLD; REPRESENTATIONS; NETWORKS; CONTEXT; INTEGRATION AB Memories are thought to be retrieved by attractor dynamics if a given input is sufficiently similar to a stored attractor state [1-5]. The hippocampus, a region crucial for spatial navigation [6-12] and episodic memory [13-18], has been associated with attractorbased computations [5, 9], receiving support from the way rodent place cells ``remap'' nonlinearly between spatial representations [19-22]. In humans, nonlinear response patterns have been reported in perceptual categorization tasks [23-25]; however, it remains elusive whether human memory retrieval is driven by attractor dynamics and what neural mechanisms might underpin them. To test this, we used a virtual reality [7, 11, 26-28] task where participants learned object-location associations within two distinct virtual reality environments. Participants were subsequently exposed to four novel intermediate environments, generated by linearly morphing the background landscapes of the familiar environments, while tracking fMRI activity. We show that linear changes in environmental context cause linear changes in activity patterns in sensory cortex but cause dynamic, nonlinear changes in both hippocampal activity pattern and remembered locations. Furthermore, the sigmoidal response in the hippocampus scaled with the strength of the sigmoidal pattern in spatial memory. These results indicate that mnemonic decisions in an ambiguous novel context relate to putative attractor dynamics in the hippocampus, which support the dynamic remapping of memories. C1 [Steemers, Ben; Vicente-Grabovetsky, Alejandro; Smulders, Peter; Schroder, Tobias Navarro; Doeller, Christian F.] Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6525 EN Nijmegen, Netherlands. [Steemers, Ben] NIMH, Neuropsychol Lab, NIH, Bldg 9, Bethesda, MD 20892 USA. [Barry, Caswell] UCL, Res Dept Cell & Dev Biol, Gower St, London WC1E 6BT, England. [Burgess, Neil] UCL Inst Cognit Neurosci, 17 Queen Sq, London WC1N 3AZ, England. [Burgess, Neil] UCL Inst Neurol, Queen Sq, London WC1 3BG, England. RP Steemers, B; Doeller, CF (reprint author), Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6525 EN Nijmegen, Netherlands.; Steemers, B (reprint author), NIMH, Neuropsychol Lab, NIH, Bldg 9, Bethesda, MD 20892 USA. EM ben.steemers@nih.gov; christian.doeller@donders.ru.nl FU European Research Council [ERC-StG 261177]; Netherlands Organization for Scientific Research [NWO-Vidi 452-12-009]; Wellcome Trust; Medical Research Council, UK; Royal Society, UK [101208/z/13/z] FX This work was supported by European Research Council (ERC-StG 261177) and Netherlands Organization for Scientific Research (NWO-Vidi 452-12-009) fellowships awarded to C.F.D. N.B. is supported by the Wellcome Trust and the Medical Research Council, UK. C.B. is funded by the Wellcome Trust and the Royal Society, UK (101208/z/13/z). The authors would like to thank S. Auger and O. Vikbladh for earlier behavioral pilot work; S. Bosch for help with data acquisition; and A. Backus and J. Bellmund for useful discussions. NR 45 TC 1 Z9 1 U1 3 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 EI 1879-0445 J9 CURR BIOL JI Curr. Biol. PD JUL 11 PY 2016 VL 26 IS 13 BP 1750 EP 1757 DI 10.1016/j.cub.2016.04.063 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DY0PU UT WOS:000384799500042 PM 27345167 ER PT J AU Lu, R Wang, P Parton, T Zhou, Y Chrysovergis, K Rockowitz, S Chen, WY Abdel-Wahab, O Wade, PA Zheng, DY Wang, GG AF Lu, Rui Wang, Ping Parton, Trevor Zhou, Yang Chrysovergis, Kaliopi Rockowitz, Shira Chen, Wei-Yi Abdel-Wahab, Omar Wade, Paul A. Zheng, Deyou Wang, Gang Greg TI Epigenetic Perturbations by Arg882-Mutated DNMT3A Potentiate Aberrant Stem Cell Gene-Expression Program and Acute Leukemia Development SO CANCER CELL LA English DT Article ID ACUTE MYELOID-LEUKEMIA; MLL-REARRANGED LEUKEMIA; HEMATOPOIETIC STEM; DNA METHYLATION; CLONAL HEMATOPOIESIS; H3K79 METHYLATION; HOX GENES; MUTATIONS; LEUKEMOGENESIS; TRANSFORMATION AB DNA methyltransferase 3A(DNMT3A) is frequently mutated in hematological cancers; however, the underlying oncogenic mechanism remains elusive. Here, we report that the DNMT3A mutational hotspot at Arg882 (DNMT3A(R882H)) cooperates with NRAS mutation to transform hematopoietic stem/progenitor cells and induce acute leukemia development. Mechanistically, DNMT3A(R882H) directly binds to and potentiates transactivation of stemness genes critical for leukemogenicity including Meis1, Mn1, and Hoxa gene cluster. DNMT3A(R882H) induces focal epigenetic alterations, including CpG hypomethylation and concurrent gain of active histone modifications, at cis-regulatory elements such as enhancers to facilitate gene transcription. CRISPR/Cas9-mediated ablation of a putative Meis1 enhancer carrying DNMT3A(R882H)-induced DNA hypomethylation impairs Meis1 expression. Importantly, DNMT3A(R882H)-induced gene-expression programs can be repressed through Dot1l inhibition, providing an attractive therapeutic strategy for DNMT3A-mutated leukemias. C1 [Lu, Rui; Parton, Trevor; Wang, Gang Greg] Univ N Carolina, Sch Med, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Lu, Rui; Wang, Gang Greg] Univ N Carolina, Sch Med, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. [Wang, Ping; Zheng, Deyou] Albert Einstein Coll Med, Dept Neurol, Bronx, NY 10461 USA. [Zhou, Yang] Univ N Carolina, McAllister Heart Inst, Dept Pathol & Lab Med, Sch Med, Chapel Hill, NC 27599 USA. [Chrysovergis, Kaliopi; Wade, Paul A.] NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. [Rockowitz, Shira; Zheng, Deyou] Albert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USA. [Rockowitz, Shira; Zheng, Deyou] Albert Einstein Coll Med, Dept Neurosci, Bronx, NY 10461 USA. [Chen, Wei-Yi] Natl Yang Ming Univ, Inst Biochem & Mol Biol, Taipei 11221, Taiwan. [Abdel-Wahab, Omar] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. [Wang, Gang Greg] Univ North Carolina Chapel Hill, Curriculum Genet & Mol Biol, Chapel Hill, NC 27599 USA. RP Wang, GG (reprint author), Univ N Carolina, Sch Med, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA.; Wang, GG (reprint author), Univ N Carolina, Sch Med, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA.; Zheng, DY (reprint author), Albert Einstein Coll Med, Dept Neurol, Bronx, NY 10461 USA.; Zheng, DY (reprint author), Albert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USA.; Zheng, DY (reprint author), Albert Einstein Coll Med, Dept Neurosci, Bronx, NY 10461 USA.; Wang, GG (reprint author), Univ North Carolina Chapel Hill, Curriculum Genet & Mol Biol, Chapel Hill, NC 27599 USA. EM deyou.zheng@einstein.yu.edu; greg_wang@med.unc.edu OI Wang, G Greg/0000-0002-7210-9940; Lu, Rui/0000-0003-1593-2612 FU NCI [K99/R00, CA151683]; DoD [CA130247]; Gabrielle's Angel Foundation; North Carolina Biotech Center Institutional Support Grant [2012-IDG-1006]; UNC Cancer Center Core Support Grant [P30 CA016086] FX We graciously thank Drs. Y. Xiong and K. Humphries for providing constructs, M. Kamps and M. Minden for leukemia lines, M. Torres for Meis1 antibody, D. Bauer and F. Zhang for CRISPR/Cas9 systems, M. Rehli for a CpG-free reporter, and J. Bear for an shRNA vector used in this study. Thanks to Drs. D. Allison and L. Cai and other members of the Wang laboratory for helpful discussion and technical support. We thank UNC's Genomics Core, Animal Studies Core, Flow Core, and HTSF core for their support of this work. This work is supported by NCI K99/R00 grant CA151683 to G.G.W., a DoD grant CA130247 to G.G.W., and grants of Gabrielle's Angel Foundation to O.A. and G.G.W. G.G.W. is an American Society of Hematology Scholar and a Kimmel Scholar. R.L. is a Lymphoma Research Foundation Postdoctorate Fellow. UNC Cores including the flow cytometry facility are supported in part by the North Carolina Biotech Center Institutional Support Grant 2012-IDG-1006 and UNC Cancer Center Core Support Grant P30 CA016086. NR 45 TC 5 Z9 5 U1 3 U2 10 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 JUL 11 PY 2016 VL 30 IS 1 BP 92 EP 107 DI 10.1016/j.ccell.2016.05.008 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DR7JY UT WOS:000380077100014 PM 27344947 ER PT J AU Di Biase, S Lee, C Brandhorst, S Manes, B Buono, R Cheng, CW Cacciottolo, M Martin-Montalvo, A de Cabo, R Wei, M Morgan, TE Longo, VD AF Di Biase, Stefano Lee, Changhan Brandhorst, Sebastian Manes, Brianna Buono, Roberta Cheng, Chia-Wei Cacciottolo, Mafalda Martin-Montalvo, Alejandro de Cabo, Rafael Wei, Min Morgan, Todd E. Longo, Valter D. TI Fasting-Mimicking Diet Reduces HO-1 to Promote T Cell-Mediated Tumor Cytotoxicity SO CANCER CELL LA English DT Article ID HEME OXYGENASE-1; CARBON-MONOXIDE; BREAST-CANCER; IMMUNITY; CHEMOTHERAPY; MECHANISMS; GROWTH; MICE; IMMUNOSUPPRESSION; CYCLOPHOSPHAMIDE AB Immune-based interventions are promising strategies to achieve long-term cancer-free survival. Fasting was previously shown to differentially sensitize tumors to chemotherapy while protecting normal cells, including hematopoietic stem and immune cells, from its toxic side effects. Here, we show that the combination of chemotherapy and a fasting-mimicking diet (FMD) increases the levels of bone marrow common lymphoid progenitor cells and cytotoxic CD8(+) tumor-infiltrating lymphocytes (TILs), leading to a major delay in breast cancer and melanoma progression. In breast tumors, this effect is partially mediated by the downregulation of the stress-responsive enzyme heme oxygenase-1 (HO-1). These data indicate that FMD cycles combined with chemotherapy can enhance T cell-dependent targeted killing of cancer cells both by stimulating the hematopoietic system and by enhancing CD8(+)-dependent tumor cytotoxicity. C1 [Di Biase, Stefano; Lee, Changhan; Brandhorst, Sebastian; Manes, Brianna; Buono, Roberta; Cheng, Chia-Wei; Cacciottolo, Mafalda; Wei, Min; Morgan, Todd E.; Longo, Valter D.] Univ So Calif, Leonard Davis Sch Gerontol, Longev Inst, Los Angeles, CA 90089 USA. [Di Biase, Stefano; Lee, Changhan; Brandhorst, Sebastian; Manes, Brianna; Buono, Roberta; Cheng, Chia-Wei; Cacciottolo, Mafalda; Wei, Min; Morgan, Todd E.; Longo, Valter D.] Univ So Calif, Dept Biol Sci, Los Angeles, CA 90089 USA. [Martin-Montalvo, Alejandro; de Cabo, Rafael] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Longo, Valter D.] FIRC Inst Mol Oncol, IFOM, I-20139 Milan, Italy. RP Longo, VD (reprint author), Univ So Calif, Leonard Davis Sch Gerontol, Longev Inst, Los Angeles, CA 90089 USA.; Longo, VD (reprint author), Univ So Calif, Dept Biol Sci, Los Angeles, CA 90089 USA.; Longo, VD (reprint author), FIRC Inst Mol Oncol, IFOM, I-20139 Milan, Italy. EM vlongo@usc.edu RI Martin-Montalvo, Alejandro/C-2031-2017; OI Martin-Montalvo, Alejandro/0000-0002-3886-5355; , rafael/0000-0003-2830-5693; Wei, Min/0000-0002-2649-9271 FU NIH [P01 AG034906]; NCI [HHSN261201200051C]; Intramural Research Program of the National Institute on Aging, NIH FX This study was funded by NIH grant P01 AG034906 to V.D.L. and subcontract HHSN261201200051C from NCI to M.W. R.d.C and A.M.M. were funded by the Intramural Research Program of the National Institute on Aging, NIH. We thank William Wood, Elin Lehrmann, and Yongqing Zhang for assistance with microarray analyses. V.D.L. and T.M. have equity interest in L-Nutra, a company developing medical food. NR 45 TC 11 Z9 11 U1 12 U2 17 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 JUL 11 PY 2016 VL 30 IS 1 BP 136 EP 146 DI 10.1016/j.ccell.2016.06.005 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DR7JY UT WOS:000380077100017 PM 27411588 ER PT J AU Meker, S Braitbard, O Hall, MD Hochman, J Tshuva, EY AF Meker, Sigalit Braitbard, Ori Hall, Matthew D. Hochman, Jacob Tshuva, Edit Y. TI Specific Design of Titanium(IV) Phenolato Chelates Yields Stable and Accessible, Effective and Selective Anticancer Agents SO CHEMISTRY-A EUROPEAN JOURNAL LA English DT Article DE antitumor agents; drug design; ligand design; N,O ligands; titanium ID HUMAN OVARIAN-CANCER; SUBSTITUTED AROMATIC RINGS; RAY-STRUCTURE ANALYSIS; TITANOCENE DICHLORIDE; METAL-COMPLEXES; CELL-LINES; SALAN-TITANIUM(IV) COMPLEXES; ANTIPROLIFERATIVE ACTIVITY; BIS(PHENOLATO) LIGANDS; MECHANISTIC INSIGHTS AB Octahedral titanium(IV) complexes of phenolato hexadentate ligands were developed and showed very high stability for days in water solutions. In vitro cytotoxicity studies showed that, whereas tetrakis(phenolato) systems are generally of low activity presumably due to inaccessibility, smaller bis(phenolato)bis(alkoxo) complexes feature high anticancer activity and accessibility even without formulations, also toward a cisplatin-resistant cell line. An all-aliphatic control complex was unstable and inactive. A leading phenolato complex also revealed: 1) high durability in fully aqueous solutions; accordingly, negligible loss of activity after preincubation for three days in medium or in serum; 2) maximal cellular accumulation and induction of apoptosis following 24-48 h of administration; 3) reduced impact on noncancerous fibroblast cells; 4) in vivo efficacy toward lymphoma cells in murine model; 5) high activity in NCI-60 panel, with average GI(50) of 4.6 +/- 2 mu m. This newly developed family of Ti-IV complexes is thus of great potential for anticancer therapy. C1 [Meker, Sigalit; Tshuva, Edit Y.] Hebrew Univ Jerusalem, Inst Chem, IL-9190401 Jerusalem, Israel. [Braitbard, Ori; Hochman, Jacob] Hebrew Univ Jerusalem, Alexander Silberman Inst Life Sci, Dept Cell & Dev Biol, IL-9190401 Jerusalem, Israel. [Hall, Matthew D.] NIH, NCATS Chem Genom Ctr, Natl Ctr Adv Translat Sci, 9800 Med Ctr Dr, Rockville, MD 20850 USA. RP Tshuva, EY (reprint author), Hebrew Univ Jerusalem, Inst Chem, IL-9190401 Jerusalem, Israel. EM edit.tshuva@mail.huji.ac.il RI Tshuva, Edit/B-5229-2015 OI Tshuva, Edit/0000-0001-7452-3611 FU European Council under the European Community [239603] FX We thank Dr. Benny Bogoslaysky for crystallographic analyses, and Dr. Karina Hazan for elemental analyses and MS measurements. Funding was received from the European Council under the European Community's Seventh Framework Programme (FP7/2007-2013)/ERC Grant agreement (No. 239603). NR 59 TC 3 Z9 3 U1 10 U2 13 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 0947-6539 EI 1521-3765 J9 CHEM-EUR J JI Chem.-Eur. J. PD JUL 11 PY 2016 VL 22 IS 29 BP 9986 EP 9995 DI 10.1002/chem.201601389 PG 10 WC Chemistry, Multidisciplinary SC Chemistry GA DS0FX UT WOS:000380271900019 PM 27320784 ER PT J AU Schoborg, TA Rusan, NM AF Schoborg, Todd A. Rusan, Nasser M. TI Taking Centrioles to the Elimination Round SO DEVELOPMENTAL CELL LA English DT Editorial Material ID STARFISH OOCYTES; POLAR BODIES; CENTROSOME AB Two recent papers published in The Journal of Cell Biology (Borrego-Pinto et al., 2016) and Science (Pimenta-Marques et al., 2016) have begun to shed light on the mechanism of centriole elimination during female oogenesis, highlighting a protective role for Polo kinase and the pericentriolar material. C1 [Schoborg, Todd A.; Rusan, Nasser M.] NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Rusan, NM (reprint author), NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM nasser@nih.gov RI Rusan, Nasser/P-3511-2016 FU Intramural NIH HHS [ZIA HL006126-05] NR 9 TC 0 Z9 0 U1 3 U2 3 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 JUL 11 PY 2016 VL 38 IS 1 BP 10 EP 12 DI 10.1016/j.devcel.2016.06.027 PG 3 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA DR7IO UT WOS:000380073400005 PM 27404354 ER PT J AU Chaudhari, SN Mukherjee, M Vagasi, AS Bi, G Rahman, MM Nguyen, CQ Paul, L Selhub, J Kipreos, ET AF Chaudhari, Snehal N. Mukherjee, Madhumati Vagasi, Alexandra S. Bi, Gaofeng Rahman, Mohammad M. Nguyen, Christine Q. Paul, Ligi Selhub, Jacob Kipreos, Edward T. TI Bacterial Folates Provide an Exogenous Signal for C. elegans Germline Stem Cell Proliferation SO DEVELOPMENTAL CELL LA English DT Article ID CAENORHABDITIS-ELEGANS; ESCHERICHIA-COLI; RECEPTOR-ALPHA; FOLIC-ACID; CANCER; TRANSPORTER; BIOLOGY; PROTEIN; PHOSPHORYLATION; DEFICIENCY AB Here we describe an in vitro primary culture system for Caenorhabditis elegans germline stem cells. This culture system was used to identify a bacterial folate as a positive regulator of germ cell proliferation. Folates are a family of B-complex vitamins that function in one-carbon metabolism to allow the de novo synthesis of amino acids and nucleosides. We show that germ cell proliferation is stimulated by the folate 10-formyl-tetrahydrofolate-Glun both in vitro and in animals. Other folates that can act as vitamins to rescue folate deficiency lack this germ cell stimulatory activity. The bacterial folate precursor dihydropteroate also promotes germ cell proliferation in vitro and in vivo, despite its inability to promote one-carbon metabolism. The folate receptor homolog FOLR-1 is required for the stimulation of germ cells by 10-formyl-tetrahydrofolate-Glun and dihydropteroate. This work defines a folate and folate-related compound as exogenous signals to modulate germ cell proliferation. C1 [Chaudhari, Snehal N.; Vagasi, Alexandra S.; Nguyen, Christine Q.; Kipreos, Edward T.] Univ Georgia, Dept Cellular Biol, Athens, GA 30602 USA. [Mukherjee, Madhumati; Rahman, Mohammad M.] Univ Georgia, Dept Genet, Athens, GA 30602 USA. [Bi, Gaofeng; Paul, Ligi; Selhub, Jacob] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Rahman, Mohammad M.] NIDDK, LCMB, Bethesda, MD 20892 USA. RP Kipreos, ET (reprint author), Univ Georgia, Dept Cellular Biol, Athens, GA 30602 USA. EM ekipreos@uga.edu FU NIH Office of Research Infrastructure Programs [P40 OD010440]; NSF [MCB-1138454]; NIH/NIGMS [R01 GM074212]; United States Department of Agriculture [51520-008-04S] FX We thank M.J. McEachern and members of the Kipreos laboratory for critical comments on the manuscript, as well as M.C. Zetka, D.B. Hausman, and S. Dougan for reagents or resources. Some C. elegans strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). This work was supported by grants from NSF (MCB-1138454) and NIH/NIGMS (R01 GM074212) (E.T.K.), and support from United States Department of Agriculture cooperative agreement 51520-008-04S (J.S.). Any opinions, findings, conclusion, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the United States Department of Agriculture. NR 60 TC 0 Z9 0 U1 10 U2 10 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 JUL 11 PY 2016 VL 38 IS 1 BP 33 EP 46 DI 10.1016/j.devcel.2016.06.013 PG 14 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA DR7IO UT WOS:000380073400008 PM 27404357 ER PT J AU Choi, CH Chung, JY Chung, EJ Sears, JD Lee, JW Bae, DS Hewitt, SM AF Choi, Chel Hun Chung, Joon-Yong Chung, Eun Joo Sears, John D. Lee, Jeong-Won Bae, Duk-Soo Hewitt, Stephen M. TI Prognostic significance of annexin A2 and annexin A4 expression in patients with cervical cancer SO BMC CANCER LA English DT Article DE ANXA2; ANXA4; Prognosis; Survival; Uterine cervical neoplasms ID CLEAR-CELL CARCINOMA; HUMAN-PAPILLOMAVIRUS; HEPATOCELLULAR-CARCINOMA; PROSTATE-CANCER; ENHANCED EXPRESSION; II EXPRESSION; TENASCIN-C; PROGRESSION; IV; MIGRATION AB Background: The annexins (ANXs) have diverse roles in tumor development and progression, however, their clinical significance in cervical cancer has not been elucidated. The present study was to investigate the clinical significance of annexin A2 (ANXA2) and annexin A4 (ANXA4) expression in cervical cancer. Methods: ANXA2 and ANXA4 immunohistochemical staining were performed on a cervical cancer tissue microarray consisting of 46 normal cervical epithelium samples and 336 cervical cancer cases and compared the data with clinicopathological variables, including the survival of cervical cancer patients. Results: ANXA2 expression was lower in cancer tissue (p = 0.002), whereas ANXA4 staining increased significantly in cancer tissues (p < 0.001). ANXA2 expression was more prominent in squamous cell carcinoma (p < 0.001), whereas ANXA4 was more highly expressed in adeno/adenosquamous carcinoma (p < 0.001). ANXA2 overexpression was positively correlated with advanced cancer phenotypes, whereas ANXA4 expression was associated with resistance to radiation with or without chemotherapy (p = 0.029). Notably, high ANXA2 and ANXA4 expression was significantly associated with shorter disease-free survival (p = 0.004 and p = 0.033, respectively). Multivariate analysis indicated that ANXA2+ (HR = 2.72, p = 0.003) and ANXA2+/ANXA4+ (HR = 2.69, p = 0.039) are independent prognostic factors of disease-free survival in cervical cancer. Furthermore, a random survival forest model using combined ANXA2, ANXA4, and clinical variables resulted in improved predictive power (mean C-index, 0.76) compared to that of clinical-variable-only models (mean C-index, 0.70) (p = 0.006). Conclusions: These findings indicate that detecting ANXA2 and ANXA4 expression may aid the evaluation of cervical carcinoma prognosis. C1 [Choi, Chel Hun; Chung, Joon-Yong; Sears, John D.; Hewitt, Stephen M.] NCI, Expt Pathol Lab, Pathol Lab, Ctr Canc Res,NIH, MSC 1500, Bethesda, MD 20892 USA. [Choi, Chel Hun; Lee, Jeong-Won; Bae, Duk-Soo] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Obstet & Gynecol, 50 Irwon Dong, Seoul 135710, South Korea. [Chung, Eun Joo] NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Hewitt, SM (reprint author), NCI, Expt Pathol Lab, Pathol Lab, Ctr Canc Res,NIH, MSC 1500, Bethesda, MD 20892 USA.; Bae, DS (reprint author), Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Obstet & Gynecol, 50 Irwon Dong, Seoul 135710, South Korea. EM ds123.bae@samsung.com; genejock@helix.nih.gov RI lee, jw/O-6237-2014; OI Chung, Joon-Yong/0000-0001-5041-5982 FU Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education, Republic of Korea [2013R1A1A2013629]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This study was supported in part by a grant from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Republic of Korea (2013R1A1A2013629) and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 52 TC 0 Z9 0 U1 3 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD JUL 11 PY 2016 VL 16 AR 448 DI 10.1186/s12885-016-2459-y PG 11 WC Oncology SC Oncology GA DR6MD UT WOS:000380015100001 PM 27402115 ER PT J AU Goff, SL Dudley, ME Citrin, DE Somerville, RP Wunderlich, JR Danforth, DN Zlott, DA Yang, JC Sherry, RM Kammula, US Klebanoff, CA Hughes, MS Restifo, NP Langhan, MM Shelton, TE Lu, L Kwong, MLM Ilyas, S Klemen, ND Payabyab, EC Morton, KE Toomey, MA Steinberg, SM White, DE Rosenberg, SA AF Goff, Stephanie L. Dudley, Mark E. Citrin, Deborah E. Somerville, Robert P. Wunderlich, John R. Danforth, David N. Zlott, Daniel A. Yang, James C. Sherry, Richard M. Kammula, Udai S. Klebanoff, Christopher A. Hughes, Marybeth S. Restifo, Nicholas P. Langhan, Michelle M. Shelton, Thomas E. Lu, Lily Kwong, Mei Li M. Ilyas, Sadia Klemen, Nicholas D. Payabyab, Eden C. Morton, Kathleen E. Toomey, Mary Ann Steinberg, Seth M. White, Donald E. Rosenberg, Steven A. TI Randomized, Prospective Evaluation Comparing Intensity of Lymphodepletion Before Adoptive Transfer of Tumor-Infiltrating Lymphocytes for Patients With Metastatic Melanoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CELL TRANSFER THERAPY; T-CELLS; UNTREATED MELANOMA; IPILIMUMAB; CANCER; INTERLEUKIN-2; CHEMOTHERAPY; NIVOLUMAB; ANTI-PD-1; EFFICACY AB Purpose Adoptive cell transfer, the infusion of large numbers of activated autologous lymphocytes, can mediate objective tumor regression in a majority of patients with metastatic melanoma (52 of 93; 56%). Addition and intensification of total body irradiation (TBI) to the preparative lymphodepleting chemotherapy regimen in sequential trials improved objective partial and complete response (CR) rates. Here, we evaluated the importance of adding TBI to the adoptive transfer of tumor-infiltrating lymphocytes (TIL) in a randomized fashion. Patients and Methods A total of 101 patients with metastatic melanoma, including 76 patients with M1c disease, were randomly assigned to receive nonmyeloablative chemotherapy with or without 1,200 cGy TBI before transfer of tumor-infiltrating lymphcytes. Primary end points were CR rate (as defined by Response Evaluation Criteria in Solid Tumors v1.0) and overall survival (OS). Clinical and laboratory data were analyzed for correlates of response. Results CR rates were 24% in both groups (12 of 50 v 12 of 51), and OS was also similar (median OS, 38.2 v 36.6 months; hazard ratio, 1.11; 95% CI, 0.65 to 1.91; P=.71). Thrombotic microangiopathy was an adverse event unique to the TBI arm and occurred in 13 of 48 treated patients. With a median potential follow-up of 40.9 months, only one of 24 patients who achieved a CR recurred. Conclusion Adoptive cell transfer can mediate durable complete regressions in 24% of patients with metastatic melanoma, with median survival. 3 years. Results were similar using chemotherapy preparative regimens with or without addition of TBI. (C) 2016 by American Society of Clinical Oncology C1 [Goff, Stephanie L.; Citrin, Deborah E.; Somerville, Robert P.; Wunderlich, John R.; Danforth, David N.; Yang, James C.; Sherry, Richard M.; Kammula, Udai S.; Klebanoff, Christopher A.; Hughes, Marybeth S.; Restifo, Nicholas P.; Langhan, Michelle M.; Shelton, Thomas E.; Lu, Lily; Kwong, Mei Li M.; Ilyas, Sadia; Klemen, Nicholas D.; Payabyab, Eden C.; Morton, Kathleen E.; Toomey, Mary Ann; Steinberg, Seth M.; White, Donald E.; Rosenberg, Steven A.] NCI, NIH, Bethesda, MD 20892 USA. [Zlott, Daniel A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Dudley, Mark E.] Novartis Inst BioMed Res, Cambridge, MA USA. RP Goff, SL (reprint author), NCI, Surg Branch, NIH, 10 Ctr Dr,Rm 3-3940, Bethesda, MD 20892 USA. EM stephanie.goff@nih.gov FU Center for Cancer Research at the National Cancer Institute of the US National Institutes of Health FX Supported by the Center for Cancer Research at the National Cancer Institute of the US National Institutes of Health, by a generous gift from the Adelson Medical Research Foundation, and through a cooperative research and development agreement with Lion Biotechnologies. NR 35 TC 11 Z9 11 U1 1 U2 8 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 10 PY 2016 VL 34 IS 20 BP 2389 EP U145 DI 10.1200/JCO.2016.66.7220 PG 16 WC Oncology SC Oncology GA DQ3TW UT WOS:000379127400010 PM 27217459 ER PT J AU Beumer, JH Tawbi, H Ivy, SP AF Beumer, Jan H. Tawbi, Hussein Ivy, S. Percy TI Harmonization of Renal Function Assessment Is Needed Throughout the Whole Process of Anticancer Drug Development Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID CREATININE C1 [Beumer, Jan H.] Univ Pittsburgh, Pittsburgh, PA USA. [Tawbi, Hussein] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Ivy, S. Percy] NCI, Bethesda, MD 20892 USA. RP Beumer, JH (reprint author), Univ Pittsburgh, Pittsburgh, PA USA. OI Beumer, Jan/0000-0002-8978-9401 FU NCI NIH HHS [P30 CA047904, UM1 CA186690] NR 11 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 JUL 10 PY 2016 VL 34 IS 20 BP 2430 EP U195 DI 10.1200/JCO.2016.67.2790 PG 3 WC Oncology SC Oncology GA DQ3TW UT WOS:000379127400017 PM 27185845 ER PT J AU Shi, YH Posse, V Zhu, XF Hyvarinen, AK Jacobs, HT Falkenberg, M Gustafsson, CM AF Shi, Yonghong Posse, Viktor Zhu, Xuefeng Hyvarinen, Anne K. Jacobs, Howard T. Falkenberg, Maria Gustafsson, Claes M. TI Mitochondrial transcription termination factor 1 directs polar replication fork pausing SO NUCLEIC ACIDS RESEARCH LA English DT Article ID DNA-POLYMERASE-GAMMA; IN-VITRO; BINDING PROTEIN; RNA-POLYMERASE; RIBOSOMAL-RNA; FACTOR MTERF; LAGGING-STRAND; HUMAN MTDNA; TWINKLE; CELLS AB During replication of nuclear ribosomal DNA (rDNA), clashes with the transcription apparatus can cause replication fork collapse and genomic instability. To avoid this problem, a replication fork barrier protein is situated downstream of rDNA, there preventing replication in the direction opposite rDNA transcription. A potential candidate for a similar function in mitochondria is the mitochondrial transcription termination factor 1 (MTERF1, also denoted mTERF), which binds to a sequence just downstream of the ribosomal transcription unit. Previous studies have shown that MTERF1 prevents antisense transcription over the ribosomal RNA genes, a process which we here show to be independent of the transcription elongation factor TEFM. Importantly, we now demonstrate that MTERF1 arrests mitochondrial DNA (mtDNA) replication with distinct polarity. The effect is explained by the ability of MTERF1 to act as a directional contrahelicase, blocking mtDNA unwinding by the mitochondrial helicase TWINKLE. This conclusion is also supported by in vivo evidence that MTERF1 stimulates TWINKLE pausing. We conclude that MTERF1 can direct polar replication fork arrest in mammalian mitochondria. C1 [Shi, Yonghong; Posse, Viktor; Zhu, Xuefeng; Falkenberg, Maria; Gustafsson, Claes M.] Univ Gothenburg, Inst Biomed, POB 440, SE-40530 Gothenburg, Sweden. [Shi, Yonghong; Zhu, Xuefeng] NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. [Hyvarinen, Anne K.; Jacobs, Howard T.] Univ Tampere, BioMediTech, FI-33014 Tampere, Finland. [Hyvarinen, Anne K.; Jacobs, Howard T.] Univ Tampere, Tampere Univ Hosp, FI-33014 Tampere, Finland. [Jacobs, Howard T.] Univ Helsinki, Inst Biotechnol, FI-00014 Helsinki, Finland. RP Falkenberg, M; Gustafsson, CM (reprint author), Univ Gothenburg, Inst Biomed, POB 440, SE-40530 Gothenburg, Sweden. EM maria.falkenberg@medkem.gu.se; claes.gustafsson@medkem.gu.se RI shi, yonghong/E-8254-2017 OI shi, yonghong/0000-0002-5265-7982 FU Swedish Research Council [2013-3621, 2012-2583]; Swedish Cancer Foundation; European Research Council [261248, 268897]; IngaBritt and Arne Lundberg foundation; Knut and Alice Wallenbergs foundation; Academy of Finland (FinMIT Centre of Excellence) [118654, 256615] FX Swedish Research Council grants [2013-3621 to M.F., 2012-2583 to C.M.G.]; Swedish Cancer Foundation (to M.F. and C.M.G.); European Research Council [261248 to M.F., 268897 to C.G.]; IngaBritt and Arne Lundberg foundation (to M.F.); Knut and Alice Wallenbergs foundation (to M.F. and C.M.G.); Academy of Finland (FinMIT Centre of Excellence 118654 and Professorship 256615 to H.T.J.). Funding for open access charge: European Research Council. NR 53 TC 0 Z9 0 U1 4 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUL 8 PY 2016 VL 44 IS 12 BP 5732 EP 5742 DI 10.1093/nar/gkw302 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DT0ZG UT WOS:000381210900024 PM 27112570 ER PT J AU Thomas, MA Nyanhete, T Tuero, I Venzon, D Robert-Guroff, M AF Thomas, Michael A. Nyanhete, Tinashe Tuero, Iskra Venzon, David Robert-Guroff, Marjorie TI Beyond Oncolytics: E1B55K-Deleted Adenovirus as a Vaccine Delivery Vector SO PLOS ONE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; T-CELL RESPONSES; RHESUS MACAQUES; PROTECTIVE EFFICACY; IMMUNE-RESPONSES; E1B PROTEINS; CHALLENGE; IMMUNIZATION; EXPRESSION; REPLICATION AB Type 5 human adenoviruses (Ad5) deleted of genes encoding the early region 1B 55-kDa (E1B55K) protein including Onyx-015 (dl1520) and H101 are best known for their oncolytic potential. As a vaccine vector the E1B55K deletion may allow for the insertion of a transgene nearly 1,000 base pairs larger than now possible. This has the potential of extending the application for which the vectors are clinically known. However, the immune priming ability of E1B55K-deleted vectors is unknown, undermining our ability to gauge their usefulness in vaccine applications. For this reason, we created an E1B55K-deleted Ad5 vector expressing full-length single chain HIV(BaL)gp120 attached to a flexible linker and the first two domains of rhesus CD4 (rhFLSC) in exchange for the E3 region. In cell-based experiments the E1B55K-deleted vector promoted higher levels of innate immune signals including chemokines, cytokines, and the NKG2D ligands MIC A/B compared to an E1B55K wild-type vector expressing the same immunogen. Based on these results we evaluated the immune priming ability of the E1B55K-deleted vector in mice. The E1B55K-deleted vector promoted similar levels of Ad5-, HIVgp120, and rhFLSC-specific cellular and humoral immune responses as the E1B55K wild-type vector. In pre-clinical HIV-vaccine studies the wild-type vector has been employed as part of a very effective prime-boost strategy. This study demonstrates that E1B55K-deleted adenoviruses may serve as effective vaccine delivery vectors. C1 [Thomas, Michael A.; Nyanhete, Tinashe; Tuero, Iskra; Robert-Guroff, Marjorie] NCI, Sect Immune Biol Retroviral Infect, Vaccine Branch, NIH, Bethesda, MD USA. [Venzon, David] NCI, Biostat & Data Management Sect, NIH, Bethesda, MD USA. [Thomas, Michael A.] Howard Univ, Dept Biol, Washington, DC USA. [Nyanhete, Tinashe] Duke Univ, Durham, NC USA. RP Thomas, MA; Robert-Guroff, M (reprint author), NCI, Sect Immune Biol Retroviral Infect, Vaccine Branch, NIH, Bethesda, MD USA.; Thomas, MA (reprint author), Howard Univ, Dept Biol, Washington, DC USA. EM michael.thomas1@howard.edu; guroffm@mail.nih.gov FU Pathway to Independence Award (K99) [1K99AI114379 - 01]; Intramural Research Program of the National Institutes of Health, National Cancer Institute FX This work was supported by a Pathway to Independence Award (K99) Grant Number 1K99AI114379 - 01 to MAT and by the Intramural Research Program of the National Institutes of Health, National Cancer Institute to MRG. NR 29 TC 0 Z9 0 U1 5 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 JUL 8 PY 2016 VL 11 IS 7 AR e0158505 DI 10.1371/journal.pone.0158505 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR6IK UT WOS:000380005400072 PM 27391605 ER PT J AU Valm, AM Oldenbourg, R Borisy, GG AF Valm, Alex M. Oldenbourg, Rudolf Borisy, Gary G. TI Multiplexed Spectral Imaging of 120 Different Fluorescent Labels SO PLOS ONE LA English DT Article ID ARCHITECTURE; MICROSCOPY; PROTEINS AB The number of fluorescent labels that can unambiguously be distinguished in a single image when acquired through band pass filters is severely limited by the spectral overlap of available fluorophores. The recent development of spectral microscopy and the application of linear unmixing algorithms to spectrally recorded image data have allowed simultaneous imaging of fluorophores with highly overlapping spectra. However, the number of distinguishable fluorophores is still limited by the unavoidable decrease in signal to noise ratio when fluorescence signals are fractionated over multiple wavelength bins. Here we present a spectral image analysis algorithm to greatly expand the number of distinguishable objects labeled with binary combinations of fluorophores. Our algorithm utilizes a priori knowledge about labeled specimens and imposes a binary label constraint on the unmixing solution. We have applied our labeling and analysis strategy to identify microbes labeled by fluorescence in situ hybridization and here demonstrate the ability to distinguish 120 differently labeled microbes in a single image. C1 [Valm, Alex M.; Oldenbourg, Rudolf] Marine Biol Lab, Woods Hole, MA 02543 USA. [Valm, Alex M.; Oldenbourg, Rudolf] Brown Univ, Providence, RI 02912 USA. [Borisy, Gary G.] Forsyth Inst, Cambridge, MA USA. [Valm, Alex M.] NICHHD, NIH, NIH NICHD, Bethesda, MD 20892 USA. RP Valm, AM (reprint author), Marine Biol Lab, Woods Hole, MA 02543 USA.; Valm, AM (reprint author), Brown Univ, Providence, RI 02912 USA.; Valm, AM (reprint author), NICHHD, NIH, NIH NICHD, Bethesda, MD 20892 USA. EM Alex.Valm@nih.gov FU Alfred P. Sloan Foundation [2007-3-13]; National Institutes of Health from the National Institute of Dental and Craniofacial Research (NIDCR) [1RC1-DE020630]; National Institutes of Health from NIDCR [1F31-DE019576] FX This work was supported by Grant 2007-3-13 from the Alfred P. Sloan Foundation (to GGB), National Institutes of Health Grant 1RC1-DE020630 from the National Institute of Dental and Craniofacial Research (NIDCR) (to GGB) and by National Institutes of Health Fellowship 1F31-DE019576 from NIDCR (to AMV). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 17 TC 0 Z9 0 U1 2 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 8 PY 2016 VL 11 IS 7 AR e0158495 DI 10.1371/journal.pone.0158495 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR6IK UT WOS:000380005400069 PM 27391327 ER PT J AU Li, MH Simonetti, FL Goncearenco, A Panchenko, AR AF Li, Minghui Simonetti, Franco L. Goncearenco, Alexander Panchenko, Anna R. TI MutaBind estimates and interprets the effects of sequence variants on protein-protein interactions SO NUCLEIC ACIDS RESEARCH LA English DT Article ID MISSENSE MUTATIONS; BINDING-AFFINITY; FREE-ENERGIES; DYNAMICS; STABILITY; MODELS; IMPACT AB Proteins engage in highly selective interactions with their macromolecular partners. Sequence variants that alter protein binding affinity may cause significant perturbations or complete abolishment of function, potentially leading to diseases. There exists a persistent need to develop a mechanistic understanding of impacts of variants on proteins. To address this need we introduce a new computational method MutaBind to evaluate the effects of sequence variants and disease mutations on protein interactions and calculate the quantitative changes in binding affinity. The MutaBind method uses molecular mechanics force fields, statistical potentials and fast side-chain optimization algorithms. The MutaBind server maps mutations on a structural protein complex, calculates the associated changes in binding affinity, determines the deleterious effect of a mutation, estimates the confidence of this prediction and produces a mutant structural model for download. MutaBind can be applied to a large number of problems, including determination of potential driver mutations in cancer and other diseases, elucidation of the effects of sequence variants on protein fitness in evolution and protein design. MutaBind is available at http://www.ncbi.nlm.nih.gov/projects/mutabind/. C1 [Li, Minghui; Goncearenco, Alexander; Panchenko, Anna R.] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Simonetti, Franco L.] Inst Leloir Fdn, C1405BWE, Buenos Aires, DF, Argentina. RP Panchenko, AR (reprint author), NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM panch@ncbi.nlm.nih.gov RI Goncearenco, Alexander/M-3946-2015 OI Goncearenco, Alexander/0000-0002-9738-7146 FU Intramural Research Program of the National Library of Medicine at the U.S. National Institutes of Health; Argentine Government/BEC.AR; Argentine Fulbright Commission; National Science Foundation (NSF) [PHY11-25915]; National Institutes of Health FX Intramural Research Program of the National Library of Medicine at the U.S. National Institutes of Health (to M.L., A.G., A.R.P.); Argentine Government/BEC.AR (to F.L.S.); Argentine Fulbright Commission (to F.L.S.); National Science Foundation [NSF PHY11-25915, in part]. Funding for open access charge: National Institutes of Health. NR 32 TC 3 Z9 3 U1 2 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUL 8 PY 2016 VL 44 IS W1 BP W494 EP W501 DI 10.1093/nar/gkw374 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DR3FA UT WOS:000379786800081 PM 27150810 ER PT J AU Hao, M Bryant, SH Wang, YL AF Hao, Ming Bryant, Stephen H. Wang, Yanli TI Cheminformatics analysis of the AR agonist and antagonist datasets in PubChem SO JOURNAL OF CHEMINFORMATICS LA English DT Article ID MOLECULAR PAIR ANALYSIS; ACTIVITY CLIFFS; SYSTEMATIC IDENTIFICATION; EFFICIENT ALGORITHM; BIOASSAY DATA; DATA SETS; INHIBITORS; DRUGS; SCAFFOLDS AB Background: As one of the largest publicly accessible databases for hosting chemical structures and biological activities, PubChem has been processing bioassay submissions from the community since 2004. With the increase in volume for the deposited data in PubChem, the diversity and wealth of information content also grows. Recently, the Tox21 program, has deposited a series of pairwise data in PubChem regarding to different mechanism of actions (MOA), such as androgen receptor (AR) agonist and antagonist datasets, to study cell toxicity. To the best of our knowledge, little work has been reported from cheminformatics study for these especially pairwise datasets, which may provide insight into the mechanism of actions of the compounds and relationship between chemical structures and functions, as well as guidance for lead compound selection and optimization. Thus, to fill the gap, we performed a comprehensive cheminformatics analysis, including scaffold analysis, matched molecular pair (MMP) analysis as well as activity cliff analysis to investigate the structural characteristics and discontinued structure-activity relationship of the individual dataset (i.e., AR agonist dataset or AR antagonist dataset) and the combined dataset (i.e., the common compounds between the AR agonist and antagonist datasets). Results: Scaffolds associated only with potential agonists or antagonists were identified. MMP-based activity cliffs, as well as a small group of compounds with dual MOA reported were recognized and analyzed. Moreover, MOA-cliff, a novel concept, was proposed to indicate one pair of structurally similar molecules which exhibit opposite MOA. Conclusions: Cheminformatics methods were successfully applied to the pairwise AR datasets and the identified molecular scaffold characteristics, MMPs as well as activity cliffs might provide useful information when designing new lead compounds for the androgen receptor. C1 [Hao, Ming; Bryant, Stephen H.; Wang, Yanli] NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Wang, YL (reprint author), NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM ywang@ncbi.nlm.nih.gov FU Intramural Research Program of the NIH, National Library of Medicine FX This research was supported by the Intramural Research Program of the NIH, National Library of Medicine. NR 33 TC 0 Z9 0 U1 3 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1758-2946 J9 J CHEMINFORMATICS JI J. Cheminformatics PD JUL 8 PY 2016 VL 8 AR 37 DI 10.1186/s13321-016-0150-6 PG 13 WC Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Chemistry; Computer Science GA DQ6OB UT WOS:000379323500001 PM 27398098 ER PT J AU Deleage, C Schuetz, A Alvord, WG Johnston, L Hao, XP Morcock, DR Rerknimitr, R Fletcher, JLK Puttamaswin, S Phanuphak, N Dewar, R McCune, JM Sereti, I Robb, M Kim, JH Schacker, TW Hunt, P Lifson, JD Ananworanich, J Estes, JD AF Deleage, Claire Schuetz, Alexandra Alvord, W. Gregory Johnston, Leslie Hao, Xing-Pei Morcock, David R. Rerknimitr, Rungsun Fletcher, James L. K. Puttamaswin, Suwanna Phanuphak, Nittaya Dewar, Robin McCune, Joseph M. Sereti, Irini Robb, Merlin Kim, Jerome H. Schacker, Timothy W. Hunt, Peter Lifson, Jeffrey D. Ananworanich, Jintanat Estes, Jacob D. CA RV254 SEARCH Study Grp RV304 SEARCH Study Grp TI Impact of early cART in the gut during acute HIV infection SO JCI INSIGHT LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; T-CELL-ACTIVATION; MUCOSAL IMMUNE RECONSTITUTION; ACTIVE ANTIRETROVIRAL THERAPY; LYMPHOID-TISSUE; MICROBIAL TRANSLOCATION; LENTIVIRAL INFECTIONS; SYSTEMIC INFLAMMATION; EPITHELIAL BARRIER; VIRAL RESERVOIRS AB Early after HIV infection there is substantial depletion of CD4(+) T cells in the gastrointestinal (GI) tract lamina propria (LP), with associated epithelial barrier damage, leading to microbial translocation and systemic inflammation and immune activation. In this study, we analyzed these early events in the GI tract in a cohort of Thai acute HIV-infected patients and determined the effect of early combination antiretroviral treatment (cART). HIV-uninfected and chronically and acutely HIV-infected patients at different Fiebig stages (I-V) underwent colonic biopsies and then received cART. Immunohistochemistry and quantitative image analysis were performed on cross-sectional and longitudinal colon biopsy specimens (day 0 to week 96) to measure GI tract damage (infiltration of polymorphonuclear cells), inflammation (Mx1, TNF-alpha), immune activation (Ki-67), and the CD4(+) T cell population in the LP. The magnitude of GI tract damage, immune activation, and inflammation was significantly increased, with significantly depleted CD4(+) T cells in the LP in all acutely infected groups prior to cART compared with HIV-uninfected control participants. While most patients treated during acute infection resolved GI tract inflammation and immune activation back to baseline levels after 24 weeks of cART, most acutely infected participants did not restore their CD4(+) T cells after 96 weeks of cART. C1 [Deleage, Claire; Johnston, Leslie; Morcock, David R.; Lifson, Jeffrey D.; Estes, Jacob D.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, Frederick, MD USA. [Schuetz, Alexandra] Armed Forces Res Inst Med Sci, Dept Retrovirol, Bangkok, Thailand. [Schuetz, Alexandra; Robb, Merlin; Kim, Jerome H.; Ananworanich, Jintanat] Henry M Jackson Fdn Adv Mil Med, US Mil HIV Res Program, Bethesda, MD USA. [Alvord, W. Gregory] Data Management Serv Inc, Stat Consulting, Frederick, MD USA. [Hao, Xing-Pei] Leidos Biomedical Res Inc, Frederick Natl Lab Canc Res, Pathol & Histotechnol Lab, Frederick, MD USA. [Rerknimitr, Rungsun] Chulalongkorn Univ, Bangkok, Thailand. [Fletcher, James L. K.; Puttamaswin, Suwanna; Phanuphak, Nittaya; Kim, Jerome H.; Ananworanich, Jintanat] SEARCH, Bangkok, Thailand. [Fletcher, James L. K.; Puttamaswin, Suwanna; Phanuphak, Nittaya] Thai Red Cross AIDS Res Ctr, Bangkok, Thailand. [Dewar, Robin] NCI, Virus Isolat & Serol Lab, Appl & Dev Res Directorate, Sci Applicat Int Corp,Frederick Inc,Frederick Can, Frederick, MD 21701 USA. [McCune, Joseph M.] UCSF, Dept Med, Div Expt Med, San Francisco, CA USA. [Sereti, Irini] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Kim, Jerome H.] Int Vaccine Inst, Seoul, South Korea. [Schacker, Timothy W.] Univ Minnesota, Dept Med, Box 736 UMHC, Minneapolis, MN 55455 USA. [Hunt, Peter] UCSF, Dept Med, Posit Hlth Program, San Francisco, CA USA. RP Estes, JD (reprint author), Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, 1050 Boyles St,Bldg 535,Rm 411, Frederick, MD 21702 USA. EM estesj@mail.nih.gov NR 71 TC 2 Z9 2 U1 1 U2 1 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD JUL 7 PY 2016 VL 1 IS 10 AR e87065 DI 10.1172/jci.insight.87065 PG 18 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EB1LL UT WOS:000387113300015 ER PT J AU Myles, IA Williams, KW Reckhow, JD Jammeh, ML Pincus, NB Sastalla, I Saleem, D Stone, KD Datta, SK AF Myles, Ian A. Williams, Kelli W. Reckhow, Jensen D. Jammeh, Momodou L. Pincus, Nathan B. Sastalla, Inka Saleem, Danial Stone, Kelly D. Datta, Sandip K. TI Transplantation of human skin microbiota in models of atopic dermatitis SO JCI INSIGHT LA English DT Article ID DESORPTION IONIZATION-TIME; FLIGHT MASS-SPECTROMETRY; THYMIC STROMAL LYMPHOPOIETIN; TRANSEPIDERMAL WATER-LOSS; STAPHYLOCOCCUS-AUREUS; METHICILLIN-RESISTANT; GENE POLYMORPHISM; DOUBLE-BLIND; VITAMIN-D; BARRIER AB Atopic dermatitis (AD) is characterized by reduced barrier function, reduced innate immune activation, and susceptibility to Staphylococcus aureus. Host susceptibility factors are suggested by monogenic disorders associated with AD-like phenotypes and can be medically modulated. S. aureus contributes to AD pathogenesis and can be mitigated by antibiotics and bleach baths. Recent work has revealed that the skin microbiome differs significantly between healthy controls and patients with AD, including decreased Gram-negative bacteria in AD. However, little is known about the potential therapeutic benefit of microbiome modulation. To evaluate whether parameters of AD pathogenesis are altered after exposure to different culturable Gram-negative bacteria (CGN) collected from human skin, CGN were collected from healthy controls and patients with AD. Then, effects on cellular and culture-based models of immune, epithelial, and bacterial function were evaluated. Representative strains were evaluated in the MC903 mouse model of AD. We found that CGN taken from healthy volunteers but not from patients with AD were associated with enhanced barrier function, innate immunity activation, and control of S. aureus. Treatment with CGN from healthy controls improved outcomes in a mouse model of AD. These findings suggest that a live-biotherapeutic approach may hold promise for treatment of patients with AD. C1 [Myles, Ian A.; Williams, Kelli W.; Reckhow, Jensen D.; Jammeh, Momodou L.; Pincus, Nathan B.; Sastalla, Inka; Saleem, Danial; Datta, Sandip K.] NIAID, Bacterial Pathogenesis Unit, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Stone, Kelly D.] NIAID, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Myles, IA; Datta, SK (reprint author), 9000 Rockville Pike,Bldg 33,Room 2W10A, Bethesda, MD 20892 USA. EM mylesi@niaid.nih.gov; dattas@niaid.nih.gov OI Datta, Sandip/0000-0003-0243-7815 NR 53 TC 4 Z9 4 U1 3 U2 3 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD JUL 7 PY 2016 VL 1 IS 10 AR e86955 DI 10.1172/jci.insight.86955 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EB1LL UT WOS:000387113300013 ER PT J AU Liu, CT Raghavan, S Maruthur, N Kabagambe, EK Hong, J Ng, MCY Hivert, MF Lu, YC An, P Bentley, AR Drolet, AM Gaulton, KJ Guo, XQ Armstrong, LL Irvin, MR Li, M Lipovich, L Rybin, DV Taylor, KD Agyemang, C Palmer, ND Cade, BE Chen, WM Dauriz, M Delaney, JAC Edwards, TL Evans, DS Evans, MK Lange, LA Leong, A Liu, JM Liu, YM Nayak, U Patel, SR Porneala, BC Rasmussen-Torvik, LJ Snijder, MB Stallings, SC Tanaka, T Yanek, LR Zhao, W Becker, DM Bielak, LF Biggs, ML Bottinger, EP Bowden, DW Chen, GJ Correa, A Couper, DJ Crawford, DC Cushman, M Eicher, JD Fornage, M Franceschini, N Fu, YP Goodarzi, MO Gottesman, O Hara, K Harris, TB Jensen, RA Johnson, AD Jhun, MA Karter, AJ Keller, MF Kho, AN Kizer, JR Krauss, RM Langefeld, CD Li, XH Liang, JL Liu, SM Lowe, WL Mosley, TH North, KE Pacheco, JA Peyser, PA Patrick, AL Rice, KM Selvin, E Sims, M Smith, JA Tajuddin, SM Vaidya, D Wren, MP Yao, J Zhu, XF Ziegler, JT Zmuda, JM Zonderman, AB Zwinderman, AH Adeyemo, A Boerwinkle, E Ferrucci, L Hayes, MG Kardia, SLR Miljkovic, I Pankow, JS Rotimi, CN Sale, MM Wagenknecht, LE Arnett, DK Chen, YDI Nalls, MA Province, MA Kao, WHL Siscovick, DS Psaty, BM Wilson, JG Loos, RJF Dupuis, J Rich, SS Florez, JC Rotter, JI Morris, AP Meigs, JB AF Liu, Ching-Ti Raghavan, Sridharan Maruthur, Nisa Kabagambe, Edmond Kato Hong, Jaeyoung Ng, Maggie C. Y. Hivert, Marie-France Lu, Yingchang An, Ping Bentley, Amy R. Drolet, Anne M. Gaulton, Kyle J. Guo, Xiuqing Armstrong, Loren L. Irvin, Marguerite R. Li, Man Lipovich, Leonard Rybin, Denis V. Taylor, Kent D. Agyemang, Charles Palmer, Nicholette D. Cade, Brian E. Chen, Wei-Min Dauriz, Marco Delaney, Joseph A. C. Edwards, Todd L. Evans, Daniel S. Evans, Michele K. Lange, Leslie A. Leong, Aaron Liu, Jingmin Liu, Yongmei Nayak, Uma Patel, Sanjay R. Porneala, Bianca C. Rasmussen-Torvik, Laura J. Snijder, Marieke B. Stallings, Sarah C. Tanaka, Toshiko Yanek, Lisa R. Zhao, Wei Becker, Diane M. Bielak, Lawrence F. Biggs, Mary L. Bottinger, Erwin P. Bowden, Donald W. Chen, Guanjie Correa, Adolfo Couper, David J. Crawford, Dana C. Cushman, Mary Eicher, John D. Fornage, Myriam Franceschini, Nora Fu, Yi-Ping Goodarzi, Mark O. Gottesman, Omri Hara, Kazuo Harris, Tamara B. Jensen, Richard A. Johnson, Andrew D. Jhun, Min A. Karter, Andrew J. Keller, Margaux F. Kho, Abel N. Kizer, Jorge R. Krauss, Ronald M. Langefeld, Carl D. Li, Xiaohui Liang, Jingling Liu, Simin Lowe, William L., Jr. Mosley, Thomas H. North, Kari E. Pacheco, Jennifer A. Peyser, Patricia A. Patrick, Alan L. Rice, Kenneth M. Selvin, Elizabeth Sims, Mario Smith, Jennifer A. Tajuddin, Salman M. Vaidya, Dhananjay Wren, Mary P. Yao, Jie Zhu, Xiaofeng Ziegler, Julie T. Zmuda, Joseph M. Zonderman, Alan B. Zwinderman, Aeilko H. Adeyemo, Adebowale Boerwinkle, Eric Ferrucci, Luigi Hayes, M. Geoffrey Kardia, Sharon L. R. Miljkovic, Iva Pankow, James S. Rotimi, Charles N. Sale, Michele M. Wagenknecht, Lynne E. Arnett, Donna K. Chen, Yii-Der Ida Nalls, Michael A. Province, Michael A. Kao, W. H. Linda Siscovick, David S. Psaty, Bruce M. Wilson, James G. Loos, Ruth J. F. Dupuis, Josee Rich, Stephen S. Florez, Jose C. Rotter, Jerome I. Morris, Andrew P. Meigs, James B. CA AAAG Consortium CARe Consortium COGENT-BP Consortium eMERGE Consortium MEDIA Consortium MAGIC Consortium TI Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; TYPE-2 DIABETES RISK; GLUCOKINASE REGULATORY PROTEIN; BETA-CELL FUNCTION; BODY-MASS INDEX; TRIGLYCERIDE LEVELS; PLASMA-GLUCOSE; TRANSETHNIC METAANALYSIS; AFRICAN-ANCESTRY; GLYCEMIC TRAITS AB Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci. C1 [Liu, Ching-Ti; Hong, Jaeyoung; Rybin, Denis V.; Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Raghavan, Sridharan; Leong, Aaron; Porneala, Bianca C.; Meigs, James B.] Harvard Med Sch, Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. [Raghavan, Sridharan] Eastern Colorado Hlth Care Syst, Dept Vet Affairs Med Ctr, Denver, CO 80220 USA. [Raghavan, Sridharan] Univ Colorado, Sch Med, Dept Med, Div Gen Internal Med, Denver, CO 80220 USA. [Maruthur, Nisa] Johns Hopkins Univ, Sch Med, Div Gen Internal Med, Baltimore, MD 21287 USA. [Maruthur, Nisa; Selvin, Elizabeth] Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21287 USA. [Maruthur, Nisa; Li, Man; Selvin, Elizabeth; Vaidya, Dhananjay; Kao, W. H. Linda] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21287 USA. [Kabagambe, Edmond Kato; Edwards, Todd L.] Vanderbilt Univ, Med Ctr, Sch Med, Div Epidemiol,Dept Med, Nashville, TN 37203 USA. [Ng, Maggie C. Y.; Palmer, Nicholette D.; Bowden, Donald W.] Wake Forest Univ, Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC 27157 USA. [Ng, Maggie C. Y.; Bowden, Donald W.] Wake Forest Univ, Bowman Gray Sch Med, Ctr Diabet Res, Winston Salem, NC 27157 USA. [Hivert, Marie-France] Harvard Med Sch, Harvard Pilgrim Hlth Care Inst, Dept Populat Med, Boston, MA 02215 USA. [Hivert, Marie-France; Florez, Jose C.] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. [Hivert, Marie-France] Univ Sherbrooke, Dept Med, Sherbrooke, PQ J1G 0A2, Canada. [Lu, Yingchang; Bottinger, Erwin P.; Gottesman, Omri; Hara, Kazuo; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA. [Lu, Yingchang; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA. [An, Ping; Province, Michael A.] Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63108 USA. [Bentley, Amy R.; Chen, Guanjie; Adeyemo, Adebowale; Rotimi, Charles N.] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. [Drolet, Anne M.; Lipovich, Leonard] Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Gaulton, Kyle J.; Morris, Andrew P.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Guo, Xiuqing; Taylor, Kent D.; Li, Xiaohui; Yao, Jie; Chen, Yii-Der Ida; Rotter, Jerome I.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Dept Pediat, Inst Translat Genom & Populat Sci, Torrance, CA 90502 USA. [Armstrong, Loren L.; Kho, Abel N.; Lowe, William L., Jr.; Pacheco, Jennifer A.; Hayes, M. Geoffrey] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Irvin, Marguerite R.] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA. [Lipovich, Leonard] Wayne State Univ, Sch Med, Dept Neurol, Detroit, MI 48201 USA. [Agyemang, Charles; Snijder, Marieke B.; Zwinderman, Aeilko H.] Acad Med Ctr Amsterdam, Dept Publ Hlth, Meibergdreef 15, NL-1105 AZ Amsterdam, Netherlands. [Palmer, Nicholette D.; Bowden, Donald W.; Wren, Mary P.] Wake Forest Univ, Bowman Gray Sch Med, Dept Biochem, Winston Salem, NC 27157 USA. [Cade, Brian E.] Harvard Med Sch, Brigham & Womens Hosp, Div Sleep & Circadian Disorders, Boston, MA 02115 USA. [Chen, Wei-Min; Nayak, Uma; Sale, Michele M.; Rich, Stephen S.] Univ Virginia, Sch Med, Dept Publ Hlth Sci, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA. [Dauriz, Marco] Univ Verona, Dept Med, Div Endocrinol Diabet & Metab, I-37126 Verona, Italy. [Delaney, Joseph A. C.; Siscovick, David S.; Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Evans, Daniel S.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA 94107 USA. [Evans, Michele K.; Tajuddin, Salman M.] NIA, Hlth Dispar Res Sect, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA. [Lange, Leslie A.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27607 USA. [Liu, Jingmin] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. [Liu, Yongmei] Wake Forest Univ, Bowman Gray Sch Med, Div Publ Hlth Sci, Ctr Human Genet, Winston Salem, NC 27157 USA. [Patel, Sanjay R.] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15213 USA. [Rasmussen-Torvik, Laura J.] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Tanaka, Toshiko; Ferrucci, Luigi] NIA, Translat Gerontol Branch, Harbor Hosp, Baltimore, MD 21225 USA. [Yanek, Lisa R.; Becker, Diane M.; Vaidya, Dhananjay] Johns Hopkins Univ, Dept Med, Div Gen Internal Med, GeneSTAR Res Program, Baltimore, MD 21287 USA. [Zhao, Wei; Bielak, Lawrence F.; Jhun, Min A.; Peyser, Patricia A.; Smith, Jennifer A.; Kardia, Sharon L. R.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Becker, Diane M.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD 21287 USA. [Biggs, Mary L.; Rice, Kenneth M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Biggs, Mary L.; Jensen, Richard A.; Siscovick, David S.; Psaty, Bruce M.] Univ Washington, Sch Med, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Correa, Adolfo; Sims, Mario] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Couper, David J.] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Biostat, Collaborat Studies Coordinating Ctr, Chapel Hill, NC 27514 USA. [Crawford, Dana C.] Case Western Reserve Univ, Inst Computat Biol, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Cushman, Mary] Univ Vermont, Coll Med, Dept Pathol & Med, Burlington, VT 05405 USA. [Eicher, John D.; Dupuis, Josee] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Eicher, John D.; Johnson, Andrew D.] NHLBI, Populat Sci Branch, Div Intramural Res, NIH, Framingham, MA 01702 USA. [Fornage, Myriam; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA. [Fornage, Myriam; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Franceschini, Nora; North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27514 USA. [Fu, Yi-Ping] NHLBI, Cardiovasc Epidemiol & Human Genom Branch, NIH, Framingham, MA 01702 USA. [Goodarzi, Mark O.] Cedars Sinai Med Ctr, Div Endocrinol Diabet & Metab, Los Angeles, CA 90048 USA. [Hara, Kazuo] Univ Tokyo, Grad Sch Med, Dept Diabet & Metab Dis, Tokyo 1138655, Japan. [Hara, Kazuo] Tokyo Med Univ, Dept Diabet Endocrinol & Metab, Tokyo 1630023, Japan. [Harris, Tamara B.] NIH, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. [Karter, Andrew J.] Kaiser Permanente, Div Res, Oakland, CA 94612 USA. [Keller, Margaux F.] Merck Res Labs, Dept Genet & Pharmacogen, 33 Ave Louis Pasteur, Boston, MA 02115 USA. [Kizer, Jorge R.] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Med, Bronx, NY 10461 USA. [Kizer, Jorge R.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10461 USA. [Krauss, Ronald M.] Childrens Hosp Oakland, Res Inst, Oakland, CA 94609 USA. [Langefeld, Carl D.; Ziegler, Julie T.] Wake Forest Univ, Bowman Gray Sch Med, Ctr Publ Hlth Genom, Winston Salem, NC 27157 USA. [Langefeld, Carl D.; Ziegler, Julie T.] Wake Forest Univ, Bowman Gray Sch Med, Dept Biostat Sci, Winston Salem, NC 27157 USA. [Liang, Jingling; Zhu, Xiaofeng] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Liu, Simin] Brown Univ, Dept Epidemiol, Providence, RI 02912 USA. [Liu, Simin] Brown Univ, Dept Med, Providence, RI 02903 USA. [Mosley, Thomas H.] Univ Mississippi, Med Ctr, Dept Med, Div Geriatr Gerontol, Jackson, MS 39216 USA. [Patrick, Alan L.] Tobago Hlth Studies Off, Scarborough, Trinid & Tobago. [Zmuda, Joseph M.; Miljkovic, Iva] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Zonderman, Alan B.] NIA, Behav Epidemiol Sect, Lab Epidemiol & Populat Sci, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Pankow, James S.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55455 USA. [Wagenknecht, Lynne E.] Wake Forest Univ, Bowman Gray Sch Med, Div Publ Hlth Sci, Winston Salem, NC 27157 USA. [Arnett, Donna K.] Univ Kentucky, Coll Publ Hlth, Lexington, KY 40563 USA. [Nalls, Michael A.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Siscovick, David S.] New York Acad Med, New York, NY 10029 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98101 USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Florez, Jose C.] Broad Inst, Program Metab, Cambridge, MA 02142 USA. [Florez, Jose C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Florez, Jose C.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Morris, Andrew P.] Univ Liverpool, Dept Biostat, Inst Translat Med, Liverpool L69 3BX, Merseyside, England. [Stallings, Sarah C.] Vanderbilt Univ, Med Ctr, Vanderbilt Inst Clin & Translat Res, Nashville, TN 37203 USA. RP Liu, CT (reprint author), Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA.; Meigs, JB (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. EM ctliu@bu.edu; jmeigs@partners.org RI Johnson, Andrew/G-6520-2013; Dauriz, Marco/S-5843-2016; OI Dauriz, Marco/0000-0002-5542-5941; Tajuddin, Salman M./0000-0002-7919-8528; Patel, Sanjay/0000-0002-9142-5172; Zonderman, Alan B/0000-0002-6523-4778; Vaidya, Dhananjay/0000-0002-7164-1601; Smith, Jennifer/0000-0002-3575-5468; Pankow, James/0000-0001-7076-483X FU Johnson Johnson FX B.M.P. serves on the DSMB of a clinical trial for the device manufacturer Zoll LifeCor and on the Steering Committee for the Yale Open Data Access Project funded by Johnson & Johnson. D.V. is a consultant for Consumable Science, Inc. J.R.K. holds stock in Pfizer, Inc., and Gilead Sciences, Inc. NR 61 TC 1 Z9 1 U1 1 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUL 7 PY 2016 VL 99 IS 1 BP 56 EP 75 DI 10.1016/j.ajhg.2016.05.006 PG 20 WC Genetics & Heredity SC Genetics & Heredity GA DT6TI UT WOS:000381616600005 PM 27321945 ER PT J AU Yu, P Yang, WL Han, D Wang, X Guo, S Li, JC Li, F Zhang, XX Wong, SW Bai, BJ Liu, Y Du, J Sun, ZS Shi, ST Feng, HL Cai, T AF Yu, Ping Yang, Wenli Han, Dong Wang, Xi Guo, Sen Li, Jinchen Li, Fang Zhang, Xiaoxia Wong, Sing-Wai Bai, Baojing Liu, Yao Du, Jie Sun, Zhong Sheng Shi, Songtao Feng, Hailan Cai, Tao TI Mutations in WNT10B Are Identified in Individuals with Oligodontia SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID EPITHELIAL-MESENCHYMAL INTERACTIONS; AUTOSOMAL-DOMINANT OLIGODONTIA; IN-VITRO; TOOTH; EXPRESSION; GENE; DIFFERENTIATION; DISEASE; MORPHOGENESIS; POPULATION AB Tooth agenesis is one of the most common developmental anomalies in humans. Oligodontia, a severe form of tooth agenesis, is genetically and phenotypically a heterogeneous condition. Although significant efforts have been made, the genetic etiology of dental agenesis remains largely unknown. In the present study, we performed whole-exome sequencing to identify the causative mutations in Chinese families in whom oligodontia segregates with dominant inheritance. We detected a heterozygous missense mutation (c.632G > A [p.Arg211Gln]) in WNT10B in all affected family members. By Sanger sequencing a cohort of 145 unrelated individuals with non-syndromic oligodontia, we identified three additional mutations (c.569C > G [p.Pro190Arg], c.786G > A [p.Trp262*], and c.851T > G [p.Phe284Cys]). Interestingly, analysis of genotype-phenotype correlations revealed that mutations in WNT10B affect the development of permanent dentition, particularly the lateral incisors. Furthermore, a functional assay demonstrated that each of these mutants could not normally enhance the canonical Wnt signaling in HEPG2 epithelial cells, in which activity of the TOPFlash luciferase reporter was measured. Notably, these mutant WNT10B ligands could not efficiently induce endothelial differentiation of dental pulp stem cells. Our findings provide the identification of autosomal-dominant WNT10B mutations in individuals with oligodontia, which increases the spectrum of congenital tooth agenesis and suggests attenuated Wnt signaling in endothelial differentiation of dental pulp stem cells. C1 [Yu, Ping; Guo, Sen; Li, Jinchen; Cai, Tao] Wenzhou Med Univ, Inst Genom Med, Wenzhou 325000, Peoples R China. [Yang, Wenli; Wang, Xi] Zhengzhou Univ, Stomatol Hosp, Zhengzhou 450052, Peoples R China. [Han, Dong; Li, Fang; Zhang, Xiaoxia; Wong, Sing-Wai; Feng, Hailan] Peking Univ, Sch & Hosp Stomatol, Dept Prosthodont, Beijing 100081, Peoples R China. [Wong, Sing-Wai] Univ North Carolina Chapel Hill, Sch Dent, Oral Biol Curriculum, Chapel Hill, NC 27599 USA. [Bai, Baojing] Beijing Stomatol Hosp, Dept Prosthodont, Beijing 100050, Peoples R China. [Liu, Yao; Shi, Songtao] Univ Penn, Sch Dent Med, Dept Anat & Cell Biol, Philadelphia, PA 19104 USA. [Du, Jie] Capital Med Univ, Beijing Anzhen Hosp, Beijing 100000, Peoples R China. [Sun, Zhong Sheng] Chinese Acad Sci, Beijing Inst Life Sci, Beijing 100000, Peoples R China. [Cai, Tao] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20982 USA. RP Cai, T (reprint author), Wenzhou Med Univ, Inst Genom Med, Wenzhou 325000, Peoples R China.; Feng, HL (reprint author), Peking Univ, Sch & Hosp Stomatol, Dept Prosthodont, Beijing 100081, Peoples R China.; Cai, T (reprint author), Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20982 USA. EM kqfenghl@bjmu.edu.cn; tcai@mail.nih.gov FU Wenzhou Medical University Research Fund; Beijing Collaborative Innovative Research Center for Cardiovascular Diseases [PXM2014_014226_000002]; National Natural Science Foundation of China [81110114] FX We are indebted to the individuals with tooth agenesis and their families for their participation in this study. We thank Dr. Curtis Harris's lab for the wild-type WNT10B plasmid, Dr. DeeDee Smart's lab for the pTOPFLASH and pCMV beta-gal plasmids, and Qianzhi Shao for bioinformatics analysis. We wish to thank Drs. Yan Jin and Weidong Li for thoughtful suggestions. Research reported in this publication was supported by the Wenzhou Medical University Research Fund (to P.Y.), the Beijing Collaborative Innovative Research Center for Cardiovascular Diseases (PXM2014_014226_000002 to D.J.), and National Natural Science Foundation of China grant 81110114 (to Z.S.S.). NR 38 TC 0 Z9 0 U1 3 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUL 7 PY 2016 VL 99 IS 1 BP 195 EP 201 DI 10.1016/j.ajhg.2016.05.012 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA DT6TI UT WOS:000381616600016 PM 27321946 ER PT J AU McKiernan, EC Bourne, PE Brown, CT Buck, S Kenall, A Lin, J McDougall, D Nosek, BA Ram, K Soderberg, CK Spies, JR Thaney, K Updegrove, A Woo, KH Yarkoni, T AF McKiernan, Erin C. Bourne, Philip E. Brown, C. Titus Buck, Stuart Kenall, Amye Lin, Jennifer McDougall, Damon Nosek, Brian A. Ram, Karthik Soderberg, Courtney K. Spies, Jeffrey R. Thaney, Kaitlin Updegrove, Andrew Woo, Kara H. Yarkoni, Tal TI How open science helps researchers succeed SO ELIFE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; OPEN-ACCESS ARTICLES; CITATION ADVANTAGE; SCHOLARLY COMMUNICATION; SUBSCRIPTION JOURNALS; RESEARCH IMPACT; PUBLICATIONS; DOWNLOADS; REVIEWERS; SYSTEM AB Open access, open data, open source and other open scholarship practices are growing in popularity and necessity. However, widespread adoption of these practices has not yet been achieved. One reason is that researchers are uncertain about how sharing their work will affect their careers. We review literature demonstrating that open research is associated with increases in citations, media attention, potential collaborators, job opportunities and funding opportunities. These findings are evidence that open research practices bring significant benefits to researchers relative to more traditional closed practices. C1 [McKiernan, Erin C.] Univ Nacl Autonoma Mexico, Fac Sci, Dept Phys, Mexico City, DF, Mexico. [Bourne, Philip E.] NIH, Bethesda, MD 20892 USA. [Brown, C. Titus] Univ Calif Davis, Populat Hlth & Reprod, Davis, CA 95616 USA. [Buck, Stuart] Laura & John Arnold Fdn, Houston, TX USA. [Kenall, Amye] BioMed Cent, London, England. [Lin, Jennifer] CrossRef, Oxford, England. [McDougall, Damon] Univ Texas Austin, Inst Computat Engn & Sci, Austin, TX 78712 USA. [Nosek, Brian A.; Soderberg, Courtney K.; Spies, Jeffrey R.] Ctr Open Sci, Charlottesville, VA USA. [Ram, Karthik] Univ Calif Berkeley, Berkeley Inst Data Sci, Berkeley, CA 94720 USA. [Spies, Jeffrey R.] Univ Virginia, Dept Engn & Soc, Charlottesville, VA USA. [Thaney, Kaitlin] Mozilla Fdn, Mozilla Sci Lab0, New York, NY USA. [Updegrove, Andrew] Gesmer Updegrove LLP, Boston, MA USA. [Woo, Kara H.] Washington State Univ, Ctr Environm Res Educ & Outreach, Pullman, WA USA. [Woo, Kara H.] Univ Washington, Informat Sch, Seattle, WA 98195 USA. [Yarkoni, Tal] Univ Texas Austin, Dept Psychol, Austin, TX 78712 USA. RP McKiernan, EC (reprint author), Univ Nacl Autonoma Mexico, Fac Sci, Dept Phys, Mexico City, DF, Mexico. EM emckiernan@ciencias.unam.mx OI McKiernan, Erin/0000-0002-9430-5221; Lin, Jennifer/0000-0002-9680-2328; Woo, Kara/0000-0002-5125-4188; Bourne, Philip/0000-0002-7618-7292; Kenall, Amye/0000-0002-3030-8001 NR 140 TC 7 Z9 7 U1 24 U2 25 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD JUL 7 PY 2016 VL 5 AR e16800 DI 10.7554/eLife.16800 PG 19 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DV2HA UT WOS:000382740200001 ER PT J AU Chami, N Chen, MH Slater, AJ Eicher, JD Evangelou, E Tajuddin, SM Love-Gregory, L Kacprowski, T Schick, UM Nomura, A Giri, A Lessard, S Brody, JA Schurmann, C Pankratz, N Yanek, LR Manichaikul, A Pazoki, R Mihailov, E Hill, WD Raffield, LM Burt, A Bartz, TM Becker, DM Becker, LC Boerwinkle, E Bork-Jensen, J Bottinger, EP O'Donoghue, ML Crosslin, DR de Denus, S Dube, MP Elliott, P Engstrom, G Evans, MK Floyd, JS Fornage, M Gao, H Greinacher, A Gudnason, V Hansen, T Harris, TB Hayward, C Hernesniemi, J Highland, HM Hirschhorn, JN Hofman, A Irvin, MR Kahonen, M Lange, E Launer, LJ Lehtimaki, T Li, J Liewald, DCM Linneberg, A Liu, YM Lu, YC Lyytikainen, LP Magi, R Mathias, RA Melander, O Metspalu, A Mononen, N Nalls, MA Nickerson, DA Nikus, K O'Donnell, CJ Orho-Melander, M Pedersen, O Petersmann, A Polfus, L Psaty, BM Raitakari, OT Raitoharju, E Richard, M Rice, KM Rivadeneira, F Rotter, JI Schmidt, F Smith, AV Starr, JM Taylor, KD Teumer, A Thuesen, BH Torstenson, ES Tracy, RP Tzoulaki, I Zakai, NA Vacchi-Suzzi, C van Duijn, CM van Rooij, FJA Cushman, M Deary, IJ Edwards, DRV Vergnaud, AC Wallentin, L Waterworth, DM White, HD Wilson, JG Zonderman, AB Kathiresan, S Grarup, N Esko, T Loos, RJF Lange, LA Faraday, N Abumrad, NA Edwards, TL Ganesh, SK Auer, PL Johnson, AD Reiner, AP Lettre, G AF Chami, Nathalie Chen, Ming-Huei Slater, Andrew J. Eicher, John D. Evangelou, Evangelos Tajuddin, Salman M. Love-Gregory, Latisha Kacprowski, Tim Schick, Ursula M. Nomura, Akihiro Giri, Ayush Lessard, Samuel Brody, Jennifer A. Schurmann, Claudia Pankratz, Nathan Yanek, Lisa R. Manichaikul, Ani Pazoki, Raha Mihailov, Evelin Hill, W. David Raffield, Laura M. Burt, Amber Bartz, Traci M. Becker, Diane M. Becker, Lewis C. Boerwinkle, Eric Bork-Jensen, Jette Bottinger, Erwin P. O'Donoghue, Michelle L. Crosslin, David R. de Denus, Simon Dube, Marie-Pierre Elliott, Paul Engstrom, Gunnar Evans, Michele K. Floyd, James S. Fornage, Myriam Gao, He Greinacher, Andreas Gudnason, Vilmundur Hansen, Torben Harris, Tamara B. Hayward, Caroline Hernesniemi, Jussi Highland, Heather M. Hirschhorn, Joel N. Hofman, Albert Irvin, Marguerite R. Kahonen, Mika Lange, Ethan Launer, Lenore J. Lehtimaki, Terho Li, Jin Liewald, David C. M. Linneberg, Allan Liu, Yongmei Lu, Yingchang Lyytikainen, Leo-Pekka Magi, Reedik Mathias, Rasika A. Melander, Olle Metspalu, Andres Mononen, Nina Nalls, Mike A. Nickerson, Deborah A. Nikus, Kjell O'Donnell, Chris J. Orho-Melander, Marju Pedersen, Oluf Petersmann, Astrid Polfus, Linda Psaty, Bruce M. Raitakari, Olli T. Raitoharju, Emma Richard, Melissa Rice, Kenneth M. Rivadeneira, Fernando Rotter, Jerome I. Schmidt, Frank Smith, Albert Vernon Starr, John M. Taylor, Kent D. Teumer, Alexander Thuesen, Betina H. Torstenson, Eric S. Tracy, Russell P. Tzoulaki, Ioanna Zakai, Neil A. Vacchi-Suzzi, Caterina van Duijn, Cornelia M. van Rooij, Frank J. A. Cushman, Mary Deary, Ian J. Edwards, Digna R. Velez Vergnaud, Anne-Claire Wallentin, Lars Waterworth, Dawn M. White, Harvey D. Wilson, James G. Zonderman, Alan B. Kathiresan, Sekar Grarup, Niels Esko, Tonu Loos, Ruth J. F. Lange, Leslie A. Faraday, Nauder Abumrad, Nada A. Edwards, Todd L. Ganesh, Santhi K. Auer, Paul L. Johnson, Andrew D. Reiner, Alexander P. Lettre, Guillaume TI Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; CORONARY-HEART-DISEASE; AFRICAN-AMERICANS; DILATED CARDIOMYOPATHY; NATURAL-SELECTION; SEQUENCE VARIANTS; PYRUVATE-KINASE; LOW-FREQUENCY; LOCI; GENE AB Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 x 10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 x 10(-8) for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 x 10(-11)) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 x 10(-9)). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 x 10(-7)). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated. C1 [Chami, Nathalie; Lessard, Samuel; Dube, Marie-Pierre; Lettre, Guillaume] Univ Montreal, Dept Med, Montreal, PQ H3T 1J4, Canada. [Chami, Nathalie; Lessard, Samuel; de Denus, Simon; Dube, Marie-Pierre; Lettre, Guillaume] Montreal Heart Inst, Montreal, PQ H1T 1CB, Canada. [Chen, Ming-Huei; Eicher, John D.; O'Donnell, Chris J.; Johnson, Andrew D.] NHLBI, Populat Sci Branch, Framingham Heart Study, Framingham, MA 01702 USA. [Slater, Andrew J.] GlaxoSmithKline, Genet Target Sci, Res Triangle Pk, Res Triangle Pk, NC 27709 USA. [Slater, Andrew J.] OmicSoft Corp, Cary, NC 27513 USA. [Evangelou, Evangelos; Elliott, Paul; Gao, He; Tzoulaki, Ioanna; Vergnaud, Anne-Claire] Imperial Coll London, Dept Epidemiol & Biostat, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, London W2 1PG, England. [Evangelou, Evangelos; Tzoulaki, Ioanna] Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, Ioannina 45110, Greece. [Tajuddin, Salman M.; Evans, Michele K.; Zonderman, Alan B.] NIA, Lab Epidemiol & Populat Sci, Baltimore, MD 21224 USA. [Love-Gregory, Latisha; Abumrad, Nada A.] Washington Univ, Sch Med, Dept Med, Ctr Human Nutr, St Louis, MO 63110 USA. [Kacprowski, Tim; Schmidt, Frank] Ernst Moritz Arndt Univ Greifswald, Dept Funct Gen, Interfaculty Inst Genet & Funct Gen, Univ Med, D-17475 Greifswald, Germany. [Kacprowski, Tim] DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany. [Schick, Ursula M.; Schurmann, Claudia; Bottinger, Erwin P.; Lu, Yingchang; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10069 USA. [Nomura, Akihiro; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Nomura, Akihiro; Hirschhorn, Joel N.; Kathiresan, Sekar; Esko, Tonu] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Nomura, Akihiro; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Nomura, Akihiro; Kathiresan, Sekar] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Nomura, Akihiro] Kanazawa Univ, Grad Sch Med Sci, Div Cardiovasc Med, Kanazawa, Ishikawa 9200942, Japan. [Giri, Ayush; Torstenson, Eric S.; Edwards, Todd L.] Vanderbilt Univ, Inst Med & Publ Hlth, Vanderbilt Genet Inst, Div Epidemiol, Nashville, TN 37235 USA. [Brody, Jennifer A.; Floyd, James S.] Univ Washington, Dept Med, Seattle, WA 98101 USA. [Schurmann, Claudia; Lu, Yingchang; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10069 USA. [Pankratz, Nathan] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55454 USA. [Yanek, Lisa R.; Becker, Diane M.] Johns Hopkins Univ, Sch Med, Dept Med Div Gen Internal Med icine, Div Gen Internal Med, Baltimore, MD 21205 USA. [Manichaikul, Ani] Univ Virginia, Ctr Publ Hlth Gen, Charlottesville, VA 22908 USA. [Pazoki, Raha; Hofman, Albert; Rivadeneira, Fernando; van Duijn, Cornelia M.; van Rooij, Frank J. A.] Erasmus, Dept Epidemiol, NL-3000 Mcrotterdam, Netherlands. [Mihailov, Evelin; Magi, Reedik; Metspalu, Andres; Esko, Tonu] Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia. [Hill, W. David; Liewald, David C. M.; Starr, John M.; Deary, Ian J.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland. [Hill, W. David; Liewald, David C. M.; Deary, Ian J.] Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland. [Raffield, Laura M.; Lange, Leslie A.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27514 USA. [Burt, Amber] Univ Washington, Div Med Genet, Dept Med, Seattle, WA 98195 USA. [Bartz, Traci M.; Rice, Kenneth M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Becker, Lewis C.] Johns Hopkins Univ Sch Med, Dept Med, Div Cardiol & Gen Internal Med, Baltimore, MD 21205 USA. [Boerwinkle, Eric; Highland, Heather M.; Polfus, Linda] Univ Texas Hlth Sci Ctr, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA. [Boerwinkle, Eric] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Bork-Jensen, Jette; Hansen, Torben; Pedersen, Oluf; Grarup, Niels] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metabol Res, DK-2100 Copenhagen, Denmark. [O'Donoghue, Michelle L.] Brigham & Womens Hosp, Cardiovasc Div, TIMI Study Grp, Boston, MA 02115 USA. [Crosslin, David R.] Univ Washington, Dept Biomed Informat & Med Educ, Seattle, WA 98195 USA. [de Denus, Simon] Univ Montreal, Fac Pharm, Montreal, PQ H3T 1J4, Canada. [Engstrom, Gunnar; Melander, Olle; Orho-Melander, Marju] Lund Univ, Dept Clin Sci, S-22100 Malmo, Sweden. [Engstrom, Gunnar; Melander, Olle; Orho-Melander, Marju] Skane Univ Hosp, S-22241 Malmo, Sweden. [Fornage, Myriam; Richard, Melissa] Univ Texas Hlth Sci Ctr, Inst Mol Med, Houston, TX 77030 USA. [Greinacher, Andreas] Univ Med Greifswald, Inst Immunol & Transfus Med, D-17475 Greifswald, Germany. [Gudnason, Vilmundur; Smith, Albert Vernon] Iceland Heart Assoc, IS-201 Kopavogur, Iceland. [Gudnason, Vilmundur; Smith, Albert Vernon] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. [Harris, Tamara B.; Launer, Lenore J.] NIA, Intramural Res Program, NIH, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Hayward, Caroline] Univ Edinburgh, MRC Human Genet Unit, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland. [Hernesniemi, Jussi; Lehtimaki, Terho; Lyytikainen, Leo-Pekka; Mononen, Nina; Raitoharju, Emma] Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland. [Hernesniemi, Jussi; Lehtimaki, Terho; Lyytikainen, Leo-Pekka; Mononen, Nina; Raitoharju, Emma] Univ Tampere, Dept Clin Chem, Sch Med, Tampere 33014, Finland. [Hernesniemi, Jussi; Nikus, Kjell] Univ Tampere, Sch Med, Tampere 33014, Finland. [Highland, Heather M.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27514 USA. [Hirschhorn, Joel N.] Boston Childrens Hosp, Dept Endocrinol, Boston, MA 02115 USA. [Hofman, Albert] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Irvin, Marguerite R.] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35233 USA. [Kahonen, Mika] Tampere Univ Hosp, Dept Clin Physiol, Tampere 33521, Finland. [Kahonen, Mika] Univ Tampere, Dept Clin Physiol, Sch Med, Tampere 33014, Finland. [Lange, Ethan] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Lange, Ethan] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. [Li, Jin] Stanford Univ, Sch Med, Div Cardiovasc Med, Dept Med, Palo Alto, CA 94305 USA. [Linneberg, Allan; Thuesen, Betina H.] Capital Region Denmark, Res Ctr Prevent & Hlth, DK-2600 Copenhagen, Denmark. [Linneberg, Allan] Rigshosp, Dept Clin Expt Res, DK-2100 Glostrup, Denmark. [Linneberg, Allan] Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, DK-2200 Copenhagen, Denmark. [Liu, Yongmei] Wake Forest Sch Med, Div Publ Hlth Sci, Ctr Human Genet, Winston Salem, NC 27157 USA. [Mathias, Rasika A.] Johns Hopkins Univ Sch Med, Dept Med, Div Allergy & Clin Immunol, Baltimore, MD 21205 USA. [Mathias, Rasika A.] Johns Hopkins Univ Sch Med, Div Gen Internal Med, Baltimore, MD 21205 USA. [Nalls, Mike A.] NIA, NIH, Neurogenet Lab, Bethesda, MD 20892 USA. [Nickerson, Deborah A.] Univ Washington, Dept Genome Sci, Seattle, WA 98105 USA. [Nikus, Kjell] Tampere Univ Hosp, Dept Cardiol, Ctr Heart, Tampere 33521, Finland. [O'Donnell, Chris J.] Boston Vet Adm VA Healthcare, Cardiol Sect, Boston, MA 02118 USA. [O'Donnell, Chris J.] Boston Vet Adm VA Healthcare, Ctr Populat Gen, Boston, MA 02118 USA. [Petersmann, Astrid] Univ Med Greifswald, Inst Clin Chem & Lab Med, D-17475 Greifswald, Germany. [Psaty, Bruce M.] Univ Washington, Dept Med Epidemiol & Hlth Serv, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA. [Psaty, Bruce M.] Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA 98101 USA. [Raitakari, Olli T.] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku 20521, Finland. [Raitakari, Olli T.] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku 20520, Finland. [Rivadeneira, Fernando] Erasmus MC, Dept Internal Med, NL-3000 Rotterdam, Netherlands. [Rivadeneira, Fernando] NCHA, NL-3015 Rotterdam, Netherlands. [Rotter, Jerome I.; Taylor, Kent D.] Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90502 USA. [Rotter, Jerome I.; Taylor, Kent D.] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90502 USA. [Starr, John M.] Alzheimer Scotland Res Ctr, Edinburgh EH8 9JZ, Midlothian, Scotland. [Teumer, Alexander] Univ Med Greifswald, Inst Community Med, D-17475 Greifswald, Germany. [Tracy, Russell P.] Univ Vermont Coll Med, Dept Pathol, Colchester, VT 05446 USA. [Tracy, Russell P.] Univ Vermont Coll Med, Dept Lab Med, Colchester, VT 05446 USA. [Tracy, Russell P.] Univ Vermont Coll Med, Dept Biochem, Colchester, VT 05446 USA. [Zakai, Neil A.; Cushman, Mary] Univ Vermont Coll Med, Dept Med, Burlington, VT 05405 USA. [Zakai, Neil A.; Cushman, Mary] Univ Vermont Coll Med, Dept Pathol, Burlington, VT 05405 USA. [Vacchi-Suzzi, Caterina] SUNY Stony Brook, Dept Family Populat & Prevent Med, Stony Brook, NY 11794 USA. [Edwards, Digna R. Velez] Vanderbilt Univ, Vanderbilt Epidemiol Ctr, Dept Obstet & Gynecol, Inst Med & Publ Hlth,Vanderbilt Genet Inst, Nashville, TN 37203 USA. [Wallentin, Lars] Uppsala Univ, Dept Med Sci, Cardiol & Uppsala Clin Res Ctr, S-75185 Uppsala, Sweden. [Waterworth, Dawn M.] Genet Target Sci, GlaxoSmithKline, King Of Prussia, PA 19406 USA. [White, Harvey D.] Auckland City Hosp, Green Lane Cardiovasc Serv, Auckland 1142, New Zealand. [White, Harvey D.] Univ Auckland, Auckland 1142, New Zealand. [Wilson, James G.] Univ Mississippi Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10069 USA. [Faraday, Nauder] Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA. [Ganesh, Santhi K.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48108 USA. [Ganesh, Santhi K.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48108 USA. [Auer, Paul L.] Univ Wisconsin, Zilber Sch Publ Hlth, Milwaukee, WI 53205 USA. [Reiner, Alexander P.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Reiner, Alexander P.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. RP Lettre, G (reprint author), Univ Montreal, Dept Med, Montreal, PQ H3T 1J4, Canada.; Lettre, G (reprint author), Montreal Heart Inst, Montreal, PQ H1T 1CB, Canada.; Reiner, AP (reprint author), Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA.; Reiner, AP (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. EM apreiner@u.washington.edu; guillaume.lettre@umontreal.ca RI Schurmann, Claudia/L-1204-2016; Floyd, James/G-7563-2015; Johnson, Andrew/G-6520-2013; Kacprowski, Tim/K-8650-2013; Dube, Marie-Pierre/B-9364-2008; Grarup, Niels/K-2807-2015; OI Schurmann, Claudia/0000-0003-4158-9192; Evangelou, Evangelos/0000-0002-5488-2999; Linneberg, Allan/0000-0002-0994-0184; Kacprowski, Tim/0000-0002-5393-2413; Dube, Marie-Pierre/0000-0001-8442-4393; Grarup, Niels/0000-0001-5526-1070; Manichaikul, Ani/0000-0002-5998-795X; Tajuddin, Salman M./0000-0002-7919-8528; Zonderman, Alan B/0000-0002-6523-4778 FU Fonds de Recherche du Queebec-Santee (FRQS); Canadian Institute of Health Research (Banting-CIHR); Canadian Institute of Health Research (operating grant MOP) [123382]; Canada Research Chair program; NHLBI [R21 HL121422-02]; NIH [DK060022]; Yoshida Scholarship Foundation; Research Scholar award from the Massachusetts General Hospital (MGH); Howard Goodman Fellowship from MGH; Donovan Family Foundation [R01HL107816]; Fondation Leducq FX We thank all participants, staff, and study coordinating centers. We also thank Raymond Doty and Jan Abkowitz for discussion of the ALAS2 finding. We would like to thank Liling Warren for contributions to the genetic analysis of the SOLID-TIMI-52 and STABILITY datasets. Young Finns Study (YFS) acknowledges the expert technical assistance in the statistical analyses by Ville Aalto and Irina Lisinen. Estonian Genome Center, University of Tartu (EGCUT) thanks co-workers at the Estonian Biobank, especially Mr. V. Soo, Mr. S. Smith, and Dr. L. Milani. Airwave thanks Louisa Cavaliero who assisted in data collection and management as well as Peter McFarlane and the Glasgow CARE, Patricia Munroe at Queen Mary University of London, and Joanna Sarnecka and Ania Zawodniak at Northwick Park for their contributions to the study. This work was supported by the Fonds de Recherche du Queebec-Santee (FRQS, scholarship to N.C.), the Canadian Institute of Health Research (Banting-CIHR, scholarship to S.L. and operating grant MOP#123382 to G.L.), and the Canada Research Chair program (to G.L.). P.L.A. was supported by NHLBI R21 HL121422-02. N.A.A. is funded by NIH DK060022. A.N. was supported by the Yoshida Scholarship Foundation. S.K. was supported by a Research Scholar award from the Massachusetts General Hospital (MGH), the Howard Goodman Fellowship from MGH, the Donovan Family Foundation, R01HL107816, and a grant from Fondation Leducq. Additional acknowledgments and funding information is provided in the Supplemental Data. NR 65 TC 3 Z9 3 U1 5 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUL 7 PY 2016 VL 99 IS 1 BP 8 EP 21 DI 10.1016/j.ajhg.2016.05.007 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA DT6TI UT WOS:000381616600002 PM 27346685 ER PT J AU Tajuddin, SM Schick, UM Eicher, JD Chami, N Giri, A Brody, JA Hill, WD Kacprowski, T Li, J Lyytikainen, LP Manichaikul, A Mihailov, E O'Donoghue, ML Pankratz, N Pazoki, R Polfus, LM Smith, AV Schurmann, C Vacchi-Suzzi, C Waterworth, DM Evangelou, E Yanek, LR Burt, A Chen, MH van Rooij, FJA Floyd, JS Greinacher, A Harris, TB Highland, HM Lange, LA Liu, Y Magi, R Nalls, MA Mathias, RA Nickerson, DA Nikus, K Starr, JM Tardif, JC Tzoulaki, I Edwards, DRV Wallentin, L Bartz, TM Becker, LC Denny, JC Raffield, LM Rioux, JD Friedrich, N Fornage, M Gao, H Hirschhorn, JN Liewald, DCM Rich, SS Uitterlinden, A Bastarache, L Becker, DM Boerwinkle, E de Denus, S Bottinger, EP Hayward, C Hofman, A Homuth, G Lange, E Launer, LJ Lehtimaki, T Lu, YC Metspalu, A O'Donnell, CJ Quarells, RC Richard, M Torstenson, ES Taylor, KD Vergnaud, AC Zonderman, AB Crosslin, DR Deary, IJ Dorr, M Elliott, P Evans, MK Gudnason, V Kahonen, M Psaty, BM Rotter, JI Slater, AJ Dehghan, A White, HD Ganesh, SK Loos, RJF Esko, T Faraday, N Wilson, JG Cushman, M Johnson, AD Edwards, TL Zakai, NA Lettre, G Reiner, AP Auer, PL AF Tajuddin, Salman M. Schick, Ursula M. Eicher, John D. Chami, Nathalie Giri, Ayush Brody, Jennifer A. Hill, W. David Kacprowski, Tim Li, Jin Lyytikainen, Leo-Pekka Manichaikul, Ani Mihailov, Evelin O'Donoghue, Michelle L. Pankratz, Nathan Pazoki, Raha Polfus, Linda M. Smith, Albert Vernon Schurmann, Claudia Vacchi-Suzzi, Caterina Waterworth, Dawn M. Evangelou, Evangelos Yanek, Lisa R. Burt, Amber Chen, Ming-Huei van Rooij, Frank J. A. Floyd, James S. Greinacher, Andreas Harris, Tamara B. Highland, Heather M. Lange, Leslie A. Liu, Yongmei Magi, Reedik Nalls, Mike A. Mathias, Rasika A. Nickerson, Deborah A. Nikus, Kjell Starr, John M. Tardif, Jean-Claude Tzoulaki, Ioanna Edwards, Digna R. Velez Wallentin, Lars Bartz, Traci M. Becker, Lewis C. Denny, Joshua C. Raffield, Laura M. Rioux, John D. Friedrich, Nele Fornage, Myriam Gao, He Hirschhorn, Joel N. Liewald, David C. M. Rich, Stephen S. Uitterlinden, Andre Bastarache, Lisa Becker, Diane M. Boerwinkle, Eric de Denus, Simon Bottinger, Erwin P. Hayward, Caroline Hofman, Albert Homuth, Georg Lange, Ethan Launer, Lenore J. Lehtimaki, Terho Lu, Yingchang Metspalu, Andres O'Donnell, Chris J. Quarells, Rakale C. Richard, Melissa Torstenson, Eric S. Taylor, Kent D. Vergnaud, Anne-Claire Zonderman, Alan B. Crosslin, David R. Deary, Ian J. Dorr, Marcus Elliott, Paul Evans, Michele K. Gudnason, Vilmundur Kahonen, Mika Psaty, Bruce M. Rotter, Jerome I. Slater, Andrew J. Dehghan, Abbas White, Harvey D. Ganesh, Santhi K. Loos, Ruth J. F. Esko, Tonu Faraday, Nauder Wilson, James G. Cushman, Mary Johnson, Andrew D. Edwards, Todd L. Zakai, Neil A. Lettre, Guillaume Reiner, Alex P. Auer, Paul L. TI Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID ACUTE MYELOID-LEUKEMIA; UROKINASE RECEPTOR; GENETIC-VARIANTS; LYMPHOBLASTIC-LEUKEMIA; TRANSCRIPTION FACTORS; SUSCEPTIBILITY LOCI; LYMPHOID ORGANS; EMERGE NETWORK; RISK LOCI; EXPRESSION AB White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of similar to 157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3 ' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases. C1 [Tajuddin, Salman M.; Zonderman, Alan B.; Evans, Michele K.] NIA, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA. [Schick, Ursula M.; Schurmann, Claudia; Bottinger, Erwin P.; Lu, Yingchang; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA. [Schick, Ursula M.; Schurmann, Claudia; Lu, Yingchang; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA. [Eicher, John D.; Chen, Ming-Huei; Johnson, Andrew D.] NHLBI, Populat Sci Branch, Framingham Heart Study, Framingham, MA 01702 USA. [Chami, Nathalie; Tardif, Jean-Claude; Rioux, John D.; Lettre, Guillaume] Univ Montreal, Dept Med, Montreal, PQ H3T 1J4, Canada. [Chami, Nathalie; Tardif, Jean-Claude; Rioux, John D.; de Denus, Simon; Lettre, Guillaume] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Giri, Ayush; Torstenson, Eric S.] Vanderbilt Univ, Div Epidemiol, Inst Med & Publ Hlth, Nashville, TN 37235 USA. [Brody, Jennifer A.; Floyd, James S.] Univ Washington, Dept Med, Seattle, WA 98101 USA. [Hill, W. David; Starr, John M.; Liewald, David C. M.; Deary, Ian J.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland. [Hill, W. David; Liewald, David C. M.; Deary, Ian J.] Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland. [Kacprowski, Tim; Homuth, Georg] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Dept Funct Genom, D-17475 Greifswald, Germany. [Kacprowski, Tim; Homuth, Georg] Ernst Moritz Arndt Univ Greifswald, D-17475 Greifswald, Germany. [Kacprowski, Tim; Friedrich, Nele; Dorr, Marcus] DZHK German Ctr Cardiovasc Res, Greifswald, Germany. [Li, Jin] Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Palo Alto, CA 94305 USA. [Lyytikainen, Leo-Pekka; Lehtimaki, Terho] Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland. [Lyytikainen, Leo-Pekka; Lehtimaki, Terho] Univ Tampere, Sch Med, Dept Clin Chem, Tampere 33014, Finland. [Manichaikul, Ani; Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA. [Mihailov, Evelin; Magi, Reedik; Metspalu, Andres; Esko, Tonu] Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia. [O'Donoghue, Michelle L.] Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. [Pankratz, Nathan] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55454 USA. [Pazoki, Raha; van Rooij, Frank J. A.; Uitterlinden, Andre; Hofman, Albert; Dehghan, Abbas] Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3000 DR Rotterdam, Netherlands. [Polfus, Linda M.; Highland, Heather M.; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA. [Smith, Albert Vernon; Gudnason, Vilmundur] Iceland Heart Assoc, IS-201 Kopavogur, Iceland. [Smith, Albert Vernon; Gudnason, Vilmundur] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. [Vacchi-Suzzi, Caterina] SUNY Stony Brook, Dept Family Populat & Prevent Med, Stony Brook, NY 11794 USA. [Waterworth, Dawn M.] GlaxoSmithKline, Target Sci, Genet, King Of Prussia, PA 19406 USA. [Evangelou, Evangelos; Tzoulaki, Ioanna; Gao, He; Vergnaud, Anne-Claire; Elliott, Paul] Imperial Coll London, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, Dept Epidemiol & Biostat, London W2 1PG, England. [Evangelou, Evangelos; Tzoulaki, Ioanna] Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, GR-45110 Ioannina, Greece. [Yanek, Lisa R.; Becker, Diane M.] Johns Hopkins Univ, Sch Med, Dept Med, Div Gen Internal Med, Baltimore, MD 21205 USA. [Burt, Amber] Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA. [Greinacher, Andreas] Univ Med Greifswald, Inst Immunol & Transfus Med, D-17475 Greifswald, Germany. [Harris, Tamara B.; Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Highland, Heather M.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27514 USA. [Lange, Leslie A.; Raffield, Laura M.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27514 USA. [Liu, Yongmei] Wake Forest Sch Med, Div Publ Hlth Sci, Ctr Human Genet, Winston Salem, NC 27157 USA. [Nalls, Mike A.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Mathias, Rasika A.] Johns Hopkins Univ, Sch Med, Dept Med, Div Allergy & Clin Immunol, Baltimore, MD 21205 USA. [Mathias, Rasika A.; Becker, Lewis C.] Johns Hopkins Univ, Sch Med, Dept Med, Div Gen Internal Med, Baltimore, MD 21205 USA. [Nickerson, Deborah A.] Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA 98105 USA. [Nikus, Kjell] Tampere Univ Hosp, Dept Cardiol, Ctr Heart, Tampere 33521, Finland. [Nikus, Kjell] Univ Tampere, Sch Med, Tampere 33014, Finland. [Starr, John M.] Alzheimer Scotland Dementia Res Ctr, Edinburgh EH8 9JZ, Midlothian, Scotland. [Edwards, Digna R. Velez] Vanderbilt Univ, Vanderbilt Genet Inst, Inst Med & Publ Hlth, Vanderbilt Epidemiol Ctr,Dept Obstet & Gynecol, Nashville, TN 37203 USA. [Wallentin, Lars] Uppsala Univ, Cardiol, Dept Med Sci, S-75185 Uppsala, Sweden. [Wallentin, Lars] Uppsala Univ, Uppsala Clin Res Ctr, S-75185 Uppsala, Sweden. [Bartz, Traci M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Becker, Lewis C.] Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. [Denny, Joshua C.; Bastarache, Lisa] Vanderbilt Univ, Sch Med, Dept Biomed Informat, Nashville, TN 37203 USA. [Friedrich, Nele] Univ Med Greifswald, Inst Clin Chem & Lab Med, D-13347 Greifswald, Germany. [Fornage, Myriam; Richard, Melissa] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA. [Hirschhorn, Joel N.; Esko, Tonu] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Hirschhorn, Joel N.] Boston Childrens Hosp, Dept Endocrinol, Boston, MA 02115 USA. [Uitterlinden, Andre] Erasmus Univ, Med Ctr, Dept Internal Med, NL-3000 DR Rotterdam, Netherlands. [Uitterlinden, Andre] NCHA, NL-3015 GD Rotterdam, Netherlands. [Boerwinkle, Eric] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [de Denus, Simon] Univ Montreal, Fac Pharm, Montreal, PQ H3T 1J4, Canada. [Hayward, Caroline] Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland. [Hofman, Albert] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Lange, Ethan] Univ N Carolina, Dept Genet & Biostat, Chapel Hill, NC 27599 USA. [O'Donnell, Chris J.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [O'Donnell, Chris J.] Boston Vet Adm Healthcare, Cardiol Sect, Boston, MA 02118 USA. [O'Donnell, Chris J.] Boston Vet Adm Healthcare, Ctr Populat Genom, Boston, MA 02118 USA. [Quarells, Rakale C.] Morehouse Sch Med, Social Epidemiol Res Ctr, Cardiovasc Res Inst, Atlanta, GA 30310 USA. [Taylor, Kent D.; Rotter, Jerome I.] Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90502 USA. [Taylor, Kent D.; Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90502 USA. [Crosslin, David R.] Univ Washington, Dept Biomed Informat & Med Educ, Seattle, WA 98195 USA. [Dorr, Marcus] Univ Med Greifswald, Dept Cardiol, D-17475 Greifswald, Germany. [Kahonen, Mika] Tampere Univ Hosp, Dept Clin Physiol, Tampere 33521, Finland. [Kahonen, Mika] Univ Tampere, Sch Med, Dept Clin Physiol, Tampere 33014, Finland. [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Epidemiol, Seattle, WA 98101 USA. [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Hlth Serv, Seattle, WA 98101 USA. [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98101 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98101 USA. [Slater, Andrew J.] OmicSoft Corp, Cary, NC 27513 USA. [Slater, Andrew J.] GlaxoSmithKline, Genet Target Sci, Res Triangle Pk, NC 27709 USA. [White, Harvey D.] Auckland City Hosp, Green Lane Cardiovasc Serv, Auckland 1142, New Zealand. [White, Harvey D.] Univ Auckland, Auckland 1142, New Zealand. [Ganesh, Santhi K.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48108 USA. [Ganesh, Santhi K.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48108 USA. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. [Faraday, Nauder] Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Cushman, Mary; Zakai, Neil A.] Univ Vermont, Dept Med, Div Hematol Oncol, Colchester, VT 05446 USA. [Edwards, Todd L.] Vanderbilt Univ, Vanderbilt Genet Inst, Inst Med & Publ Hlth, Div Epidemiol,Dept Med, Nashville, TN 37203 USA. [Reiner, Alex P.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Reiner, Alex P.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Auer, Paul L.] Univ Wisconsin Milwaukee, Zilber Sch Publ Hlth, Milwaukee, WI 53205 USA. RP Reiner, AP (reprint author), Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA.; Reiner, AP (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA.; Auer, PL (reprint author), Univ Wisconsin Milwaukee, Zilber Sch Publ Hlth, Milwaukee, WI 53205 USA. EM apreiner@u.washington.edu; pauer@uwm.edu RI Schurmann, Claudia/L-1204-2016; Floyd, James/G-7563-2015; Rioux, John/A-9599-2015; Johnson, Andrew/G-6520-2013; Kacprowski, Tim/K-8650-2013; OI Schurmann, Claudia/0000-0003-4158-9192; Rioux, John/0000-0001-7560-8326; Kacprowski, Tim/0000-0002-5393-2413; Manichaikul, Ani/0000-0002-5998-795X; Tajuddin, Salman M./0000-0002-7919-8528; Zonderman, Alan B/0000-0002-6523-4778; Evangelou, Evangelos/0000-0002-5488-2999; Dehghan, Abbas/0000-0001-6403-016X FU NHLBI [R21 HL121422-02, R01 HL086694]; Canada Research Chair program; Canadian Institute of Health Research MOP [123382]; National Institute on Aging, NIH Intramural Research Program; a component of the NIH Roadmap for Medical Research [UL1RR025005] FX We thank all participants and study coordinating centers of the participating studies and cohorts. P.L.A. was supported by NHLBI R21 HL121422-02. G.L. was supported by the Canada Research Chair program and the Canadian Institute of Health Research MOP#123382. This work was supported in part by the National Institute on Aging, NIH Intramural Research Program. Data analyses utilized the computational resources of the NIH HPC Biowulf cluster at the NIH. The Framingham Heart Study (FHS) acknowledges the Shared Computing Cluster at Boston University. Infrastructure and data analysis for the ARIC study was partly supported by Grant Number UL1RR025005, a component of the NIH Roadmap for Medical Research, and grant R01 HL086694 from the NHLBI. Airwave study thanks Louisa Cavaliero who assisted in data collection and management, Peter McFarlane and the Glasgow CARE, Patricia Munroe at Queen Mary University of London, and Joanna Sarnecka and Ania Zawodniak at Northwick Park for their contributions to the study. SOLID-TIMI-52 and STABILITY thank Liling Warren for contributions to the genetic analysis of the study datasets. Estonian Genome Center, University of Tartu (EGCUT) thanks Mr. V. Soo, Mr. S. Smith, and Dr. L. Milani for their contribution. The Rotterdam Study (RS) thanks Ms. Mila Jhamai, Ms. Sarah Higgins, and Mr. Marijn Verkerk for their help in creating the Exomechip database, and Ms. Carolina MedinaGomez, Mr. Lennard Karsten, and Dr. Linda Broer. Additional acknowledgments and funding information are provided in the Supplemental Data. NR 96 TC 3 Z9 3 U1 7 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUL 7 PY 2016 VL 99 IS 1 BP 22 EP 39 DI 10.1016/j.ajhg.2016.05.003 PG 18 WC Genetics & Heredity SC Genetics & Heredity GA DT6TI UT WOS:000381616600003 PM 27346689 ER PT J AU Eicher, JD Chami, N Kacprowski, T Nomura, A Chen, MH Yanek, LR Tajuddin, SM Schick, UM Slater, AJ Pankratz, N Polfus, L Schurmann, C Giri, A Brody, JA Lange, LA Manichaikul, A Hill, WD Pazoki, R Elliot, P Evangelou, E Tzoulaki, I Gao, H Vergnaud, AC Mathias, RA Becker, DM Becker, LC Burt, A Crosslin, DR Lyytikainen, LP Nikus, K Hernesniemi, J Kahonen, M Raitoharju, E Mononen, N Raitakari, OT Lehtimaki, T Cushman, M Zakai, NA Nickerson, DA Raffield, LM Quarells, R Willer, CJ Peloso, GM Abecasis, GR Liu, DJJ Deloukas, P Samani, NJ Schunkert, H Erdmann, J Fornage, M Richard, M Tardif, JC Rioux, JD Dube, MP de Denus, S Lu, YC Bottinger, EP Loos, RJF Smith, AV Harris, TB Launer, LJ Gudnason, V Edwards, DRV Torstenson, ES Liu, YM Tracy, RP Rotter, JI Rich, SS Highland, HM Boerwinkle, E Li, J Lange, E Wilson, JG Mihailov, E Magi, R Hirschhorn, J Metspalu, A Esko, T Vacchi-Suzzi, C Nalls, MA Zonderman, AB Evans, MK Engstrom, G Orho-Melander, M Melander, O O'Donoghue, ML Waterworth, DM Wallentin, L White, HD Floyd, JS Bartz, TM Rice, KM Psaty, BM Starr, JM Liewald, DCM Hayward, C Deary, IJ Greinacher, A Volker, U Thiele, T Volzke, H van Rooij, FJA Uitterlinden, AG Franco, OH Dehghan, A Edwards, TL Ganesh, SK Kathiresan, S Faraday, N Auer, PL Reiner, AP Lettre, G Johnson, AD AF Eicher, John D. Chami, Nathalie Kacprowski, Tim Nomura, Akihiro Chen, Ming-Huei Yanek, Lisa R. Tajuddin, Salman M. Schick, Ursula M. Slater, Andrew J. Pankratz, Nathan Polfus, Linda Schurmann, Claudia Giri, Ayush Brody, Jennifer A. Lange, Leslie A. Manichaikul, Ani Hill, W. David Pazoki, Raha Elliot, Paul Evangelou, Evangelos Tzoulaki, Ioanna Gao, He Vergnaud, Anne-Claire Mathias, Rasika A. Becker, Diane M. Becker, Lewis C. Burt, Amber Crosslin, David R. Lyytikainen, Leo-Pekka Nikus, Kjell Hernesniemi, Jussi Kahonen, Mika Raitoharju, Emma Mononen, Nina Raitakari, Olli T. Lehtimaki, Terho Cushman, Mary Zakai, Neil A. Nickerson, Deborah A. Raffield, Laura M. Quarells, Rakale Willer, Cristen J. Peloso, Gina M. Abecasis, Goncalo R. Liu, Dajiang J. Deloukas, Panos Samani, Nilesh J. Schunkert, Heribert Erdmann, Jeanette Fornage, Myriam Richard, Melissa Tardif, Jean-Claude Rioux, John D. Dube, Marie-Pierre de Denus, Simon Lu, Yingchang Bottinger, Erwin P. Loos, Ruth J. F. Smith, Albert Vernon Harris, Tamara B. Launer, Lenore J. Gudnason, Vilmundur Edwards, Digna R. Velez Torstenson, Eric S. Liu, Yongmei Tracy, Russell P. Rotter, Jerome I. Rich, Stephen S. Highland, Heather M. Boerwinkle, Eric Li, Jin Lange, Ethan Wilson, James G. Mihailov, Evelin Magi, Reedik Hirschhorn, Joel Metspalu, Andres Esko, Tonu Vacchi-Suzzi, Caterina Nalls, Mike A. Zonderman, Alan B. Evans, Michele K. Engstrom, Gunnar Orho-Melander, Marju Melander, Olle O'Donoghue, Michelle L. Waterworth, Dawn M. Wallentin, Lars White, Harvey D. Floyd, James S. Bartz, Traci M. Rice, Kenneth M. Psaty, Bruce M. Starr, J. M. Liewald, David C. M. Hayward, Caroline Deary, Ian J. Greinacher, Andreas Volker, Uwe Thiele, Thomas Volzke, Henry van Rooij, Frank J. A. Uitterlinden, Andre G. Franco, Oscar H. Dehghan, Abbas Edwards, Todd L. Ganesh, Santhi K. Kathiresan, Sekar Faraday, Nauder Auer, Paul L. Reiner, Alex P. Lettre, Guillaume Johnson, Andrew D. CA Global Lipids Genetics Consortium CARDIoGRAM Exome Consortium Myocardial Infarction Genetics TI Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; EPSILON-RI-ALPHA; PIAS-LIKE PROTEIN; IMMUNE THROMBOCYTOPENIA; MYOCARDIAL-INFARCTION; AFRICAN-AMERICANS; SEQUENCE VARIANTS; BLOOD-PRESSURE; BINDING-SITE; IGE BINDING AB Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common(ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV(PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors. C1 [Eicher, John D.; Chen, Ming-Huei; Johnson, Andrew D.] NHLBI, Populat Sci Branch, Framingham Heart Study, Framingham, MA 01702 USA. [Chami, Nathalie; Tardif, Jean-Claude; Rioux, John D.; Dube, Marie-Pierre; Lettre, Guillaume] Univ Montreal, Dept Med, Montreal, PQ H3T 1J4, Canada. [Chami, Nathalie; Tardif, Jean-Claude; Rioux, John D.; Dube, Marie-Pierre; de Denus, Simon; Lettre, Guillaume] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. 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[O'Donoghue, Michelle L.] Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc, Boston, MA 02115 USA. [Waterworth, Dawn M.] GlaxoSmithKline, Target Sci, Genet, King Of Prussia, PA 19406 USA. [Wallentin, Lars] Uppsala Univ, Dept Med Sci, Cardiol, S-75185 Uppsala, Sweden. [Wallentin, Lars] Uppsala Univ, Dept Med Sci, Uppsala Clin Res Ctr, S-75185 Uppsala, Sweden. [White, Harvey D.] Auckland City Hosp, Green Lane Cardiovasc Serv, Auckland 1142, New Zealand. [White, Harvey D.] Univ Auckland, Auckland 1142, New Zealand. [Bartz, Traci M.; Rice, Kenneth M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98101 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98101 USA. [Psaty, Bruce M.] Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA 98101 USA. [Starr, J. M.] Alzheimer Scotland Res Ctr, Edinburgh EH8 9JZ, Midlothian, Scotland. [Hayward, Caroline] Univ Edinburgh, MRC Human Genet Unit, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland. [Greinacher, Andreas; Thiele, Thomas] Univ Med Greifswald, Inst Immunol & Transfus Med, D-17475 Greifswald, Germany. [Volzke, Henry] Univ Med Greifswald, Inst Community Med, D-13347 Greifswald, Germany. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, NL-3000 Rotterdam, Netherlands. [Uitterlinden, Andre G.] Netherlands Consortium Hlth Ageing, NL-3015 Rotterdam, Netherlands. [Ganesh, Santhi K.] Univ Michigan, Dept Internal & Human Genet, Ann Arbor, MI 48108 USA. [Faraday, Nauder] Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA. [Auer, Paul L.] Univ Wisconsin, Zilber Sch Publ Hlth, Milwaukee, WI 53205 USA. [Reiner, Alex P.] Univ Washington, Dept Epidemiol, Seattle, WA 98105 USA. [Eicher, John D.; Chami, Nathalie; Kacprowski, Tim; Nomura, Akihiro; Faraday, Nauder; Auer, Paul L.; Reiner, Alex P.; Lettre, Guillaume; Johnson, Andrew D.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. RP Johnson, AD (reprint author), NHLBI, Populat Sci Branch, Framingham Heart Study, Framingham, MA 01702 USA.; Johnson, AD (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. EM johnsonad2@nhlbi.nih.gov RI Schurmann, Claudia/L-1204-2016; Floyd, James/G-7563-2015; Rioux, John/A-9599-2015; Johnson, Andrew/G-6520-2013; Kacprowski, Tim/K-8650-2013; Deloukas, Panos/B-2922-2013; Dube, Marie-Pierre/B-9364-2008; OI Evangelou, Evangelos/0000-0002-5488-2999; Dehghan, Abbas/0000-0001-6403-016X; Schurmann, Claudia/0000-0003-4158-9192; Rioux, John/0000-0001-7560-8326; Kacprowski, Tim/0000-0002-5393-2413; Deloukas, Panos/0000-0001-9251-070X; Dube, Marie-Pierre/0000-0001-8442-4393; Manichaikul, Ani/0000-0002-5998-795X; Tajuddin, Salman M./0000-0002-7919-8528; Zonderman, Alan B/0000-0002-6523-4778 FU British Heart Foundation [RG/14/5/30893]; Medical Research Council [MC_PC_U127561128, MR/K026992/1]; NCATS NIH HHS [UL1 TR000124, UL1 TR000445]; NHGRI NIH HHS [U01 HG004402, U01 HG004603]; NHLBI NIH HHS [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, HHSN268201100037C, HHSN268201300026C, HHSN268201300028C, N01 HC025195, N01 HC095159, N01 HC095160, R01 HL059367, R01 HL086694, R01 HL087641, R01 HL087698, R01 HL112064, R01 HL122684, R01 HL127564, RC2 HL102419, U01 HL072518]; NICHD NIH HHS [R01 HD074711]; NIDDK NIH HHS [P30 DK063491] NR 77 TC 4 Z9 4 U1 3 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUL 7 PY 2016 VL 99 IS 1 BP 40 EP 55 DI 10.1016/j.ajhg.2016.05.005 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA DT6TI UT WOS:000381616600004 PM 27346686 ER PT J AU Gigante, ED Benaliouad, F Zamora-Olivencia, V Wise, RA AF Gigante, Eduardo D. Benaliouad, Faiza Zamora-Olivencia, Veronica Wise, Roy A. TI Optogenetic Activation of a Lateral Hypothalamic-Ventral Tegmental Drive-Reward Pathway SO PLOS ONE LA English DT Article ID MEDIAL FOREBRAIN-BUNDLE; BRAIN-STIMULATION REWARD; SELF-STIMULATION; ELECTRICAL-STIMULATION; REFRACTORY PERIODS; PREOPTIC AREA; RAT; DOPAMINE; SEEKING; FIBERS AB Electrical stimulation of the lateral hypothalamus can motivate feeding or can serve as a reward in its own right. It remains unclear whether the same or independent but anatomically overlapping circuitries mediate the two effects. Electrical stimulation findings implicate medial forebrain bundle (MFB) fibers of passage in both effects, and optogenetic studies confirm a contribution from fibers originating in the lateral hypothalamic area and projecting to or through the ventral tegmental area. Here we report that optogenetic activation of ventral tegmental fibers from cells of origin in more anterior or posterior portions of the MFB failed to induce either reward or feeding. The feeding and reward induced by optogenetic activation of fibers from the lateral hypothalamic cells of origin were influenced similarly by variations in stimulation pulse width and pulse frequency, consistent with the hypothesis of a common substrate for the two effects. There were, however, several cases where feeding but not self-stimulation or self-stimulation but not feeding were induced, consistent with the hypothesis that distinct but anatomically overlapping systems mediate the two effects. Thus while optogenetic stimulation provides a more selective tool for characterizing the mechanisms of stimulation-induced feeding and reward, it does not yet resolve the question of common or independent substrates. C1 [Gigante, Eduardo D.; Benaliouad, Faiza; Zamora-Olivencia, Veronica; Wise, Roy A.] NIDA, Intramural Res Program, NIH, Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Wise, RA (reprint author), NIDA, Intramural Res Program, NIH, Dept Hlth & Human Serv, Baltimore, MD 21224 USA. EM rwise@intra.nida.nih.gov FU Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health FX This study was funded by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. NR 48 TC 0 Z9 0 U1 4 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 7 PY 2016 VL 11 IS 7 AR e0158885 DI 10.1371/journal.pone.0158885 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR3OC UT WOS:000379811500058 PM 27387668 ER PT J AU Jones, K Ballesteros, A Mentink-Kane, M Warren, J Rattila, S Malech, H Kang, E Dveksler, G AF Jones, Karlie Ballesteros, Angela Mentink-Kane, Margaret Warren, James Rattila, Shemona Malech, Harry Kang, Elizabeth Dveksler, Gabriela TI PSG9 Stimulates Increase in FoxP3(+) Regulatory T-Cells through the TGF-beta 1 Pathway SO PLOS ONE LA English DT Article ID LATENT TGF-BETA; PREGNANCY-SPECIFIC BETA-1-GLYCOPROTEIN; GROWTH-FACTOR-BETA; TRANSCRIPTION FACTOR FOXP3; GLYCOPROTEIN 1 PSG1; CUTTING EDGE; EXPRESSION; ACTIVATION; RECEPTOR; SURFACE AB The pregnancy-specific glycoproteins (PSGs) are a family of proteins secreted by the syncytiotrophoblast of the placenta and are the most abundant trophoblastic proteins in maternal blood during the third trimester. The human PSG family consists of 10 protein-coding genes, some of which have a possible role in maintaining maternal immune tolerance to the fetus. PSG9 was reported as a potential predictive biomarker of pre-eclampsia, a serious complication of pregnancy that has been related to immunological dysfunction at the fetal-maternal interface. Therefore, we hypothesized that PSG9 may have an immunoregulatory role during pregnancy. We found that PSG9 binds to LAP and activates the latent form of TGF-beta 1. In addition, PSG9 induces the secretion of TGF-beta 1 from macrophages but not from CD4(+) T-cells. TGF-beta 1 is required for the ex vivo differentiation of regulatory T-cells and, consistent with the ability of PSG9 to activate this cytokine, we observed that PSG9 induces the differentiation of FoxP3(+) regulatory T-cells from naive murine and human T-cells. Cytokines that are associated with inflammatory responses were also reduced in the supernatants of T-cells treated with PSG9, suggesting that PSG9, through its activation of TGF beta-1, could be a potent inducer of immune tolerance. C1 [Jones, Karlie; Malech, Harry; Kang, Elizabeth] NIAID, NIH, Bethesda, MD USA. [Ballesteros, Angela] NIDCD, NIH, Bethesda, MD USA. [Mentink-Kane, Margaret; Warren, James; Rattila, Shemona; Dveksler, Gabriela] USUHS, Dept Pathol, Bethesda, MD USA. RP Dveksler, G (reprint author), USUHS, Dept Pathol, Bethesda, MD USA. EM gabriela.dveksler@usuhs.edu FU USUHS [R0742495]; Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH) [Z-A1-00-0989] FX This work was supported by the USUHS intramural award R0742495 to GD and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH) under intramural project number Z-A1-00-0989 supported the research reported in this publication. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 1 Z9 1 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 7 PY 2016 VL 11 IS 7 AR e0158050 DI 10.1371/journal.pone.0158050 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR3OC UT WOS:000379811500012 PM 27389696 ER PT J AU Curtis, LM Pavletic, SZ AF Curtis, Lauren M. Pavletic, Steven Z. TI IL-2, the next best thing in chronic GVHD therapy? SO BLOOD LA English DT Editorial Material ID VERSUS-HOST-DISEASE C1 [Curtis, Lauren M.; Pavletic, Steven Z.] NCI, Bethesda, MD 20892 USA. RP Curtis, LM (reprint author), NCI, Bethesda, MD 20892 USA. NR 8 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUL 7 PY 2016 VL 128 IS 1 BP 13 EP 15 DI 10.1182/blood-2016-05-711796 PG 5 WC Hematology SC Hematology GA DQ5MN UT WOS:000379249600007 PM 27389542 ER PT J AU Saba, NS Liu, DL Herman, SEM Underbayev, C Tian, X Behrend, D Weniger, MA Skarzynski, M Gyamfi, J Fontan, L Melnick, A Grant, C Roschewski, M Navarro, A Bea, S Pittaluga, S Dunleavy, K Wilson, WH Wiestner, A AF Saba, Nakhle S. Liu, Delong Herman, Sarah E. M. Underbayev, Chingiz Tian, Xin Behrend, David Weniger, Marc A. Skarzynski, Martin Gyamfi, Jennifer Fontan, Lorena Melnick, Ari Grant, Cliona Roschewski, Mark Navarro, Alba Bea, Silvia Pittaluga, Stefania Dunleavy, Kieron Wilson, Wyndham H. Wiestner, Adrian TI Pathogenic role of B-cell receptor signaling and canonical NF-kappa B activation in mantle cell lymphoma SO BLOOD LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; NON-HODGKIN-LYMPHOMA; SMALL-MOLECULE INHIBITORS; WALDENSTROMS MACROGLOBULINEMIA; TARGETING BTK; IBRUTINIB; EXPRESSION; THERAPY; KINASE; SOX11 AB To interrogate signaling pathways activated in mantle cell lymphoma (MCL) in vivo, we contrasted gene expression profiles of 55 tumor samples isolated from blood and lymph nodes from 43 previously untreated patients with active disease. In addition to lymph nodes, MCL often involves blood, bone marrow, and spleen and is incurable for most patients. Recently, the Bruton tyrosine kinase (BTK) inhibitor ibrutinib demonstrated important clinical activity in MCL. However, the role of specific signaling pathways in the lymphomagenesis of MCL and the biologic basis for ibrutinib sensitivity of these tumors are unknown. Here, we demonstrate activation of B-cell receptor (BCR) and canonical NF-kappa B signaling specifically in MCL cells in the lymph node. Quantification of BCR signaling strength, reflected in the expression of BCR regulated genes, identified a subset of patients with inferior survival after cytotoxic therapy. Tumor proliferation was highest in the lymph node and correlated with the degree of BCR activation. A subset of leukemic tumors showed active BCR and NF-kB signaling apparently independent of microenvironmental support. In one of these samples, we identified a novel somatic mutation in RELA (E39Q). This sample was resistant to ibrutinib-mediated inhibition of NF-kappa B and apoptosis. In addition, we identified germ line variants in genes encoding regulators of the BCR and NF-kB pathway previously implicated in lymphomagenesis. In conclusion, BCR signaling, activated in the lymph node microenvironment in vivo, appears to promote tumor proliferation and survival and may explain the sensitivity of this lymphoma to BTK inhibitors. C1 [Saba, Nakhle S.; Liu, Delong; Herman, Sarah E. M.; Underbayev, Chingiz; Behrend, David; Weniger, Marc A.; Skarzynski, Martin; Gyamfi, Jennifer; Wiestner, Adrian] NHLBI, Hematol Branch, NIH, Bld 10,CRC 3-5140,10 Ctr Dr, Bethesda, MD 20892 USA. [Saba, Nakhle S.] Tulane Univ, Dept Med, Sect Hematol & Med Oncol, New Orleans, LA 70118 USA. [Tian, Xin] NHLBI, Off Biostat Res, NIH, Bld 10,CRC 3-5140,10 Ctr Dr, Bethesda, MD 20892 USA. [Fontan, Lorena; Melnick, Ari] Weill Cornell Med Coll, Dept Med, Div Hematol & Med Oncol, New York, NY USA. [Grant, Cliona; Roschewski, Mark; Wilson, Wyndham H.] NCI, Lymphoid Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Navarro, Alba; Bea, Silvia] Inst Invest Biomed August Pi & Sunyer, Barcelona, Spain. [Pittaluga, Stefania] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Wiestner, A (reprint author), NHLBI, Hematol Branch, NIH, Bld 10,CRC 3-5140,10 Ctr Dr, Bethesda, MD 20892 USA. EM wiestnera@mail.nih.gov RI Navarro, Alba/H-2611-2015 OI Navarro, Alba/0000-0002-4041-0974 FU Intramural Research Programs of the National Heart, Lung, and Blood Institute; National Cancer Institute, National Institutes of Health FX This work was funded by the Intramural Research Programs of the National Heart, Lung, and Blood Institute and the National Cancer Institute, National Institutes of Health. NR 45 TC 5 Z9 5 U1 3 U2 9 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUL 7 PY 2016 VL 128 IS 1 BP 82 EP 92 DI 10.1182/blood-2015-11-681460 PG 11 WC Hematology SC Hematology GA DQ5MN UT WOS:000379249600016 PM 27127301 ER PT J AU Torres-Salgado, JF Comas-Garcia, M Villagrana-Escareno, MV Duran-Meza, AL Ruiz-Garcia, J Cadena-Nava, RD AF Torres-Salgado, Jose F. Comas-Garcia, Mauricio Villagrana-Escareno, Maria V. Duran-Meza, Ana L. Ruiz-Garcia, Jaime Cadena-Nava, Ruben D. TI Physicochemical Study of Viral Nanoparticles at the Air/Water Interface SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID LANGMUIR-BLODGETT-FILMS; GOLD NANOPARTICLES; PROTEIN ADSORPTION; COLLOIDAL CRYSTALS; CARBON NANOTUBES; CAPSID PROTEIN; PHASE-DIAGRAM; AIR-WATER; MONOLAYERS; PARTICLES AB The assembly of most single-stranded RNA (ssRNA) viruses into icosahedral nucleocapsids is a spontaneous process driven by protein protein and RNA protein interactions. The precise nature of these interactions results in the assembly of extremely monodisperse and structurally indistinguishable nucleocapsids. In this work, by using a ssRNA plant virus (cowpea chlorotic mottle virus [CCMV]) as a charged nanoparticle we show that the diffusion of these nanoparticles from the bulk solution to the air/water interface is an irreversible adsorption process. By using the Langmuir technique, we measured the diffusion and adsorption of viral nucleocapsids at the air/water interface at different pH conditions. The pH changes, and therefore in the net surface charge of the virions, have a great influence in the diffusion rate from the bulk solution to the air/water interface. Moreover, assembly of mesoscopic and microscopic viral aggregates at this interface depends on the net surface charge of the virions and the surface pressure. By using Brewster's angle microscopy we characterized these structures at the interface. Most common structures observed were clusters of virions and soap-frothlike micron-size structures. Furthermore, the CCMV films were compressed to form monolayers and multilayers from moderate to high surface pressures, respectively. After transferring the films from the air/water interface onto mica by using the Langmuir-Blodgett technique, their morphology was characterized by atomic force microscopy. These viral monolayers showed closed-packing nano- and microscopic arrangements. C1 [Torres-Salgado, Jose F.; Villagrana-Escareno, Maria V.; Duran-Meza, Ana L.; Ruiz-Garcia, Jaime] Univ Autonoma San Luis Potosi, Inst Fis, Alvaro Obregon 64, San Luis Potosi 78000, San Luis Potosi, Mexico. [Comas-Garcia, Mauricio] NCI, HIV Dynam & Replicat Program, Frederick, MD 21702 USA. [Cadena-Nava, Ruben D.] Univ Nacl Autonoma Mexico, Ctr Nanociencias & Nanotecnol, Carretera Tijuana Ensenada Km 107, Ensenada 22860, Baja California, Mexico. RP Ruiz-Garcia, J (reprint author), Univ Autonoma San Luis Potosi, Inst Fis, Alvaro Obregon 64, San Luis Potosi 78000, San Luis Potosi, Mexico.; Cadena-Nava, RD (reprint author), Univ Nacl Autonoma Mexico, Ctr Nanociencias & Nanotecnol, Carretera Tijuana Ensenada Km 107, Ensenada 22860, Baja California, Mexico. EM jaime@dec1.ifisica.uaslp.mx; rcadena74@gmail.com OI Comas-Garcia, Mauricio/0000-0002-7733-5138 FU Consejo Nacional de Ciencia y Tecnologia (CONACYT) [237439, 239878, 225019, 248787] FX We would like to acknowledge the support from the Consejo Nacional de Ciencia y Tecnologia (CONACYT) Grants 237439, 239878, 225019, and 248787. NR 48 TC 0 Z9 0 U1 9 U2 15 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD JUL 7 PY 2016 VL 120 IS 26 BP 5864 EP 5873 DI 10.1021/acs.jpcb.6b00624 PG 10 WC Chemistry, Physical SC Chemistry GA DQ8JN UT WOS:000379457200010 PM 26999022 ER PT J AU Berezhkovskii, AM Szabo, A AF Berezhkovskii, Alexander M. Szabo, Attila TI Theory of Crowding Effects on Bimolecular Reaction Rates SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID PHYSIOLOGICAL CONSEQUENCES; DIFFUSION; CONFINEMENT; CYTOPLASM; BINDING; VOLUME AB An analytical expression for the rate constant of a diffusion-influenced bimolecular reaction in a crowded environment is derived in the framework of a microscopic model that accounts for: (1) the slowdown of diffusion due to crowding and the dependence of the diffusivity on the distance between the reactants, (2) a crowding induced attractive short-range potential of mean force, and (3) nonspecific reversible binding to the crowders. This expression spans the range from reaction to diffusion control. Crowding can increase the reaction-controlled rate by inducing an effective attraction between reactants but decrease the diffusion-controlled rate by reducing their relative diffusivity. C1 [Berezhkovskii, Alexander M.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. [Szabo, Attila] Natl Inst Diabet & Digest & Kidney Dis, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Szabo, A (reprint author), Natl Inst Diabet & Digest & Kidney Dis, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM attilas@niddk.nih.gov RI Szabo, Attila/H-3867-2012 FU Intramural Research Program of the NIH, Center for Information Technology; National Institute of Diabetes and Digestive and Kidney Diseases FX We are grateful to Allen Minton for helpful discussions. This study was supported by the Intramural Research Program of the NIH, Center for Information Technology and National Institute of Diabetes and Digestive and Kidney Diseases. NR 26 TC 0 Z9 0 U1 7 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD JUL 7 PY 2016 VL 120 IS 26 BP 5998 EP 6002 DI 10.1021/acs.jpcb.6b01892 PG 5 WC Chemistry, Physical SC Chemistry GA DQ8JN UT WOS:000379457200025 PM 27096470 ER PT J AU Behrens, T Gross, I Siemiatycki, J Conway, DI Olsson, A Stucker, I Guida, F Jockel, KH Pohlabeln, H Ahrens, W Bruske, I Wichmann, HE Gustavsson, P Consonni, D Merletti, F Richiardi, L Simonato, L Fortes, C Parent, ME McLaughlin, J Demers, P Landi, MT Caporaso, N Zaridze, D Szeszenia-Dabrowska, N Rudnai, P Lissowska, J Fabianova, E Tardon, A Field, JK Dumitru, RS Bencko, V Foretova, L Janout, V Kromhout, H Vermeulen, R Boffetta, P Straif, K Schuz, J Hovanec, J Kendzia, B Pesch, B Bruning, T AF Behrens, Thomas Gross, Isabelle Siemiatycki, Jack Conway, David I. Olsson, Ann Stuecker, Isabelle Guida, Florence Joeckel, Karl-Heinz Pohlabeln, Hermann Ahrens, Wolfgang Brueske, Irene Wichmann, Heinz-Erich Gustavsson, Per Consonni, Dario Merletti, Franco Richiardi, Lorenzo Simonato, Lorenzo Fortes, Cristina Parent, Marie-Elise McLaughlin, John Demers, Paul Landi, Maria Teresa Caporaso, Neil Zaridze, David Szeszenia-Dabrowska, Neonila Rudnai, Peter Lissowska, Jolanta Fabianova, Eleonora Tardon, Adonina Field, John K. Dumitru, Rodica Stanescu Bencko, Vladimir Foretova, Lenka Janout, Vladimir Kromhout, Hans Vermeulen, Roel Boffetta, Paolo Straif, Kurt Schuez, Joachim Hovanec, Jan Kendzia, Benjamin Pesch, Beate Bruening, Thomas TI Occupational prestige, social mobility and the association with lung cancer in men SO BMC CANCER LA English DT Article DE Life course; Occupational history; Social prestige; Socio-economic status; SYNERGY; Transitions ID SOCIOECONOMIC-STATUS; EDUCATIONAL INEQUALITIES; HEALTH RESEARCH; LIFE-COURSE; RISK; MORTALITY; SMOKING; INDICATORS; POSITION; US AB Background: The nature of the association between occupational social prestige, social mobility, and risk of lung cancer remains uncertain. Using data from the international pooled SYNERGY case-control study, we studied the association between lung cancer and the level of time-weighted average occupational social prestige as well as its lifetime trajectory. Methods: We included 11,433 male cases and 14,147 male control subjects. Each job was translated into an occupational social prestige score by applying Treiman's Standard International Occupational Prestige Scale (SIOPS). SIOPS scores were categorized as low, medium, and high prestige (reference). We calculated odds ratios (OR) with 95 % confidence intervals (CI), adjusting for study center, age, smoking, ever employment in a job with known lung carcinogen exposure, and education. Trajectories in SIOPS categories from first to last and first to longest job were defined as consistent, downward, or upward. We conducted several subgroup and sensitivity analyses to assess the robustness of our results. Results: We observed increased lung cancer risk estimates for men with medium (OR = 1.23; 95 % CI 1.13-1.33) and low occupational prestige (OR = 1.44; 95 % CI 1.32-1.57). Although adjustment for smoking and education reduced the associations between occupational prestige and lung cancer, they did not explain the association entirely. Traditional occupational exposures reduced the associations only slightly. We observed small associations with downward prestige trajectories, with ORs of 1.13, 95 % CI 0.88-1.46 for high to low, and 1.24; 95 % CI 1.08-1.41 for medium to low trajectories. Conclusions: Our results indicate that occupational prestige is independently associated with lung cancer among men. C1 [Behrens, Thomas; Gross, Isabelle; Hovanec, Jan; Kendzia, Benjamin; Pesch, Beate; Bruening, Thomas] Inst Ruhr Univ Bochum, Inst Prevent & Occupat Med German Social Accident, Brkle de La Camp Pl 1, D-44789 Bochum, Germany. [Siemiatycki, Jack] Univ Montreal, Hosp Res Ctr CRCHUM, Montreal, PQ, Canada. [Siemiatycki, Jack] Univ Montreal, Sch Publ Hlth, Montreal, PQ, Canada. [Conway, David I.] Univ Glasgow, Sch Dent, Coll Med Vet & Life Sci, Glasgow G2 3JZ, Lanark, Scotland. [Olsson, Ann; Straif, Kurt; Schuez, Joachim] IARC, Lyon, France. [Olsson, Ann] Karolinska Inst, Inst Environm Med, Stockholm, Sweden. [Stuecker, Isabelle; Guida, Florence] INSERM, Ctr Res Epidemiol & Populat Hlth CESP, F-94807 Villejuif, France. [Stuecker, Isabelle; Guida, Florence] Univ Paris 11, UMRS 1018, F-94807 Villejuif, France. [Joeckel, Karl-Heinz] Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany. [Pohlabeln, Hermann; Ahrens, Wolfgang] Leibniz Inst Prevent Res & Epidemiol BIPS GmbH, Bremen, Germany. [Ahrens, Wolfgang] Univ Bremen, Inst Stat, Bremen, Germany. [Brueske, Irene; Wichmann, Heinz-Erich] Helmholtz Zentrum Munchen, Inst Epidemiol, Neuherberg, Germany. [Consonni, Dario] Fdn IRCCS Ca Granda Osped Maggiore Policlin, Milan, Italy. [Merletti, Franco; Richiardi, Lorenzo] Univ Turin, Dept Med Sci, Canc Epidemiol Unit, Turin, Italy. [Simonato, Lorenzo] Univ Padua, Dept Mol Med, Lab Publ Hlth & Populat Studies, Padua, Italy. [Fortes, Cristina] Ist Dermopatico Immacolata, Epidemiol Unit, Rome, Italy. [Parent, Marie-Elise] Univ Quebec, INRS Inst Armand Frappier, Laval, PQ, Canada. [McLaughlin, John] Occupat Canc Res Ctr, Canc Care Ontario, Toronto, ON, Canada. [Landi, Maria Teresa; Caporaso, Neil] NCI, Div Canc Epidemiol & Genet, Bethesda, MD USA. [Zaridze, David] Russian Canc Res Ctr, Inst Carcinogenesis, Moscow, Russia. [Szeszenia-Dabrowska, Neonila] Nofer Inst Occupat Med, Lodz, Poland. [Rudnai, Peter] Natl Ctr Publ Hlth, Budapest, Hungary. [Lissowska, Jolanta] M Sklodowska Curie Canc Ctr, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Fabianova, Eleonora] Prevent Occupat Med, Reg Author Publ Hlth, Banska Bystrica, Slovakia. [Tardon, Adonina] Univ Oviedo Ciber Epidemiol, CIBERESP, Mol Epidemiol Canc Unit, Oviedo, Spain. [Field, John K.] Univ Liverpool, Canc Res Ctr, Roy Castle Lung Canc Res Programme, Liverpool, Merseyside, England. [Field, John K.] Univ Liverpool, Inst Translat Med, Dept Mol & Clin Canc Med, Liverpool, Merseyside, England. [Dumitru, Rodica Stanescu] Natl Inst Publ Hlth, Bucharest, Romania. [Bencko, Vladimir] Charles Univ Prague, Fac Med 1, Inst Hyg & Epidemiol, Prague, Czech Republic. [Foretova, Lenka] Masaryk Univ, Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic. [Foretova, Lenka] Masaryk Univ, Fac Med, Brno, Czech Republic. [Janout, Vladimir] Palacky Univ, Fac Med, Olomouc, Czech Republic. [Kromhout, Hans; Vermeulen, Roel] Univ Utrecht, Inst Risk Assessment Sci, Environm Epidemiol Div, Utrecht, Netherlands. [Boffetta, Paolo] Icahn Sch Med Mt Sinai, Inst Canc, New York, NY USA. [Wichmann, Heinz-Erich] Icahn Sch Med Mt Sinai, Inst Translat Epidemiol, New York, NY USA. [Janout, Vladimir] Tech Univ Munich, Inst Med Stat & Epidemiol, Munich, Germany. Univ Ostrava, Fac Med, Ostrava, Czech Republic. RP Behrens, T (reprint author), Inst Ruhr Univ Bochum, Inst Prevent & Occupat Med German Social Accident, Brkle de La Camp Pl 1, D-44789 Bochum, Germany. EM behrens@ipa-dguv.de RI Consonni, Dario/K-7943-2016; Bruning, Thomas/G-8120-2015; Vermeulen, Roel/F-8037-2011; OI Consonni, Dario/0000-0002-8935-3843; Bruning, Thomas/0000-0001-9560-5464; Vermeulen, Roel/0000-0003-4082-8163; Ahrens, Wolfgang/0000-0003-3777-570X FU German Social Accident Insurance [FP 271]; Canadian Institutes of Health Research and Guzzo-SRC Chair in Environment and Cancer; Fondation de France; German Federal Ministry of Education, Science, Research, and Technology; Ministry of Labour and Social Affairs; EC's INCO-COPERNICUS Program; Polish State Committee for Science Research; Roy Castle Foundation; NIH/NCI/DCEG Intramural Research Program; Lombardy Region; INAIL; European Union Nuclear Fission Safety Program; Italian Association for Cancer Research; Region Piedmont; Compagnia di San Paolo; Europe Against Cancer Program; Swedish Council for Work Life Research; Swedish EPA; University of Oviedo; European Regional Development Fund; State Budget of the Czech Republic (RECAMO) [CZ.1.05/2.1.00/03.0101]; CIBERESP; [FISS-PI060604] FX This work was supported by the German Social Accident Insurance (grant number FP 271). Grant sponsors of the individual studies were the Canadian Institutes of Health Research and Guzzo-SRC Chair in Environment and Cancer; the Fondation de France; the German Federal Ministry of Education, Science, Research, and Technology and the Ministry of Labour and Social Affairs; EC's INCO-COPERNICUS Program; Polish State Committee for Science Research; Roy Castle Foundation; NIH/NCI/DCEG Intramural Research Program; Lombardy Region; INAIL and the European Union Nuclear Fission Safety Program; Italian Association for Cancer Research; Region Piedmont; Compagnia di San Paolo; Europe Against Cancer Program, the Swedish Council for Work Life Research and the Swedish EPA; the University of Oviedo; the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101); CIBERESP; and FISS-PI060604. NR 37 TC 0 Z9 0 U1 9 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD JUL 7 PY 2016 VL 16 AR 395 DI 10.1186/s12885-016-2432-9 PG 12 WC Oncology SC Oncology GA DQ3TB UT WOS:000379124600001 PM 27388894 ER PT J AU Ding, HY Smith, RG Poleg-Polsky, A Diamond, JS Briggman, KL AF Ding, Huayu Smith, Robert G. Poleg-Polsky, Alon Diamond, Jeffrey S. Briggman, Kevin L. TI Species-specific wiring for direction selectivity in the mammalian retina SO NATURE LA English DT Article ID STARBURST AMACRINE CELLS; RABBIT RETINA; MOUSE RETINA; GANGLION-CELLS; NEURAL COMPUTATION; SYNAPTIC INPUT; AXIAL LENGTH; DENDRITES; CIRCUIT; MOTION AB Directionally tuned signalling in starburst amacrine cell (SAC) dendrites lies at the heart of the circuit that detects the direction of moving stimuli in the mammalian retina. The relative contributions of intrinsic cellular properties and network connectivity to SAC direction selectivity remain unclear. Here we present a detailed connectomic reconstruction of SAC circuitry in mouse retina and describe two previously unknown features of synapse distributions along SAC dendrites: input and output synapses are segregated, with inputs restricted to proximal dendrites; and the distribution of inhibitory inputs is fundamentally different from that observed in rabbit retina. An anatomically constrained SAC network model suggests that SAC-SAC wiring differences between mouse and rabbit retina underlie distinct contributions of synaptic inhibition to velocity and contrast tuning and receptive field structure. In particular, the model indicates that mouse connectivity enables SACs to encode lower linear velocities that account for smaller eye diameter, thereby conserving angular velocity tuning. These predictions are confirmed with calcium imaging of mouse SAC dendrites responding to directional stimuli. C1 [Ding, Huayu; Poleg-Polsky, Alon; Diamond, Jeffrey S.] NINDS, Synapt Physiol Sect, Bethesda, MD 20892 USA. [Smith, Robert G.] Univ Penn, Dept Neurosci, Philadelphia, PA 19104 USA. [Briggman, Kevin L.] Max Planck Inst Med Res, Dept Biomed Opt, Jahnstr 29, D-69120 Heidelberg, Germany. [Briggman, Kevin L.] NINDS, Circuit Dynam & Connect Unit, Bethesda, MD 20892 USA. RP Briggman, KL (reprint author), Max Planck Inst Med Res, Dept Biomed Opt, Jahnstr 29, D-69120 Heidelberg, Germany.; Briggman, KL (reprint author), NINDS, Circuit Dynam & Connect Unit, Bethesda, MD 20892 USA. EM kevin.briggman@nih.gov RI Diamond, Jeffrey/C-1835-2015 OI Diamond, Jeffrey/0000-0002-1770-2629 FU NIH [EY016607, EY022070]; NINDS [NS003145, NS003133]; Max-Planck Society; Pew Charitable Trusts FX We thank W. Denk for supporting the collection of the serial block-face scanning electron microscopy data in his laboratory. This work was supported by NIH grants EY016607 and EY022070 (RGS), by the NINDS Intramural Research Program (NS003145; J.S.D.) and (NS003133; K.L.B.), the Max-Planck Society (K.L.B.), and the Pew Charitable Trusts (K.L.B.). NR 47 TC 7 Z9 7 U1 6 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD JUL 7 PY 2016 VL 535 IS 7610 BP 105 EP + DI 10.1038/nature18609 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ2EU UT WOS:000379015600033 PM 27350241 ER PT J AU Zhang, R Miner, JJ Gorman, MJ Rausch, K Ramage, H White, JP Zuiani, A Zhang, P Fernandez, E Zhang, Q Dowd, KA Pierson, TC Cherry, S Diamond, MS AF Zhang, Rong Miner, Jonathan J. Gorman, Matthew J. Rausch, Keiko Ramage, Holly White, James P. Zuiani, Adam Zhang, Ping Fernandez, Estefania Zhang, Qiang Dowd, Kimberly A. Pierson, Theodore C. Cherry, Sara Diamond, Michael S. TI A CRISPR screen defines a signal peptide processing pathway required by flaviviruses SO NATURE LA English DT Article ID WEST-NILE-VIRUS; BORNE ENCEPHALITIS-VIRUS; HEPATITIS-C VIRUS; MONOCLONAL-ANTIBODIES; ENVELOPE PROTEIN; HUMAN-CELLS; INFECTION; GENES; NEUTRALIZATION; IDENTIFICATION AB Flaviviruses infect hundreds of millions of people annually, and no antiviral therapy is available(1,2). We performed a genome-wide CRISPR/Cas9-based screen to identify host genes that, when edited, resulted in reduced flavivirus infection. Here, we validated nine human genes required for flavivirus infectivity, and these were associated with endoplasmic reticulum functions including translocation, protein degradation, and N-linked glycosylation. In particular, a subset of endoplasmic reticulum-associated signal peptidase complex (SPCS) proteins was necessary for proper cleavage of the flavivirus structural proteins (prM and E) and secretion of viral particles. Loss of SPCS1 expression resulted in markedly reduced yield of all Flaviviridae family members tested (West Nile, dengue, Zika, yellow fever, Japanese encephalitis, and hepatitis C viruses), but had little impact on alphavirus, bunyavirus, or rhabdovirus infection or the surface expression or secretion of diverse host proteins. We found that SPCS1 dependence could be bypassed by replacing the native prM protein leader sequences with a class I major histocompatibility complex (MHC) antigen leader sequence. Thus, SPCS1, either directly or indirectly via its interactions with host proteins, preferentially promotes the processing of specific protein cargo, and Flaviviridae have a unique dependence on this signal peptide processing pathway. SPCS1 and other signal processing pathway members could represent pharmacological targets for inhibiting infection by the expanding number of flaviviruses of medical concern. C1 [Zhang, Rong; Miner, Jonathan J.; Gorman, Matthew J.; White, James P.; Zuiani, Adam; Zhang, Ping; Fernandez, Estefania; Zhang, Qiang; Diamond, Michael S.] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Rausch, Keiko; Ramage, Holly; Cherry, Sara] Univ Penn, Dept Microbiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Zhang, Ping] Sun Yat Sen Univ, Inst Human Virol, Zhongshan Sch Med, Dept Immunol, Guangzhou 510080, Guangdong, Peoples R China. [Dowd, Kimberly A.; Pierson, Theodore C.] NIAID, Viral Pathogenesis Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Diamond, Michael S.] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. [Diamond, Michael S.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Diamond, Michael S.] Washington Univ, Sch Med, Ctr Human Immunol & Immunotherapy Programs, St Louis, MO 63110 USA. RP Diamond, MS (reprint author), Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA.; Diamond, MS (reprint author), Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA.; Diamond, MS (reprint author), Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA.; Diamond, MS (reprint author), Washington Univ, Sch Med, Ctr Human Immunol & Immunotherapy Programs, St Louis, MO 63110 USA. EM diamond@borcim.wustl.edu FU NIH [U19 AI083019, U19 AI106772, R01 AI104972, T32 AI007163]; Washington University Institute of Clinical and Translational Sciences from the National Center for Advancing Translational Sciences [UL1 TR000448]; Washington University Institute of Clinical and Translational Sciences from the National Institute of General Medical Sciences [P41 GM103422-35]; NIAID FX This work was supported by NIH grants U19 AI083019 (M.S.D.), U19 AI106772 (M.S.D.), R01 AI104972 (M.S.D.), and T32 AI007163 (E.F.) and by the Washington University Institute of Clinical and Translational Sciences (UL1 TR000448 from the National Center for Advancing Translational Sciences and P41 GM103422-35 from the National Institute of General Medical Sciences). T.C.P and K.A.D are supported by the intramural program of NIAID. We thank R. Kuhn, A. Garcia-Sastre, H. Zhao, D. Fremont, X. Wang, and R. Townsend for reagents, experimental advice, and data analysis; P. Erdmann-Gilmore, R. Connors, Y. Mi, and H. Lin for expert technical assistance; and X. de Lamballerie and the European Virus Archive goes Global (EVAg) for consenting to the use of H/PF/2013 ZIKV strain for this study under a material transfer agreement with the EVAg parter, Aix-Marseille Universite. NR 49 TC 23 Z9 23 U1 28 U2 69 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 JUL 7 PY 2016 VL 535 IS 7610 BP 164 EP + DI 10.1038/nature18625 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ2EU UT WOS:000379015600045 PM 27383988 ER PT J AU Boyden, SE Metcalfe, DD Komarow, HD AF Boyden, Steven E. Metcalfe, Dean D. Komarow, Hirsh D. TI Vibratory Urticaria and ADGRE2 REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID PHYSICAL HYPERSENSITIVITY; ANGIOEDEMA C1 [Boyden, Steven E.] NHGRI, Bethesda, MD 20892 USA. [Metcalfe, Dean D.; Komarow, Hirsh D.] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Komarow, HD (reprint author), NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM komarowh@mail.nih.gov NR 3 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 7 PY 2016 VL 375 IS 1 BP 95 EP 95 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA DQ1ZP UT WOS:000379000200024 PM 27406365 ER PT J AU Volkow, ND McLellan, AT AF Volkow, Nora D. McLellan, A. Thomas TI Mitigation Strategies for Opioid Abuse REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Volkow, Nora D.] NIH, Bldg 10, Bethesda, MD 20892 USA. [McLellan, A. Thomas] Treatment Res Inst, Philadelphia, PA USA. RP Volkow, ND (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM nvolkow@nida.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 7 PY 2016 VL 375 IS 1 BP 96 EP 96 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA DQ1ZP UT WOS:000379000200027 PM 27406367 ER PT J AU Bronte, V Brandau, S Chen, SH Colombo, MP Frey, AB Greten, TF Mandruzzato, S Murray, PJ Ochoa, A Ostrand-Rosenberg, S Rodriguez, PC Sica, A Umansky, V Vonderheide, RH Gabrilovich, DI AF Bronte, Vincenzo Brandau, Sven Chen, Shu-Hsia Colombo, Mario P. Frey, Alan B. Greten, Tim F. Mandruzzato, Susanna Murray, Peter J. Ochoa, Augusto Ostrand-Rosenberg, Suzanne Rodriguez, Paulo C. Sica, Antonio Umansky, Viktor Vonderheide, Robert H. Gabrilovich, Dmitry I. TI Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards SO NATURE COMMUNICATIONS LA English DT Review ID TUMOR-BEARING MICE; T-CELLS; IMMUNE-RESPONSE; DENDRITIC CELLS; HUMAN CANCERS; LUNG-CANCER; CROSS-TALK; IN-VIVO; MACROPHAGES; DIFFERENTIATION AB Myeloid-derived suppressor cells (MDSCs) have emerged as major regulators of immune responses in cancer and other pathological conditions. In recent years, ample evidence supports key contributions of MDSC to tumour progression through both immune-mediated mechanisms and those not directly associated with immune suppression. MDSC are the subject of intensive research with >500 papers published in 2015 alone. However, the phenotypic, morphological and functional heterogeneity of these cells generates confusion in investigation and analysis of their roles in inflammatory responses. The purpose of this communication is to suggest characterization standards in the burgeoning field of MDSC research. C1 [Bronte, Vincenzo] Univ Verona, Univ Hosp, Dept Med, I-37134 Verona, Italy. [Brandau, Sven] Univ Hosp Essen, Dept Otorhinolaryngol, D-45122 Essen, Germany. [Chen, Shu-Hsia] Icahn Sch Med Mt Sinai, Inst Immunol, Tisch Canc Inst, Dept Oncol Sci, New York, NY 10029 USA. [Colombo, Mario P.] Fdn IRCCS Ist Nazl Tumori, Dept Expt Oncol & Mol Med, Mol Immunol Unit, I-20133 Milan, Italy. [Frey, Alan B.] New York Univ, Sch Med, New York, NY 10029 USA. [Greten, Tim F.] NCI, Thorac & GI Oncol Branch, GI Malignancy Sect, Bethesda, MD 20892 USA. [Mandruzzato, Susanna] Univ Padua, Dept Surg Oncol & Gastroenterol, Sect Oncol & Immunol, I-35128 Padua, Italy. [Mandruzzato, Susanna] IRCCS, Veneto Inst Oncol IOV, I-35128 Padua, Italy. [Murray, Peter J.] St Jude Childrens Res Hosp, Dept Infect Dis, Memphis, TN 38105 USA. [Murray, Peter J.] St Jude Childrens Res Hosp, Dept Immunol, Memphis, TN 38105 USA. [Ochoa, Augusto] Louisiana State Univ, Stanley S Scott Canc Ctr, New Orleans, LA 70112 USA. [Ostrand-Rosenberg, Suzanne] Univ Maryland Baltimore Cty, Baltimore, MD 21250 USA. [Rodriguez, Paulo C.] Georgia Regents Univ, Ctr Canc, Augusta, GA 30912 USA. [Sica, Antonio] Humanitas Clin & Res Ctr, Via Manzoni 56, I-20089 Milan, Italy. [Sica, Antonio] Univ Piemonte Orientale Amedeo Avogadro, Dept Pharmaceut Sci, Via Bovio 6, I-20089 Novara, Italy. [Umansky, Viktor] German Canc Res Ctr, Skin Canc Unit, D-69120 Heidelberg, Germany. [Umansky, Viktor] Ruprecht Karl Univ Heidelberg, Univ Med Ctr Mannheim, Dept Dermatol Venereol & Allergol, D-69120 Mannheim, Germany. [Vonderheide, Robert H.; Gabrilovich, Dmitry I.] Univ Penn, Abramson Canc Ctr, Sch Med, Philadelphia, PA 19104 USA. [Gabrilovich, Dmitry I.] Wistar Inst Anat & Biol, Translat Tumor Immunol, Philadelphia, PA 19104 USA. RP Bronte, V (reprint author), Univ Verona, Univ Hosp, Dept Med, I-37134 Verona, Italy.; Gabrilovich, DI (reprint author), Wistar Inst Anat & Biol, Translat Tumor Immunol, Philadelphia, PA 19104 USA. EM vincenzo.bronte@univr.it; dgabrilovich@wistar.org RI Bronte, Vincenzo/K-7902-2016 OI Bronte, Vincenzo/0000-0002-3741-5141 FU NIH [CA 141438, CA 084488, GM021248, CA 184185]; Italian Ministry of Education, Universities and Research (FIRB cup) [B31J11000420001, RBAP11H2R9_005]; Italian Ministry of Education, Universities and Research (PRIN cup) [20103FMJEN_003]; Italian Association for Cancer Research [AIRC 6599, 12182, 12886, 14103, 14194, 15585]; Italian Ministry of Health (FINALIZZATA cup) [E35G1400019001]; Action BM1404 Mye-EUNITER - COST (European Cooperation in Science and Technology); German Research Association (DFG) [2278/2-1]; American Lebanese Syrian Associated Charities of St. Jude Children's Research Hospital [P30 CA21765]; American Lebanese Syrian Associated Charities of Cancer Center Core grant [P30 CA21765]; DKFZ-MOST Cooperation in Cancer Research [CA157] FX This work was supported by NIH grants CA 141438 and CA 084488 to D.I.G., GM021248 to S.O.-R., CA 184185 to P.C.R., grants from the Italian Ministry of Education, Universities and Research (FIRB cup: B31J11000420001; FIRB cup: RBAP11H2R9_005; PRIN cup: 20103FMJEN_003) to V.B. and A.S.; the Italian Association for Cancer Research (AIRC 6599, 12182, 12886, 14103, 14194, 14103 and 15585) and the Italian Ministry of Health (FINALIZZATA cup: E35G1400019001) to V.B., M.P.C., A.S., S.M.; Action BM1404 Mye-EUNITER supported by COST (European Cooperation in Science and Technology) to S.B. and V.U.; the German Research Association (DFG, grant 2278/2-1) to S.B., The American Lebanese Syrian Associated Charities of St. Jude Children's Research Hospital and Cancer Center Core grant P30 CA21765 to P.M. and the DKFZ-MOST Cooperation in Cancer Research (CA157) to V.U. NR 81 TC 33 Z9 34 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JUL 6 PY 2016 VL 7 AR 12150 DI 10.1038/ncomms12150 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH6ET UT WOS:000391866300001 PM 27381735 ER PT J AU Alderson, TR Kim, JH Markley, JL AF Alderson, Thomas Reid Kim, Jin Hae Markley, John Lute TI Dynamical Structures of Hsp70 and Hsp70-Hsp40 Complexes SO STRUCTURE LA English DT Review ID NUCLEOTIDE-BINDING DOMAIN; ESCHERICHIA-COLI DNAJ; HEAT-SHOCK-PROTEIN; X-RAY-SCATTERING; MOLECULAR CHAPERONE HSC70; SUBSTRATE-BINDING; CONFORMATIONAL DYNAMICS; ALLOSTERIC REGULATION; INTERDOMAIN COMMUNICATION; MITOCHONDRIAL HSP70 AB Protein misfolding and aggregation are pathological events that place a significant amount of stress on the maintenance of protein homeostasis (proteostasis). For prevention and repair of protein misfolding and aggregation, cells are equipped with robust mechanisms that mainly rely on molecular chaperones. Two classes of molecular chaperones, heat shock protein 70 kDa (Hsp70) and Hsp40, recognize and bind to mis-folded proteins, preventing their toxic biomolecular aggregation and enabling refolding or targeted degradation. Here, we review the current state of structural biology of Hsp70 and Hsp40-Hsp70 complexes and examine the link between their structures, dynamics, and functions. We highlight the power of nuclear magnetic resonance spectroscopy to untangle complex relationships behind molecular chaperones and their mechanism(s) of action. C1 [Alderson, Thomas Reid] Univ Oxford, Dept Chem, South Parks Rd, Oxford OX1 3TA, England. [Alderson, Thomas Reid] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Kim, Jin Hae; Markley, John Lute] Univ Wisconsin, Dept Biochem, Natl Magnet Resonance Facil Madison, Madison, WI 53706 USA. RP Alderson, TR (reprint author), Univ Oxford, Dept Chem, South Parks Rd, Oxford OX1 3TA, England.; Alderson, TR (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM reid.alderson@pmb.ox.ac.uk FU NIH Oxford-Cambridge Scholars Program; US NIH [5U01GM094584] FX The authors thank William Ford Freyberg, Justin L. P. Benesch, and Iva Pritisanac for critically reading the manuscript and providing helpful comments and suggestions. Supported in part by the NIH Oxford-Cambridge Scholars Program and US NIH grant 5U01GM094584. NR 117 TC 4 Z9 4 U1 17 U2 17 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 EI 1878-4186 J9 STRUCTURE JI Structure PD JUL 6 PY 2016 VL 24 IS 7 BP 1014 EP 1030 DI 10.1016/j.str.2016.05.011 PG 17 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA DV9EU UT WOS:000383243800002 PM 27345933 ER PT J AU DiMattia, MA Watts, NR Cheng, NQ Huang, R Heymann, JB Grimes, JM Wingfield, PT Stuart, DI Steven, AC AF DiMattia, Michael A. Watts, Norman R. Cheng, Naiqian Huang, Rick Heymann, J. Bernard Grimes, Jonathan M. Wingfield, Paul T. Stuart, David I. Steven, Alasdair C. TI The Structure of HIV-1 Rev Filaments Suggests a Bilateral Model for Rev-RRE Assembly SO STRUCTURE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; NUCLEAR EXPORT SIGNALS; RESPONSE ELEMENT RRE; MESSENGER-RNA EXPORT; PROTEIN COMPLEXES; GENE-EXPRESSION; BINDING-SITE; ALPHA-HELIX; TYPE-1; RECOGNITION AB HIV-1 Rev protein mediates the nuclear export of viral RNA genomes. To do so, Rev oligomerizes cooperatively onto an RNA motif, the Rev response element (RRE), forming a complex that engages with the host nuclear export machinery. To better understand Rev oligomerization, we determined four crystal structures of Rev N-terminal domain dimers, which show that they can pivot about their dyad axis, giving crossing angles of 90 degrees to 140 degrees. In parallel, we performed cryoelectron microscopy of helical Rev filaments. Filaments vary from 11 to 15 nm in width, reflecting variations in dimer crossing angle. These structures contain additional density, indicating that C-terminal domains become partially ordered in the context of filaments. This conformational variability may be exploited in the assembly of RRE/Rev complexes. Our data also revealed a third interface between Revs, which offers an explanation for how the arrangement of Rev subunits adapts to the "A"-shaped architecture of the RRE in export-active complexes. C1 [DiMattia, Michael A.; Cheng, Naiqian; Huang, Rick; Heymann, J. Bernard; Steven, Alasdair C.] NIAMSD, Lab Struct Biol Res, NIH, Bethesda, MD 20892 USA. [Watts, Norman R.; Wingfield, Paul T.] NIAMSD, Prot Express Lab, NIH, Bethesda, MD 20892 USA. [DiMattia, Michael A.; Grimes, Jonathan M.; Stuart, David I.] Univ Oxford, Div Struct Biol, Henry Wellcome Bldg Genom Med,Roosevelt Dr, Headington OX3 7BN, England. [Grimes, Jonathan M.; Stuart, David I.] Diamond Light Source, Diamond House,Harwell Sci & Innovat Campus, Didcot OX11 0DE, Oxon, England. [DiMattia, Michael A.] Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Struct Biol Program, 1275 York Ave, New York, NY 10065 USA. [Huang, Rick] Howard Hughes Med Inst, Janelia Res Campus,19700 Helix Dr, Ashburn, VA 20147 USA. RP Steven, AC (reprint author), NIAMSD, Lab Struct Biol Res, NIH, Bethesda, MD 20892 USA. EM stevena@mail.nih.gov FU National Institute for Arthritis and Musculoskeletal and Skin Diseases; NIH; UK Medical Research Council [G100099]; SPINE2COMPLEXES [LSHGST-2006-031220]; Wellcome Trust [075491/Z/09] FX We thank Stephen J. Stahl, Ira Palmer, and Joshua Kaufman (NIH/NIAMS) for support with preparation of reagents and Dennis Winkler (NIH/NIAMS) for installation and calibration of SerialEM, and the staff at Diamond Light Source (Didcot, UK) beamlines I02 and I24 and European Synchrotron Radiation Facility (Grenoble, France) beamline ED23-EH2 for support in data collection. This work was supported in part by the Intramural Research Programs of the National Institute for Arthritis and Musculoskeletal and Skin Diseases, the NIH Intramural AIDS Targeted Antiviral Program, and the NIH-Oxford Scholars Program. D.I.S. is supported by the UK Medical Research Council (G100099) and J.M.G. by SPINE2COMPLEXES (LSHGST-2006-031220). The Wellcome Trust is acknowledged for providing administrative support (Grant 075491/Z/09). NR 56 TC 1 Z9 1 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 EI 1878-4186 J9 STRUCTURE JI Structure PD JUL 6 PY 2016 VL 24 IS 7 BP 1068 EP 1080 DI 10.1016/j.str.2016.04.015 PG 13 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA DV9EU UT WOS:000383243800006 PM 27265851 ER PT J AU Zacharchenko, T Qian, XL Goult, BT Jethwa, D Almeida, TB Ballestrem, C Critchley, DR Lowy, DR Barsukov, IL AF Zacharchenko, Thomas Qian, Xiaolan Goult, Benjamin T. Jethwa, Devina Almeida, Teresa B. Ballestrem, Christoph Critchley, David R. Lowy, Douglas R. Barsukov, Igor L. TI LD Motif Recognition by Talin: Structure of the Talin-DLC1 Complex SO STRUCTURE LA English DT Article ID FOCAL ADHESION KINASE; VINCULIN-BINDING-SITE; CELL-MIGRATION; ACTIVATION; DOMAIN; ROD; RECRUITMENT; ACTIN; RIAM; FAK AB Cell migration requires coordination between integrin-mediated cell adhesion to the extracellular matrix and force applied to adhesion sites. Talin plays a key role in coupling integrin receptors to the actomyosin contractile machinery, while deleted in liver cancer 1 (DLC1) is a Rho GAP that binds talin and regulates Rho, and therefore actomyosin contractility. We show that the LD motif of DLC1 forms a helix that binds to the four-helix bundle of the talin R8 domain in a canonical triple-helix arrangement. We demonstrate that the same R8 surface interacts with the paxillin LD1 and LD2 motifs. We identify key charged residues that stabilize the R8 interactions with LD motifs and demonstrate their importance in vitro and in cells. Our results suggest a network of competitive interactions in adhesion complexes that involve LD motifs, and identify mutations that can be used to analyze the biological roles of specific protein-protein interactions in cell migration. C1 [Zacharchenko, Thomas; Almeida, Teresa B.; Barsukov, Igor L.] Univ Liverpool, Inst Integrat Biol, BioSci Bldg,Crown St, Liverpool L69 7ZB, Merseyside, England. [Qian, Xiaolan; Lowy, Douglas R.] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. [Goult, Benjamin T.] Univ Kent, Sch Biosci, Canterbury CT2 7NJ, Kent, England. [Jethwa, Devina; Ballestrem, Christoph] Univ Manchester, Wellcome Trust Ctr Cell Matrix Res, Oxford Rd, Manchester M13 9PT, Lancs, England. [Critchley, David R.] Univ Leicester, Dept Biochem, Lancaster Rd, Leicester LE1 9HN, Leics, England. RP Barsukov, IL (reprint author), Univ Liverpool, Inst Integrat Biol, BioSci Bldg,Crown St, Liverpool L69 7ZB, Merseyside, England. EM igb2@liv.ac.uk OI Goult, Ben/0000-0002-3438-2807 FU Biotechnology and Biological Sciences Research Council (BBSRC) DTP fellowship; BBSRC [BB/N007336/1]; Wellcome Trust [088785/Z/09/Z]; BBSRC DTP studentship FX T.Z. was supported by the Biotechnology and Biological Sciences Research Council (BBSRC) DTP fellowship. B.T.G is funded by BBSRC (BB/N007336/1). The C.B. laboratory is part of the Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, which is supported by core funding from the Wellcome Trust (grant number 088785/Z/09/Z). D.J. is supported by a BBSRC DTP studentship. We thank the staff of the Bioimaging facility at the University of Manchester for help with imaging. The X-ray data were collected at the Diamond Light Source under Liverpool BAG allocation. NR 34 TC 0 Z9 0 U1 5 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 EI 1878-4186 J9 STRUCTURE JI Structure PD JUL 6 PY 2016 VL 24 IS 7 BP 1130 EP 1141 DI 10.1016/j.str.2016.04.016 PG 12 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA DV9EU UT WOS:000383243800011 PM 27265849 ER PT J AU Takahashi, YK Langdon, AJ Niv, Y Schoenbaum, G AF Takahashi, Yuji K. Langdon, Angela J. Niv, Yael Schoenbaum, Geoffrey TI Temporal Specificity of Reward Prediction Errors Signaled by Putative Dopamine Neurons in Rat VTA Depends on Ventral Striatum SO NEURON LA English DT Article ID TEGMENTAL AREA; NUCLEUS-ACCUMBENS; ORBITOFRONTAL CORTEX; DIFFERENCE MODELS; DORSAL STRIATUM; BASAL GANGLIA; SIZED REWARDS; TIME; REPRESENTATION; HIPPOCAMPUS AB Dopamine neurons signal reward prediction errors. This requires accurate reward predictions. It has been suggested that the ventral striatum provides these predictions. Here we tested this hypothesis by recording from putative dopamine neurons in the VTA of rats performing a task in which prediction errors were induced by shifting reward timing or number. In controls, the neurons exhibited error signals in response to both manipulations. However, dopamine neurons in rats with ipsilateral ventral striatal lesions exhibited errors only to changes in number and failed to respond to changes in timing of reward. These results, supported by computational modeling, indicate that predictions about the temporal specificity and the number of expected reward are dissociable and that dopaminergic prediction-error signals rely on the ventral striatum for the former but not the latter. C1 [Takahashi, Yuji K.; Schoenbaum, Geoffrey] NIDA, Intramural Res Program, Baltimore, MD 21224 USA. [Langdon, Angela J.; Niv, Yael] Princeton Univ, Dept Psychol, Princeton, NJ 08544 USA. [Langdon, Angela J.; Niv, Yael] Princeton Univ, Inst Neurosci, Princeton, NJ 08544 USA. [Schoenbaum, Geoffrey] Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. [Schoenbaum, Geoffrey] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. [Schoenbaum, Geoffrey] Johns Hopkins Univ, Solomon H Snyder Dept Neurosci, Baltimore, MD 21287 USA. RP Takahashi, YK; Schoenbaum, G (reprint author), NIDA, Intramural Res Program, Baltimore, MD 21224 USA.; Schoenbaum, G (reprint author), Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA.; Schoenbaum, G (reprint author), Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA.; Schoenbaum, G (reprint author), Johns Hopkins Univ, Solomon H Snyder Dept Neurosci, Baltimore, MD 21287 USA. EM yuji.takahashi@nih.gov; geoffrey.schoenbaum@nih.gov FU NIDA; Human Frontier Science Program Organization; NIMH [R01MH098861] FX This work was supported by funding from NIDA (to Y.K.T. and G.S.), the Human Frontier Science Program Organization (to A.J.L.), and NIMH grant R01MH098861 (to Y.N.). The opinions expressed in this article are the authors' own and do not reflect the view of the NIH, the Department of Health and Human Services, or the United States government. The authors would like to acknowledge Nathaniel Daw for helpful suggestions regarding the semi-Markov model of the task. NR 56 TC 8 Z9 8 U1 4 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD JUL 6 PY 2016 VL 91 IS 1 BP 182 EP 193 DI 10.1016/j.neuron.2016.05.015 PG 12 WC Neurosciences SC Neurosciences & Neurology GA DU7KY UT WOS:000382394300021 PM 27292535 ER PT J AU Goossens, ME Isa, F Brinkman, M Mak, D Reulen, R Wesselius, A Benhamou, S Bosetti, C Bueno-de-Mesquita, B Carta, A Allam, MF Golka, K Grant, EJ Jiang, XJ Johnson, KC Karagas, MR Kellen, E La Vecchia, C Lu, CM Marshall, J Moysich, K Pohlabeln, H Porru, S Steineck, G Stern, MC Tang, L Taylor, JA van den Brandt, P Villeneuve, PJ Wakai, K Weiderpass, E White, E Wolk, A Zhang, ZF Buntinx, F Zeegers, MP AF Goossens, Maria E. Isa, Fatima Brinkman, Maree Mak, David Reulen, Raoul Wesselius, Anke Benhamou, Simone Bosetti, Cristina Bueno-de-Mesquita, Bas Carta, Angela Allam, Md Farouk Golka, Klaus Grant, Eric J. Jiang, Xuejuan Johnson, Kenneth C. Karagas, Margaret R. Kellen, Eliane La Vecchia, Carlo Lu, Chih-Ming Marshall, James Moysich, Kirsten Pohlabeln, Hermann Porru, Stefano Steineck, Gunnar Stern, Marianne C. Tang, Li Taylor, Jack A. van den Brandt, Piet Villeneuve, Paul J. Wakai, Kenji Weiderpass, Elisabete White, Emily Wolk, Alicja Zhang, Zuo-Feng Buntinx, Frank Zeegers, Maurice P. TI International pooled study on diet and bladder cancer: the bladder cancer, epidemiology and nutritional determinants (BLEND) study: design and baseline characteristics SO ARCHIVES OF PUBLIC HEALTH LA English DT Article DE Bladder cancer; Diet; Risk; Pooled analysis ID RISK-FACTORS; FLUID INTAKE; CONSUMPTION; RATIONALE; SMOKING; COHORT; POLYMORPHISMS; VITAMINS; SYSTEM; FRUIT AB Background: In 2012, more than 400,000 urinary bladder cancer cases occurred worldwide, making it the 7th most common type of cancer. Although many previous studies focused on the relationship between diet and bladder cancer, the evidence related to specific food items or nutrients that could be involved in the development of bladder cancer remains inconclusive. Dietary components can either be, or be activated into, potential carcinogens through metabolism, or act to prevent carcinogen damage. Methods/design: The BLadder cancer, Epidemiology and Nutritional Determinants (BLEND) study was set up with the purpose of collecting individual patient data from observational studies on diet and bladder cancer. In total, data from 11,261 bladder cancer cases and 675,532 non-cases from 18 case-control and 6 cohort studies from all over the world were included with the aim to investigate the association between individual food items, nutrients and dietary patterns and risk of developing bladder cancer. Discussion: The substantial number of cases included in this study will enable us to provide evidence with large statistical power, for dietary recommendations on the prevention of bladder cancer. C1 [Goossens, Maria E.; Buntinx, Frank] Katholieke Univ Leuven, ACHG KU Leuven, Dept Gen Practice, Kapucijnenvoer 33,Blok J,Bus 7001, B-3000 Leuven, Belgium. [Isa, Fatima; Mak, David; Reulen, Raoul] Univ Birmingham, Dept Publ Hlth Epidemiol & Biostat, Birmingham, W Midlands, England. [Brinkman, Maree] Canc Council Victoria, Melbourne, Vic, Australia. [Wesselius, Anke; Zeegers, Maurice P.] Maastricht Univ, NUTRIM Sch Nutr & Translat Res Metab, Maastricht, Netherlands. [Benhamou, Simone] Fondat Jean Dausset CEPH, Variabilite Genet & Malad Humaines, INSERM U946, Paris, France. [Bosetti, Cristina] Ist Ric Farmacol Mario Negri, Lab Gen Epidemiol, Milan, Italy. [Bueno-de-Mesquita, Bas] Natl Inst Publ Hlth & Environm RIVM, DCD, Bilthoven, Netherlands. [Bueno-de-Mesquita, Bas] Univ Med Ctr, Gastroenterol & Hepatol, Utrecht, Netherlands. [Bueno-de-Mesquita, Bas] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Epidemiol & Biostat, London, England. [Bueno-de-Mesquita, Bas] Univ Malaya, Social & Prevent Med, Fac Med, Kuala Lumpur, Malaysia. [Carta, Angela; Porru, Stefano] Univ Brescia, Sect Publ Hlth & Human Sci, Dept Med & Surg Specialties Radiol Sci & Publ Hlt, Brescia, Italy. [Allam, Md Farouk] Univ Cordoba, Dept Prevent Med & Publ Hlth, Fac Med, Cordoba, Spain. [Golka, Klaus] TU Dortmund, Leibniz Res Ctr Working Environm & Human Factors, Dortmund, Germany. [Grant, Eric J.] Dept Epidemiol Radiat Effects Res Fdn, Hiroshima, Japan. [Jiang, Xuejuan; Stern, Marianne C.] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. [Johnson, Kenneth C.] Univ Ottawa, Dept Epidemiol & Community Med, Ottawa, ON, Canada. [Karagas, Margaret R.] Geisel Sch Med Dartmouth, Dept Epidemiol, Hanover, NH USA. [Kellen, Eliane] Leuven Univ Ctr Canc Prevent LUCK, Leuven, Belgium. [La Vecchia, Carlo] Univ Milan, Dept Clin Med & Community Hlth, Milan, Italy. [Lu, Chih-Ming] Buddhist Dalin Tzu Chi Gen Hosp, Dept Urol, Dalin Township 62247, Chiayi County, Taiwan. [Marshall, James; Moysich, Kirsten; Tang, Li] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Pohlabeln, Hermann] Leibniz Inst Prevent Res & Epidemiol BIPS, Bremen, Germany. [Steineck, Gunnar] Karolinska Hosp, Div Clin Canc Epidemiol, Dept Oncol & Pathol, Stockholm, Sweden. [Taylor, Jack A.] Natl Inst Environm Hlth Sci, Epidemiol Branch, NIH, Res Triangle Pk, NC USA. [Taylor, Jack A.] Natl Inst Environm Hlth Sci, Epigenet & Stem Cell Biol Lab, NIH, Res Triangle Pk, NC USA. [van den Brandt, Piet] Maastricht Univ, Dept Epidemiol, Sch Oncol & Dev Biol, Med Ctr, Maastricht, Netherlands. [van den Brandt, Piet] Maastricht Univ, Med Ctr, Sch Publ Hlth & Primary Care, Maastricht, Netherlands. [Villeneuve, Paul J.] Populat Studies Div Hlth Canada, Ottawa, ON, Canada. [Wakai, Kenji] Nagoya Univ, Dept Prevent Med, Grad Sch Med, Nagoya, Aichi, Japan. [Weiderpass, Elisabete] Karolinska Inst, Dept Med Epidemiol & Biostat, Med Epidemiol, Stockholm, Sweden. [Weiderpass, Elisabete] Canc Registry Norway, Inst Populat Based Canc Res, Res, Oslo, Norway. [Weiderpass, Elisabete] Folkhalsan Res Ctr, Genet Epidemiol Grp, Helsinki, Finland. [Weiderpass, Elisabete] Univ Tromso, Arctic Univ Norway, Dept Community Med, Tromso, Norway. [White, Emily] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Wolk, Alicja] Karolinska Inst, Inst Environm Med, Div Nutr Epidemiol, Stockholm, Sweden. [Zhang, Zuo-Feng] Univ Calif Los Angeles, Fielding Sch Publ Hlth, UCLA Ctr Environm Genom, Dept Epidemiol, Los Angeles, CA USA. [Buntinx, Frank; Zeegers, Maurice P.] Maastricht Univ, CAPHRI Sch Publ Hlth & Primary Care, Maastricht, Netherlands. [Zeegers, Maurice P.] Univ Birmingham, Sch Canc Sci, Birmingham, W Midlands, England. RP Goossens, ME (reprint author), Katholieke Univ Leuven, ACHG KU Leuven, Dept Gen Practice, Kapucijnenvoer 33,Blok J,Bus 7001, B-3000 Leuven, Belgium. EM mieke.goossens@med.kuleuven.be RI Benhamou, Simone/K-6554-2015; Weiderpass, Elisabete/M-4029-2016; OI Weiderpass, Elisabete/0000-0003-2237-0128; La Vecchia, Carlo/0000-0003-1441-897X; taylor, jack/0000-0001-5303-6398 FU NCI NIH HHS [P30 CA016056, R01 CA057494, R01 CA074846, T32 CA009142, U01 CA096116]; NIEHS NIH HHS [P42 ES007373] NR 40 TC 0 Z9 0 U1 1 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 0778-7367 EI 2049-3258 J9 ARCH PUBLIC HEALTH JI Arch. Public Health PD JUL 6 PY 2016 VL 74 AR 30 DI 10.1186/s13690-016-0140-1 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DS0ZI UT WOS:000380325100001 PM 27386115 ER PT J AU Thomas, A Pommier, Y AF Thomas, Anish Pommier, Yves TI Small cell lung cancer: Time to revisit DNA-damaging chemotherapy SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Editorial Material ID ATR INHIBITORS; STRESS AB Rational use of DNA-damaging chemotherapy, with new combinations to heighten DNA replication stress, could improve outcomes in small cell lung cancer. C1 [Thomas, Anish] NCI, Thorac & Gastrointestinal Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Pommier, Yves] NCI, Dev Therapeut Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Thomas, A (reprint author), NCI, Thorac & Gastrointestinal Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA.; Pommier, Y (reprint author), NCI, Dev Therapeut Branch, Ctr Canc Res, Bethesda, MD 20892 USA.; Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. EM anish.thomas@mail.nih.gov; pommier@nih.gov NR 10 TC 1 Z9 1 U1 0 U2 1 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD JUL 6 PY 2016 VL 8 IS 346 AR 346fs12 DI 10.1126/scitranslmed.aaf6282 PG 3 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA DR6RP UT WOS:000380029300001 PM 27384345 ER PT J AU Beachler, DC Yanik, EL Martin, BI Pfeiffer, RM Mirza, SK Deyo, RA Engels, EA AF Beachler, Daniel C. Yanik, Elizabeth L. Martin, Brook I. Pfeiffer, Ruth M. Mirza, Sohail K. Deyo, Richard A. Engels, Eric A. TI Bone Morphogenetic Protein Use and Cancer Risk Among Patients Undergoing Lumbar Arthrodesis SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID SPINAL ARTHRODESIS; FUSION; SURVEILLANCE; VALIDATION; SURGERY; DESIGN; COHORT; CLAIMS AB Background: Recombinant bone morphogenetic proteins (BMPs) are growth factors utilized in lumbar arthrodeses. Limited data from randomized trials suggest that BMP may increase cancer risk. We sought to evaluate cancer risk and mortality following the use of BMP in lumbar arthrodesis. Methods: Within the linked Surveillance, Epidemiology, and End Results (SEER) Program-Medicare cohort, we conducted a case-cohort study of 7,278 individuals who were >= 65 years of age and had undergone a lumbar arthrodesis from 2004 to 2011. Of these patients, 3,627 were individuals in a 5% random subcohort of Medicare enrollees in SEER areas including 191 who developed cancer, and there were 3,651 individuals outside the subcohort who developed cancer. Weighted Cox proportional-hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for cancer on the basis of exposure to BMP. Results: In the SEER-Medicare subcohort, 30.7% of individuals who underwent a lumbar arthrodesis received BMP. BMP was not associated with overall cancer risk in univariate analyses (HR, 0.92 [95% CI, 0.82 to 1.02]) or after adjustment for demographic characteristics, comorbidities, hospital size, history of cancer, and calendar year (adjusted HR, 0.94 [95% CI, 0.84 to 1.05]). Individual cancer types were also not significantly elevated (p > 0.05 for all) in BMP users compared with nonusers. In addition, BMP use was not associated with a new cancer in people who had cancer prior to undergoing lumbar arthrodesis (adjusted HR, 1.04 [95% CI, 0.71 to 1.52]) or withmortality after a cancer diagnosis (adjusted HR, 1.05 [95% CI, 0.93 to 1.19]). Conclusions: In a large population of elderly U.S. adults undergoing lumbar arthrodesis, BMP use was not associated with cancer risk or mortality. C1 [Beachler, Daniel C.; Yanik, Elizabeth L.; Martin, Brook I.; Pfeiffer, Ruth M.; Mirza, Sohail K.; Deyo, Richard A.; Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Martin, Brook I.; Mirza, Sohail K.] Dartmouth Geisel Sch Med, Dartmouth Inst Hlth Policy & Clin Practice, Hanover, NH USA. [Mirza, Sohail K.] Dartmouth Geisel Sch Med, Dept Orthopaed Surg, Hanover, NH USA. [Deyo, Richard A.] Oregon Hlth & Sci Univ, Dept Family Med, Portland, OR 97201 USA. [Deyo, Richard A.] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Deyo, Richard A.] Oregon Hlth & Sci Univ, Dept Publ Hlth & Preventat Med, Portland, OR 97201 USA. [Deyo, Richard A.] Oregon Hlth & Sci Univ, Oregon Inst Occupat Hlth Sci, Portland, OR 97201 USA. RP Beachler, DC (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM Daniel.beachler@nih.gov FU National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institutes of Health and the Agency for Healthcare Research and Quality FX One author of this study (B.I.M.) received, through his institution, a grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases; funds were used to pay for salary support. One author of this study (S.K.M.) received grants from the National Institutes of Health and the Agency for Healthcare Research and Quality; funds were used to pay for salary support. One author of this study (R.A.D.) received, through his institution, a gift from Kaiser Permanente; funds were used to pay for an endowed chair that supports part of his salary. NR 28 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0021-9355 EI 1535-1386 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD JUL 6 PY 2016 VL 98 IS 13 BP 1064 EP 1072 DI 10.2106/JBJS.15.01106 PG 9 WC Orthopedics; Surgery SC Orthopedics; Surgery GA DR5ID UT WOS:000379935800005 PM 27385679 ER PT J AU Markunas, CA Wilcox, AJ Xu, ZL Joubert, BR Harlid, S Panduri, V Haberg, SE Nystad, W London, SJ Sandler, DP Lie, RT Wade, PA Taylor, JA AF Markunas, Christina A. Wilcox, Allen J. Xu, Zongli Joubert, Bonnie R. Harlid, Sophia Panduri, Vijayalakshmi Haberg, Siri E. Nystad, Wenche London, Stephanie J. Sandler, Dale P. Lie, Rolv T. Wade, Paul A. Taylor, Jack A. TI Maternal Age at Delivery Is Associated with an Epigenetic Signature in Both Newborns and Adults SO PLOS ONE LA English DT Article ID DNA METHYLATION CHANGES; DEVELOPMENTAL ORIGINS; NORWEGIAN MOTHER; CHILD COHORT; PREGNANCY; EXPRESSION; SMOKING; RISK; PERSPECTIVE; POPULATION AB Offspring of older mothers are at increased risk of adverse birth outcomes, childhood cancers, type 1 diabetes, and neurodevelopmental disorders. The underlying biologic mechanisms for most of these associations remain obscure. One possibility is that maternal aging may produce lasting changes in the epigenetic features of a child's DNA. To test this, we explored the association of mothers' age at pregnancy with methylation in her offspring, using blood samples from 890 Norwegian newborns and measuring DNA methylation at more than 450,000 CpG sites across the genome. We examined replication of a maternal-age finding in an independent group of 1062 Norwegian newborns, and then in 200 US middle-aged women. Older maternal age was significantly associated with reduced methylation at four adjacent CpGs near the 2nd exon of KLHL35 in newborns (p-values ranging from 3x10(-6) to 8x10(-7)). These associations were replicated in the independent set of newborns, and replicated again in women 40 to 60 years after their birth. This study provides the first example of parental age permanently affecting the epigenetic profile of offspring. While the specific functions of the affected gene are unknown, this finding opens the possibility that a mother's age at pregnancy could affect her child's health through epigenetic mechanisms. C1 [Markunas, Christina A.; Wilcox, Allen J.; Xu, Zongli; Joubert, Bonnie R.; London, Stephanie J.; Sandler, Dale P.; Taylor, Jack A.] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Harlid, Sophia; Panduri, Vijayalakshmi; Wade, Paul A.; Taylor, Jack A.] NIEHS, Epigenet & Stem Cell Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Haberg, Siri E.; Nystad, Wenche; Lie, Rolv T.] Norwegian Inst Publ Hlth, Oslo, Norway. [Lie, Rolv T.] Univ Bergen, Dept Global Publ Hlth & Primary Care, Bergen, Norway. [Markunas, Christina A.] RTI Int, Res Triangle Pk, NC USA. RP Taylor, JA (reprint author), NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA.; Taylor, JA (reprint author), NIEHS, Epigenet & Stem Cell Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. EM taylor@niehs.nih.gov OI Harlid, Sophia/0000-0001-8540-6891; xu, zongli/0000-0002-9034-8902; Wilcox, Allen/0000-0002-3376-1311; taylor, jack/0000-0001-5303-6398; Sandler, Dale/0000-0002-6776-0018; London, Stephanie/0000-0003-4911-5290 FU Intramural Research Program of the NIH, National Institute of Environmental Health Science, Sister Study [Z01 ES044005]; Intramural Research Program of the NIH, National Institute of Environmental Health Science, MoBa [Z01-ES-49019]; Intramural Research Program of the NIH, National Institute of Environmental Health Science, Norway Facial Clefts Study; Norwegian Ministry of Health; Ministry of Education and Research; NIH/NIEHS [N01-ES-75558]; NIH/NINDS [1 UO1 NS 047537-01]; Norwegian Research Council/FUGE [151918/S10] FX This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (http://www.niehs.nih.gov/, Z01 ES044005, Sister Study (DPS); Z01-ES-49019, MoBa (SJL); Norway Facial Clefts Study (AJW)). The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health and the Ministry of Education and Research (https://www.regjeringen.no/en/dep/kd/id586/), NIH/NIEHS (http://www.niehs.nih.gov/, contract no N01-ES-75558), NIH/NINDS (http://www.ninds.nih.gov/, grant no. 1 UO1 NS 047537-01), and the Norwegian Research Council/FUGE (http://www.forskningsradet.no/prognett-fuge/Home_page/1226993493114, grant no. 151918/S10 (WN)). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 2 Z9 3 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 6 PY 2016 VL 11 IS 7 AR e0156361 DI 10.1371/journal.pone.0156361 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR3NH UT WOS:000379809400003 PM 27383059 ER PT J AU Fernando, RI Hamilton, DH Dominguez, C David, JM McCampbell, KK Palena, C AF Fernando, Romaine I. Hamilton, Duane H. Dominguez, Charli David, Justin M. McCampbell, Kristen K. Palena, Claudia TI IL-8 signaling is involved in resistance of lung carcinoma cells to erlotinib SO ONCOTARGET LA English DT Article DE erlotinib; tumor resistance; IL-8; epithelial-mesenchymal transition ID EPITHELIAL-MESENCHYMAL TRANSITION; TRANSCRIPTION FACTOR BRACHYURY; EGFR KINASE DOMAIN; ACQUIRED-RESISTANCE; TARGETED THERAPY; COLORECTAL-CARCINOMA; MONOCLONAL-ANTIBODY; MET AMPLIFICATION; CANCER; GROWTH AB A signaling pathway that is frequently deregulated in human carcinomas and has been explored as a therapeutic target involves the activation of the epidermal growth factor receptor (EGFR). Inhibition of EGFR via the small molecule inhibitors erlotinib and gefitinib commonly results in tumor resistance, even in patients with EGFR-mutant tumors that initially show substantial clinical responses. This study was designed to broaden our understanding of the molecular mechanisms of acquired resistance to erlotinib in lung cancer cells bearing wild type or mutated EGFR. We report here that generation of erlotinib-resistant lung cancer cells in vitro resulted in a phenotypic alteration reminiscent of an epithelial-mesenchymal transition (EMT) concomitant with a robust upregulation of the IL-8/IL-8R axis. Our results also demonstrate that upregulation of p38 MAPK signaling is responsible for the enhanced IL-8 secretion in the erlotinib-resistant tumor cells. Blockade of IL-8 signaling effectively reduced mesenchymal features of the resistant cells and also markedly enhanced their susceptibility to erlotinib. These results provide a rationale for the development of new therapeutic approaches involving blockade of IL-8 signaling for the management of acquired resistance to EGFR inhibition in patients with lung cancer. C1 [Fernando, Romaine I.; Hamilton, Duane H.; Dominguez, Charli; David, Justin M.; McCampbell, Kristen K.; Palena, Claudia] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Palena, C (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM palenac@mail.nih.gov FU NIH Intramural Research Program, National Cancer Institute, Center for Cancer Research FX This research was supported by funds of the NIH Intramural Research Program, National Cancer Institute, Center for Cancer Research. NR 50 TC 3 Z9 3 U1 2 U2 2 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD JUL 5 PY 2016 VL 7 IS 27 BP 42031 EP 42044 DI 10.18632/oncotarget.9662 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DS7DI UT WOS:000380942600084 PM 27248176 ER PT J AU Zhang, Q Doucet, M Tomlinson, RE Han, XB Quarles, LD Collins, MT Clemens, TL AF Zhang, Qian Doucet, Michele Tomlinson, Ryan E. Han, Xiaobin Quarles, L. Darryl Collins, Michael T. Clemens, Thomas L. TI The hypoxia-inducible factor-1 alpha activates ectopic production of fibroblast growth factor 23 in tumor-induced osteomalacia SO Bone Research LA English DT Article ID OF-THE-LITERATURE; RICKETS; FGF-23; FGF23 AB Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome in which ectopic production of fibroblast growth factor 23 (FGF23) by non-malignant mesenchymal tumors causes phosphate wasting and bone fractures. Recent studies have implicated the hypoxia-inducible factor-1 alpha (HIF-1 alpha) in other phosphate wasting disorders caused by elevated FGF23, including X-linked hypophosphatemic rickets and autosomal dominant hypophosphatemia. Here we provide evidence that HIF-1 alpha mediates aberrant FGF23 in TIO by transcriptionally activating its promoter. Immunohistochemical studies in phosphaturic mesenchymal tumors resected from patients with documented TIO showed that HIF-1 alpha and FGF23 were co-localized in spindle-shaped cells adjacent to blood vessels. Cultured tumor tissue produced high levels of intact FGF23 and demonstrated increased expression of HIF-1 alpha protein. Transfection of MC3T3-E1 and Saos-2 cells with a HIF-1 alpha expression construct induced the activity of a FGF23 reporter construct. Prior treatment of tumor organ cultures with HIF-1 alpha inhibitors decreased HIF-1 alpha and FGF23 protein accumulation and inhibited HIF-1 alpha-induced luciferase reporter activity in transfected cells. Chromatin immunoprecipitation assays confirmed binding to a HIF-1 alpha consensus sequence within the proximal FGF23 promoter, which was eliminated by treatment with a HIF-1 alpha inhibitor. These results show for the first time that HIF-1 alpha is a direct transcriptional activator of FGF23 and suggest that upregulation of HIF-1 alpha activity in TIO contributes to the aberrant FGF23 production in these patients. C1 [Zhang, Qian; Doucet, Michele; Tomlinson, Ryan E.; Clemens, Thomas L.] Johns Hopkins Univ, Dept Orthopaed Surg, Baltimore, MD USA. [Han, Xiaobin; Quarles, L. Darryl] Univ Tennessee, Hlth Sci Ctr, Dept Med, Memphis, TN USA. [Collins, Michael T.] NIH, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, Bethesda, MD USA. [Clemens, Thomas L.] Baltimore Vet Adm Med Ctr, Baltimore, MD USA. RP Clemens, TL (reprint author), Johns Hopkins Univ, Dept Orthopaed Surg, Baltimore, MD USA.; Clemens, TL (reprint author), Baltimore Vet Adm Med Ctr, Baltimore, MD USA. EM tclemen5@jhmi.edu FU NIH [AR049510, AR045955]; Department of Veterans Affairs FX This work was supported by NIH grants AR049510 (TLC) and AR045955 (LDQ). TLC is the recipient of a Senior Career Scientist Award from the Department of Veterans Affairs. We thank Dr Edward McCarthy for advice on the histopathology of the tumor specimens. NR 18 TC 1 Z9 1 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2095-4700 EI 2095-6231 J9 BONE RES JI Bone Res. PD JUL 5 PY 2016 VL 4 AR 16011 DI 10.1038/boneres.2016.11 PG 6 WC Cell & Tissue Engineering SC Cell Biology GA DS5CM UT WOS:000380798200001 PM 27468359 ER PT J AU Ambrosis, N Boyd, CD O'Toole, GA Fernandez, J Sisti, F AF Ambrosis, Nicolas Boyd, Chelsea D. O'Toole, George A. Fernandez, Julieta Sisti, Federico TI Homologs of the LapD-LapG c-di-GMP Effector System Control Biofilm Formation by Bordetella bronchiseptica SO PLOS ONE LA English DT Article ID PSEUDOMONAS-FLUORESCENS PF0-1; ADENYLATE-CYCLASE TOXIN; RESPIRATORY-TRACT; MECHANISM; INFECTION; VIRULENCE; PERTUSSIS; MOTILITY; PROTEASE AB Biofilm formation is important for infection by many pathogens. Bordetella bronchiseptica causes respiratory tract infections in mammals and forms biofilm structures in nasal epithelium of infected mice. We previously demonstrated that cyclic di-GMP is involved in biofilm formation in B. bronchiseptica. In the present work, based on their previously reported function in Pseudomonas fluorescens, we identified three genes in the B. bronchiseptica genome likely involved in c-di-GMP-dependent biofilm formation: brtA, lapD and lapG. Genetic analysis confirmed a role for BrtA, LapD and LapG in biofilm formation using microtiter plate assays, as well as scanning electron and fluorescent microscopy to analyze the phenotypes of mutants lacking these proteins. In vitro and in vivo studies showed that the protease LapG of B. bronchiseptica cleaves the N-terminal domain of BrtA, as well as the LapA protein of P. fluorescens, indicating functional conservation between these species. Furthermore, while BrtA and LapG appear to have little or no impact on colonization in a mouse model of infection, a B. bronchiseptica strain lacking the LapG protease has a significantly higher rate of inducing a severe disease outcome compared to the wild type. These findings support a role for c-di-GMP acting through BrtA/LapD/LapG to modulate biofilm formation, as well as impact pathogenesis, by B. bronchiseptica C1 [Ambrosis, Nicolas; Fernandez, Julieta; Sisti, Federico] Univ Nacl La Plata, Fac Ciencias Exactas, Dept Ciencias Biol, IBBM,CCT,CONICET La Plata, La Plata, Buenos Aires, Argentina. [Boyd, Chelsea D.; O'Toole, George A.] Geisel Sch Med Dartmouth, Dept Microbiol & Immunol, Hanover, NH USA. [Boyd, Chelsea D.] NIAID, Div Extramural Act, Sci Review Program, Rockville, MD USA. RP Fernandez, J; Sisti, F (reprint author), Univ Nacl La Plata, Fac Ciencias Exactas, Dept Ciencias Biol, IBBM,CCT,CONICET La Plata, La Plata, Buenos Aires, Argentina. EM julietafernandez3@gmail.com; federico.sisti@gmail.com OI Sisti, Federico/0000-0001-7548-0422 FU NIH [R01-AI097307]; NSF [MCB-9984521]; CONICET; PICT [2013-0092]; PIP [0092, 0486]; CONICET doctoral fellowship FX This work was supported by NIH grant R01-AI097307 and NSF grant MCB-9984521 to GAO, and International Cooperation grants (2012 and 2013) from CONICET to FS and JF, PICT 2013-0092, PIP No 0092 and PIP No 0486 to FS and JF. NA was supported by CONICET doctoral fellowship. NR 26 TC 1 Z9 1 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 5 PY 2016 VL 11 IS 7 AR e0158752 DI 10.1371/journal.pone.0158752 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR3JE UT WOS:000379798700044 PM 27380521 ER PT J AU Du, MM Jiao, S Bien, SA Gala, M Abecasis, G Bezieau, S Brenner, H Butterbach, K Caan, BJ Carlson, CS Casey, G Chang-Claude, J Conti, DV Curtis, KR Duggan, D Gallinger, S Haile, RW Harrison, TA Hayes, RB Hoffmeister, M Hopper, JL Hudson, TJ Jenkins, MA Kury, S Le Marchand, L Leal, SM Newcomb, PA Nickerson, DA Potter, JD Schoen, RE Schumacher, FR Seminara, D Slattery, ML Hsu, L Chan, AT White, E Berndt, SI Peters, U AF Du, Mengmeng Jiao, Shuo Bien, Stephanie A. Gala, Manish Abecasis, Goncalo Bezieau, Stephane Brenner, Hermann Butterbach, Katja Caan, Bette J. Carlson, Christopher S. Casey, Graham Chang-Claude, Jenny Conti, David V. Curtis, Keith R. Duggan, David Gallinger, Steven Haile, Robert W. Harrison, Tabitha A. Hayes, Richard B. Hoffmeister, Michael Hopper, John L. Hudson, Thomas J. Jenkins, Mark A. Kury, Sebastien Le Marchand, Loic Leal, Suzanne M. Newcomb, Polly A. Nickerson, Deborah A. Potter, John D. Schoen, Robert E. Schumacher, Fredrick R. Seminara, Daniela Slattery, Martha L. Hsu, Li Chan, Andrew T. White, Emily Berndt, Sonja I. Peters, Ulrike TI Fine-Mapping of Common Genetic Variants Associated with Colorectal Tumor Risk Identified Potential Functional Variants SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; CANCER SUSCEPTIBILITY LOCI; PROSTATE-CANCER; GENOTYPE IMPUTATION; CHROMOSOME 8Q24; COMPLEX TRAITS; SNP RS6983267; TARGET GENES; METAANALYSIS; EXPRESSION AB Genome-wide association studies (GWAS) have identified many common single nucleotide polymorphisms (SNPs) associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs). We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33). We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s). C1 [Du, Mengmeng] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Du, Mengmeng; Jiao, Shuo; Bien, Stephanie A.; Carlson, Christopher S.; Curtis, Keith R.; Harrison, Tabitha A.; Newcomb, Polly A.; Hsu, Li; White, Emily; Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Bien, Stephanie A.; Newcomb, Polly A.; Potter, John D.; White, Emily; Peters, Ulrike] Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. [Gala, Manish; Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Gala, Manish; Chan, Andrew T.] Harvard Med Sch, Boston, MA USA. [Abecasis, Goncalo] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. [Bezieau, Stephane; Kury, Sebastien] CHU Nantes, Serv Genet Med, Nantes, France. [Brenner, Hermann; Butterbach, Katja; Hoffmeister, Michael] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Brenner, Hermann] German Canc Consortium DKTK, Heidelberg, Germany. [Caan, Bette J.] Kaiser Permanente Med Care Program Northern Calif, Div Res, Oakland, CA USA. [Casey, Graham; Conti, David V.; Haile, Robert W.; Schumacher, Fredrick R.] Univ Southern Calif, Keck Sch Med, Los Angeles, CA USA. [Chang-Claude, Jenny] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Duggan, David] Translat Genom Res Inst, Phoenix, AZ USA. [Gallinger, Steven] Mt Sinai Hosp, Dept Surg, Toronto, ON, Canada. [Hayes, Richard B.] NYU, Sch Med, Dept Populat Hlth, Div Epidemiol, New York, NY USA. [Hopper, John L.; Jenkins, Mark A.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Melbourne, Vic, Australia. [Hudson, Thomas J.] Ontario Inst Canc Res, Toronto, ON, Canada. [Hudson, Thomas J.] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. [Hudson, Thomas J.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. [Leal, Suzanne M.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Nickerson, Deborah A.] Univ Washington, Genome Sci, Seattle, WA 98195 USA. [Potter, John D.] Massey Univ, Ctr Publ Hlth Res, Wellington, New Zealand. [Schoen, Robert E.] Univ Pittsburgh, Med Ctr, Dept Med & Epidemiol, Pittsburgh, PA USA. [Seminara, Daniela] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Slattery, Martha L.] Univ Utah, Hlth Sci Ctr, Dept Internal Med, Salt Lake City, UT USA. [Chan, Andrew T.] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Berndt, Sonja I.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Du, MM (reprint author), Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA.; Du, MM; Peters, U (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA.; Peters, U (reprint author), Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. EM dumeng@mskcc.org; upeters@fhcrc.org RI Jenkins, Mark/P-7803-2015; Gallinger, Steven/E-4575-2013; Brenner, Hermann/B-4627-2017; OI Jenkins, Mark/0000-0002-8964-6160; Brenner, Hermann/0000-0002-6129-1572; Hayes, Richard/0000-0002-0918-661X; Bien, Stephanie/0000-0002-8713-4583; Hoffmeister, Michael/0000-0002-8307-3197 FU GECCO: National Cancer Institute; GECCO: National Institutes of Health; GECCO: U.S. Department of Health and Human Services [U01 CA137088, R01 CA059045, U01 CA164930]; National Cancer Institute [R25 CA94880, P30 CA008748]; Regional Council of Pays de la Loire; Groupement des Entreprises Francaises dans la Lutte contre le Cancer (GEFLUC); Association Anne de Bretagne Genetique; Ligue Regionale Contre le Cancer (LRCC); National Cancer Institute, National Institutes of Health [U01 CA122839]; National Institutes of Health: Australasian Colorectal Cancer Family Registry [U01 CA097735]; National Institutes of Health: Ontario Registry for Studies of Familial Colorectal Cancer [U01 CA074783]; National Institutes of Health: Seattle Colorectal Cancer Family Registry [U01 CA074794]; DACHS: German Research Council (Deutsche Forschungsgemeinschaft) [BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1]; COLO2&3: National Institutes of Health [R01 CA60987]; CCFR: National Institutes of Health (RFA) [CA-95-011]; German Federal Ministry of Education and Research [01KH0404, 01ER0814]; DALS: National Institutes of Health [R01 CA48998]; NHS; PHS: HPFS by National Institutes of Health [P01 CA 055075, UM1 CA167552, R01 137178, P50 CA 127003]; NHS by the National Institutes of Health [P50 CA 127003, R01 CA137178, P01 CA 087969]; National Institutes of Health [CA42182]; Damon Runyon Clinical investigator Award; MEC: National Institutes of Health [R37 CA54281, P01 CA033619, R01 CA63464]; OFCCR: National Institutes of Health [U01 CA074783]; GL2 grant from Ontario Research Fund; Canadian Institutes of Health Research; Cancer Risk Evaluation (CaRE) Program grant from Canadian Cancer Society Research Institute; Senior Investigator Awards from Ontario Institute for Cancer Research; Ontario Ministry of Research and Innovation; PLCO: Intramural Research Program of the Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention, National Cancer Institute, NIH, DHHS; National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI) [Z01 CP 010200]; NIH [U01 HG004446]; NIH GEI [U01 HG 004438]; PMH-CCFR: National Institutes of Health [R01 CA076366]; VITAL: National Institutes of Health [K05 CA154337]; National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]; CORECT: National Cancer Institute, National Institutes of Health under RFA [CA-09-002 (U19 CA148107)]; [K24 DK098311] FX This work was supported by the following: GECCO: National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (U01 CA137088; R01 CA059045; U01 CA164930), M.D. is supported by grants R25 CA94880 and P30 CA008748 from the National Cancer Institute. ASTERISK: Hospital Clinical Research Program (PHRC) and supported by the Regional Council of Pays de la Loire, the Groupement des Entreprises Francaises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne Genetique and the Ligue Regionale Contre le Cancer (LRCC). COLO2&3: National Institutes of Health (R01 CA60987). CCFR: National Institutes of Health (RFA # CA-95-011) and through cooperative agreements with members of the Colon Cancer Family Registry and P.I.s. This genome wide scan was supported by the National Cancer Institute, National Institutes of Health by U01 CA122839. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the CFRs, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the CFR. The following Colon CFR centers contributed data to this manuscript and were supported by National Institutes of Health: Australasian Colorectal Cancer Family Registry (U01 CA097735), Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783), and Seattle Colorectal Cancer Family Registry (U01 CA074794). DACHS: German Research Council (Deutsche Forschungsgemeinschaft, BR 1704/6-1, BR 1704/6-3, BR 1704/6-4 and CH 117/1-1), and the German Federal Ministry of Education and Research (01KH0404 and 01ER0814). DALS: National Institutes of Health (R01 CA48998 to M.L.S.); HPFS, NHS, and PHS: HPFS by the National Institutes of Health (P01 CA 055075, UM1 CA167552, R01 137178, and P50 CA 127003), NHS by the National Institutes of Health (R01 CA137178, P01 CA 087969 and P50 CA 127003,) and PHS by the National Institutes of Health (CA42182). A.T.C. is also supported by a Damon Runyon Clinical investigator Award and K24 DK098311. MEC: National Institutes of Health (R37 CA54281, P01 CA033619, and R01 CA63464). OFCCR: National Institutes of Health, through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783); see CCFR section above. As subset of ARCTIC, OFCCR is supported by a GL2 grant from the Ontario Research Fund, the Canadian Institutes of Health Research, and the Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute. T.J.H. is a recipient of Senior Investigator Awards from the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation. PLCO: Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. Additionally, a subset of control samples were genotyped as part of the Cancer Genetic Markers of Susceptibility (CGEMS) Prostate Cancer GWAS (Yeager, M et al. Nat Genet 2007 May;39(5):645-9), Colon CGEMS pancreatic cancer scan (PanScan) (Amundadottir, L et al. Nat Genet. 2009 Sep;41(9):986-90 and Petersen, GM et al Nat Genet. 2010 Mar;42(3):2248), and the Lung Cancer and Smoking study. The prostate and PanScan study datasets were accessed with appropriate approval through the dbGaP online resource (http://cgems.cancer.gov/data/) accession numbers phs000207v.1p1 and phs000206.v3.; p2, respectively, and the lung datasets were accessed from the dbGaP website (http://www.ncbi.nlm.nih.gov/gap) through accession number phs000093v2.p2. Funding for the Lung Cancer and Smoking study was provided by National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446, and NIH GEI U01 HG 004438. For the lung study, the GENEVA Coordinating Center provided assistance with genotype cleaning and general study coordination, and the Johns Hopkins University Center for Inherited Disease Research conducted genotyping. PMH-CCFR: National Institutes of Health (R01 CA076366 to P.A.N.). VITAL: National Institutes of Health (K05 CA154337). WHI: The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. CORECT: National Cancer Institute, National Institutes of Health under RFA #CA-09-002 (U19 CA148107). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in CORECT, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or CORECT. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 75 TC 1 Z9 1 U1 3 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 5 PY 2016 VL 11 IS 7 AR e0157521 DI 10.1371/journal.pone.0157521 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR3JE UT WOS:000379798700007 PM 27379672 ER PT J AU Wilson, LE D'Aloisio, AA Sandler, DP Taylor, JA AF Wilson, Lauren E. D'Aloisio, Aimee A. Sandler, Dale P. Taylor, Jack A. TI Long-term use of calcium channel blocking drugs and breast cancer risk in a prospective cohort of US and Puerto Rican women SO BREAST CANCER RESEARCH LA English DT Article DE Calcium channel blockers; Antihypertensive drugs; Breast cancer risk ID ANTIHYPERTENSIVE MEDICATION USE; CELL-LINES; IN-VITRO; BLOCKERS; APOPTOSIS; VERAPAMIL; HYPERTENSION; ASSOCIATION; MORTALITY; CARCINOMA AB Background: In a recent case-control study, long-term use of calcium channel blocking drugs was associated with a greater-than-twofold increased breast cancer risk. If prospectively collected data confirm that calcium channel blocker use increases breast cancer risk, this would have major implications for hypertension treatment. The objective of this study was to determine whether women using calcium channel blockers for 10 years or more were at increased risk of developing breast cancer compared with women not using calcium channel blockers. Methods: The Sister Study is a prospective volunteer cohort study of women from the USA and Puerto Rico designed to evaluate environmental and genetic risk factors for breast cancer. Beginning in 2003, women between the ages of 35 and 74 were recruited. They were eligible to participate if they had a sister with breast cancer but had not been diagnosed with breast cancer themselves. In total, 50,884 women enrolled in the cohort between 2003 and 2009; 50,757 women with relevant baseline data and available follow-up data are included in this study. The exposure of interest is current use of calcium channel blocking drugs and the reported duration of use at entry into the cohort. Secondary exposures of interest were the duration and frequency of use for all other subclasses of antihypertensive drugs. Our main outcome is a self-reported diagnosis of breast cancer during the study follow-up period. With patient permission, self-reported diagnoses were confirmed using medical records. Results: Results showed 15,817 participants were currently using an antihypertensive drug, and 3316 women were currently using a calcium channel blocker at study baseline; 1965 women reported a breast cancer diagnosis during study follow-up. Using Cox proportional hazards modeling, we found no increased risk of breast cancer among women who had been using calcium channel blockers for 10 years or more compared with never users of calcium channel blockers (HR 0.88, 95 % CI 0.58-1.33). Conclusions: We saw no evidence of increased risk of breast cancer from 10 years or more of current calcium channel blocker use. Our results do not support avoiding calcium channel blocking drugs in order to reduce breast cancer risk. C1 [Wilson, Lauren E.; D'Aloisio, Aimee A.; Sandler, Dale P.; Taylor, Jack A.] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. [D'Aloisio, Aimee A.] Social & Sci Syst Inc, Durham, NC 27703 USA. RP Taylor, JA (reprint author), NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. EM taylor@niehs.nih.gov OI taylor, jack/0000-0001-5303-6398; Sandler, Dale/0000-0002-6776-0018; Wilson, Lauren/0000-0002-5953-2293 FU Intramural Research Program of the National Institute of Environmental Health Sciences, NIH [Z01 ES044005, Z01 ES044032, Z01 ES049033] FX This research was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, NIH (Z01 ES044005, Z01 ES044032, and Z01 ES049033), which provided funding for design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript. NR 33 TC 3 Z9 3 U1 1 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-542X EI 1465-5411 J9 BREAST CANCER RES JI Breast Cancer Res. PD JUL 5 PY 2016 VL 18 AR 61 DI 10.1186/s13058-016-0720-6 PG 8 WC Oncology SC Oncology GA DQ6KN UT WOS:000379313800001 PM 27378129 ER PT J AU Pauli, R Bowring, A Reynolds, R Chen, G Nichols, TE Maumet, C AF Pauli, Ruth Bowring, Alexander Reynolds, Richard Chen, Gang Nichols, Thomas E. Maumet, Camille TI Exploring fMRI Results Space: 31 Variants of an fMRI Analysis in AFNI, FSL, and SPM SO FRONTIERS IN NEUROINFORMATICS LA English DT Article DE data sharing; functional MRI; provenance; fMRI analysis; neuroimaging ID PROJECT C1 [Pauli, Ruth; Bowring, Alexander; Nichols, Thomas E.; Maumet, Camille] Univ Warwick, Warwick Mfg Grp, Coventry, W Midlands, England. [Reynolds, Richard; Chen, Gang] NIMH, Sci & Stat Comp Core, NIH, Bethesda, MD 20892 USA. [Nichols, Thomas E.] Univ Warwick, Dept Stat, Coventry, W Midlands, England. RP Pauli, R (reprint author), Univ Warwick, Warwick Mfg Grp, Coventry, W Midlands, England. EM r.pauli@warwick.ac.uk FU Git Large File Storage (Git-LFS); Welcome Trust; BBSRC; NIMH intramural Research Programs of the NIH/HHS, USA [ZICMH002888]; NINDS intramural Research Programs of the NIH/HHS, USA [ZICMH002888] FX The INCF provided funding for the use of Git Large File Storage (Git-LFS). AB, CM, and TN were supported by the Welcome Trust. RP was supported by the BBSRC-funded Midlands Integrative Biosciences Training Partnership (MIBTP), and RR and GC were supported by the NIMH and NINDS intramural Research Programs (ZICMH002888) of the NIH/HHS, USA. NR 14 TC 1 Z9 1 U1 4 U2 4 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5196 J9 FRONT NEUROINFORM JI Front. Neuroinformatics PD JUL 5 PY 2016 VL 10 AR 24 DI 10.3389/fninf.2016.00024 PG 6 WC Mathematical & Computational Biology; Neurosciences SC Mathematical & Computational Biology; Neurosciences & Neurology GA DQ3FU UT WOS:000379089000001 PM 27458367 ER PT J AU Hripcsak, G Ryan, PB Duke, JD Shah, NH Park, RW Huser, V Suchard, MA Schuemie, MJ DeFalco, FJ Perotte, A Banda, JM Reich, CG Schilling, LM Matheny, ME Meeker, D Pratt, N Madigan, D AF Hripcsak, George Ryan, Patrick B. Duke, Jon D. Shah, Nigam H. Park, Rae Woong Huser, Vojtech Suchard, Marc A. Schuemie, Martijn J. DeFalco, Frank J. Perotte, Adler Banda, Juan M. Reich, Christian G. Schilling, Lisa M. Matheny, Michael E. Meeker, Daniella Pratt, Nicole Madigan, David TI Characterizing treatment pathways at scale using the OHDSI network SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE observational research; data network; treatment pathways ID CONTROLLED CASE SERIES; CLINICAL PATHWAYS; CONTROLLED-TRIALS; TASK-FORCE; HEALTH; MEDICATION; OUTCOMES; QUALITY; TIME; RECOMMENDATIONS AB Observational research promises to complement experimental research by providing large, diverse populations that would be infeasible for an experiment. Observational research can test its own clinical hypotheses, and observational studies also can contribute to the design of experiments and inform the generalizability of experimental research. Understanding the diversity of populations and the variance in care is one component. In this study, the Observational Health Data Sciences and Informatics (OHDSI) collaboration created an international data network with 11 data sources from four countries, including electronic health records and administrative claims data on 250 million patients. All data were mapped to common data standards, patient privacy was maintained by using a distributed model, and results were aggregated centrally. Treatment pathways were elucidated for type 2 diabetes mellitus, hypertension, and depression. The pathways revealed that the world is moving toward more consistent therapy over time across diseases and across locations, but significant heterogeneity remains among sources, pointing to challenges in generalizing clinical trial results. Diabetes favored a single first-line medication, metformin, to a much greater extent than hypertension or depression. About 10% of diabetes and depression patients and almost 25% of hypertension patients followed a treatment pathway that was unique within the cohort. Aside from factors such as sample size and underlying population (academic medical center versus general population), electronic health records data and administrative claims data revealed similar results. Large-scale international observational research is feasible. C1 [Hripcsak, George; Perotte, Adler] Columbia Univ, Med Ctr, Dept Biomed Informat, New York, NY 10032 USA. [Hripcsak, George] NewYork Presbyterian Hosp, Med Informat Serv, New York, NY 10032 USA. [Hripcsak, George; Ryan, Patrick B.; Duke, Jon D.; Shah, Nigam H.; Park, Rae Woong; Huser, Vojtech; Suchard, Marc A.; Schuemie, Martijn J.; DeFalco, Frank J.; Perotte, Adler; Banda, Juan M.; Reich, Christian G.; Schilling, Lisa M.; Matheny, Michael E.; Meeker, Daniella; Pratt, Nicole; Madigan, David] Observat Hlth Data Sci & Informat, New York, NY 10032 USA. [Ryan, Patrick B.; Schuemie, Martijn J.; DeFalco, Frank J.] Janssen Res & Dev, Epidemiol Analyt, Titusville, NJ 08560 USA. [Duke, Jon D.] Regenstrief Inst Hlth Care, Ctr Biomed Informat, Indianapolis, IN 46205 USA. [Shah, Nigam H.; Banda, Juan M.] Stanford Univ, Ctr Biomed Informat Res, Stanford, CA 94305 USA. [Park, Rae Woong] Ajou Univ, Sch Med, Dept Biomed Informat, Suwon 443380, South Korea. [Huser, Vojtech] NIH, Lister Hill Natl Ctr Biomed Commun, Natl Lib Med, Bethesda, MD 20894 USA. [Suchard, Marc A.] Univ Calif Los Angeles, Dept Biomath, Los Angeles, CA 90095 USA. [Suchard, Marc A.] Univ Calif Los Angeles, Dept Biostat, Los Angeles, CA 90095 USA. [Suchard, Marc A.] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA 90095 USA. [Reich, Christian G.] IMS Hlth, Real World Evidence Solut, Burlington, MA 01809 USA. [Schilling, Lisa M.] Univ Colorado, Sch Med, Dept Med, Aurora, CO 80045 USA. [Matheny, Michael E.] Vanderbilt Univ, Med Ctr, Dept Biomed Informat, Nashville, TN 37212 USA. [Matheny, Michael E.] VA Tennessee Valley Healthcare Syst, Geriatr Res Educ & Clin Ctr, Nashville, TN 37212 USA. [Meeker, Daniella] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. [Meeker, Daniella] Univ So Calif, Dept Pediat, Los Angeles, CA 90089 USA. [Pratt, Nicole] Univ S Australia, Div Hlth Sci, Adelaide, SA 5001, Australia. [Madigan, David] Columbia Univ, Dept Stat, New York, NY 10027 USA. RP Hripcsak, G (reprint author), Columbia Univ, Med Ctr, Dept Biomed Informat, New York, NY 10032 USA.; Hripcsak, G (reprint author), NewYork Presbyterian Hosp, Med Informat Serv, New York, NY 10032 USA.; Hripcsak, G (reprint author), Observat Hlth Data Sci & Informat, New York, NY 10032 USA. EM hripcsak@columbia.edu OI Banda, Juan/0000-0001-8499-824X FU National Library of Medicine [R01 LM006910, R01 LM011369]; National Institute of General Medical Sciences [R01 GM101430]; National Science Foundation [NSF IIS 1251151]; Smart Family Foundation; Janssen Research and Development; AstraZeneca; Takeda Pharmaceuticals International FX This work was funded in part by Grants R01 LM006910 and R01 LM011369 from the National Library of Medicine, Grant R01 GM101430 from the National Institute of General Medical Sciences, Grant NSF IIS 1251151 from the National Science Foundation, and by the Smart Family Foundation. Infrastructure to carry out the project was funded in part by Janssen Research and Development, AstraZeneca, and Takeda Pharmaceuticals International. Use of the CPRD data set was approved by the CPRD Independent Scientific Advisory Committee as protocol 15_019R. NR 39 TC 4 Z9 4 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 5 PY 2016 VL 113 IS 27 BP 7329 EP 7336 DI 10.1073/pnas.1510502113 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ2GW UT WOS:000379021700036 PM 27274072 ER PT J AU Kasbekara, M Fischer, G Mott, BT Yasgar, A Hyvonen, M Boshoff, HIM Abell, C Barry, CE Thomas, CJ AF Kasbekar, Monica Fischer, Gerhard Mott, Bryan T. Yasgar, Adam Hyvonen, Marko Boshoff, Helena I. M. Abell, Chris Barry, Clifton E., III Thomas, Craig J. TI Selective small molecule inhibitor of the Mycobacterium tuberculosis fumarate hydratase reveals an allosteric regulatory site SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE allosteric regulation; selective inhibition; fumarate hydratase; Mycobacterium tuberculosis; TCA cycle ID ESCHERICHIA-COLI; MOONLIGHTING PROTEINS; METABOLISM; LIBRARIES; PARADIGM; BINDING; ENZYME; ASSAYS; GENE AB Enzymes in essential metabolic pathways are attractive targets for the treatment of bacterial diseases, but in many cases, the presence of homologous human enzymes makes them impractical candidates for drug development. Fumarate hydratase, an essential enzyme in the tricarboxylic acid (TCA) cycle, has been identified as one such potential therapeutic target in tuberculosis. We report the discovery of the first small molecule inhibitor, to our knowledge, of the Mycobacterium tuberculosis fumarate hydratase. A crystal structure at 2.0-angstrom resolution of the compound in complex with the protein establishes the existence of a previously unidentified allosteric regulatory site. This allosteric site allows for selective inhibition with respect to the homologous human enzyme. We observe a unique binding mode in which two inhibitor molecules interact within the allosteric site, driving significant conformational changes that preclude simultaneous substrate and inhibitor binding. Our results demonstrate the selective inhibition of a highly conserved metabolic enzyme that contains identical active site residues in both the host and the pathogen. C1 [Kasbekar, Monica; Mott, Bryan T.; Yasgar, Adam; Thomas, Craig J.] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20850 USA. [Kasbekar, Monica; Abell, Chris] Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England. [Fischer, Gerhard; Hyvonen, Marko] Univ Cambridge, Dept Biochem, Cambridge CB2 1GA, England. [Boshoff, Helena I. M.; Barry, Clifton E., III] NIAID, NIH, Bethesda, MD 20850 USA. RP Thomas, CJ (reprint author), NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20850 USA. EM craigt@mail.nih.gov OI Fischer, Gerhard/0000-0001-9861-1528 FU National Institutes of Health-Oxford-Cambridge Scholars Program; Washington University in St. Louis Medical Scientist Training Program; Division of Preclinical Innovation, National Center for Advancing Translational Sciences; Intramural Research Program of the National Institute of Allergy and Infectious Diseases FX We thank Dr. Christina Spry, Dr. David Garboczi, Dr. Apostolos Gittis, Dr. Paresma Patel, and Dr. Tathagata Mukherjee for helpful advice and discussions. We also thank Sam Michael, Charles Bonney, Dr. Rajarshi Guha, and Paul Shinn for help with the high-throughput screen and compound management. Some experiments were performed in the Crystallographic X-Ray Facility at the Department of Biochemistry, University of Cambridge. We thank Dr. Dimitri Chirgadze for his assistance in using these facilities. We also thank Diamond Light Source and staff for the provision of beam time at beamlines I04 and I24. M.K. is supported by the National Institutes of Health-Oxford-Cambridge Scholars Program and the Washington University in St. Louis Medical Scientist Training Program. This work was supported by the Division of Preclinical Innovation, National Center for Advancing Translational Sciences and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases. NR 35 TC 3 Z9 3 U1 3 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 5 PY 2016 VL 113 IS 27 BP 7503 EP 7508 DI 10.1073/pnas.1600630113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ2GW UT WOS:000379021700064 PM 27325754 ER PT J AU Zhang, Y Yokoyama, S Herriges, JC Zhang, Z Young, RE Verheyden, JM Sun, X AF Zhang, Yan Yokoyama, Shigetoshi Herriges, John C. Zhang, Zhen Young, Randee E. Verheyden, Jamie M. Sun, Xin TI E3 ubiquitin ligase RFWD2 controls lung branching through protein-level regulation of ETV transcription factors SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE lung branching; RFWD2; COP1; ETV transcription factors; E3 ubiquitin ligases ID HORMONE-RELATED PROTEIN; MOUSE LUNG; NEGATIVE REGULATOR; TUMOR-SUPPRESSOR; MULTIPLE ROLES; C/EBP-ALPHA; COP1; MORPHOGENESIS; DEGRADATION; EXPRESSION AB The mammalian lung is an elaborate branching organ, and it forms following a highly stereotypical morphogenesis program. It is well established that precise control at the transcript level is a key genetic underpinning of lung branching. In comparison, little is known about how regulation at the protein level may play a role. Ring finger and WD domain 2 (RFWD2, also termed COP1) is an E3 ubiquitin ligase that modifies specific target proteins, priming their degradation via the ubiquitin proteasome system. RFWD2 is known to function in the adult in pathogenic processes such as tumorigenesis. Here, we show that prenatal inactivation of Rfwd2 gene in the lung epithelium led to a striking halt in branching morphogenesis shortly after secondary branch formation. This defect is accompanied by distalization of the lung epithelium while growth and cellular differentiation still occurred. In the mutant lung, two E26 transformation-specific (ETS) transcription factors essential for normal lung branching, ETS translocation variant 4 (ETV4) and ETV5, were up-regulated at the protein level, but not at the transcript level. Introduction of Etv loss-of-function alleles into the Rfwd2 mutant background attenuated the branching phenotype, suggesting that RFWD2 functions, at least in part, through degrading ETV proteins. Because a number of E3 ligases are known to target factors important for lung development, our findings provide a preview of protein-level regulatory network essential for lung branching morphogenesis. C1 [Zhang, Yan; Yokoyama, Shigetoshi; Herriges, John C.; Zhang, Zhen; Young, Randee E.; Verheyden, Jamie M.; Sun, Xin] Univ Wisconsin, Dept Med Genet, Lab Genet, Madison, WI 53706 USA. [Yokoyama, Shigetoshi] Natl Canc Inst, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Zhang, Zhen] NGM Biopharmaceut Inc, San Francisco, CA 94080 USA. RP Sun, X (reprint author), Univ Wisconsin, Dept Med Genet, Lab Genet, Madison, WI 53706 USA. EM xsun@wisc.edu RI yokoyama, shigetoshi/S-5912-2016 OI yokoyama, shigetoshi/0000-0003-4175-0548 FU American Heart Association [15POST25670070]; National Heart, Lung, and Blood Institute [RO1 HL113870, HL097134]; Wisconsin Partnership Program [2897] FX We thank members of the X.S. laboratory for constructive discussions and readings of the manuscript, Dr. Vishva M. Dixit (Genentech) for sharing the Rfwd2fl mice, and Dr. Scott Berry and Dr. David Beebe (University of Wisconsin-Madison) for guidance on immunoprecipitation experiments. This work was supported by American Heart Association Postdoctoral Fellowship 15POST25670070 (to Y.Z.) and by National Heart, Lung, and Blood Institute Grants RO1 HL113870 and HL097134 and Wisconsin Partnership Program Grant 2897 (to X.S.). NR 55 TC 0 Z9 0 U1 7 U2 10 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 5 PY 2016 VL 113 IS 27 BP 7557 EP 7562 DI 10.1073/pnas.1603310113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ2GW UT WOS:000379021700073 PM 27335464 ER PT J AU Li, QS Sodroski, C Lowey, B Schweitzer, CJ Cha, HL Zhang, F Liang, TJ AF Li, Qisheng Sodroski, Catherine Lowey, Brianna Schweitzer, Cameron J. Cha, Helen Zhang, Fang Liang, T. Jake TI Hepatitis C virus depends on E-cadherin as an entry factor and regulates its expression in epithelial-to-mesenchymal transition SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE hepatitis C virus; viral entry; E-cadherin; tight junction; epithelial-mesenchymal transition ID B TYPE-I; PRIMARY HUMAN HEPATOCYTES; LIFE-CYCLE; HEPATOCELLULAR-CARCINOMA; SUPERINFECTION EXCLUSION; CORE-PROTEIN; CELL-CULTURE; HOST FACTORS; INFECTION; RECEPTOR AB Hepatitis C virus (HCV) enters the host cell through interactions with a cascade of cellular factors. Although significant progress has been made in understanding HCV entry, the precise mechanisms by which HCV exploits the receptor complex and host machinery to enter the cell remain unclear. This intricate process of viral entry likely depends on additional yet-to-be-defined cellular molecules. Recently, by applying integrative functional genomics approaches, we identified and interrogated distinct sets of host dependencies in the complete HCV life cycle. Viral entry assays using HCV pseudoparticles (HCVpps) of various genotypes uncovered multiple previously unappreciated host factors, including E-cadherin, that mediate HCV entry. E-cadherin silencing significantly inhibited HCV infection in Huh7.5.1 cells, HepG2/miR122/CD81 cells, and primary human hepatocytes at a postbinding entry step. Knockdown of E-cadherin, however, had no effect on HCV RNA replication or internal ribosomal entry site (IRES)-mediated translation. In addition, an E-cadherin monoclonal antibody effectively blocked HCV entry and infection in hepatocytes. Mechanistic studies demonstrated that E-cadherin is closely associated with claudin-1 (CLDN1) and occludin (OCLN) on the cell membrane. Depletion of E-cadherin drastically diminished the cell-surface distribution of these two tight junction proteins in various hepatic cell lines, indicating that E-cadherin plays an important regulatory role in CLDN1/OCLN localization on the cell surface. Furthermore, loss of E-cadherin expression in hepatocytes is associated with HCV-induced epithelial-to-mesenchymal transition (EMT), providing an important link between HCV infection and liver cancer. Our data indicate that a dynamic interplay among E-cadherin, tight junctions, and EMT exists and mediates an important function in HCV entry. C1 [Li, Qisheng; Sodroski, Catherine; Lowey, Brianna; Schweitzer, Cameron J.; Cha, Helen; Zhang, Fang; Liang, T. Jake] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. RP Li, QS; Liang, TJ (reprint author), NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. EM liqisheng@niddk.nih.gov; jakel@bdg10.niddk.nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX We thank Ching-Sheng Hsu and Veronique Pene for technical assistance; Francis Chisari, Charles Rice, Takaji Wakita, Francois-Loic Cosset, Michael Niepmann, Jens Bukh, Tetsuro Suzuki, and Takanobu Kato for their generosity in providing reagents; and all members of the Liver Diseases Branch for discussion and support. This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 52 TC 3 Z9 3 U1 3 U2 9 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 5 PY 2016 VL 113 IS 27 BP 7620 EP 7625 DI 10.1073/pnas.1602701113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ2GW UT WOS:000379021700084 PM 27298373 ER PT J AU Davoli-Ferreira, M Fonseca, DM Mota, CM Dias, MS Lima, DS da Silva, MV Quirino, GFS Zamboni, DS Silva, JS Mineo, TWP AF Davoli-Ferreira, Marcela Fonseca, Denise M. Mota, Caroline M. Dias, Murilo S. Lima-Junior, Djalma S. da Silva, Murilo V. Quirino, Gustavo F. S. Zamboni, Dario S. Silva, Joao S. Mineo, Tiago W. P. TI Nucleotide-binding oligomerization domain-containing protein 2 prompts potent inflammatory stimuli during Neospora caninum infection SO SCIENTIFIC REPORTS LA English DT Article ID TOLL-LIKE RECEPTORS; IMMUNE-RESPONSES; HOST-DEFENSE; KAPPA-B; NOD2; DISEASE; INNATE; ACTIVATION; CELLS; PEPTIDOGLYCAN AB Neospora caninum is an apicomplexan parasite responsible for major economic losses due to abortions in cattle. Innate immune responses are crucial for host resistance against the infection, however the molecules involved in parasite recognition are still poorly understood. Nod2 is a cytosolic receptor that recognizes several pathogens and its role during N. caninum infection has not yet been described. In that sense, we evaluated the role of Nod2 in host response against this parasite. We found that infection of macrophages induced increased expression of Nod2, which colocalized with the parasites' vacuoles. Nod2-deficient macrophages showed an impaired induction of pro-inflammatory cytokines, increased production of modulatory molecules, and failure to restrict parasite replication. In vivo, Nod2-knockout mice showed a reduction of MAPK phosphorylation and proinflammatory cytokines, followed by decreased inflammation in target organs and increment in parasite burden. Surprisingly, these mice were partially resistant to lethal doses of tachyzoites. In addition, these phenomena were not observed in Rip2-/- mice. In conclusion, our study indicates that Nod2-dependent responses account for N. caninum elimination. On the other hand, the inflammatory milieu induced by this innate receptor provoked pathogenesis and death in severe experimental neosporosis. C1 [Davoli-Ferreira, Marcela; Mota, Caroline M.; da Silva, Murilo V.; Mineo, Tiago W. P.] Univ Fed Uberlandia, Inst Biomed Sci, Lab Immunoparasitol Dr Mario Endsfeldz Camargo, Uberlandia, MG, Brazil. [Davoli-Ferreira, Marcela; Fonseca, Denise M.; Dias, Murilo S.; Lima-Junior, Djalma S.; Quirino, Gustavo F. S.; Silva, Joao S.] Univ Sao Paulo, Ribeirao Preto Sch Med, Dept Biochem & Immunol, Ribeirao Preto, SP, Brazil. [Fonseca, Denise M.] NIAID, Program Barrier Immun & Repair Mucosal Immunol Se, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Zamboni, Dario S.] Univ Sao Paulo, Ribeirao Preto Sch Med, Dept Cell Biol, Ribeirao Preto, SP, Brazil. RP Mineo, TWP (reprint author), Univ Fed Uberlandia, Inst Biomed Sci, Lab Immunoparasitol Dr Mario Endsfeldz Camargo, Uberlandia, MG, Brazil. EM tiago.mineo@ufu.br RI Mineo, Tiago/B-4153-2009; Silva, Joao/A-4484-2008; CEPID, CRID/J-2644-2015; OI Mineo, Tiago/0000-0002-2339-2743; Souza Lima Junior, Djalma/0000-0002-2092-8047; Zamboni, Dario/0000-0002-7856-7512 NR 40 TC 1 Z9 1 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUL 5 PY 2016 VL 6 AR 29289 DI 10.1038/srep29289 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ6AE UT WOS:000379285600001 PM 27377650 ER PT J AU Smith, RH Hallwirth, CV Westerman, M Hetherington, NA Tseng, YS Cecchini, S Virag, T Ziegler, ML Rogozin, IB Koonin, EV Agbandje-McKenna, M Kotin, RM Alexander, IE AF Smith, Richard H. Hallwirth, Claus V. Westerman, Michael Hetherington, Nicola A. Tseng, Yu-Shan Cecchini, Sylvain Virag, Tamas Ziegler, Mona-Larissa Rogozin, Igor B. Koonin, Eugene V. Agbandje-McKenna, Mavis Kotin, Robert M. Alexander, Ian E. TI Germline viral "fossils" guide in silico Ereconstruction of a mid-Cenozoic era marsupial adeno-associated virus SO SCIENTIFIC REPORTS LA English DT Article ID MULTIPLE SEQUENCE ALIGNMENT; HUMAN GENE-THERAPY; DNA-REPLICATION; PHYLOGENETIC INFERENCE; TRANSCRIPTION FACTOR; MAMMALIAN GENOMES; CRYSTAL-STRUCTURE; BINDING-SITE; EVOLUTION; PROTEIN AB Germline endogenous viral elements (EVEs) genetically preserve viral nucleotide sequences useful to the study of viral evolution, gene mutation, and the phylogenetic relationships among host organisms. Here, we describe a lineage-specific, adeno-associated virus (AAV)-derived endogenous viral element (mAAV-EVE1) found within the germline of numerous closely related marsupial species. Molecular screening of a marsupial DNA panel indicated that mAAV-EVE1 occurs specifically within the marsupial suborder Macropodiformes (present-day kangaroos, wallabies, and related macropodoids), to the exclusion of other Diprotodontian lineages. Orthologous mAAV-EVE1 locus sequences from sixteen macropodoid species, representing a speciation history spanning an estimated 30 million years, facilitated compilation of an inferred ancestral sequence that recapitulates the genome of an ancient marsupial AAV that circulated among Australian metatherian fauna sometime during the late Eocene to early Oligocene. In silico gene reconstruction and molecular modelling indicate remarkable conservation of viral structure over a geologic timescale. Characterisation of AAV-EVE loci among disparate species affords insight into AAV evolution and, in the case of macropodoid species, may offer an additional genetic basis for assignment of phylogenetic relationships among the Macropodoidea. From an applied perspective, the identified AAV "fossils" provide novel capsid sequences for use in translational research and clinical applications. C1 [Smith, Richard H.; Cecchini, Sylvain; Virag, Tamas; Kotin, Robert M.] NHLBI, Lab Mol Virol & Gene Therapy, Bldg 10, Bethesda, MD 20892 USA. [Hallwirth, Claus V.; Hetherington, Nicola A.; Ziegler, Mona-Larissa; Alexander, Ian E.] Childrens Med Res Inst, Gene Therapy Res Unit, Westmead, NSW, Australia. [Hallwirth, Claus V.; Hetherington, Nicola A.; Ziegler, Mona-Larissa; Alexander, Ian E.] Childrens Hosp Westmead, Westmead, NSW, Australia. [Westerman, Michael] La Trobe Univ, Dept Biochem & Genet, Bundoora, Vic, Australia. [Tseng, Yu-Shan; Agbandje-McKenna, Mavis] Univ Florida, McKnight Brain Inst, Gainesville, FL USA. [Rogozin, Igor B.; Koonin, Eugene V.] NIH, Evolutionary Genom Res Grp, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. [Alexander, Ian E.] Univ Sydney, Discipline Paediat & Child Hlth, Westmead, NSW, Australia. [Kotin, Robert M.] Voyager Therapeut, Cambridge, MA USA. [Kotin, Robert M.] Univ Massachusetts, Sch Med, Gene Therapy Ctr, Worcester, MA USA. RP Kotin, RM (reprint author), NHLBI, Lab Mol Virol & Gene Therapy, Bldg 10, Bethesda, MD 20892 USA.; Alexander, IE (reprint author), Childrens Med Res Inst, Gene Therapy Res Unit, Westmead, NSW, Australia.; Alexander, IE (reprint author), Childrens Hosp Westmead, Westmead, NSW, Australia.; Alexander, IE (reprint author), Univ Sydney, Discipline Paediat & Child Hlth, Westmead, NSW, Australia.; Kotin, RM (reprint author), Voyager Therapeut, Cambridge, MA USA.; Kotin, RM (reprint author), Univ Massachusetts, Sch Med, Gene Therapy Ctr, Worcester, MA USA. EM robert_kotin@umassmed.edu; ian.alexander@health.nsw.gov.au FU Intramural Research Program of the National Library of Medicine (National Institutes of Health, US Department of Health and Human Services); Australian Research Council [DP150101253]; NIH [R01 GM082946]; Intramural Research Program of the National Heart, Lung, and Blood Institute, of the National Institutes of Health FX We thank the San Diego Zoo Global and Mark Springer (University of California, Riverside, California, USA) for providing marsupial DNA samples. IBR and EVK were supported by the Intramural Research Program of the National Library of Medicine (National Institutes of Health, US Department of Health and Human Services). CVH and NAH are supported by a Discovery Project grant (DP150101253) from the Australian Research Council. MA-M was supported by NIH R01 GM082946. RHS, SC, TV, and RMK were supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute, of the National Institutes of Health. NR 95 TC 1 Z9 1 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUL 5 PY 2016 VL 6 AR 28965 DI 10.1038/srep28965 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ4QO UT WOS:000379188600001 PM 27377618 ER PT J AU Carson, SS Cox, CE Wallenstein, S Hanson, LC Danis, M Tulsky, JA Chai, E Nelson, JE AF Carson, Shannon S. Cox, Christopher E. Wallenstein, Sylvan Hanson, Laura C. Danis, Marion Tulsky, James A. Chai, Emily Nelson, Judith E. TI Effect of Palliative Care-Led Meetings for Families of Patients With Chronic Critical Illness A Randomized Clinical Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID PROLONGED MECHANICAL VENTILATION; OF-LIFE CARE; COMMUNICATION-SKILLS; RESOURCE UTILIZATION; DEPRESSION SCALE; HOSPITAL ANXIETY; UNITED-STATES; ILL PATIENTS; ICU; VALIDATION AB IMPORTANCE Family caregivers of patients with chronic critical illness experience significant psychological distress. OBJECTIVE To determine whether family informational and emotional support meetings led by palliative care clinicians improve family anxiety and depression. DESIGN, SETTING, AND PARTICIPANTS A multicenter randomized clinical trial conducted from October 2010 through November 2014 in 4 medical intensive care units (ICUs). Adult patients (aged >= 21 years) requiring 7 days of mechanical ventilation were randomized and their family surrogate decision makers were enrolled in the study. Observers were blinded to group allocation for the measurement of the primary outcomes. INTERVENTIONS At least 2 structured family meetings led by palliative care specialists and provision of an informational brochure (intervention) compared with provision of an informational brochure and routine family meetings conducted by ICU teams (control). There were 130 patients with 184 family surrogate decision makers in the intervention group and 126 patients with 181 family surrogate decision makers in the control group. MAIN OUTCOMES AND MEASURES The primary outcome was Hospital Anxiety and Depression Scale symptom score (HADS; score range, 0[best] to 42[worst]; minimal clinically important difference, 1.5) obtained during 3-month follow-up interviews with the surrogate decision makers. Secondary outcomes included posttraumatic stress disorder experienced by the family and measured by the Impact of Events Scale-Revised (IES-R; total score range, 0 [best] to 88 [worst]), discussion of patient preferences, hospital length of stay, and 90-day survival. RESULTS Among 365 family surrogate decision makers (mean age, 51 years; 71% female), 312 completed the study. At 3 months, there was no significant difference in anxiety and depression symptoms between surrogate decision makers in the intervention group and the control group (adjusted mean HADS score, 12.2 vs 11.4, respectively; between-group difference, 0.8 [95% CI, -0.9 to 2.6]; P = .34). Posttraumatic stress disorder symptoms were higher in the intervention group (adjusted mean IES-R score, 25.9) compared with the control group (adjusted mean IES-R score, 21.3) (between-group difference, 4.60 [95% CI, 0.01 to 9.10]; P = .0495). There was no difference between groups regarding the discussion of patient preferences (intervention, 75%; control, 83%; odds ratio, 0.63[95% CI, 0.34 to 1.16; P = .14]). The median number of hospital days for patients in the intervention vs the control group (19 days vs 23 days, respectively; between-group difference, -4 days [95% CI, -6 to 3 days]; P = .51) and 90-day survival (hazard ratio, 0.95 [95% CI, 0.65 to 1.38], P = .96) were not significantly different. CONCLUSIONS AND RELEVANCE Among families of patients with chronic critical illness, the use of palliative care-led informational and emotional support meetings compared with usual care did not reduce anxiety or depression symptoms and may have increased posttraumatic stress disorder symptoms. These findings do not support routine or mandatory palliative care-led discussion of goals of care for all families of patients with chronic critical illness. C1 [Carson, Shannon S.; Hanson, Laura C.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Cox, Christopher E.] Duke Univ, Med Ctr, Durham, NC USA. [Wallenstein, Sylvan; Chai, Emily] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Danis, Marion] NIH, Bldg 10, Bethesda, MD 20892 USA. [Tulsky, James A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. [Tulsky, James A.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA USA. [Nelson, Judith E.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Nelson, Judith E.] Weill Cornell Med Coll, New York, NY USA. RP Carson, SS (reprint author), Univ N Carolina, Sch Med, Div Pulm & Crit Care Med, Marsico Lung Inst,Cecil B Sheps Ctr Hlth Serv Res, 4125 Bioinformat Bldg,CB 7020, Chapel Hill, NC 27599 USA. EM scarson@med.unc.edu FU National Institute of Nursing Research [R01-NR012413] FX This project was funded by grant R01-NR012413 from the National Institute of Nursing Research. NR 36 TC 15 Z9 16 U1 13 U2 15 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 JUL 5 PY 2016 VL 316 IS 1 BP 51 EP 62 DI 10.1001/jama.2016.8474 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA DQ2MY UT WOS:000379037600018 PM 27380343 ER PT J AU Katz, JN Minder, M Olenchock, B Price, S Goldfarb, M Washam, JB Barnett, CF Newby, LK van Diepen, S AF Katz, Jason N. Minder, Michael Olenchock, Benjamin Price, Susanna Goldfarb, Michael Washam, Jeffrey B. Barnett, Christopher F. Newby, L. Kristin van Diepen, Sean TI The Genesis, Maturation, and Future of Critical Care Cardiology SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Review DE quality of care; research; training ID ELEVATION MYOCARDIAL-INFARCTION; INTENSIVE-CARE; ILL PATIENTS; UNITED-STATES; NURSE-PRACTITIONERS; AMERICAN-COLLEGE; TEMPORAL TRENDS; CARDIAC-ARREST; SEPTIC SHOCK; TASK-FORCE AB The cardiac intensive care unit (CICU) has changed considerably over time and now serves a unique patient population with a high burden of cardiovascular and noncardiovascular critical illness. Patient complexity and technological evolutions in the CICU have catalyzed the development of critical care cardiology, a fledgling discipline that combines specialization in cardiovascular diseases with knowledge and experience in critical care medicine. Numerous uncertainties and challenges threaten to stymie the growth of this field. A multidisciplinary dialogue focused on the best care design for the CICU patient is needed as we consider alternative approaches to clinical training, staffing, and investigation in this rapidly evolving arena. (J Am Coll Cardiol 2016; 68:67-79) (C) 2016 by the American College of Cardiology Foundation. C1 [Katz, Jason N.] Univ N Carolina, Sch Med, Div Cardiol, Chapel Hill, NC USA. [Katz, Jason N.] Univ N Carolina, Sch Med, Div Pulm & Crit Care Med, Chapel Hill, NC USA. [Minder, Michael; Washam, Jeffrey B.; Newby, L. Kristin] Duke Univ, Div Cardiol, Durham, NC USA. [Olenchock, Benjamin] Brigham & Womens Hosp, Div Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA. [Price, Susanna] Royal Brompton Hosp, Div Cardiol, London SW3 6LY, England. [Price, Susanna] Royal Brompton Hosp, Div Crit Care, London SW3 6LY, England. [Goldfarb, Michael] McGill Univ, Div Cardiol, Montreal, PQ, Canada. [Barnett, Christopher F.] Univ Calif San Francisco, Div Cardiol, San Francisco, CA USA. [Barnett, Christopher F.; Newby, L. Kristin] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [Newby, L. Kristin] Duke Clin Res Inst, Durham, NC USA. [van Diepen, Sean] Univ Alberta Hosp, Div Cardiol, Edmonton, AB, Canada. [van Diepen, Sean] Univ Alberta Hosp, Div Crit Care, Edmonton, AB, Canada. RP Katz, JN (reprint author), UNC Ctr Heart & Vasc Care, 160 Dent Circle,CB 7075, Chapel Hill, NC 27599 USA. EM katzj@med.unc.edu FU Heart and Stroke Foundation; University Hospital Foundation; National Institutes of Health; Patient-Centered Outcomes Research Institute FX Dr. van Diepen has received grant support from the Heart and Stroke Foundation and the University Hospital Foundation. Dr. Newby is a consultant for BioKier, Metanomics, Merck, Roche Diagnostics, and Philips Healthcare; is a researcher for Metanomics, Sanofi, GlaxoSmithKline, and Verily (formerly Google Life Sciences); is on the data and safety monitoring board of DemeRx; is on the advisory board of MedScape/theHeart.org; has received research funding from the National Institutes of Health and the Patient-Centered Outcomes Research Institute; and has received honoraria from JACC: Basic to Translational Science and the Journal of the American Heart Association. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 79 TC 1 Z9 1 U1 3 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUL 5 PY 2016 VL 68 IS 1 BP 67 EP 79 DI 10.1016/j.jacc.2016.04.036 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DP5IB UT WOS:000378528400011 PM 27364053 ER PT J AU Sakamuri, SSVP Valente, AJ Siddesha, JM Delafontaine, P Siebenlist, U Gardner, JD Bysani, C AF Sakamuri, Siva S. V. P. Valente, Anthony J. Siddesha, Jalahalli M. Delafontaine, Patrice Siebenlist, Ulrich Gardner, Jason D. Bysani, Chandrasekar TI TRAF3IP2 mediates aldosterone/salt-induced cardiac hypertrophy and fibrosis SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE RAAS; Aldosterone; TRAF3IP2; CIKS; Act1; Cardiac fibrosis; Cardiac hypertrophy ID LEFT-VENTRICULAR HYPERTROPHY; ACTIVATED PROTEIN-KINASE; ANGIOTENSIN-II; HEART-FAILURE; DIASTOLIC DYSFUNCTION; MYOCARDIAL-INFARCTION; FIBROBLAST MIGRATION; OXIDATIVE STRESS; RECEPTOR; EXPRESSION AB Aberrant activation of the renin-angiotensin-aldosterone system (RAAS) contributes to adverse cardiac remodeling and eventual failure. Here we investigated whether TRAF3 Interacting Protein 2 (TRAF3IP2), a redox-sensitive cytoplasmic adaptor molecule and an upstream regulator of nuclear factor-kappa B (NF-kappa B) and activator protein-1 (AP-1), mediates aldosterone-induced cardiac hypertrophy and fibrosis. Wild type (WT) and TRAF3IP2-null mice were infused with aldosterone (0.2 mg/kg/day) for 4 weeks along with 1%NaCl in drinking water. Aldosterone/salt, but not salt alone, upregulated TRAF3IP2 expression in WT mouse hearts. Further, aldosterone elevated blood pressure to a similar extent in both WT and TRAF3IP2-null groups. However, TRAF3IP2 gene deletion attenuated aldosterone/salt-induced (i) p65 and c-Jun activation, (ii) extracellular matrix (collagen I alpha 1 and collagen III alpha 1), matrix metalloproteinase (MMP2), lysyl oxidase (LOX), inflammatory cytokine (IL-6 and IL-18), chemokine (CXCL1 and CXCL2), and adhesion molecule (ICAM1) mRNA expression in hearts, (iii) IL-6, IL-18, and MMP2 protein levels, (iv) systemic IL-6 and IL-18 levels, and (iv) cardiac hypertrophy and fibrosis. These results indicate that TRAF3IP2 is a critical signaling intermediate in aldosterone/salt-induced myocardial hypertrophy and fibrosis, and thus a potential therapeutic target in hypertensive heart disease. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Sakamuri, Siva S. V. P.; Siddesha, Jalahalli M.; Delafontaine, Patrice; Bysani, Chandrasekar] Tulane Univ, Sch Med, Inst Heart & Vasc, New Orleans, LA 70112 USA. [Valente, Anthony J.] Univ Texas Hlth Sci Ctr San Antonio, Med, San Antonio, TX 78229 USA. [Siebenlist, Ulrich] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Gardner, Jason D.] Louisiana State Univ, Hlth Sci Ctr, Physiol, New Orleans, LA 70112 USA. [Sakamuri, Siva S. V. P.] Univ Alberta, Dept Physiol, Edmonton, AB T6G 2S2, Canada. [Siddesha, Jalahalli M.] Univ Vermont, Lab Pathol & Med, Burlington, VT 05405 USA. [Delafontaine, Patrice; Bysani, Chandrasekar] Univ Missouri, Sch Med, Dept Med, Columbia, MO 65212 USA. [Bysani, Chandrasekar] Harry S Truman Mem Vet Hosp, Res Serv, Columbia, MO 65212 USA. RP Bysani, C (reprint author), Harry S Truman Mem Vet Hosp, Res Serv, 800 Hosp Dr, Columbia, MO 65201 USA. EM chandrasekarb@health.missouri.edu OI Delafontaine, Patrice/0000-0003-3744-3617 FU Department of Veterans Affairs; VA Office of Research and Development Biomedical Laboratory Research and Development Service [I01-BX002255]; NIH/NHLBI [HL-86787]; NHLBI [HL-70241, HL-80682]; NIH/NIAID FX BC is a recipient of the Department of Veterans Affairs Research Career Scientist award and is supported by VA Office of Research and Development Biomedical Laboratory Research and Development Service Award I01-BX002255 and the NIH/NHLBI grant HL-86787. PD is supported by NHLBI grants HL-70241 and HL-80682. US is supported by the Intramural Research Program of the NIH/NIAID. The contents of this report do not represent the views of the Department of Veterans Affairs or the United States government. NR 40 TC 1 Z9 1 U1 0 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD JUL 5 PY 2016 VL 429 IS C BP 84 EP 92 DI 10.1016/j.mce.2016.03.038 PG 9 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA DN1CI UT WOS:000376803500009 PM 27040306 ER PT J AU Zhou, B Yu, PP Lin, MY Sun, T Chen, YM Sheng, ZH AF Zhou, Bing Yu, Panpan Lin, Mei-Yao Sun, Tao Chen, Yanmin Sheng, Zu-Hang TI Facilitation of axon regeneration by enhancing mitochondrial transport and rescuing energy deficits SO JOURNAL OF CELL BIOLOGY LA English DT Article ID RETINAL GANGLION-CELLS; SPINAL-CORD-INJURY; WALLERIAN DEGENERATION; NERVE REGENERATION; CORTICAL-NEURONS; GROWTH; GUIDANCE; SURVIVAL; PROTEIN; WLD(S) AB Although neuronal regeneration is a highly energy-demanding process, axonal mitochondria! transport progressively declines with maturation. Mature neurons typically fail to regenerate after injury, thus raising a fundamental question as to whether mitochondrial transport is necessary to meet enhanced metabolic requirements during regeneration. Here, we reveal that reduced mitochondrial motility and energy deficits in injured axons are intrinsic mechanisms controlling regrowth in mature neurons. Axotomy induces acute mitochondria! depolarization and ATP depletion in injured axons. Thus, mature neuron-associated increases in mitochondria-anchoring protein syntaphilin (SNPH) and decreases in mitochondrial transport cause local energy deficits. Strikingly, enhancing mitochondria! transport via genetic manipulation facilitates regenerative capacity by replenishing healthy mitochondria in injured axons, thereby rescuing energy deficits. An in vivo sciatic nerve crush study further shows that enhanced mitochondrial transport in snph knockout mice accelerates axon regeneration. Understanding deficits in mitochondria! trafficking and energy supply in injured axons of mature neurons benefits development of new strategies to stimulate axon regeneration. C1 [Zhou, Bing; Lin, Mei-Yao; Sun, Tao; Chen, Yanmin; Sheng, Zu-Hang] NINDS, Synapt Funct Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. [Yu, Panpan] Jinan Univ, Guangdong Hong Kong Macau Inst CNS Regenerat, Joint Int Res Lab CNS Regenerat, Minist Educ, Guangzhou 510632, Guangdong, Peoples R China. RP Sheng, ZH (reprint author), NINDS, Synapt Funct Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. EM shengz@ninds.nih.gov FU NIH [ZIA NS003029, ZIA NS002946]; Intramural Research Program of NINDS FX The work was supported by the Intramural Research Program of NINDS and NIH ZIA NS003029 and ZIA NS002946 (to Z.-H. Sheng). NR 65 TC 8 Z9 8 U1 10 U2 14 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD JUL 4 PY 2016 VL 214 IS 1 BP 103 EP 119 DI 10.1083/jcb.201605101 PG 17 WC Cell Biology SC Cell Biology GA DQ5ZJ UT WOS:000379283500012 PM 27268498 ER PT J AU Shao, W Shan, JG Kearney, MF Wu, XL Maldarelli, F Mellors, JW Luke, B Coffin, JM Hughes, SH AF Shao, Wei Shan, Jigui Kearney, Mary F. Wu, Xiaolin Maldarelli, Frank Mellors, John W. Luke, Brian Coffin, John M. Hughes, Stephen H. TI Retrovirus Integration Database (RID): a public database for retroviral insertion sites into host genomes SO RETROVIROLOGY LA English DT Article DE Retrovirus; HIV; Integration site; Database; Integration site assay; ISA; Expanded clones ID HIV-1 INTEGRATION; GENES; CELLS; DNA; VIRUS; ENHANCERS; SELECTION; SEQUENCE; THERAPY; TARGETS AB The NCI Retrovirus Integration Database is a MySql-based relational database created for storing and retrieving comprehensive information about retroviral integration sites, primarily, but not exclusively, HIV-1. The database is accessible to the public for submission or extraction of data originating from experiments aimed at collecting information related to retroviral integration sites including: the site of integration into the host genome, the virus family and subtype, the origin of the sample, gene exons/introns associated with integration, and proviral orientation. Information about the references from which the data were collected is also stored in the database. Tools are built into the website that can be used to map the integration sites to UCSC genome browser, to plot the integration site patterns on a chromosome, and to display provirus LTRs in their inserted genome sequence. The website is robust, user friendly, and allows users to query the database and analyze the data dynamically. C1 [Shao, Wei; Shan, Jigui; Luke, Brian] FNLCR, Leidos Biomed Res Inc, Adv Biomed Comp Ctr, Frederick, MD USA. [Kearney, Mary F.; Maldarelli, Frank; Hughes, Stephen H.] NCI, HIV Dynam & Replicat Program, Frederick, MD 21701 USA. [Wu, Xiaolin] Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, Frederick, MD 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), FNLCR, Leidos Biomed Res Inc, Adv Biomed Comp Ctr, Frederick, MD USA. EM shaow@mail.nih.gov FU NCI CCR; Office of AIDS Research, NIH; NCI [HHSN261200800001E] FX We acknowledge the funding sources for this study from NCI CCR, the Office of AIDS Research, NIH, and NCI Contract No. HHSN261200800001E. NR 20 TC 1 Z9 1 U1 3 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD JUL 4 PY 2016 VL 13 AR 47 DI 10.1186/s12977-016-0277-6 PG 9 WC Virology SC Virology GA DQ5TL UT WOS:000379267800001 PM 27377064 ER PT J AU Louis, JM Roche, J AF Louis, John M. Roche, Julien TI Evolution under Drug Pressure Remodels the Folding Free-Energy Landscape of Mature HIV-1 Protease SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE HIV protease; drug resistance; protein folding landscape; high-pressure NMR; calorimetry ID CLINICAL INHIBITORS; RESISTANT MUTANT; NMR-SPECTROSCOPY; MUTATIONS; DYNAMICS; SIMULATIONS; STABILITY; VARIANTS; PROTEINS; MONOMER AB Using high-pressure NMR spectroscopy and differential scanning calorimetry, we investigate the folding landscape of the mature HIV-1 protease homodimer. The cooperativity of unfolding was measured in the absence or presence of a symmetric active site inhibitor for the optimized wild type protease (PR), its inactive variant PRD25N, and an extremely multidrug-resistant mutant, PR20. The individual fit of the pressure denaturation profiles gives rise to first order, Delta G(NMR), and second order, Delta V-NMR (the derivative of Delta G(NMR) with pressure); apparent thermodynamic parameters for each amide proton considered. Heterogeneity in the apparent Delta V-NMR values reflects departure from an ideal cooperative unfolding transition. The narrow to broad distribution of Delta V-NMR spanning the extremes from inhibitor-free PR20(D25N) to PR-DMP323 complex, and distinctively for PRD25N-DMP323 complex, indicated large variations in folding cooperativity. Consistent with this data, the shape of thermal unfolding transitions varies from asymmetric for PR to nearly symmetric for PR20, as dimer-inhibitor ternary complexes. Lack of structural cooperativity was observed between regions located close to the active site, including the hinge and tip of the glycine-rich flaps, and the rest of the protein. These results strongly suggest that inhibitor binding drastically decreases the cooperativity of unfolding by trapping the closed flap conformation in a deep energy minimum. To evade this conformational trap, PR20 evolves exhibiting a smoother folding landscape with nearly an ideal two-state (cooperative) unfolding transition. This study highlights the malleability of retroviral protease folding pathways by illustrating how the selection of mutations under drug pressure remodels the free-energy landscape as a primary mechanism. Published by Elsevier Ltd. C1 [Louis, John M.; Roche, Julien] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Roche, Julien] Iowa State Univ, Roy J Carver Dept Biochem Biophys & Mol Biol, Ames, IA 50011 USA. RP Louis, JM; Roche, J (reprint author), NIDDK, LCP, NIH, Bldg 5,Room B1-27, Bethesda, MD 20892 USA. EM johnl@niddk.nih.gov; julien.roche@nih.gov FU Intramural Research Program of the NIDDK, National Institutes of Health; Intramural AIDS-Targeted Program of the Office of the Director, NIH FX We thank Hoi Sung Chung and Jane M. Sayer for discussions, Annie Aniana for technical assistance, and Ad Bax for critical review of the work and support. This research was supported by the Intramural Research Program of the NIDDK, National Institutes of Health, and the Intramural AIDS-Targeted Program of the Office of the Director, NIH. Clinical protease inhibitor daruvanir was obtained through the NIH AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH. We acknowledge the use of the NIDDK Advanced Mass Spectrometry Core Facility. NR 48 TC 2 Z9 2 U1 5 U2 21 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 EI 1089-8638 J9 J MOL BIOL JI J. Mol. Biol. PD JUL 3 PY 2016 VL 428 IS 13 BP 2780 EP 2792 DI 10.1016/j.jmb.2016.05.005 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DQ1JY UT WOS:000378958500009 PM 27170547 ER PT J AU Farmer, C Golden, C Thurm, A AF Farmer, Cristan Golden, Christine Thurm, Audrey TI Concurrent validity of the differential ability scales, second edition with the Mullen Scales of Early Learning in young children with and without neurodevelopmental disorders SO CHILD NEUROPSYCHOLOGY LA English DT Article DE IQ; Mullen Scales of Early Learning; Cognitive testing; DAS-II; Developmental quotient; Autism ID AUTISM SPECTRUM DISORDERS; INTELLECTUAL DISABILITIES; WISC-IV; INTELLIGENCE; PRESCHOOL; LEVEL; LIMITATIONS; DIAGNOSIS; STABILITY AB Estimates of intelligence in young children with neurodevelopmental disorders are critical for making diagnoses, in characterizing symptoms of disorders, and in predicting future outcomes. The limitations of standardized testing for children with developmental delay or cognitive impairment are well known: Tests do not exist that provide developmentally appropriate material along with norms that extend to the lower reaches of ability. Two commonly used and interchanged instruments are the Mullen Scales of Early Learning (MSEL), a test of developmental level, and the Differential Ability Scales, second edition (DAS-II), a more traditional cognitive test. We evaluated the correspondence of contemporaneous MSEL and the DAS-II scores in a mixed sample of children aged 2-10years with autism spectrum disorder (ASD), non-ASD developmental delays, and typically developing children across the full spectrum of cognitive ability. Consistent with published data on the original DAS and the MSEL, scores on the DAS-II and MSEL were highly correlated. However, curve estimation revealed large mean differences that varied as a function of the child's cognitive ability level. We conclude that interchanging MSEL and DAS-II scores without regard to the discrepancy in scores may produce misleading results in both cross-sectional and longitudinal studies of children with and without ASD, and, thus, this practice should be implemented with caution. C1 [Farmer, Cristan; Golden, Christine; Thurm, Audrey] NIH, Pediat & Dev Neurosci Branch, Bldg 10, Bethesda, MD 20892 USA. RP Thurm, A (reprint author), NIMH, Pediat & Dev Neurosci Branch, 10 Ctr Dr MSC 1255,Bldg 10,Room 1C250, Bethesda, MD 20892 USA. EM athurm@mail.nih.gov FU Intramural Program of National Institute of Mental Health of National Institutes of Health [NCT00298246, 06-M-0102] FX This work was supported by the Intramural Program of the National Institute of Mental Health of the National Institutes of Health, NCT00298246, 06-M-0102. The views expressed in this paper do not necessarily represent the views of the NIMH, NIH, HHS, or the United States Government. The authors extend their gratitude to the children and their families who volunteered their time and efforts during the research. NR 34 TC 2 Z9 2 U1 6 U2 19 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0929-7049 EI 1744-4136 J9 CHILD NEUROPSYCHOL JI Child Neuropsychol. PD JUL 3 PY 2016 VL 22 IS 5 BP 556 EP 569 DI 10.1080/09297049.2015.1020775 PG 14 WC Clinical Neurology SC Neurosciences & Neurology GA DJ0FC UT WOS:000373876200003 PM 25833070 ER PT J AU Solomon, BD Lee, T Nguyen, AD Wolfsberg, TG AF Solomon, Benjamin D. Lee, Teresa Anh-Dao Nguyen Wolfsberg, Tyra G. TI A 2.5-year snapshot of Mendelian discovery SO MOLECULAR GENETICS & GENOMIC MEDICINE LA English DT Editorial Material ID CLINICAL GENOME; DISORDERS; DISEASE C1 [Solomon, Benjamin D.] Inova Hlth Syst, Inova Translat Med Inst, Div Med Genom, Falls Church, VA 22042 USA. [Solomon, Benjamin D.; Lee, Teresa] Inova Hlth Syst, Inova Childrens Hosp, Dept Pediat, Falls Church, VA 22042 USA. [Solomon, Benjamin D.] Virginia Commonwealth Univ, Sch Med, Dept Pediat, Richmond, VA 23298 USA. [Anh-Dao Nguyen; Wolfsberg, Tyra G.] Natl Human Genome Res Inst, Computat & Stat Genom Branch, Bethesda, MD 20892 USA. RP Solomon, BD (reprint author), Inova Hlth Syst, Inova Translat Med Inst, Div Med Genom, Falls Church, VA 22042 USA.; Solomon, BD (reprint author), Inova Hlth Syst, Inova Childrens Hosp, Dept Pediat, Falls Church, VA 22042 USA.; Solomon, BD (reprint author), Virginia Commonwealth Univ, Sch Med, Dept Pediat, Richmond, VA 23298 USA. FU Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health FX This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, the National Institutes of Health. NR 12 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2324-9269 J9 MOL GENET GENOM MED JI Mol. Genet. Genom. Med. PD JUL PY 2016 VL 4 IS 4 BP 392 EP 394 DI 10.1002/mgg3.221 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA EL2KX UT WOS:000394449700003 PM 27468415 ER PT J AU Tobe, R Carlson, BA Huh, JH Castro, NP Xu, XM Tsuji, PA Lee, SG Bang, J Na, JW Kong, YY Beaglehole, D Southon, E Seifried, H Tessarollo, L Salomon, DS Schweizer, U Gladyshev, VN Hatfield, DL Lee, BJ AF Tobe, Ryuta Carlson, Bradley A. Huh, Jang Hoe Castro, Nadia P. Xu, Xue-Ming Tsuji, Petra A. Lee, Sang-Goo Bang, Jeyoung Na, Ji-Woon Kong, Young-Yun Beaglehole, Daniel Southon, Eileen Seifried, Harold Tessarollo, Lino Salomon, David S. Schweizer, Ulrich Gladyshev, Vadim N. Hatfield, Dolph L. Lee, Byeong Jae TI Selenophosphate synthetase 1 is an essential protein with roles in regulation of redox homoeostasis in mammals SO BIOCHEMICAL JOURNAL LA English DT Article DE cancer; reactive oxygen species (ROS); redox regulation; selenium; selenocysteine; selenophosphate synthetase 1 ID SELENOPROTEIN BIOSYNTHESIS; GLUTATHIONE TRANSFERASE; THIOREDOXIN REDUCTASE; GENETIC-CODE; SELENOCYSTEINE; SELENIUM; METABOLISM; EXPRESSION; DROSOPHILA; CELLS AB Selenophosphate synthetase (SPS) was initially detected in bacteria and was shown to synthesize selenophosphate, the active selenium donor. However, mammals have two SPS paralogues, which are designated SPS1 and SPS2. Although it is known that SPS2 catalyses the synthesis of selenophosphate, the function of SPS1 remains largely unclear. To examine the role of SPS1 in mammals, we generated a Sps1-knockout mouse and found that systemic SPS1 deficiency led to embryos that were clearly underdeveloped by embryonic day (E)8.5 and virtually resorbed by E14.5. The knockout of Sps1 in the liver preserved viability, but significantly affected the expression of a large number of mRNAs involved in cancer, embryonic development and the glutathione system. Particularly notable was the extreme deficiency of glutaredoxin 1 (GLRX1) and glutathione transferase Omega 1 (GSTO1). To assess these phenotypes at the cellular level, we targeted the removal of SPS1 in F9 cells, a mouse embryonal carcinoma (EC) cell line, which affected the glutathione system proteins and accordingly led to the accumulation of hydrogen peroxide in the cell. Furthermore, we found that several malignant characteristics of SPS1-deficient F9 cells were reversed, suggesting that SPS1 played a role in supporting and/or sustaining cancer. In addition, the overexpression of mouse or human GLRX1 led to a reversal of observed increases in reactive oxygen species (ROS) in the F9 SPS1/GLRX1-deficient cells and resulted in levels that were similar to those in F9 SPS1-sufficient cells. The results suggested that SPS1 is an essential mammalian enzyme with roles in regulating redox homoeostasis and controlling cell growth. C1 [Tobe, Ryuta; Carlson, Bradley A.; Xu, Xue-Ming; Beaglehole, Daniel; Hatfield, Dolph L.] NIH, Mol Biol Selenium, Mouse Canc Genet Program, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. [Huh, Jang Hoe; Bang, Jeyoung; Na, Ji-Woon; Kong, Young-Yun; Lee, Byeong Jae] Seoul Natl Univ, Sch Biol Sci, Seoul 151742, South Korea. [Castro, Nadia P.; Salomon, David S.] NIH, Tumor Growth Factor Sect, Mouse Canc Genet Program, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. [Tsuji, Petra A.] Towson Univ, Dept Biol Sci, Towson, MD 21252 USA. [Lee, Sang-Goo; Gladyshev, Vadim N.] Harvard Med Sch, Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Southon, Eileen] NCI Frederick, Basic Sci Program, SAIC Frederick, Frederick, MD 21702 USA. [Seifried, Harold] NCI, Nutr Sci Res Grp, Bethesda, MD 20892 USA. [Tessarollo, Lino] NIH, Neural Dev Sect, Mouse Canc Genet Program, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. [Schweizer, Ulrich] Rhein Friedrich Wilhelms Univ Bonn, Inst Biochem & Mol Biol, D-53115 Bonn, Germany. [Xu, Xue-Ming] Genecopoeia Inc, 9620 Med Ctr Dr 101, Rockville, MD 20850 USA. RP Hatfield, DL (reprint author), NIH, Mol Biol Selenium, Mouse Canc Genet Program, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA.; Lee, BJ (reprint author), Seoul Natl Univ, Sch Biol Sci, Seoul 151742, South Korea. EM hatfield@mail.nih.gov; imbglmg@snu.ac.kr OI Schweizer, Ulrich/0000-0003-1380-4780 FU Basic Science Research Program through National Research Foundation of Korea (NRF) - Ministry of Education [2015R1D1A1A01059170]; Bio & Medical Technology Development Program of the National Research Foundation (NRF); Ministry of Science [2012M3A9D1054622]; Intramural Research Program of the National Institutes of Health; National Institutes of Health [CA080946, GM061603, GM065204]; National Cancer Institute Center for Cancer Research; Deutsche Forschungsgemeinschaft (DFG) [SCHW914/2-1]; Towson University's Jess and Mildred Fisher College of Science and Mathematics Endowed Chair FX This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education [grant number 2015R1D1A1A01059170]; the Bio & Medical Technology Development Program of the National Research Foundation (NRF), awarded by the Ministry of Science [grant number 2012M3A9D1054622 (to B.J.L.)]; the Intramural Research Program of the National Institutes of Health; the National Institutes of Health [grant numbers CA080946, GM061603 and GM065204 (to V.N.G.)]; the National Cancer Institute Center for Cancer Research (to D.L.H., D.S.S. and L.T.); the Deutsche Forschungsgemeinschaft (DFG) [grant number SCHW914/2-1 (to U.S.)]; and the Towson University's Jess and Mildred Fisher College of Science and Mathematics Endowed Chair (to P.A.T.). NR 46 TC 0 Z9 0 U1 1 U2 1 PU PORTLAND PRESS LTD PI LONDON PA CHARLES DARWIN HOUSE, 12 ROGER STREET, LONDON WC1N 2JU, ENGLAND SN 0264-6021 EI 1470-8728 J9 BIOCHEM J JI Biochem. J. PD JUL PY 2016 VL 473 BP 2141 EP 2154 DI 10.1042/BCJ20160393 PN 14 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EK1TA UT WOS:000393707500014 PM 27208177 ER PT J AU Shen, HM Li, Z AF Shen, Hongmei Li, Zheng TI miRNAs in NMDA receptor-dependent synaptic plasticity and psychiatric disorders SO CLINICAL SCIENCE LA English DT Review DE miRNA; NMDA receptor; psychiatric disorders; synaptic plasticity ID LONG-TERM DEPRESSION; GLUTAMATE METABOTROPIC RECEPTORS; AUTISM SPECTRUM DISORDERS; 22Q11.2 DELETION SYNDROME; ADULT-MOUSE FOREBRAIN; COPY-NUMBER VARIATION; HIPPOCAMPAL-NEURONS; GENE-EXPRESSION; MICRORNA TARGETS; MORPHOLOGICAL PLASTICITY AB The identification and functional delineation of miRNAs (a class of small non-coding RNAs) have added a new layer of complexity to our understanding of the molecular mechanisms underlying synaptic plasticity. Genome-wide association studies in conjunction with investigations in cellular and animal models, moreover, provide evidence that miRNAs are involved in psychiatric disorders. In the present review, we examine the current knowledge about the roles played by miRNAs in NMDA (N-methyl-D-aspartate) receptor-dependent synaptic plasticity and psychiatric disorders. C1 [Shen, Hongmei; Li, Zheng] NIMH, Sect Synapse Dev & Plast, NIH, Bethesda, MD 20892 USA. RP Li, Z (reprint author), NIMH, Sect Synapse Dev & Plast, NIH, Bethesda, MD 20892 USA. EM lizheng2@mail.nih.gov NR 124 TC 0 Z9 0 U1 1 U2 1 PU PORTLAND PRESS LTD PI LONDON PA CHARLES DARWIN HOUSE, 12 ROGER STREET, LONDON WC1N 2JU, ENGLAND SN 0143-5221 EI 1470-8736 J9 CLIN SCI JI Clin. Sci. PD JUL 1 PY 2016 VL 130 IS 14 BP 1137 EP 1146 DI 10.1042/CS20160046 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EK2MI UT WOS:000393761000001 PM 27252401 ER PT J AU Drelon, C Berthon, A Mathieu, M Ragazzon, B Kuick, R Tabbal, H Septier, A Rodriguez, S Batisse-Lignier, M Sahut-Barnola, I Dumontet, T Pointud, JC Lefrancois-Martinez, AM Baron, S Giordano, TJ Bertherat, J Martinez, A Val, P AF Drelon, Coralie Berthon, Annabel Mathieu, Mickael Ragazzon, Bruno Kuick, Rork Tabbal, Houda Septier, Amandine Rodriguez, Stephanie Batisse-Lignier, Marie Sahut-Barnola, Isabelle Dumontet, Typhanie Pointud, Jean-Christophe Lefrancois-Martinez, Anne-Marie Baron, Silvere Giordano, Thomas J. Bertherat, Jerome Martinez, Antoine Val, Pierre TI EZH2 is overexpressed in adrenocortical carcinoma and is associated with disease progression SO HUMAN MOLECULAR GENETICS LA English DT Article ID HISTONE METHYLTRANSFERASE EZH2; BETA-CATENIN; PROSTATE-CANCER; PRB-E2F PATHWAY; GENE-EXPRESSION; TUMORS; CELLS; METHYLATION; ACTIVATION; REVEALS AB Adrenal Cortex Carcinoma (ACC) is an aggressive tumour with poor prognosis. Common alterations in patients include constitutive WNT/beta-catenin signalling and overexpression of the growth factor IGF2. However, the combination of both alterations in transgenic mice is not sufficient to trigger malignant tumour progression, suggesting that other alterations are required to allow development of carcinomas. Here, we have conducted a study of publicly available gene expression data from three cohorts of ACC patients to identify relevant alterations. Our data show that the histone methyltransferase EZH2 is overexpressed in ACC in the three cohorts. This overexpression is the result of deregulated P53/RB/E2F pathway activity and is associated with increased proliferation and poorer prognosis in patients. Inhibition of EZH2 by RNA interference or pharmacological treatment with DZNep inhibits cellular growth, wound healing and clonogenic growth and induces apoptosis of H295R cells in culture. Further growth inhibition is obtained when DZNep is combined with mitotane, the gold-standard treatment for ACC. Altogether, these observations suggest that overexpression of EZH2 is associated with aggressive progression and may constitute an interesting therapeutic target in the context of ACC. C1 [Drelon, Coralie; Berthon, Annabel; Mathieu, Mickael; Tabbal, Houda; Septier, Amandine; Rodriguez, Stephanie; Batisse-Lignier, Marie; Sahut-Barnola, Isabelle; Dumontet, Typhanie; Pointud, Jean-Christophe; Lefrancois-Martinez, Anne-Marie; Baron, Silvere; Martinez, Antoine; Val, Pierre] Clermont Univ, INSERM, U1103, CNRS,GReD,UMR6293, F-63001 Clermont Ferrand, France. [Berthon, Annabel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. [Ragazzon, Bruno; Bertherat, Jerome] Univ Paris 05, INSERM, U1016, Inst Cochin,CNRS,UMR 8104, Paris, France. [Kuick, Rork] Univ Michigan Hlth Syst, Dept Biostat, Ann Arbor, MI 48109 USA. [Batisse-Lignier, Marie] Ctr Hosp Univ, Fac Med, Serv Endocrinol, F-63000 Clermont Ferrand, France. [Giordano, Thomas J.] Univ Michigan Hlth Syst, Dept Pathol, Ann Arbor, MI 48109 USA. RP Val, P (reprint author), GReD, CNRS, UMR 6293, 24 Ave Landais, F-63171 Aubiere, France. EM pierre.val@univ-bpclermont.fr RI Ragazzon, Bruno/E-6541-2017 OI Ragazzon, Bruno/0000-0001-9476-4973 FU Centre National de la Recherche Scientifique; Institut National de la Sante et de la Recherche Medicale; Universite Blaise Pascal; Universite d'Auvergne; Fondation de France; La Ligue Contre le Cancer (Allier & Puy de Dome committees); Fondation ARC [PJA20141201894]; Societe Francaise d'Endocrinologie; University of Michigan Cancer Center [P30-CA046592] FX This work was supported by institutional support from Centre National de la Recherche Scientifique, Institut National de la Sante et de la Recherche Medicale, Universite Blaise Pascal, Universite d'Auvergne and through grants from Fondation de France, La Ligue Contre le Cancer (Allier & Puy de Dome committees), Fondation ARC (PJA20141201894), Societe Francaise d'Endocrinologie (young researcher grant to C.D. and Researcher Prize to P.V.) and University of Michigan Cancer Center Support Grant P30-CA046592 (NIH to R.K. and T.J.G.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the article. NR 51 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JUL 1 PY 2016 VL 25 IS 13 BP 2789 EP 2800 DI 10.1093/hmg/ddw136 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA EJ2TP UT WOS:000393064400014 PM 27149985 ER PT J AU Leslie, EJ Carlson, JC Shaffer, JR Feingold, E Wehby, G Laurie, CA Jain, D Laurie, CC Doheny, KF McHenry, T Resick, J Sanchez, C Jacobs, J Emanuele, B Vieira, AR Neiswanger, K Lidral, AC Valencia-Ramirez, LC Lopez-Palacio, AM Valencia, DR Arcos-Burgos, M Czeizel, AE Field, LL Padilla, CD Maria, E Cutiongco-de la Paz, C Deleyiannis, F Christensen, K Munger, RG Lie, RT Wilcox, A Romitti, PA Castilla, EE Mereb, JC Poletta, FA Orioli, IM Carvalho, FM Hecht, JT Blanton, SH Buxo, CJ Butali, A Mossey, PA Adeyemo, WL James, O Braimah, RO Aregbesola, BS Eshete, MA Abate, F Koruyucu, M Seymen, F Ma, L de Salamanca, JE Weinberg, SM Moreno, L Murray, JC Marazita, ML AF Leslie, Elizabeth J. Carlson, Jenna C. Shaffer, John R. Feingold, Eleanor Wehby, George Laurie, Cecelia A. Jain, Deepti Laurie, Cathy C. Doheny, Kimberly F. McHenry, Toby Resick, Judith Sanchez, Carla Jacobs, Jennifer Emanuele, Beth Vieira, Alexandre R. Neiswanger, Katherine Lidral, Andrew C. Consuelo Valencia-Ramirez, Luz Maria Lopez-Palacio, Ana Rivera Valencia, Dora Arcos-Burgos, Mauricio Czeizel, Andrew E. Field, L. Leigh Padilla, Carmencita D. Maria, Eva Cutiongco-de la Paz, C. Deleyiannis, Frederic Christensen, Kaare Munger, Ronald G. Lie, Rolv T. Wilcox, Allen Romitti, Paul A. Castilla, Eduardo E. Mereb, Juan C. Poletta, Fernando A. Orioli, Ieda M. Carvalho, Flavia M. Hecht, Jacqueline T. Blanton, Susan H. Buxo, Carmen J. Butali, Azeez Mossey, Peter A. Adeyemo, Wasiu L. James, Olutayo Braimah, Ramat O. Aregbesola, Babatunde S. Eshete, Mekonen A. Abate, Fikre Koruyucu, Mine Seymen, Figen Ma, Lian Enriquez de Salamanca, Javier Weinberg, Seth M. Moreno, Lina Murray, Jeffrey C. Marazita, Mary L. TI A multi-ethnic genome-wide association study identifies novel loci for non-syndromic cleft lip with or without cleft palate on 2p24.2, 17q23 and 19q13 SO HUMAN MOLECULAR GENETICS LA English DT Article ID SUSCEPTIBILITY LOCUS; CAUSE VAN; GENE; RISK; POPULATION; EXPRESSION; MUTATIONS; VARIANTS; CANCER; ENDOTHELIN-1 AB Orofacial clefts (OFCs), which include non-syndromic cleft lip with or without cleft palate (CL/P), are among the most common birth defects in humans, affecting approximately 1 in 700 newborns. CL/P is phenotypically heterogeneous and has a complex etiology caused by genetic and environmental factors. Previous genome-wide association studies (GWASs) have identified at least 15 risk loci for CL/P. As these loci do not account for all of the genetic variance of CL/P, we hypothesized the existence of additional risk loci. We conducted am ultiethnic GWAS in 6480 participants (823 unrelated cases, 1700 unrelated controls and 1319 case-parent trios) with European, Asian, African and Central and South American ancestry. Our GWAS revealed novel associations on 2p24 near FAM49A, a gene of unknown function (P = 4.22 x 10(-8)), and 19q13 near RHPN2, a gene involved in organizing the actin cytoskeleton (P = 4.17 x 10(-8)). Other regions reaching genome-wide significance were 1p36 (PAX7), 1p22 (ARHGAP29), 1q32 (IRF6), 8q24 and 17p13 (NTN1), all reported in previous GWASs. Stratification by ancestry group revealed a novel association with a region on 17q23 (P = 2.92 x 10(-8)) among individuals with European ancestry. This region included several promising candidates including TANC2, an oncogene required for development, and DCAF7, a scaffolding protein required for craniofacial development. In the Central and South American ancestry group, significant associations with loci previously identified in Asian or European ancestry groups reflected their admixed ancestry. In summary, we have identified novel CL/P risk loci and suggest new genes involved in craniofacial development, confirming the highly heterogeneous etiology of OFCs. C1 [Leslie, Elizabeth J.; Carlson, Jenna C.; Shaffer, John R.; Feingold, Eleanor; McHenry, Toby; Resick, Judith; Sanchez, Carla; Jacobs, Jennifer; Emanuele, Beth; Vieira, Alexandre R.; Neiswanger, Katherine; Weinberg, Seth M.; Marazita, Mary L.] Univ Pittsburgh, Ctr Craniofacial & Dent Genet, Dept Oral Biol, Sch Dent Med, Pittsburgh, PA 15219 USA. [Carlson, Jenna C.; Feingold, Eleanor] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. [Shaffer, John R.; Feingold, Eleanor; Vieira, Alexandre R.; Marazita, Mary L.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA. [Wehby, George] Univ Iowa, Coll Publ Hlth, Dept Hlth Management & Policy, Iowa City, IA 52246 USA. [Laurie, Cecelia A.; Jain, Deepti; Laurie, Cathy C.] Univ Washington, Dept Biostat, Genet Coordinating Ctr, Seattle, WA 98195 USA. [Doheny, Kimberly F.] Johns Hopkins Univ, Ctr Inherited Dis Res, Baltimore, MD 21224 USA. [Lidral, Andrew C.; Moreno, Lina] Univ Iowa, Dept Orthodont, Coll Publ Hlth, Iowa City, IA 52242 USA. [Romitti, Paul A.] Univ Iowa, Dept Epidemiol, Coll Publ Hlth, Iowa City, IA 52242 USA. [Butali, Azeez; Marazita, Mary L.] Univ Iowa, Coll Dent, Dept Oral Pathol Radiol & Med, Dows Inst Dent Res, Iowa City, IA 52242 USA. [Murray, Jeffrey C.] Univ Iowa, Dept Pediat, Carver Coll Med, Iowa City, IA 52242 USA. [Consuelo Valencia-Ramirez, Luz] Fdn Clin Noel, Medellin 050012, Colombia. [Maria Lopez-Palacio, Ana] Univ Antioquia, Dept Basic Integrated Studies, Coll Dent, Medellin 050001, Colombia. [Rivera Valencia, Dora] Univ Antioquia, Populat Genet & Mutacarcinogenesis Grp, Medellin 050001, Colombia. [Arcos-Burgos, Mauricio] Australian Natl Univ, ANU Coll Med Biol & Environm, John Curtin Sch Med Res, Genom & Predict Med,Genome Biol Dept, Canberra, ACT 0200, Australia. [Czeizel, Andrew E.] Fdn Community Control Hereditary Dis, H-1051 Budapest, Hungary. [Field, L. Leigh] Univ British Columbia, Dept Med Genet, Vancouver, BC V6H 3N1, Canada. [Padilla, Carmencita D.; Cutiongco-de la Paz, C.] Coll Med, Dept Pediat, Manila 1000, Philippines. [Padilla, Carmencita D.; Cutiongco-de la Paz, C.] Natl Inst Hlth, Inst Human Genet, Manila 1000, Philippines. [Padilla, Carmencita D.; Cutiongco-de la Paz, C.] Univ Philippines Manila, Manila 1000, Philippines. [Padilla, Carmencita D.; Cutiongco-de la Paz, C.] Univ Philippines Syst, Philippine Genome Ctr, Manila 1101, Philippines. [Deleyiannis, Frederic] Univ Colorado, Dept Surg Plast & Reconstruct Surg, Sch Med, Denver, CO 80045 USA. [Christensen, Kaare] Univ Southern Denmark, Dept Epidemiol, Inst Publ Hlth, DK-5230 Odense, Denmark. [Munger, Ronald G.] Utah State Univ, Dept Nutr Dietet & Food Sci, Logan, UT 84322 USA. [Lie, Rolv T.] Univ Bergen, Dept Global Publ Hlth & Primary Care, NO-5020 Bergen, Norway. [Wilcox, Allen] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Castilla, Eduardo E.; Poletta, Fernando A.] CEMIC Ctr Med Educ & Clin Res, RA-1431 Buenos Aires, DF, Argentina. [Castilla, Eduardo E.; Poletta, Fernando A.; Carvalho, Flavia M.] Fiocruz MS, Inst Oswaldo Cruz, Lab Congenital Malformat Epidemiol, BR-21040360 Rio De Janeiro, Brazil. [Castilla, Eduardo E.; Poletta, Fernando A.; Orioli, Ieda M.; Carvalho, Flavia M.] Univ Fed Rio de Janeiro, ECLAMC Latin Amer Collaborat Study Congenital Mal, INAGEMP Natl Inst Populat Med Genet, BR-21941617 Rio De Janeiro, Brazil. [Orioli, Ieda M.] Univ Fed Rio de Janeiro, Dept Genet, Inst Biol, BR-21941617 Rio De Janeiro, Brazil. [Mereb, Juan C.] Hosp Area, ECLAMC Latin Amer Collaborat Study Congenital Mal, RA-8430 El Bolson, Argentina. [Hecht, Jacqueline T.] Univ Texas Hlth Sci Ctr Houston, Dept Pediat, Houston, TX 77030 USA. [Blanton, Susan H.] Univ Miami, Hussman Inst Human Gen, Mailman Sch Med, Dr John T Macdonald Fdn,Dept Human Genet, Coral Gables, FL 33124 USA. [Buxo, Carmen J.] Univ Puerto Rico, Sch Dent Med, San Juan, PR 00936 USA. [Mossey, Peter A.] Univ Dundee, Dept Orthodont, Dundee DD1 4HN, Scotland. [Adeyemo, Wasiu L.; James, Olutayo] Univ Lagos, Coll Med, Dept Oral & Maxillofacial Surg, PMB 12003, Lagos, Nigeria. [Braimah, Ramat O.; Aregbesola, Babatunde S.] Obafemi Awolowo Univ, Dept Oral & Maxillofacial Surg, PMB 13, Ife, Nigeria. [Eshete, Mekonen A.; Abate, Fikre] Univ Addis Ababa, Sch Med, Dept Surg, POB 26493, Addis Ababa, Ethiopia. [Koruyucu, Mine; Seymen, Figen] Istanbul Univ, Dept Pedodont, TR-34116 Istanbul, Turkey. [Ma, Lian] Peking Univ, Sch Stomatol, Beijing 100081, Peoples R China. [Enriquez de Salamanca, Javier] Hosp Infantil Univ Nino Jesus, Unidad Cirugia Plast, Madrid 28009, Spain. [Marazita, Mary L.] Univ Pittsburgh, Sch Med, Clin & Translat Sci, Pittsburgh, PA 15213 USA. RP Marazita, ML (reprint author), Suite 500 Bridgeside Point,100 Technol Dr, Pittsburgh, PA 15219 USA. EM marazita@pitt.edu OI Wilcox, Allen/0000-0002-3376-1311; Christensen, Kaare/0000-0002-5429-5292 FU National Institutes of Health [X01-HG007485, R01-DE016148, U01-DE024425, R37-DE008559, R01-DE009886, R01-DE014667, R21-DE016930, R01-DE012472, R01-DE011931, R01-DE011948, R01-DD000295, U54-MD007587]; Robert Wood Johnson Foundation, AMFDP [72429]; Research Institute of the Children's Hospital of Colorado (FWD); Institute of Human Genetics, National Institutes of Health, University of the Philippines, Manila; Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro, Brazil [E-26/102.797/2012, E-26/110.140/2013]; CNPq, Brazil [481069/2012-7, 306396/2013-0, 400427/2013-3]; Danish National Research Foundation; Pharmacy Foundation; Egmont Foundation; March of Dimes Birth Defects Foundation; Augustinus Foundation; Health Foundation; National Institute of Environmental Health Sciences/National Institutes of Health Intramural Research Program; Norwegian Research Council; The National Institutes of Health [R25-MD007607, K99-DE024571, K99/R00-DE022378, K99-DE025060, R01-DE020895, HHSN268201200008I] FX National Institutes of Health (X01-HG007485 to MLM, R01-DE016148 to M.L.M., U01-DE024425 to M.L.M, R37-DE008559 to J.C.M. and MLM, R01-DE009886 to M.L.M., R21-DE016930 to M.L.M., R01-DE014667 to A.C.L. and L.M.M., R21-DE016930 to M.L.M., R01-DE012472 to M.L.M., R01-DE011931 to J.T.H., R01-DE011948 to K.C., R01-DD000295 to G.L.W., U54-MD007587 to C.J.B., R25-MD007607 to C.J.B., K99-DE024571 to C.J.B., K99/R00-DE022378 to A.B., K99-DE025060 to E.J.L., and R01-DE020895 to G.L.W.). Genotyping and data cleaning were provided via an National Institutes of Health contract HHSN268201200008I to the Johns Hopkins Center for Inherited Disease Research. Additional support provided by: the Robert Wood Johnson Foundation, AMFDP Grant (72429 to A.B.); an intramural grant from the Research Institute of the Children's Hospital of Colorado (FWD); operating costs support in the Philippines was provided by the Institute of Human Genetics, National Institutes of Health, University of the Philippines, Manila (C.P.); grants through Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro, Brazil (I.M.O.): grant numbers (E-26/102.797/2012, E-26/110.140/2013); grants through CNPq, Brazil (I.M.O.): grant numbers: (481069/2012-7, 306396/2013-0, 400427/2013-3). Some replication samples were from the Utah Child and Family Health study (R01-DE016877 [R.G.M.]. Some replication samples were from the Danish National Birth Cohort (PIs Mads Melbye and Jorn Olsen) funded by a major grant from the Danish National Research Foundation and initiated by the Danish Epidemiology Science Centre. Additional support for the Danish National Birth Cohort was obtained from the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation, the Augustinus Foundation, and the Health Foundation. Some replication samples were from the Norwegian Cleft Study and from the Norwegian MoBa Study, both supported by the National Institute of Environmental Health Sciences/National Institutes of Health Intramural Research Program and the Norwegian Research Council. NR 52 TC 5 Z9 5 U1 1 U2 1 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 JUL 1 PY 2016 VL 25 IS 13 BP 2862 EP 2872 DI 10.1093/hmg/ddw104 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA EJ2TP UT WOS:000393064400020 PM 27033726 ER PT J AU Yale, K Tackett, AJ Neuman, M Bulley, E Chait, BT Wiley, E AF Yale, Katerina Tackett, Alan J. Neuman, Monica Bulley, Emily Chait, Brian T. Wiley, Emily TI Phosphorylation-Dependent Targeting of Tetrahymena HP1 to Condensed Chromatin SO MSPHERE LA English DT Article DE HP1; Tetrahymena; chromatin; chromodomain; ciliates; heterochromatin; protein phosphorylation ID HETEROCHROMATIN PROTEIN-1 HP1; HISTONE H3; HP1-LIKE PROTEIN; DNA ELIMINATION; SHADOW DOMAIN; DROSOPHILA-MELANOGASTER; MACRONUCLEAR ANLAGEN; GENE-EXPRESSION; CELL-CYCLE; BINDING AB The evolutionarily conserved proteins related to heterochromatin protein 1 (HP1), originally described in Drosophila, are well known for their roles in heterochromatin assembly and gene silencing. Targeting of HP1 proteins to specific chromatin locales is mediated, at least in part, by the HP1 chromodomain, which binds to histone H3 methylated at lysine 9 that marks condensed regions of the genome. Mechanisms that regulate HP1 targeting are emerging from studies with yeast and metazoans and point to roles for posttranslational modifications. Here, we report that modifications of an HP1 homolog (Hhp1) in the ciliate model Tetrahymena thermophila correlated with the physiological state and with nuclear differentiation events involving the restructuring of chromatin. Results support the model in which Hhp1 chromodomain binds lysine 27-methylated histone H3, and we show that colocalization with this histone mark depends on phosphorylation at a single Cdc2/Cdk1 kinase site in the "hinge region" adjacent to the chromodomain. These findings help elucidate important functional roles of reversible posttranslational modifications of proteins in the HP1 family, in this case, regulating the targeting of a ciliate HP1 to chromatin regions marked with methylated H3 lysine 27. IMPORTANCE Compacting the genome to various degrees influences processes that use DNA as a template, such as gene transcription and replication. This project was aimed at learning more about the cellular mechanisms that control genome compaction. Posttranslational modifications of proteins involved in genome condensation are emerging as potentially important points of regulation. To help elucidate protein modifications and how they affect the function of condensation proteins, we investigated the phosphorylation of the chromatin protein called Hhp1 in the ciliated protozoan Tetrahymena thermophila. This is one of the first functional investigations of these modifications of a nonhistone chromatin condensation protein that acts on the ciliate genome, and discoveries will aid in identifying common, evolutionarily conserved strategies that control the dynamic compaction of genomes. C1 [Yale, Katerina; Neuman, Monica; Bulley, Emily; Wiley, Emily] Pitzer, WM Keck Sci Ctr Claremont McKenna, Claremont, CA 91711 USA. [Yale, Katerina; Neuman, Monica; Bulley, Emily; Wiley, Emily] Scripps Coll, Claremont, CA 91711 USA. [Tackett, Alan J.; Chait, Brian T.] Rockefeller Univ, Lab Mass Spectrometry & Gaseous Ion Chem, 1230 York Ave, New York, NY 10021 USA. [Yale, Katerina] George Washington Univ, Sch Med & Hlth Sci, Washington, DC 63130 USA. [Tackett, Alan J.] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. [Neuman, Monica] NIH, Bethesda, MD USA. [Wiley, Emily] Univ Washington, Sch Med, Seattle, WA USA. EM ewiley@kecksci.claremont.edu FU HHS \ National Institutes of Health (NIH) [GM18785-04, GM103314]; National Science Foundation (NSF) [MCB 0545560] FX This work, including the efforts of Emily Wiley, was funded by HHS vertical bar National Institutes of Health (NIH) (GM18785-04). This work, including the efforts of Brian T. Chait, was funded by HHS vertical bar National Institutes of Health (NIH) (GM103314). This work, including the efforts of Emily Wiley, was funded by National Science Foundation (NSF) (MCB 0545560). NR 59 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2379-5042 J9 MSPHERE JI mSphere PD JUL-AUG PY 2016 VL 1 IS 4 AR e00142-16 DI 10.1128/mSphere.00142-16 PG 14 WC Microbiology SC Microbiology GA EI6DU UT WOS:000392586000010 ER PT J AU Bohon, KS Hermann, KL Hansen, T Conway, BR AF Bohon, Kaitlin S. Hermann, Katherine L. Hansen, Thorsten Conway, Bevil R. TI Representation of Perceptual Color Space in Macaque Posterior Inferior Temporal Cortex (the V4 Complex) SO ENEURO LA English DT Article DE color; macaque; monkey; neurophysiology; v4; vision ID PRIMARY VISUAL-CORTEX; LATERAL GENICULATE-NUCLEUS; UNIQUE HUES; CHROMATIC MECHANISMS; STRIATE CORTEX; AREA V4; EXTRASTRIATE CORTEX; CARDINAL DIRECTIONS; SELECTIVE CELLS; CONE SIGNALS AB The lateral geniculate nucleus is thought to represent color using two populations of cone-opponent neurons [ L vs M; S vs (L + M)], which establish the cardinal directions in color space (reddish vs cyan; lavender vs lime). How is this representation transformed to bring about color perception? Prior work implicates populations of glob cells in posterior inferior temporal cortex (PIT; the V4 complex), but the correspondence between the neural representation of color in PIT/V4 complex and the organization of perceptual color space is unclear. We compared color-tuning data for populations of glob cells and interglob cells to predictions obtained using models that varied in the color-tuning narrowness of the cells, and the color preference distribution across the populations. Glob cells were best accounted for by simulated neurons that have nonlinear (narrow) tuning and, as a population, represent a color space designed to be perceptually uniform (CIELUV). Multidimensional scaling and representational similarity analyses showed that the color space representations in both glob and interglob populations were correlated with the organization of CIELUV space, but glob cells showed a stronger correlation. Hue could be classified invariant to luminance with high accuracy given glob responses and above-chance accuracy given interglob responses. Luminance could be read out invariant to changes in hue in both populations, but interglob cells tended to prefer stimuli having luminance contrast, regardless of hue, whereas glob cells typically retained hue tuning as luminance contrast was modulated. The combined luminance/hue sensitivity of glob cells is predicted for neurons that can distinguish two colors of the same hue at different luminance levels (orange/brown). C1 [Bohon, Kaitlin S.; Hermann, Katherine L.; Conway, Bevil R.] Wellesley Coll, Program Neurosci, Wellesley, MA 02481 USA. [Bohon, Kaitlin S.; Hermann, Katherine L.; Conway, Bevil R.] MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA. [Hansen, Thorsten] Justus Liebig Univ Giessen, Dept Psychol, D-35396 Giessen, Germany. RP Conway, BR (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM bevil@mit.edu FU National Institutes of Health [EY023322]; National Science Foundation [1353571] FX This research was supported by National Institutes of Health Grant EY023322 and National Science Foundation Grant 1353571. NR 102 TC 1 Z9 1 U1 1 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 2373-2822 J9 ENEURO JI eNeuro PD JUL-AUG PY 2016 VL 3 IS 4 DI 10.1523/ENEURO.0039-16.2016 PG 28 WC Neurosciences SC Neurosciences & Neurology GA EH7BV UT WOS:000391928700005 ER PT J AU Cheng, N Jiao, S Gumaste, A Bai, L Belluscio, L AF Cheng, Ning Jiao, Song Gumaste, Ankita Bai, Li Belluscio, Leonardo TI APP Overexpression Causes A beta-Independent Neuronal Death through Intrinsic Apoptosis Pathway SO ENEURO LA English DT Article DE amyloid precursor protein; apoptosis; neurodegeneration; olfactory ID MODERATE ALZHEIMERS-DISEASE; NEURODEGENERATIVE DISEASES; PATHOLOGICAL FEATURES; AMYLOID DEPOSITION; GENE-EXPRESSION; CELL-DEATH; KINASE-II; MODEL; SECRETASE; MOUSE AB Accumulation of amyloid-beta (A beta) peptide in the brain is a central hallmark of Alzheimer's disease (AD) and is thought to be the cause of the observed neurodegeneration. Many animal models have been generated that overproduce A yet do not exhibit clear neuronal loss, questioning this A beta hypothesis. We previously developed an in vivo mouse model that expresses a humanized amyloid precursor protein (hAPP) in olfactory sensory neurons (OSNs) showing robust apoptosis and olfactory dysfunction by 3 weeks of age, which is consistent with early OSN loss and smell deficits, as observed in AD patients. Here we show, by deleting the beta-site APP cleaving enzyme 1 (BACE1) in two distinct transgenic mouse models, that hAPP-induced apoptosis of OSNs is A beta independent and remains cell autonomous. In addition, we reveal that the intrinsic apoptosis pathway is responsible for hAPP-induced OSN death, as marked by mitochondrial damage and caspase-9 activation. Given that hAPP expression causes OSN apoptosis despite the absence of BACE1, we propose that A beta is not the sole cause of hAPP-induced neurodegeneration and that the early loss of olfactory function in AD may be based on a cell-autonomous mechanism, which could mark an early phase of AD, prior to A beta accumulation. Thus, the olfactory system could serve as an important new platform to study the development of AD, providing unique insight for both early diagnosis and intervention. C1 [Cheng, Ning; Jiao, Song; Gumaste, Ankita; Bai, Li; Belluscio, Leonardo] NINDS, Dev Neural Plast Sect, NIH, 35 Convent Dr, Bethesda, MD 20892 USA. RP Belluscio, L (reprint author), NINDS, Dev Neural Plast Sect, NIH, 35 Convent Dr, Bethesda, MD 20892 USA. EM belluscl@ninds.nih.gov FU Intramural Research Program of the National Institute of Neurological Disorders and Stroke FX This research was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke. NR 46 TC 1 Z9 1 U1 1 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 2373-2822 J9 ENEURO JI eNeuro PD JUL-AUG PY 2016 VL 3 IS 4 DI 10.1523/ENEURO.0150-16.2016 PG 12 WC Neurosciences SC Neurosciences & Neurology GA EH7BV UT WOS:000391928700029 ER PT J AU Nordestgaard, BG Langsted, A Mora, S Kolovou, G Baum, H Bruckert, E Watts, GF Sypniewska, G Wiklund, O Boren, J Chapman, MJ Cobbaert, C Descamps, OS von Eckardstein, A Kamstrup, PR Pulkki, K Kronenberg, F Remaley, AT Rifai, N Ros, E Langlois, M AF Nordestgaard, Borge G. Langsted, Anne Mora, Samia Kolovou, Genovefa Baum, Hannsjorg Bruckert, Eric Watts, Gerald F. Sypniewska, Grazyna Wiklund, Olov Boren, Jan Chapman, M. John Cobbaert, Christa Descamps, Olivier S. von Eckardstein, Arnold Kamstrup, Pia R. Pulkki, Kari Kronenberg, Florian Remaley, Alan T. Rifai, Nader Ros, Emilio Langlois, Michel CA EAS European Federation Clinical Chem TI Fasting Is Not Routinely Required for Determination of a Lipid Profile: Clinical and Laboratory Implications Including Flagging at Desirable Concentration Cutpoints-A Joint Consensus Statement from the European Atherosclerosis Society and European Federation of Clinical Chemistry and Laboratory Medicine SO CLINICAL CHEMISTRY LA English DT Article ID DENSITY-LIPOPROTEIN CHOLESTEROL; ISCHEMIC-HEART-DISEASE; GENERAL-POPULATION; FAMILIAL HYPERCHOLESTEROLEMIA; NONFASTING TRIGLYCERIDES; CARDIOVASCULAR-DISEASE; ELEVATED LIPOPROTEIN(A); MYOCARDIAL-INFARCTION; REMNANT CHOLESTEROL; RISK-FACTOR AB AIMS: To critically evaluate the clinical implications of the use of non-fasting rather than fasting lipid profiles and to provide guidance for the laboratory reporting of abnormal non-fasting or fasting lipid profiles. METHODS AND RESULTS: Extensive observational data, in which random non-fasting lipid profiles have been compared with those determined under fasting conditions, indicate that the maximal mean changes at 1-6 h after habitual meals are not clinically significant [+0.3 mmol/L (26 mg/dL) for triglycerides; -0.2 mmol/L (8 mg/dL) for total cholesterol; -0.2 mmol/L (8 mg/dL) for LDL cholesterol; +0.2 mmol/L (8 mg/dL) for calculated remnant cholesterol; -0.2 mmol/L (8 mg/dL) for calculated non-HDL cholesterol]; concentrations of HDL cholesterol, apolipoprotein A1, apolipoprotein B, and lipoprotein(a) are not affected by fasting/non-fasting status. In addition, non-fasting and fasting concentrations vary similarly over time and are comparable in the prediction of cardiovascular disease. To improve patient compliance with lipid testing, we therefore recommend the routine use of non-fasting lipid profiles, whereas fasting sampling may be considered when non-fasting triglycerides are > 5 mmol/L (440 mg/dL). For non-fasting samples, laboratory reports should flag abnormal concentrations as triglycerides >= 2 mmol/L (175 mg/dL), total cholesterol >= 5 mmol/L (190 mg/dL), LDL cholesterol >= 3 mmol/L (115 mg/dL), calculated remnant cholesterol >= 0.9 mmol/L (35 mg/dL), calculated non-HDL cholesterol >= 3.9 mmol/L (150 mg/dL), HDL cholesterol <= 1 mmol/L (40 mg/dL), apolipoprotein A1 <= 1.25 g/L (125 mg/dL), apolipoprotein B >= 1.0 g/L (100 mg/dL), and lipoprotein(a) >= 50 mg/dL (80th percentile); for fasting samples, abnormal concentrations correspond to triglycerides >= 1.7 mmol/L (150 mg/dL). Life-threatening concentrations require separate referral for the risk of pancreatitis when triglycerides are >10 mmol/L (880 mg/dL), for homozygous familial hyper-cholesterolemia when LDL cholesterol is >13 mmol/L (500 mg/dL), for heterozygous familial hypercholesterol-emia when LDL cholesterol is >5 mmol/L (190 mg/dL), and for very high cardiovascular risk when lipoprotein(a) > 150 mg/dL (99th percentile). CONCLUSIONS: We recommend that non-fasting blood samples be routinely used for the assessment of plasma lipid profiles. Laboratory reports should flag abnormal values on the basis of desirable concentration cutpoints. Non-fasting and fasting measurements should be complementary but not mutually exclusive. (C) 2016 American Association for Clinical Chemistry C1 [Nordestgaard, Borge G.; Langsted, Anne; Kamstrup, Pia R.] Univ Copenhagen, Dept Clin Biochem, Herlev & Gentofte Hosp, Copenhagen Univ Hosp, Herlev, Denmark. [Mora, Samia] Harvard Med Sch, Brigham & Womens Hosp, Div Prevent Med, Boston, MA USA. [Mora, Samia] Harvard Med Sch, Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA USA. [Kolovou, Genovefa] Onassis Cardiac Surg Ctr, Dept Cardiol, Athens, Greece. [Baum, Hannsjorg] Reg Kliniken Holding RKH GmbH, Inst Lab Med Blutdepot & Krankenhaushyg, Ludwigsburg, Germany. [Bruckert, Eric] Pitie Salpetriere Univ Hosp, Paris, France. [Watts, Gerald F.] Univ Western Australia, Perth, WA, Australia. [Sypniewska, Grazyna] NC Univ, Coll Med, Dept Lab Med, Bydgoszcz, Poland. [Wiklund, Olov; Boren, Jan] Sahlgrens Univ Hosp, Gothenburg, Sweden. [Chapman, M. John] Pitie Salpetriere Univ Hosp, INSERM, U939, Paris, France. [Cobbaert, Christa] Leiden Univ, Med Ctr, Dept Clin Chem & Lab Med, Leiden, Netherlands. [Descamps, Olivier S.] Hop Jolimont, Haine St Paul, Belgium. [von Eckardstein, Arnold] Univ Zurich Hosp, Inst Clin Chem, Zurich, Switzerland. [Pulkki, Kari] Univ Eastern Finland, Dept Clin Chem, Kuopio, Finland. [Kronenberg, Florian] Med Univ Innsbruck, Dept Med Genet Mol & Clin Pharmacol, Div Genet Epidemiol, Innsbruck, Austria. [Remaley, Alan T.] NHLBI, Lipoprot Metab Sect, Cardiovasc Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Rifai, Nader] Harvard Univ, Childrens Hosp, Lab Med, Boston, MA 02115 USA. [Ros, Emilio] Hosp Clin Barcelona, Lipid Clin, Dept Endocrinol & Nutr, Inst Invest Biomed August Pi Sunyer, Barcelona, Spain. [Ros, Emilio] Inst Salud Carlos III, Ciber Fisiopatol Obesidad & Nutr, Madrid, Spain. [Langlois, Michel] Acad Hosp St Jan, Dept Lab Med, Brugge, Belgium. [Langlois, Michel] Univ Ghent, Ghent, Belgium. RP Nordestgaard, BG (reprint author), Copenhagen Univ Hosp, Dept Clin Biochem, Herlev & Gentofte Hosp, DK-2730 Herlev, Denmark. EM boerge.nordestgaard@regionh.dk RI Kronenberg, Florian/B-1736-2008 OI Kronenberg, Florian/0000-0003-2229-1120 FU Merck; Roche Diagnostics; Denka Seiken; European Atherosclerosis Society; European Federation of Clinical Chemistry and Laboratory Medicine FX Supported by unrestricted educational grants to EAS and EFLM from Merck, Roche Diagnostics, and Denka Seiken. These companies were not present at the Joint Consensus Panel meetings, had no role in the design or content of the joint consensus statement, and had no right to approve or disapprove of the final document. Funding to pay the Open Access publication charges for this article was provided by the European Atherosclerosis Society and the European Federation of Clinical Chemistry and Laboratory Medicine. NR 47 TC 5 Z9 5 U1 6 U2 6 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 EI 1530-8561 J9 CLIN CHEM JI Clin. Chem. PD JUL PY 2016 VL 62 IS 7 BP 930 EP 946 DI 10.1373/clinchem.2016.258897 PG 17 WC Medical Laboratory Technology SC Medical Laboratory Technology GA EF2CL UT WOS:000390132000009 PM 27235445 ER PT J AU Gordon, LB Kieran, MW Kleinman, ME Misteli, T AF Gordon, Leslie B. Kieran, Mark W. Kleinman, Monica E. Misteli, Tom TI The decision-making process and criteria in selecting candidate drugs for progeria clinical trials SO EMBO MOLECULAR MEDICINE LA English DT Editorial Material ID HUTCHINSON-GILFORD PROGERIA AB Hutchinson-Gilford progeria syndrome (progeria) is an extremely rare premature aging disease with a population prevalence of 1 in 20 million. Nevertheless, propelled by the discovery of a causal mutation in the lamin A/C gene (LMNA) (De Sandre-Giovannoli et al, 2003; Eriksson et al, 2003) and strong patient advocacy (Gordon & Gordon, 2014), progeria has rapidly become a vibrant field of study, attracting a wide range of researchers from basic cell biologists to clinicians. C1 [Gordon, Leslie B.; Kleinman, Monica E.] Boston Childrens Hosp, Dept Anesthesiol Perioperat & Pain Med, Boston, MA 02115 USA. [Gordon, Leslie B.; Kleinman, Monica E.] Harvard Med Sch, Boston, MA 02115 USA. [Gordon, Leslie B.] Brown Univ, Dept Pediat, Hasbro Childrens Hosp, Providence, RI 02912 USA. [Gordon, Leslie B.] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. [Kieran, Mark W.] Dana Farber Canc Inst, Dana Farber Boston Childrens Canc & Blood Disorde, Boston, MA 02115 USA. [Misteli, Tom] NCI, NIH, Bethesda, MD 20892 USA. RP Gordon, LB (reprint author), Boston Childrens Hosp, Dept Anesthesiol Perioperat & Pain Med, Boston, MA 02115 USA.; Gordon, LB (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Gordon, LB (reprint author), Brown Univ, Dept Pediat, Hasbro Childrens Hosp, Providence, RI 02912 USA.; Gordon, LB (reprint author), Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. EM leslie_gordon@brown.edu NR 8 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1757-4676 EI 1757-4684 J9 EMBO MOL MED JI EMBO Mol. Med. PD JUL PY 2016 VL 8 IS 7 BP 685 EP 687 DI 10.15252/emmm.201606280 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DW4SC UT WOS:000383632300001 PM 27234439 ER PT J AU Yoon, SL Roh, YG Chu, IS Heo, J Kim, SI Chang, H Kang, TH Chung, JW Koh, SS Larionov, V Leem, SH AF Yoon, Se-Lyun Roh, Yun-Gil Chu, In-Sun Heo, Jeonghoon Kim, Seung Il Chang, Heekyung Kang, Tae-Hong Chung, Jin Woong Koh, Sang Seok Larionov, Vladimir Leem, Sun-Hee TI A polymorphic minisatellite region of BORIS regulates gene expression and its rare variants correlate with lung cancer susceptibility SO EXPERIMENTAL AND MOLECULAR MEDICINE LA English DT Article ID TRANSCRIPTION FACTORS; GASTRIC-CARCINOMA; VARIABLE NUMBER; PROSTATE-CANCER; BREAST-CANCER; TESTIS GENE; CELLS; CTCF; ALLELES; DEREPRESSION AB Aberrant expression of BORIS/CTCFL (Brother of the Regulator of Imprinted Sites/CTCF-like protein) is reported in different malignancies. In this study, we characterized the entire promoter region of BORIS/CTCFL, including the CpG islands, to assess the relationship between BORIS expression and lung cancer. To simplify the construction of luciferase reporter cassettes with various-sized portions of the upstream region, genomic copies of BORIS were isolated using TAR cloning technology. We analyzed three promoter blocks: the GATA/CCAAT box, the CpG islands and the minisatellite region BORIS-MS2. Polymorphic minisatellite sequences were isolated from genomic DNA prepared from the blood of controls and cases. Of the three promoter blocks, the GATA/CCAAT box was determined to be a critical element of the core promoter, while the CpG islands and the BORIS-MS2 minisatellite region were found to act as regulators. Interestingly, the polymorphic minisatellite region BORIS-MS2 was identified as a negative regulator that repressed the expression levels of luciferase reporter cassettes less effectively in cancer cells compared with normal cells. We also examined the association between the size of BORIS-MS2 and lung cancer in a case-control study with 590 controls and 206 lung cancer cases. Rare alleles of BORIS-MS2 were associated with a statistically significantly increased risk of lung cancer (odds ratio, 2.04; 95% confidence interval, 1.02-4.08; and P=0.039). To conclude, our data provide information on the organization of the BORIS promoter region and gene regulation in normal and cancer cells. In addition, we propose that specific alleles of the BORIS-MS2 region could be used to identify the risk for lung cancer. C1 [Yoon, Se-Lyun; Roh, Yun-Gil; Kang, Tae-Hong; Chung, Jin Woong; Koh, Sang Seok; Leem, Sun-Hee] Dong A Univ, Dept Biol Sci, 37 Nakdong Daero 550 Beon Gil, Busan 49315, South Korea. [Chu, In-Sun] Korea Res Inst Biosci & Biotechnol, Korean Bioinformat Ctr, Daejeon, South Korea. [Heo, Jeonghoon] Kosin Univ, Dept Mol Biol & Immunol, Coll Med, Busan, South Korea. [Kim, Seung Il] Korea Basic Sci Inst, Drug & Dis Target Team, Daejeon, South Korea. [Chang, Heekyung] Kosin Univ, Dept Pathol, Coll Med, Busan, South Korea. [Larionov, Vladimir] NCI, Dev Therapeut Branch, Bethesda, MD 20892 USA. RP Leem, SH (reprint author), Dong A Univ, Dept Biol Sci, 37 Nakdong Daero 550 Beon Gil, Busan 49315, South Korea. EM shleem@dau.ac.kr FU Mid-Career Researcher Program through the National Research Foundation of Korea (NRF) - Korea government (MEST) [NRF-2013R1A2A2A04008115]; Brain Busan 21 Project; Bio-Synergy Research Project of the Ministry of Science, ICT and Future Planning through the National Research Foundation [NRF-2014M3A9C4066461]; Korea Basic Science Institute research program [D35402] FX We gratefully acknowledge the patients, families and their caregivers for their willing participation in this project and for providing consent for the use of their information in this study. The study design and procedures were approved by the Committee of Bioethics at Dong-A University (#IRB-06-10-02 & IRB-07-10-7; Busan, Korea). This research was supported by the Mid-Career Researcher Program through the National Research Foundation of Korea (NRF) grant (NRF-2013R1A2A2A04008115) funded by the Korea government (MEST). This work was supported by the Brain Busan 21 Project in 2015. SIK was supported by the Bio-Synergy Research Project (NRF-2014M3A9C4066461) of the Ministry of Science, ICT and Future Planning through the National Research Foundation and the Korea Basic Science Institute research program (D35402). NR 34 TC 1 Z9 1 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1226-3613 EI 2092-6413 J9 EXP MOL MED JI Exp. Mol. Med. PD JUL PY 2016 VL 48 AR e246 DI 10.1038/emm.2016.50 PG 10 WC Biochemistry & Molecular Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Research & Experimental Medicine GA EE5LG UT WOS:000389648400001 PM 27416782 ER PT J AU Klinger, SC Hojland, A Jain, S Kjolby, M Madsen, P Svendsen, AD Olivecrona, G Bonifacino, JS Nielsen, MS AF Klinger, Stine C. Hojland, Anne Jain, Shweta Kjolby, Mads Madsen, Peder Svendsen, Anna Dorst Olivecrona, Gunilla Bonifacino, Juan S. Nielsen, Morten S. TI Polarized trafficking of the sorting receptor SorLA in neurons and MDCK cells SO FEBS JOURNAL LA English DT Article DE adaptor protein; AP1; cell polarity; epithelial cell; intracellular trafficking; LR11; neurons; SorLA; sorting ID AMYLOID PRECURSOR PROTEIN; CYTOPLASMIC DOMAIN; LIPOPROTEIN-LIPASE; EPITHELIAL-CELLS; HIPPOCAMPAL-NEURONS; STRUCTURAL BASIS; ADIPOSE-TISSUE; SIGNAL; BINDING; MOTIF AB The sorting receptor SorLA is highly expressed in neurons and is also found in other polarized cells. The receptor has been reported to participate in the trafficking of several ligands, some of which are linked to human diseases, including the amyloid precursor protein, TrkB, and Lipoprotein Lipase (LpL). Despite this, only the trafficking in nonpolarized cells has been described so far. Due to the many differences between polarized and nonpolarized cells, we examined the localization and trafficking of SorLA in epithelial Madin-Darby canine kidney (MDCK) cells and rat hippocampal neurons. We show that SorLA is mainly found in sorting endosomes and on the basolateral surface of MDCK cells and in the somatodendritic domain of neurons. This polarized distribution of SorLA respectively depends on an acidic cluster and an extended version of this cluster and involves the cellular adaptor complex AP-1. Furthermore, we show that SorLA can mediate transcytosis across a tight cell layer. C1 [Klinger, Stine C.; Hojland, Anne; Madsen, Peder; Svendsen, Anna Dorst; Nielsen, Morten S.] Aarhus Univ, Lundbeck Fdn Initiat Brain Barriers & Drug Delive, Dept Biomed, Aarhus, Denmark. [Klinger, Stine C.; Hojland, Anne; Kjolby, Mads; Madsen, Peder; Svendsen, Anna Dorst; Nielsen, Morten S.] Aarhus Univ, MIND Ctr, Dept Biomed, Aarhus, Denmark. [Klinger, Stine C.; Jain, Shweta; Bonifacino, Juan S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD USA. [Kjolby, Mads] Aarhus Univ, Danish Diabet Acad, Dept Biomed, Aarhus, Denmark. [Olivecrona, Gunilla] Umea Univ, Physiol Chem, Dept Med Biosci, Umea, Sweden. RP Nielsen, MS (reprint author), Ole Worms Alle 1170, DK-8000 Aarhus, Denmark. EM mn@biomed.au.dk OI Bonifacino, Juan S./0000-0002-5673-6370 FU Alfred Benzon Foundation; Lundbeck Foundation [R108-A10265, R93-A8846]; Lundbeck Foundation Research Initiative on Blood Brain and Drug Delivery; Danish Diabetes Academy; Novo Nordisk Foundation; Intramural Program of NICHD, NIH FX We thank F. Kamakh, N. Mahler, X. Zhu, and N. Tsai for expert technical assistance and T. Ryan and R. Fenton for kind gifts of reagents or cells. The work was supported by the Alfred Benzon Foundation (to SCK), The Lundbeck Foundation (project number R108-A10265 (to SCK) and project number R93-A8846), The Lundbeck Foundation Research Initiative on Blood Brain and Drug Delivery, The Danish Diabetes Academy, Novo Nordisk Foundation (MK) and The Intramural Program of NICHD, NIH. The funders had no role in study design, data collection, and interpretation, or the decision to submit the work for publication. NR 48 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD JUL PY 2016 VL 283 IS 13 BP 2476 EP 2493 DI 10.1111/febs.13758 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DW4GR UT WOS:000383601600007 PM 27192064 ER PT J AU Boikos, SA Pappo, AS Killian, JK LaQuaglia, MP Weldon, CB George, S Trent, JC von Mehren, M Wright, JA Schiffman, JD Raygada, M Pacak, K Meltzer, PS Miettinen, MM Stratakis, C Janeway, KA Helman, LJ AF Boikos, Sosipatros A. Pappo, Alberto S. Killian, J. Keith LaQuaglia, Michael P. Weldon, Chris B. George, Suzanne Trent, Jonathan C. von Mehren, Margaret Wright, Jennifer A. Schiffman, Josh D. Raygada, Margarita Pacak, Karel Meltzer, Paul S. Miettinen, Markku M. Stratakis, Constantine Janeway, Katherine A. Helman, Lee J. TI Molecular Subtypes of KIT/PDGFRA Wild-Type Gastrointestinal Stromal Tumors A Report From the National Institutes of Health Gastrointestinal Stromal Tumor Clinic SO JAMA ONCOLOGY LA English DT Article ID SUCCINATE-DEHYDROGENASE; GERMLINE MUTATIONS; IDH2 MUTATIONS; KIT; PDGFRA; GENES; GIST; GENETICS; IMATINIB; CANCER AB IMPORTANCE Wild-type (WT) gastrointestinal stromal tumors (GISTs), which lack KIT and PDGFRA gene mutations, are the primary form of GIST in children and occasionally occur in adults. They respond poorly to standard targeted therapy. Better molecular and clinical characterization could improve management. OBJECTIVE To evaluate the clinical and tumor genomic features of WT GIST. DESIGN, SETTING, AND PARTICIPANTS Patients enrolled in an observational study at the National Institutes of Health starting in 2008 and were evaluated in a GIST clinic held once or twice yearly. Patients provided access to existing medical records and tumor specimens. Self-referred or physician-referred patients younger than 19 years with GIST or 19 years or older with known WT GIST (no mutations in KIT or PDGFRA) were recruited; 116 patients with WT GIST were enrolled, and 95 had adequate tumor specimen available. Tumors were characterized by immunohistochemical analysis (IHC) for succinate dehydrogenase (SDH) subunit B, sequencing of SDH genes, and determination of SDHC promoter methylation. Testing of germline SDH genes was offered to consenting patients and families. MAIN OUTCOMES AND MEASURES For classification, tumors were characterized by SDHA, B, C, or D (SDHX) mutations and other genetic and epigenetic alterations, including presence of mutations in germline. Clinical characteristics were categorized. RESULTS Wild-type GIST specimens from 95 patients (median age, 23 [range, 7-78] years; 70% female) were classified into 3 molecular subtypes: SDH-competent (n = 11), defined by detection of SDHB by IHC; and 2 types of SDH-deficient GIST (n = 84). Of SDH-deficient tumors, 63 (67%) had SDH mutations, and in 31 of 38 (82%), the SDHX mutation was also present in germline. Twenty-one (22%) SDH-deficient tumors had methylation of the SDHC promoter leading to silencing of expression. Mutations in known cancer-associated pathways were identified in 9 of 11 SDH-competent tumors. Among patients with SDH-mutant tumors, 62% were female (39 of 63), median (range) age was 23 (7-58) years, and approximately 30% presented with metastases (liver [12 of 58], peritoneal [6 of 58], lymph node [15 of 23]). SDHC-epimutant tumors mostly affected young females (20 of 21; median [range] age, 15 [8-50] years), and approximately 40% presented with metastases (liver [7 of 19], peritoneal [1 of 19], lymph node [3 of 8]). SDH-deficient tumors occurred only in the stomach and had an indolent course. CONCLUSIONS AND RELEVANCE An observational study of WT GIST permitted the evaluation of a large number of patients with this rare disease. Three molecular subtypes with implications for prognosis and clinical management were identified. C1 [Boikos, Sosipatros A.; Helman, Lee J.] NCI, Pediat Oncol Branch, Ctr Canc Res, 9000 Rockville Pike,Bldg 31,Room 3A11, Bethesda, MD 20892 USA. [Boikos, Sosipatros A.] Virginia Commonwealth Univ, Massey Canc Ctr, Sarcoma & Rare Tumors Program, Div Hematol Oncol & Palliat Care, Richmond, VA 23284 USA. [Pappo, Alberto S.] St Jude Childrens Res Hosp, Dept Oncol, 332 N Lauderdale St, Memphis, TN 38105 USA. [Killian, J. Keith; Meltzer, Paul S.] NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [LaQuaglia, Michael P.] Mem Sloan Kettering Canc Ctr, Pediat Surg Serv, 1275 York Ave, New York, NY 10021 USA. [Weldon, Chris B.] Boston Childrens Hosp, Dept Surg, Boston, MA USA. [George, Suzanne] Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol, Boston, MA 02115 USA. [Trent, Jonathan C.] Univ Miami, Div Hematol Oncol, Dept Med, Sylvester Comprehens Canc Ctr, Miami, FL USA. [von Mehren, Margaret] Fox Chase Canc Ctr, Div Hematol Oncol, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Wright, Jennifer A.; Schiffman, Josh D.] Huntsman Canc Inst, Pediat Hematol & Oncol, Salt Lake City, UT USA. [Raygada, Margarita] Natl Inst Child Hlth & Human Dev, Div Intramural Res, Bethesda, MD USA. [Pacak, Karel] Natl Inst Child Hlth & Human Dev, Sect Med Neuroendocrinol, Bethesda, MD USA. [Miettinen, Markku M.] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Stratakis, Constantine] NICHHD, Sect Endocrinol & Genet, Bethesda, MD 20892 USA. [Janeway, Katherine A.] Dana Farber Boston Childrens Canc & Blood Disorde, Boston, MA USA. RP Helman, LJ (reprint author), NCI, Pediat Oncol Branch, Ctr Canc Res, 9000 Rockville Pike,Bldg 31,Room 3A11, Bethesda, MD 20892 USA. EM helmanl@nih.gov FU intramural National Cancer Institute (NCI), National Institutes of Health (NIH) FX The study was funded by the intramural National Cancer Institute (NCI), National Institutes of Health (NIH). NR 33 TC 8 Z9 8 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD JUL PY 2016 VL 2 IS 7 BP 922 EP 928 DI 10.1001/jamaoncol.2016.0256 PG 7 WC Oncology SC Oncology GA DW5RK UT WOS:000383704300016 PM 27011036 ER PT J AU Ramalingam, TR Gieseck, RL Acciani, TH Hart, KM Cheever, AW Mentink-Kane, MM Vannella, KM Wynn, TA AF Ramalingam, Thirumalai R. Gieseck, Richard L. Acciani, Thomas H. Hart, Kevin M. Cheever, Allen W. Mentink-Kane, Margaret M. Vannella, Kevin M. Wynn, Thomas A. TI Enhanced protection from fibrosis and inflammation in the combined absence of IL-13 and IFN-gamma SO JOURNAL OF PATHOLOGY LA English DT Article DE fibrosis; interleukin 13; interferon; lung; liver; hydroxyproline; collagen; fibroblast; tumour necrosis factor ID IDIOPATHIC PULMONARY-FIBROSIS; SCHISTOSOMA-MANSONI INFECTION; INNATE LYMPHOID-CELLS; HEPATIC-FIBROSIS; INTERFERON-GAMMA; TGF-BETA; TNF-ALPHA; MURINE SCHISTOSOMIASIS; MOLECULAR-MECHANISMS; PERIPORTAL FIBROSIS AB Persistent or dysregulated IL-13 responses are key drivers of fibrosis in multiple organ systems, and this identifies this cytokine as an important therapeutic target. Nevertheless, the mechanisms by which IL-13 blockade leads to the amelioration of fibrosis remain unclear. Because IFN-gamma exhibits potent anti-fibrotic activity, and IL-4R alpha signalling antagonizes IFN-gamma effector function, compensatory increases in IFN-gamma activity following IL-13/IL-4R alpha blockade might contribute to the reduction in fibrosis. To investigate the role of IFN-gamma, we developed novel IL-13(-/-)/IFN-gamma(-/-) double cytokine-deficient mice and examined disease progression in models of type 2-driven fibrosis. As predicted, we showed that fibrosis in the lung and liver are both highly dependent on IL-13. We also observed increased IFN-gamma production and inflammatory activity in the tissues of IL-13-deficient mice. Surprisingly, however, an even greater reduction in fibrosis was observed in IL-13/IFN-gamma double deficient mice, most notably in the livers of mice chronically infected with Schistosoma mansoni. The increased protection was associated with marked decreases in Tgfb1, Mmp12, and Timp1 mRNA expression in the tissues; reduced inflammation; and decreased expression of important pro-inflammatory mediators such as TNF-alpha. Experiments conducted with neutralizing monoclonal antibodies to IL-13 and IFN-gamma validated the findings with the genetically deficient mice. Together, these studies demonstrate that the reduction in fibrosis observed when IL-13 signalling is suppressed is not dependent on increased IFN-gamma activity. Instead, by reducing compensatory increases in type 1-associated inflammation, therapeutic strategies that block IFN-gamma and IL-13 activity simultaneously can confer greater protection from progressive fibrosis than IL-13 blockade alone. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. C1 [Ramalingam, Thirumalai R.; Gieseck, Richard L.; Acciani, Thomas H.; Hart, Kevin M.; Cheever, Allen W.; Vannella, Kevin M.; Wynn, Thomas A.] NIAID, Parasit Dis Lab, Bethesda, MD USA. [Mentink-Kane, Margaret M.] Biomed Res Inst, Rockville, MD 20852 USA. RP Wynn, TA (reprint author), NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH,DHHS, 4 Mem Dr,Rm 211C, Bethesda, MD 20892 USA. EM twynn@niaid.nih.gov FU NIAID/NIH; NIH-NIAID [HHSN272201000005I] FX This work was supported by the intramural program of NIAID/NIH. Schistosome-infected mice were provided by the NIAID Schistosomiasis Resource Center at the Biomedical Research Institute (Rockville, MD, USA) through NIH-NIAID Contract HHSN272201000005I for distribution through BEI Resources. This work is dedicated to the memory of Dr Allen W Cheever, who passed away during the preparation of this paper. NR 59 TC 2 Z9 2 U1 19 U2 19 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 2016 VL 239 IS 3 BP 344 EP 354 DI 10.1002/path.4733 PG 11 WC Oncology; Pathology SC Oncology; Pathology GA DW4EC UT WOS:000383594300010 PM 27125685 ER PT J AU Pilotto, A Gallina, P Copetti, M Pilotto, A Marcato, F Mello, AM Simonato, M Logroscino, G Padovani, A Ferrucci, L Panza, F AF Pilotto, Alberto Gallina, Pietro Copetti, Massimiliano Pilotto, Andrea Marcato, Francesco Mello, Anna M. Simonato, Matteo Logroscino, Giancarlo Padovani, Alessandro Ferrucci, Luigi Panza, Francesco CA Multidimensional Prognostic TI Warfarin Treatment and All-Cause Mortality in Community-Dwelling Older Adults with Atrial Fibrillation: A Retrospective Observational Study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE atrial fibrillation; all-cause mortality; warfarin; aging; frailty; multidimensional prognostic index ID MULTIDIMENSIONAL PROGNOSTIC INDEX; RISK STRATIFICATION SCHEMES; STROKE PREVENTION; ANTITHROMBOTIC THERAPY; ELDERLY-PATIENTS; GERIATRIC ASSESSMENT; PREDICTING STROKE; GENERAL-PRACTICE; ANTICOAGULATION; MANAGEMENT AB OBJECTIVES: To investigate the relationship between warfarin treatment and different strata of all-cause mortality risk assessed using the Multidimensional Prognostic Index (MPI) based on information collected using the Standardized Multidimensional Assessment Schedule for Adults and Aged Persons (SVaMA) in community-dwelling older adults with atrial fibrillation (AF). DESIGN: Retrospective observational study. SETTING: Older community-dwelling adults who underwent a SVaMA evaluation establishing accessibility to homecare services and nursing home admission from 2005 to 2013 in the Padova Health District, Italy. PARTICIPANTS: Community-dwelling individuals with AF aged 65 and older (N = 1,827). MEASUREMENTS: Participants were classified as being at mild (MPI-SVaMA-1), moderate (MPI-SVaMA-2), or severe (MPI-SVaMA-3) risk of mortality using the MPI-SVaMA, a validated prognostic tool based on age, sex, comorbidity, cognitive status, mobility and functional disability, pressure sore risk, and social support. The association between warfarin treatment and mortality was tested using multivariate-and propensity score-adjusted Cox regression models, controlling for age, sex, all SVaMA domains, concomitant diseases, and drug treatments. RESULTS: Higher MPI-SVaMA scores were associated with lower rates of warfarin treatment and higher 3-year mortality. After adjustment for propensity score quintiles, warfarin treatment was significantly associated with lower 2-year mortality in individuals with MPI-SVaMA-1 (hazard ratio (HR) = 0.64, 95% confidence interval (CI) = 0.50-0.82), MPI-SVaMA-2 (HR = 0.68, 95% CI = 0.55-0.85), and MPI-SVaMA-3 (HR = 0.55, 95% CI = 0.44-0.67). Heterogeneity analyses confirmed that the effect of warfarin treatment was not different between MPI-SVaMA groups (P for heterogeneity = .48). CONCLUSION: Community-dwelling older adults with AF benefitted from anticoagulation in terms of lower all-cause mortality over a mean follow-up of 2 years, regardless of poor health and functional condition. Although this benefit can be ascribed to the treatment, it may also reflect better overall care. C1 [Pilotto, Alberto; Mello, Anna M.] EO Galliera Hosp Natl Relevance & High Specializa, Frailty Area, Dept Geriatr Care Orthogeriatr & Rehabil, Genoa, Italy. [Gallina, Pietro; Marcato, Francesco; Simonato, Matteo] S Antonio Hosp, Azienda Unita Locale Socio Sanitaria Padova 16, Padua, Italy. [Copetti, Massimiliano; Panza, Francesco] Ist Ricovero & Cura Carattere Sci Casa Sollievo S, Unit Biostat, Foggia, Italy. [Pilotto, Andrea; Padovani, Alessandro] Univ Brescia, Neurol Clin, Brescia, Italy. [Logroscino, Giancarlo; Panza, Francesco] Univ Bari Aldo Moro, Dept Basic Med Neurosci & Sense Organs, Neurodegenerat Dis Unit, Bari, Italy. [Logroscino, Giancarlo] Univ Bari Aldo Moro, Dept Clin Res Neurol, Lecce, Italy. [Ferrucci, Luigi] NIA, Baltimore, MD 21224 USA. RP Pilotto, A (reprint author), EO Galliera Hosp, NR HS, Frailty Area, Dept Geriatr Care Orthogeriatr & Rehabil, Mura Cappuccine 14, I-16128 Genoa, Italy. EM alberto.pilotto@galliera.it RI LOGROSCINO, GIANCARLO/K-5148-2016; Trifiro, Gianluca/K-9744-2016; Fontana, Andrea/J-8584-2016; OI LOGROSCINO, GIANCARLO/0000-0003-0423-3242; Trifiro, Gianluca/0000-0003-1147-7296; Fontana, Andrea/0000-0002-6660-5315; Panza, Francesco/0000-0002-7220-0656; Pilotto, Andrea/0000-0003-2029-6606 FU MPI_Age European project; Executive Agency for Health and Consumers of the European Innovation Partnership on Active and Healthy Ageing Second Health Programme FX Funding for this study was provided by the MPI_Age European project, cofunded by the Executive Agency for Health and Consumers of the European Innovation Partnership on Active and Healthy Ageing Second Health Programme 2008-2013. NR 48 TC 1 Z9 1 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUL PY 2016 VL 64 IS 7 BP 1416 EP 1424 DI 10.1111/jgs.14221 PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DW3NN UT WOS:000383548400005 PM 27295351 ER PT J AU Wang, SM Fan, JH Jia, MM Yang, Z Zhang, YQ Qiao, YL Taylor, PR AF Wang, Shao-Ming Fan, Jin-Hu Jia, Meng-Meng Yang, Zhao Zhang, Yu-Qing Qiao, You-Lin Taylor, Philip R. TI Body mass index and long-term risk of death from esophageal squamous cell carcinoma in a Chinese population SO THORACIC CANCER LA English DT Article DE Body mass index (BMI); Chinese population; esophageal squamous cell carcinoma (ESCC); overweight; underweight ID GASTRIC CANCERS; FOLLOW-UP; MORTALITY; OBESITY; ADENOCARCINOMA; METAANALYSIS; NUTRITION; LINXIAN; MEN; SUPPLEMENTATION AB Background: Studies based on Western populations have found that body mass index (BMI) is positively related to the risk of esophageal adenocarcinoma but inversely associated with esophageal squamous cell carcinoma (ESCC). Little reliable evidence exists of an association between BMI and ESCCin China, where ESCC incidence is high but BMI is low. Methods: We evaluated the BMI-ESCC association in a population-based prospective study of 29 446 Chinese aged 40-69 with 27 years of follow-up. China-specific BMI cut-offs (underweight < 18.5, healthy >= 18.5 to <24, overweight >= 24 to <28, and obese >= 28) and quartile categories were used to define BMI subgroups. Adjusted hazard ratios (HRs) and confidence intervals (CIs) for death from ESCC by BMI subgroups were calculated using Cox proportional hazards models. Results: During a median follow-up duration of 21.2 years (555 439 person-years), 2436 ESCC deaths were identified. BMI was protective for death from ESCC with an HR of 0.97 (95% CI 0.95-0.99) for each unit increase in BMI. Relative to healthy weight, HRs for BMI were 1.21 (95% CI 1.02-1.43) for the underweight group and 0.87 (95% CI 0.78-0.98) for the overweight. Categorical quartile analyses found people with BMIs in the Q3 and Q4 groups had 16% and 13% reductions in the risk of ESCC, respectively. Gender-specific analyses found that clear effects were evident in women only. Conclusions: Higher BMI was associated with a reduced risk of ESCC in a Chinese population. C1 [Wang, Shao-Ming; Fan, Jin-Hu; Jia, Meng-Meng; Yang, Zhao; Zhang, Yu-Qing; Qiao, You-Lin] Chinese Acad Med Sci, Canc Inst Hosp, 17 South Panjiayuan Lane,POB 2258, Beijing 100021, Peoples R China. [Wang, Shao-Ming; Fan, Jin-Hu; Jia, Meng-Meng; Yang, Zhao; Zhang, Yu-Qing; Qiao, You-Lin] Peking Union Med Coll, 17 South Panjiayuan Lane,POB 2258, Beijing, Peoples R China. [Taylor, Philip R.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Qiao, YL (reprint author), Chinese Acad Med Sci, Canc Inst Hosp, 17 South Panjiayuan Lane,POB 2258, Beijing 100021, Peoples R China.; Qiao, YL (reprint author), Peking Union Med Coll, 17 South Panjiayuan Lane,POB 2258, Beijing, Peoples R China. EM qiaoy@cicams.ac.cn OI Qiao, You-Lin/0000-0001-6380-0871 FU US National Cancer Institute [HHSN261201200034C]; [2013JKB01] FX This study was funded by a US National Cancer Institute contract (HHSN261201200034C) to the Cancer Hospital/ Institute, Chinese Academy of Medical Sciences and a basic research grant (2013JKB01) to the Cancer Hospital/Institute, Chinese Academy of Medical Sciences. NR 23 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1759-7706 EI 1759-7714 J9 THORAC CANCER JI Thorac. Cancer PD JUL PY 2016 VL 7 IS 4 BP 387 EP 392 DI 10.1111/1759-7714.12340 PG 6 WC Oncology; Respiratory System SC Oncology; Respiratory System GA DW5YY UT WOS:000383724800002 PM 27385979 ER PT J AU Cansu, GB Taskiran, B Trivellin, G Faucz, FR Stratakis, CA AF Cansu, Guven Baris Taskiran, Bengur Trivellin, Giampaolo Faucz, Fabio R. Stratakis, Constantine A. TI A novel truncating AIP mutation, p.W279*, in a familial isolated pituitary adenoma (FIPA) kindred SO HORMONES-INTERNATIONAL JOURNAL OF ENDOCRINOLOGY AND METABOLISM LA English DT Article DE AIP mutation; Familial isolated pituitary adenoma; Gigantism ID GENE AB Familial isolated pituitary adenomas (FIPA) constitute 2-3% of pituitary tumours. AIP is the most commonly mutated gene in FIPA. We herein report a novel germline mutation of the AIP gene in a family with FIPA. We present two patients, a father and his 12-year-old daughter, diagnosed clinically and using laboratory measures with acromegaly-gigantism. Both underwent transsphenoidal hypophyseal surgery for macroadenomas. We initially detected a novel heterozygous germline AIP mutation, c.836G> A (p.W279*), in the father's DNA. We then found the same mutation in his affected daughter. Pituitary adenomas associated with AIP mutations mostly present as FIPA (68%) at an early age (78% occur at <30 years old). They are often growth hormone (GH) - or prolactin - secreting macroadenomas (88%) that have already extended beyond the sella at the time of diagnosis. Acromegalic cases are resistant to somatostatin analogues and multimodal management is frequently essential to control the disease. Our patients had normalized GH/IGF-1 values soon after surgery, although enough time may not have elapsed to reach final cure. While penetrance of the disease can be as low as 10% in FIPA, especially children and young patients with somatotropinoma and prolactinoma should be surveyed for inactivating mutations or deletions in AIP. Determining the causative mutations may be of assistance in early diagnosis, treatment success, and genetic counseling. C1 [Cansu, Guven Baris; Taskiran, Bengur] Yunus Emre State Hosp, Div Endocrinol & Metab, Uluonder Mah Salih Bozok Cad 23, TR-26190 Tepebasi, Eskisehir, Turkey. [Trivellin, Giampaolo; Faucz, Fabio R.; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. RP Cansu, GB (reprint author), Yunus Emre State Hosp, Div Endocrinol & Metab, Uluonder Mah Salih Bozok Cad 23, TR-26190 Tepebasi, Eskisehir, Turkey. EM bcansu74@hotmail.com OI Trivellin, Giampaolo/0000-0003-2384-4153; Cansu, Guven Baris/0000-0003-2606-1103 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA [Z01-HD008920] FX This study was supported by the research project Z01-HD008920 (Principal Investigator: Dr. Constantine A. Stratakis) of the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA. NR 12 TC 0 Z9 0 U1 0 U2 0 PU HELLENIC ENDOCRINE SOC PI ATHENS PA 14 ALEXANDRAS AVE, ATHENS, 106 82, GREECE SN 1109-3099 J9 HORM-INT J ENDOCRINO JI Horm.-Int. J. Endocrinol. Metab. PD JUL-SEP PY 2016 VL 15 IS 3 BP 441 EP 444 DI 10.14310/horm.2002.1692 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EA8JQ UT WOS:000386881500012 PM 27838609 ER PT J AU Markantes, GK Theodoropoulou, A Armeni, AK Vasileiou, V Stratakis, CA Georgopoulos, NA AF Markantes, Georgios K. Theodoropoulou, Anastasia Armeni, Anastasia K. Vasileiou, Vasiliki Stratakis, Constantine A. Georgopoulos, Neoklis A. TI Cyclopes and Giants: From Homer's Odyssey to contemporary genetic diagnosis SO HORMONES-INTERNATIONAL JOURNAL OF ENDOCRINOLOGY AND METABOLISM LA English DT Article DE Acromegaly; Cyclops gigantism; Familial Isolated Pituitary Adenoma; Hemianopia; Homer; Odysseus; Pituitary adenoma ID PITUITARY-ADENOMA PREDISPOSITION; AIP GENE; MUTATIONS; GIGANTISM; FEATURES; DISEASE; GROWTH C1 [Markantes, Georgios K.; Theodoropoulou, Anastasia; Armeni, Anastasia K.; Georgopoulos, Neoklis A.] Univ Patras, Sch Med, Dept Obstet & Gynecol, Div Reprod Endocrinol, Patras, Greece. [Vasileiou, Vasiliki] Alexandra Hosp, Ctr Diabet, Dept Endocrinol 1, Athens, Greece. [Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, NIH, Bethesda, MD USA. RP Georgopoulos, NA (reprint author), Univ Patras, Sch Med, Div Reprod Endocrinol, Dept Obstet & Gynecol, Rion 26500, Greece. EM neoklisg@hol.gr NR 21 TC 0 Z9 0 U1 0 U2 0 PU HELLENIC ENDOCRINE SOC PI ATHENS PA 14 ALEXANDRAS AVE, ATHENS, 106 82, GREECE SN 1109-3099 J9 HORM-INT J ENDOCRINO JI Horm.-Int. J. Endocrinol. Metab. PD JUL-SEP PY 2016 VL 15 IS 3 BP 459 EP 463 DI 10.14310/horm.2002.1687 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EA8JQ UT WOS:000386881500015 PM 27394709 ER PT J AU Ahluwalia, A Gladwin, M Coleman, GD Hord, N Howard, G Kim-Shapiro, DB Lajous, M Larsen, FJ Lefer, DJ McClure, LA Nolan, BT Pluta, R Schechter, A Wang, CY Ward, MH Harman, JL AF Ahluwalia, Amrita Gladwin, Mark Coleman, Gary D. Hord, Norman Howard, George Kim-Shapiro, Daniel B. Lajous, Martin Larsen, Filip J. Lefer, David J. McClure, Leslie A. Nolan, Bernard T. Pluta, Ryszard Schechter, Alan Wang, Chia-Yih Ward, Mary H. Harman, Jane L. TI Dietary Nitrate and the Epidemiology of Cardiovascular Disease: Report From a National Heart, Lung, and Blood Institute Workshop SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE national registry; nitrate; nitric oxide; nutrition ID N-NITROSO COMPOUNDS; PRESERVED EJECTION FRACTION; VIVO ISCHEMIA-REPERFUSION; NITRIC-OXIDE SYNTHASE; GASTRIC-CANCER RISK; INORGANIC NITRATE; VEGETABLE INTAKE; ENDOGENOUS NITROSATION; DRINKING-WATER; IN-VIVO C1 [Ahluwalia, Amrita] Queen Mary Univ London, William Harvey Res Inst, Barts & London Med Sch, London, England. [Gladwin, Mark] Univ Pittsburgh, Vasc Med Inst, Pittsburgh, PA USA. [Coleman, Gary D.] Univ Maryland, College Pk, MD 20742 USA. [Hord, Norman] Oregon State Univ, Corvallis, OR 97331 USA. [Howard, George] Univ Alabama Birmingham, Birmingham, AL USA. [Kim-Shapiro, Daniel B.] Wake Forest Univ, Winston Salem, NC 27109 USA. [Lajous, Martin] Nacl Salud Publ Mexico, Mexico, Albania. [Larsen, Filip J.] Karolinska Inst, Stockholm, Sweden. [Lefer, David J.] Louisiana State Univ, Hlth Sci Ctr, New Orleans, LA USA. [McClure, Leslie A.] Drexel Univ, Dornsife Sch Publ Hlth, Philadelphia, PA 19104 USA. [Nolan, Bernard T.] US Geol Survey, 959 Natl Ctr, Reston, VA 22092 USA. [Pluta, Ryszard] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Schechter, Alan] NIDDKD, Bethesda, MD USA. [Wang, Chia-Yih] CDC, Natl Ctr Hlth Stat, Hyattsville, MD USA. [Ward, Mary H.] NCI, Rockville, MD USA. [Harman, Jane L.] NHLBI, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA. RP Ahluwalia, A (reprint author), Queen Mary Univ London, William Harvey Res Inst, Charterhouse Sq, London EC1M 6BQ, England. EM a.ahluwalia@qmul.ac.uk FU National Heart, Lung, and Blood Institute FX The workshop was convened and funded by the National Heart, Lung, and Blood Institute. NR 120 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD JUL PY 2016 VL 5 IS 7 AR e003402 DI 10.1161/JAHA.116.003402 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EA6CT UT WOS:000386713800029 ER PT J AU Bulluck, H Rosmini, S Abdel-Gadir, A White, SK Bhuva, AN Treibel, TA Fontana, M Gonzalez-Lopez, E Reant, P Ramlall, M Hamarneh, A Sirker, A Herrey, AS Manisty, C Yellon, DM Kellman, P Moon, JC Hausenloy, DJ AF Bulluck, Heerajnarain Rosmini, Stefania Abdel-Gadir, Amna White, Steven K. Bhuva, Anish N. Treibel, Thomas A. Fontana, Marianna Gonzalez-Lopez, Esther Reant, Patricia Ramlall, Manish Hamarneh, Ashraf Sirker, Alex Herrey, Anna S. Manisty, Charlotte Yellon, Derek M. Kellman, Peter Moon, James C. Hausenloy, Derek J. TI Automated Extracellular Volume Fraction Mapping Provides Insights Into the Pathophysiology of Left Ventricular Remodeling Post-Reperfused ST-Elevation Myocardial Infarction SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE extracellular volume fraction; left ventricular remodeling; ST-segment elevation myocardial infarction; T1 mapping; T2 mapping ID CARDIOVASCULAR MAGNETIC-RESONANCE; MICROVASCULAR OBSTRUCTION; T2 QUANTIFICATION; HEART-ASSOCIATION; TASK-FORCE; SALVAGE; CMR; MORTALITY; EDEMA; SIZE AB Background-Whether the remote myocardium of reperfused ST-segment elevation myocardial infarction (STEMI) patients plays a part in adverse left ventricular (LV) remodeling remains unclear. We aimed to use automated extracellular volume fraction (ECV) mapping to investigate whether changes in the ECV of the remote (ECVRemote) and infarcted myocardium (ECVInfarct) impacted LV remodeling. Methods and Results-Forty-eight of 50 prospectively recruited reperfused STEMI patients completed a cardiovascular magnetic resonance at 4 +/- 2 days and 40 had a follow-up scan at 5 +/- 2 months. Twenty healthy volunteers served as controls. Mean segmental values for native T1, T2, and ECV were obtained. Adverse LV remodeling was defined as >= 20% increase in LV end-diastolic volume. ECVRemote was higher on the acute scan when compared to control (27.9 +/- 2.1% vs 26.4 +/- 2.1%; P=0.01). Eight patients developed adverse LV remodeling and had higher ECVRemote acutely (29.5 +/- 1.4% vs 27.4 +/- 2.0%; P=0.01) and remained higher at follow-up (28.6 +/- 1.5% vs 26.6 +/- 2.1%; P=0.02) compared to those without. Patients with a higher ECVRemote and a lower myocardial salvage index (MSI) acutely were significantly associated with adverse LV remodeling, independent of T1(Remote), T1(Core) and microvascular obstruction, whereas a higher ECVInfarct was significantly associated with worse wall motion recovery. Conclusions-ECVRemote was increased acutely in reperfused STEMI patients. Those with adverse LV remodeling had higher ECVRemote acutely, and this remained higher at follow-up than those without adverse LV remodeling. A higher ECVRemote and a lower MSI acutely were significantly associated with adverse LV remodeling whereas segments with higher ECVInfarct were less likely to recover wall motion. C1 [Bulluck, Heerajnarain; White, Steven K.; Ramlall, Manish; Hamarneh, Ashraf; Yellon, Derek M.; Hausenloy, Derek J.] UCL, Inst Cardiovasc Sci, Hatter Cardiovasc Inst, London, England. [Bulluck, Heerajnarain; White, Steven K.; Ramlall, Manish; Hamarneh, Ashraf; Sirker, Alex; Yellon, Derek M.; Moon, James C.; Hausenloy, Derek J.] UCL, Hosp Biomed Res Ctr, Natl Inst Hlth Res, London, England. [Bulluck, Heerajnarain; Rosmini, Stefania; Abdel-Gadir, Amna; White, Steven K.; Bhuva, Anish N.; Treibel, Thomas A.; Fontana, Marianna; Ramlall, Manish; Hamarneh, Ashraf; Sirker, Alex; Herrey, Anna S.; Manisty, Charlotte; Moon, James C.; Hausenloy, Derek J.] St Bartholomews Hosp, Barts Heart Ctr, London, England. [Gonzalez-Lopez, Esther] Hosp Univ Puerta de Hierro Majadahonda, Madrid, Spain. [Reant, Patricia] Univ Bordeaux, CHU Bordeaux, Bordeaux, France. [Kellman, Peter] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Hausenloy, Derek J.] Duke Natl Univ Singapore, Cardiovasc & Metab Disorders Program, Singapore, Singapore. [Hausenloy, Derek J.] Natl Heart Ctr Singapore, Natl Heart Res Inst Singapore, Singapore, Singapore. RP Hausenloy, DJ (reprint author), Duke NUS Grad Med Sch Singapore, Cardiovasc & Metab Dis Program, 8 Coll Rd, Singapore 169857, Singapore. EM derek.hausenloy@duke-nus.edu.sg OI Hamarneh, Ashraf/0000-0002-9489-4476; Bulluck, Heerajnarain/0000-0002-1985-1783 FU British Heart Foundation [FS/10/039/28270]; Rosetrees Trust; National Institute for Health Research University College London Hospitals Biomedical Research Center FX This work was supported by the British Heart Foundation (FS/10/039/28270), the Rosetrees Trust, and the National Institute for Health Research University College London Hospitals Biomedical Research Center NR 34 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD JUL PY 2016 VL 5 IS 7 AR e003555 DI 10.1161/JAHA.116.003555 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EA6CT UT WOS:000386713800045 ER PT J AU Dember, LM Imrey, PB Duess, MA Hamburg, NM Larive, B Radeva, M Himmelfarb, J Kraiss, LW Kusek, JW Roy-Chaudhury, P Terry, CM Vazquez, MA Vongpatanasin, W Beck, GJ Vita, JA AF Dember, Laura M. Imrey, Peter B. Duess, Mai-Ann Hamburg, Naomi M. Larive, Brett Radeva, Milena Himmelfarb, Jonathan Kraiss, Larry W. Kusek, John W. Roy-Chaudhury, Prabir Terry, Christi M. Vazquez, Miguel A. Vongpatanasin, Wanpen Beck, Gerald J. Vita, Joseph A. CA Hemodialysis Fistula Maturation St TI Vascular Function at Baseline in the Hemodialysis Fistula Maturation Study SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE chronic kidney disease; end-stage renal disease; flow-mediated dilation; nitroglycerin-mediated dilation; pulse wave velocity; vascular function; venous occlusion plethysmography ID FLOW-MEDIATED DILATION; STAGE RENAL-DISEASE; PULSE-WAVE VELOCITY; DEPENDENT DIABETES-MELLITUS; ARTERIAL STIFFNESS; PROGNOSTIC-SIGNIFICANCE; CARDIOVASCULAR RESEARCH; ARTERIOVENOUS-FISTULA; ENDOTHELIAL FUNCTION; AORTIC STIFFNESS AB Background-End-stage renal disease is accompanied by functional and structural vascular abnormalities. The objective of this study was to characterize vascular function in a large cohort of patients with end-stage renal disease, using noninvasive physiological measurements, and to correlate function with demographic and clinical factors. Methods and Results-We analyzed cross-sectional baseline data from the Hemodialysis Fistula Maturation Study, a multicenter prospective observational cohort study of 602 patients with end-stage renal disease from 7 centers. Brachial artery flow-and nitroglycerin-mediated dilation, carotid-femoral and -radial pulse wave velocity, and venous occlusion plethysmography were performed prior to arteriovenous fistula creation. Relationships of these vascular function measures with demographic, clinical, and laboratory factors were evaluated using linear mixed-effects models. Arterial function, as assessed by flow-and nitroglycerin-mediated dilation and carotid-femoral pulse wave velocity, worsened with increasing age and diabetes mellitus. Venous capacitance decreased with diabetes mellitus but not with age. Flow-mediated dilation was higher among patients undergoing maintenance dialysis than for those at predialysis, and a U-shaped relationship between serum phosphorus concentration and flow-mediated dilation was evident. Partial correlations among different measures of vascular function, adjusting for demographic factors, diabetes mellitus, and clinical center, were modest or essentially nonexistent. Conclusions-Multiple demographic and clinical factors were associated with the functions of vessels of different sizes and types in this large cohort of patients with end-stage renal disease. Low correlations between the different measures, controlling for demographic factors, diabetes mellitus, and center, indicated that these different types of vascular function otherwise vary heterogeneously across patients. C1 [Dember, Laura M.] Univ Penn, Perelman Sch Med, 920 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. [Imrey, Peter B.; Larive, Brett; Radeva, Milena; Beck, Gerald J.] Case Western Reserve Univ, Dept Quantitat Hlth Sci, Cleveland Clin, Lerner Coll Med, Cleveland, OH 44106 USA. [Duess, Mai-Ann; Hamburg, Naomi M.; Vita, Joseph A.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Himmelfarb, Jonathan] Univ Washington, Seattle, WA 98195 USA. [Kraiss, Larry W.; Terry, Christi M.] Univ Utah, Salt Lake City, UT USA. [Kusek, John W.] NIDDKD, Bethesda, MD USA. [Roy-Chaudhury, Prabir] Univ Arizona, Tucson, AZ USA. [Vazquez, Miguel A.; Vongpatanasin, Wanpen] Univ Texas Southwestern, Dallas, TX USA. RP Dember, LM (reprint author), Univ Penn, Renal Electrolyte & Hypertens Div, Ctr Clin Epidemiol & Biostat, Perelman Sch Med, 920 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM ldember@upenn.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [U01DK066597, U01DK082179, U01DK082189, U01DK082218, U01DK082222, U01DK082232, U01DK082236, U01DK082240] FX The Hemodialysis Fistula Maturation Study was funded by grants U01DK066597, U01DK082179, U01DK082189, U01DK082218, U01DK082222, U01DK082232, U01DK082236, and U01DK082240 from the National Institute of Diabetes and Digestive and Kidney Diseases. NR 33 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD JUL PY 2016 VL 5 IS 7 AR e003227 DI 10.1161/JAHA.116.003227 PG 26 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EA6CT UT WOS:000386713800019 ER PT J AU Haring, R Enserro, D Xanthakis, V Mitchell, GF Benjamin, EJ Hamburg, NM Sullivan, L Nauck, M Wallaschofski, H Vasan, RS AF Haring, Robin Enserro, Danielle Xanthakis, Vanessa Mitchell, Gary F. Benjamin, Emelia J. Hamburg, Naomi M. Sullivan, Lisa Nauck, Matthias Wallaschofski, Henri Vasan, Ramachandran S. TI Plasma Fibroblast Growth Factor 23: Clinical Correlates and Association With Cardiovascular Disease and Mortality in the Framingham Heart Study SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE cardiovascular disease risk factors; epidemiology; metabolism; mineral ID CHRONIC KIDNEY-DISEASE; CORONARY-ARTERY-DISEASE; MINERAL METABOLISM; PARATHYROID-HORMONE; ELDERLY-MEN; COMMUNITY; EVENTS; PHOSPHORUS; FGF-23; RISK AB Background-Fibroblast growth factor 23 (FGF23) is emerging as a novel biomarker of bone metabolism, chronic kidney disease, and cardiovascular disease (CVD). However, its clinical correlates and potential predictive role in a community-based setting are incompletely understood. Methods and Results-We evaluated participants of the Framingham Heart Study (seventh examination cycle of the Offspring cohort plus second examination cycle of the multiethnic Omni cohort) to identify clinical correlates of plasma FGF23 (N=3236) and examine its cross-sectional association with vascular function (N=2209), and longitudinal association with 10-year incidence of CVD (N=2823), and all-cause mortality (N=3223). Circulating FGF23 concentrations were positively related to African-American and Asian ethnicity, waist circumference, current smoking, serum glucose, history of CVD, and antihypertensive medication use; and negatively related to male sex, hormone replacement therapy, and estimated glomerular filtration rate. Multivariable-adjusted cross-sectional analyses showed no consistent association of FGF23 with vascular function measures. During a median follow-up time of 10.8 years, 347 incident CVD events and 412 deaths occurred. Multivariable-adjusted Cox regression models revealed a positive association of FGF23 with all-cause mortality (hazard ratio [HR] per SD increase, 1.31; 95% CI, 1.20-1.42), but not with incident CVD (HR per SD increase, 1.05; 95% CI, 0.94-1.17). Conclusions-In our large, community-based sample, FGF23 was associated with mortality risk, but not with vascular function or incident CVD. C1 [Haring, Robin; Xanthakis, Vanessa; Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Prevent Med & Epidemiol Sect, Boston, MA 02118 USA. [Benjamin, Emelia J.; Hamburg, Naomi M.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Evans Dept Med, Cardiol Sect, Boston, MA 02118 USA. [Haring, Robin] European Univ Appl Sci, Fac Appl Publ Hlth, Rostock, Germany. [Enserro, Danielle; Sullivan, Lisa] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA. [Xanthakis, Vanessa; Benjamin, Emelia J.; Vasan, Ramachandran S.] NHLBI, Framingham, MA USA. [Xanthakis, Vanessa; Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Framingham Heart Study, Framingham, MA USA. [Mitchell, Gary F.] Cardiovasc Engn Inc, Norwood, MA USA. [Nauck, Matthias; Wallaschofski, Henri] Univ Med Greifswald, Inst Clin Chem & Lab Med, Ferdinand Sauerbruch Str, D-17475 Greifswald, Germany. [Nauck, Matthias] German Ctr Cardiovasc Res DZHK eV Partner Site Gr, Greifswald, Germany. RP Haring, R (reprint author), Univ Med Greifswald, Inst Clin Chem & Lab Med, Ferdinand Sauerbruch Str, D-17475 Greifswald, Germany. EM robin.haring@uni-greifswald.de FU Framingham Heart Study [HHSN268201500001I, 1R01HL60040, 1RO1HL70100, N01-HC-25195] FX The Framingham Heart Study is funded National Heart, Lung, and Blood Institute (N01-HC-25195, HHSN268201500001I, 1R01HL60040, 1RO1HL70100). NR 42 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD JUL PY 2016 VL 5 IS 7 AR e003486 DI 10.1161/JAHA.116.003486 PG 14 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EA6CT UT WOS:000386713800038 ER PT J AU Kaess AF Kaess TI Circulating Brain-Derived Neurotrophic Factor Concentrations and the Risk of Cardiovascular Disease in the Community (vol 4, e001544, 2015) SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Correction C1 NHLBI, Framingham Heart Study, Framingham, MA USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD JUL PY 2016 VL 5 IS 7 AR e002098 DI 10.1161/JAHA.116.002098 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EA6CT UT WOS:000386713800005 ER PT J AU Kaess AF Kaess TI Relations of Central Hemodynamics and Aortic Stiffness with Left Ventricular Structure and Function: The Framingham Heart Study (vol 5, e002693, 2016) SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Correction C1 NHLBI, Framingham Heart Study, Framingham, MA USA. NR 1 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD JUL PY 2016 VL 5 IS 7 AR e002100 DI 10.1161/JAHA.116.002100 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EA6CT UT WOS:000386713800006 ER PT J AU Lin, GM Redline, S Klein, R Colangelo, LA Cotch, MF Wong, TY Klein, BEK Patel, SR Shea, SJ Liu, K AF Lin, Gen-Min Redline, Susan Klein, Ronald Colangelo, Laura A. Cotch, Mary Frances Wong, Tien Y. Klein, Barbara E. K. Patel, Sanjay R. Shea, Steven J. Liu, Kiang TI Sex-Specific Association of Obstructive Sleep Apnea With Retinal Microvascular Signs: The Multi-Ethnic Study of Atherosclerosis SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE apnea-hypopnea index; epidemiology; microvascular dysfunction; obstructive sleep apnea; retinal vascular calibers; retinopathy; sex-specific ID CARDIOVASCULAR-DISEASE; DIABETIC-RETINOPATHY; VASCULAR CALIBER; HEART HEALTH; RISK-FACTORS; RHO KINASE; ENDOTHELIN-1; ARTERIOLES; ABNORMALITIES; EPIDEMIOLOGY AB Background-Obstructive sleep apnea (OSA) is a common condition affecting more men than women. The relationship of OSA with microvascular disease is unclear, complicated by possible sex difference. Assessment of the relationship of OSA with retinal microvascular signs in men and women may provide insights into such a relationship. Methods and Results-We examined the sex-specific cross-sectional association of OSA severity with retinal vascular calibers in 1808 participants, and with specific retinopathy signs in 1831 participants from a sample of 2060 participants aged 54 to 93 years who underwent successful polysomnography in the Multi-Ethnic Study of Atherosclerosis, 2010-2012. OSA severity was defined by the apnea-hypopnea index (events/h) as none (<5), mild (5-14.9), moderate (15-29.9), and severe (>= 30). As compared to no OSA, moderate/severe OSA in men was associated with retinal arteriolar narrowing (odds ratio [OR] and 95% CI for the narrowest quartile: 1.65 [1.00-2.71]) and retinal venular widening (1.80 [1.07-3.04] for the widest quartile), but not in women (odds ratio: 1.10 [0.671.81] and 0.91 [0.58-1.43], respectively) after adjusting for age, race/ethnicity, body mass index, pack-years of cigarette smoking, alcohol intake, hypertension duration, diabetes mellitus duration, HbA1c levels, lipid profile, micro-/macroalbuminuria, estimated glomerular filtration rate, beta-blockers use, antihypertensive therapy, and lipid-lowering therapy. In contrast, severe OSA was associated with retinal microaneurysms in women, but not in men (odds ratio: 3.22 [1.16- 8.97] and 0.59 [0.27-1.30], respectively). Conclusions-The associations of OSA severity with retinal microvascular signs may differ by sex. Whether these findings were related to sex differences in OSA exposure needs further investigation. C1 [Lin, Gen-Min; Colangelo, Laura A.; Liu, Kiang] Northwestern Univ, Dept Prevent Med, Chicago, IL 60611 USA. [Lin, Gen-Min] Hualien Armed Forces Gen Hosp, Dept Med, Hualien, Taiwan. [Lin, Gen-Min] Natl Def Med Ctr, Tri Serv Gen Hosp, Taipei, Taiwan. [Redline, Susan] Harvard Med Sch, Dept Med, Boston, MA USA. [Redline, Susan] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Redline, Susan] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Klein, Ronald; Klein, Barbara E. K.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Ophthalmol & Visual Sci, Madison, WI USA. [Cotch, Mary Frances] NEI, Div Epidemiol & Clin Applicat, NIH Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Wong, Tien Y.] Natl Univ Singapore, Singapore, Singapore. [Wong, Tien Y.] Natl Univ Singapore, Singapore Eye Res Inst, Singapore Natl Eye Ctr, Duke NUS Grad Med Sch, Singapore, Singapore. [Patel, Sanjay R.] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15260 USA. [Shea, Steven J.] Columbia Univ, Dept Med, New York, NY USA. [Shea, Steven J.] Columbia Univ, Dept Epidemiol, New York, NY USA. RP Lin, GM (reprint author), Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, 680 North Lake Shore Dr,Suite 1400, Chicago, IL 60611 USA. EM gen-min.lin@northwestern.edu OI Patel, Sanjay/0000-0002-9142-5172 FU National Heart, Lung, and Blood Institute at the National Institutes of Health [N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169]; National Center for Research Resources [UL1-TR-000040, UL1-RR-025005, R01HL098433, R21 HL121348, T32-HL069764]; Intramural Research Program at the National Eye Institute, National Institutes of Health [ZIAEY000403]; Ministry of Defense, Taiwan FX This research was supported by contracts N01-HC-95159 through N01-HC-95169 from the National Heart, Lung, and Blood Institute at the National Institutes of Health, by grants UL1-TR-000040, UL1-RR-025005 from the National Center for Research Resources, R01HL098433 (MESA Sleep, R21 HL121348) and T32-HL069764. Support for the visit 5 retinal component was provided by the Intramural Research Program at the National Eye Institute, National Institutes of Health (ZIAEY000403). A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. Lin was supported by a scholarship grant from the Ministry of Defense, Taiwan. NR 47 TC 1 Z9 1 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD JUL PY 2016 VL 5 IS 7 AR e003598 DI 10.1161/JAHA.116.003598 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EA6CT UT WOS:000386713800046 ER PT J AU Menard, MT Farber, A Assmann, SF Choudhry, NK Conte, MS Creager, MA Dake, MD Jaff, MR Kaufman, JA Powell, RJ Reid, DM Siami, FS Sopko, G White, CJ Rosenfield, K AF Menard, Matthew T. Farber, Alik Assmann, Susan F. Choudhry, Niteesh K. Conte, Michael S. Creager, Mark A. Dake, Michael D. Jaff, Michael R. Kaufman, John A. Powell, Richard J. Reid, Diane M. Siami, Flora Sandra Sopko, George White, Christopher J. Rosenfield, Kenneth TI Design and Rationale of the Best Endovascular Versus Best Surgical Therapy for Patients With Critical Limb Ischemia (BEST-CLI) Trial SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE atherosclerosis; cost-effectiveness; critical limb ischemia; endovascular; outcome; quality; stent treatment; surgery ID PERIPHERAL ARTERIAL-DISEASE; COST-EFFECTIVENESS ANALYSIS; LEG BASIL TRIAL; LOWER-EXTREMITY; THREATENING ISCHEMIA; AMPUTATION-FREE; SAPHENOUS-VEIN; TASK-FORCE; BYPASS; ANGIOPLASTY AB Background-Critical limb ischemia (CLI) is increasing in prevalence, and remains a significant source of mortality and limb loss. The decision to recommend surgical or endovascular revascularization for patients who are candidates for both varies significantly among providers and is driven more by individual preference than scientific evidence. Methods and Results-The Best Endovascular Versus Best Surgical Therapy for Patients With Critical Limb Ischemia (BEST-CLI) Trial is a prospective, randomized, multidisciplinary, controlled, superiority trial designed to compare treatment efficacy, functional outcomes, quality of life, and cost in patients undergoing best endovascular or best open surgical revascularization. Approximately 140 clinical sites in the United States and Canada will enroll 2100 patients with CLI who are candidates for both treatment options. A pragmatic trial design requires consensus on patient eligibility by at least 2 investigators, but leaves the choice of specific procedural strategy within the assigned revascularization approach to the individual treating investigator. Patients with suitable single-segment of saphenous vein available for potential bypass will be randomized within Cohort 1 (n=1620), while patients without will be randomized within Cohort 2 (n= 480). The primary efficacy end point of the trial is Major Adverse Limb Event-Free Survival. Key secondary end points include Re-intervention and Amputation-Free-Survival and Amputation Free-Survival. Conclusions-The BEST-CLI trial is the first randomized controlled trial comparing endovascular therapy to open surgical bypass in patients with CLI to be carried out in North America. This landmark comparative effectiveness trial aims to provide Level I data to clarify the appropriate role for both treatment strategies and help define an evidence-based standard of care for this challenging patient population. C1 [Menard, Matthew T.] Brigham & Womens Hosp, Div Vasc & Endovasc Surg, 75 Francis St, Boston, MA 02115 USA. [Choudhry, Niteesh K.] Brigham & Womens Hosp, Div Pharmacoepidemiol & Pharmacoecon, 75 Francis St, Boston, MA 02115 USA. [Farber, Alik] Boston Med Ctr, Div Vasc & Endovasc Surg, Boston, MA USA. [Assmann, Susan F.; Siami, Flora Sandra] New England Res Inst, 9 Galen St, Watertown, MA 02172 USA. [Conte, Michael S.] Univ Calif San Francisco, Med Ctr, Div Vasc & Endovasc Surg, San Francisco, CA USA. [Creager, Mark A.] Dartmouth Hitchcock Med Ctr, Dartmouth Hitchcock Heart & Vasc Ctr, Lebanon, NH 03766 USA. [Powell, Richard J.] Dartmouth Hitchcock Med Ctr, Div Vasc Surg, Lebanon, NH 03766 USA. [Dake, Michael D.] Stanford Hosp & Clin, Dept Cardiothorac Surg, Stanford, CA USA. [Jaff, Michael R.] Massachusetts Gen Hosp, Fireman Vasc Ctr, Boston, MA 02114 USA. [Rosenfield, Kenneth] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Kaufman, John A.] Dotter Intervent Inst OHSU, Portland, OR USA. [Reid, Diane M.; Sopko, George] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [White, Christopher J.] Ochsner Med Ctr, Dept Cardiol, New Orleans, LA USA. RP Menard, MT (reprint author), Brigham & Womens Hosp, Dept Vasc Surg, 75 Francis St, Boston, MA 02115 USA. EM mmenard@partners.org FU National Heart, Lung, and Blood Institute [U01HL107407, U01HL107352, U01HL115662] FX This trial is funded by National Heart, Lung, and Blood Institute through grant numbers U01HL107407, U01HL107352, and U01HL115662. NR 42 TC 6 Z9 7 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD JUL PY 2016 VL 5 IS 7 AR e003219 DI 10.1161/JAHA.116.003219 PG 21 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EA6CT UT WOS:000386713800018 ER PT J AU Sandfort, V Lai, SH Ahlman, MA Mallek, M Liu, ST Sibley, CT Turkbey, EB Lima, JAC Bluemke, DA AF Sandfort, Veit Lai, Shenghan Ahlman, Mark A. Mallek, Marissa Liu, Songtao Sibley, Christopher T. Turkbey, Evrim B. Lima, Joao A. C. Bluemke, David A. TI Obesity Is Associated With Progression of Atherosclerosis During Statin Treatment SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE carotid artery; carotid magnetic resonance imaging; obesity ID LIPID-LOWERING THERAPY; RANDOMIZED CONTROLLED-TRIAL; CORONARY-HEART-DISEASE; C-REACTIVE PROTEIN; CAROTID ATHEROSCLEROSIS; PLAQUE PROGRESSION; RISK; EVENTS; MRI; PREDICTION AB Background-This study aimed to determine the relationship of statin therapy and cardiovascular risk factors to changes in atherosclerosis in the carotid artery. Methods and Results-Carotid magnetic resonance imaging was used to evaluate 106 hyperlipidemic participants at baseline and after 12 months of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) treatment. Multivariable logistic regression was used to determine factors associated with progression (change in carotid wall volume >0) or regression (change <= 0) of carotid atherosclerosis. Computed tomography coronary calcium scores were obtained at baseline for all participants. The median age was 65 years (interquartile range 60-69 years), and 63% of the participants were male. Body mass index >30, elevated C-reactive protein, and hypertension were associated with increased carotid wall volume (obesity: odds ratio for progression 4.6, 95% CI 1.8-12.4, P<0.01; C-reactive protein: odds ratio for progression 2.56, 95% CI 1.17-5.73, P=0.02; hypertension: odds ratio 2.4, 95% CI 1.1-5.3, P<0.05). Higher statin dose was associated with regression of carotid wall volume (P<0.05). In multivariable analysis, obesity remained associated with progression (P<0.01), whereas statin use remained associated with regression (P<0.05). Change in atheroma volume in obese participants was +4.8% versus -4.2% in nonobese participants (P<0.05) despite greater low-density lipoprotein cholesterol reduction in obese participants. Conclusions-In a population with hyperlipidemia, obese patients showed atheroma progression despite optimized statin therapy. C1 [Sandfort, Veit; Ahlman, Mark A.; Mallek, Marissa; Liu, Songtao; Sibley, Christopher T.; Turkbey, Evrim B.] Natl Inst Hlth Clin Ctr, Dept Radiol & Imaging Sci, Bethesda, MD USA. [Lai, Shenghan; Lima, Joao A. C.] Johns Hopkins Sch Med, Baltimore, MD USA. RP Bluemke, DA (reprint author), NIH, Radiol & Imaging Sci, CC, 9000 Rockville Pike,10 Ctr Dr,Bld 10,Room 1C356, Bethesda, MD 20892 USA. EM bluemked@cc.nih.gov FU NIH intramural research program FX Funding was provided by the NIH intramural research program. NR 31 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD JUL PY 2016 VL 5 IS 7 AR e003621 DI 10.1161/JAHA.116.003621 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EA6CT UT WOS:000386713800051 ER PT J AU Akrami, K Sweeney, DA Malhotra, A AF Akrami, Kevan Sweeney, Daniel A. Malhotra, Atul TI Antibiotic stewardship in the intensive care unit: tools for de-escalation from the American Thoracic Society Meeting 2016 SO JOURNAL OF THORACIC DISEASE LA English DT Editorial Material ID RANDOMIZED CONTROLLED-TRIAL; ANTIMICROBIAL STEWARDSHIP; PNEUMONIA; PROCALCITONIN C1 [Akrami, Kevan] Univ Calif San Diego, Dept Infect Dis, San Diego, CA 92103 USA. [Akrami, Kevan] NIH, Crit Care Med, Bldg 10, Bethesda, MD 20892 USA. [Sweeney, Daniel A.; Malhotra, Atul] Univ Calif San Diego, Dept Pulm Crit Care & Sleep Med, San Diego, CA 92103 USA. RP Malhotra, A (reprint author), Univ Calif San Diego, Div Pulm Crit Care & Sleep, San Diego, CA 92103 USA. EM amalhotra@ucsd.edu FU NHLBI NIH HHS [K24 HL132105, R01 HL081823, R01 HL085188, R01 HL119201, R21 HL121794] NR 12 TC 0 Z9 0 U1 1 U2 1 PU PIONEER BIOSCIENCE PUBL CO PI HONG KONG PA 9A GOLD SHINE TOWER, 346-348 QUEEN'S RD CENTRAL, SHEUNG WAN, HONG KONG, 00000, PEOPLES R CHINA SN 2072-1439 EI 2077-6624 J9 J THORAC DIS JI J. Thorac. Dis. PD JUL PY 2016 VL 8 SU 7 BP S533 EP S535 DI 10.21037/jtd.2016.07.28 PG 3 WC Respiratory System SC Respiratory System GA DY9FK UT WOS:000385438900003 PM 27606085 ER PT J AU Noinaj, N Mayclin, S Stanley, AM Jao, CC Buchanan, SK AF Noinaj, Nicholas Mayclin, Stephen Stanley, Ann M. Jao, Christine C. Buchanan, Susan K. TI From Constructs to Crystals - Towards Structure Determination of beta-barrel Outer Membrane Proteins SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Chemistry; Issue 113; beta-barrel; membrane protein; protein crystallization; structural biology; membranes; protein refolding; protein purification ID HIGH-THROUGHPUT CRYSTALLIZATION; LIGATION-INDEPENDENT CLONING; ANGSTROM RESOLUTION; ESCHERICHIA-COLI; FIMD USHER; RECEPTOR; TRANSPORTER; BIOGENESIS; SECRETION; NEISSERIA AB Membrane proteins serve important functions in cells such as nutrient transport, motility, signaling, survival and virulence, yet constitute only similar to 1% percent of known structures. There are two types of membrane proteins, alpha-helical and beta-barrel. While alpha-helical membrane proteins can be found in nearly all cellular membranes, beta-barrel membrane proteins can only be found in the outer membranes of mitochondria, chloroplasts, and Gram-negative bacteria. One common bottleneck in structural studies of membrane proteins in general is getting enough pure sample for analysis. In hopes of assisting those interested in solving the structure of their favorite beta-barrel outer membrane protein (OMP), general protocols are presented for the production of target beta-barrel OMPs at levels useful for structure determination by either X-ray crystallography and/or NMR spectroscopy. Here, we outline construct design for both native expression and for expression into inclusion bodies, purification using an affinity tag, and crystallization using detergent screening, bicelle, and lipidic cubic phase techniques. These protocols have been tested and found to work for most OMPs from Gram-negative bacteria; however, there are some targets, particularly for mitochondria and chloroplasts that may require other methods for expression and purification. As such, the methods here should be applicable for most projects that involve OMPs from Gram-negative bacteria, yet the expression levels and amount of purified sample will vary depending on the target OMP. C1 [Noinaj, Nicholas] Purdue Univ, Dept Biol Sci, Markey Ctr Struct Biol, W Lafayette, IN 47907 USA. [Mayclin, Stephen; Stanley, Ann M.; Jao, Christine C.; Buchanan, Susan K.] NIDDK, NIH, Bethesda, MD USA. [Stanley, Ann M.; Jao, Christine C.] NIGMS, NIH, Bethesda, MD USA. RP Noinaj, N (reprint author), Purdue Univ, Dept Biol Sci, Markey Ctr Struct Biol, W Lafayette, IN 47907 USA. EM nnoinaj@purdue.edu FU National Institute of Diabetes and Digestive and Kidney Diseases; Intramural Research Program at the National Institutes of Health; National Institute of General Medical Sciences; National Institute of Allergy and Infectious Diseases [1K22AI113078-01]; Department of Biological Sciences at Purdue University FX We would like to thank Herve Celia of the CNRS for providing the UV images and Chris Dettmar and Garth Simpson in the Department of Chemistry at Purdue University for providing the SONICC images. We would like to acknowledge funding from the National Institute of Diabetes and Digestive and Kidney Diseases and the Intramural Research Program at the National Institutes of Health. Additionally, we would like to acknowledge additional funding from the National Institute of General Medical Sciences (A.M.S. and C.J.), National Institute of Allergy and Infectious Diseases (N.N. 1K22AI113078-01), and the Department of Biological Sciences at Purdue University (N.N.). NR 44 TC 0 Z9 0 U1 4 U2 4 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD JUL PY 2016 IS 113 AR e53245 DI 10.3791/53245 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ1TG UT WOS:000385622600009 ER PT J AU Rosenheck, R Leslie, D Sint, K Lin, HQ Robinson, DG Schooler, NR Mueser, KT Penn, DL Addington, J Brunette, MF Correll, CU Estroff, SE Marcy, P Robinson, J Severe, J Rupp, A Schoenbaum, M Kane, JM AF Rosenheck, Robert Leslie, Douglas Sint, Kyaw Lin, Haiqun Robinson, Delbert G. Schooler, Nina R. Mueser, Kim T. Penn, David L. Addington, Jean Brunette, Mary F. Correll, Christoph U. Estroff, Sue E. Marcy, Patricia Robinson, James Severe, Joanne Rupp, Agnes Schoenbaum, Michael Kane, John M. TI Cost-Effectiveness of Comprehensive, Integrated Care for First Episode Psychosis in the NIMH RAISE Early Treatment Program SO SCHIZOPHRENIA BULLETIN LA English DT Article DE schizophrenia; cost-effectiveness; quality adjusted life years ID RANDOMIZED CONTROLLED-TRIAL; EARLY INTERVENTION SERVICE; NEGATIVE SYNDROME SCALE; ADJUSTED LIFE-YEAR; HEALTH-CARE; CATCHMENT-AREA; HOSPITAL USE; SCHIZOPHRENIA; DISORDERS; QUALITY AB This study compares the cost-effectiveness of Navigate (NAV), a comprehensive, multidisciplinary, team-based treatment approach for first episode psychosis (FEP) and usual Community Care (CC) in a cluster randomization trial. Patients at 34 community treatment clinics were randomly assigned to either NAV (N = 223) or CC (N = 181) for 2 years. Effectiveness was measured as a one standard deviation change on the Quality of Life Scale (QLS-SD). Incremental cost effectiveness ratios were evaluated with bootstrap distributions. The Net Health Benefits Approach was used to evaluate the probability that the value of NAV benefits exceeded its costs relative to CC from the perspective of the health care system. The NAV group improved significantly more on the QLS and had higher outpatient mental health and antipsychotic medication costs. The incremental cost-effectiveness ratio was $ 12 081/QLS-SD, with a.94 probability that NAV was more cost-effective than CC at $ 40 000/QLS-SD. When converted to monetized Quality Adjusted Life Years, NAV benefits exceeded costs, especially at future generic drug prices. C1 [Rosenheck, Robert; Sint, Kyaw; Lin, Haiqun] Yale Med Sch, Dept Psychiat & Publ Hlth, New Haven, CT USA. [Leslie, Douglas] Penn State Coll Med, Dept Publ Hlth Sci, Hershey, PA USA. [Robinson, Delbert G.; Schooler, Nina R.; Correll, Christoph U.; Marcy, Patricia; Kane, John M.] North Shore Long Isl Jewish, Zucker Hillside Hosp, Psychiat Res, Glen Oaks, NY USA. [Robinson, Delbert G.; Correll, Christoph U.; Kane, John M.] Feinstein Inst Med Res, Manhasset, NY USA. [Robinson, Delbert G.; Correll, Christoph U.; Kane, John M.] Hofstra North Shore LIJ Sch Med, Dept Psychiat, Hempstead, NY USA. [Robinson, Delbert G.; Correll, Christoph U.; Kane, John M.] Hofstra North Shore LIJ Sch Med, Dept Mol Med, Hempstead, NY USA. [Schooler, Nina R.; Correll, Christoph U.; Kane, John M.] Albert Einstein Coll Med, Dept Psychiat & Behav Sci, Bronx, NY 10467 USA. [Schooler, Nina R.] Suny Downstate Med Ctr, Dept Psychiat, Brooklyn, NY 11203 USA. [Mueser, Kim T.] Boston Univ, Dept Occupat Therapy, Ctr Psychiat Rehabil, Boston, MA 02215 USA. [Mueser, Kim T.] Boston Univ, Dept Psychiat, Ctr Psychiat Rehabil, Boston, MA 02215 USA. [Mueser, Kim T.] Boston Univ, Dept Psychol, Ctr Psychiat Rehabil, 64 Cummington St, Boston, MA 02215 USA. [Penn, David L.] Univ North Carolina Chapel Hill, Dept Psychol, Chapel Hill, NC USA. [Penn, David L.] Australian Catholic Univ, Sch Psychol, Melbourne, Vic, Australia. [Addington, Jean] Univ Calgary, Hotchkiss Brain Inst, Dept Psychiat, Calgary, AB, Canada. [Brunette, Mary F.] Geisel Sch Med Dartmouth, Lebanon, NH USA. [Brunette, Mary F.] DHHS, Bur Behav Hlth, Concord, NH USA. [Estroff, Sue E.] Univ N Carolina, Dept Social Med, Chapel Hill, NC USA. [Robinson, James] Nathan S Kline Inst Psychiat Res, Orangeburg, NY USA. [Severe, Joanne; Rupp, Agnes; Schoenbaum, Michael] NIMH, Rockville, MD 20857 USA. RP Rosenheck, R (reprint author), VA Connecticut Hlth Care Syst, VA New England Mental Illness Res Educ & Clin Ctr, 950 Campbell Ave, West Haven, CT 06516 USA. EM Robert.Rosenheck@Yale.Edu FU American Recovery and Reinvestment Act; National Institute of Mental Health [HHSN271200900019C] FX This work was supported with funds from the American Recovery and Reinvestment Act and from the National Institute of Mental Health, under Contract No. HHSN271200900019C. The contents of this article are solely the responsibility of the authors and do not necessarily represent the views of National Institute of Mental Health or the US Department of Health and Human Services. NR 44 TC 2 Z9 2 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD JUL PY 2016 VL 42 IS 4 BP 896 EP 906 DI 10.1093/schbul/sbv224 PG 11 WC Psychiatry SC Psychiatry GA DY7AF UT WOS:000385280800011 PM 26834024 ER PT J AU Xu, Y Yue, WH Shugart, YY Li, S Cai, L Li, Q Cheng, ZH Wang, GQ Zhou, ZH Jin, CH Yuan, JM Tian, L Wang, J Zhang, K Zhang, KR Liu, S Song, YQ Zhang, FQ AF Xu, Yong Yue, Weihua Shugart, Yin Yao Li, Sheng Cai, Lei Li, Qiang Cheng, Zaohuo Wang, Guoqiang Zhou, Zhenhe Jin, Chunhui Yuan, Jianmin Tian, Lin Wang, Jun Zhang, Kai Zhang, Kerang Liu, Sha Song, Yuqing Zhang, Fuquan TI Exploring Transcription Factors-microRNAs Co-regulation Networks in Schizophrenia SO SCHIZOPHRENIA BULLETIN LA English DT Article DE schizophrenia; transcriptional factor; microRNA; miR-124-3p; EGRl ID GENE COEXPRESSION NETWORKS; R PACKAGE; COMMON VARIANTS; BRAIN DISORDERS; CONFERRING RISK; HUMAN-DISEASE; EXPRESSION; MICROARRAY; DATABASE; GENOME AB Background: Transcriptional factors (TFs) and microRNAs (miRNAs) have been recognized as 2 classes of principal gene regulators that may be responsible for genome coexpression changes observed in schizophrenia (SZ). Methods: This study aims to (1) identify differentially coexpressed genes (DCGs) in 3 mRNA expression microarray datasets; (2) explore potential interactions among the DCGs, and differentially expressed miRNAs identified in our dataset composed of early-onset SZ patients and healthy controls; (3) validate expression levels of some key transcripts; and (4) explore the druggability of DCGs using the curated database. Results: We detected a differential coexpression network associated with SZ and found that 9 out of the 12 regulators were replicated in either of the 2 other datasets. Leveraging the differentially expressed miRNAs identified in our previous dataset, we constructed a miRNA-TF-gene network relevant to SZ, including an EGR1-miR-1243p-SKIL feed-forward loop. Our real-time quantitative PCR analysis indicated the overexpression of miR-124-3p, the under expression of SKIL and EGR1 in the blood of SZ patients compared with controls, and the direction of change of miR-124-3p and SKIL mRNA levels in SZ cases were reversed after a 12-week treatment cycle. Our druggability analysis revealed that many of these genes have the potential to be drug targets. Conclusions: Together, our results suggest that coexpression network abnormalities driven by combinatorial and interactive action from TFs and miRNAs may contribute to the development of SZ and be relevant to the clinical treatment of the disease. C1 [Xu, Yong; Zhang, Kerang; Liu, Sha] Shanxi Med Univ, Hosp 1, Clin Med Coll 1, Dept Psychiat, Taiyuan, Peoples R China. [Yue, Weihua; Song, Yuqing] Peking Univ, Hosp 6, Inst Mental Hlth, Dept Psychiat, Beijing, Peoples R China. [Yue, Weihua] Peking Univ, Key Lab Mental Hlth, Minist Hlth, Beijing, Peoples R China. [Yue, Weihua] Peking Univ, Natl Clin Res Ctr Mental Disorders, Beijing, Peoples R China. [Shugart, Yin Yao] NIMH, Unit Stat Genom, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Li, Sheng; Cai, Lei] Shanghai Jiao Tong Univ, Minist Educ, BioX Inst, Key Lab Genet Dev & Neuropsychiat Disorders, Shanghai, Peoples R China. [Li, Qiang] Fudan Univ, Childrens Hosp, Shanghai Key Lab Birth Defect, Shanghai, Peoples R China. [Cheng, Zaohuo; Wang, Guoqiang; Zhou, Zhenhe; Jin, Chunhui; Yuan, Jianmin; Tian, Lin; Wang, Jun; Zhang, Kai; Zhang, Fuquan] Nanjing Med Univ, Dept Psychiat, Wuxi Mental Hlth Ctr, 156 Qianrong Rd, Wuxi, Peoples R China. RP Zhang, FQ (reprint author), Nanjing Med Univ, Dept Psychiat, Wuxi Mental Hlth Ctr, 156 Qianrong Rd, Wuxi, Peoples R China. EM zhangfq@njmu.edu.cn FU National Natural Science Foundation of China [81271482, 81471364, 81571319, 81222017]; Program for New Century Excellent Talents in University [NCET-12-1036]; Construction Plan for Shanxi Science & Technology Infrastructure Platforms [2015091002-0102]; Intramural Research Program of National Institute of Mental Health, National Institutes of Health [MH002929-05] FX This work was supported by National Natural Science Foundation of China (81271482, 81471364, 81571319, 81222017), Program for New Century Excellent Talents in University (NCET-12-1036), and Construction Plan for Shanxi Science & Technology Infrastructure Platforms (2015091002-0102). Shugart was supported by the Intramural Research Program of National Institute of Mental Health, National Institutes of Health (MH002929-05). NR 58 TC 2 Z9 2 U1 2 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD JUL PY 2016 VL 42 IS 4 BP 1037 EP 1045 DI 10.1093/schbul/sbv170 PG 9 WC Psychiatry SC Psychiatry GA DY7AF UT WOS:000385280800026 PM 26609121 ER PT J AU Bhadriraju, K Halter, M Amelot, J Bajcsy, P Chalfoun, J Vandecreme, A Mallon, BS Park, KY Sista, S Elliott, JT Plant, AL AF Bhadriraju, Kiran Halter, Michael Amelot, Julien Bajcsy, Peter Chalfoun, Joe Vandecreme, Antoine Mallon, Barbara S. Park, Kye-yoon Sista, Subhash Elliott, John T. Plant, Anne L. TI Large-scale time-lapse microscopy of Oct4 expression in human embryonic stem cell colonies SO STEM CELL RESEARCH LA English DT Article DE Fluorescence microscopy; Stem cells; Live cell imaging; Cell therapy; Pluripotency ID SELF-RENEWAL; TRANSCRIPTIONAL REGULATION; FLUORESCENCE MICROSCOPE; ES CELLS; PLURIPOTENCY; NANOG; DIFFERENTIATION; SOX2; ENHANCER; NETWORK AB Identification and quantification of the characteristics of stemcell preparations is critical for understanding stem cell biology and for the development and manufacturing of stem cell based therapies. We have developed image analysis and visualization software that allows effective use of time-lapse microscopy to provide spatial and dynamic information from large numbers of human embryonic stem cell colonies. To achieve statistically relevant sampling, we examined >680 colonies from 3 different preparations of cells over 5 days each, generating a total experimental dataset of 0.9 terabyte (TB). The 0.5 Giga-pixel images at each time point were represented by multi-resolution pyramids and visualized using the Deep Zoom Javascript library extended to support viewing Giga-pixel images over time and extracting data on individual colonies. We present a methodology that enables quantification of variations in nominally-identical preparations and between colonies, correlation of colony characteristics with Oct4 expression, and identification of rare events. (C) Published by Elsevier B.V. C1 [Bhadriraju, Kiran] Univ Maryland, Dept Bioengn, College Pk, MD 20742 USA. [Halter, Michael; Sista, Subhash; Elliott, John T.; Plant, Anne L.] NIST, Biosyst & Biomat Div, Mat Measurement Lab, Gaithersburg, MD 20899 USA. [Amelot, Julien; Bajcsy, Peter; Chalfoun, Joe; Vandecreme, Antoine] NIST, Software Syst Div, Informat Technol Lab, Gaithersburg, MD 20899 USA. [Mallon, Barbara S.; Park, Kye-yoon] NINDS, NIH Stem Cell Unit, Div Intramural Res, NIH,US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Halter, M (reprint author), NIST, Biosyst & Biomat Div, Mat Measurement Lab, Gaithersburg, MD 20899 USA. FU ISAC Scholars Program FX We would like to thank Michael Majurski, Jing Gao, and Mylene Simon for data processing and web application development. We would also like to thank Steven Lund and James Filliben for help with statistical analysis. MH acknowledges support from the ISAC Scholars Program. NR 36 TC 1 Z9 1 U1 6 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1873-5061 EI 1876-7753 J9 STEM CELL RES JI Stem Cell Res. PD JUL PY 2016 VL 17 IS 1 BP 122 EP 129 DI 10.1016/j.scr.2016.05.012 PG 8 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA DY6ZF UT WOS:000385278000024 PM 27286574 ER PT J AU Sirenko, SG Maltsev, VA Yaniv, Y Bychkov, R Yaeger, D Vinogradova, T Spurgeon, HA Lakatta, EG AF Sirenko, Syevda G. Maltsev, Victor A. Yaniv, Yael Bychkov, Rostislav Yaeger, Daniel Vinogradova, Tatiana Spurgeon, Harold A. Lakatta, Edward G. TI Electrochemical Na+ and Ca2+ gradients drive coupled-clock regulation of automaticity of isolated rabbit sinoatrial nodal pacemaker cells SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE cardiac automaticity; sodium; calcium; electrochemical driving forces ID CARDIAC PURKINJE-FIBERS; RYANODINE RECEPTORS; DIGITALIS TOXICITY; INTRACELLULAR PH; REDOX MODIFICATION; SODIUM ACTIVITY; ATPASE ACTIVITY; SINUS NODE; HEART; OUABAIN AB Coupling of an intracellular Ca2+ clock to surface membrane ion channels, i.e., a "membrane clock," via coupling of electrochemical Na+ and Ca2+ gradients (E-Na and E-Ca, respectively) has been theorized to regulate sinoatrial nodal cell (SANC) normal automaticity. To test this hypothesis, we measured responses of [Na+](i), [Ca2+](i), membrane potential, action potential cycle length (APCL), and rhythm in rabbit SANCs to Na+ /K+ pump inhibition by the digitalis glycoside, digoxigenin (DG, 10-20 mu mol/l). Initial small but significant increases in [Na+](i) and [Ca2+](i) and reductions in E-Na and E-Ca in response to DG led to a small reduction in maximum diastolic potential (MDP), significantly enhanced local diastolic Ca2+ releases (LCRs), and reduced the average APCL. As [Na+](i) and [Ca2+](i) continued to increase at longer times following DG exposure, further significant reductions in MDP, E-Na, and E-Ca occurred; LCRs became significantly reduced, and APCL became progressively and significantly prolonged. This was accompanied by increased APCL variability. We also employed a coupled-clock numerical model to simulate changes in E-Na and E-Ca simultaneously with ion currents not measured experimentally. Numerical modeling predicted that, as the E-Na and E-Ca monotonically reduced over time in response to DG, ion currents (I-CaL, I-CaT, I-f, I-Kr, and I-bNa) monotonically decreased. In parallel with the biphasic APCL, diastolic I-NCX manifested biphasic changes; initial I-NCX increase attributable to enhanced LCR ensemble Ca2+ signal was followed by I-NCX reduction as E-NCX (E-NCX = 3E(Na) - 2E(Ca)) decreased. Thus SANC automaticity is tightly regulated by E-Na, E-Ca, and E-NCX via a complex interplay of numerous key clock components that regulate SANC clock coupling. C1 [Sirenko, Syevda G.; Maltsev, Victor A.; Yaniv, Yael; Bychkov, Rostislav; Yaeger, Daniel; Vinogradova, Tatiana; Spurgeon, Harold A.; Lakatta, Edward G.] NIA, Cardiovasc Sci Lab, NIH, Intramural Res Program, Baltimore, MD 21224 USA. [Yaniv, Yael] Technion IIT, Biomed Engn Fac, Haifa, Israel. [Bychkov, Rostislav] Univ Cent Caribe, Bayamon, PR USA. RP Lakatta, EG (reprint author), NIA, Cardiovasc Sci Lab, NIH, Biomed Res Ctr, 51 Bayview Blvd, Baltimore, MD 21224 USA. EM lakattae@grc.nia.nih.gov FU Intramural Research Program of the NIH, National Institute on Aging FX This work was supported by the Intramural Research Program of the NIH, National Institute on Aging. NR 57 TC 0 Z9 0 U1 0 U2 0 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 JUL PY 2016 VL 311 IS 1 BP H251 EP H267 DI 10.1152/ajpheart.00667.2015 PG 17 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA DY3CZ UT WOS:000384969700026 PM 27208164 ER PT J AU Karschner, EL Swortwood, MJ Hirvonen, J Goodwin, RS Bosker, WM Ramaekers, JG Huestis, MA AF Karschner, Erin L. Swortwood, Madeleine J. Hirvonen, Jussi Goodwin, Robert S. Bosker, Wendy M. Ramaekers, Johannes G. Huestis, Marilyn A. TI Extended plasma cannabinoid excretion in chronic frequent cannabis smokers during sustained abstinence and correlation with psychomotor performance SO DRUG TESTING AND ANALYSIS LA English DT Article DE cannabinoid; Delta(9)-tetrahydrocannabinol; cannabis; chronic; abstinence ID MASS-SPECTROMETRY; GLUCURONIDATED CANNABINOIDS; SIMULTANEOUS QUANTIFICATION; GAS-CHROMATOGRAPHY; MARIJUANA USERS; HUMAN-URINE; ORAL FLUID; BLOOD; DELTA-9-TETRAHYDROCANNABINOL; THC AB Cannabis smoking increases motor vehicle accident risk. Empirically defined cannabinoid detection windows are important to drugged driving legislation. Our aims were to establish plasma cannabinoid detection windows in frequent cannabis smokers and to determine if residual cannabinoid concentrations were correlated with psychomotor performance. Twenty-eight male chronic frequent cannabis smokers resided on a secure research unit for up to 33 days with daily blood collection. Plasma specimens were analyzed for Delta(9)-tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OH-THC), and 11-nor-9-carboxy-THC (THCCOOH) by gas chromatography-mass spectrometry. Critical tracking and divided attention tasks were administered at baseline (after overnight stay to ensure lack of acute intoxication) and after 1, 2, and 3 weeks of cannabis abstinence. Twenty-seven of the twenty-eight participants were THC-positive at admission (median 4.2 mu g/L). THC concentrations significantly decreased 24 h after admission, but were still >= 2 mu g/L in 16 of the 28 participants 48 h after admission. THC was detected in 3 of 5 specimens on day 30. The last positive 11-OH-THC specimen was 15 days after admission. THCCOOH was measureable in 4 of 5 participants after 30 days of abstinence. Years of prior cannabis use significantly correlated with THC concentrations on admission, and days 7 and 14. Tracking error, evaluated by the Divided Attention Task, was the only evaluated psychomotor assessment significantly correlated with cannabinoid concentrations at baseline and day 8 (11-OH-THC only). Median THC was 0.3 mu g/L in 5 chronic frequent cannabis smokers' plasma samples after 30 days of sustained abstinence. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. C1 [Karschner, Erin L.; Swortwood, Madeleine J.; Goodwin, Robert S.; Bosker, Wendy M.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab, Intramural Res Program, NIH, 251 Bayview Blvd,Suite 05A721, Baltimore, MD 21224 USA. [Karschner, Erin L.] Armed Forces Med Examiner Syst, Div Forens Toxicol, 115 Purple Heart Dr, Dover Afb, DE 19902 USA. [Hirvonen, Jussi] NIMH, Mol Imaging Branch, IRP, NIH, 6001 Execut Blvd, Bethesda, MD 20892 USA. [Hirvonen, Jussi] Univ Turku, Dept Diagnost Radiol, Turun 20014, Finland. [Goodwin, Robert S.] 7 Church Lane,Suite 15A, Pikesville, MD 21208 USA. [Bosker, Wendy M.] Forschungszentrum Julich, Inst Neurosci & Med 4, D-52425 Julich, Germany. [Bosker, Wendy M.; Ramaekers, Johannes G.] Maastricht Univ, Fac Psychol & Neurosci, Dept Neuropsychol & Psychopharmacol, NL-6211 LK Maastricht, Netherlands. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab, Intramural Res Program, NIH,Biomed Res Ctr, 251 Bayview Blvd,Room 05A721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural Research Programs of the National Institute on Drug Abuse; National Institutes of Mental Health, National Institutes of Health FX This research was funded by the Intramural Research Programs of the National Institute on Drug Abuse and National Institutes of Mental Health, National Institutes of Health. NR 56 TC 0 Z9 0 U1 5 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1942-7603 EI 1942-7611 J9 DRUG TEST ANAL JI Drug Test. Anal. PD JUL PY 2016 VL 8 IS 7 BP 682 EP 689 DI 10.1002/dta.1825 PG 8 WC Biochemical Research Methods; Chemistry, Analytical; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Chemistry; Pharmacology & Pharmacy GA DY0RI UT WOS:000384803500009 PM 26097154 ER PT J AU Hartman, RL Brown, TL Milavetz, G Spurgin, A Gorelick, DA Gaffney, G Huestis, MA AF Hartman, Rebecca L. Brown, Timothy L. Milavetz, Gary Spurgin, Andrew Gorelick, David A. Gaffney, Gary Huestis, Marilyn A. TI Controlled vaporized cannabis, with and without alcohol: subjective effects and oral fluid-blood cannabinoid relationships SO DRUG TESTING AND ANALYSIS LA English DT Article DE cannabis; alcohol; subjective; blood; oral fluid ID WHOLE-BLOOD; SMOKED CANNABIS; DELTA(9)-TETRAHYDROCANNABINOL THC; PHARMACOKINETIC PROPERTIES; PSYCHOMOTOR PERFORMANCE; MASS-SPECTROMETRY; MARIJUANA SMOKING; HUMAN VOLUNTEERS; MOTOR CONTROL; PLASMA AB Vaporized cannabis and concurrent cannabis and alcohol intake are commonplace. We evaluated the subjective effects of cannabis, with and without alcohol, relative to blood and oral fluid (OF, advantageous for cannabis exposure screening) cannabinoid concentrations and OF/blood and OF/plasma vaporized-cannabinoid relationships. Healthy adult occasional-to-moderate cannabis smokers received a vaporized placebo or active cannabis (2.9% and 6.7% Delta(9)-tetrahydrocannabinol, THC) with or without oral low-dose alcohol (similar to 0.065g/210L peak breath alcohol concentration [BrAC]) in a within-subjects design. Blood and OF were collected up to 8.3 h post-dose and subjective effects measured at matched time points with visual-analogue scales and 5-point Likert scales. Linear mixed models evaluated subjective effects by THC concentration, BrAC, and interactions. Effects by time point were evaluated by dose-wise analysis of variance (ANOVA). OF versus blood or plasma cannabinoid ratios and correlations were evaluated in paired-positive specimens. Nineteen participants (13 men) completed the study. Blood THC concentration or BrAC significantly associated with subjective effects including 'high', while OF contamination prevented significant OF concentration associations <1.4 h post-dose. Subjective effects persisted through 3.3-4.3 h, with alcohol potentiating the duration of the cannabis effects. Effect-versus-THC concentration and effect-versus-alcohol concentration hystereses were counterclockwise and clockwise, respectively. OF/blood and OF/plasma THC significantly correlated (all Spearman r >= 0.71), but variability was high. Vaporized cannabis subjective effects were similar to those previously reported after smoking, with duration extended by concurrent alcohol. Cannabis intake was identified by OF testing, but OF concentration variability limited interpretation. Blood THC concentrations were more consistent across subjects and more accurate at predicting cannabis' subjective effects. Copyright (C) 2015 John Wiley & Sons, Ltd. C1 [Hartman, Rebecca L.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab, Intramural Res Program, NIH, Baltimore, MD USA. [Hartman, Rebecca L.] Univ Maryland, Toxicol Program, Baltimore, MD 21201 USA. [Brown, Timothy L.] Univ Iowa, Natl Adv Driving Simulator, Iowa City, IA USA. [Milavetz, Gary; Spurgin, Andrew] Univ Iowa, Coll Pharm, Iowa City, IA 52242 USA. [Gorelick, David A.] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. [Gaffney, Gary] Univ Iowa, Carver Coll Med, Iowa City, IA USA. RP Huestis, MA (reprint author), Biomed Res Ctr, Suite 200,Room 05A-721,251 Bayview Blvd, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural Research Program, National Institute on Drug Abuse, NIH; United States Office of National Drug Control Policy; National Highway Traffic Safety Administration FX We thank the nurses and staff of the University of Iowa Clinical Research Unit and National Advanced Driving Simulator, especially Cheryl Roe, Jennifer Henderson, Rose Schmitt, and Kayla Smith, for excellent contributions to successful study completion. We also thank Drs Dereece Smither and Richard Compton, National Highway Traffic Safety Administration, for invaluable input. We acknowledge University of Maryland, Baltimore Toxicology Program, and Graduate Partnership Program, National Institutes of Health (NIH). Quantisal TM and Volcano (R) devices were provided by the manufacturers to NIH through Materials Transfer Agreements, but manufacturers played no role in study design, data analysis, or manuscript writing. Research was funded by the Intramural Research Program, National Institute on Drug Abuse, NIH, the United States Office of National Drug Control Policy, and the National Highway Traffic Safety Administration. NR 53 TC 1 Z9 1 U1 5 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1942-7603 EI 1942-7611 J9 DRUG TEST ANAL JI Drug Test. Anal. PD JUL PY 2016 VL 8 IS 7 BP 690 EP 701 DI 10.1002/dta.1839 PG 12 WC Biochemical Research Methods; Chemistry, Analytical; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Chemistry; Pharmacology & Pharmacy GA DY0RI UT WOS:000384803500010 PM 26257143 ER PT J AU Arai, AE AF Arai, Andrew E. TI Area at risk in acute myocardial infarction: oedema imaging and species-specific findings SO EUROPEAN HEART JOURNAL-CARDIOVASCULAR IMAGING LA English DT Editorial Material ID ISCHEMIC AREA; BIMODAL PATTERN; AT-RISK; SALVAGE; ISCHEMIA/REPERFUSION; GADOLINIUM; MRI C1 [Arai, Andrew E.] NHLBI, Dept Hlth & Human Serv, NIH, Bldg 10,Room B1D416,MSC 1061,10 Ctr Dr, Bethesda, MD 20892 USA. RP Arai, AE (reprint author), NHLBI, Dept Hlth & Human Serv, NIH, Bldg 10,Room B1D416,MSC 1061,10 Ctr Dr, Bethesda, MD 20892 USA. EM araia@nih.gov NR 16 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 2047-2404 EI 2047-2412 J9 EUR HEART J-CARD IMG JI Eur. Heart J.-Cardiovasc. Imaging PD JUL 1 PY 2016 VL 17 IS 7 BP 754 EP 755 DI 10.1093/ehjci/jew074 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DX9OP UT WOS:000384725300009 PM 27145801 ER PT J AU Kuhl, JT George, RT Mehra, VC Linde, JJ Chen, M Arai, AE Di Carli, M Kitagawa, K Dewey, M Lima, JAC Kofoed, KF AF Kuhl, Jorgen Tobias George, Richard T. Mehra, Vishal C. Linde, Jesper J. Chen, Marcus Arai, Andrew E. Di Carli, Marcelo Kitagawa, Kakuya Dewey, Marc Lima, Joao A. C. Kofoed, Klaus Fuglsang TI Endocardial-epicardial distribution of myocardial perfusion reserve assessed by multidetector computed tomography in symptomatic patients without significant coronary artery disease: insights from the CORE320 multicentre study SO EUROPEAN HEART JOURNAL-CARDIOVASCULAR IMAGING LA English DT Article DE myocardial perfusion; multi-detector computed tomography; coronary artery disease ID POSITRON-EMISSION-TOMOGRAPHY; BLOOD-FLOW; INSULIN-RESISTANCE; CT; ANGIOGRAPHY; HETEROGENEITY; DYSFUNCTION; ISCHEMIA; HUMANS; RISK AB Aim Previous animal studies have demonstrated differences in perfusion and perfusion reserve between the subendocardium and subepicardium. 320-row computed tomography (CT) with sub-millimetre spatial resolution allows for the assessment of transmural differences in myocardial perfusion reserve (MPR) in humans. We aimed to test the hypothesis that MPR in all myocardial layers is determined by age, gender, and cardiovascular risk profile in patients with ischaemic symptoms or equivalent but without obstructive coronary artery disease (CAD). Methods and results A total of 149 patients enrolled in the CORE320 study with symptoms or signs of myocardial ischaemia and absence of significant CAD by invasive coronary angiography were scanned with static rest and stress CT perfusion. Myocardial attenuation densities were assessed at rest and during adenosine stress, segmented into 3 myocardial layers and 13 segments. MPR was higher in the subepicardium compared with the subendocardium (124% interquartile range [45, 235] vs. 68% [22,102], P < 0.001). Moreover, MPR in the septum was lower than in the inferolateral and anterolateral segments of the myocardium (55% [19, 104] vs. 89% [37, 168] and 124% [54, 270], P < 0.001). By multivariate analysis, high body mass index was significantly associated with reduced MPR in all myocardial layers when adjusted for cardiovascular risk factors (P = 0.02). Conclusion In symptomatic patients without significant coronary artery stenosis, distinct differences in endocardial-epicardial distribution of perfusion reserve may be demonstrated with static CT perfusion. Low MPR in all myocardial layers was observed specifically in obese patients. C1 [Kuhl, Jorgen Tobias; Linde, Jesper J.; Kofoed, Klaus Fuglsang] Univ Copenhagen, Dept Cardiol, Ctr Heart 2012, Rigshosp, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. [George, Richard T.; Mehra, Vishal C.; Lima, Joao A. C.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Mehra, Vishal C.; Chen, Marcus; Arai, Andrew E.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Di Carli, Marcelo] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Kitagawa, Kakuya] Mie Univ Hosp, Tsu, Mie, Japan. [Dewey, Marc] Charite, Berlin, Germany. [Kofoed, Klaus Fuglsang] Univ Copenhagen, Dept Radiol, Rigshosp, Copenhagen, Denmark. RP Kuhl, JT (reprint author), Univ Copenhagen, Dept Cardiol, Ctr Heart 2012, Rigshosp, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. EM tobiaskh@gmail.com FU Toshiba Medical Systems Corporation FX The study sponsor, Toshiba Medical Systems Corporation, was not involved in any stage of the study design, data acquisition, data analysis, or manuscript preparation. NR 28 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 2047-2404 EI 2047-2412 J9 EUR HEART J-CARD IMG JI Eur. Heart J.-Cardiovasc. Imaging PD JUL 1 PY 2016 VL 17 IS 7 BP 779 EP 787 DI 10.1093/ehjci/jev206 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DX9OP UT WOS:000384725300015 PM 26341292 ER PT J AU Sandfort, V Ahlman, MA Jones, EC Selwaness, M Chen, MY Folio, LR Bluemke, DA AF Sandfort, Veit Ahlman, Mark A. Jones, Elizabeth C. Selwaness, Mariana Chen, Marcus Y. Folio, Les R. Bluemke, David A. TI High pitch third generation dual-source CT: Coronary and cardiac visualization on routine chest CT SO JOURNAL OF CARDIOVASCULAR COMPUTED TOMOGRAPHY LA English DT Article DE CT; Cardiac imaging; Incidental findings ID COMPUTED TOMOGRAPHIC ANGIOGRAPHY; PULMONARY NODULES; IMAGE QUALITY; ARTERY-DISEASE; DIAGNOSIS AB Background: Chest CT scans are frequently performed in radiology departments but have not previously contained detailed depiction of cardiac structures. Objectives: To evaluate myocardial and coronary visualization on high-pitch non-gated CT of the chest using 3rd generation dual-source computed tomography (CT). Methods: Cardiac anatomy of patients who had 3rd generation, non-gated high pitch contrast enhanced chest CT and who also had prior conventional (low pitch) chest CT as part of a chest abdomen pelvis exam was evaluated. Cardiac image features were scored by reviewers blinded to diagnosis and pitch. Paired analysis was performed. Results: 3862 coronary segments and 2220 cardiac structures were evaluated by two readers in 222 CT scans. Most patients (97.2%) had chest CT for oncologic evaluation. The median pitch was 2.34 (IQR 2.05, 2.65) in high pitch and 0.8 (IQR 0.8, 0.8) in low pitch scans (p < 0.001). High pitch CT showed higher image visualization scores for all cardiovascular structures compared with conventional pitch scans (p < 0.0001). Coronary arteries were visualized in 9 coronary segments per exam in high pitch scans versus 2 segments for conventional pitch (p < 0.0001). Radiation exposure was lower in the high pitch group compared with the conventional pitch group (median CTDIvol 10.83 vs. 12.36 mGy and DLP 790 vs. 827 mGycm respectively, p < 0.01 for both) with comparable image noise (p = 0.43). Conclusion: Myocardial structure and coronary arteries are frequently visualized on non-gated 3rd generation chest CT. These results raise the question of whether the heart and coronary arteries should be routinely interpreted on routine chest CT that is otherwise obtained for non-cardiac indications. Published by Elsevier Inc. on behalf of Society of Cardiovascular Computed Tomography. C1 [Sandfort, Veit; Ahlman, Mark A.; Jones, Elizabeth C.; Selwaness, Mariana; Chen, Marcus Y.; Folio, Les R.; Bluemke, David A.] NIH, Radiol & Imaging Sci, Ctr Clin, 9000 Rockville Pike,10 Ctr Dr,Bld 10,Room 1C356, Bethesda, MD 20892 USA. RP Bluemke, DA (reprint author), NIH, Radiol & Imaging Sci, Ctr Clin, 9000 Rockville Pike,10 Ctr Dr,Bld 10,Room 1C356, Bethesda, MD 20892 USA. EM bluemked@cc.nih.gov OI Bluemke, David/0000-0002-8323-8086 FU NIH intramural program [CL090019, EB000072] FX Funding was provided by the NIH (grant numbers: CL090019, EB000072) intramural program. NR 25 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1934-5925 J9 J CARDIOVASC COMPUT JI J. Cardiovasc. Comput. Tomogr. PD JUL-AUG PY 2016 VL 10 IS 4 BP 282 EP 288 DI 10.1016/j.jcct.2016.03.007 PG 7 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA DY3SN UT WOS:000385014800003 PM 27133589 ER PT J AU Gudino, N Duan, Q de Zwart, JA Murphy-Boesch, J Dodd, SJ Merkle, H van Gelderen, P Duyn, JH AF Gudino, Natalia Duan, Qi de Zwart, Jacco A. Murphy-Boesch, Joe Dodd, Stephen J. Merkle, Hellmut van Gelderen, Peter Duyn, Jeff H. TI Optically Controlled Switch-Mode Current-Source Amplifiers for On-Coil Implementation in High-Field Parallel Transmission SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE parallel transmission; high-field MRI; RF amplifiers ID CURRENT AMPLITUDE; RF POWER; INHOMOGENEITY; FEEDBACK; ARRAYS; HEAD; MRI AB Purpose: We tested the feasibility of implementing parallel transmission (pTX) for high-field MRI using a radiofrequency (RF) amplifier design to be located on or in the immediate vicinity of an RF transmit coil. Method: We designed a current-source switch-mode amplifier based on miniaturized, nonmagnetic electronics. Optical RF carrier and envelope signals to control the amplifier were derived, through a custom-built interface, from the RF source accessible in the scanner control. Amplifier performance was tested by benchtop measurements as well as with imaging at 7T (300 MHz) and 11.7 T (500 MHz). The ability to perform pTX was evaluated by measuring interchannel coupling and phase adjustment in a two-channel setup. Results: The amplifier delivered in excess of 44 W RF power and caused minimal interference with MRI. The interface derived accurate optical control signals with carrier frequencies ranging from 64 to 750 MHz. Decoupling better than 14 dB was obtained between two coil loops separated by only 1 cm. Application to MRI was demonstrated by acquiring artifact-free images at 7 T and 11.7 T. Conclusion: We propose an optically controlled miniaturized RF amplifier for on-coil implementation at high fields that should facilitate implementation of high-density pTX arrays. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. C1 [Gudino, Natalia; Duan, Qi; de Zwart, Jacco A.; Murphy-Boesch, Joe; Dodd, Stephen J.; Merkle, Hellmut; van Gelderen, Peter; Duyn, Jeff H.] NINDS, Lab Funct & Mol Imaging, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Gudino, N (reprint author), NINDS, Adv MRI Sect, LFMI, 10 Ctr Dr,Bld 10,B1D728, Bethesda, MD 20892 USA. EM natalia.gudino@nih.gov RI Duan, Qi/J-7916-2016 OI Duan, Qi/0000-0002-2407-6611 FU National Institute of Neurological Disorders and Stroke FX Grant sponsor: National Institute of Neurological Disorders and Stroke, Intramural Research Program. NR 24 TC 1 Z9 1 U1 0 U2 0 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 2016 VL 76 IS 1 BP 340 EP 349 DI 10.1002/mrm.25857 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DY3MK UT WOS:000384996900034 PM 26256671 ER PT J AU Klinman, DM Sato, T Shimosato, T AF Klinman, Dennis M. Sato, Takashi Shimosato, Takeshi TI Use of nanoparticles to deliver immunomodulatory oligonucleotides SO WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY LA English DT Review ID CELL LUNG-CANCER; RECEPTOR 9 AGONIST; BACTERIAL-DNA; CPG-OLIGODEOXYNUCLEOTIDES; CARBONATE APATITE; DRUG-DELIVERY; TLR9 AGONIST; PLASMID DNA; COMPUTED-TOMOGRAPHY; GOLD NANOPARTICLES AB Synthetic oligonucleotides (ODNs) containing unmethylated 'CpG motifs' stimulate the innate immune system to produce cytokines, chemokines, and polyreactive antibodies. CpG ODNs have shown promise as vaccine adjuvants and for the treatment of infectious diseases and cancer. The immunostimulatory activity of CpG ODNs is inhibited by DNA-containing 'suppressive' motifs. ODNs expressing suppressive motifs (Sup ODNs) reduce ongoing immune reactions and show promise in the treatment of autoimmune and inflammatory diseases. This work reviews recent progress in the use of nanoparticles as carriers of CpG and Sup ODNs to target their delivery to the GI tract and lungs. (C) 2015 Wiley Periodicals, Inc. C1 [Klinman, Dennis M.] Frederick Natl Lab Canc Res, Canc & Inflammat Program, Frederick, MD 21702 USA. [Sato, Takashi] Yokohama City Univ, Dept Internal Med & Clin Immunol, Grad Sch Med, Yokohama, Kanagawa, Japan. [Shimosato, Takeshi] Shinshu Univ, Interdisciplinary Grad Sch Sci & Technol, Kamiina, Japan. RP Klinman, DM (reprint author), Frederick Natl Lab Canc Res, Canc & Inflammat Program, Frederick, MD 21702 USA. EM klinmand@mail.nih.gov FU Intramural Research Program of the NIH, NCI FX This work was supported by the Intramural Research Program of the NIH, NCI. 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 United States government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article. The assertions herein are the private ones of the authors and are not to be construed as official or as reflecting the views of the National Cancer Institute at large. NR 59 TC 1 Z9 1 U1 7 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1939-5116 EI 1939-0041 J9 WIRES NANOMED NANOBI JI Wiley Interdiscip. Rev.-Nanomed. Nanobiotechnol. PD JUL-AUG PY 2016 VL 8 IS 4 BP 631 EP 637 DI 10.1002/wnan.1382 PG 7 WC Nanoscience & Nanotechnology; Medicine, Research & Experimental SC Science & Technology - Other Topics; Research & Experimental Medicine GA DY3XN UT WOS:000385031200008 PM 26663867 ER PT J AU Bayefsky, MJ Berkman, BE AF Bayefsky, Michelle J. Berkman, Benjamin E. TI The Ethics of Allocating Uterine Transplants SO CAMBRIDGE QUARTERLY OF HEALTHCARE ETHICS LA English DT Article DE uterine transplantation; infertility; allocation; scarce supply; eligibility; motivation; age; child-rearing capacity ID ADVANCED MATERNAL AGE; UTERUS TRANSPLANTATION; MONTREAL-CRITERIA; INFERTILITY; FEASIBILITY; IMPACT; RISKS AB In September 2014, a healthy male child was born in Sweden following a successful uterine transplantation (UTx). The event brought hope to many women without functional uteruses around the world. Having a child with a transplanted uterus is now possible, and as knowledge of the procedure proliferates and interest in UTx grows, it is important to begin thinking about how a scarce supply of uteruses will be allocated. This article represents a first discussion of the range of factors that must be considered in answering the allocation question. The primary issues addressed are (1) the motivation to seek treatment, (2) allocation by age, (3) child-rearing capacity, and (4) the amount of infertility treatment required. A set of eligibility and ranking criteria are presented. These criteria are not exhaustive but are intended to spark discussion about how uteruses can be allocated in a just manner. C1 [Bayefsky, Michelle J.] NIH, Dept Bioeth, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Berkman, Benjamin E.] NIH, Dept Bioeth, Bldg 10, Bethesda, MD 20892 USA. [Berkman, Benjamin E.] NIH, Sect Eth Genet & Emerging Technol, Bldg 10, Bethesda, MD 20892 USA. [Berkman, Benjamin E.] NHGRI, Bethesda, MD 20892 USA. [Berkman, Benjamin E.] NHGRI, Bioeth Core, Bethesda, MD 20892 USA. RP Bayefsky, MJ (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. FU Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health FX The opinions expressed herein are the authors' and do not reflect the policies and positions of the National Institutes of Health, the U.S. Public Health Service, or the U.S. Department of Health and Human Services. This research was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 48 TC 0 Z9 0 U1 2 U2 2 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0963-1801 EI 1469-2147 J9 CAMB Q HEALTHC ETHIC JI Camb. Q. Healthc. Ethics PD JUL PY 2016 VL 25 IS 3 BP 350 EP 365 DI 10.1017/S0963180115000687 PG 16 WC Health Care Sciences & Services; Health Policy & Services; Social Sciences, Biomedical SC Health Care Sciences & Services; Biomedical Social Sciences GA DX5PA UT WOS:000384432000002 PM 26864991 ER PT J AU Sera, Y Yamasaki, N Oda, H Nagamachi, A Wolff, L Inukai, T Inaba, T Honda, H AF Sera, Yasuyuki Yamasaki, Norimasa Oda, Hideaki Nagamachi, Akiko Wolff, Linda Inukai, Takeshi Inaba, Toshiya Honda, Hiroaki TI Identification of cooperative genes for E2A-PBX1 to develop acute lymphoblastic leukemia SO CANCER SCIENCE LA English DT Article DE Acute lymphoblastic leukemia; conditional knock-in mice; E2A-PBX1; retroviral insertional mutagenesis; Zfp521/ZNF521 ID ZINC-FINGER PROTEIN; ACUTE MYELOID-LEUKEMIA; T-CELL LYMPHOMAGENESIS; B-LINEAGE LEUKEMIA; TRANSGENIC MICE; N-MYC; C-MYC; TRANSCRIPTION FACTOR; PRE-B; EXPRESSION AB E2A-PBX1 is a chimeric gene product detected in t(1;19)-bearing acute lymphoblastic leukemia (ALL) with B-cell lineage. To investigate the leukemogenic process, we generated conditional knock-in (cKI) mice for E2A-PBX1, in which E2A-PBX1 is inducibly expressed under the control of the endogenous E2A promoter. Despite the induced expression of E2A-PBX1, no hematopoietic disease was observed, strongly suggesting that additional genetic alterations are required to develop leukemia. To address this possibility, retroviral insertional mutagenesis was used. Virus infection efficiently induced T-cell, B-cell, and biphenotypic ALL in E2A-PBX1 cKI mice. Inverse PCR identified eight retroviral common integration sites, in which enhanced expression was observed in the Gfi1, Mycn, and Pim1 genes. In addition, it is of note that viral integration and overexpression of the Zfp521 gene was detected in one tumor with B-cell lineage; we previously identified Zfp521 as a cooperative gene with E2A-HLF, another E2A-involving fusion gene with B-lineage ALL. The cooperative oncogenicity of E2A-PBX1 with overexpressed Zfp521 in B-cell tumorigenesis was indicated by the finding that E2A-PBX1 cKI, Zfp521 transgenic compound mice developed B-lineage ALL. Moreover, upregulation of ZNF521, the human counterpart of Zfp521, was found in several human leukemic cell lines bearing t(1; 19). These results indicate that E2A-PBX1 cooperates with additional gene alterations to develop ALL. Among them, enhanced expression of ZNF521 may play a clinically relevant role in E2A fusion genes to develop B-lineage ALL. C1 [Sera, Yasuyuki; Yamasaki, Norimasa; Honda, Hiroaki] Hiroshima Univ, Res Inst Radiat Biol & Med, Dept Dis Model, Hiroshima, Japan. [Oda, Hideaki] Tokyo Womens Med Univ, Dept Pathol, Tokyo, Japan. [Nagamachi, Akiko; Inaba, Toshiya] Hiroshima Univ, Res Inst Radiat Biol & Med, Dept Mol Oncol, Hiroshima, Japan. [Wolff, Linda] NCI, Cellular Oncol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Inukai, Takeshi] Univ Yamanashi, Dept Pediat, Fac Med, Yamanashi, Japan. RP Honda, H (reprint author), Hiroshima Univ, Res Inst Radiat Biol & Med, Dept Dis Model, Minami Ku, 1-2-3 Kasumi, Hiroshima 7348553, Japan. EM hhonda@hiroshima-u.ac.jp FU Ministry of Education, Science and Culture of Japan FX Ministry of Education, Science and Culture of Japan. NR 45 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1347-9032 EI 1349-7006 J9 CANCER SCI JI Cancer Sci. PD JUL PY 2016 VL 107 IS 7 BP 890 EP 898 DI 10.1111/cas.12945 PG 9 WC Oncology SC Oncology GA DX9OD UT WOS:000384724100004 PM 27088431 ER PT J AU Moses, HL Roberts, AB Derynck, R AF Moses, Harold L. Roberts, Anita B. Derynck, Rik TI The Discovery and Early Days of TGF-beta: A Historical Perspective SO COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY LA English DT Article ID TRANSFORMING-GROWTH-FACTOR; SERINE THREONINE KINASE; EPITHELIAL-MESENCHYMAL TRANSITION; MOLECULAR-WEIGHT COMPLEX; DAUER LARVA DEVELOPMENT; HUMAN ENDOTHELIAL-CELLS; HUMAN-LUNG FIBROBLASTS; AMINO-ACID-SEQUENCE; MAD-RELATED PROTEIN; II RECEPTOR AB Transforming growth factors (TGFs) were discovered as activities that were secreted by cancer cells, and later by normal cells, and had the ability to phenotypically and reversibly transform immortalized fibroblasts. TGF-beta distinguished itself from TGF-alpha because it did not bind to the same epidermal growth factor (EGF) receptor as TGF-alpha and, therefore, acted through different cell-surface receptors and signaling mediators. This review summarizes the discovery of TGF-beta, the early developments in its molecular and biological characterization with its many biological activities in different cell and tissue contexts and its roles in disease, the realization that there is a family of secreted TGF-beta-related proteins with many differentiation functions in development and activities in normal cell and tissue physiology, and the subsequent identification and characterization of the receptors and effectors that mediate TGF-beta family signaling responses. C1 [Moses, Harold L.] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA. [Roberts, Anita B.] NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. [Derynck, Rik] Univ Calif San Francisco, Dept Cell & Tissue Biol, San Francisco, CA 94143 USA. RP Derynck, R (reprint author), Univ Calif San Francisco, Dept Cell & Tissue Biol, San Francisco, CA 94143 USA. EM rik.derynck@ucsf.edu NR 219 TC 2 Z9 2 U1 3 U2 3 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1943-0264 J9 CSH PERSPECT BIOL JI Cold Spring Harbor Perspect. Biol. PD JUL PY 2016 VL 8 IS 7 AR a021865 DI 10.1101/cshperspect.a021865 PG 26 WC Cell Biology SC Cell Biology GA DY1CE UT WOS:000384831700006 ER PT J AU Lipsky, LM Strawderman, MS Olson, CM AF Lipsky, Leah M. Strawderman, Myla S. Olson, Christine M. TI Weight-related self-efficacy in relation to maternal body weight from early pregnancy to 2 years post-partum SO MATERNAL AND CHILD NUTRITION LA English DT Article DE maternal weight change; weight-related behaviours; behaviour-specific self-efficacy; prospective cohort ID PSYCHOSOCIAL FACTORS; YOUNG-ADULTS; LIFE-STYLE; WOMEN; RETENTION; GAIN; OBESITY; RISK; CHILDBEARING; ASSOCIATION AB Excessive gestational weight gain may lead to long-term increases in maternal body weight and associated health risks. The purpose of this study was to examine the relationship between maternal body weight and weight-related self-efficacy from early pregnancy to 2 years post-partum. Women with live, singleton term infants from a population-based cohort study were included (n = 595). Healthy eating self-efficacy and weight control self-efficacy were assessed prenatally and at 1 year and 2 years post-partum. Body weight was measured at early pregnancy, before delivery, and 6 weeks, 1 year and 2 years post-partum. Behavioural (smoking, breastfeeding) and sociodemographic (age, education, marital status, income) covariates were assessed by medical record review and baseline questionnaires. Multi-level linear regression models were used to examine the longitudinal associations of self-efficacy measures with body weight. Approximately half of the sample (57%) returned to early pregnancy weight at some point by 2 years post-partum, and 9% became overweight or obese at 2 years post-partum. Body weight over time was inversely related to healthy eating (beta = -0.57, P = 0.02) and weight control (beta = -0.99, P < 0.001) self-efficacy in the model controlling for both self-efficacy measures as well as time and behavioural and sociodemographic covariates. Weight-related self-efficacy may be an important target for interventions to reduce excessive gestational weight gain and post-partum weight gain. C1 [Lipsky, Leah M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Hlth Behav Branch, Div Intramural Publ Hlth Res, Bethesda, MD USA. [Strawderman, Myla S.; Olson, Christine M.] Cornell Univ, Div Nutr Sci, Ithaca, NY 14853 USA. RP Lipsky, LM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Publ Hlth Res, 6100 Execut Blvd,Suite 7B13, Rockville, MD 20852 USA. EM lipskylm@mail.nih.gov OI Lipsky, Leah/0000-0003-2645-4388 FU NIH [HD29549]; Cornell University; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This research was funded by NIH grant #HD29549, Cornell University, and the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 46 TC 1 Z9 1 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1740-8695 EI 1740-8709 J9 MATERN CHILD NUTR JI Matern. Child Nutr. PD JUL PY 2016 VL 13 IS 3 BP 569 EP 578 DI 10.1111/mcn.12149 PG 10 WC Nutrition & Dietetics; Pediatrics SC Nutrition & Dietetics; Pediatrics GA DX8PV UT WOS:000384651900003 PM 25244078 ER PT J AU Narayanan, M Martins, AJ Tsang, JS AF Narayanan, Manikandan Martins, Andrew J. Tsang, John S. TI Robust Inference of Cell-to-Cell Expression Variations from Single-and K-Cell Profiling SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID RNA-SEQ; GENE-EXPRESSION; REGULATORY HETEROGENEITIES; NOISE; TRANSCRIPTOMICS; CIRCUITS; TISSUES AB Quantifying heterogeneity in gene expression among single cells can reveal information inaccessible to cell-population averaged measurements. However, the expression level of many genes in single cells fall below the detection limit of even the most sensitive technologies currently available. One proposed approach to overcome this challenge is to measure random pools of k cells (e.g., 10) to increase sensitivity, followed by computational "deconvolution" of cellular heterogeneity parameters (CHPs), such as the biological variance of single-cell expression levels. Existing approaches infer CHPs using either single-cell or k-cell data alone, and typically within a single population of cells. However, integrating both single-and k-cell data may reap additional benefits, and quantifying differences in CHPs across cell populations or conditions could reveal novel biological information. Here we present a Bayesian approach that can utilize single-cell, k-cell, or both simultaneously to infer CHPs within a single condition or their differences across two conditions. Using simulated as well as experimentally generated single-and k-cell data, we found situations where each data type would offer advantages, but using both together can improve precision and better reconcile CHP information contained in single-and k-cell data. We illustrate the utility of our approach by applying it to jointly generated single-and k-cell data to reveal CHP differences in several key inflammatory genes between resting and inflammatory cytokine-activated human macrophages, delineating differences in the distribution of 'ON' versus 'OFF' cells and in continuous variation of expression level among cells. Our approach thus offers a practical and robust framework to assess and compare cellular heterogeneity within and across biological conditions using modern multiplexed technologies. C1 [Narayanan, Manikandan; Martins, Andrew J.; Tsang, John S.] NIAID, Syst Genom & Bioinformat Unit, Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Tsang, JS (reprint author), NIAID, Syst Genom & Bioinformat Unit, Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM john.tsang@nih.gov FU Intramural Research Program of NIAID, NIH FX This work is supported by the Intramural Research Program of NIAID, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 0 Z9 0 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD JUL PY 2016 VL 12 IS 7 AR e1005016 DI 10.1371/journal.pcbi.1005016 PG 33 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA DW0SC UT WOS:000383351400029 PM 27438699 ER PT J AU Nussinov, R Papin, JA AF Nussinov, Ruth Papin, Jason A. TI Computing Biology SO PLOS COMPUTATIONAL BIOLOGY LA English DT Editorial Material C1 [Nussinov, Ruth] NCI, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21701 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Inst Mol Med, Sackler Sch Med, Dept Human Genet & Mol Med, Tel Aviv, Israel. [Papin, Jason A.] Univ Virginia, Dept Biomed Engn, Charlottesville, VA USA. RP Nussinov, R (reprint author), NCI, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21701 USA.; Nussinov, R (reprint author), Tel Aviv Univ, Sackler Inst Mol Med, Sackler Sch Med, Dept Human Genet & Mol Med, Tel Aviv, Israel. EM nussinor@helix.nih.gov; papin@virginia.edu OI Papin, Jason/0000-0002-2769-5805 NR 0 TC 0 Z9 0 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD JUL PY 2016 VL 12 IS 7 AR e1005050 DI 10.1371/journal.pcbi.1005050 PG 3 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA DW0SC UT WOS:000383351400040 PM 27403659 ER PT J AU Subramanian, S Krishna, MC AF Subramanian, Sankaran Krishna, Murali C. TI Electron Paramagnetic Resonance Imaging 1. CW-EPR Imaging SO RESONANCE-JOURNAL OF SCIENCE EDUCATION LA English DT Article DE EPR; imaging; spatial encoding; back-projection; gradients; spectral-spatial imaging; line width; relaxation; oxygen partial pressure; spin probes; CW- and FT-EPR; rapid scan; rotating gradients; redox status; oxidative stress; anti-oxidants; ischaemia ID RAPID-SCAN AB EPR (Electron Paramagnetic Resonance) imaging is particularly useful in monitoring hypoxic zones in tumors which are highly resistant to radiation and chemotherapeutic treatment. This first part of the article covers aspects of CW (continuous wave) imaging with details of FT (pulsed Fourier Transform)-EPR imaging covered in Part 2, to be published in the next issue of Resonance. C1 [Subramanian, Sankaran] IIT Madras, Chem, Madras, Tamil Nadu, India. [Krishna, Murali C.] NCI, Biophys Spect & Imaging Sect, NIH, Bethesda, MD 20892 USA. RP Subramanian, S (reprint author), Indian Inst Technol, Madras 600036, Tamil Nadu, India.; Krishna, MC (reprint author), NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM subukannan@gmail.com; cherukum@mail.nih.gov NR 10 TC 0 Z9 0 U1 3 U2 3 PU INDIAN ACAD SCIENCES PI BANGALORE PA C V RAMAN AVENUE, SADASHIVANAGAR, P B #8005, BANGALORE 560 080, INDIA SN 0971-8044 EI 0973-712X J9 RESONANCE JI Resonance PD JUL PY 2016 VL 21 IS 7 BP 597 EP 619 PG 23 WC Education, Scientific Disciplines SC Education & Educational Research GA DX7XP UT WOS:000384603000003 ER PT J AU Tran, TM Hong, S Bennett, J Colbert, RA AF Tran, T. M. Hong, S. Bennett, J. Colbert, R. A. TI THE ROLE OF ERAP1 IN SPONDYLOARTHRITIS IN HLA-B27 TRANSGENIC RATS SO CLINICAL AND EXPERIMENTAL RHEUMATOLOGY LA English DT Meeting Abstract C1 [Tran, T. M.; Hong, S.; Bennett, J.; Colbert, R. A.] NIAMSD, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 4 U2 4 PU CLINICAL & EXPER RHEUMATOLOGY PI PISA PA VIA SANTA MARIA 31, 56126 PISA, ITALY SN 0392-856X EI 1593-098X J9 CLIN EXP RHEUMATOL JI Clin. Exp. Rheumatol. PD JUL-AUG PY 2016 VL 34 IS 4 MA INV19 BP 727 EP 728 PG 2 WC Rheumatology SC Rheumatology GA DW8TG UT WOS:000383927800038 ER PT J AU Gensler, LS Reveille, JD Ward, MM Lee, M Learch, T Brown, MA Rahbar, MH Weisman, MH AF Gensler, L. S. Reveille, J. D. Ward, M. M. Lee, M. Learch, T. Brown, M. A. Rahbar, M. H. Weisman, M. H. TI HIGH DOSE NSAIDs AND TUMOR NECROSIS FACTOR INHIBITOR USE SYNERGIZE TOWARDS LESS RADIOGRAPHIC PROGRESSION IN ANKYLOSING SPONDYLITIS - A LONGITUDINAL ANALYSIS SO CLINICAL AND EXPERIMENTAL RHEUMATOLOGY LA English DT Meeting Abstract C1 [Gensler, L. S.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Reveille, J. D.; Lee, M.; Rahbar, M. H.] Univ Texas Hlth Sci Ctr Houston, Dept Med, Houston, TX 77030 USA. [Ward, M. M.] Natl Inst Arthrit & Musculoskeletal & Skin Dis NI, NIH, Bethesda, MD USA. [Learch, T.; Weisman, M. H.] Cedars Sinai Med Ctr, Dept Med, Los Angeles, CA 90048 USA. [Brown, M. A.] Queensland Univ Technol, Brisbane, Qld, Australia. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CLINICAL & EXPER RHEUMATOLOGY PI PISA PA VIA SANTA MARIA 31, 56126 PISA, ITALY SN 0392-856X EI 1593-098X J9 CLIN EXP RHEUMATOL JI Clin. Exp. Rheumatol. PD JUL-AUG PY 2016 VL 34 IS 4 MA O9 BP 731 EP 732 PG 2 WC Rheumatology SC Rheumatology GA DW8TG UT WOS:000383927800050 ER PT J AU Reveille, J Ward, M Lee, M Weisman, M Gensler, L Rahbar, M Brown, M AF Reveille, J. Ward, M. Lee, M. Weisman, M. Gensler, L. Rahbar, M. Brown, M. TI ETHNICITY AND DISEASE SEVERITY IN ANKYLOSING SPONDYLITIS SO CLINICAL AND EXPERIMENTAL RHEUMATOLOGY LA English DT Meeting Abstract C1 [Reveille, J.; Lee, M.; Rahbar, M.] Univ Texas Houston, Houston, TX USA. [Ward, M.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Weisman, M.] Cedars Sinai, Los Angeles, CA USA. [Gensler, L.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Brown, M.] Queensland Univ Technol, Brisbane, Qld, Australia. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CLINICAL & EXPER RHEUMATOLOGY PI PISA PA VIA SANTA MARIA 31, 56126 PISA, ITALY SN 0392-856X EI 1593-098X J9 CLIN EXP RHEUMATOL JI Clin. Exp. Rheumatol. PD JUL-AUG PY 2016 VL 34 IS 4 MA P90 BP 763 EP 763 PG 1 WC Rheumatology SC Rheumatology GA DW8TG UT WOS:000383927800143 ER PT J AU Jones-Lopez, EC Acuna-Villaorduna, C Ssebidandi, M Gaeddert, M Kubiak, RW Ayakaka, I White, LF Joloba, M Okwera, A Fennelly, KP AF Jones-Lopez, Edward C. Acuna-Villaorduna, Carlos Ssebidandi, Martin Gaeddert, Mary Kubiak, Rachel W. Ayakaka, Irene White, Laura F. Joloba, Moses Okwera, Alphonse Fennelly, Kevin P. TI Cough Aerosols of Mycobacterium tuberculosis in the Prediction of Incident Tuberculosis Disease in Household Contacts SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE Mycobacterium tuberculosis; cough-generated aerosols; inoculum; predictors of disease progression; transmission ID AIRBORNE TRANSMISSION; GROWTH-RATES; INFECTION; VARIABILITY; RISK; RESPONSES AB Background. Tuberculosis disease develops in only 5%-10% of humans infected with Mycobacterium tuberculosis. The mechanisms underlying this variability remain poorly understood. We recently demonstrated that colony-forming units of M. tuberculosis in cough-generated aerosols are a better predictor of infection than the standard sputum acid-fast bacilli smear. We hypothesized that cough aerosol cultures may also predict progression to tuberculosis disease in contacts. Methods. We conducted a retrospective cohort study of 85 patients with smear-positive tuberculosis and their 369 household contacts in Kampala, Uganda. Index case patients underwent a standard evaluation, and we cultured M. tuberculosis from cough aerosols. Contacts underwent a standard evaluation at enrollment, and they were later traced to determine their tuberculosis status. Results. During a median follow-up of 3.9 years, 8 (2%) of the contacts developed tuberculosis disease. In unadjusted and adjusted analyses, incident tuberculosis disease in contacts was associated with sputum Mycobacterial Growth Indicator Tube culture (odds ratio, 8.2; 95% confidence interval, 1.1-59.2; P=.04), exposure to a high-aerosol tuberculosis case patient (6.0, 1.4-25.2; P=.01), and marginally, human immunodeficiency virus in the contact (6.11; 0.89-41.7; P=.07). We present data demonstrating that sputum and aerosol specimens measure 2 related but different phenomena. Conclusions. We found an increased risk of tuberculosis progression among contacts of high-aerosol case patients. The hypothesis that a larger infectious inoculum, represented by high aerosol production, determines the risk of disease progression deserves evaluation in future prospective studies. C1 [Jones-Lopez, Edward C.; Acuna-Villaorduna, Carlos; Gaeddert, Mary; Kubiak, Rachel W.] Boston Med Ctr, Dept Med, Sect Infect Dis, Boston, MA USA. [Jones-Lopez, Edward C.; Acuna-Villaorduna, Carlos; Gaeddert, Mary; Kubiak, Rachel W.] Boston Univ, Sch Med, Boston, MA 02118 USA. [White, Laura F.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Fennelly, Kevin P.] NHLBI, Pulm Clin Med Sect, Cardiovasc & Pulm Branch, Div Intramural Res,NIH, Bldg 10, Bethesda, MD 20892 USA. [Jones-Lopez, Edward C.; Ssebidandi, Martin; Ayakaka, Irene; Okwera, Alphonse] Makerere Univ, Boston Med Ctr Res Collaborat, Kampala, Uganda. [Joloba, Moses] Makerere Univ, Coll Hlth Sci, Dept Microbiol, Kampala, Uganda. [Okwera, Alphonse] Mulago Hosp, Mulago Hosp, TB Clin, Kampala, Uganda. RP Jones-Lopez, EC (reprint author), Boston Univ, Sch Med, Infect Dis Sect, 801 Massachusetts Ave,Crosstown Rm 2009, Boston, MA 02118 USA.; Jones-Lopez, EC (reprint author), Boston Med Ctr, 801 Massachusetts Ave,Crosstown Rm 2009, Boston, MA 02118 USA. EM edward.jones@bmc.org OI Joloba, Moses/0000-0002-0334-9983 FU Division of Global Medicine, Department of Medicine, University of Florida; Section of Infectious Diseases, Department of Medicine, Boston Medical Center and Boston University School of Medicine FX This work was supported by personal funds from the Division of Global Medicine, Department of Medicine, University of Florida, and from the Section of Infectious Diseases, Department of Medicine, Boston Medical Center and Boston University School of Medicine. NR 40 TC 1 Z9 1 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL 1 PY 2016 VL 63 IS 1 BP 10 EP 20 DI 10.1093/cid/ciw199 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DT1FH UT WOS:000381226600007 PM 27025837 ER PT J AU Cohen, JI Dropulic, L Hsu, AP Zerbe, CS Krogmann, T Dowdell, K Hornung, RL Lovell, J Hardy, N Hickstein, D Cowen, EW Calvo, KR Pittaluga, S Holland, SM AF Cohen, Jeffrey I. Dropulic, Lesia Hsu, Amy P. Zerbe, Christa S. Krogmann, Tammy Dowdell, Kennichi Hornung, Ronald L. Lovell, Jana Hardy, Nancy Hickstein, Dennis Cowen, Edward W. Calvo, Katherine R. Pittaluga, Stefania Holland, Steven M. TI Association of GATA2 Deficiency With Severe Primary Epstein-Barr Virus (EBV) Infection and EBV-associated Cancers SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE GATA2; Epstein-Barr virus; hydroa vacciniforme; chronic active Epstein-Barr disease; Epstein-Barr virus smooth muscle tumors ID NATURAL-KILLER-CELLS; TRANSCRIPTION FACTOR GATA-2; ACUTE MYELOID-LEUKEMIA; PRIMARY IMMUNODEFICIENCIES; SPORADIC MONOCYTOPENIA; HUMAN CYTOMEGALOVIRUS; AUTOSOMAL-DOMINANT; MONOMAC SYNDROME; DENDRITIC CELL; MUTATIONS AB Background. Most patients infected with Epstein-Barr virus (EBV) are asymptomatic, have nonspecific symptoms, or have self-imiting infectious mononucleosis. EBV, however, may result in severe primary disease or cancer. Methods. We report EBV diseases associated with GATA2 deficiency at one institution and describe the hematology, virology, and cytokine findings. Results. Seven patients with GATA2 deficiency developed severe EBV disease. Three presented with EBV infectious mononucleosis requiring hospitalization, 1 had chronic active EBV disease (B-cell type), 1 had EBV-associated hydroa vacciniforme-like lymphoma with hemophagocytic lymphohistiocytosis, and 2 had EBV-positive smooth muscle tumors. Four of the 7 patients had severe warts and 3 had disseminated nontuberculous mycobacterial infections. All of the patients had low numbers of monocytes, B cells, CD4 T cells, and natural killer cells. All had elevated levels of EBV in the blood; 2 of 3 patients tested had expression of the EBV major immediate-early gene in the blood indicative of active EBV lytic infection. Mean plasma levels of tumor necrosis factor a, interferon., and interferon gamma-induced protein 10 were higher in patients with GATA2 deficiency than in controls. Conclusions. GATA2 is the first gene associated with EBV hydroa vacciniforme-like lymphoma. GATA2 deficiency should be considered in patients with severe primary EBV infection or EBV-associated cancer, especially in those with disseminated nontuberculous mycobacterial disease and warts. C1 [Cohen, Jeffrey I.; Dropulic, Lesia; Krogmann, Tammy; Dowdell, Kennichi] NIAID, Infect Dis Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Hsu, Amy P.; Zerbe, Christa S.; Lovell, Jana; Holland, Steven M.] NIAID, Lab Clin Infect Dis, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Hardy, Nancy; Hickstein, Dennis] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. [Cowen, Edward W.] NCI, Dermatol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Pittaluga, Stefania] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Calvo, Katherine R.] NIH, Ctr Clin, Dept Lab Med, Hematol Sect, Bldg 10, Bethesda, MD 20892 USA. [Hornung, Ronald L.] Frederick Natl Lab Canc Res, Leidos Biomed Res, Clin Serv Program, Frederick, MD USA. RP Cohen, JI (reprint author), NIH, Infect Dis Lab, Bldg 50,Rm 6134,50 S Dr,MSC8007, Bethesda, MD 20892 USA. EM jcohen@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases; National Cancer Institute; Clinical Center; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported by the intramural research programs of the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, and the Clinical Center. This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health (contract HHSN261200800001E). NR 36 TC 2 Z9 2 U1 3 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL 1 PY 2016 VL 63 IS 1 BP 41 EP 47 DI 10.1093/cid/ciw160 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DT1FH UT WOS:000381226600011 PM 27169477 ER PT J AU Van Dyke, RB Patel, K Kagan, RM Karalius, B Traite, S Meyer, WA Tassiopoulos, KK Seage, GR Seybolt, LM Burchett, S Hazra, R AF Van Dyke, Russell B. Patel, Kunjal Kagan, Ron M. Karalius, Brad Traite, Shirley Meyer, William A., III Tassiopoulos, Katherine K. Seage, George R., III Seybolt, Lorna M. Burchett, Sandra Hazra, Rohan CA Pediat HIV AIDS Cohort Study PHACS TI Antiretroviral Drug Resistance Among Children and Youth in the United States With Perinatal HIV SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE human immunodeficiency virus; antiviral resistance; children; adolescents; perinatal infection ID MEDICATION ADHERENCE; VIROLOGICAL FAILURE; INFECTION; MUTATIONS AB Among 234 US youths with perinatal human immunodeficiency virus, 75% had antiretroviral resistance, substantially higher than that of the reference laboratory overall (36%-44%). Resistance to newer antiretrovirals and to all antiretrovirals in a class was uncommon. The only factor independently associated with future resistance was a higher peak viral load. C1 [Van Dyke, Russell B.] Tulane Univ, Sch Med, Dept Pediat, 8408,1440 Canal St,Ste 1600, New Orleans, LA 70112 USA. [Patel, Kunjal; Karalius, Brad; Tassiopoulos, Katherine K.; Seage, George R., III] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Kagan, Ron M.] Focus Diagnost, San Juan Capistrano, CA USA. [Traite, Shirley] Harvard TH Chan Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA USA. [Meyer, William A., III] Quest Diagnost, Baltimore, MD USA. [Seybolt, Lorna M.] Louisiana State Univ, Dept Pediat, Hlth Sci Ctr, New Orleans, LA USA. [Burchett, Sandra] Harvard Med Sch, Dept Pediat, Boston, MA USA. [Hazra, Rohan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Van Dyke, RB (reprint author), Tulane Univ, Sch Med, Dept Pediat, 8408,1440 Canal St,Ste 1600, New Orleans, LA 70112 USA. EM vandyke@tulane.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute on Drug Abuse; National Institute of Allergy and Infectious Diseases; Office of AIDS Research; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; National Institute on Deafness and Other Communication Disorders; National Heart, Lung, and Blood Institute; National Institute of Dental and Craniofacial Research; National Institute on Alcohol Abuse and Alcoholism; Harvard T.H. Chan School of Public Health [HD052102]; Tulane University School of Medicine [HD052104] FX This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development with co-funding from the National Institute on Drug Abuse, the National Institute of Allergy and Infectious Diseases, the Office of AIDS Research, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Institute on Deafness and Other Communication Disorders, the National Heart, Lung, and Blood Institute, the National Institute of Dental and Craniofacial Research, and the National Institute on Alcohol Abuse and Alcoholism through cooperative agreements with the Harvard T.H. Chan School of Public Health (HD052102) (Principal Investigator [PI]: George Seage; Project Director: Julie Alperen) and the Tulane University School of Medicine (HD052104) (PI: Russell Van Dyke; Co-PI: Kenneth Rich; Project Director: Patrick Davis). Data management services were provided by Frontier Science and Technology Research Foundation (PI: Suzanne Siminski), and regulatory services and logistical support were provided by Westat, Inc (PI: Julie Davidson). NR 12 TC 4 Z9 4 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL 1 PY 2016 VL 63 IS 1 BP 133 EP 137 DI 10.1093/cid/ciw213 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DT1FH UT WOS:000381226600024 PM 27056398 ER PT J AU Zhu, XG Kim, DW Zhao, L Willingham, MC Cheng, SY AF Zhu, Xuguang Kim, Dong Wook Zhao, Li Willingham, Mark C. Cheng, Sheue-yann TI SAHA-induced loss of tumor suppressor Pten gene promotes thyroid carcinogenesis in a mouse model SO ENDOCRINE-RELATED CANCER LA English DT Article DE thyroid hormone receptors; tumorigenesis; genetically engineered mouse model; thyroid cancer; vorinostat; SAHA; tumor suppressor PTEN ID T-CELL LYMPHOMA; HISTONE DEACETYLASE INHIBITORS; HORMONE-BETA-RECEPTOR; SUBEROYLANILIDE HYDROXAMIC ACID; CANCER CELLS; MOLECULAR-MECHANISMS; SIGNALING PATHWAYS; RADIOIODINE UPTAKE; TARGETED MUTATION; SOLID TUMORS AB Thyroid cancer is on the rise. Novel approaches are needed to improve the outcome of patients with recurrent and advanced metastatic thyroid cancers. FDA approval of suberoylanilide hydroxamic acid (SAHA; vorinostat), an inhibitor of histone deacetylase, for the treatment of hematological malignancies led to the clinical trials of vorinostat for advanced thyroid cancer. However, patients were resistant to vorinostat treatment. To understand the molecular basis of resistance, we tested the efficacy of SAHA in two mouse models of metastatic follicular thyroid cancer: Thrb(PV/PV) and Thrb(PV/PV)Pten(+/-) mice. In both, thyroid cancer is driven by overactivation of PI3K-AKT signaling. However, the latter exhibit more aggressive cancer progression due to haplodeficiency of the tumor suppressor, the Pten gene. SAHA had no effects on thyroid cancer progression in Thrb(PV/PV) mice, indicative of resistance to SAHA. Unexpectedly, thyroid cancer progressed in SAHA-treated Thrb(PV/PV)Pten(+/-) mice with accelerated occurrence of vascular invasion, anaplastic foci, and lung metastasis. Molecular analyses showed further activated PI3K-AKT in thyroid tumors of SAHA-treated Thrb(PV/PV)Pten(+/-) mice, resulting in the activated effectors, p-Rb, CDK6, p21(Cip1), p-cSrc, ezrin, and matrix metalloproteinases, to increase proliferation and invasion of tumor cells. Single-molecule DNA analysis indicated that the wild-type allele of the Pten gene was progressively lost, whereas carcinogenesis progressed in SAHA-treated Thrb(PV/PV)Pten(+/-) mice. Thus, this study has uncovered a novel mechanism by which SAHA-induced loss of the tumor suppressor Pten gene to promote thyroid cancer progression. Effectors downstream of the Pten loss-induced signaling may be potential targets to overcome resistance of thyroid cancer to SAHA. C1 [Zhu, Xuguang; Kim, Dong Wook; Zhao, Li; Willingham, Mark C.; Cheng, Sheue-yann] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. RP Cheng, SY (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM chengs@mail.nih.gov FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 43 TC 0 Z9 0 U1 1 U2 1 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1351-0088 EI 1479-6821 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD JUL PY 2016 VL 23 IS 7 BP 521 EP 533 DI 10.1530/ERC-16-0103 PG 13 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA DX2HD UT WOS:000384187900003 PM 27267120 ER PT J AU Alamri, AM Kang, K Groeneveld, S Wang, WS Zhong, XG Kallakury, B Hennighausen, L Liu, XF Furth, PA AF Alamri, Ahmad M. Kang, Keunsoo Groeneveld, Svenja Wang, Weisheng Zhong, Xiaogang Kallakury, Bhaskar Hennighausen, Lothar Liu, Xuefeng Furth, Priscilla A. TI Primary cancer cell culture: mammary-optimized vs conditional reprogramming SO ENDOCRINE-RELATED CANCER LA English DT Article DE primary cell culture; mammary cancer; Brca1; genetically engineered mouse models; transcriptome ID EPITHELIAL-MESENCHYMAL TRANSITION; INTEGRATIVE GENOMICS VIEWER; ESTROGEN-RECEPTOR-ALPHA; NEGATIVE BREAST-CANCER; STEM-CELLS; KERATIN EXPRESSION; ROCK INHIBITOR; MOUSE MODEL; ER-ALPHA; GENE AB The impact of different culture conditions on biology of primary cancer cells is not always addressed. Here, conditional reprogramming (CRC) was compared with mammary-optimized EpiCult-B (EpiC) for primary mammary epithelial cell isolation and propagation, allograft generation, and genome-wide transcriptional consequences using cancer and non-cancer mammary tissue from mice with different dosages of Brca1 and p53. Selective comparison to DMEM was included. Primary cultures were established with all three media, but CRC was most efficient for initial isolation (P < 0.05). Allograft development was faster using cells grown in EpiC compared with CRC (P < 0.05). Transcriptome comparison of paired CRC and EpiC cultures revealed 1700 differentially expressed genes by passage 20. CRC promoted Trp53 gene family upregulation and increased expression of epithelial differentiation genes, whereas EpiC elevated expression of epithelial-mesenchymal transition genes. Differences did not persist in allografts where both methods yielded allografts with relatively similar transcriptomes. Restricting passage (<7) reduced numbers of differentially expressed genes below 50. In conclusion, CRC was most efficient for initial cell isolation but EpiC was quicker for allograft generation. The extensive culture-specific gene expression patterns that emerged with longer passage could be limited by reducing passage number when both culture transcriptomes were equally similar to that of the primary tissue. Defining impact of culture condition and passage on the transcriptome of primary cells could assist experimental design and interpretation. For example, differences that appear with passage and culture condition are potentially exploitable for comparative studies targeting specific biological networks in different transcriptional environments. C1 [Alamri, Ahmad M.; Groeneveld, Svenja; Wang, Weisheng; Furth, Priscilla A.] Georgetown Univ, Dept Oncol, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. [Alamri, Ahmad M.] King Khalid Univ, Dept Clin Lab Sci, Coll Appl Med Sci, Abha, Saudi Arabia. [Kang, Keunsoo; Hennighausen, Lothar] Natl Inst Diabet & Digest & Kidney Dis, Lab Genet & Physiol, NIH, 8 Ctr Dr, Bethesda, MD USA. [Kang, Keunsoo] Dankook Univ, Dept Microbiol, Cheonan, South Korea. [Groeneveld, Svenja] Univ Munich, Dept Pharm, Munich, Germany. [Zhong, Xiaogang] Georgetown Univ, Dept Biostat Bioinformat & Biomath, Washington, DC USA. [Kallakury, Bhaskar; Liu, Xuefeng] Georgetown Univ, Dept Pathol, Lombardi Comprehens Canc Ctr, Washington, DC USA. [Furth, Priscilla A.] Georgetown Univ, Dept Med, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. RP Furth, PA (reprint author), Georgetown Univ, Dept Oncol, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA.; Furth, PA (reprint author), Georgetown Univ, Dept Med, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. EM Paf3@georgetown.edu FU NIH NCI [RO1 CA112176, 5P30CA051008]; Intramural Research Program of NIDDK/NIH; King Khalid University, Abha, Saudi Arabia FX Research performed here was supported by NIH NCI RO1 CA112176 (PAF), NIH NCI 5P30CA051008 (Histology and Tissue, Genomics and Epigenomics, and Animal Shared Resources), the Intramural Research Program of NIDDK/NIH, and King Khalid University, Abha, Saudi Arabia (AMA). NR 58 TC 0 Z9 0 U1 3 U2 3 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1351-0088 EI 1479-6821 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD JUL PY 2016 VL 23 IS 7 BP 535 EP 554 DI 10.1530/ERC-16-0071 PG 20 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA DX2HD UT WOS:000384187900004 PM 27267121 ER PT J AU Gul, M Katz, J Chaudhry, AA Hannah-Shmouni, F Skarulis, M Cochran, CS AF Gul, Maryam Katz, James Chaudhry, Ammar A. Hannah-Shmouni, Fady Skarulis, Monica Cochran, Craig S. TI Clinical Images: Rheumatologic and imaging manifestations of thyroid acropachy SO ARTHRITIS & RHEUMATOLOGY LA English DT Editorial Material C1 [Gul, Maryam; Katz, James; Hannah-Shmouni, Fady; Skarulis, Monica; Cochran, Craig S.] NIH, Bethesda, MD 20892 USA. [Chaudhry, Ammar A.] Johns Hopkins Univ, Baltimore, MD USA. RP Gul, M (reprint author), NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD JUL PY 2016 VL 68 IS 7 BP 1636 EP 1636 DI 10.1002/art.39693 PG 1 WC Rheumatology SC Rheumatology GA DW2UO UT WOS:000383497500010 PM 27014857 ER PT J AU Gupta, S Tatouli, IP Rosen, LB Hasni, S Alevizos, I Manna, ZG Rivera, J Jiang, C Siegel, RM Holland, SM Moutsopoulos, HM Browne, SK AF Gupta, Sarthak Tatouli, Ioanna P. Rosen, Lindsey B. Hasni, Sarfaraz Alevizos, Ilias Manna, Zerai G. Rivera, Juan Jiang, Chao Siegel, Richard M. Holland, Steven M. Moutsopoulos, Haralampos M. Browne, Sarah K. TI Distinct Functions of Autoantibodies Against Interferon in Systemic Lupus Erythematosus A Comprehensive Analysis of Anticytokine Autoantibodies in Common Rheumatic Diseases SO ARTHRITIS & RHEUMATOLOGY LA English DT Article ID PULMONARY ALVEOLAR PROTEINOSIS; COLONY-STIMULATING FACTOR; ANTI-CYTOKINE AUTOANTIBODIES; IFN-GAMMA; MICROARRAY ANALYSIS; RITUXIMAB THERAPY; REVISED CRITERIA; GENE-EXPRESSION; ALPHA; AUTOIMMUNITY AB Objective. Anticytokine autoantibodies occur across a range of hematologic, pulmonary, and infectious diseases. However, systematic investigation of their presence and significance in autoimmune diseases is lacking. This study was undertaken to examine the distinct functions of anticytokine autoantibodies in patients with systemic lupus erythematosus (SLE) compared to patients with other rheumatic diseases and healthy controls. Methods. Serum samples from patients with SLE (n=199), patients with primary Sjogren's syndrome (SS) (n=150), patients with rheumatoid arthritis (RA) (n5149), and healthy controls (n=200) were screened for 24 anticytokine autoantibodies using a multiplex bead-based assay. To evaluate the biologic activity of anticytokine autoantibodies, their ability to block cytokine-induced signal transduction or protein expression was measured. RNA sequencing was performed on whole blood in a subset of healthy controls and patients with SLE. Results. Patients with SLE and those with SS had a striking excess of autoantibodies against interferons and the interferon-responsive chemokine interferon-inducible protein 10 (IP-10). Only autoantibodies against type I interferon, interleukin-12 (IL-12), and IL-22 exhibited neutralizing activity. In SLE, the presence of antiinterferon-gamma autoantibodies was correlated with more severe disease activity, higher levels of anti-doublestranded DNA antibodies, and elevated expression of interferon-a/b-inducible genes. Conversely, in SLE patients with blocking anti-interferon-a autoantibodies, the type I interferon gene expression signature was normalized. Anti-type III interferon autoantibodies (lambda(2), lambda(3)) and anti-IP-10 autoantibodies were newly recognized in SLE patient serum, and autoantibodies against macrophagecolony stimulating factor, IL-4, IL-7, IL-17, and IL-22, none of which have been previously identified in rheumatic conditions, were discovered. Conclusion. Anticytokine autoantibodies are associated with distinct patterns of disease in SLE, SS, and RA. Anti-interferon autoantibodies are overrepresented in patients with SLE and those with SS, and fall into distinct functional classes, with only a subset of anti-type I interferon antibodies exhibiting neutralizing activity. Anti-interferon-gamma autoantibodies are correlated with increased disease activity and interferon-related gene expression, suggesting that such autoantibodies may contribute to the pathogenesis of SLE. C1 [Gupta, Sarthak; Rosen, Lindsey B.; Holland, Steven M.; Browne, Sarah K.] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Gupta, Sarthak; Siegel, Richard M.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Tatouli, Ioanna P.; Moutsopoulos, Haralampos M.] Natl Univ Athens, Athens, Greece. [Rosen, Lindsey B.; Holland, Steven M.; Browne, Sarah K.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Hasni, Sarfaraz; Manna, Zerai G.; Rivera, Juan; Jiang, Chao] Natl Ctr Complementary & Integrat Hlth, NIH, Bethesda, MD USA. [Alevizos, Ilias] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. RP Holland, SM (reprint author), NIAID, Lab Clin Infect Dis, NIH, CRC B3-4141,MSC 1684, Bethesda, MD 20892 USA.; Moutsopoulos, HM (reprint author), Natl Univ Athens, Sch Med, Dept Pathophysiol, 75 M Asias St, Athens 11527, Greece. EM smh@nih.gov; hmoutsop@med.uoa.gr FU Divisions of the Intramural Research Program at the National Institute of Allergy and Infectious Diseases; National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH; Rheumatology Research Foundation Scientist Development Award FX Supported by the Divisions of the Intramural Research Program at the National Institute of Allergy and Infectious Diseases and National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH. Dr. Gupta is recipient of a Rheumatology Research Foundation Scientist Development Award. NR 49 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD JUL PY 2016 VL 68 IS 7 BP 1677 EP 1687 DI 10.1002/art.39607 PG 11 WC Rheumatology SC Rheumatology GA DW2UO UT WOS:000383497500015 PM 26815287 ER PT J AU Fradkin, JE Hanlon, MC Rodgers, GP AF Fradkin, Judith E. Hanlon, Mary C. Rodgers, Griffin P. TI NIH Precision Medicine Initiative: Implications for Diabetes Research SO DIABETES CARE LA English DT Article ID DISEASE AB In his January 2015 State of the Union address, President Barack Obama announced a new Precision Medicine Initiative (PMI) to personalize approaches toward improving health and treating disease (www.whitehouse.gov/precisionmedicine). He stated that the goal of such an initiative was "to bring us closer to curing diseases like cancer and diabetes, and to give all of us access to the personalized information we need to keep ourselves and our families healthier." Since that time, the National Institutes of Health (NIH) has taken a leadership role in implementing the President's vision related to biomedical research (www.nih.gov/precisionmedicine). Here, we discuss the NIH component of the PMI, related ongoing diabetes research, and near-term research that could position the diabetes field to take full advantage of the opportunities that stem from the PMI. C1 [Fradkin, Judith E.] NIDDK, Div Diabet Endocrinol & Metab Dis, NIH, Bethesda, MD 20892 USA. [Hanlon, Mary C.] NIDDK, Off Sci Program & Policy Anal, NIH, Bethesda, MD 20892 USA. [Rodgers, Griffin P.] NIDDK, NIH, Bethesda, MD 20892 USA. RP Fradkin, JE (reprint author), NIDDK, Div Diabet Endocrinol & Metab Dis, NIH, Bethesda, MD 20892 USA. EM fradkinj@mail.nih.gov NR 20 TC 5 Z9 5 U1 2 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD JUL PY 2016 VL 39 IS 7 BP 1080 EP 1084 DI 10.2337/dc16-0541 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DT3YG UT WOS:000381416500012 PM 27289128 ER PT J AU Chew, EY Lovato, JF Davis, MD Gerstein, HC Danis, RP Ismail-Beigi, F Genuth, S Greven, CM Perdue, LH Cushman, WC Elam, MB Bigger, JT Ginsberg, HN Goff, DC Ambrosius, WT AF Chew, Emily Y. Lovato, James F. Davis, Matthew D. Gerstein, Hertzel C. Danis, Ronald P. Ismail-Beigi, Faramarz Genuth, Saul Greven, Craig M. Perdue, Letitia H. Cushman, William C. Elam, Marshall B. Bigger, J. Thomas Ginsberg, Henry N. Goff, David C., Jr. Ambrosius, Walter T. CA Action Control Cardiovasc Risk Action Control Cardiovasc Risk TI Persistent Effects of Intensive Glycemic Control on Retinopathy in Type 2 Diabetes in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Follow-On Study SO DIABETES CARE LA English DT Article ID THERAPY; FENOFIBRATE; PROGRESSION; TRIAL; MELLITUS; OUTCOMES AB OBJECTIVES This study investigated whether the beneficial effects of intensive glycemic control and fenofibrate treatment of dyslipidemia in reducing retinopathy progression demonstrated in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye Study persisted beyond the clinical trial. RESEARCH DESIGN AND METHODS The ACCORD Study (2003-2009) randomized participants with type 2 diabetes to intensive or standard treatment for glycemia (A1C level at <6.0% [42 mmol/mol] vs. 7.0-7.9% [53-63 mmol/mol]), systolic blood pressure (<120 vs. 140 mmHg), and dyslipidemia (fenofibrate [160 mg] plus simvastatin or placebo plus simvastatin). ACCORD Eye Study participants, who had baseline and year 4 eye examinations and fundus photographs, were reexamined in the ACCORD Follow-On (ACCORDION) Eye Study (2010-2014) 4 years after the ACCORD trial closeout. The outcome measure was diabetic retinopathy progression of three or more steps on the Early Treatment Diabetic Retinopathy Study scale. RESULTS Diabetic retinopathy progressed in 5.8% with intensive glycemic treatment versus 12.7% with standard (adjusted odds ratio [aOR] 0.42, 95% CI 0.28-0.63, P < 0.0001), 7.5% with intensive blood pressure treatment versus 6.0% for standard (aOR 1.21, 95% CI 0.61-2.40, P = 0.59), and 11.8% with fenofibrate versus 10.2% with placebo (aOR 1.13, 95% CI 0.71-1.79, P = 0.60) in ACCORDION Eye participants (n = 1,310). CONCLUSIONS Prior intensive glycemic control continued to reduce diabetic retinopathy progression, despite similar A1C levels, when the ACCORD Study ended. This is the first study in people with type 2 diabetes of 10 years' duration and established cardiovascular disease, unlike the newly diagnosed participants of the UK Prospective Diabetes Study, to demonstrate this effect. The benefit of fenofibrate, however, did not persist. Intensive blood pressure control had no effect. C1 [Chew, Emily Y.] NEI, NIH, Bethesda, MD 20892 USA. [Lovato, James F.; Greven, Craig M.; Perdue, Letitia H.; Ambrosius, Walter T.] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. [Davis, Matthew D.; Danis, Ronald P.] Univ Wisconsin, Madison, WI USA. [Gerstein, Hertzel C.] McMaster Univ, Hamilton, ON, Canada. [Gerstein, Hertzel C.] Hamilton Hlth Sci, Populat Hlth Res Inst, Hamilton, ON, Canada. [Ismail-Beigi, Faramarz; Genuth, Saul] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Elam, Marshall B.] Memphis Vet Affairs Med Ctr, Memphis, TN USA. [Bigger, J. Thomas; Ginsberg, Henry N.] Columbia Univ Coll Phys & Surg, 630 W 168th St, New York, NY 10032 USA. [Goff, David C., Jr.] Colorado Sch Publ Hlth, Aurora, CO USA. RP Chew, EY (reprint author), NEI, NIH, Bethesda, MD 20892 USA. EM echew@nei.nih.gov 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, HHSN268201100027C]; IAA [Y1-HC-9035, Y1-HC-1010]; National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute on Aging; National Eye Institute; Centers for Disease Control and Prevention FX ACCORD was supported by National Heart, Lung, and Blood Institute 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. 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, contributed funding. The Centers for Disease Control and Prevention funded substudies within ACCORD on cost-effectiveness and health-related quality of life. General Clinical Research Centers provide support at many sites. ACCORDION activities were supported by National Heart, Lung, and Blood Institute contract HHSN268201100027C. NR 23 TC 0 Z9 0 U1 1 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD JUL PY 2016 VL 39 IS 7 BP 1089 EP 1100 DI 10.2337/dc16-0024 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DT3YG UT WOS:000381416500014 ER PT J AU Purnell, JQ Selzer, F Wahed, AS Pender, J Pories, W Pomp, A Dakin, G Mitchell, J Garcia, L Staten, MA McCloskey, C Cummings, DE Flum, DR Courcoulas, A Wolfe, BM AF Purnell, Jonathan Q. Selzer, Faith Wahed, Abdus S. Pender, John Pories, Walter Pomp, Alfons Dakin, Greg Mitchell, James Garcia, Luis Staten, Myrlene A. McCloskey, Carol Cummings, David E. Flum, David R. Courcoulas, Anita Wolfe, Bruce M. TI Type 2 Diabetes Remission Rates After Laparoscopic Gastric Bypass and Gastric Banding: Results of the Longitudinal Assessment of Bariatric Surgery Study SO DIABETES CARE LA English DT Article ID MORBIDLY OBESE-PATIENTS; WEIGHT-LOSS; INSULIN SENSITIVITY; INCRETIN LEVELS; BILE-ACIDS; LEPTIN; MELLITUS; GLUCOSE; METAANALYSIS; OUTCOMES AB OBJECTIVE The goals of this study were to determine baseline and postbariatric surgical characteristics associated with type 2 diabetes remission and if, after controlling for differences in weight loss, diabetes remission was greater after Roux-en-Y gastric bypass (RYGBP) than laparoscopic gastric banding (LAGB). RESEARCH DESIGN AND METHODS An observational cohort of obese participants was studied using generalized linear mixed models to examine the associations of bariatric surgery type and diabetes remission rates for up to 3 years. Of 2,458 obese participants enrolled, 1,868 (76%) had complete data to assess diabetes status at both baseline and at least one follow-up visit. Of these, 627 participants (34%) were classified with diabetes: 466 underwent RYGBP and 140 underwent LAGB. RESULTS After 3 years, 68.7% of RYGBP and 30.2% of LAGB participants were in diabetes remission. Baseline factors associated with diabetes remission included a lower weight for LAGB, greater fasting C-peptide, lower leptin-to-fat mass ratio for RYGBP, and a lower hemoglobin A(1c) without need for insulin for both procedures. After both procedures, greater postsurgical weight loss was associated with remission. However, even after controlling for differences in amount of weight lost, relative diabetes remission rates remained nearly twofold higher after RYGBP than LAGB. CONCLUSIONS Diabetes remission up to 3 years after RYGBP and LAGB was proportionally higher with increasing postsurgical weight loss. However, the nearly twofold greater weight loss-adjusted likelihood of diabetes remission in subjects undergoing RYGBP than LAGB suggests unique mechanisms contributing to improved glucose metabolism beyond weight loss after RYGBP. C1 [Purnell, Jonathan Q.; Wolfe, Bruce M.] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Purnell, Jonathan Q.; Wolfe, Bruce M.] Oregon Hlth & Sci Univ, Dept Surg, Portland, OR 97201 USA. [Selzer, Faith; Wahed, Abdus S.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Pender, John; Pories, Walter] East Carolina Univ, Brody Sch Med, Greenville, NC USA. [Pomp, Alfons; Dakin, Greg] Weill Cornell Med Coll, New York, NY USA. [Mitchell, James; Garcia, Luis] Neuropsychiat Res Inst, Grand Forks, ND USA. [Mitchell, James; Garcia, Luis] Univ North Dakota, Sch Med & Hlth Sci, Grand Forks, ND USA. [Staten, Myrlene A.] NIDDK, Bethesda, MD 20892 USA. [McCloskey, Carol; Courcoulas, Anita] Univ Pittsburgh, Med Ctr, Dept Surg, Pittsburgh, PA USA. [Cummings, David E.; Flum, David R.] Univ Washington, Dept Med, Seattle, WA USA. [Cummings, David E.; Flum, David R.] Univ Washington, Dept Surg, Seattle, WA 98195 USA. RP Purnell, JQ (reprint author), Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA.; Purnell, JQ (reprint author), Oregon Hlth & Sci Univ, Dept Surg, Portland, OR 97201 USA. EM purnellj@ohsu.edu FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DCC-U01-DK066557]; Cornell University Medical Center Clinical Translational Research Center (CTRC) [U01-DK66667, UL1-RR024996]; University of Washington [U01-DK66568]; CTRC [UL1-RR024153, M01RR-00037]; Neuropsychiatric Research Institute [U01-DK66471]; East Carolina University [U01-DK66526]; University of Pittsburgh Medical Center [U01-DK66585]; Oregon Health & Science University [U01-DK66555] FX This clinical study was a cooperative agreement funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DCC-U01-DK066557; Columbia, U01-DK66667 [in collaboration with Cornell University Medical Center Clinical Translational Research Center (CTRC), UL1-RR024996]; University of Washington, U01-DK66568 [in collaboration with CTRC, M01RR-00037]; Neuropsychiatric Research Institute, U01-DK66471; East Carolina University, U01-DK66526; University of Pittsburgh Medical Center, U01-DK66585 [in collaboration with CTRC, UL1-RR024153]; Oregon Health & Science University, U01-DK66555). NR 32 TC 5 Z9 5 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD JUL PY 2016 VL 39 IS 7 BP 1101 EP 1107 DI 10.2337/dc15-2138 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DT3YG UT WOS:000381416500015 PM 27289123 ER PT J AU Cefalu, WT Buse, JB Tuomilehto, J Fleming, GA Ferrannini, E Gerstein, HC Bennett, PH Ramachandran, A Raz, I Rosenstock, J Kahn, SE AF Cefalu, William T. Buse, John B. Tuomilehto, Jaakko Fleming, G. Alexander Ferrannini, Ele Gerstein, Hertzel C. Bennett, Peter H. Ramachandran, Ambady Raz, Itamar Rosenstock, Julio Kahn, Steven E. TI Update and Next Steps for Real-World Translation of Interventions for Type 2 Diabetes Prevention: Reflections From a Diabetes Care Editors' Expert Forum SO DIABETES CARE LA English DT Article ID IMPAIRED GLUCOSE-TOLERANCE; LIFE-STYLE INTERVENTION; RANDOMIZED-CONTROLLED-TRIAL; CORONARY-HEART-DISEASE; 10-YEAR FOLLOW-UP; BETA-CELL FUNCTION; DA QING IGT; FASTING GLUCOSE; INSULIN-SECRETION; PROGRAM OUTCOMES AB The International Diabetes Federation estimates that 415 million adults worldwide now have diabetes and 318 million have impaired glucose tolerance. These numbers are expected to increase to 642 million and 482 million, respectively, by 2040. This burgeoning pandemic places an enormous burden on countries worldwide, particularly resource-poor regions. Numerous landmark trials evaluating both intensive lifestyle modification and pharmacological interventions have persuasively demonstrated that type 2 diabetes can be prevented or its onset can be delayed in high-risk individuals with impaired glucose tolerance. However, key challenges remain, including how to scale up such approaches for widespread translation and implementation, how to select appropriately from various interventions and tailor them for different populations and settings, and how to ensure that preventive interventions yield clinically meaningful, cost-effective outcomes. In June 2015, a Diabetes Care Editors' Expert Forum convened to discuss these issues. This article, an outgrowth of the forum, begins with a summary of seminal prevention trials, followed by a discussion of considerations for selecting appropriate populations for intervention and the clinical implications of the various diagnostic criteria for prediabetes. The authors outline knowledge gaps in need of elucidation and explore a possible new avenue for securing regulatory approval of a prevention-related indication for metformin, as well as specific considerations for future pharmacological interventions to delay the onset of type 2 diabetes. They conclude with descriptions of some innovative, pragmatic translational initiatives already under way around the world. C1 [Cefalu, William T.] Louisiana State Univ, Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. [Buse, John B.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Tuomilehto, Jaakko] Natl Inst Hlth & Welf, Chron Dis Prevent Unit, Helsinki, Finland. [Tuomilehto, Jaakko] Dasman Diabet Inst, Dasman, Kuwait. [Tuomilehto, Jaakko] King Abdulaziz Univ, Saudi Diabet Res Grp, Jeddah, Saudi Arabia. [Tuomilehto, Jaakko] Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria. [Fleming, G. Alexander] Kinexum, Harpers Ferry, WV USA. [Ferrannini, Ele] CNR, Inst Clin Physiol, Pisa, Italy. [Gerstein, Hertzel C.] McMaster Univ, Hamilton, ON, Canada. [Gerstein, Hertzel C.] Hamilton Hlth Sci, Hamilton, ON, Canada. [Bennett, Peter H.] NIH, Phoenix, AZ USA. [Ramachandran, Ambady] India Diabet Res Fdn, Madras, Tamil Nadu, India. [Bennett, Peter H.] Dr A Ramachandrans Diabet Hosp, Madras, Tamil Nadu, India. [Raz, Itamar] Hadassah Hebrew Univ Hosp, Dept Internal Med, Diabet Unit, Jerusalem, Israel. [Rosenstock, Julio] Med City, Dallas Diabet & Endocrine Ctr, Dallas, TX USA. [Rosenstock, Julio] Univ Texas Southwestern Med Ctr, Dallas, TX USA. [Kahn, Steven E.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Kahn, Steven E.] Univ Washington, Seattle, WA 98195 USA. RP Cefalu, WT (reprint author), Louisiana State Univ, Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. EM william.cefalu@pbrc.edu OI Kahn, Steven/0000-0001-7307-9002 FU National Institutes of Health (NIH) [1U54-GM-104940]; NIH [P50-AT-002776] FX Writing and editing support services for this article were provided by Debbie Kendall of Kendall Editorial in Richmond, VA. The Editorial Committee recognizes that the work of the journal and contributions such as this Expert Forum would not be possible without the dedicated work and continued support of many individuals. Specifically, the planning, logistics, and funding of the meeting and the incredible editorial support would not have been possible without the tireless efforts of Chris Kohler and his staff at the ADA Publishing office. In addition, the Editorial Committee thanks Lyn Reynolds and her staff in the ADA editorial office for support and Anne Gooch at the Pennington Biomedical Research Center for her valuable assistance in helping to organize the Expert Forum. W.T.C. is supported in part by National Institutes of Health (NIH) grant 1U54-GM-104940, which funds the Louisiana Clinical and Translational Science Center, and NIH grant P50-AT-002776. NR 138 TC 5 Z9 5 U1 2 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD JUL PY 2016 VL 39 IS 7 BP 1186 EP 1201 DI 10.2337/dc16-0873 PG 16 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DT3YG UT WOS:000381416500027 PM 27631469 ER PT J AU Hering, BJ Clarke, WR Bridges, ND Eggerman, TL Alejandro, R Bellin, MD Chaloner, K Czarniecki, CW Goldstein, JS Hunsicker, LG Kaufman, DB Korsgren, O Larsen, CP Luo, XR Markmann, JF Naji, A Oberholzer, J Posselt, AM Rickels, MR Ricordi, C Robien, MA Senior, PA Shapiro, AMJ Stock, PG Turgeon, NA AF Hering, Bernhard J. Clarke, William R. Bridges, Nancy D. Eggerman, Thomas L. Alejandro, Rodolfo Bellin, Melena D. Chaloner, Kathryn Czarniecki, Christine W. Goldstein, Julia S. Hunsicker, Lawrence G. Kaufman, Dixon B. Korsgren, Olle Larsen, Christian P. Luo, Xunrong Markmann, James F. Naji, Ali Oberholzer, Jose Posselt, Andrew M. Rickels, Michael R. Ricordi, Camillo Robien, Mark A. Senior, Peter A. Shapiro, A. M. James Stock, Peter G. Turgeon, Nicole A. CA Clinical Islet Transplantation Con TI Phase 3 Trial of Transplantation of Human Islets in Type 1 Diabetes Complicated by Severe Hypoglycemia SO DIABETES CARE LA English DT Article ID EXCHANGE CLINIC REGISTRY; INSULIN PUMP THERAPY; PANCREAS TRANSPLANTATION; GLYCEMIC CONTROL; CURRENT STATE; AWARENESS; ADULTS; MELLITUS; OUTCOMES; IDDM AB OBJECTIVE Impaired awareness of hypoglycemia (IAH) and severe hypoglycemic events (SHEs) cause substantial morbidity and mortality in patients with type 1 diabetes (T1D). Current therapies are effective in preventing SHEs in 50-80% of patients with IAH and SHEs, leaving a substantial number of patients at risk. We evaluated the effectiveness and safety of a standardized human pancreatic islet product in subjects in whom IAH and SHEs persisted despite medical treatment. RESEARCH DESIGN AND METHODS This multicenter, single-arm, phase 3 study of the investigational product purified human pancreatic islets (PHPI) was conducted at eight centers in North America. Forty-eight adults with T1D for >5 years, absent stimulated C-peptide, and documented IAH and SHEs despite expert care were enrolled. Each received immunosuppression and one or more transplants of PHPI, manufactured on-site under good manufacturing practice conditions using a common batch record and standardized lot release criteria and test methods. The primary end point was the achievement of HbA(1c) <7.0% (53 mmol/mol) at day 365 and freedom from SHEs from day 28 to day 365 after the first transplant. RESULTS The primary end point was successfully met by 87.5% of subjects at 1 year and by 71% at 2 years. The median HbA(1c) level was 5.6% (38 mmol/mol) at both 1 and 2 years. Hypoglycemia awareness was restored, with highly significant improvements in Clarke and HYPO scores (P > 0.0001). No study-related deaths or disabilities occurred. Five of the enrollees (10.4%) experienced bleeds requiring transfusions (corresponding to 5 of 75 procedures), and two enrollees (4.1%) had infections attributed to immunosuppression. Glomerular filtration rate decreased significantly on immunosuppression, and donor-specific antibodies developed in two patients. CONCLUSIONS Transplanted PHPI provided glycemic control, restoration of hypoglycemia awareness, and protection from SHEs in subjects with intractable IAH and SHEs. Safety events occurred related to the infusion procedure and immunosuppression, including bleeding and decreased renal function. Islet transplantation should be considered for patients with T1D and IAH in whom other, less invasive current treatments have been ineffective in preventing SHEs. C1 [Hering, Bernhard J.; Bellin, Melena D.] Univ Minnesota, Schulze Diabet Inst, Minneapolis, MN 55455 USA. [Hering, Bernhard J.] Univ Minnesota, Dept Surg, Box 242 UMHC, Minneapolis, MN 55455 USA. [Clarke, William R.; Chaloner, Kathryn; Hunsicker, Lawrence G.] Univ Iowa, Clin Trials Stat & Data Management Ctr, Iowa City, IA USA. [Bridges, Nancy D.; Czarniecki, Christine W.; Goldstein, Julia S.; Robien, Mark A.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Eggerman, Thomas L.] NIDDK, NIH, Bethesda, MD 20892 USA. [Alejandro, Rodolfo; Ricordi, Camillo] Univ Miami, Miller Sch Med, Diabet Res Inst, Miami, FL 33136 USA. [Bellin, Melena D.] Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA. [Kaufman, Dixon B.] Univ Wisconsin, Dept Surg, Div Transplantat, Madison, WI USA. [Korsgren, Olle] Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden. [Larsen, Christian P.; Turgeon, Nicole A.] Emory Univ, Emory Transplant Ctr, Atlanta, GA 30322 USA. [Luo, Xunrong] Northwestern Univ, Feinberg Sch Med, Comprehens Transplant Ctr, Chicago, IL 60611 USA. [Markmann, James F.] Harvard Med Sch, Massachusetts Gen Hosp, Div Transplant Surg, Boston, MA USA. [Naji, Ali; Rickels, Michael R.] Univ Penn, Perelman Sch Med, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA. [Naji, Ali; Rickels, Michael R.] Univ Penn, Perelman Sch Med, Dept Surg, Philadelphia, PA 19104 USA. [Naji, Ali; Rickels, Michael R.] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Oberholzer, Jose] Univ Illinois Hosp & Hlth Sci Syst, Div Transplantat, Chicago, IL USA. [Posselt, Andrew M.; Stock, Peter G.] Univ Calif San Francisco, Dept Surg, San Francisco, CA USA. [Senior, Peter A.; Shapiro, A. M. James] Univ Alberta, Clin Islet Transplant Program, Edmonton, AB, Canada. [Senior, Peter A.; Shapiro, A. M. James] Univ Alberta, Fac Med & Dent, Edmonton, AB, Canada. RP Hering, BJ (reprint author), Univ Minnesota, Schulze Diabet Inst, Minneapolis, MN 55455 USA.; Hering, BJ (reprint author), Univ Minnesota, Dept Surg, Box 242 UMHC, Minneapolis, MN 55455 USA. EM bhering@umn.edu OI Ricordi, Camillo/0000-0001-8092-7153 FU National Institute of Allergy and Infectious Diseases; National Institute for Diabetes and Digestive and Kidney Diseases [U01-AI-089317, U01-AI-089316, U01-AI-065191, U01-DK-085531, 5U01-DK-070431-10, U01-DK-070431, U01-DK070460, U01-AI-065193, U01-DK-070430, U01-AI-065192]; General Clinical Research Center Awards and Clinical and Translational Science Awards [UL1-TR-000454, 5UL1-RR-025741, 8UL1-TR-000150, UL1-TR-000004, UL1-TR-000050, 1UL1-TR-000460, 5M01-RR-000400, UL1-TR-000114, M01-RR-00040, UL1-TR-000003]; National Institute of Allergy and Infectious Diseases of the National Institutes of Health [NO1-AI-15416, UM1-AI-109565] FX This research was supported by grants from the National Institute of Allergy and Infectious Diseases and the National Institute for Diabetes and Digestive and Kidney Diseases to the following institutions: Emory University (Atlanta, GA), U01-AI-089317; Northwestern University (Evanston, IL), U01-AI-089316; University of Alberta(Edmonton, Alberta, Canada), U01-AI-065191; University of California, San Francisco (San Francisco, CA) U01-DK-085531; University of Illinois, Chicago(Chicago, IL), 5U01-DK-070431-10; University of Iowa (Iowa City, IA), U01-DK-070431; University of Miami (Miami, FL), U01-DK070460; University of Minnesota (Minneapolis, MN), U01-AI-065193; University of Pennsylvania (Philadelphia, PA), U01-DK-070430; and Uppsala University (Uppsala, Sweden), U01-AI-065192. In addition, the study was supported by the following General Clinical Research Center Awards and Clinical and Translational Science Awards: to Emory University, UL1-TR-000454; Northwestern University, 5UL1-RR-025741 and 8UL1-TR-000150; University of California, San Francisco, UL1-TR-000004; University of Illinois, Chicago, UL1-TR-000050; University of Miami, 1UL1-TR-000460; University of Minnesota, 5M01-RR-000400 and UL1-TR-000114; and University of Pennsylvania, M01-RR-00040 and UL1-TR-000003. TrialShare, a public database maintained by the Immune Tolerance Network, is supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award numbers NO1-AI-15416 and UM1-AI-109565. NR 40 TC 19 Z9 19 U1 3 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD JUL PY 2016 VL 39 IS 7 BP 1230 EP 1240 DI 10.2337/dc15-1988 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DT3YG UT WOS:000381416500032 PM 27208344 ER PT J AU Yeung, EH Sundaram, R Bell, EM Druschel, C Kus, C Xie, Y Louis, GMB AF Yeung, E. H. Sundaram, R. Bell, E. M. Druschel, C. Kus, C. Xie, Y. Louis, G. M. Buck TI Infertility treatment and children's longitudinal growth between birth and 3 years of age SO HUMAN REPRODUCTION LA English DT Article DE assisted reproductive technologies; infertility treatment; growth; infant weight gain; ovulation induction ID IN-VITRO FERTILIZATION; INTRACYTOPLASMIC SPERM INJECTION; ASSISTED REPRODUCTIVE TECHNOLOGY; PHYSICAL HEALTH; UPSTATE KIDS; BORN; WEIGHT; IVF; CHILDHOOD; FERTILITY AB STUDY QUESTION: Does early childhood growth from birth through to 3 years of age differ by mode of conception? SUMMARY ANSWER: Findings suggest early childhood growth was comparable for children irrespective of infertility treatment, but twins conceived with ovulation induction with or without intrauterine insemination (OI/IUI) were slightly smaller than twins conceived without treatment. WHAT IS KNOWN ALREADY: Although studies have found that babies conceived with infertility treatment are born lighter and earlier than infants conceived without treatment, little research especially forn on-assisted reproductive technology (ART) treatments has focused on their continued growth during early childhood. STUDY DESIGN, SIZE, DURATION: Upstate KIDS recruited infants born (2008-2010) to resident upstate New York mothers. Infants were sampled based on birth certificate indication of infertility treatment; specifically, for every singleton conceived by infertility treatment, three singletons without infertility treatment were recruited and matched on region of birth. All multiple births irrespective of treatment were also recruited. Children were prospectively followed, returning questionnaires every 4-6 months until 3 years of age. In total, 3905 singletons, 1129 sets of multiples (96% of whom were twins) enrolled into the study. Analyses included 3440 (88%) singletons (969 conceived with treatment; specifically, 433 with ART and 535 with OI/IUI) and 991 (88%) sets of multiples (439 conceived with treatment; specifically 233 with ART and 206 with OI/IUI) with growth data available. PARTICIPANTS/MATERIALS, SETTING, METHODS: Mothers reported infertility treatment use at baseline and children's height and weight from pediatric visits. Self-reported use of ART was previously verified by linkage with the US Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) database. Mixed linear models with cubic splines accounting for age and age-gender interactions were used to estimate mean differences in growth from birth to 3 years by infertility treatment status and adjusting for maternal age, race, education, private insurance, smoking status during pregnancy, maternal pre-pregnancy and paternal body mass indices (BMI). MAIN RESULTS AND THE ROLE OF CHANCE: Compared with singletons conceived without treatment (n = 2471), singletons conceived by infertility treatment (433 by assisted reproductive technologies(ART), 535 by OI/IUI and 1 unknown specific type) did not differ ingrowth. Compared with twins not conceived with treatment (n = 1076), twins conceived with OI/IUI (n = 368) weighed slightly less over follow-up (122 g). They were also proportionally smaller for their length (-0.17 weight-for-length z-score units). No differences in mean size over the 3 years were observed for twins conceived by ART, though some evidence of rapid weight gain from birth to 4 months (adjusted OR 1.08; 95% CI: 1.00-1.16) suggestive of catch up growth was observed. LIMITATIONS, REASONS FOR CAUTION: Participants from upstate New York may not be representative of US infants. Although accounted for in statistical analysis, attrition during follow-up may have limited power to detect small differences. WIDER IMPLICATIONS OF THE FINDINGS: This study is the first to prospectively track the growth of children conceived with and without infertility treatment in the USA, including a substantial number of twins. Our findings are similar to what was previously observed in the ART literature outside of the states. STUDY FUNDING/COMPETING INTEREST(S): Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD; contracts #HHSN275201200005C, #HHSN267200700019C). Authors have no competing interests to declare. C1 [Yeung, E. H.; Sundaram, R.; Xie, Y.; Louis, G. M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Rockville, MD 20852 USA. [Bell, E. M.; Druschel, C.] SUNY Albany, Sch Publ Hlth, Dept Environm Hlth Sci, Albany, NY 12144 USA. [Bell, E. M.] SUNY Albany, Dept Epidemiol & Biostat, Sch Publ Hlth, Albany, NY 12144 USA. [Druschel, C.] New York State Dept Hlth, Ctr Environm Hlth, Bur Environm & Occupat Epidemiol, Albany, NY 12237 USA. [Kus, C.] New York State Dept Hlth, Div Family Hlth, Albany, NY 12237 USA. RP Yeung, EH (reprint author), 6710B Rockledge Dr,MSC7004, Bethesda, MD 20892 USA. EM yeungedw@mail.nih.gov OI Yeung, Edwina/0000-0002-3851-2613; Sundaram, Rajeshwari/0000-0002-6918-5002 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HHSN275201200005C, HHSN267200700019C] FX Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD; contracts #HHSN275201200005C, #HHSN267200700019C). NR 48 TC 0 Z9 0 U1 2 U2 3 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 2016 VL 31 IS 7 BP 1621 EP 1628 DI 10.1093/humrep/dew106 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA DV9EM UT WOS:000383242900029 PM 27165624 ER PT J AU Chuang, LT Randall, TC Denny, L Johnston, CM Schmeler, KM Covens, AL Cibula, D Bookman, MA Rawal, S DePetrillo, D Nam, JH Goodman, A Naik, R Manchanda, R Gaffney, DK Small, W Creutzberg, C Rattray, C Kesic, V Paraja, R Eiken, M Belleson, K Coleman, RL Barakat, RR Trimble, EL Quinn, M AF Chuang, Linus T. Randall, Thomas C. Denny, Lynette Johnston, Carolyn M. Schmeler, Kathleen M. Covens, Allan L. Cibula, David Bookman, Michael A. Rawal, Sudhir DePetrillo, Denny Nam, Joo-Hyun Goodman, Annekathryn Naik, Raj Manchanda, Ranjit Gaffney, David K. Small, William, Jr. Creutzberg, Carien Rattray, Carole Kesic, Vesna Paraja, Rene Eiken, Mary Belleson, Kristin Coleman, Robert L. Barakat, Richard R. Trimble, Edward L. Quinn, Michael TI Sister Society Meeting on Global Education Development and Collaboration Meeting Report SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER LA English DT Article DE Sister society; Low- and middle-income countries; Global education; Collaboration ID GYNECOLOGIC ONCOLOGY; HEALTH; SURGERY AB Objectives: To identify common barriers to teaching and training and to identify strategies that would be useful in developing future training programs in gynecologic oncology in low- and middle-income countries. Methods: There is a lack of overall strategy to meet the needs of education and training in gynecologic oncology in low- and middle-income countries, the leaderships of sister societies and global health volunteers met at the European Society of Gynecologic Oncology in October 23, 2015. The challenges of the training programs supported by gynecologic oncology societies, major universities and individual efforts were presented and discussed. Strategies to improve education and training were identified. Results: Major challenges include language barriers, limited surgical equipment, inadequate internet access, lack of local support for sustainability in training programs, inadequate pathology and radiation oncology, finance and a global deficiency in identifying sites and personnel in partnering or developing training programs. The leaderships identified various key components including consultation with the local Ministry of Health, local educational institutions; inclusion of the program into existing local programs, a needs assessment, and the development of curriculum and regional centers of excellence. Conclusions: Proper preparation of training sites and trainers, the development of global curriculum, the establishment of centers of excellence, and the ability to measure outcomes are important to improve education and training in gynecologic oncology in low- and middle- income countries. C1 [Chuang, Linus T.] Icahn Sch Med Mt Sinai, 1176 Fifth Ave,Box 1173, New York, NY 10029 USA. [Randall, Thomas C.; Goodman, Annekathryn] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Denny, Lynette] Univ Cape Town, Schuur Hosp, ZA-7700 Rondebosch, South Africa. [Johnston, Carolyn M.] Univ Michigan, Ann Arbor, MI 48109 USA. [Schmeler, Kathleen M.; Coleman, Robert L.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Covens, Allan L.] Univ Toronto, Odette Canc Ctr, Toronto, ON M5S 1A1, Canada. [Cibula, David] Charles Univ Prague, Prague, Czech Republic. [Cibula, David] Gen Univ Hosp, Prague, Czech Republic. [Bookman, Michael A.] US Oncol Network, The Woodlands, TX USA. [Rawal, Sudhir] Rajiv Gandhi Canc Inst, New Delhi, India. [DePetrillo, Denny] Univ Toronto, CAREpath Canada, Toronto, ON M5S 1A1, Canada. [Nam, Joo-Hyun] Univ Ulsan, Coll Med, Seoul, South Korea. [Naik, Raj] Queen Elizabeth Hosp, Gateshead, England. [Manchanda, Ranjit] Queen Mary Univ London, Barts Canc Inst, London, England. [Gaffney, David K.] Univ Utah, Huntsman Canc Hosp, Salt Lake City, UT 84112 USA. [Small, William, Jr.] Loyola Univ, Stritch Sch Med, Chicago, IL 60611 USA. [Creutzberg, Carien] Leiden Univ, Med Ctr, Leiden, Netherlands. [Rattray, Carole] Univ West Indies, Mona Campus, Kingston, Jamaica. [Kesic, Vesna] Clin Ctr Serbia, Belgrade, Serbia. [Paraja, Rene] Inst Cancerol Amer, Antioquia, Colombia. [Eiken, Mary] Int Gynecol Canc Soc, Louisville, KY USA. [Belleson, Kristin] Soc Gynecol Oncol, Chicago, IL USA. [Barakat, Richard R.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Trimble, Edward L.] NCI, Bethesda, MD 20892 USA. [Quinn, Michael] Royal Womens Hosp, Melbourne, Vic, Australia. RP Chuang, LT (reprint author), Icahn Sch Med Mt Sinai, 1176 Fifth Ave,Box 1173, New York, NY 10029 USA. EM linus.chuang@mssm.edu OI Cibula, David/0000-0001-6387-9356 FU NCI NIH HHS [P30 CA008748] NR 6 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1048-891X EI 1525-1438 J9 INT J GYNECOL CANCER JI Int. J. Gynecol. Cancer PD JUL PY 2016 VL 26 IS 6 BP 1186 EP 1188 DI 10.1097/IGC.0000000000000735 PG 3 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA DW9CV UT WOS:000383953500030 PM 27327155 ER PT J AU Singhal, A Simmons, M Lu, ZY AF Singhal, Ayush Simmons, Michael Lu, Zhiyong TI Text mining for precision medicine: automating disease-mutation relationship extraction from biomedical literature SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article DE precision medicine; disease-mutation relationship; automated extraction; machine learning; text mining; breast cancer; prostate cancer ID SEQUENCE VARIANTS; SYSTEM; TOOL AB Objective Identifying disease-mutation relationships is a significant challenge in the advancement of precision medicine. The aim of this work is to design a tool that automates the extraction of disease-related mutations from biomedical text to advance database curation for the support of precision medicine. Materials and Methods We developed a machine-learning (ML) based method to automatically identify the mutations mentioned in the biomedical literature related to a particular disease. In order to predict a relationship between the mutation and the target disease, several features, such as statistical features, distance features, and sentiment features, were constructed. Our ML model was trained with a pre-labeled dataset consisting of manually curated information about mutation-disease associations. The model was subsequently used to extract disease-related mutations from larger biomedical literature corpora. Results The performance of the proposed approach was assessed using a benchmarking dataset. Results show that our proposed approach gains significant improvement over the previous state of the art and obtains F-measures of 0.880 and 0.845 for prostate and breast cancer mutations, respectively. Discussion To demonstrate its utility, we applied our approach to all abstracts in PubMed for 3 diseases (including a non-cancer disease). The mutations extracted were then manually validated against human-curated databases. The validation results show that the proposed approach is useful in a real-world setting to extract uncurated disease mutations from the biomedical literature. Conclusions The proposed approach improves the state of the art for mutation-disease extraction from text. It is scalable and generalizable to identify mutations for any disease at a PubMed scale. C1 [Singhal, Ayush; Simmons, Michael; Lu, Zhiyong] Natl Lib Med, NCBI, NIH, MSC3825,Bldg 38A,Rm 1003A,8600 Rockville Pike, Bethesda, MD 20894 USA. RP Lu, ZY (reprint author), Natl Lib Med, NCBI, NIH, MSC3825,Bldg 38A,Rm 1003A,8600 Rockville Pike, Bethesda, MD 20894 USA. EM zhiyong.lu@nih.gov FU NIH Intramural Research Program; National Library of Medicine; NIH Medical Research Scholars Program; NIH FX This research was supported by the NIH Intramural Research Program, National Library of Medicine, and the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from the Doris Duke Charitable Foundation, the Howard Hughes Medical Institute, the American Association for Dental Research, the Colgate-Palmolive Company, and other private donors. No funds from the Doris Duke Charitable Foundation were used to support research that used animals. NR 26 TC 1 Z9 1 U1 8 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1067-5027 EI 1527-974X J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD JUL PY 2016 VL 23 IS 4 BP 766 EP 772 DI 10.1093/jamia/ocw041 PG 7 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA DW6SS UT WOS:000383782100013 PM 27121612 ER PT J AU Roberts, K Demner-Fushman, D AF Roberts, Kirk Demner-Fushman, Dina TI Interactive use of online health resources: a comparison of consumer and professional questions SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article DE consumer health informatics; online information seeking; consumer language; question answering ID INFORMATION-SEEKING; CLINICAL QUESTIONS; CARE; POINT AB Objective To understand how consumer questions on online resources differ from questions asked by professionals, and how such consumer questions differ across resources. Materials and Methods Ten online question corpora, 5 consumer and 5 professional, with a combined total of over 40 000 questions, were analyzed using a variety of natural language processing techniques. These techniques analyze questions at the lexical, syntactic, and semantic levels, exposing differences in both form and content. Results Consumer questions tend to be longer than professional questions, more closely resemble open-domain language, and focus far more on medical problems. Consumers ask more sub-questions, provide far more background information, and ask different types of questions than professionals. Furthermore, there is substantial variance of these factors between the different consumer corpora. Discussion The form of consumer questions is highly dependent upon the individual online resource, especially in the amount of background information provided. Professionals, on the other hand, provide very little background information and often ask much shorter questions. The content of consumer questions is also highly dependent upon the resource. While professional questions commonly discuss treatments and tests, consumer questions focus disproportionately on symptoms and diseases. Further, consumers place far more emphasis on certain types of health problems (eg, sexual health). Conclusion Websites for consumers to submit health questions are a popular online resource filling important gaps in consumer health information. By analyzing how consumers write questions on these resources, we can better understand these gaps and create solutions for improving information access. This article is part of the Special Focus on Person-Generated Health and Wellness Data, which published in the May 2016 issue, Volume 23, Issue 3. C1 [Roberts, Kirk; Demner-Fushman, Dina] US Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, NIH, 8600 Rockville Pike,Bldg 38A-1003H, Bethesda, MD 20894 USA. RP Roberts, K (reprint author), US Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, NIH, 8600 Rockville Pike,Bldg 38A-1003H, Bethesda, MD 20894 USA. EM kirk.roberts@nih.gov FU National Institutes of Health [1K99LM012104]; US National Library of Medicine, National Institutes of Health FX This work was supported by the National Institutes of Health (1K99LM012104), as well as the intramural research program at the US National Library of Medicine, National Institutes of Health. NR 34 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1067-5027 EI 1527-974X J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD JUL PY 2016 VL 23 IS 4 BP 802 EP 811 DI 10.1093/jamia/ocw024 PG 10 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA DW6SS UT WOS:000383782100020 PM 27147494 ER PT J AU Cranfill, PJ Sell, BR Baird, MA Allen, JR Lavagnino, Z de Gruiter, HM Kremers, GJ Davidson, MW Ustione, A Piston, DW AF Cranfill, Paula J. Sell, Brittney R. Baird, Michelle A. Allen, John R. Lavagnino, Zeno de Gruiter, H. Martijn Kremers, Gert-Jan Davidson, Michael W. Ustione, Alessandro Piston, David W. TI Quantitative assessment of fluorescent proteins SO NATURE METHODS LA English DT Article ID MONOMERIC RED; IN-VIVO; GREEN; MICROSCOPY; BRIGHT; GFP; ORANGE; FRET; EVOLUTION; VARIANTS AB The advent of fluorescent proteins (FPs) for genetic labeling of molecules and cells has revolutionized fluorescence microscopy. Genetic manipulations have created a vast array of bright and stable FPs spanning blue to red spectral regions. Common to autofluorescent FPs is their tight beta-barrel structure, which provides the rigidity and chemical environment needed for effectual fluorescence. Despite the common structure, each FP has unique properties. Thus, there is no single 'best' FP for every circumstance, and each FP has advantages and disadvantages. To guide decisions about which FP is right for a given application, we have quantitatively characterized the brightness, photostability, pH stability and monomeric properties of more than 40 FPs to enable straightforward and direct comparison between them. We focus on popular and/or top-performing FPs in each spectral region. C1 [Cranfill, Paula J.; Sell, Brittney R.; Baird, Michelle A.; Allen, John R.; Davidson, Michael W.] Florida State Univ, Natl High Field Magnet Lab, Tallahassee, FL 32306 USA. [Cranfill, Paula J.; Lavagnino, Zeno; Ustione, Alessandro; Piston, David W.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Lavagnino, Zeno; Ustione, Alessandro; Piston, David W.] Washington Univ, Dept Cell Biol & Physiol, St Louis, MO USA. [de Gruiter, H. Martijn; Kremers, Gert-Jan] Erasmus MC, Josephine Nefkens Inst, Erasmus Opt Imaging Ctr, Rotterdam, Netherlands. [Cranfill, Paula J.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Sell, Brittney R.] George Washington Univ, Dept Biochem & Mol Med, Washington, DC USA. [Baird, Michelle A.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Allen, John R.] Nikon Instruments, Melville, NY USA. RP Piston, DW (reprint author), Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA.; Piston, DW (reprint author), Washington Univ, Dept Cell Biol & Physiol, St Louis, MO USA. EM piston@wustl.edu OI Lavagnino, Zeno/0000-0002-7247-8084 FU NIH [R01DK085064, R01DK098659, S100D010681, P20GM072048] FX This work was supported in part by NIH grants R01DK085064, R01DK098659, S10OD010681 and P20GM072048 to D.W.P. NR 65 TC 20 Z9 20 U1 18 U2 21 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 EI 1548-7105 J9 NAT METHODS JI Nat. Methods PD JUL PY 2016 VL 13 IS 7 BP 557 EP + DI 10.1038/NMETH.3891 PG 7 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA DW6XK UT WOS:000383794500012 PM 27240257 ER PT J AU Essa, MM Akbar, M Khan, MAS AF Essa, Musthafa Mohamed Akbar, Mohammed Khan, Mohammed Abdul Sattar TI Beneficial effects of date palm fruits on neurodegenerative diseases SO NEURAL REGENERATION RESEARCH LA English DT Editorial Material ID DIETARY SUPPLEMENTATION; ANTIOXIDANT ACTIVITY; ALZHEIMERS-DISEASE; AMYLOID-BETA C1 [Essa, Musthafa Mohamed] Sultan Qaboos Univ, Coll Agr & Marine Sci, Dept Food Sci & Nutr, Muscat, Oman. [Essa, Musthafa Mohamed] Sultan Qaboos Univ, Ageing & Dementia Res Grp, Muscat, Oman. [Akbar, Mohammed] NIAAA, Sect Mol Pharmacol & Toxicol, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD USA. [Khan, Mohammed Abdul Sattar] Massachusetts Gen Hosp, Shriners Hosp Children, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Khan, Mohammed Abdul Sattar] Harvard Med Sch, Boston, MA USA. RP Essa, MM (reprint author), Sultan Qaboos Univ, Coll Agr & Marine Sci, Dept Food Sci & Nutr, Muscat, Oman.; Essa, MM (reprint author), Sultan Qaboos Univ, Ageing & Dementia Res Grp, Muscat, Oman. EM drmdessa@gmail.com NR 15 TC 0 Z9 0 U1 2 U2 2 PU MEDKNOW PUBLICATIONS & MEDIA PVT LTD PI MUMBAI PA B-9, KANARA BUSINESS CENTRE, OFF LINK RD, GHAKTOPAR-E, MUMBAI, 400075, INDIA SN 1673-5374 EI 1876-7958 J9 NEURAL REGEN RES JI Neural Regen. Res. PD JUL PY 2016 VL 11 IS 7 BP 1071 EP 1072 DI 10.4103/1673-5374.187032 PG 2 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA DW6YW UT WOS:000383798300015 PM 27630684 ER PT J AU Van Voorhis, WC Adams, JH Adelfio, R Ahyong, V Akabas, MH Alano, P Alday, A Resto, YA Alsibaee, A Alzualde, A Andrews, KT Avery, SV Avery, VM Ayong, L Baker, M Baker, S Ben Mamoun, C Bhatia, S Bickle, Q Bounaadja, L Bowling, T Bosch, J Boucher, LE Boyom, FF Brea, J Brennan, M Burton, A Caffrey, CR Camarda, G Carrasquilla, M Carter, D Cassera, MB Cheng, KCC Chindaudomsate, W Chubb, A Colon, BL Colon-Lopez, DD Corbett, Y Crowther, GJ Cowan, N D'Alessandro, S Le Dang, N Delves, M DeRisi, JL Du, AY Duffy, S El-Sayed, SA Ferdig, MT Robledo, JAF Fidock, DA Florent, I Fokou, PVT Galstian, A Gamo, FJ Gokool, S Gold, B Golub, T Goldgof, GM Guha, R Guiguemde, WA Gural, N Guy, RK Hansen, MAE Hanson, KK Hemphill, A van Huijsduijnen, RH Horii, T Horrocks, P Hughes, TB Huston, C Igarashi, I Ingram-Sieber, K Itoe, MA Jadhav, A Jensen, AN Jensen, LT Jiang, RHY Kaiser, A Keiser, J Ketas, T Kicka, S Kim, S Kirk, K Kumar, VP Kyle, DE Lafuente, MJ Landfear, S Lee, N Lee, S Lehane, AM Li, FW Little, D Liu, LQ Llinas, M Loza, MI Lubar, A Lucantoni, L Lucet, I Maes, L Mancama, D Mansour, NR March, S McGowan, S Vera, IM Meister, S Mercer, L Mestres, J Mfopa, AN Misra, RN Moon, S Moore, JP da Costa, FMR Muller, J Muriana, A Hewitt, SN Nare, B Nathan, C Narraidoo, N Nawaratna, S Ojo, KK Ortiz, D Panic, G Papadatos, G Parapini, S Patra, K Pham, N Prats, S Plouffe, DM Poulsen, SA Pradhan, A Quevedo, C Quinn, RJ Rice, CA Rizk, MA Ruecker, A St Onge, R Ferreira, RS Samra, J Robinett, NG Schlecht, U Schmitt, M Villela, FS Silvestrini, F Sinden, R Smith, DA Soldati, T Spitzmuller, A Stamm, SM Sullivan, DJ Sullivan, W Suresh, S Suzuki, BM Suzuki, Y Swamidass, SJ Taramelli, D Tchokouaha, LRY Theron, A Thomas, D Tonissen, KF Townson, S Tripathi, AK Trofimov, V Udenze, KO Ullah, I Vallieres, C Vigil, E Vinetz, JM Vinh, PV Vu, H Watanabe, NA Weatherby, K White, PM Wilks, AF Winzeler, EA Wojcik, E Wree, M Wu, W Yokoyama, N Zollo, PHA Abla, N Blasco, B Burrows, J Laleu, B Leroy, D Spangenberg, T Wells, T Willis, PA AF Van Voorhis, Wesley C. Adams, John H. Adelfio, Roberto Ahyong, Vida Akabas, Myles H. Alano, Pietro Alday, Aintzane Resto, Yesmalie Aleman Alsibaee, Aishah Alzualde, Ainhoa Andrews, Katherine T. Avery, Simon V. Avery, Vicky M. Ayong, Lawrence Baker, Mark Baker, Stephen Ben Mamoun, Choukri Bhatia, Sangeeta Bickle, Quentin Bounaadja, Lotfi Bowling, Tana Bosch, Juergen Boucher, Lauren E. Boyom, Fabrice F. Brea, Jose Brennan, Marian Burton, Audrey Caffrey, Conor R. Camarda, Grazia Carrasquilla, Manuela Carter, Dee Cassera, Maria Belen Cheng, Ken Chih-Chien Chindaudomsate, Worathad Chubb, Anthony Colon, Beatrice L. Colon-Lopez, Daisy D. Corbett, Yolanda Crowther, Gregory J. Cowan, Noemi D'Alessandro, Sarah Le Dang, Na Delves, Michael DeRisi, Joseph L. Du, Alan Y. Duffy, Sandra El-Sayed, Shimaa Abd El-Salam Ferdig, Michael T. Robledo, Jose A. Fernandez Fidock, David A. Florent, Isabelle Fokou, Patrick V. T. Galstian, Ani Javier Gamo, Francisco Gokool, Suzanne Gold, Ben Golub, Todd Goldgof, Gregory M. Guha, Rajarshi Guiguemde, W. Armand Gural, Nil Guy, R. Kiplin Hansen, Michael A. E. Hanson, Kirsten K. Hemphill, Andrew van Huijsduijnen, Rob Hooft Horii, Takaaki Horrocks, Paul Hughes, Tyler B. Huston, Christopher Igarashi, Ikuo Ingram-Sieber, Katrin Itoe, Maurice A. Jadhav, Ajit Jensen, Amornrat Naranuntarat Jensen, Laran T. Jiang, Rays H. Y. Kaiser, Annette Keiser, Jennifer Ketas, Thomas Kicka, Sebastien Kim, Sunyoung Kirk, Kiaran Kumar, Vidya P. Kyle, Dennis E. Jose Lafuente, Maria Landfear, Scott Lee, Nathan Lee, Sukjun Lehane, Adele M. Li, Fengwu Little, David Liu, Liqiong Llinas, Manuel Loza, Maria I. Lubar, Aristea Lucantoni, Leonardo Lucet, Isabelle Maes, Louis Mancama, Dalu Mansour, Nuha R. March, Sandra McGowan, Sheena Vera, Iset Medina Meister, Stephan Mercer, Luke Mestres, Jordi Mfopa, Alvine N. Misra, Raj N. Moon, Seunghyun Moore, John P. Rodrigues da Costa, Francielly Morais Mueller, Joachim Muriana, Arantza Hewitt, Stephen Nakazawa Nare, Bakela Nathan, Carl Narraidoo, Nathalie Nawaratna, Sujeevi Ojo, Kayode K. Ortiz, Diana Panic, Gordana Papadatos, George Parapini, Silvia Patra, Kailash Ngoc Pham Prats, Sarah Plouffe, David M. Poulsen, Sally-Ann Pradhan, Anupam Quevedo, Celia Quinn, Ronald J. Rice, Christopher A. Rizk, Mohamed Abdo Ruecker, Andrea St Onge, Robert Ferreira, Rafaela Salgado Samra, Jasmeet Robinett, Natalie G. Schlecht, Ulrich Schmitt, Marjorie Villela, Filipe Silva Silvestrini, Francesco Sinden, Robert Smith, Dennis A. Soldati, Thierry Spitzmueller, Andreas Stamm, Serge Maximilian Sullivan, David J. Sullivan, William Suresh, Sundari Suzuki, Brian M. Suzuki, Yo Swamidass, S. Joshua Taramelli, Donatella Tchokouaha, Lauve R. Y. Theron, Anjo Thomas, David Tonissen, Kathryn F. Townson, Simon Tripathi, Abhai K. Trofimov, Valentin Udenze, Kenneth O. Ullah, Imran Vallieres, Cindy Vigil, Edgar Vinetz, Joseph M. Phat Voong Vinh Hoan Vu Watanabe, Nao-aki Weatherby, Kate White, Pamela M. Wilks, Andrew F. Winzeler, Elizabeth A. Wojcik, Edward Wree, Melanie Wu, Wesley Yokoyama, Naoaki Zollo, Paul H. A. Abla, Nada Blasco, Benjamin Burrows, Jeremy Laleu, Benoit Leroy, Didier Spangenberg, Thomas Wells, Timothy Willis, Paul A. TI Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond SO PLOS PATHOGENS LA English DT Article ID STAGE PLASMODIUM-FALCIPARUM; IN-VITRO; INFECTED ERYTHROCYTES; THEILERIA PARASITES; IDENTIFICATION; INHIBITORS; TRANSMISSION; TARGET; BABESIA; BLOOD AB A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could especially be bridged through a scale-up of open sharing of physical compounds, which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compounds representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-analysis of the combined dataset. The combined biochemical and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compounds active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addition, many compounds demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicological, pharmacokinetic and metabolic properties were collected on all the compounds, assisting in the selection of the most promising candidates for murine proof-of-concept experiments and medicinal chemistry programs. The data for all of these assays are presented and analyzed to show how outstanding leads for many indications can be selected. These results reveal the immense potential for translating the dispersed expertise in biological assays involving human pathogens into drug discovery starting points, by providing open access to new families of molecules, and emphasize how a small additional investment made to help acquire and distribute compounds, and sharing the data, can catalyze drug discovery for dozens of different indications. Another lesson is that when multiple screens from different groups are run on the same library, results can be integrated quickly to select the most valuable starting points for subsequent medicinal chemistry efforts. C1 [Van Voorhis, Wesley C.; Crowther, Gregory J.; Hewitt, Stephen Nakazawa; Ojo, Kayode K.] Univ Washington, Dept Med, CERID, Seattle, WA 98195 USA. [Van Voorhis, Wesley C.; Crowther, Gregory J.; Hewitt, Stephen Nakazawa; Ojo, Kayode K.] Univ Washington, Dept Microbiol, CERID, Seattle, WA 98195 USA. [Van Voorhis, Wesley C.; Crowther, Gregory J.; Hewitt, Stephen Nakazawa; Ojo, Kayode K.] Univ Washington, Dept Global Hlth, CERID, Seattle, WA 98195 USA. [Adams, John H.; Jiang, Rays H. Y.; Kyle, Dennis E.; Pradhan, Anupam; Rice, Christopher A.; Udenze, Kenneth O.] Univ S Florida, Dept Global Hlth, Ctr Global Hlth & Infect Dis Res, Tampa, FL USA. [Adelfio, Roberto; Cowan, Noemi; Ingram-Sieber, Katrin; Keiser, Jennifer; Panic, Gordana] Swiss Trop & Publ Hlth Inst, Med Parasitol & Infect Biol, Basel, Switzerland. [Adelfio, Roberto; Cowan, Noemi; Ingram-Sieber, Katrin; Keiser, Jennifer; Panic, Gordana] Univ Basel, Basel, Switzerland. [Ahyong, Vida; DeRisi, Joseph L.; Wu, Wesley] Univ Calif San Francisco, Dept Biochem & Biophys, Howard Hughes Med Inst, San Francisco, CA 94143 USA. [Akabas, Myles H.] Albert Einstein Coll Med, Dept Physiol & Biophys, New York, NY USA. [Akabas, Myles H.] Albert Einstein Coll Med, Dept Neurosci, New York, NY USA. [Akabas, Myles H.] Albert Einstein Coll Med, Dept Med, New York, NY USA. [Alano, Pietro; Camarda, Grazia; Silvestrini, Francesco] Ist Super Sanita, Dipartimento Malattie Infett Parassitarie & Immun, Rome, Italy. [Alday, Aintzane; Alzualde, Ainhoa; Muriana, Arantza; Quevedo, Celia] BBD BioPhenix SL BIOBIDE, Donostia San Sebastian, Gipuzkoa, Spain. [Resto, Yesmalie Aleman; Robledo, Jose A. Fernandez] Bigelow Lab Ocean Sci, East Boothbay, ME USA. [Alsibaee, Aishah; Brennan, Marian; Chubb, Anthony] Royal Coll Surgeons Ireland, Mol & Cellular Therapeut, Dublin, Ireland. [Andrews, Katherine T.; Avery, Vicky M.; Duffy, Sandra; Lucantoni, Leonardo; Nawaratna, Sujeevi; Ngoc Pham; Poulsen, Sally-Ann; Quinn, Ronald J.; Tonissen, Kathryn F.; Hoan Vu] Griffith Univ, Eskitis Inst Drug Discovery, Nathan, Qld, Australia. [Andrews, Katherine T.; Nawaratna, Sujeevi] QIMR Berghofer Med Res Inst Herston, Brisbane, Qld, Australia. [Avery, Simon V.; Narraidoo, Nathalie; Vallieres, Cindy] Univ Nottingham, Sch Life Sci, Nottingham, Notts, England. [Ayong, Lawrence; Hansen, Michael A. E.; Lee, Sukjun; Moon, Seunghyun] Inst Pasteur Korea, Pangyo Techno Valley, Gyeonggi Provin, South Korea. [Baker, Mark] Novartis Consumer Hlth, Clin Pharmacol, Nyon, Switzerland. [Baker, Stephen; Phat Voong Vinh] Univ Oxford, Clin Res Unit, Wellcome Trust Major Overseas Programme, Hosp Trop Dis, Ho Chi Minh City, Vietnam. [Baker, Stephen] Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England. [Baker, Stephen] London Sch Hyg & Trop Med, London, England. [Ben Mamoun, Choukri; Kumar, Vidya P.] Yale Univ, Internal Med, New Haven, CT USA. [Bhatia, Sangeeta; Gural, Nil; March, Sandra] MIT, Inst Med Engn & Sci, Hlth Sci & Technol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Bickle, Quentin; Mansour, Nuha R.] London Sch Hyg & Trop Med, Dept Immunol & Infect, London, England. [Bounaadja, Lotfi; Florent, Isabelle] Sorbonne Univ, Museum Natl Hist, Paris, France. [Bowling, Tana; Burton, Audrey; Mercer, Luke; Nare, Bakela] SCYNEXIS Inc, Durham, NC USA. [Bosch, Juergen; Boucher, Lauren E.; Colon-Lopez, Daisy D.; Robinett, Natalie G.; Stamm, Serge Maximilian] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biochem & Mol Biol, Baltimore, MD USA. [Bosch, Juergen; Boucher, Lauren E.; Colon-Lopez, Daisy D.; Robinett, Natalie G.; Stamm, Serge Maximilian] Johns Hopkins Bloomberg Sch Publ Hlth, Johns Hopkins Malaria Res Inst, Baltimore, MD USA. [Boyom, Fabrice F.; Fokou, Patrick V. T.; Mfopa, Alvine N.; Tchokouaha, Lauve R. Y.; Zollo, Paul H. A.] Univ Yaounde, Dept Biochem, Yaounde, Cameroon. [Brea, Jose; Loza, Maria I.] Univ Santiago de Compostela, CIMUS Res Ctr, Santiago De Compostela, A Coruna, Spain. [Caffrey, Conor R.; Suzuki, Brian M.] Univ Calif San Francisco, Dept Pathol, Ctr Discovery & Innovat Parasit Dis, San Francisco, CA 94140 USA. [Carrasquilla, Manuela; Llinas, Manuel; Samra, Jasmeet] Penn State Univ, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. [Carrasquilla, Manuela; Llinas, Manuel; Samra, Jasmeet] Penn State Univ, Huck Ctr Malaria Res, University Pk, PA 16802 USA. [Carter, Dee; Weatherby, Kate] Univ Sydney, Sch Life & Environm Sci, Darlington, NSW, Australia. [Cassera, Maria Belen] Virginia Polytech Inst & State Univ, Dept Biochem, Blacksburg, VA 24061 USA. [Cassera, Maria Belen] Virginia Polytech Inst & State Univ, Virginia Tech Ctr Drug Discovery, Blacksburg, VA 24061 USA. [Cheng, Ken Chih-Chien; Guha, Rajarshi; Jadhav, Ajit] NIH, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. [Chindaudomsate, Worathad; Jensen, Laran T.] Mahidol Univ, Dept Biochem, Bangkok, Thailand. [Colon, Beatrice L.] Univ S Florida, Morsani Coll Med, Dept Mol Med, Tampa, FL USA. [Corbett, Yolanda; D'Alessandro, Sarah; Parapini, Silvia] Univ Milan, Dept Pharmacol & Biomol Sci, Milan, Italy. [Le Dang, Na; Hughes, Tyler B.; Taramelli, Donatella] Washington Univ, Dept Pathol & Immunol, St Louis, MO USA. [Delves, Michael; Ruecker, Andrea; Swamidass, S. Joshua] Imperial Coll London, Dept Life Sci, London, England. [Du, Alan Y.; Meister, Stephan; Vigil, Edgar; Winzeler, Elizabeth A.; Wree, Melanie] Univ Calif San Diego, Sch Med, Dept Pediat, Div Pharmacol & Drug Discovery, La Jolla, CA 92093 USA. [El-Sayed, Shimaa Abd El-Salam; Igarashi, Ikuo; Rizk, Mohamed Abdo; Yokoyama, Naoaki] Obihiro Univ Agr & Vet Med, Natl Res Ctr Protozoan Dis, Obihiro, Hokkaido, Japan. [El-Sayed, Shimaa Abd El-Salam] Mansoura Univ, Dept Biochem & Chem Nutr, Mansoura, Egypt. [Ferdig, Michael T.] Univ Notre Dame, Dept Biol Sci, Eck Inst Global Hlth, Notre Dame, IN 46556 USA. [Fidock, David A.] Columbia Univ, Dept Med, Med Ctr, Dept Microbiol & Immunol, New York, NY USA. [Fidock, David A.] Columbia Univ, Dept Med, Med Ctr, Div Infect Dis, New York, NY USA. [Galstian, Ani; Golub, Todd; Thomas, David] Broad Inst, Cambridge, MA USA. [Javier Gamo, Francisco; Jose Lafuente, Maria; Prats, Sarah] GlaxoSmithKline R&D, Biochem & Parasitol Dept, Malaria DPU, DDW, Madrid, Spain. [Gokool, Suzanne; Townson, Simon] Northwick Pk Inst Med Res, Trop Parasit Dis Unit, Harrow, Middx, England. [Gold, Ben; Ketas, Thomas; Little, David; Moore, John P.; Nathan, Carl] Weill Cornell Med Coll, Dept Microbiol & Immunol, New York, NY USA. [Goldgof, Gregory M.] Univ Calif San Diego, Med Scientist Training Program, San Diego, CA 92103 USA. [Guiguemde, W. Armand; Guy, R. Kiplin] St Jude Childrens Res Hosp, Dept Chem Biol & Therapeut, 332 N Lauderdale St, Memphis, TN 38105 USA. [Hanson, Kirsten K.] Univ Texas San Antonio, Dept Biol, San Antonio, TX USA. [Hanson, Kirsten K.] Univ Texas San Antonio, South Texas Ctr Emerging Infect Dis, San Antonio, TX USA. [Hanson, Kirsten K.; Itoe, Maurice A.; Vera, Iset Medina] Inst Med Mol, Lisbon, Portugal. [Hemphill, Andrew; Mueller, Joachim] Univ Bern, Inst Parasitol, Bern, Switzerland. [van Huijsduijnen, Rob Hooft; Lee, Nathan; Abla, Nada; Blasco, Benjamin; Burrows, Jeremy; Laleu, Benoit; Leroy, Didier; Spangenberg, Thomas; Wells, Timothy; Willis, Paul A.] Med Malaria Venture, Geneva, Switzerland. [Horii, Takaaki; Watanabe, Nao-aki] Eisai & Co Ltd, Hhc Data Creat Ctr, Global Hlth Res Sect, Tsukuba, Ibaraki, Japan. [Horrocks, Paul; Ullah, Imran] Keele Univ, Inst Sci & Technol Med, Keele, Staffs, England. [Huston, Christopher] Univ Vermont, Coll Med, Dept Med, Burlington, VT 05405 USA. [Jensen, Amornrat Naranuntarat] Mahidol Univ, Fac Sci, Dept Pathobiol, Bangkok, Thailand. [Kaiser, Annette] Inst Pharmacogenet, Med Res Ctr, Essen, Germany. [Kicka, Sebastien; Soldati, Thierry; Trofimov, Valentin] Univ Geneva, Dept Biochem, Geneva, Switzerland. [Kim, Sunyoung; Liu, Liqiong; Wojcik, Edward] LSU Hlth Sci Ctr, Dept Biochem & Mol Biol, New Orleans, LA USA. [Kirk, Kiaran; Lehane, Adele M.] Australian Natl Univ, Res Sch Biol, Canberra, ACT, Australia. [Landfear, Scott; Li, Fengwu; Ortiz, Diana] Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97201 USA. [Lubar, Aristea; Patra, Kailash; Vinetz, Joseph M.] Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA. [Lucet, Isabelle] Monash Univ, Dept Biochem & Mol Biol, Clayton, Vic, Australia. [Maes, Louis] Univ Antwerp, Dept Biomed Sci, Antwerp, Belgium. [Mancama, Dalu; Theron, Anjo] CSIR, Biosci Unit, Pretoria, South Africa. [McGowan, Sheena] Monash Univ, Dept Microbiol, Clayton, Vic, Australia. [Mestres, Jordi; Spitzmueller, Andreas] IMIM Hosp del Mar, Inst Med Res, Chemotargets SL, Barcelona, Catalonia, Spain. [Mestres, Jordi; Spitzmueller, Andreas] IMIM Hosp del Mar, Inst Med Res, Res Grp Syst Pharmacol, Res Program Biomed Informat GRIB, Barcelona, Catalonia, Spain. [Mestres, Jordi; Spitzmueller, Andreas] Univ Pompeu Fabra, Barcelona, Catalonia, Spain. [Misra, Raj N.] NCI, Div Canc Therapeut & Diag, Drug Synth & Chem Branch, NIH, Bethesda, MD 20892 USA. [Rodrigues da Costa, Francielly Morais] Univ Fed Minas Gerais, Grad Program Bioinformat, Belo Horizonte, MG, Brazil. [Papadatos, George] EBI, EMBL, ChEMBL Grp, Hinxton, Cambs, England. [Plouffe, David M.] Novartis Res Fdn, Genom Inst, San Diego, CA USA. [Rizk, Mohamed Abdo] Mansoura Univ, Dept Internal Med & Infect Dis, Fac Vet Med, Mansoura, Egypt. [St Onge, Robert; Schlecht, Ulrich] Stanford Univ, Dept Biochem, Palo Alto, CA 94304 USA. [St Onge, Robert; Schlecht, Ulrich] Stanford Univ, Stanford Genome Technol Ctr, Palo Alto, CA 94304 USA. [Ferreira, Rafaela Salgado; Villela, Filipe Silva; Suresh, Sundari] Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Bioquim & Imunol, Belo Horizonte, MG, Brazil. [Robinett, Natalie G.; Schmitt, Marjorie] IRJBD, Lab Chim Mol, COB, CNRS,UMR 7509, Mulhouse, France. [Sinden, Robert] Univ Oxford, Jenner Inst, Oxford, England. [Smith, Dennis A.] Univ Cape Town, Dept Chem, Cape Town, South Africa. [Sullivan, David J.; Tripathi, Abhai K.] Johns Hopkins Sch Publ Hlth, H Feinstone Dept Mol Microbiol & Immunol, Baltimore, MD USA. [Sullivan, William; White, Pamela M.] Univ Calif Santa Cruz, Mol Cell & Dev Biol, Santa Cruz, CA 95064 USA. [Suzuki, Yo] J Craig Venter Inst, Dept Synthet Biol & Bioenergy, La Jolla, CA USA. [Tonissen, Kathryn F.] Griffith Univ, Sch Nat Sci, Nathan, Qld, Australia. [Wilks, Andrew F.] Walter & Eliza Hall Inst Med Res, Hudson Inst Med Res, Parkville, Vic, Australia. [Wilks, Andrew F.] SYNth Res, Parkville, Vic, Australia. [Carrasquilla, Manuela] Wellcome Trust Sanger Inst, Wellcome Genome Campus, Hinxton, Cambs, England. [Spangenberg, Thomas] Merck, Global Hlth, Coinsins, Switzerland. RP Van Voorhis, WC (reprint author), Univ Washington, Dept Med, CERID, Seattle, WA 98195 USA.; Van Voorhis, WC (reprint author), Univ Washington, Dept Microbiol, CERID, Seattle, WA 98195 USA.; Van Voorhis, WC (reprint author), Univ Washington, Dept Global Hlth, CERID, Seattle, WA 98195 USA. EM wesley@uw.edu RI Quinn, Ronald/A-7931-2008; Gasull, Martina/A-6630-2013; Kirk, Kiaran/C-8299-2009; Maes, Louis/A-2384-2017; Adams, John/G-1800-2015; Poulsen, Sally-Ann/C-4500-2008; duffy, sandra/B-8479-2017; Tonissen, Kathryn/E-9424-2010; Andrews, Katherine/F-9586-2011; Mestres, Jordi/B-3673-2009; OI McGowan, Sheena/0000-0001-6863-1106; Avery, Simon/0000-0002-2102-2255; Rice, Christopher/0000-0003-0672-9604; SOLDATI, Thierry/0000-0002-2056-7931; Quinn, Ronald/0000-0002-4022-2623; Kirk, Kiaran/0000-0002-5613-2622; Maes, Louis/0000-0002-2324-9509; Adams, John/0000-0003-3707-7979; Poulsen, Sally-Ann/0000-0003-4494-3687; duffy, sandra/0000-0002-2814-1193; Tonissen, Kathryn/0000-0002-1018-2798; Andrews, Katherine/0000-0002-1591-8979; Mestres, Jordi/0000-0002-5202-4501; Du, Alan/0000-0003-3223-9705; Crowther, Gregory/0000-0003-0530-9130; alano, pietro/0000-0003-0092-9840 FU UK DFID; Bill and Melinda Gates Foundation Grand Challenges Explorations; Medicines for Malaria Venture MMV Challenge Grant [MMV 12/0048, MMV 12/0076]; Australian Research Council [FT10100185, FT0991213, LP120200557]; Bill & Melinda Gates Foundation [OPP1040394, OPP1040399, OPP1086189, OPP1069393, OPP1119049, OPP1024029]; Bloomberg Family Foundation (JBr); JHMRI; US NIH [T32GM080189, R01GM104486, R01AI117017]; National Science Foundation Graduate Research Fellowship Program [DGE-1232825]; South African Medical Research Council [V6YBT51]; Council for Scientific and Industrial Research [V1YTB95]; French ANR program Mammamia [ANR-12-BS07-0020-01] FX Thanks to the UK DFID and the Bill and Melinda Gates Foundation Grand Challenges Explorations for providing funding for testing of the Malaria Box and funding the support of individual groups including: Medicines for Malaria Venture MMV Challenge Grant, Grant Numbers MMV 12/0048 and MMV 12/0076 (to JHA), the Australian Research Council (FT10100185 to SAP; FT0991213 to KTA and LP120200557 awarded to VMA), Bill & Melinda Gates Foundation Grant OPP1040394 to PA, OPP1040399 to DAF and VMA and OPP1086189 to KKH, OPP1069393 and OPP1119049 to ML, OPP1024029 to CN, the Bloomberg Family Foundation (JBr), JHMRI for a predoctoral fellowship, the US NIH for the CBI training grant T32GM080189 (to LEB), R01GM104486 (to PAW & WS), R01AI117017 (to JHA) the National Science Foundation Graduate Research Fellowship Program Grant No. DGE-1232825 (DDCL), the South African Medical Research Council Strategic Health Innovation Partnerships (grant V6YBT51 to DM) and the Council for Scientific and Industrial Research (grant V1YTB95, to DM), and the French ANR program Mammamia (ANR-12-BS07-0020-01). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 75 TC 7 Z9 7 U1 12 U2 15 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD JUL PY 2016 VL 12 IS 7 AR e1005763 DI 10.1371/journal.ppat.1005763 PG 23 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA DW0XN UT WOS:000383366400043 PM 27467575 ER PT J AU Hsu, PF Cheng, HM Wu, CH Sung, SH Chuang, SY Lakatta, EG Yin, FCP Chou, P Chen, CH AF Hsu, Pai-Feng Cheng, Hao-Min Wu, Cheng-Hsueh Sung, Shih-Hsien Chuang, Shao-Yuan Lakatta, Edward G. Yin, Frank C. P. Chou, Pesus Chen, Chen-Huan TI High Short-Term Blood Pressure Variability Predicts Long-Term Cardiovascular Mortality in Untreated Hypertensives But Not in Normotensives SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article DE ambulatory blood pressure; blood pressure variability; cardiovascular mortality; hypertension ID LEFT-VENTRICULAR MASS; TARGET-ORGAN DAMAGE; E-LORO-ASSOCIAZIONI; PROGNOSTIC VALUE; GENERAL-POPULATION; HOME; MANAGEMENT; ARTERIAL; TAIWAN; DEATH AB BACKGROUND The prognostic value of the short-term blood pressure variability (BPV) from the 24-hour ambulatory blood pressure monitoring (ABPM) remains controversial. The present study aimed to investigate the longterm prognostic value of a high BPV in normotensive and hypertensive subjects from a community-based population. METHODS A cohort of 624 normotensive and 633 untreated hypertensive Taiwanese participants (overall 669 men, aged 30-79 years) with baseline ABPM and 20-year all-cause and cardiovascular mortality data was drawn from a community-based survey. BPV was assessed by the read-to-read average real variability of the 24-hour diastolic and systolic blood pressure (SBP) (ARVd and ARVs, respectively). RESULTS In Cox proportional hazards analysis, ARVd predicted cardiovascular mortality independently of office SBP (hazard ratios (HRs) and 95% confidence intervals (CIs) per 1 SD: 1.31 (1.10-1.55), respectively, bivariate analysis), 24-hour SBP (HR: 1.19, 95% CI: 1.00-1.43), and conventional risk factors (age, sex, smoking, total cholesterol, high-density lipoprotein cholesterol, and fasting blood glucose, HR: 1.40, 95% CI: 1.18-1.67). In subjects with hypertension, a high vs. low ARVd (median: 8.8 mm Hg) significantly predicted cardiovascular mortality (HR: 2.11, 95% CI: 1.23-3.62 and HR: 2.04, 95% CI: 1.19-3.51, respectively), when the conventional risk factors plus office SBP or 24-hour SBP were accounted for, respectively. Similar but less significant results were obtained with ARVs. A high ARVd or ARVs did not significantly predict cardiovascular mortality in the normotensive subjects. CONCLUSIONS A high short-term BPV is significantly predictive of long-term cardiovascular mortality in untreated hypertensive but not normotensive community-based subjects, independently of office or 24-hour SBP. C1 [Hsu, Pai-Feng; Cheng, Hao-Min; Wu, Cheng-Hsueh; Sung, Shih-Hsien; Chen, Chen-Huan] Taipei Vet Gen Hosp, Dept Med, Taipei, Taiwan. [Hsu, Pai-Feng; Cheng, Hao-Min; Sung, Shih-Hsien; Chou, Pesus; Chen, Chen-Huan] Natl Yang Ming Univ, Inst Publ Hlth, Taipei, Taiwan. [Hsu, Pai-Feng; Wu, Cheng-Hsueh; Sung, Shih-Hsien; Chen, Chen-Huan] Natl Yang Ming Univ, Fac Med, Taipei, Taiwan. [Cheng, Hao-Min; Chen, Chen-Huan] Taipei Vet Gen Hosp, Dept Med Educ, Taipei, Taiwan. [Chuang, Shao-Yuan] Natl Hlth Res Inst, Miaoli, Taiwan. [Lakatta, Edward G.] NIA, Cardiovasc Sci Lab, Intramural Res Program Baltimore, Baltimore, MD 21224 USA. [Yin, Frank C. P.] Washington Univ, Dept Biomed Engn, St Louis, MO 63105 USA. RP Chen, CH (reprint author), Taipei Vet Gen Hosp, Dept Med, Taipei, Taiwan.; Chen, CH (reprint author), Natl Yang Ming Univ, Inst Publ Hlth, Taipei, Taiwan.; Chen, CH (reprint author), Natl Yang Ming Univ, Fac Med, Taipei, Taiwan.; Chen, CH (reprint author), Taipei Vet Gen Hosp, Dept Med Educ, Taipei, Taiwan. EM chench@vghtpe.gov.tw FU National Science Council [NSC 99-2314-B-010-034-MY3, MOST 103-2314-B-010-050-MY2]; Taipei Veterans General Hospital [V104C-140]; Ministry of Health and Welfare [NO1-AG-1-2118, MOHW104-TDU-B-211-113-003]; Intramural Research Program of the National Institute on Aging, National Institutes of Health FX This work was supported in part by grants from the National Science Council (NSC 99-2314-B-010-034-MY3 and MOST 103-2314-B-010-050-MY2), an intramural grant from the Taipei Veterans General Hospital (grant V104C-140), Research and Development contract NO1-AG-1-2118, grants from the Ministry of Health and Welfare (MOHW104-TDU-B-211-113-003), and the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 24 TC 2 Z9 2 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0895-7061 EI 1941-7225 J9 AM J HYPERTENS JI Am. J. Hypertens. PD JUL PY 2016 VL 29 IS 7 BP 806 EP 813 DI 10.1093/ajh/hpw002 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DV8HL UT WOS:000383178000004 PM 26837643 ER PT J AU Horbal, SR Seffens, W Davis, AR Silvestrov, N Gibbons, GH Quarells, RC Bidulescu, A AF Horbal, Steven R. Seffens, William Davis, Adam R. Silvestrov, Natalia Gibbons, Gary H. Quarells, Rakale C. Bidulescu, Aurelian TI Associations of Apelin, Visfatin, and Urinary 8-Isoprostane With Severe Hypertension in African Americans: The MH-GRID Study SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article DE adipokines; African Americans; apelin; blood pressure; hypertension; severe hypertension; urinary 8-isoprostane; visfatin ID ADIPOSE-TISSUE; ENDOTHELIAL DYSFUNCTION; RESISTANT HYPERTENSION; INFLAMMATION; OBESITY; ADIPOKINES AB BACKGROUND Apelin is an adipokine directly associated with adiposity, insulin resistance, and decreased blood pressure. Urinary 8-isoprostane is a marker of chronic oxidative endothelial stress. Visfatin, an adipokine that acts by binding and activating the insulin receptor, has been associated with hypertension. As severe hypertension (SH) is highly prevalent among African Americans (AA), we aimed to assess the association of these biomarkers with SH status. METHODS A sample of 250 AA participants (134 normotensive controls and 116 with SH (including 98 treatment controlled, SCH: severe controlled hypertension, and 18 treatment resistant, SRH: severe resistant hypertension)) from the Minority Health Genomics and Translational Research Bio-Repository Database (MH-GRID) in metro Atlanta had blood analyzed for apelin and visfatin and urine for 8-isoprostane. T-tests, sex-specific age-adjusted correlation coefficients, and multivariable logistic regression models were used to assess the association of biomarkers with hypertensive status. RESULTS Levels of apelin and 8-isoprostane were not statistically different between controls and SCH or SRH. Statistically significant differences were present in levels of visfatin between controls (1.03 +/- 0.84 pg/ml), SCH (1.34 +/- 1.14 pg/ml), and SRH (1.59 +/- 0.85 pg/ml). After multivariable adjustment, categorization in the middle 2 quartiles of urinary 8-isoprostane were associated with SH. In similar models, categorization into the highest quartile of visfatin was associated with SH (odds ratio = 2.80; 95% confidence interval: 1.02-7.02). A continuous association of visfatin with SH was present. CONCLUSION In our community sample of AA, there were increased odds of SH with increased levels of urinary 8-isoprostane and visfatin, but not with apelin. C1 [Horbal, Steven R.; Bidulescu, Aurelian] Indiana Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Bloomington, IN 47405 USA. [Seffens, William; Silvestrov, Natalia; Quarells, Rakale C.] Morehouse Sch Med, Dept Community Hlth & Prevent Med, Atlanta, GA 30310 USA. [Davis, Adam R.] NHGRI, Bethesda, MD 20892 USA. [Gibbons, Gary H.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Bidulescu, A (reprint author), Indiana Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Bloomington, IN 47405 USA. EM abidules@indiana.edu FU NIH/National Institute on Minority Health and Health Disparities [1RC4MD005964] FX We would like to acknowledge the Minority Health-GRID Network (Rakale C. Quarells, Gary H. Gibbons, Donna K. Arnett, Robert L. Davis, Suzanne M. Leal, Deborah A. Nickerson, James Perkins, Charles N. Rotimi, Joel H. Saltz, Herman A. Taylor, and James G. Wilson). This work was supported, in part, by a grant from the NIH/National Institute on Minority Health and Health Disparities (grant #1RC4MD005964). NR 22 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0895-7061 EI 1941-7225 J9 AM J HYPERTENS JI Am. J. Hypertens. PD JUL PY 2016 VL 29 IS 7 BP 814 EP 820 DI 10.1093/ajh/hpw007 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DV8HL UT WOS:000383178000005 PM 26869250 ER PT J AU Trasande, L Zoeller, RT Hass, U Kortenkamp, A Grandjean, P Myers, JP DiGangi, J Hunt, PM Rudel, R Sathyanarayana, S Bellanger, M Hauser, R Legler, J Skakkebaek, NE Heindel, JJ AF Trasande, L. Zoeller, R. T. Hass, U. Kortenkamp, A. Grandjean, P. Myers, J. P. DiGangi, J. Hunt, P. M. Rudel, R. Sathyanarayana, S. Bellanger, M. Hauser, R. Legler, J. Skakkebaek, N. E. Heindel, J. J. TI Burden of disease and costs of exposure to endocrine disrupting chemicals in the European Union: an updated analysis SO ANDROLOGY LA English DT Article DE disease burden; economic costs; endocrine disrupting chemicals ID REPRODUCTIVE DISORDERS; HEALTH; RECOMMENDATIONS; STRENGTH; QUALITY; GRADE AB A previous report documented that endocrine disrupting chemicals contribute substantially to certain forms of disease and disability. In the present analysis, our main objective was to update a range of health and economic costs that can be reasonably attributed to endocrine disrupting chemical exposures in the European Union, leveraging new burden and disease cost estimates of female reproductive conditions from accompanying report. Expert panels evaluated the epidemiologic evidence, using adapted criteria from the WHO Grading of Recommendations Assessment, Development and Evaluation Working Group, and evaluated laboratory and animal evidence of endocrine disruption using definitions recently promulgated by the Danish Environmental Protection Agency. The Delphi method was used to make decisions on the strength of the data. Expert panels consensus was achieved for probable (>20%) endocrine disrupting chemical causation for IQ loss and associated intellectual disability; autism; attention deficit hyperactivity disorder; endometriosis; fibroids; childhood obesity; adult obesity; adult diabetes; cryptorchidism; male infertility, and mortality associated with reduced testosterone. Accounting for probability of causation, and using the midpoint of each range for probability of causation, Monte Carlo simulations produced a median annual cost of (sic)163 billion (1.28% of EU Gross Domestic Product) across 1000 simulations. We conclude that endocrine disrupting chemical exposures in the EU are likely to contribute substantially to disease and dysfunction across the life course with costs in the hundreds of billions of Euros per year. These estimates represent only those endocrine disrupting chemicals with the highest probability of causation; a broader analysis would have produced greater estimates of burden of disease and costs. C1 [Trasande, L.] NYU, Sch Med, New York, NY USA. [Trasande, L.] NYU, Wagner Sch Publ Serv, New York, NY USA. [Trasande, L.] NYU, Dept Nutr Food & Publ Hlth, Steinhardt Sch Culture Educ & Human Dev, New York, NY USA. [Trasande, L.] NYU, Global Inst Publ Hlth, New York, NY USA. [Zoeller, R. T.] Univ Massachusetts, Amherst, MA 01003 USA. [Hass, U.] Tech Univ Denmark, Natl Food Inst, Soborg, Denmark. [Kortenkamp, A.] Brunel Univ, Inst Environm Hlth & Soc, Uxbridge, Middx, England. [Grandjean, P.; Hauser, R.] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Grandjean, P.] Univ Southern Denmark, Odense, Denmark. [Myers, J. P.] Environm Hlth Sci, Charlottesville, VA USA. [DiGangi, J.] IPEN, Gothenburg, Sweden. [Hunt, P. M.] Washington State Univ, Sch Mol Biosci, Pullman, WA 99164 USA. [Rudel, R.] Silent Spring Inst, Newton, MA USA. [Sathyanarayana, S.] Seattle Childrens Res Inst, Ctr Child Hlth Behav & Dev, Seattle, WA USA. [Bellanger, M.] EHESP Sch Publ Hlth, Paris, France. [Legler, J.] Vrije Univ Amsterdam, Inst Environm Studies, Dept Biol & Chem, Amsterdam, Netherlands. [Skakkebaek, N. E.] EDMaRC, Rigshosp, Dept Growth & Reprod, Copenhagen, Denmark. [Skakkebaek, N. E.] Univ Copenhagen, Copenhagen, Denmark. [Heindel, J. J.] NIEHS, Div Extramural Res & Training, POB 12233, Res Triangle Pk, NC 27709 USA. RP Trasande, L (reprint author), NYU, Sch Med, Dept Pediat, 403 East 34th St,Room 115, New York, NY 10016 USA. EM leonardo.trasande@nyumc.org OI Legler, Juliette/0000-0001-6321-1567 FU Endocrine Society; John Merck Fund; Broad Reach Foundation; Oak Foundation; NIEHS Division of Extramural Research and Training FX Research reported in this publication was supported by the Endocrine Society, the John Merck Fund, the Broad Reach Foundation, and the Oak Foundation. The funders and supporters had no role in the writing of the manuscript or the decision to submit it for publication. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIEHS, the National Institutes of Health or the US government. We thank Charles Persoz, Robert Barouki and Marion Le Gal of the French National Alliance for Life Sciences and Health, and Barbara Demeneix, Lindsey Marshall, Bilal Mughal, and Bolaji Seffou of the UMR 7221 Paris for providing technical and logistical support throughout the project. We also wish to thank Roberto Bertollini, Annette Pruss-Ustun, and David Tordrup of the World Health Organization for their consultation and support in developing the guidelines for evaluating epidemiologic evidence. The contribution of JJH was supported by the NIEHS Division of Extramural Research and Training. NR 19 TC 5 Z9 5 U1 9 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-2919 EI 2047-2927 J9 ANDROLOGY-US JI Andrology PD JUL PY 2016 VL 4 IS 4 SI SI BP 565 EP 572 DI 10.1111/andr.12178 PG 8 WC Andrology SC Endocrinology & Metabolism GA DV9VT UT WOS:000383291000004 PM 27003928 ER PT J AU Louis, GMB Barr, DB Kannan, K Chen, Z Kim, S Sundaram, R AF Louis, G. M. Buck Barr, D. B. Kannan, K. Chen, Z. Kim, S. Sundaram, R. TI Paternal exposures to environmental chemicals and time-to-pregnancy: overview of results from the LIFE study SO ANDROLOGY LA English DT Article DE endocrine disrupters; epidemiology; fecundity; men; time to pregnancy ID ENDOCRINE-DISRUPTING CHEMICALS; URINARY BISPHENOL-A; TANDEM MASS-SPECTROMETRY; TESTICULAR CANCER; HUMAN-SERUM; SCIENTIFIC STATEMENT; REGIONAL DIFFERENCES; PROSPECTIVE COHORT; REGRESSION-MODELS; COUPLE FECUNDITY AB Published findings from the Longitudinal Investigation of Fertility and the Environment (LIFE) Study regarding the relation between environmental chemicals and couple fecundity, as measured by time-to-pregnancy (TTP), are reviewed with a particular focus on role of the male partner. The LIFE Study recruited 501 couples from 16 counties in two U.S. states upon discontinuing contraception for purposes of becoming pregnant. Upon enrollment, couples provided a blood and urine sample for the quantification of persistent and non-persistent environmental chemicals, respectively, and then completed daily journals until pregnant or up to one year of trying. Female partners used fertility monitors to aid the timing of intercourse relative to ovulation, and digital home pregnancy test kits on the day of expected menses. Chemical classes included: metals, persistent organic pollutants, environmental phenols, and phthalates that were quantified using inductively coupled plasma mass spectrometry or isotope dilution high-resolution or tandem mass spectrometry. Time-to-pregnancy (TTP) was defined as the number of prospectively observed menstrual cycles required for pregnancy. Fecundability odds ratios (FORs) and 95% confidence intervals (CIs) were estimated for each chemical and partner after adjusting for potential confounders and accounting for right censoring and time off contraception. FORs < 1 are suggestive of diminished fecundity or a longer TTP. Significant reductions (ranging from 17-31%) in couple fecundity were observed for male partners' concentration of lead (0.83; 0.70, 0.98), 2,2',4,4'-tetrahydroxybenzophenone (0.69; 0.49, 0.97), monobenzyl (0.80; 0.67, 0.97), and monomethyl (0.81; 0.70, 0.94) phthalates after adjusting for the female partners' concentrations. Seven PCB congeners quantified in men's serum were associated with a 17-29% reduction in couple fecundity. Our findings underscore the importance of a couple-based exposure design, inclusive of the male partner, when assessing couple-dependent outcomes such as TTP to avoid misinterpretation of results based only upon the female partner. C1 [Louis, G. M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd,Room 7B05, Rockville, MD 20852 USA. [Barr, D. B.] Emory Univ, Dept Environm Hlth, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Kannan, K.] New York State Dept Hlth, Wadsworth Ctr, Albany, NY USA. [Chen, Z.; Kim, S.; Sundaram, R.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, NIH, Rockville, MD USA. RP Louis, GMB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd,Room 7B05, Rockville, MD 20852 USA. EM louisg@mail.nih.gov OI Sundaram, Rajeshwari/0000-0002-6918-5002; Buck Louis, Germaine/0000-0002-1774-4490 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [N01-HD-3-3355, N01-HD-3-3356, NOH-HD-3-3358, HHSN27500001, HHSN2750002]; NICHD FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts #N01-HD-3-3355; N01-HD-3-3356; NOH-HD-3-3358; HHSN27500001; HHSN2750002). Members of the LIFE Study acknowledge the laboratory staff members at the Division of Laboratory Sciences, Centers for Disease Control and Prevention who performed the analytic chemistry work for the persistent chemicals under a Memo of Understanding with the NICHD, and the laboratory staff members at the Wadsworth Center for the analysis of non-persistent chemicals under contracts with the NICHD. This work was presented on April 27, 2015 at the 8th Copenhagen Workshop on Endocrine Disrupters. NR 68 TC 0 Z9 0 U1 7 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-2919 EI 2047-2927 J9 ANDROLOGY-US JI Andrology PD JUL PY 2016 VL 4 IS 4 SI SI BP 639 EP 647 DI 10.1111/andr.12171 PG 9 WC Andrology SC Endocrinology & Metabolism GA DV9VT UT WOS:000383291000012 ER PT J AU Mills, JL Dimopoulos, A Bailey, RL AF Mills, James L. Dimopoulos, Aggeliki Bailey, Regan L. TI What Is Standing in the Way of Complete Prevention of Folate Preventable Neural Tube Defects? SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Editorial Material ID FOLIC-ACID FORTIFICATION; POPULATION; TRENDS; SUPPLEMENTATION; VITAMIN-B-12; INDIVIDUALS; EUROPE C1 [Mills, James L.; Dimopoulos, Aggeliki] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD 20892 USA. [Bailey, Regan L.] Purdue Univ, Dept Nutr Sci, W Lafayette, IN 47907 USA. RP Mills, JL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 HD999999] NR 15 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD JUL PY 2016 VL 106 IS 7 BP 517 EP 519 DI 10.1002/bdra.23518 PG 3 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA DV3RH UT WOS:000382840300002 PM 27418028 ER PT J AU Kannan, L Ramos, M Re, A El-Hachem, N Safikhani, Z Gendoo, DMA Davis, S Gomez-Cabrero, D Castelo, R Hansen, KD Carey, VJ Morgan, M Culhane, AC Haibe-Kains, B Waldron, L AF Kannan, Lavanya Ramos, Marcel Re, Angela El-Hachem, Nehme Safikhani, Zhaleh Gendoo, Deena M. A. Davis, Sean Gomez-Cabrero, David Castelo, Robert Hansen, Kasper D. Carey, Vincent J. Morgan, Martin Culhane, Aedin C. Haibe-Kains, Benjamin Waldron, Levi TI Public data and open source tools for multi-assay genomic investigation of disease SO BRIEFINGS IN BIOINFORMATICS LA English DT Article DE multiple assays (multi-assays); public data; bioconductor; integrative genomics; cancer; pharmacogenomics; omics ID BRITISH BIRTH COHORT; CANONICAL CORRELATION-ANALYSIS; GENE-EXPRESSION SIGNATURES; CANCER-CELL LINES; DRUG-SENSITIVITY; WIDE ASSOCIATION; SMALL MOLECULES; COPY NUMBER; TUMOR TYPES; DATA SETS AB Molecular interrogation of a biological sample through DNA sequencing, RNA and microRNA profiling, proteomics and other assays, has the potential to provide a systems level approach to predicting treatment response and disease progression, and to developing precision therapies. Large publicly funded projects have generated extensive and freely available multi-assay data resources; however, bioinformatic and statistical methods for the analysis of such experiments are still nascent. We review multi-assay genomic data resources in the areas of clinical oncology, pharmacogenomics and other perturbation experiments, population genomics and regulatory genomics and other areas, and tools for data acquisition. Finally, we review bioinformatic tools that are explicitly geared toward integrative genomic data visualization and analysis. This review provides starting points for accessing publicly available data and tools to support development of needed integrative methods. C1 [Kannan, Lavanya; Ramos, Marcel] CUNY Hunter Coll, Sch Publ Hlth, New York, NY 10021 USA. [Re, Angela] Univ Trento, Ctr Integrat Biol, Trento, Italy. [El-Hachem, Nehme] Univ Montreal, Montreal, PQ H3C 3J7, Canada. [Safikhani, Zhaleh; Gendoo, Deena M. A.; Haibe-Kains, Benjamin] Princess Margaret Canc Ctr, Toronto, ON, Canada. [Davis, Sean] NCI, NIH, Bethesda, MD 20892 USA. [Gomez-Cabrero, David] Karolinska Inst, Unit Computat Med, S-10401 Stockholm, Sweden. [Castelo, Robert] Univ Pompeu Fabra, Bioinformat & Biostat, Barcelona, Spain. [Hansen, Kasper D.] Johns Hopkins Univ, Biostat, Baltimore, MD 21218 USA. [Carey, Vincent J.] Harvard Med Sch, Med Biostat, Boston, MA USA. [Morgan, Martin] Roswell Pk Canc Inst, Biostat & Bioinformat, Buffalo, NY 14263 USA. [Culhane, Aedin C.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Waldron, Levi] CUNY Hunter Coll, Sch Publ Hlth, Biostat, New York, NY 10021 USA. RP Waldron, L (reprint author), 2180 3rd Ave, New York, NY 10040 USA. EM levi.waldron@hunter.cuny.edu RI Castelo, Robert/A-4679-2010; Gasull, Martina/A-6630-2013; OI Castelo, Robert/0000-0003-2229-4508; Haibe-Kains, Benjamin/0000-0002-7684-0079; Waldron, Levi/0000-0003-2725-0694 FU National Cancer Institute [U24CA180996, 1U19 AI111224-01]; National Institute on Minority Health and Health Disparities [MD007599]; NCI Intramural Research Program of the National Institutes of Health; Spanish MINECO [TIN2011-22826]; Gattuso Slaight Personalized Cancer Medicine Fund at Princess Margaret Cancer Centre; Cancer Research Society (Canada); Brain Canada-CIBC Brain Cancer Research Training Award; University of Trento; Breast Cancer Research Program [W81XWH-15-1-0013] FX The authors' work was funded by the National Cancer Institute [U24CA180996 to MM], the National Institute on Minority Health and Health Disparities [MD007599 to LW] and the NCI Intramural Research Program [SD] of the National Institutes of Health. Spanish MINECO grant TIN2011-22826 to RC. BHK was supported by the Gattuso Slaight Personalized Cancer Medicine Fund at Princess Margaret Cancer Centre. ZS was supported by the Cancer Research Society (Canada). DMAG was supported by the Brain Canada-CIBC Brain Cancer Research Training Award AR was supported by the Biotechnology start-up project of the University of Trento. AC was supported by National Cancer Institute 1U19 AI111224-01 and the Assistant Secretary of Defense Health Program, through the Breast Cancer Research Program, Award No. W81XWH-15-1-0013. NR 96 TC 2 Z9 2 U1 9 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1467-5463 EI 1477-4054 J9 BRIEF BIOINFORM JI Brief. Bioinform. PD JUL PY 2016 VL 17 IS 4 SI SI BP 603 EP 615 DI 10.1093/bib/bbv080 PG 13 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA DV7XI UT WOS:000383151200005 PM 26463000 ER PT J AU Hart, SN Maxwell, KN Thomas, T Ravichandran, V Wubberhorst, B Klein, RJ Schrader, K Szabo, C Weitzel, JN Neuhausen, SL Nathanson, K Offit, K Couch, FJ Vijai, J AF Hart, Steven N. Maxwell, Kara N. Thomas, Tinu Ravichandran, Vignesh Wubberhorst, Bradley Klein, Robert J. Schrader, Kasmintan Szabo, Csilla Weitzel, Jeffrey N. Neuhausen, Susan L. Nathanson, Katherine Offit, Kenneth Couch, Fergus J. Vijai, Joseph TI Collaborative science in the next-generation sequencing era: a viewpoint on how to combine exome sequencing data across sites to identify novel disease susceptibility genes SO BRIEFINGS IN BIOINFORMATICS LA English DT Article DE genomics; exome ID GENOME-WIDE ASSOCIATION; BREAST-CANCER; MISSING HERITABILITY; READ ALIGNMENT; VARIANTS; ANNOTATION; ALGORITHMS; MUTATIONS; SINGLE; TOOLS AB The purpose of this article is to inform readers about technical challenges that we encountered when assembling exome sequencing data from the 'Simplifying Complex Exomes' (SIMPLEXO) consortium-whose mandate is the discovery of novel genes predisposing to breast and ovarian cancers. Our motivation is to share these obstacles-and our solutions to them-as a means of communicating important technical details that should be discussed early in projects involving massively parallel sequencing. C1 [Hart, Steven N.] Mayo Clin, Biomed Informat, Rochester, MN USA. [Maxwell, Kara N.] Univ Penn, Perelman Sch Med, Div Hematol Oncol, Philadelphia, PA 19104 USA. [Thomas, Tinu; Ravichandran, Vignesh] Mem Sloan Kettering Canc Ctr, Clin Genet Res Lab, 1275 York Ave, New York, NY 10021 USA. [Klein, Robert J.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Schrader, Kasmintan] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Schrader, Kasmintan] BC Canc Agcy, Dept Med Genet, Vancouver, BC, Canada. [Schrader, Kasmintan] BC Canc Agcy, Hereditary Canc Program, Vancouver, BC, Canada. [Szabo, Csilla] NHGRI, NIH, Bethesda, MD 20892 USA. [Weitzel, Jeffrey N.] City Hope Comprehens Canc Ctr, Div Clin Canc Genet, Duarte, CA USA. [Weitzel, Jeffrey N.] City Hope Comprehens Canc Ctr, Canc Screening & Prevent Program, Duarte, CA USA. [Weitzel, Jeffrey N.] City Hope Natl Med Ctr, Oncol & Populat Sci, Duarte, CA USA. [Nathanson, Katherine] Abramson Canc Ctr, Div Translat Med, Philadelphia, PA USA. [Nathanson, Katherine] Abramson Canc Ctr, Philadelphia, PA USA. [Offit, Kenneth] Mem Hosp, Clin Genet Serv, Belleville, IL USA. [Offit, Kenneth] Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Canc Biol & Genet Program, 1275 York Ave, New York, NY 10021 USA. [Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Med Res, Rochester, MN USA. [Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Div Expt Pathol, Rochester, MN USA. [Vijai, Joseph] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. [Vijai, Joseph] Mem Sloan Kettering Canc Ctr, Clin Genet Res Lab, 1275 York Ave, New York, NY 10021 USA. RP Hart, SN (reprint author), Mayo Clin, Mayo Coll Med, Dept Hlth Sci Res, Bioinformat,CGSL, 200 First St SW, Rochester, MN 55905 USA.; Hart, SN (reprint author), Mayo Clin, Mayo Coll Med, Dept Hlth Sci Res, Biomed Informat,Div Biomed Stat & Informat, 200 First St SW, Rochester, MN 55905 USA.; Vijai, J (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, Clin Genet Serv, New York, NY 10065 USA. EM Hart.steven@mayo.edu; josephv@mskcc.org FU National Institutes of Health [R01CA176785]; Breast Cancer Research Foundation [R21-CA139396]; Department of Defense [W81XWH-13-1-0338]; Niehaus Clinical Genetics Initiative; Miele family initiative; National Cancer Institute [RC4CA153828]; Office of the Director, National Institutes of Health; MSKCC Core grant [NIH P30CA008748] FX This work was supported by the National Institutes of Health R01CA176785 and the Breast Cancer Research Foundation [F.J.C., K.N. and K.O], R21-CA139396 [J.V]. K.N.M. was supported by the Department of Defense (W81XWH-13-1-0338); views and opinions of, and endorsements by, the authors do not reflect those of the US Army or the Department of Defense. Other funding was provided by The Niehaus Clinical Genetics Initiative and The Miele family initiative [K.O.]. City of Hope Clinical Cancer Genetics Community Research Network and the Hereditary Cancer Research Registry, supported in part by Award Number RC4CA153828 (PI: J. Weitzel) from the National Cancer Institute and the Office of the Director, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The work was also supported by the MSKCC Core grant NIH P30CA008748. NR 29 TC 0 Z9 0 U1 4 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1467-5463 EI 1477-4054 J9 BRIEF BIOINFORM JI Brief. Bioinform. PD JUL PY 2016 VL 17 IS 4 SI SI BP 672 EP 677 DI 10.1093/bib/bbv075 PG 6 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA DV7XI UT WOS:000383151200010 PM 26358132 ER PT J AU Wolf, C Mohr, H Diekhof, EK Vieker, H Goya-Maldonado, R Trost, S Kramer, B Keil, M Binder, EB Gruber, O AF Wolf, Claudia Mohr, Holger Diekhof, Esther K. Vieker, Henning Goya-Maldonado, Roberto Trost, Sarah Kraemer, Bernd Keil, Maria Binder, Elisabeth B. Gruber, Oliver TI CREB1 Genotype Modulates Adaptive Reward-Based Decisions in Humans SO CEREBRAL CORTEX LA English DT Article DE CREB1; decision-making; fMRI; genetics; reward ID ELEMENT-BINDING PROTEIN; RESIST IMPULSIVE DESIRES; NUCLEUS-ACCUMBENS; FEAR MEMORY; BEHAVIORAL-RESPONSES; PREFRONTAL CORTEX; NEURAL MECHANISMS; EMOTIONAL STIMULI; MAJOR DEPRESSION; BIPOLAR DISORDER AB Cyclic AMP response element-binding protein (CREB) contributes to adaptation of mesocorticolimbic networks by modulating activity-regulated transcription and plasticity in neurons. Activity or expression changes of CREB in the nucleus accumbens (NAc) and orbital frontal cortex (OFC) interact with behavioral changes during reward-motivated learning. However, these findings from animal models have not been evaluated in humans. We tested whether CREB1 genotypes affect reward-motivated decisions and related brain activation, using BOLD fMRI in 224 young and healthy participants. More specifically, participants needed to adapt their decision to either pursue or resist immediate rewards to optimize the reward outcome. We found significant CREB1 genotype effects on choices to pursue increases of the reward outcome and on BOLD signal in the NAc, OFC, insula cortex, cingulate gyrus, hippocampus, amygdala, and precuneus during these decisions in comparison with those decisions avoiding total reward loss. Our results suggest that CREB1 genotype effects in these regions could contribute to individual differences in reward-and associative memory-based decision-making. C1 [Wolf, Claudia; Mohr, Holger; Diekhof, Esther K.; Vieker, Henning; Goya-Maldonado, Roberto; Trost, Sarah; Kraemer, Bernd; Keil, Maria; Gruber, Oliver] Univ Gottingen, Dept Psychiat & Psychotherapy, Ctr Translat Res Syst Neurosci & Psychiat, D-37075 Gottingen, Germany. [Wolf, Claudia] NIA, Lab Behav Neurosci, Baltimore, MD 21224 USA. [Mohr, Holger] Tech Univ Dresden, Dept Gen Psychol, D-01069 Dresden, Germany. [Diekhof, Esther K.] Univ Hamburg, Grindel Bioctr, D-20146 Hamburg, Germany. [Diekhof, Esther K.] Univ Hamburg, Inst Humanbiol, Zool Museum, D-20146 Hamburg, Germany. [Vieker, Henning] Univ Med Ctr Hamburg Eppendorf, Dept Psychiat & Psychotherapy, D-20246 Hamburg, Germany. [Binder, Elisabeth B.] Max Planck Inst Psychiat, D-80804 Munich, Germany. RP Wolf, C (reprint author), Univ Gottingen, Dept Psychiat & Psychotherapy, Ctr Translat Res Syst Neurosci & Psychiat, D-37075 Gottingen, Germany.; Wolf, C (reprint author), NIA, Lab Behav Neurosci, Baltimore, MD 21224 USA. EM claudia.wolf@nih.gov FU NIH Intramural Research Program FX C.W. was partly supported by the NIH Intramural Research Program. NR 51 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 EI 1460-2199 J9 CEREB CORTEX JI Cereb. Cortex PD JUL PY 2016 VL 26 IS 7 BP 2970 EP 2981 DI 10.1093/cercor/bhv104 PG 12 WC Neurosciences SC Neurosciences & Neurology GA DV8QC UT WOS:000383200500003 PM 26045569 ER PT J AU Lee, NR Adeyemi, EI Lin, A Clasen, LS Lalonde, FM Condon, E Driver, DI Shaw, P Gogtay, N Raznahan, A Giedd, JN AF Lee, Nancy Raitano Adeyemi, Elizabeth I. Lin, Amy Clasen, Liv S. Lalonde, Franois M. Condon, Ellen Driver, David I. Shaw, Philip Gogtay, Nitin Raznahan, Armin Giedd, Jay N. TI Dissociations in Cortical Morphometry in Youth with Down Syndrome: Evidence for Reduced Surface Area but Increased Thickness SO CEREBRAL CORTEX LA English DT Article DE Alzheimer's disease; cerebral cortex; intellectual disability; magnetic resonance imaging; Trisomy 21 ID AUTOMATED 3-D EXTRACTION; HUMAN CEREBRAL-CORTEX; HIGH-RESOLUTION MRI; FRAGILE-X-SYNDROME; SHORT-TERM-MEMORY; DEVELOPMENTAL TRAJECTORIES; AMYLOID DEPOSITION; ALZHEIMERS-DISEASE; BRAIN; CHILDREN AB Detailed descriptions of cortical anatomy in youth with Down syndrome (DS), the most common genetic cause of intellectual disability (ID), are scant. Thus, the current study examined deviations in cortical thickness (CT) and surface area (SA), at high spatial resolution, in youth with DS, to identify focal differences relative to typically developing (TD) youth. Participants included 31 youth with DS and 45 age-and sex-matched TD controls (mean age similar to 16 years; range = 5-24 years). All participants completed T-1-weighted ASSET-calibrated magnetization prepared rapid gradient echo scans on a 3-T magnetic resonance imaging scanner. Replicating prior investigations, cortical volume was reduced in DS compared with controls. However, a novel dissociation for SA and CT was found-namely, SA was reduced (predominantly in frontal and temporal regions) while CT was increased (notably in several regions thought to belong to the default mode network; DMN). These findings suggest that reductions in SA rather than CT are driving the cortical volume reductions reported in prior investigations of DS. Moreover, given the link between DMN functionality and Alzheimer's symptomatology in chromosomally typical populations, future DS studies may benefit from focusing on the cortex in DMN regions, as such investigations may provide clues to the precocious onset of Alzheimer's disease in this at-risk group. C1 [Lee, Nancy Raitano; Adeyemi, Elizabeth I.; Lin, Amy; Clasen, Liv S.; Lalonde, Franois M.; Driver, David I.; Gogtay, Nitin; Raznahan, Armin; Giedd, Jay N.] NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. [Condon, Ellen] NIMH, Funct MRI Core Facil, NIH, Bethesda, MD 20892 USA. [Lee, Nancy Raitano] Drexel Univ, Dept Psychol, 3141 Chestnut St,Suite 119, Philadelphia, PA 19103 USA. [Shaw, Philip] Natl Human Genome Res Inst, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. [Giedd, Jay N.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. RP Lee, NR (reprint author), Drexel Univ, Dept Psychol, 3141 Chestnut St,Suite 119, Philadelphia, PA 19103 USA. EM nrl39@drexel.edu RI Lee, Nancy/M-7492-2016 OI Lee, Nancy/0000-0002-6663-0713 FU Intramural Research Program of the National Institutes of Health, National Institute of Mental Health [1 ZIA MH002794-13, 89-M-0006] FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Mental Health (1 ZIA MH002794-13; Protocol ID 89-M-0006). NR 65 TC 0 Z9 0 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 EI 1460-2199 J9 CEREB CORTEX JI Cereb. Cortex PD JUL PY 2016 VL 26 IS 7 BP 2982 EP 2990 DI 10.1093/cercor/bhv107 PG 9 WC Neurosciences SC Neurosciences & Neurology GA DV8QC UT WOS:000383200500004 PM 26088974 ER PT J AU Tomasi, D Shokri-Kojori, E Volkow, ND AF Tomasi, Dardo Shokri-Kojori, Ehsan Volkow, Nora D. TI High-Resolution Functional Connectivity Density: Hub Locations, Sensitivity, Specificity, Reproducibility, and Reliability SO CEREBRAL CORTEX LA English DT Article DE aging; FCDM; global signal regression; motion; multiband; physiologic noise; resting state ID GLOBAL SIGNAL REGRESSION; HUMAN CONNECTOME PROJECT; TEST-RETEST RELIABILITY; INDEPENDENT COMPONENT ANALYSIS; ANTI-CORRELATED NETWORKS; RESTING STATE NETWORKS; HUMAN BRAIN; SMALL-WORLD; ALZHEIMERS-DISEASE; NEURONAL-ACTIVITY AB Brain regions with high connectivity have high metabolic cost and their disruption is associated with neuropsychiatric disorders. Prior neuroimaging studies have identified at the group-level local functional connectivity density (lFCD) hubs, network nodes with high degree of connectivity with neighboring regions, in occipito-parietal cortices. However, the individual patterns and the precision for the location of the hubs were limited by the restricted spatiotemporal resolution of the magnetic resonance imaging (MRI) measures collected at rest. In this work, we show that MRI datasets with higher spatiotemporal resolution (2-mm isotropic; 0.72 s), collected under the Human Connectome Project (HCP), provide a significantly higher precision for hub localization and for the first time reveal lFCD patterns with gray matter (GM) specificity >96% and sensitivity >75%. High temporal resolution allowed effective 0.01-0.08 Hz band-pass filtering, significantly reducing spurious lFCD effects in white matter. These high spatiotemporal resolution lFCD measures had high reliability [intraclass correlation, ICC(3,1) > 0.6] but lower reproducibility (>67%) than the low spatiotemporal resolution equivalents. GM sensitivity and specificity benchmarks showed the robustness of lFCD to changes in model parameter and preprocessing steps. Mapping individual's brain hubs with high sensitivity, specificity, and reproducibility supports the use of lFCD as a biomarker for clinical applications in neuropsychiatric disorders. C1 [Tomasi, Dardo; Shokri-Kojori, Ehsan; Volkow, Nora D.] NIAAA, Bethesda, MD USA. [Volkow, Nora D.] NIDA, Bethesda, MD 20892 USA. RP Tomasi, D (reprint author), 10 Ctr Dr,Rm B2L124, Bethesda, MD 20892 USA. EM dardo.tomasi@nih.gov FU Human Connectome Project, WU-Minn Consortium - 16 NIH Institutes and Centers [1U54MH091657]; McDonnell Center for Systems Neuroscience at Washington University; National Institutes of Alcohol Abuse and Alcoholism [2RO1AA09481] FX Data were provided by the Human Connectome Project, WU-Minn Consortium (Principal Investigators: David Van Essen and Kamil Ugurbil; 1U54MH091657) funded by the 16 NIH Institutes and Centers that support the NIH Blueprint for Neuroscience Research and by the McDonnell Center for Systems Neuroscience at Washington University. This work was accomplished with support from the National Institutes of Alcohol Abuse and Alcoholism (2RO1AA09481). NR 73 TC 3 Z9 3 U1 4 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 EI 1460-2199 J9 CEREB CORTEX JI Cereb. Cortex PD JUL PY 2016 VL 26 IS 7 BP 3249 EP 3259 DI 10.1093/cercor/bhv171 PG 11 WC Neurosciences SC Neurosciences & Neurology GA DV8QC UT WOS:000383200500025 PM 26223259 ER PT J AU Damiano, D Forssberg, H AF Damiano, Diane Forssberg, Hans TI We are the world: meeting the global challenge of childhood disability SO DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY LA English DT Editorial Material C1 [Damiano, Diane] NIH, Dept Rehabil Med, Bethesda, MD 20892 USA. [Forssberg, Hans] Karolinska Inst, Astrid Lindgren Childrens Hosp, Neuropaediat, Stockholm, Sweden. RP Damiano, D (reprint author), NIH, Dept Rehabil Med, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0012-1622 EI 1469-8749 J9 DEV MED CHILD NEUROL JI Dev. Med. Child Neurol. PD JUL PY 2016 VL 58 IS 7 BP 649 EP 649 DI 10.1111/dmcn.13154 PG 1 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA DV3VZ UT WOS:000382854000002 PM 27307194 ER PT J AU Ghassabian, A Sundaram, R Wylie, A Bell, E Bello, SC Yeung, E AF Ghassabian, Akhgar Sundaram, Rajeshwari Wylie, Amanda Bell, Erin Bello, Scott C. Yeung, Edwina TI Maternal medical conditions during pregnancy and gross motor development up to age 24 months in the Upstate KIDS study SO DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY LA English DT Article ID GESTATIONAL DIABETES-MELLITUS; DNA METHYLATION; CHILDREN BORN; BIRTH COHORT; INFANTS BORN; SCHOOL-AGE; MOTHERS; POPULATION; MILESTONES; OBESITY AB AIM We examined whether children of mothers with a medical condition diagnosed before or during pregnancy took longer to achieve gross motor milestones up to age 24 months. METHOD We obtained information on medical conditions using self-reports, birth certificates, and hospital records in 4909 mothers participating in Upstate KIDS, a population-based birth cohort. Mothers reported on their children's motor milestone achievement at 4, 8, 12, 18, and 24 months of age. RESULTS After adjustment for covariates (including pre-pregnancy body mass index), children of mothers with gestational diabetes took longer to achieve sitting without support (hazard ratio [HR]=0.84, 95% confidence interval [CI] 0.75-0.93), walking with assistance (HR=0.88, 95% CI 0.77-0.98), and walking alone (HR=0.88, 95% CI 0.77-0.99) than children of females with no gestational diabetes. Similar findings emerged for maternal diabetes. Gestational hypertension was associated with a longer time to achieve walking with assistance. These associations did not change after adjustment for gestational age or birthweight. Severe hypertensive disorders of pregnancy were related to a longer time to achieve milestones, but not after adjustment for perinatal factors. INTERPRETATION Children exposed to maternal diabetes, gestational or pre-gestational, may take longer to achieve motor milestones than non-exposed children, independent of maternal obesity. C1 [Ghassabian, Akhgar; Wylie, Amanda; Yeung, Edwina] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD 20892 USA. [Sundaram, Rajeshwari] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD 20892 USA. [Bell, Erin] SUNY Albany, Sch Publ Hlth, Dept Environm Hlth Sci, Albany, NY 12222 USA. [Bell, Erin] SUNY Albany, Sch Publ Hlth, Dept Epidemiol & Biostat, Albany, NY 12222 USA. [Bello, Scott C.] CapitalCare Pediat Troy, Troy, NY USA. RP Yeung, E (reprint author), 6100 Execut Blvd,7B03, Bethesda, MD 20892 USA. EM yeungedw@mail.nih.gov OI Ghassabian, Akhgar/0000-0001-9551-4706; Yeung, Edwina/0000-0002-3851-2613; Sundaram, Rajeshwari/0000-0002-6918-5002 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HHSN275201200005C, HHSN267200700019C] FX Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD; contracts #HHSN275201200005C, #HHSN267200700019C). The authors thank all the Upstate KIDS families and staff for their important contributions. The funders had no role in the study design, data collection, analysis, interpretation of the data, or writing of the report. The corresponding author (EY) 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. The authors have stated that they had no interests that might be perceived as posing a conflict or bias. NR 25 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0012-1622 EI 1469-8749 J9 DEV MED CHILD NEUROL JI Dev. Med. Child Neurol. PD JUL PY 2016 VL 58 IS 7 BP 728 EP 734 DI 10.1111/dmcn.12947 PG 7 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA DV3VZ UT WOS:000382854000022 PM 26502927 ER PT J AU Iranzo, J Krupovic, M Koonin, EV AF Iranzo, Jaime Krupovic, Mart Koonin, Eugene V. TI The Double-Stranded DNA Virosphere as a Modular Hierarchical Network of Gene Sharing SO MBIO LA English DT Article ID PROTEIN-INTERACTION NETWORK; ARCHAEAL VIRUSES; GENOME EVOLUTION; DSDNA BACTERIOPHAGES; REPLICATOR SYSTEMS; ORTHOLOGOUS GENES; CAPSID PROTEINS; MARINE VIRUSES; PSI-BLAST; TELL US AB Virus genomes are prone to extensive gene loss, gain, and exchange and share no universal genes. Therefore, in a broad-scale study of virus evolution, gene and genome network analyses can complement traditional phylogenetics. We performed an exhaustive comparative analysis of the genomes of double-stranded DNA (dsDNA) viruses by using the bipartite network approach and found a robust hierarchical modularity in the dsDNA virosphere. Bipartite networks consist of two classes of nodes, with nodes in one class, in this case genomes, being connected via nodes of the second class, in this case genes. Such a network can be partitioned into modules that combine nodes from both classes. The bipartite network of dsDNA viruses includes 19 modules that form 5 major and 3 minor supermodules. Of these modules, 11 include tailed bacteriophages, reflecting the diversity of this largest group of viruses. The module analysis quantitatively validates and refines previously proposed nontrivial evolutionary relationships. An expansive supermodule combines the large and giant viruses of the putative order "Megavirales" with diverse moderate-sized viruses and related mobile elements. All viruses in this supermodule share a distinct morphogenetic tool kit with a double jelly roll major capsid protein. Herpesviruses and tailed bacteriophages comprise another supermodule, held together by a distinct set of morphogenetic proteins centered on the HK97-like major capsid protein. Together, these two supermodules cover the great majority of currently known dsDNA viruses. We formally identify a set of 14 viral hallmark genes that comprise the hubs of the network and account for most of the intermodule connections. IMPORTANCE Viruses and related mobile genetic elements are the dominant biological entities on earth, but their evolution is not sufficiently understood and their classification is not adequately developed. The key reason is the characteristic high rate of virus evolution that involves not only sequence change but also extensive gene loss, gain, and exchange. Therefore, in the study of virus evolution on a large scale, traditional phylogenetic approaches have limited applicability and have to be complemented by gene and genome network analyses. We applied state-of-the art methods of such analysis to reveal robust hierarchical modularity in the genomes of double-stranded DNA viruses. Some of the identified modules combine highly diverse viruses infecting bacteria, archaea, and eukaryotes, in support of previous hypotheses on direct evolutionary relationships between viruses from the three domains of cellular life. We formally identify a set of 14 viral hallmark genes that hold together the genomic network. C1 [Iranzo, Jaime; Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Krupovic, Mart] Inst Pasteur, Unite Biol Mol Gene Chez Extremophiles, Paris, France. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov RI Krupovic, Mart/I-4209-2012; Iranzo, Jaime/H-5197-2011 OI Krupovic, Mart/0000-0001-5486-0098; Iranzo, Jaime/0000-0002-4538-7726 FU US Department of Health and Human Services FX This work was funded by US Department of Health and Human Services (Intramural funds). NR 101 TC 3 Z9 3 U1 6 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD JUL-AUG PY 2016 VL 7 IS 4 AR e00978 DI 10.1128/mBio.00978-16 PG 21 WC Microbiology SC Microbiology GA DW1YQ UT WOS:000383440500044 ER PT J AU Kohler, LJ Reed, SR Sarraf, SA Arteaga, DD Newton, HJ Roy, CR AF Kohler, Lara J. Reed, Shawna R. Sarraf, Shireen A. Arteaga, David D. Newton, Hayley J. Roy, Craig R. TI Effector Protein Cig2 Decreases Host Tolerance of Infection by Directing Constitutive Fusion of Autophagosomes with the Coxiella-Containing Vacuole SO MBIO LA English DT Article ID INTRACELLULAR REPLICATION; PARASITOPHOROUS VACUOLE; GALLERIA-MELLONELLA; AXENIC GROWTH; CELL-DEATH; PHASE-I; BURNETII; SECRETION; PATHWAY; IDENTIFICATION AB Coxiella burnetii replicates in an acidified lysosome-derived vacuole. Biogenesis of the Coxiella-containing vacuole (CCV) requires bacterial effector proteins delivered into host cells by the Dot/Icm secretion system. Genetic and cell biological analysis revealed that an effector protein called Cig2 promotes constitutive fusion of autophagosomes with the CCV to maintain this compartment in an autolysosomal stage of maturation. This distinguishes the CCV from other pathogen-containing vacuoles that are targeted by the host autophagy pathway, which typically confers host resistance to infection by delivering the pathogen to a toxic lysosomal environment. By maintaining the CCV in an autolysosomal stage of maturation, Cig2 enabled CCV homotypic fusion and enhanced bacterial virulence in the Galleria mellonella (wax moth) model of infection by a mechanism that decreases host tolerance. Thus, C. burnetii residence in an autolysosomal organelle alters host tolerance of infection, which indicates that Cig2-dependent manipulation of a lysosome-derived vacuole influences the host response to infection. IMPORTANCE Coxiella burnetii is an obligate, intracellular bacterial pathogen that replicates inside a unique, lysosome-like compartment called the Coxiella-containing vacuole (CCV). Over 130 bacterial effector proteins are delivered into the host cell cytosol by the C. burnetii Dot/Icm type IV secretion system. Although the Dot/Icm system is essential for pathogenesis, the functions of most effectors remain unknown. Here we show that the effector protein Cig2 is essential for converting the CCV to an organelle that is similar to the autolysosome. Cig2 function promotes constitutive fusion between the CCV and autophagosomes generated by selective autophagy. Cig2-directed biogenesis of an autolysosomal vacuole is essential for the unique fusogenic properties of the CCV and for virulence in an animal model of disease. This work highlights how bacterial subversion of the host autophagy pathway can influence the cell biological properties of the CCV and influence the host response to infection. C1 [Kohler, Lara J.; Reed, Shawna R.; Arteaga, David D.; Roy, Craig R.] Yale Univ, Sch Med, Dept Microbial Pathogenesis, Boyer Ctr Mol Med, New Haven, CT 06510 USA. [Sarraf, Shireen A.] NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Newton, Hayley J.] Univ Melbourne, Dept Microbiol & Immunol, Peter Doherty Inst Infect & Immun, Melbourne, Vic, Australia. RP Roy, CR (reprint author), Yale Univ, Sch Med, Dept Microbial Pathogenesis, Boyer Ctr Mol Med, New Haven, CT 06510 USA. EM craig.roy@yale.edu OI Newton, Hayley/0000-0002-9240-2001 FU HHS \ National Institutes of Health (NIH) [R01 AI114760, F32 AI114196]; National Science Foundation (NSF) FX This work, including the efforts of Craig R Roy, was funded by HHS vertical bar National Institutes of Health (NIH) (R01 AI114760). This work, including the efforts of Shawna R Reed, was funded by HHS vertical bar National Institutes of Health (NIH) (F32 AI114196). This work, including the efforts of Lara J Kohler, was funded by National Science Foundation (NSF) (Pre Doctoral Fellowship). NR 53 TC 1 Z9 1 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD JUL-AUG PY 2016 VL 7 IS 4 AR e01127 DI 10.1128/mBio.01127-16 PG 14 WC Microbiology SC Microbiology GA DW1YQ UT WOS:000383440500062 ER PT J AU Kohler, LJ Reed, SCO Sarraf, SA Arteaga, DD Newton, HJ Roy, CR AF Kohler, Lara J. Reed, Shawna C. O. Sarraf, Shireen A. Arteaga, David D. Newton, Hayley J. Roy, Craig R. TI Effector Protein Cig2 Decreases Host Tolerance of Infection by Directing Constitutive Fusion of Autophagosomes with the Coxiella-Containing Vacuole (vol 7, e01127, 2016) SO MBIO LA English DT Correction C1 [Kohler, Lara J.; Reed, Shawna C. O.; Arteaga, David D.; Roy, Craig R.] Yale Univ, Sch Med, Boyer Ctr Mol Med, Dept Microbial Pathogenesis, New Haven, CT 06510 USA. [Sarraf, Shireen A.] NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Newton, Hayley J.] Univ Melbourne, Peter Doherty Inst Infect & Immun, Dept Microbiol & Immunol, Melbourne, Vic, Australia. RP Roy, CR (reprint author), Yale Univ, Sch Med, Boyer Ctr Mol Med, Dept Microbial Pathogenesis, New Haven, CT 06510 USA. EM craig.roy@yale.edu NR 1 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD JUL-AUG PY 2016 VL 7 IS 4 AR e01327 DI 10.1128/mBio.01327-16 PG 1 WC Microbiology SC Microbiology GA DW1YQ UT WOS:000383440500063 ER PT J AU Ntumngia, FB Thomson-Luque, R Torres, LD Gunalan, K Carvalho, LH Adams, JH AF Ntumngia, Francis B. Thomson-Luque, Richard Torres, Leticia de Menezes Gunalan, Karthigayan Carvalho, Luzia H. Adams, John H. TI A Novel Erythrocyte Binding Protein of Plasmodium vivax Suggests an Alternate Invasion Pathway into Duffy-Positive Reticulocytes SO MBIO LA English DT Article ID BLOOD-GROUP; MALARIA PARASITES; ANTIBODIES; FALCIPARUM; INFECTION; AFRICANS; RECEPTOR; REVEALS; DOMAINS; ANTIGEN AB Erythrocyte invasion by malaria parasites is essential for blood-stage development and an important determinant of host range. In Plasmodium vivax, the interaction between the Duffy binding protein (DBP) and its cognate receptor, the Duffy antigen receptor for chemokines (DARC), on human erythrocytes is central to blood-stage infection. Contrary to this established pathway of invasion, there is growing evidence of P. vivax infections occurring in Duffy blood group-negative individuals, suggesting that the parasite might have gained an alternative pathway to infect this group of individuals. Supporting this concept, a second distinct erythrocyte binding protein (EBP2), representing a new member of the DBP family, was discovered in P. vivax and may be the ligand in an alternate invasion pathway. Our study characterizes this novel ligand and determines its potential role in reticulocyte invasion by P. vivax merozoites. EBP2 binds preferentially to young (CD71(high)) Duffy-positive (Fy(+)) reticulocytes and has minimal binding capacity for Duffy-negative reticulocytes. Importantly, EBP2 is antigenically distinct from DBP and cannot be functionally inhibited by anti-DBP antibodies. Consequently, our results do not support EBP2 as a ligand for invasion of Duffy-negative blood cells, but instead, EBP2 may represent a novel ligand for an alternate invasion pathway of Duffypositive reticulocytes. IMPORTANCE For decades, P. vivax infections in humans have been defined by a unique requirement for the interaction between the Duffy binding protein ligand of the parasite and the Duffy blood group antigen receptor (DARC). Recent reports of P. vivax infections in Duffy-negative individuals challenge this paradigm and suggest an alternate pathway of infection, potentially using the recently discovered EBP2. However, we demonstrate that EBP2 host cell specificity is more restricted than DBP binding and that EBP2 binds preferentially to Duffy-positive, young reticulocytes. This finding indicates that this DBP paralog does mediate a Duffy-independent pathway of infection. C1 [Ntumngia, Francis B.; Thomson-Luque, Richard; Torres, Leticia de Menezes; Adams, John H.] Univ S Florida, Coll Publ Hlth, Ctr Global Hlth & Infect Dis Res, Tampa, FL 33620 USA. [Torres, Leticia de Menezes; Carvalho, Luzia H.] Fiocruz MS, Ctr Pesquisas Rene Rachou, Belo Horizonte, MG, Brazil. [Gunalan, Karthigayan] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. RP Ntumngia, FB; Adams, JH (reprint author), Univ S Florida, Coll Publ Hlth, Ctr Global Hlth & Infect Dis Res, Tampa, FL 33620 USA. EM fntumngi@health.usf.edu; usfmalaria@gmail.com RI Adams, John/G-1800-2015 OI Adams, John/0000-0003-3707-7979 FU HHS \ National Institutes of Health (NIH) [R01AI064478, R21AI107455]; Brazilian National Council of Technological and Scientific Development-CNPq [249764/2013-0] FX This work, including the efforts of John H Adams, was funded by HHS vertical bar National Institutes of Health (NIH) (R01AI064478). This work, including the efforts of Francis B Ntumngia, was funded by HHS vertical bar National Institutes of Health (NIH) (R21AI107455). This work, including the efforts of Leticia de Menezes Torres, was funded by Brazilian National Council of Technological and Scientific Development-CNPq for a visiting PhD student fellowship (249764/2013-0). NR 30 TC 1 Z9 1 U1 2 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD JUL-AUG PY 2016 VL 7 IS 4 AR e01261 DI 10.1128/mBio.01261-16 PG 5 WC Microbiology SC Microbiology GA DW1YQ UT WOS:000383440500079 ER PT J AU Olsen, ME Filone, CM Rozelle, D Mire, CE Agans, KN Hensley, L Connor, JH AF Olsen, Michelle E. Filone, Claire Marie Rozelle, Dan Mire, Chad E. Agans, Krystle N. Hensley, Lisa Connor, John H. TI Polyamines and Hypusination Are Required for Ebolavirus Gene Expression and Replication SO MBIO LA English DT Article ID INITIATION-FACTOR 5A; CHLORELLA-VIRUS PBCV-1; NIEMANN-PICK C1; PROMOTES TRANSLATION; RNA SYNTHESIS; AMINO-ACID; INFECTION; DECARBOXYLASE; INHIBITION; CELLS AB Ebolavirus (EBOV) is an RNA virus that is known to cause severe hemorrhagic fever in humans and other primates. EBOV successfully enters and replicates in many cell types. This replication is dependent on the virus successfully coopting a number of cellular factors. Many of these factors are currently unidentified but represent potential targets for antiviral therapeutics. Here we show that cellular polyamines are critical for EBOV replication. We found that small-molecule inhibitors of polyamine synthesis block gene expression driven by the viral RNA-dependent RNA polymerase. Short hairpin RNA (shRNA) knockdown of the polyamine pathway enzyme spermidine synthase also resulted in reduced EBOV replication. These findings led us to further investigate spermidine, a polyamine that is essential for the hypusination of eukaryotic initiation factor 5A (eIF5A). Blocking the hypusination of eIF5A (and thereby inhibiting its function) inhibited both EBOV gene expression and viral replication. The mechanism appears to be due to the importance of hypusinated eIF5A for the accumulation of VP30, an essential component of the viral polymerase. The same reduction in hypusinated eIF5A did not alter the accumulation of other viral polymerase components. This action makes eIF5A function an important gate for proper EBOV polymerase assembly and function through the control of a single virus protein. IMPORTANCE Ebolavirus (EBOV) is one of the most lethal human pathogens known. EBOV requires host factors for replication due to its small RNA genome. Here we show that the host protein eIF5A in its activated form is necessary for EBOV replication. We further show that the mechanism is through the accumulation of a single EBOV protein, VP30. To date, no other host proteins have been shown to interfere with the translation or stability of an EBOV protein. Activated eIF5A is the only protein in the cell known to contain the specific modification of hypusine; therefore, this pathway is a target for drug development. Further investigation into the mechanism of eIF5A interaction with VP30 could provide insight into therapeutics to combat EBOV. C1 [Olsen, Michelle E.; Filone, Claire Marie; Rozelle, Dan; Connor, John H.] Boston Univ, Dept Microbiol, Boston, MA 02215 USA. [Mire, Chad E.; Agans, Krystle N.] Univ Texas Med Branch, Galveston Natl Lab, Galveston, TX 77555 USA. [Hensley, Lisa] US Army Med Res Inst Infect Dis, Ft Detrick, MD USA. [Hensley, Lisa] NIAID, Integrated Res Facil, NIH, Ft Detrick, MD USA. [Filone, Claire Marie] Natl Biodef Anal & Countermeasures Ctr, Ft Detrick, MD USA. [Rozelle, Dan] Pfizer Inc, Andover, MA USA. RP Connor, JH (reprint author), Boston Univ, Dept Microbiol, Boston, MA 02215 USA. EM jhconnor@bu.edu OI Connor, John/0000-0002-8867-7256 FU HHS \ National Institutes of Health (NIH) [AI121933, AI1096159-04, UC7-AI094660]; HHS \ NIH \ National Institute of Allergy and Infectious Diseases (NIAID) [UC6AI058618] FX This work, including the efforts of John Connor, Michelle E. Olsen, Claire Marie Filone, and Dan Rozelle, was funded by HHS vertical bar National Institutes of Health (NIH) (AI121933 and AI1096159-04). This work, including the efforts of Chad Mire and Krystle Agans, was funded by HHS vertical bar National Institutes of Health (NIH) (UC7-AI094660). This work, including the efforts of John Connor, Michelle E. Olsen, Claire Marie Filone, and Dan Rozelle, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (UC6AI058618). NR 36 TC 2 Z9 2 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD JUL-AUG PY 2016 VL 7 IS 4 AR e00882-16 DI 10.1128/mBio.00882-16 PG 10 WC Microbiology SC Microbiology GA DW1YQ UT WOS:000383440500033 ER PT J AU Park, YD Sun, W Salas, A Antia, A Carvajal, C Wang, A Xu, X Meng, ZJ Zhou, M Tawa, GJ Dehdashti, J Zheng, W Henderson, CM Zelazny, AM Williamson, PR AF Park, Yoon-Dong Sun, Wei Salas, Antonio Antia, Avan Carvajal, Cindy Wang, Amy Xu, Xin Meng, Zhaojin Zhou, Ming Tawa, Gregory J. Dehdashti, Jean Zheng, Wei Henderson, Christina M. Zelazny, Adrian M. Williamson, Peter R. TI Identification of Multiple Cryptococcal Fungicidal Drug Targets by Combined Gene Dosing and Drug Affinity Responsive Target Stability Screening SO MBIO LA English DT Article ID VACUOLAR H+-ATPASE; AMPHOTERICIN-B; DEHYDROGENASE; NEOFORMANS; MENINGITIS; BITHIONOL; PARAGONIMIASIS; SIMILARITIES; METABOLITES; INHIBITORS AB Cryptococcus neoformans is a pathogenic fungus that is responsible for up to half a million cases of meningitis globally, especially in immunocompromised individuals. Common fungistatic drugs, such as fluconazole, are less toxic for patients but have low efficacy for initial therapy of the disease. Effective therapy against the disease is provided by the fungicidal drug amphotericin B; however, due to its high toxicity and the difficulty in administering its intravenous formulation, it is imperative to find new therapies targeting the fungus. The antiparasitic drug bithionol has been recently identified as having potent fungicidal activity. In this study, we used a combined gene dosing and drug affinity responsive target stability (GD-DARTS) screen as well as protein modeling to identify a common drug binding site of bithionol within multiple NAD-dependent dehydrogenase drug targets. This combination genetic and proteomic method thus provides a powerful method for identifying novel fungicidal drug targets for further development. IMPORTANCE Cryptococcosis is a neglected fungal meningitis that causes approximately half a million deaths annually. The most effective antifungal agent, amphotericin B, was developed in the 1950s, and no effective medicine has been developed for this disease since that time. A key aspect of amphotericin B's effectiveness is thought to be because of its ability to kill the fungus (fungicidal activity), rather than just stop or slow its growth. The present study utilized a recently identified fungicidal agent, bithionol, to identify potential fungicidal drug targets that can be used in developing modern fungicidal agents. A combined protein and genetic analysis approach was used to identify a class of enzymes, dehydrogenases, that the fungus uses to maintain homeostasis with regard to sugar nutrients. Similarities in the drug target site were found that resulted in simultaneous inhibition and killing of the fungus by bithionol. These studies thus identify a common, multitarget site for antifungal development. C1 [Park, Yoon-Dong; Salas, Antonio; Antia, Avan; Carvajal, Cindy; Williamson, Peter R.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Sun, Wei; Wang, Amy; Xu, Xin; Tawa, Gregory J.; Dehdashti, Jean; Zheng, Wei] NIH, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. [Meng, Zhaojin; Zhou, Ming] Frederick Natl Lab Canc Res, Prot Characterizat Lab, Canc Res Technol Program, Frederick, MD USA. [Henderson, Christina M.; Zelazny, Adrian M.] NIH, Microbiol Serv, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Williamson, Peter R.] Univ Illinois, Coll Med, Dept Med, Infect Dis Sect, Chicago, IL 60612 USA. RP Williamson, PR (reprint author), NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.; Williamson, PR (reprint author), Univ Illinois, Coll Med, Dept Med, Infect Dis Sect, Chicago, IL 60612 USA. EM williamsonpr@mail.nih.gov RI Zheng, Wei/J-8889-2014 OI Zheng, Wei/0000-0003-1034-0757 FU HHS\NIH\ National Institute of Allergy and Infectious Diseases (NIAID) [AI001123]; HHS \ NIH \ National Institute of Allergy and Infectious Diseases (NIAID) [AI001124] FX This work, including the efforts of Peter R Williamson, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (AI001123). This work, including the efforts of Peter R Williamson, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (AI001124). NR 49 TC 0 Z9 0 U1 12 U2 12 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD JUL-AUG PY 2016 VL 7 IS 4 AR e01073 DI 10.1128/mBio.01073-16 PG 11 WC Microbiology SC Microbiology GA DW1YQ UT WOS:000383440500056 ER PT J AU Tsetsarkin, KA Kenney, H Chen, RB Liu, GP Manukyan, H Whitehead, SS Laassri, M Chumakov, K Pletnev, AG AF Tsetsarkin, Konstantin A. Kenney, Heather Chen, Rubing Liu, Guangping Manukyan, Hasmik Whitehead, Stephen S. Laassri, Majid Chumakov, Konstantin Pletnev, Alexander G. TI A Full-Length Infectious cDNA Clone of Zika Virus from the 2015 Epidemic in Brazil as a Genetic Platform for Studies of Virus-Host Interactions and Vaccine Development SO MBIO LA English DT Article ID JAPANESE-ENCEPHALITIS-VIRUS; COOPERATIVE INTERACTIONS; RT-PCR; RNA; DNA; ROBUSTNESS; EVOLUTION; AMERICA; AMPLIFICATION; TRANSMISSION AB An arthropod-borne virus, Zika virus (ZIKV), has recently emerged as a major human pathogen. Associated with complications during perinatal development and Guillain-Barr syndrome in adults, ZIKV raises new challenges for understanding the molecular determinants of flavivirus pathogenesis. This underscores the necessity for the development of a reverse genetic system based on an epidemic ZIKV strain. Here, we describe the generation and characterization in cell cultures of an infectious cDNA clone of ZIKV isolated from the 2015 epidemic in Brazil. The cDNA-derived ZIKV replicated efficiently in a variety of cell lines, including those of both neuronal and placental origin. We observed that the growth of cDNA-derived virus was attenuated compared to the growth of the parental isolate in most cell lines, which correlates with substantial differences in sequence heterogeneity between these viruses that were determined by deep-sequencing analysis. Our findings support the role of genetic diversity in maintaining the replicative fitness of viral populations under changing conditions. Moreover, these results indicate that caution should be exercised when interpreting the results of reverse-genetics experiments in attempts to accurately predict the biology of natural viruses. Finally, a Vero cell-adapted cDNA clone of ZIKV was generated that can be used as a convenient platform for studies aimed at the development of ZIKV vaccines and therapeutics. IMPORTANCE The availability of genetic tools and laboratory models determines the progress in understanding mechanisms of virus emergence and pathogenesis. Recent large-scale outbreaks of Zika virus (ZIKV) that were linked to complications during perinatal development and Guillain-Barre syndrome in adults emphasize the urgency for the development of a reverse-genetics system based on an epidemic ZIKV strain. Here, we report a stable infectious cDNA clone for ZIKV isolated during the 2015 epidemic in Brazil, as well as a Vero cell-adapted version of it, which will be used for virus-host interaction studies and vaccine development. C1 [Tsetsarkin, Konstantin A.; Kenney, Heather; Liu, Guangping; Whitehead, Stephen S.; Pletnev, Alexander G.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Chen, Rubing] Univ Texas Med Branch, Dept Pathol, Inst Human Infect & Immun, Galveston, TX 77555 USA. [Manukyan, Hasmik; Laassri, Majid; Chumakov, Konstantin] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Pletnev, AG (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM apletnev@niaid.nih.gov FU Division of Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Division of Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health NR 44 TC 10 Z9 10 U1 49 U2 49 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD JUL-AUG PY 2016 VL 7 IS 4 AR e01114 DI 10.1128/mBio.01114-16 PG 8 WC Microbiology SC Microbiology GA DW1YQ UT WOS:000383440500060 ER PT J AU Wu, WM Leavitt, JC Cheng, NQ Gilcrease, EB Motwani, T Teschke, CM Casjens, SR Steven, AC AF Wu, Weimin Leavitt, Justin C. Cheng, Naiqian Gilcrease, Eddie B. Motwani, Tina Teschke, Carolyn M. Casjens, Sherwood R. Steven, Alasdair C. TI Localization of the Houdinisome (Ejection Proteins) inside the Bacteriophage P22 Virion by Bubblegram Imaging SO MBIO LA English DT Article ID COAT PROTEIN; RADIATION-DAMAGE; SALMONELLA PHAGE-P22; I-DOMAIN; NUCLEOPROTEIN COMPLEXES; 3-DIMENSIONAL STRUCTURE; SCAFFOLDING PROTEIN; ELECTRON-MICROSCOPY; BINDING DOMAIN; PORTAL VERTEX AB The P22 capsid is a T=7 icosahedrally symmetric protein shell with a portal protein dodecamer at one 5-fold vertex. Extending outwards from that vertex is a short tail, and putatively extending inwards is a 15-nm-long alpha-helical barrel formed by the C-terminal domains of portal protein subunits. In addition to the densely packed genome, the capsid contains three "ejection proteins" (E-proteins [gp7, gp16, and gp20]) destined to exit from the tightly sealed capsid during the process of DNA delivery into target cells. We estimated their copy numbers by quantitative SDS-PAGE as approximately 12 molecules per virion of gp16 and gp7 and 30 copies of gp20. To localize them, we used bubblegram imaging, an adaptation of cryo-electron microscopy in which gaseous bubbles induced in proteins by prolonged irradiation are used to map the proteins' locations. Weapplied this technique to wild-type P22, a triple mutant lacking all three E-proteins, and three mutants each lacking one E-protein. We conclude that all three E-proteins are loosely clustered around the portal axis, in the region displaced radially inwards from the portal crown. The bubblegram data imply that approximately half of the alpha-helical barrel seen in the portal crystal structure is disordered in the mature virion, and parts of the disordered region present binding sites for E-proteins. Thus positioned, the E-proteins are strategically placed to pass down the shortened barrel and through the portal ring and the tail, as they exit from the capsid during an infection. IMPORTANCE While it has long been appreciated that capsids serve as delivery vehicles for viral genomes, there is now growing awareness that viruses also deliver proteins into their host cells. P22 has three such proteins (ejection proteins [E-proteins]), whose initial locations in the virion have remained unknown despite their copious amounts (total of 2.5 MDa). This study succeeded in localizing them by the novel technique of bubblegram imaging. The P22 E-proteins are seen to be distributed around the orifice of the portal barrel. Interestingly, this barrel, 15 nm long in a crystal structure, is only about half as long in situ: the remaining, disordered, portion appears to present binding sites for E-proteins. These observations document a spectacular example of a regulatory order-disorder transition in a supramolecular system and demonstrate the potential of bubblegram imaging to map the components of other viruses as well as cellular complexes. C1 [Wu, Weimin; Cheng, Naiqian; Steven, Alasdair C.] NIAMSD, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. [Leavitt, Justin C.; Gilcrease, Eddie B.; Casjens, Sherwood R.] Univ Utah, Sch Med, Dept Pathol, Div Microbiol & Immunol, Salt Lake City, UT USA. [Motwani, Tina; Teschke, Carolyn M.] Univ Connecticut, Dept Mol & Cell Biol, Storrs, CT USA. [Teschke, Carolyn M.] Univ Connecticut, Dept Chem, U-60, Storrs, CT USA. [Leavitt, Justin C.] Texas A&M Univ, Dept Anim Sci, College Stn, TX 77843 USA. RP Steven, AC (reprint author), NIAMSD, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. EM stevena@mail.nih.gov FU HHS \ NIH \ National Institute of General Medical Sciences (NIGMS) [GM076661, GM114817]; HHS \ NIH \ National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [ZIA AR027002-38] FX This work, including the efforts of Carolyn M. Teschke, was funded by HHS vertical bar NIH vertical bar National Institute of General Medical Sciences (NIGMS) (GM076661). This work, including the efforts of Sherwood R Casjens, was funded by HHS vertical bar NIH vertical bar National Institute of General Medical Sciences (NIGMS) (GM114817). This work, including the efforts of Alasdair C. Steven, was funded by the intramural research program of HHS vertical bar NIH vertical bar National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) (ZIA AR027002-38). NR 61 TC 1 Z9 1 U1 5 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD JUL-AUG PY 2016 VL 7 IS 4 AR e01152 DI 10.1128/mBio.01152-16 PG 10 WC Microbiology SC Microbiology GA DW1YQ UT WOS:000383440500066 ER PT J AU Koch, KL Hasler, WL Yates, KP Parkman, HP Pasricha, PJ Calles-Escandon, J Snape, WJ Abell, TL Mccallum, RW Nguyen, LA Sarosiek, I Farrugia, G Tonascia, J Lee, L Miriel, L Hamilton, F AF Koch, K. L. Hasler, W. L. Yates, K. P. Parkman, H. P. Pasricha, P. J. Calles-Escandon, J. Snape, W. J. Abell, T. L. Mccallum, R. W. Nguyen, L. A. Sarosiek, I. Farrugia, G. Tonascia, J. Lee, L. Miriel, L. Hamilton, F. CA Niddk Gastroparesis Clinical Res TI Baseline features and differences in 48 week clinical outcomes in patients with gastroparesis and type 1 vs type 2 diabetes SO NEUROGASTROENTEROLOGY AND MOTILITY LA English DT Article DE gastric emptying; gastroparesis; hyperglycemia; nausea and vomiting; type 1 and type 2 diabetes mellitus ID UPPER GASTROINTESTINAL DISORDERS; IDIOPATHIC GASTROPARESIS; SYMPTOM SEVERITY; MELLITUS; PREVALENCE; NAUSEA; DYSFUNCTION; VALIDATION; COHORT; INDEX AB Background In studies of diabetic gastroparesis, patients with type 1 and type 2 diabetes mellitus (T1DM, T2DM) are often combined for analyses. We compared gastroparesis severity, healthcare utilization, psychological function, and quality of life in T1DM vs T2DM gastroparesis patients. Methods Questionnaire, laboratory, and scintigraphy data from patients with gastroparesis and T1DM and T2DM from seven centers of the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium Registry were compared at enrollment and after 48 weeks. Multiple regression models assessed baseline and follow-up differences between diabetes subtypes. Key Results At baseline, T1DM patients (N = 78) had slower gastric emptying, more hospitalizations, more gastric stimulator implantations, higher hemoglobin A1c (HbA1c), and more anxiety vs T2DM patients (N = 59). Independent discriminators of patients with T1DM vs T2DM included worse gastroesophageal reflux disease, less bloating, more peripheral neuropathy, and fewer comorbidities (p = 0.05). On follow-up, gastrointestinal (GI) symptom scores decreased only in T2DM (p < 0.05), but not in T1DM patients who reported greater prokinetic, proton pump inhibitor, anxiolytic, and gastric stimulator usage over 48 weeks (p = 0.03). Gastrointestinal symptoms at baseline and 48 weeks with both subtypes were not associated with HbA1c, peripheral neuropathy, psychological factors, or quality of life. Conclusions & Inferences Baseline symptoms were similar in T1DM and T2DM patients, even though T1DM patients had worse gastric emptying delays and higher HbA1c suggesting other factors mediate symptom severity. Symptom scores at 48 weeks decreased in T2DM, but not T1DM patients, despite increased medical and surgical treatment utilization by T1DM patients. Defining causes of different outcomes in diabetic gastroparesis warrants further investigation. C1 [Koch, K. L.] Wake Forest Univ, Gastroenterol Sect, Winston Salem, NC 27109 USA. [Hasler, W. L.] Univ Michigan, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Yates, K. P.; Tonascia, J.; Lee, L.; Miriel, L.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Parkman, H. P.] Temple Univ, Gastroenterol Sect, Philadelphia, PA 19122 USA. [Pasricha, P. J.] Johns Hopkins Bayview Med Ctr, Ctr Neurogastroenterol, Baltimore, MD USA. [Calles-Escandon, J.] MetroHlth Med Ctr, Endocrinol Sect, Cleveland, OH USA. [Snape, W. J.] Calif Pacific Med Ctr, San Francisco, CA USA. [Abell, T. L.] Univ Louisville, Digest & Liver Hlth, Louisville, KY 40292 USA. [Mccallum, R. W.; Sarosiek, I.] Texas Tech Univ, Div Gastroenterol, El Paso, TX USA. [Nguyen, L. A.] Stanford Univ, Div Gastroenterol, Palo Alto, CA 94304 USA. [Farrugia, G.] Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN USA. [Hamilton, F.] NIDDK, Bethesda, MD 20892 USA. RP Hasler, WL (reprint author), Univ Michigan Hlth Syst, Taubman Ctr 3912, SPC 5362, Ann Arbor, MI 48109 USA. EM whasler@umich.edu FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [U01DK073983, U01DK073975, U01DK073985, U01DK074007, U01DK073974, U01DK074008] FX This project received support from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (grants U01DK073983, U01DK073975, U01DK073985, U01DK074007, U01DK073974, U01DK074008) as part of its funding of the Gastroparesis Clinical Research Consortium. NR 50 TC 3 Z9 3 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1350-1925 EI 1365-2982 J9 NEUROGASTROENT MOTIL JI Neurogastroenterol. Motil. PD JUL PY 2016 VL 28 IS 7 BP 1001 EP 1015 DI 10.1111/nmo.12800 PG 15 WC Gastroenterology & Hepatology; Clinical Neurology; Neurosciences SC Gastroenterology & Hepatology; Neurosciences & Neurology GA DV9VR UT WOS:000383290800006 PM 26946489 ER PT J AU Costello, RB Dwyer, JT Bailey, RL AF Costello, Rebecca B. Dwyer, Johanna T. Bailey, Regan L. TI Chromium supplements for glycemic control in type 2 diabetes: limited evidence of effectiveness SO NUTRITION REVIEWS LA English DT Review DE chromium; fasting plasma glucose; hemoglobin A1c; type 2 diabetes mellitus ID PLACEBO-CONTROLLED TRIAL; TOTAL PARENTERAL-NUTRITION; GLUCOSE-TOLERANCE; DOUBLE-BLIND; INSULIN-RESISTANCE; BREWERS-YEAST; SERUM-LIPIDS; INORGANIC CHROMIUM; DIETARY CHROMIUM; BODY-COMPOSITION AB Some adults with type 2 diabetes mellitus (T2DM) believe that chromium-containing supplements will help control their disease, but the evidence is mixed. This narrative review examines the efficacy of chromium supplements for improving glycemic control as measured by decreases in fasting plasma glucose (FPG) or hemoglobin A1c (HbA1c). Using systematic search criteria, 20 randomized controlled trials of chromium supplementation in T2DM patients were identified. Clinically meaningful treatment goals were defined as an FPG of <= 7.2mmol/dL, a decline in HbA1c to <= 7%, or a decrease of >= 0.5% in HbA1c. In only a few randomized controlled trials did FPG (5 of 20), HbA1c (3 of 14), or both (1 of 14) reach the treatment goals with chromium supplementation. HbA1c declined by >= 0.5% in 5 of 14 studies. On the basis of the low strength of existing evidence, chromium supplements have limited effectiveness, and there is little rationale to recommend their use for glycemic control in patients with existing T2DM. Future meta-analyses should include only high-quality studies with similar forms of chromium and comparable inclusion/exclusion criteria to provide scientifically sound recommendations for clinicians. C1 [Costello, Rebecca B.; Dwyer, Johanna T.; Bailey, Regan L.] NIH, Off Dietary Supplements, 6100 Execut Blvd,Ste 3B01, Bethesda, MD 20892 USA. [Dwyer, Johanna T.] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Sch Med, Boston, MA 02111 USA. [Dwyer, Johanna T.] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA. [Bailey, Regan L.] Purdue Univ, Dept Nutr Sci, W Lafayette, IN 47907 USA. RP Costello, RB (reprint author), NIH, Off Dietary Supplements, 6100 Execut Blvd,Ste 3B01, Bethesda, MD 20892 USA. EM costellb@od.nih.gov FU Office of Dietary Supplements of the National Institutes of Health, US Department of Health and Human Services; US Department of Agriculture, Agricultural Research Service [58-1950-0-014] FX This work was supported by the Office of Dietary Supplements of the National Institutes of Health, US Department of Health and Human Services. Partial support was also provided by the US Department of Agriculture, Agricultural Research Service, under agreement no. 58-1950-0-014. NR 75 TC 1 Z9 1 U1 10 U2 10 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0029-6643 EI 1753-4887 J9 NUTR REV JI Nutr. Rev. PD JUL PY 2016 VL 74 IS 7 BP 455 EP 468 DI 10.1093/nutrit/nuw011 PG 14 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DV9RO UT WOS:000383279100004 PM 27261273 ER PT J AU Boyles, AL Yetley, EA Thayer, KA Coates, PM AF Boyles, Abee L. Yetley, Elizabeth A. Thayer, Kristina A. Coates, Paul M. TI Safe use of high intakes of folic acid: research challenges and paths forward SO NUTRITION REVIEWS LA English DT Review DE high vitamin intake; folic acid; research recommendations; safety ID AUTISM SPECTRUM DISORDERS; NATIONAL-HEALTH; UNITED-STATES; SERUM FOLATE; SUPPLEMENTATION; POPULATION; RISK AB Adequate folic acid intake is an effective dietary-based prevention tool for reducing the risk of neural tube defects. Achieving adequate intake for the prevention of neural tube defects frequently requires the consumption of foods fortified with folic acid and/or the use of folic acid-containing dietary supplements. To date, research on the potential for adverse effects of high intakes of folic acid has been limited. Without such research, it is difficult to define a value for high intake. In May 2015, an expert panel was tasked with examining the available scientific literature and making research recommendations within 4 general categories of potential folate-related adverse health effects: cancer, cognition in conjunction with vitamin B-12 deficiency, hypersensitivity-related outcomes, and thyroid and diabetes-related disorders. This article summarizes the expert panel's conclusions, outlines the challenges faced when reviewing the literature, and examines some of the panel's recommendations for research. C1 [Boyles, Abee L.; Thayer, Kristina A.] NIEHS, Off Hlth Assessment & Translat, Div Natl Toxicol Program, NIH,Dept Hlth & Human Serv, Durham, NC USA. [Yetley, Elizabeth A.; Coates, Paul M.] NIH, Off Dietary Supplements, Dept Hlth & Human Serv, Bldg 10, Bethesda, MD 20892 USA. RP Boyles, AL (reprint author), NIEHS, POB 12233,Mail Drop K2-04, Durham, NC 27709 USA. EM abee.boyles@nih.gov OI Boyles, Abee/0000-0002-8711-2077 NR 18 TC 2 Z9 2 U1 9 U2 12 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0029-6643 EI 1753-4887 J9 NUTR REV JI Nutr. Rev. PD JUL PY 2016 VL 74 IS 7 BP 469 EP 474 DI 10.1093/nutrit/nuw015 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DV9RO UT WOS:000383279100005 PM 27272334 ER PT J AU Huang, SF Wu, HDI Chen, YT Murthy, SRK Chiu, YT Chang, Y Chang, IC Yang, XY Loh, YP AF Huang, Shiu-Feng Wu, Hong-Dar Isaac Chen, Ya-Ting Murthy, Saravana R. K. Chiu, Yu-Ting Chang, Yu Chang, Il-Chi Yang, Xuyu Loh, Y. Peng TI Carboxypeptidase E is a prediction marker for tumor recurrence in early-stage hepatocellular carcinoma SO TUMOR BIOLOGY LA English DT Article DE Carboxypeptidase E; Hepatocellular carcinoma; Recurrence-free survival; Overall survival; Biomarker ID PATHWAY SORTING RECEPTOR; COLORECTAL-CANCER; POOR-PROGNOSIS; RESECTION; EXPRESSION; TRANSPLANTATION; ENDOCRINE; SURVIVAL; STRESS; CDNA AB Tumor recurrence and metastasis are the major causes of death for hepatocellular carcinoma (HCC) patients who are able to receive curative resection. Identifying the predicting biomarkers for tumor recurrence would improve their survival. RNA extracted from fresh frozen tumors and adjacent non-tumor liver tissues of 120 HCC patients were obtained from Taiwan Liver Cancer Network (TLCN) in year 2010 for determination of the carboxypeptidase E (CPE) expression level (including its splicing mutant CPE-Delta N) in the tumor tissue (T) and paired non-tumor liver tissue (N) by real-time quantitative polymerase chain reaction. All patients were male, had chronic hepatitis B virus infection, were in the early pathology stage, and received curative resection. The T/N ratio of the CPE expression level was correlated with the updated survival data from TLCN in 2015. The CPE expression level in the 120 HCC patients was divided into three groups according to the T/N ratio: < 1, aeyen1 and aecurrency sign2, and > 2, respectively. By multivariate analyses, the recurrence-free survival (RFS) was only significantly associated with the pathology stage and the CPE expression level. For overall survival (OS), only the CPE expression level was the significant prognostic factor. The CPE expression level was also significantly correlated with the tumor recurrence for both stage I (p = 0.0106) and stage II patients (p = 0.0006). The CPE mRNA expression level in HCC can be a useful biomarker for predicting tumor recurrence in HCC patients who are in the early pathology stage and able to receive curative resection. C1 [Huang, Shiu-Feng; Chen, Ya-Ting; Chiu, Yu-Ting; Chang, Yu; Chang, Il-Chi] Natl Hlth Res Inst, Inst Mol & Genom Med, 35 Keyan Rd, Miaoli 350, Taiwan. [Huang, Shiu-Feng] Chung Shan Med Univ Hosp, Dept Anat Pathol, Taichung, Taiwan. [Wu, Hong-Dar Isaac] Natl Chung Hsing Univ, Dept Appl Math, Taichung, Taiwan. [Wu, Hong-Dar Isaac] Natl Chung Hsing Univ, Inst Stat, Taichung, Taiwan. [Murthy, Saravana R. K.; Yang, Xuyu; Loh, Y. Peng] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cellular Neurobiol Sect, Program Dev Neurosci, NIH, Bldg 49,Rm 6A-10,49 Convent Dr, Bethesda, MD 20892 USA. RP Huang, SF (reprint author), Natl Hlth Res Inst, Inst Mol & Genom Med, 35 Keyan Rd, Miaoli 350, Taiwan.; Huang, SF (reprint author), Chung Shan Med Univ Hosp, Dept Anat Pathol, Taichung, Taiwan.; Loh, YP (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cellular Neurobiol Sect, Program Dev Neurosci, NIH, Bldg 49,Rm 6A-10,49 Convent Dr, Bethesda, MD 20892 USA. EM sfhuang@nhri.org.tw; lohp@mail.nih.gov FU National Science Council [NSC-100-c-2320-400-012]; National Health Research Institutes [MG103-PP-004]; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, USA [HD008804] FX This research was supported by grants from National Science Council (NSC-100-c-2320-400-012) and National Health Research Institutes (MG103-PP-004) to Dr. Shiu-Feng Huang and by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, USA (HD008804) to Dr. Y. Peng Loh. NR 29 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1010-4283 EI 1423-0380 J9 TUMOR BIOL JI Tumor Biol. PD JUL PY 2016 VL 37 IS 7 BP 9745 EP 9753 DI 10.1007/s13277-016-4814-7 PG 9 WC Oncology SC Oncology GA DU4HU UT WOS:000382174500126 PM 26803519 ER PT J AU Gliwa, C Yurkiewicz, IR Lehmann, LS Hull, SC Jones, N Berkman, BE AF Gliwa, Catherine Yurkiewicz, Ilana R. Lehmann, Lisa Soleymani Hull, Sara Chandros Jones, Nathan Berkman, Benjamin E. TI Institutional review board perspectives on obligations to disclose genetic incidental findings to research participants SO GENETICS IN MEDICINE LA English DT Article DE genomic sequencing; incidental findings; institutional review board; research ethics ID GENOMIC RESEARCH; WORKING GROUP; RECOMMENDATIONS; RETURN; FRAMEWORK; EXOME AB Purpose: Researchers' obligations to disclose genetic incidental findings (GIFs) have been widely debated, but there has been little empirical study of the engagement of institutional review boards (IRBs) with this issue. Methods: This article presents data from the first extensive (n = 796) national survey of IRB professionals' understanding of, experience with, and beliefs surrounding GIFs. Results: Most respondents had dealt with questions about GIFs (74%), but only a minority (47%) felt prepared to address them. Although a majority believed that there is an obligation to disclose GIFs (78%), there is still not consensus about the supporting ethical principles. Respondents generally did not endorse the idea that researchers' additional time and effort (7%), and lack of resources (29%), were valid reasons for diminishing a putative obligation. Most (96%) supported a right not to know, but this view became less pronounced (63%) when framed in terms of specific case studies. Conclusions: IRBs are actively engaged with GIFs but have not yet reached consensus. Respondents were uncomfortable with arguments that could be used to limit an obligation to return GIFs. This could indicate that IRBs are providing some of the impetus for the trend toward returning GIFs, although questions remain about the relative contribution of other stakeholders. C1 [Gliwa, Catherine] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Gliwa, Catherine; Hull, Sara Chandros; Berkman, Benjamin E.] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Yurkiewicz, Ilana R.] Harvard Med Sch, Boston, MA USA. [Lehmann, Lisa Soleymani] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Lehmann, Lisa Soleymani] Harvard Med Sch, Dept Global Hlth & Social Med, Boston, MA USA. [Lehmann, Lisa Soleymani] Harvard TH Chan Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. [Hull, Sara Chandros; Berkman, Benjamin E.] NHGRI, Bioeth Core, NIH, Bethesda, MD 20892 USA. [Jones, Nathan] Univ Wisconsin, Survey Ctr, Madison, WI USA. RP Berkman, BE (reprint author), NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA.; Berkman, BE (reprint author), NHGRI, Bioeth Core, NIH, Bethesda, MD 20892 USA. EM berkmanbe@mail.nih.gov OI Lehmann, Lisa Soleymani/0000-0001-8779-1244; Berkman, Benjamin/0000-0002-9098-0799; Hull, Sara/0000-0001-8742-4997 FU Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health FX The authors declare no conflict of interest. This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. The opinions expressed here are our own and do not reflect the policies or positions of the National Institutes of Health, the U.S. Public Health Service, or the U.S. Department of Health and Human Services. NR 23 TC 1 Z9 1 U1 5 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 EI 1530-0366 J9 GENET MED JI Genet. Med. PD JUL PY 2016 VL 18 IS 7 BP 705 EP 711 DI 10.1038/gim.2015.149 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA DS9XL UT WOS:000381136700009 PM 26583685 ER PT J AU Bharti, SK Awate, S Banerjee, T Brosh, RM AF Bharti, Sanjay Kumar Awate, Sanket Banerjee, Taraswi Brosh, Robert M., Jr. TI Getting Ready for the Dance: FANCJ Irons Out DNA Wrinkles SO GENES LA English DT Review DE G-quadruplex; secondary DNA structure; helicase; replication; genetic diseases; FANCJ; genomic instability; Fanconi Anemia; cancer ID G-QUADRUPLEX DNA; WERNER-SYNDROME HELICASE; ANEMIA GROUP J; REV1 PROTEIN INTERACTS; HOMOLOGOUS RECOMBINATION; REPLICATION FORK; GENOMIC STABILITY; STRUCTURED DNA; BREAST-CANCER; HUMAN-CELLS AB Mounting evidence indicates that alternate DNA structures, which deviate from normal double helical DNA, form in vivo and influence cellular processes such as replication and transcription. However, our understanding of how the cellular machinery deals with unusual DNA structures such as G-quadruplexes (G4), triplexes, or hairpins is only beginning to emerge. New advances in the field implicate a direct role of the Fanconi Anemia Group J (FANCJ) helicase, which is linked to a hereditary chromosomal instability disorder and important for cancer suppression, in replication past unusual DNA obstacles. This work sets the stage for significant progress in dissecting the molecular mechanisms whereby replication perturbation by abnormal DNA structures leads to genomic instability. In this review, we focus on FANCJ and its role to enable efficient DNA replication when the fork encounters vastly abundant naturally occurring DNA obstacles, which may have implications for targeting rapidly dividing cancer cells. C1 [Bharti, Sanjay Kumar; Awate, Sanket; Banerjee, Taraswi; Brosh, Robert M., Jr.] NIA, Lab Mol Gerontol, NIH, Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. RP Brosh, RM (reprint author), NIA, Lab Mol Gerontol, NIH, Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM sanjay.bharti@nih.gov; sanket.awate@nih.gov; taraswi.banerjee@nih.gov; broshr@mail.nih.gov FU Intramural Research Program of the NIH, National Institute on Aging; Fanconi Anemia Research Fund FX This research was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging and the Fanconi Anemia Research Fund (RMB). The authors wish to thank Jimmy Burril for the artwork presented in Figure 1. NR 101 TC 0 Z9 0 U1 6 U2 6 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 2073-4425 J9 GENES-BASEL JI Genes PD JUL PY 2016 VL 7 IS 7 DI 10.3390/genes7070031 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA DT5AO UT WOS:000381493100002 ER PT J AU Hammond, JA Carrington, M Khakoo, SI AF Hammond, John A. Carrington, Mary Khakoo, Salim I. TI A vision of KIR variation at super resolution SO IMMUNOLOGY LA English DT Review DE inhibitory; activating receptors; killer cell immunoglobulin-like receptors; natural killer cells ID CELL-RECEPTOR; DIVERSITY; CLONING; NKB1 AB The Ninth Killer Cell Immunoglobulin-Like Receptor (KIR) Workshop was held in Winchester, UK late in the summer of 2015. The extraordinary diversity of KIR and its functional consequences were key themes throughout the meeting. Novel sequencing technologies and new bioinformatics techniques continue to increase our understanding of the genetic diversity and evolution of the KIR; while a deeper understanding of KIR functions, including their specificity for MHC and its peptide ligands, are generating more refined models of their role in disease. Limited to 100 delegates from around the world, this intimate workshop facilitated vigorous discussion, generating new ideas for research in this ever-expanding field. C1 [Hammond, John A.] Pirbright, Pirbright Inst, Woking, Surrey, England. [Carrington, Mary] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Canc & Inflammat Program, Frederick, MD USA. [Carrington, Mary] Ragon Inst MGH MIT & Harvard, Cambridge, MA USA. [Khakoo, Salim I.] Univ Southampton, Clin & Expt Sci, Southampton, Hants, England. RP Khakoo, SI (reprint author), Univ Southampton, Fac Med, Southampton Gen Hosp, Mail Point 811,Level E South Acad Block, Southampton SO16 6YD, Hants, England. EM S.I.Khakoo@soton.ac.uk RI Institute, Pirbright/K-4476-2014 FU Frederick National Laboratory for Cancer Research [HHSN261200800001E]; Intramural Research Program of the NIH, Frederick National Laboratory, Center for Cancer Research; Biotechnology and Biological Sciences Research Council Institute Strategic Program on Livestock Viral Diseases awarded FX We would like to acknowledge the British Society for Immunology, the meeting sponsors, the participants and those individuals whose work has not been included in this piece. We thank Peter Parham for critical reading of the manuscript. This project has been funded in whole or in part with federal funds from the Frederick National Laboratory for Cancer Research, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. Government. This Research was supported in part by the Intramural Research Program of the NIH, Frederick National Laboratory, Center for Cancer Research. JAH was supported by a Biotechnology and Biological Sciences Research Council Institute Strategic Program on Livestock Viral Diseases awarded to The Pirbright Institute. NR 7 TC 1 Z9 1 U1 2 U2 3 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 2016 VL 148 IS 3 BP 249 EP 252 DI 10.1111/imm.12606 PG 4 WC Immunology SC Immunology GA DT2BA UT WOS:000381284600003 PM 26938992 ER PT J AU Hojeij, R Domingos-Pereira, S Nkosi, M Gharbi, D Derre, L Schiller, JT Jichlinski, P Nardelli-Haefliger, D AF Hojeij, Rim Domingos-Pereira, Sonia Nkosi, Marianne Gharbi, Dalila Derre, Laurent Schiller, John T. Jichlinski, Patrice Nardelli-Haefliger, Denise TI Immunogenic Human Papillomavirus Pseudovirus-Mediated Suicide-Gene Therapy for Bladder Cancer SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES LA English DT Article DE human papillomavirus vectors; tumor-targeting; immunogenic suicide-gene therapy; bladder cancer ID INVASIVE UROTHELIAL CARCINOMA; CELL-DEATH; EAU GUIDELINES; COMBINATION; IMMUNIZATION; VACCINATION; MANAGEMENT; DELIVERY; VECTORS; UPDATE AB Bladder cancer is the second most common urological malignancy in the world. In 70% of cases it is initially diagnosed as non-muscle-invasive bladder cancer (NMIBC) and it is amenable to local treatments, with intravesical (IVES) Bacillus-Calmette-Guerin (BCG) immunotherapy being routinely used after transurethral resection of the lesion. However, this treatment is associated with significant side-effects and treatment failures, highlighting the necessity of novel strategies. One potent approach is the suicide-gene mediated therapy/prodrug combination, provided tumor-specificity can be ensured and anti-tumor immune responses induced. Using the mouse syngeneic orthotopic MB49-bladder tumor model, here we show that IVES human papillomavirus non-replicative pseudovirions (PsV) can pseudoinfect tumors with a ten-fold higher efficacy than normal bladders. In addition, PsV carrying the suicide-gene herpes-simplex virus thymidine kinase (PsV-TK) combined to Ganciclovir (GCV) led to immunogenic cell-death of tumor cells in vitro and to MB49-specific CD8 T-cells in vivo. This was associated with reduction in bladder-tumor growth and increased mice survival. Altogether, our data show that IVES PsV-TK/GCV may be a promising alternative or combinatory treatment for NMIBC. C1 [Hojeij, Rim; Domingos-Pereira, Sonia; Nkosi, Marianne; Gharbi, Dalila; Derre, Laurent; Jichlinski, Patrice; Nardelli-Haefliger, Denise] CHU Vaudois, Dept Urol, CH-1011 Lausanne, Switzerland. [Hojeij, Rim; Domingos-Pereira, Sonia; Nkosi, Marianne; Gharbi, Dalila; Derre, Laurent; Jichlinski, Patrice; Nardelli-Haefliger, Denise] Univ Lausanne, CH-1011 Lausanne, Switzerland. [Schiller, John T.] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. RP Nardelli-Haefliger, D (reprint author), CHU Vaudois, Dept Urol, CH-1011 Lausanne, Switzerland.; Nardelli-Haefliger, D (reprint author), Univ Lausanne, CH-1011 Lausanne, Switzerland. EM reem.hojeij@gmail.com; Sonia.domingos-pereira@chuv.ch; marianne.nkosi@epfl.ch; dalilagh8@gmail.com; laurent.derre@chuv.ch; schillej@dc37a.nci.nih.gov; patrice.jichlinski@chuv.ch; dnardell@hospvd.ch OI nardelli-haefliger, denise/0000-0003-1812-9905 FU Swiss Cancer League [KFS 2808-08-2011]; Swiss National Science Foundation [32-153201] FX This work was supported by the Swiss Cancer League (KFS 2808-08-2011), the Swiss National Science Foundation (32-153201) and by institutional funds. We thank Valerie Cesson and Gregory LaSala (Dpt Urology, CHUV, Lausanne) for their technical help. NR 42 TC 1 Z9 1 U1 3 U2 3 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 1422-0067 J9 INT J MOL SCI JI Int. J. Mol. Sci. PD JUL PY 2016 VL 17 IS 7 AR UNSP 1125 DI 10.3390/ijms17071125 PG 10 WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary SC Biochemistry & Molecular Biology; Chemistry GA DT5DK UT WOS:000381500900138 ER PT J AU Han, Y Rand, KA Hazelett, DJ Ingles, SA Kittles, RA Strom, SS Rybicki, BA Nemesure, B Isaacs, WB Stanford, JL Zheng, W Schumacher, FR Berndt, SI Wang, ZM Xu, JF Rohland, N Reich, D Tandon, A Pasaniuc, B Allen, A Quinque, D Mallick, S Notani, D Rosenfeld, MG Jayani, RS Kolb, S Gapstur, SM Stevens, VL Pettaway, CA Yeboah, ED Tettey, Y Biritwum, RB Adjei, AA Tay, E Truelove, A Niwa, S Chokkalingam, AP John, EM Murphy, AB Signorello, LB Carpten, J Leske, MC Wu, SY Hennis, AJM Neslund-Dudas, C Hsing, AW Chu, LS Goodman, PJ Klein, EA Zheng, SL Witte, JS Casey, G Lubwama, A Pooler, LC Sheng, X Coetzee, GA Cook, MB Chanock, SJ Stram, DO Watya, S Blot, WJ Conti, DV Henderson, BE Haiman, CA AF Han, Ying Rand, Kristin A. Hazelett, Dennis J. Ingles, Sue A. Kittles, Rick A. Strom, Sara S. Rybicki, Benjamin A. Nemesure, Barbara Isaacs, William B. Stanford, Janet L. Zheng, Wei Schumacher, Fredrick R. Berndt, Sonja I. Wang, Zhaoming Xu, Jianfeng Rohland, Nadin Reich, David Tandon, Arti Pasaniuc, Bogdan Allen, Alex Quinque, Dominique Mallick, Swapan Notani, Dimple Rosenfeld, Michael G. Jayani, Ranveer Singh Kolb, Suzanne Gapstur, Susan M. Stevens, Victoria L. Pettaway, Curtis A. Yeboah, Edward D. Tettey, Yao Biritwum, Richard B. Adjei, Andrew A. Tay, Evelyn Truelove, Ann Niwa, Shelley Chokkalingam, Anand P. John, Esther M. Murphy, Adam B. Signorello, Lisa B. Carpten, John Leske, M. Cristina Wu, Suh-Yuh Hennis, Anslem J. M. Neslund-Dudas, Christine Hsing, Ann W. Chu, Lisa Goodman, Phyllis J. Klein, Eric A. Zheng, S. Lilly Witte, John S. Casey, Graham Lubwama, Alex Pooler, Loreall C. Sheng, Xin Coetzee, Gerhard A. Cook, Michael B. Chanock, Stephen J. Stram, Daniel O. Watya, Stephen Blot, William J. Conti, David V. Henderson, Brian E. Haiman, Christopher A. TI Prostate Cancer Susceptibility in Men of African Ancestry at 8q24 SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID GENOME-WIDE ASSOCIATION; LONG NONCODING RNA; RANGE INTERACTION; RISK; LOCI; JAPANESE; VARIANT; PCAT-1; MYC AB The 8q24 region harbors multiple risk variants for distinct cancers, including > 8 for prostate cancer. In this study, we conducted fine mapping of the 8q24 risk region (127.8-128.8 Mb) in search of novel associations with common and rare variation in 4853 prostate cancer case patients and 4678 control subjects of African ancestry. All statistical tests were two-sided. We identified three independent associations at P values of less than 5.00 x 10(-8), all of which were replicated in studies from Ghana and Uganda (combined sample = 5869 case patients, 5615 control subjects; rs114798100: risk allele frequency [RAF] = 0.04, per-allele odds ratio [OR] = 2.31, 95% confidence interval [CI] = 2.04 to 2.61, P = 2.38 x 10(-40); rs72725879: RAF = 0.33, OR = 1.37, 95% CI = 1.30 to 1.45, P = 3.04 x 10(-27); and rs111906932: RAF = 0.03, OR = 1.79, 95% CI = 1.53 to 2.08, P = 1.39 x 10(-13)). Risk variants rs114798100 and rs111906923 are only found in men of African ancestry, with rs111906923 representing a novel association signal. The three variants are located within or near a number of prostate cancer-associated long noncoding RNAs (lncRNAs), including PRNCR1, PCAT1, and PCAT2. These findings highlight ancestry-specific risk variation and implicate prostate-specific lncRNAs at the 8q24 prostate cancer susceptibility region. C1 [Han, Ying; Rand, Kristin A.; Hazelett, Dennis J.; Ingles, Sue A.; Schumacher, Fredrick R.; Casey, Graham; Pooler, Loreall C.; Sheng, Xin; Coetzee, Gerhard A.; Stram, Daniel O.; Conti, David V.; Henderson, Brian E.; Haiman, Christopher A.] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA. [Coetzee, Gerhard A.] Univ Southern Calif, Keck Sch Med, Dept Urol, Los Angeles, CA 90089 USA. [Ingles, Sue A.; Schumacher, Fredrick R.; Casey, Graham; Coetzee, Gerhard A.; Stram, Daniel O.; Conti, David V.; Henderson, Brian E.; Haiman, Christopher A.] Univ Southern Calif, Norris Comprehens Canc Ctr, Los Angeles, CA 90089 USA. [Kittles, Rick A.] Univ Arizona, Coll Med, Tucson, AZ 85724 USA. [Kittles, Rick A.] Univ Arizona, Ctr Canc, Tucson, AZ 85724 USA. [Strom, Sara S.] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Pettaway, Curtis A.] Univ Texas MD Anderson Canc Ctr, Dept Urol, Houston, TX 77030 USA. [Rybicki, Benjamin A.] Henry Ford Hosp, Dept Publ Hlth Sci, Detroit, MI 48202 USA. [Neslund-Dudas, Christine] Henry Ford Hosp, Dept Publ Hlth Sci, Detroit, MI 48202 USA. [Nemesure, Barbara; Leske, M. Cristina; Wu, Suh-Yuh; Hennis, Anslem J. M.] SUNY Stony Brook, Dept Prevent Med, Stony Brook, NY 11794 USA. [Isaacs, William B.] Johns Hopkins Hosp & Med Inst, James Buchanan Brady Urol Inst, Baltimore, MD 21205 USA. [Stanford, Janet L.; Kolb, Suzanne] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Goodman, Phyllis J.] Fred Hutchinson Canc Res Ctr, SWOG Stat Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Stanford, Janet L.] Univ Washington, Dept Epidemiol, Sch Publ Hlth, Seattle, WA 98195 USA. [Zheng, Wei; Blot, William J.] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Div Epidemiol,Dept Med, Nashville, TN 37212 USA. [Berndt, Sonja I.; Wang, Zhaoming; Cook, Michael B.; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Wang, Zhaoming] SAIC Frederick Inc, NCI DCEG, Canc Genom Res Lab, Frederick, MD 21702 USA. [Xu, Jianfeng] NorthShore Univ HealthSyst, Program Personalized Canc Care, Evanston, IL 60201 USA. [Xu, Jianfeng] NorthShore Univ HealthSyst, Dept Surg, Evanston, IL 60201 USA. [Rohland, Nadin; Reich, David; Tandon, Arti; Allen, Alex; Quinque, Dominique; Mallick, Swapan] Harvard Univ, Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Reich, David; Mallick, Swapan] Harvard Univ, Harvard Med Sch, Howard Hughes Med Inst, Boston, MA 02115 USA. [Rohland, Nadin; Reich, David; Tandon, Arti; Allen, Alex; Quinque, Dominique; Mallick, Swapan] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Pasaniuc, Bogdan] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. [Pasaniuc, Bogdan] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA. [Notani, Dimple; Rosenfeld, Michael G.; Jayani, Ranveer Singh] Univ Calif San Diego, Sch Med, Dept Med, Howard Hughes Med Inst, San Diego, CA 92103 USA. [Gapstur, Susan M.; Stevens, Victoria L.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Yeboah, Edward D.; Tettey, Yao; Biritwum, Richard B.; Adjei, Andrew A.; Tay, Evelyn] Korle Bu Teaching Hosp, Accra, Ghana. [Yeboah, Edward D.; Tettey, Yao; Biritwum, Richard B.; Adjei, Andrew A.; Tay, Evelyn] Univ Ghana, Sch Med, Accra, Ghana. [Tandon, Arti; Niwa, Shelley] Westat Corp, Rockville, MD 20850 USA. [Chokkalingam, Anand P.] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. [John, Esther M.; Hsing, Ann W.; Chu, Lisa] Canc Prevent Inst Calif, Fremont, CA 94538 USA. [John, Esther M.; Hsing, Ann W.; Chu, Lisa] Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. [John, Esther M.; Hsing, Ann W.; Chu, Lisa] Stanford Canc Inst, Palo Alto, CA 94304 USA. [Murphy, Adam B.] Northwestern Univ, Dept Urol, Chicago, IL 60611 USA. [Signorello, Lisa B.; Blot, William J.] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Carpten, John] Translat Genom Res Inst, Phoenix, AZ 85004 USA. [Hennis, Anslem J. M.] Univ West Indies, Chron Dis Res Ctr, Bridgetown, Barbados. [Hennis, Anslem J. M.] Univ West Indies, Fac Med Sci, Bridgetown, Barbados. [Klein, Eric A.] Cleveland Clin, Glickman Urol & Kidney Inst, Cleveland, OH 44106 USA. [Zheng, S. Lilly] Wake Forest Sch Med, Ctr Canc Genom, Winston Salem, NC 27157 USA. [Witte, John S.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Witte, John S.] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Lubwama, Alex; Watya, Stephen] Makerere Univ, Coll Hlth Sci, Sch Publ Hlth, Kampala, Uganda. [Watya, Stephen] Uro Care, Kampala, Uganda. RP Haiman, CA (reprint author), Harlyne Norris Res Tower,1450 Biggy St,Room 1504, Los Angeles, CA 90033 USA. EM haiman@usc.edu RI Zheng, Wei/O-3351-2013; OI Zheng, Wei/0000-0003-1226-070X; Jayani, Ranveer Singh/0000-0002-7646-0711 FU National Institutes of Health (NIH) [CA63464, CA54281, CA1326792, CA148085, HG004726]; Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), NIH; Cancer Research Fund (University of California) [99-00524V-10258, 97-12013, 98-00924V]; Department of Health Services Cancer Research Program; NCI, NIH, Department of Health and Human Services [N01-PC-35139]; California Department of Health Services as part of the statewide cancer reporting program [103885]; Centers for Disease Control and Prevention [1U58DP0008073]; NIH [CA056678, CA082664, CA092579, ES011126, S06GM08016, CA092447]; Fred Hutchinson Cancer Research Center; Intramural Program of the National Human Genome Research Institute; Public Health Service Cooperative Agreement Grant from the NCI, NIH. [CA37429, 5UM1CA182883]; Department of Defense (DOD) [W81XWH-07-1-0122]; DOD [DAMD W81XWH-07-1-0203, DAMD W81XWH-06-1-0066, DOD W81XWH-10-1-0532]; Vanderbilt-Ingram Cancer Center [CA68485]; National Program of Cancer Registries (NPCR), Centers for Disease Control and Prevention (CDC); American Cancer Society; Margaret Kersten Ponty postdoctoral fellowship endowment; Achievement Rewards for College Scientists (ARCS) Foundation; Los Angeles Founder Chapter; NCI [CA165862]; [CA68578]; [ES007784]; [DAMD W81XWH-07-1-0645]; [CA140388]; [CA88164]; [CA127298] FX The Multiethnic Cohort Study (MEC) and the genotyping in this study were supported by National Institutes of Health (NIH) grants CA63464, CA54281, CA1326792, CA148085, and HG004726. Genotyping of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) samples was funded by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), NIH. The Los Angeles Study of Aggressive Prostate Cancer (LAAPC) was funded by grant 99-00524V-10258 from the Cancer Research Fund, under Interagency Agreement #97-12013 (University of California contract #98-00924V) with the Department of Health Services Cancer Research Program. Cancer incidence data for the MEC and LAAPC studies have been collected by the Los Angeles Cancer Surveillance Program of the University of Southern California with federal funds from the NCI, NIH, Department of Health and Human Services (under Contract No. N01-PC-35139), and the California Department of Health Services as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885, and grant number 1U58DP0008073 from the Centers for Disease Control and Prevention. The King County (Washington) Prostate Cancer Study (KCPCS) was supported by NIH grants CA056678, CA082664, and CA092579, with additional support from the Fred Hutchinson Cancer Research Center and the Intramural Program of the National Human Genome Research Institute. The Prostate Cancer Case-Control Studies at MD Anderson (MDA) was supported by grants CA68578, ES007784, DAMD W81XWH-07-1-0645, and CA140388. The Prostate Cancer Genetics Study (CaP Genes) was supported by CA88164 and CA127298. The Selenium and Vitamin E Cancer Prevention Trial (SELECT) was funded by Public Health Service Cooperative Agreement Grant CA37429 and 5UM1CA182883 from the NCI, NIH. The Gene-Environment in Prostate Cancer Study (GECAP) was supported by NIH grant ES011126. The Identifying Prostate Cancer Genes study (IPCG) was supported by the Department of Defense (DOD) grant W81XWH-07-1-0122. The Case-Control Study of Prostate Cancer among African Americans in Washington, DC (DCPC) was supported by NIH grant S06GM08016 and DOD grants DAMD W81XWH-07-1-0203, DAMD W81XWH-06-1-0066, and DOD W81XWH-10-1-0532. The Southern Community Cohort Study (SCCS) was funded by NIH grant CA092447. SCCS sample preparation was conducted at the Epidemiology Biospecimen Core Lab, which is supported in part by the Vanderbilt-Ingram Cancer Center (CA68485). Data on SCCS cancer case patients used in this publication were provided by the Alabama Statewide Cancer Registry; Kentucky Cancer Registry; Tennessee Department of Health, Office of Cancer Surveillance; Florida Cancer Data System; North Carolina Central Cancer Registry, North Carolina Division of Public Health; Georgia Comprehensive Cancer Registry; Louisiana Tumor Registry; Mississippi Cancer Registry; South Carolina Central Cancer Registry; Virginia Department of Health, Virginia Cancer Registry; Arkansas Department of Health, Cancer Registry. The Arkansas Central Cancer Registry was fully funded by a grant from the National Program of Cancer Registries (NPCR), Centers for Disease Control and Prevention (CDC). Data on SCCS cancer case patients from Mississippi were collected by the Mississippi Cancer Registry, which participates in the NPCR of the CDC. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the CDC or the Mississippi Cancer Registry.; The Cancer Prevention Study II Nutrition Cohort (CPC-II) was supported by the American Cancer Society. KAR was supported in part by the Margaret Kersten Ponty postdoctoral fellowship endowment, Achievement Rewards for College Scientists (ARCS) Foundation, Los Angeles Founder Chapter. Sequencing in this study was supported by NCI grant CA165862. NR 18 TC 4 Z9 4 U1 2 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD JUL PY 2016 VL 108 IS 7 AR djv431 DI 10.1093/jnci/djv431 PG 5 WC Oncology SC Oncology GA DU9FT UT WOS:000382522500017 ER PT J AU Sabbatino, F Wang, YY Scognamiglio, G Favoino, E Feldman, SA Villani, V Flaherty, KT Nota, S Giannarelli, D Simeone, E Anniciello, AM Palmieri, G Pepe, S Botti, G Ascierto, PA Ferrone, CR Ferrone, S AF Sabbatino, Francesco Wang, Yangyang Scognamiglio, Giosue Favoino, Elvira Feldman, Steven A. Villani, Vincenzo Flaherty, Keith T. Nota, Sjoerd Giannarelli, Diana Simeone, Ester Anniciello, Anna M. Palmieri, Giuseppe Pepe, Stefano Botti, Gerardo Ascierto, Paolo A. Ferrone, Cristina R. Ferrone, Soldano TI Antitumor Activity of BRAF Inhibitor and IFN alpha Combination in BRAF-Mutant Melanoma SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID CELLS-IN-VITRO; INTERFERON-ALPHA; METASTATIC MELANOMA; HUMAN-LEUKOCYTE; PRIMARY TUMORS; UP-REGULATION; OPEN-LABEL; EXPRESSION; ANTIGEN; RECEPTOR AB Background: BRAF(V600E)-mediated MAPK pathway activation is associated in melanoma cells with IFNAR1 downregulation. IFNAR1 regulates melanoma cell sensitivity to IFN alpha, a cytokine used for the adjuvant treatment of melanoma. These findings and the limited therapeutic efficacy of BRAF-I prompted us to examine whether the efficacy of IFN alpha therapy of BRAF(V600E) melanoma can be increased by its combination with BRAF-I. Methods: BRAF/NRAS genotype, ERK activation, IFNAR1, and HLA class I expression were tested in 60 primary melanoma tumors from treatment-naive patients. The effect of BRAF-I on IFNAR1 expression was assessed in three melanoma cell lines and in four biopsies of BRAF(V600E) metastases. The antiproliferative, pro-apoptotic and immunomodulatory activity of BRAF-I and IFN alpha combination was tested in vitro and in vivo utilizing three melanoma cell lines, HLA class I-MA peptide complex-specific T-cells and immunodeficient mice (5 per group for survival and 10 per group for tumor growth inhibition). All statistical tests were two-sided. Differences were considered statistically significant when the P value was less than .05. Results: The IFNAR1 level was statistically significantly (P < .001) lower in BRAF(V600E) primary melanoma tumors than in BRAF wild-type tumors. IFNAR1 downregulation was reversed by BRAF-I treatment in the three melanoma cell lines (P <= .02) and in three out of four metastases. The IFNAR1 level in the melanoma tumors analyzed was increased as early as 10 to 14 days following the beginning of the treatment. These changes were associated with: 1) an increased susceptibility in vitro of melanoma cells to the antiproliferative (P <= .04), pro-apoptotic (P <= .009) and immunomodulatory activity, including upregulation of HLA class I antigen APM component (P <= .04) and MA expression as well as recognition by cognate T-cells (P < .001), of BRAF-I and IFN alpha combination and 2) an increased survival (P < .001) and inhibition of tumor growth of melanoma cells (P < .001) in vivo by BRAF-I and IFN alpha combination. Conclusions: The described results provide a strong rationale for the clinical trials implemented in BRAFV600E melanoma patients with BRAF-I and IFN alpha combination. C1 [Sabbatino, Francesco; Wang, Yangyang; Favoino, Elvira; Villani, Vincenzo; Ferrone, Cristina R.; Ferrone, Soldano] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, 55 Fruit St, Boston, MA 02114 USA. [Flaherty, Keith T.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med Oncol, Boston, MA 02114 USA. [Nota, Sjoerd; Ferrone, Soldano] Harvard Med Sch, Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Scognamiglio, Giosue; Anniciello, Anna M.; Botti, Gerardo] Fdn G Pascale, Ist Nazl Tumori, Unit Pathol, Naples, Italy. [Simeone, Ester; Ascierto, Paolo A.] Fdn G Pascale, Ist Nazl Tumori, Unit Melanoma Canc Immunotherapy & Innovat Therap, Naples, Italy. [Feldman, Steven A.] NCI, Surg Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Giannarelli, Diana] Regina Elena Inst Canc Res, Biostat Unit, Rome, Italy. [Palmieri, Giuseppe] CNR, Inst Biomol Chem, Unit Canc Genet, Sassari, Italy. [Sabbatino, Francesco; Pepe, Stefano] Univ Salerno, Dept Med & Surg, Salerno, Italy. [Favoino, Elvira] IRCCS Saverio de Bellis, Natl Inst Digest Dis, Lab Cellular & Mol Biol, Castellana Grotte, BA, Italy. RP Ferrone, S (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, 55 Fruit St, Boston, MA 02114 USA. EM sferrone@mgh.harvard.edu OI Palmieri, Giuseppe/0000-0002-4350-2276 FU National Cancer Institute (PHS grants) [RO1CA138188, P50CA121973]; Fondazione Umberto Veronesi; Susan G. Komen for the Cure Foundation [KG111486]; Centro per la Comunicazione e la Ricerca of the Collegio Ghislieri of Pavia FX This study was supported by the National Cancer Institute (PHS grants RO1CA138188 and P50CA121973 to SF), by Fondazione Umberto Veronesi (Fondazione Umberto Veronesi Post Doctoral Fellowship by FS), by the Susan G. Komen for the Cure Foundation (Susan Komen Post Doctoral Fellowship KG111486 by YW), and by Centro per la Comunicazione e la Ricerca of the Collegio Ghislieri of Pavia (Research Fellowship by VV). NR 38 TC 3 Z9 3 U1 5 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD JUL PY 2016 VL 108 IS 7 AR djv435 DI 10.1093/jnci/djv435 PG 11 WC Oncology SC Oncology GA DU9FT UT WOS:000382522500008 ER PT J AU Villalona-Calero, MA Duan, WR Zhao, WQ Shilo, K Schaaf, LJ Thurmond, J Westman, JA Marshall, J Li, XB Ji, JP Rose, J Lustberg, M Bekaii-Saab, T Chen, A Timmers, C AF Villalona-Calero, Miguel A. Duan, Wenrui Zhao, Weiqiang Shilo, Konstantin Schaaf, Larry J. Thurmond, Jennifer Westman, Judith A. Marshall, John Li Xiaobai Ji, Jiuping Rose, Jeffrey Lustberg, Maryam Bekaii-Saab, Tanios Chen, Alice Timmers, Cynthia TI Veliparib Alone or in Combination with Mitomycin C in Patients with Solid Tumors With Functional Deficiency in Homologous Recombination Repair SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID FANCONI-ANEMIA SUBTYPE; POLY(ADP-RIBOSE) POLYMERASE; DNA-REPAIR; OVARIAN-CANCER; BIALLELIC MUTATIONS; SOMATIC MUTATIONS; BRCA1 DEFICIENCY; LUNG-CANCER; PATHWAY; RESISTANCE AB Background: BRCA germline mutations are being targeted for development of PARP inhibitors. BRCA genes collaborate with several others in the Fanconi Anemia (FA) pathway. We screened cancer patients' tumors for FA functional defects then aimed to establish the safety/feasibility of administering PARP inhibitors as monotherapy and combined with a DNA-breaking agent. Methods: Patients underwent FA functional screening for the presence (or lack) of tumor FancD2 nuclear foci formation on their archival tumor material, utilizing a newly developed method (Fanconi Anemia triple-stain immunofluorescence [FATSI]), performed in a Clinical Laboratory Improvement Amendments-certified laboratory. FATSI-negative patients were selected for enrollment in a two-arm dose escalation trial of veliparib, or veliparib/mitomycin-C (MMC). Results: One hundred eighty-five of 643 (28.7%) screened patients were FATSI-negative. Sixty-one received veliparib or veliparib/MMC through 14 dose levels. Moderate/severe toxicities included fatigue (DLT at veliparib 400 mg BID), diarrhea, and thrombocytopenia. Recommended doses are 300 mg BID veliparib and veliparib 200 mg BID for 21 days following 10 mg/m(2) MMC every 28 days. Six antitumor responses occurred, five in the combination arm (3 breast, 1 ovarian, 1 endometrial [uterine], and 1 non-small cell lung cancer). Two patients have received 36 and 60 cycles to date. BRCA germline analysis among 51 patients revealed five deleterious mutations while a targeted FA sequencing gene panel showed missense/nonsense mutations in 29 of 49 FATSI-negative tumor specimens. Conclusions: FATSI screening showed that a substantial number of patients' tumors have FA functional deficiency, which led to germline alterations in several patients' tumors. Veliparib alone or with MMC was safely administered to these patients and produced clinical benefit in some. However, a better understanding of resistance mechanisms in this setting is needed. C1 [Villalona-Calero, Miguel A.; Duan, Wenrui; Rose, Jeffrey; Lustberg, Maryam; Bekaii-Saab, Tanios] Ohio State Univ, Div Med Oncol, Columbus, OH 43210 USA. [Westman, Judith A.] Ohio State Univ, Clin Canc Genet, Columbus, OH 43210 USA. [Zhao, Weiqiang; Shilo, Konstantin] Ohio State Univ, Dept Pathol, Columbus, OH 43210 USA. [Villalona-Calero, Miguel A.; Duan, Wenrui; Schaaf, Larry J.; Thurmond, Jennifer; Bekaii-Saab, Tanios; Timmers, Cynthia] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Li Xiaobai] Ohio State Univ, Ctr Biostat, Columbus, OH 43210 USA. [Marshall, John] Georgetown Univ, Lombardi Canc Ctr, Washington, DC 20007 USA. [Ji, Jiuping; Chen, Alice] NCI, Bethesda, MD 20892 USA. RP Villalona-Calero, MA (reprint author), Miami Canc Inst, 1575 San Ignacio Ave,Suite 100, Coral Gables, FL 33146 USA. EM miguelvil@BaptistHealth.net OI S, K/0000-0002-6702-3130 FU National Institutes of Health (NIH) [R01-CA152101, N01-CM-2011-00070(HHSN261201100070C), OSUCCC P30 CA016058-38] FX This work was supported by National Institutes of Health (NIH) grantsR01-CA152101, N01-CM-2011-00070(HHSN261201100070C) to MAV, and OSUCCC P30 CA016058-38. NR 58 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD JUL PY 2016 VL 108 IS 7 AR djv437 DI 10.1093/jnci/djv437 PG 10 WC Oncology SC Oncology GA DU9FT UT WOS:000382522500011 ER PT J AU Tisnado, D Malin, J Kahn, K Landrum, MB Fletcher, R Klabunde, C Clauser, S Rogers, SO Keating, NL AF Tisnado, Diana Malin, Jennifer Kahn, Katherine Landrum, Mary Beth Fletcher, Robert Klabunde, Carrie Clauser, Steven Rogers, Selwyn O., Jr. Keating, Nancy L. TI Variations in Oncologist Recommendations for Chemotherapy for Stage IV Lung Cancer: What Is the Role of Performance Status? SO JOURNAL OF ONCOLOGY PRACTICE LA English DT Article ID EARLY PALLIATIVE CARE; SUPPORTIVE CARE; THERAPEUTIC APPROACH; CLINICAL ONCOLOGY; AMERICAN SOCIETY; OF-LIFE; OUTCOMES; QUALITY; TRIALS; METAANALYSIS AB Purpose:Chemotherapy prolongs survival in patients with advanced non-small-cell lung cancer. However, few studies have included patients with poor performance status. This study examined rates of oncologists' recommendations for chemotherapy by patient performance status and symptoms and how physician characteristics influence chemotherapy recommendations.Methods:We surveyed medical oncologists involved in the care of a population-based cohort of patients with lung cancer from the CanCORS (Cancer Care Outcomes Research and Surveillance) study. Physicians were queried about their likelihood to recommend chemotherapy to patients with stage IV lung cancer with varying performance status (Eastern Cooperative Oncology Group performance status 0 [good] v 3 [poor]) and presence or absence of tumor-related pain. Repeated measures logistic regression was used to estimate the independent associations of patients' performance status and symptoms and physicians' demographic and practice characteristics with chemotherapy recommendations.Results:Nearly all physicians (adjusted rate, 97% to 99%) recommended chemotherapy for patients with good performance status, and approximately half (adjusted rate, 38% to 53%) recommended chemotherapy for patients with poor performance status (P < .001). Compared with patient factors, physician and practice characteristics were less strongly associated with chemotherapy recommendations in adjusted analyses.Conclusion:Strong consensus among oncologists exists for chemotherapy in patients with advanced non-small-cell lung cancer and good performance status. However, the relatively high rate of chemotherapy recommendations for patients with poor performance status despite the unfavorable risk-benefit profile highlights the need for ongoing work to define high-value care in oncology and to implement and evaluate strategies to align incentives for such care. C1 [Tisnado, Diana] Calif State Univ Fullerton, 800 N State Coll Blvd,Rm KHS 142, Fullerton, CA 92834 USA. Anthem, Woodland Hills, CA USA. Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. RAND Corp, Santa Monica, CA USA. Harvard Med Sch, Boston, MA USA. Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. NCI, Bethesda, MD 20892 USA. Patient Ctr Outcomes Res Inst, Washington, DC USA. Univ Texas Med Branch Hlth, Galveston, TX USA. RP Tisnado, D (reprint author), Calif State Univ Fullerton, 800 N State Coll Blvd,Rm KHS 142, Fullerton, CA 92834 USA. EM dtisnado@fullerton.edu FU NCI NIH HHS [K24 CA181510, U01 CA093324, U01 CA093326, U01 CA093329, U01 CA093332, U01 CA093339, U01 CA093344, U01 CA093348]; NIA NIH HHS [P30 AG021684] NR 40 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 1554-7477 EI 1935-469X J9 J ONCOL PRACT JI J. Oncol. Pract. PD JUL PY 2016 VL 12 IS 7 BP 651 EP + DI 10.1200/JOP.2015.008425 PG 14 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DT3JL UT WOS:000381376900015 PM 27271507 ER PT J AU Fragoso, CAV McAvay, G Van Ness, PH Metter, EJ Ferrucci, L Yaggi, HK Concato, J Gill, TM AF Fragoso, Carlos A. Vaz McAvay, Gail Van Ness, Peter H. Metter, E. Jeffrey Ferrucci, Luigi Yaggi, H. Klar Concato, John Gill, Thomas M. TI Aging-Related Considerations When Evaluating the Forced Expiratory Volume in 1 Second (FEV1) Over Time SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Aging; Spirometry; Lung diseases; Cardiovascular diseases; Epidemiology ID LUNG-FUNCTION; RESPIRATORY IMPAIRMENT; NATURAL-HISTORY; OLDER PERSONS; SPIROMETRY; DISEASE; PREVALENCE; VALUES AB Background: Forced expiratory volume in 1 second (FEV1) over time is commonly expressed in liters and percent predicted (%Pred), or alternatively in L/m(3) and Z-scores. which approach is more clinically meaningful has not been evaluated. Because it uniquely accounts for the effect of aging on FEV1 and spirometric performance, we hypothesized that the Z-score approach is more clinically meaningful, based on associations between cardiopulmonary predictors and FEV1 over time. Methods: Using linear mixed-effects models and data from the Baltimore Longitudinal Study on Aging, including 501 white participants aged 40-95 who had completed at least three longitudinal spirometric assessments, we evaluated the associations between cardiopulmonary predictors (obesity, smoking status, hypertension, chronic bronchitis, diabetes mellitus, and myocardial infarction) and FEV1 over time, in liters, %Pred, L/m(3), and Z-scores. Results: Mean baseline values for FEV1 were 3.240 L, 96.4% Pred, 0.621 L/m(3), and -0.239 as a Z-score (40.6th percentile). The annual decline in FEV1 was 0.040 L, 0.234 %Pred, 0.007 L/m(3), and 0.008 Z-score units. Baseline age was associated with FEV1 over time in liters and L/m(3) (p < .001), and included a time interaction for %Pred (p < .001), but was not associated with Z-scores (p = .933). The associations of cardiopulmonary predictors with FEV1 over time were all significant when using Z-scores (p < <.05.05), but varied for other methods of expressing FEV1. Conclusion: A Z-score approach is more clinically meaningful when evaluating FEV1 over time, as it accounted for the effect of aging and was more frequently associated with multiple cardiopulmonary predictors. C1 [Fragoso, Carlos A. Vaz; Yaggi, H. Klar; Concato, John] Vet Affairs Clin Epidemiol Res Ctr, West Haven, CT USA. [Fragoso, Carlos A. Vaz; McAvay, Gail; Van Ness, Peter H.; Yaggi, H. Klar; Concato, John; Gill, Thomas M.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. [Metter, E. Jeffrey] Univ Tennessee, Ctr Hlth Sci, Dept Neurol, Memphis, TN 38163 USA. [Ferrucci, Luigi] NIA, Harbor Hosp, Baltimore, MD 21224 USA. RP Fragoso, CAV (reprint author), VA Connecticut Healthcare Syst, 950 Campbell Ave, West Haven, CT 06516 USA. EM carlos.fragoso@yale.edu FU Yale Claude D. Pepper Older Americans Independence Center [P30AG021342]; VA Merit Award; VA Cooperative Studies Program; NIA Academic Leadership Award [K07AG043587] FX The analytical phase of this study was conducted at the Yale Claude D. Pepper Older Americans Independence Center (P30AG021342). C.A.V.F. is supported by a VA Merit Award. J.C. is supported by the VA Cooperative Studies Program. T.M.G is the recipient of an NIA Academic Leadership Award (K07AG043587). NR 30 TC 2 Z9 2 U1 2 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD JUL PY 2016 VL 71 IS 7 BP 929 EP 934 DI 10.1093/gerona/glv201 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DT0YW UT WOS:000381209900012 ER PT J AU Schrack, JA Zipunnikov, V Simonsick, EM Studenski, S Ferrucci, L AF Schrack, Jennifer A. Zipunnikov, Vadim Simonsick, Eleanor M. Studenski, Stephanie Ferrucci, Luigi TI Rising Energetic Cost of Walking Predicts Gait Speed Decline With Aging SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Functional performance; Gait; Metabolism; Physical function; Physiology ID LOWER-EXTREMITY FUNCTION; RESTING METABOLIC-RATE; OLDER-ADULTS; SUBSEQUENT DISABILITY; WOMEN; AGE; EXPENDITURE; TREADMILL; HEALTH; PACE AB Background: Slow gait is a robust biomarker of health and a predictor of functional decline and death in older adults, yet factors contributing to the decline in gait speed with aging are not well understood. Previous research suggests that the energetic cost of walking at preferred speed is inversely associated with gait speed, but whether individuals with a rising energetic cost of walking experience a steeper rate of gait speed decline has not been investigated. Methods: In participants of the Baltimore Longitudinal Study of Aging, the energetic cost of overground walking at preferred speed (mL/kg/m) was assessed between 2007 and 2014 using a portable indirect calorimeter. The longitudinal association between the energetic cost of walking and usual gait speed over 6 meters (m/s) was assessed with multivariate linear regression models, and the risk of slow gait (<1.0 m/s) was analyzed using Cox proportional hazards models. Results: The study population consisted of 457 participants aged 40 and older who contributed 1,121 person-visits to the analysis. In fully adjusted models, increases in the energetic cost of walking predicted the rate of gait speed decline in those older than 65 years (beta = -0.008 m/s, p < .001). Moreover, those with a higher energetic cost of walking (>0.17 mL/kg/m) had a 57% greater risk of developing slow gait compared with a normal energetic cost of walking (<= 0.17 mL/kg/m; adjusted hazard ratio = 1.57, 95% confidence interval: 1.01-2.46). Conclusions: These findings suggest that strategies to maintain walking efficiency hold significant implications for maintaining mobility in late life. Efforts to curb threats to walking efficiency should focus on therapies to treat gait and balance impairments, and reduce clinical disease burden. C1 [Schrack, Jennifer A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, 615 North Wolfe St,E7144, Baltimore, MD 21205 USA. [Schrack, Jennifer A.; Simonsick, Eleanor M.; Studenski, Stephanie; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Zipunnikov, Vadim] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. RP Schrack, JA (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, 615 North Wolfe St,E7144, Baltimore, MD 21205 USA. EM jschrac1@jhu.edu FU Intramural Research Program of the NIH, National Institute on Aging; [K01AG048765]; [HHSN311210300177P] FX This research was supported by the Intramural Research Program of the NIH, National Institute on Aging. J.A.S was supported by K01AG048765 and HHSN311210300177P. NR 36 TC 2 Z9 2 U1 5 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD JUL PY 2016 VL 71 IS 7 BP 947 EP 953 DI 10.1093/gerona/glw002 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DT0YW UT WOS:000381209900015 PM 26850913 ER PT J AU Simonsick, EM Chia, CW Mammen, JS Egan, JM Ferrucci, L AF Simonsick, Eleanor M. Chia, Chee W. Mammen, Jennifer S. Egan, Josephine M. Ferrucci, Luigi TI Free Thyroxine and Functional Mobility, Fitness, and Fatigue in Euthyroid Older Men and Women in the Baltimore Longitudinal Study of Aging SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Free thyroxine; Physical function; Aging; Fitness; Fatigue ID THYROID-FUNCTION; SUBCLINICAL HYPOTHYROIDISM; COGNITIVE FUNCTION; PHYSICAL FUNCTION; METABOLIC-RATE; ADULTS; AGE; HEALTH; POPULATION; MORTALITY AB Background: Emerging evidence suggests that mildly down-regulated thyroid function in older persons may protect and/or reflect maintained health. Methods: Using observational data collected between January 2006 and March 2014 on a volunteer sample of 602 men and women aged 68-97 years with normal thyroid function participating in the Baltimore Longitudinal Study of Aging, this study examines the concurrent relationship between reported walking ability, usual and rapid gait speed, endurance walk performance, fatigability, and reported energy level with respect to free thyroxine (FT4) within the normal range (0.76-1.50 ng/dL) as a continuous variable and categorized as low (lower quartile), medium (interquartile), or high (upper quartile). Results: Adjusting for sex, age, race, height, weight, exercise and smoking, reported walking ability, usual and rapid gait speed, 400-m time, fatigability, and reported energy level were less favorable with increasing FT4 (p =.013 to <. 001). In sex-strata, similar associations were observed except for walking ability in men and energy level in women. Categorical analyses revealed that persons with low FT4 exhibited better functional mobility, fitness, and reported energy than persons with intermediate or high levels (p < .05 for all). Persons with high-normal versus medium FT4 had slower usual and rapid gait speed (p < .05) only. Conclusion: Older adults with low-normal FT4 exhibit better mobility, fitness, and fatigue profiles. Mildly down-regulated thyroid function appears to align with better function in old age and may serve as a biomarker of healthy longevity. C1 [Simonsick, Eleanor M.; Chia, Chee W.; Egan, Josephine M.; Ferrucci, Luigi] NIA, Intramural Res Program, Baltimore, MD 21224 USA. [Simonsick, Eleanor M.; Chia, Chee W.; Mammen, Jennifer S.; Egan, Josephine M.; Ferrucci, Luigi] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. RP Simonsick, EM (reprint author), 3001 S Hanover St,5th Floor, Baltimore, MD 21224 USA. EM simonsickel@mail.nih.gov FU Intramural Research Program of the National Institute on Aging, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 33 TC 4 Z9 4 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD JUL PY 2016 VL 71 IS 7 BP 961 EP 967 DI 10.1093/gerona/glv226 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DT0YW UT WOS:000381209900017 PM 26791089 ER PT J AU Rosario, BL Rosso, AL Aizenstein, HJ Harris, T Newman, AB Satterfield, S Studenski, SA Yaffe, K Rosano, C AF Rosario, Bedda L. Rosso, Andrea L. Aizenstein, Howard J. Harris, Tamara Newman, Anne B. Satterfield, Suzanne Studenski, Stephanie A. Yaffe, Kristine Rosano, Caterina CA Hlth ABC Study TI Cerebral White Matter and Slow Gait: Contribution of Hyperintensities and Normal-appearing Parenchyma SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE White matter hyperintensities; Fractional anisotropy; Normal-appearing white matter; DTI; Gait speed ID OLDER-PEOPLE; FALL RISK; ADULTS; BRAIN; SPEED; DISORDERS; INTEGRITY AB Background. White matter hyperintensities (WMH), a common marker of cerebral small vessel disease, and lower microstructural integrity of normal-appearing white matter are associated with slower gait. How these cerebral measures interact in relation to slower gait is unknown. We assessed whether microstructural integrity of normal-appearing white matter, measured by fractional anisotropy (FA), moderates the association of higher WMH with slower gait. Methods. WMH, FA, and gait speed were acquired for 265 community-dwelling older adults (average age = 82.9 years). Results. The inverse association between WMH and gait was robust to adjustment for age, gender, muscle strength, obesity, stroke, and hypertension (fully adjusted model: beta(s) = -0.19, p = .001). The interaction between WMH and FA was significant; analyses stratified by FA showed that the inverse association between WMH and gait speed was significant only for those with low FA (FA < median, fully adjusted model: beta(s) = -0.28, p = .001). Voxel-based results were similar for participants with FA less than median, there was an inverse association between gait speed and WMH which extended throughout the white matter (genu and body of corpus callosum, anterior limb of internal capsule, corona radiata, and superior longitudinal and fronto-occipital fasciculus). In contrast, for participants with FA = median, the association was limited to the genu of corpus callosum, the cingulum, and the inferior longitudinal fasciculus. Conclusions. Microstructural integrity is a moderating factor in the association between WMH and gait. Future studies should examine whether higher microstructural integrity represents a source of compensation in those with greater WMH burden to maintain function in late life. C1 [Rosario, Bedda L.; Rosso, Andrea L.; Newman, Anne B.; Rosano, Caterina] Univ Pittsburgh, Dept Epidemiol, 130 DeSoto St,127 Parran Hall, Pittsburgh, PA 15261 USA. [Aizenstein, Howard J.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Harris, Tamara] NIH, Lab Epidemiol Demog & Biometry, Bldg 10, Bethesda, MD 20892 USA. [Satterfield, Suzanne] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. [Studenski, Stephanie A.] NIH, Longitudinal Studies Sect, Bldg 10, Bethesda, MD 20892 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. RP Rosario, BL (reprint author), Univ Pittsburgh, Dept Epidemiol, 130 DeSoto St,127 Parran Hall, Pittsburgh, PA 15261 USA. EM blr5@pitt.edu FU National Institute on Aging (NIA) NIA [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG-028050]; National Institute on Aging (NIA) NINR [R01-NR-012459]; Intramural Research Program of the NIA [K23-AG-028966, R01-AG-029232]; University of Pittsburgh Claude D. Pepper Older Americans Independence Center [P30-AG-024827-07]; NIA [T32-AG-000181] FX Health ABC was supported by the National Institute on Aging (NIA) Contracts (N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, NIA grant R01-AG-028050, and NINR grant R01-NR-012459). This research was supported in part by the Intramural Research Program of the NIA (K23-AG-028966 and R01-AG-029232), the University of Pittsburgh Claude D. Pepper Older Americans Independence Center (P30-AG-024827-07), and a training grant from the NIA (T32-AG-000181). NR 31 TC 0 Z9 0 U1 2 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD JUL PY 2016 VL 71 IS 7 BP 968 EP 973 DI 10.1093/gerona/glv224 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DT0YW UT WOS:000381209900018 PM 26755683 ER PT J AU Hong, SG Lin, YS Dunbar, CE Zou, JZ AF Hong, So Gun Lin, Yongshun Dunbar, Cynthia E. Zou, Jizhong TI The Role of Nonhuman Primate Animal Models in the Clinical Development of Pluripotent Stem Cell Therapies SO MOLECULAR THERAPY LA English DT News Item ID REGENERATIVE MEDICINE; TRANSPLANTATION C1 [Hong, So Gun; Dunbar, Cynthia E.] NHLBI, Hematol Branch, NIH, 10 Ctr Dr,Bldg 10 CRC,Room 4E-5132, Bethesda, MD 20892 USA. [Lin, Yongshun; Zou, Jizhong] NHLBI, iPSC iore, Ctr Mol Med, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Dunbar, CE (reprint author), NHLBI, Hematol Branch, NIH, 10 Ctr Dr,Bldg 10 CRC,Room 4E-5132, Bethesda, MD 20892 USA. EM dunbarc@nhlbi.nih.gov NR 23 TC 0 Z9 0 U1 5 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD JUL PY 2016 VL 24 IS 7 BP 1165 EP 1169 DI 10.1038/mt.2016.131 PG 5 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA DT3YY UT WOS:000381418300002 PM 27506376 ER PT J AU Wright, JT Tampi, MP Graham, L Estrich, C Crall, JJ Fontana, M Gillette, EJ Novy, BB Dhar, V Donly, K Hewlett, ER Quinonez, RB Chaffin, J Crespin, M Iafolla, T Siegal, MD Carrasco-Labra, A AF Wright, John T. Tampi, Malavika P. Graham, Laurel Estrich, Cameron Crall, James J. Fontana, Margherita Gillette, E. Jane Novy, Brian B. Dhar, Vineet Donly, Kevin Hewlett, Edmond R. Quinonez, Rocio B. Chaffin, Jeffrey Crespin, Matt Iafolla, Timothy Siegal, Mark D. Carrasco-Labra, Alonso TI Sealants for Preventing and Arresting Pit-and-fissure Occlusal Caries in Primary and Permanent Molars A systematic review of randomized controlled trials-a report of the American Academy of Pediatric Dentistry and the American Dental Association SO PEDIATRIC DENTISTRY LA English DT Review DE GLASS IONOMER SEALANTS; RESIN-BASED SEALANTS; CARIES PREVENTION; CARIES ARREST; PIT-AND-FISSURE SEALANTS; SYSTEMATIC REVIEW ID GLASS-IONOMER; CLINICAL-EVALUATION; FLUORIDE VARNISH; RESIN SEALANT; LOW-RISK; RETENTION AB Background: National Health and Nutrition Examination Survey 2011-2012 data indicated that, in the United States, nearly one-fourth of children and over one-half of adolescents experienced dental caries in their permanent teeth. The purpose of this review was to summarize the available clinical evidence regarding the effect of dental sealants for the prevention and management of pit-and-fissure occlusal carious lesions in primary and permanent molars, compared with a control without sealants, with fluoride varnishes, or with other head-to head comparisons. Type of Studies Reviewed: The authors included parallel and split-mouth randomized controlled trials that included at least 2 years of follow-up, which they identified using MEDLINE (via PubMed), Embase, LILACS, the Cochrane Central Register of Controlled Trials, and registers of ongoing trials. Pairs of reviewers independently conducted the selection of studies, data extraction, risk of bias assessments, and quality of the evidence assessments by using the Grading of Recommendations Assessment, Development and Evaluation approach. Results: Of 2,869 records screened, the authors determined that 24 articles (representing 23 studies) proved eligible. Moderate-quality evidence suggested that participants who received sealants had a reduced risk of developing carious lesions in occlusal surfaces of permanent molars compared with those who did not receive sealants (odds ratio [OR], 0.15; 95% confidence interval [Cl] 0.08-027) after 7 or more years of follow-up. When the authors compared studies whose investigators had compared sealants with fluoride varnishes, they found that sealants reduced the incidence of carious lesions after 7 or more years of follow-up (OR, 0.19; 95% Cl, 0.07-0.51); however, this finding was supported by low-quality evidence. On the basis of the evidence, the authors could not provide a hierarchy of effectiveness among the studies whose investigators had conducted head-to-head comparisons. The investigators of 2 trials provided information about adverse events, but they did not report any adverse events. Conclusions and Practical Implications: Available evidence suggests that sealants are effective and safe to prevent or arrest the progression of noncavitated carious lesions compared with a control without sealants or fluoride varnishes. Further research is needed to provide information about the relative merits of the different types of sealant materials. C1 [Wright, John T.] Univ N Carolina, Sch Dent, Dept Pediat Dent, Chapel Hill, NC USA. [Tampi, Malavika P.] Amer Dent Assoc, Inst Sci, Ctr Evidence Based Dent, Chicago, IL 60611 USA. [Graham, Laurel] Amer Acad Pediat Dent, Chicago, IL USA. [Estrich, Cameron] Amer Dent Assoc, Inst Sci, Sci Informat, Chicago, IL USA. [Crall, James J.] Univ Calif Los Angeles, Sch Dent, Div Publ Hlth & Community Dent, Los Angeles, CA 90024 USA. [Fontana, Margherita] Univ Michigan, Sch Dent, Dept Cariol Restorat Sci & Endodont, Ann Arbor, MI 48109 USA. [Gillette, E. Jane] Univ Washington, Sch Dent, Seattle, WA 98195 USA. [Novy, Brian B.] DentaQuest Inst, Westborough, MA USA. [Dhar, Vineet] Univ Maryland, Sch Dent, Div Pediat Dent, Baltimore, MD 21201 USA. [Donly, Kevin] Univ Texas San Antonio, Hlth Sci Ctr, Dept Dev Dent, Sch Dent, San Antonio, TX USA. [Hewlett, Edmond R.] Univ Calif Los Angeles, Sch Dent, Sect Restorat Dent, Los Angeles, CA 90024 USA. [Quinonez, Rocio B.] Univ N Carolina, Dept Pediat Dent & Pediat, Sch Dent, Chapel Hill, NC USA. [Chaffin, Jeffrey] Delta Dent Iowa, Johnston, IA USA. [Chaffin, Jeffrey] AT Still Univ, Coll Grad Hlth Studies, Mesa, AZ USA. [Chaffin, Jeffrey] Assoc State & Territorial Dent Directors, Reno, NV USA. [Crespin, Matt] Childrens Hosp Wisconsin, Childrens Hlth Alliance Wisconsin, Milwaukee, WI USA. [Iafolla, Timothy] Natl Inst Dent & Craniofacial Res, Program Anal & Reports Branch, NIH, Bethesda, MD USA. [Siegal, Mark D.] Ohio State Univ, Coll Dent, Columbus, OH 43210 USA. [Siegal, Mark D.] Amer Assoc Publ Hlth Dent, Springfield, IL USA. [Carrasco-Labra, Alonso] Amer Dent Assoc, Ctr Evidence Based Dent, Chicago, IL USA. [Carrasco-Labra, Alonso] Univ Chile, Evidence Based Dent Unit, Fac Dent, Santiago, Chile. [Carrasco-Labra, Alonso] Univ Chile, Dept Oral & Maxillofacial Surg, Fac Dent, Santiago, Chile. [Carrasco-Labra, Alonso] McMaster Univ, Dept Clin Epidemiol & Biostat, Hamilton, ON, Canada. RP Tampi, MP (reprint author), Amer Dent Assoc, Inst Sci, Ctr Evidence Based Dent, Chicago, IL 60611 USA. EM tampim@ada.org FU National Institute of Dental; Craniofacial Research; Delta Dental; Ivoclar Vivadent; Children's Dental Health Project; Delta Dental of Wisconsin; Washington Dental Services Foundation; DentaQuest Foundation; Health Resource and Services Administration Maternal and Child Health Bureau; Healthier Wisconsin Partnership Program FX Dr. Fontana is a consultant for the American Dental Association Council on Scientific Affairs. In the past, she has received funds from the National Institute of Dental and Craniofacial Research, Delta Dental, and Ivoclar Vivadent to conduct research focused on dental sealants. These grants ended before her engagement with the work involved in this manuscript. Dr. Novy's previous continuing education lecture honoraria were provided by the following manufacturers of sealant materials: GC America, SDI, and Shofu, and his previous continuing education lecture honoraria were provided by the following dental manufacturers: Air Techniques, CariFree, GlaxoSmithKline, Ivoclar, Phillips, Solutionreach, Triodent, and Xlear. Mr. Crespin is the chair of the Children's Dental Health Project's sealant work group and has received funding from Children's Dental Health Project, Delta Dental of Wisconsin, Washington Dental Services Foundation, DentaQuest Foundation, Health Resource and Services Administration Maternal and Child Health Bureau, and the Healthier Wisconsin Partnership Program. Mr. Crespin serves on the board of trustees of the American Dental Hygienists' Association. None of the other authors reported any disclosures. NR 44 TC 1 Z9 1 U1 3 U2 3 PU AMER ACAD PEDIATRIC DENTISTRY PI CHICAGO PA 211 E CHICAGO AVENUE SUITE 1036, CHICAGO, IL 60611-2616 USA SN 0164-1263 EI 1942-5473 J9 PEDIATR DENT JI Pediatr. Dent. PD JUL-AUG PY 2016 VL 38 IS 4 BP 282 EP 294 DI 10.1016/j.adaj.2016.06.003 PG 13 WC Dentistry, Oral Surgery & Medicine; Pediatrics SC Dentistry, Oral Surgery & Medicine; Pediatrics GA DT4KJ UT WOS:000381448300003 PM 27557916 ER PT J AU Cabral, WA Ishikawa, M Garten, M Makareeva, EN Sargent, BM Weis, M Barnes, AM Webb, EA Shaw, NJ Ala-Kokko, L Lacbawan, FL Hogler, W Leikin, S Blank, PS Zimmerberg, J Eyre, DR Yamada, Y Marini, JC AF Cabral, Wayne A. Ishikawa, Masaki Garten, Matthias Makareeva, Elena N. Sargent, Brandi M. Weis, MaryAnn Barnes, Aileen M. Webb, Emma A. Shaw, Nicholas J. Ala-Kokko, Leena Lacbawan, Felicitas L. Hogler, Wolfgang Leikin, Sergey Blank, Paul S. Zimmerberg, Joshua Eyre, David R. Yamada, Yoshihiko Marini, Joan C. TI Absence of the ER Cation Channel TMEM38B/TRIC-B Disrupts Intracellular Calcium Homeostasis and Dysregulates Collagen Synthesis in Recessive Osteogenesis Imperfecta SO PLOS GENETICS LA English DT Article ID ENDOPLASMIC-RETICULUM STRESS; UNFOLDED-PROTEIN RESPONSE; I COLLAGEN; CYCLOPHILIN-B; PROLYL 3-HYDROXYLATION; DELETION MUTATION; CHAIN ASSOCIATION; LYSYL HYDROXYLASE; BONE-COLLAGEN; ALPHA 2(I) AB Recessive osteogenesis imperfecta (OI) is caused by defects in proteins involved in post-translational interactions with type I collagen. Recently, a novel form of moderately severe OI caused by null mutations in TMEM38B was identified. TMEM38B encodes the ER membrane monovalent cation channel, TRIC-B, proposed to counterbalance IP3R-mediated Ca2+ release from intracellular stores. The molecular mechanisms by which TMEM38B mutations cause OI are unknown. We identified 3 probands with recessive defects in TMEM38B. TRIC-B protein is undetectable in proband fibroblasts and osteoblasts, although reduced TMEM38B transcripts are present. TRIC-B deficiency causes impaired release of ER luminal Ca2+, associated with deficient store-operated calcium entry, although SERCA and IP3R have normal stability. Notably, steady state ER Ca2+ is unchanged in TRIC-B deficiency, supporting a role for TRIC-B in the kinetics of ER calcium depletion and recovery. The disturbed Ca2+ flux causes ER stress and increased BiP, and dysregulates synthesis of proband type I collagen at multiple steps. Collagen helical lysine hydroxylation is reduced, while telopeptide hydroxylation is increased, despite increased LH1 and decreased Ca2+-dependent FKBP65, respectively. Although PDI levels are maintained, procollagen chain assembly is delayed in proband cells. The resulting misfolded collagen is substantially retained in TRIC-B null cells, consistent with a 50-70% reduction in secreted collagen. Lower-stability forms of collagen that elude proteasomal degradation are not incorporated into extracellular matrix, which contains only normal stability collagen, resulting in matrix insufficiency. These data support a role for TRIC-B in intracellular Ca2+ homeostasis, and demonstrate that absence of TMEM38B causes OI by dysregulation of calcium flux kinetics in the ER, impacting multiple collagen-specific chaperones and modifying enzymes. C1 [Cabral, Wayne A.; Sargent, Brandi M.; Barnes, Aileen M.; Marini, Joan C.] NICHD, Sect Heritable Disorders Bone & Extracellular Mat, NIH, Bethesda, MD USA. [Ishikawa, Masaki; Yamada, Yoshihiko] NIDCR, Mol Biol Sect, NIH, Bethesda, MD USA. [Garten, Matthias; Blank, Paul S.; Zimmerberg, Joshua] NICHD, Sect Integrat Biophys, NIH, Bethesda, MD USA. [Makareeva, Elena N.; Leikin, Sergey] NICHD, Sect Phys Biochem, NIH, Bethesda, MD USA. [Weis, MaryAnn; Eyre, David R.] Univ Washington, Dept Orthopaed & Sports Med, Seattle, WA 98195 USA. [Webb, Emma A.; Hogler, Wolfgang] Univ Birmingham, Sch Clin & Expt Med, Inst Biomed Res, Birmingham, W Midlands, England. [Webb, Emma A.; Shaw, Nicholas J.; Hogler, Wolfgang] Birmingham Childrens Hosp, Dept Endocrinol & Diabet, Birmingham, W Midlands, England. [Ala-Kokko, Leena] Connect Tissue Gene Tests, Allentown, PA USA. [Lacbawan, Felicitas L.] Childrens Natl Med Ctr, Dept Med Genet, Washington, DC 20010 USA. RP Marini, JC (reprint author), NICHD, Sect Heritable Disorders Bone & Extracellular Mat, NIH, Bethesda, MD USA. EM oidoc@helix.nih.gov RI Leikin, Sergey/A-5518-2008; OI Leikin, Sergey/0000-0001-7095-0739; Garten, Matthias/0000-0002-8660-1039 FU NIH [AR037318, HD070394]; NIH FX This study was supported by NIH grants AR037318 (NIAMS) and HD070394 (NICHD) to DRE, and NIH intramural funds to YY (NIDCR), SL (NICHD), JZ (NICHD) and JCM (NICHD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 69 TC 3 Z9 3 U1 4 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD JUL PY 2016 VL 12 IS 7 AR e1006156 DI 10.1371/journal.pgen.1006156 PG 27 WC Genetics & Heredity SC Genetics & Heredity GA DS8RI UT WOS:000381050100024 PM 27441836 ER PT J AU De, S Mitra, A Cheng, YZ Pfeifer, K Kassis, JA AF De, Sandip Mitra, Apratim Cheng, Yuzhong Pfeifer, Karl Kassis, Judith A. TI Formation of a Polycomb-Domain in the Absence of Strong Polycomb Response Elements SO PLOS GENETICS LA English DT Article ID DROSOPHILA ENGRAILED GENE; IN-SITU DISSECTION; BITHORAX COMPLEX; REGULATORY SEQUENCES; MELANOGASTER; PROTEINS; DNA; REPRESSION; BINDING; EXPRESSION AB Polycomb group response elements (PREs) in Drosophila are DNA-elements that recruit Polycomb proteins (PcG) to chromatin and regulate gene expression. PREs are easily recognizable in the Drosophila genome as strong peaks of PcG-protein binding over discrete DNA fragments; many small but statistically significant PcG peaks are also observed in PcG domains. Surprisingly, in vivo deletion of the four characterized strong PREs from the PcG regulated invected-engrailed (inv-en) gene complex did not disrupt the formation of the H3K27me3 domain and did not affect inv-en expression in embryos or larvae suggesting the presence of redundant PcG recruitment mechanism. Further, the 3D-structure of the inv-en domain was only minimally altered by the deletion of the strong PREs. A reporter construct containing a 7.5kb en fragment that contains three weak peaks but no large PcG peaks forms an H3K27me3 domain and is PcG-regulated. Our data suggests a model for the recruitment of PcG-complexes to Drosophila genes via interactions with multiple, weak PREs spread throughout an H3K27me3 domain. C1 [De, Sandip; Mitra, Apratim; Cheng, Yuzhong; Pfeifer, Karl; Kassis, Judith A.] Eunice Kennedy Shriver Natl Inst Child Hlth Human, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. RP Kassis, JA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth Human, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. EM jkassis@mail.nih.gov OI Pfeifer, Karl/0000-0002-0254-682X FU Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This work was supported by the Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, 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 71 TC 0 Z9 0 U1 7 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD JUL PY 2016 VL 12 IS 7 AR e1006200 DI 10.1371/journal.pgen.1006200 PG 22 WC Genetics & Heredity SC Genetics & Heredity GA DS8RI UT WOS:000381050100055 PM 27466807 ER PT J AU Xiao, Y Thoresen, DT Miao, LL Williams, JS Wang, CC Atit, RP Wong, SY Brownell, I AF Xiao, Ying Thoresen, Daniel T. Miao, Lingling Williams, Jonathan S. Wang, Chaochen Atit, Radhika P. Wong, Sunny Y. Brownell, Isaac TI A Cascade of Wnt, Eda, and Shh Signaling Is Essential for Touch Dome Merkel Cell Development SO PLOS GENETICS LA English DT Article ID HAIR FOLLICLE MORPHOGENESIS; EPIDERMAL STEM-CELLS; SONIC-HEDGEHOG; EMBRYONIC-DEVELOPMENT; BETA-CATENIN; DORSAL SKIN; MOUSE SKIN; MICE; EXPRESSION; ROLES AB The Sonic hedgehog (Shh) signaling pathway regulates developmental, homeostatic, and repair processes throughout the body. In the skin, touch domes develop in tandem with primary hair follicles and contain sensory Merkel cells. The developmental signaling requirements for touch dome specification are largely unknown. We found dermal Wnt signaling and subsequent epidermal Eda/Edar signaling promoted Merkel cell morphogenesis by inducing Shh expression in early follicles. Lineage-specific gene deletions revealed intraepithelial Shh signaling was necessary for Merkel cell specification. Additionally, a Shh signaling agonist was sufficient to rescue Merkel cell differentiation in Edar-deficient skin. Moreover, Merkel cells formed in Fgf20 mutant skin where primary hair formation was defective but Shh production was preserved. Although developmentally associated with hair follicles, fate mapping demonstrated Merkel cells primarily originated outside the hair follicle lineage. These findings suggest that touch dome development requires Wnt-dependent mesenchymal signals to establish reciprocal signaling within the developing ectoderm, including Eda signaling to primary hair placodes and ultimately Shh signaling from primary follicles to extrafollicular Merkel cell progenitors. Shh signaling often demonstrates pleiotropic effects within a structure over time. In postnatal skin, Shh is known to regulate the self-renewal, but not the differentiation, of touch dome stem cells. Our findings relate the varied effects of Shh in the touch dome to the ligand source, with locally produced Shh acting as a morphogen essential for lineage specification during development and neural Shh regulating postnatal touch dome stem cell maintenance. C1 [Xiao, Ying; Thoresen, Daniel T.; Miao, Lingling; Williams, Jonathan S.; Brownell, Isaac] Natl Canc Inst, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD USA. [Wang, Chaochen] NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. [Atit, Radhika P.] Case Western Reserve Univ, Dept Biol, Cleveland, OH 44106 USA. [Wong, Sunny Y.] Univ Michigan, Dept Dermatol, Ann Arbor, MI 48109 USA. [Wong, Sunny Y.] Univ Michigan, Dept Cell & Dev Biol, Ann Arbor, MI 48109 USA. RP Brownell, I (reprint author), Natl Canc Inst, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD USA. EM isaac.brownell@nih.gov OI Brownell, Isaac/0000-0002-0090-9914 FU NIH Intramural Research Program, CCR, NCI [ZIA BC011393]; NIH-NIDCR [R01DE01870]; NIH-NIAMS [R01AR065409] FX This work was supported by the NIH Intramural Research Program, CCR, NCI. Award number ZIA BC011393 to IB. https://ccr.cancer.gov/. NIH-NIDCR award number R01DE01870 to RPA. http://www.nidcr.nih.gov/. NIH-NIAMS award number R01AR065409 to SYW. http://www.niams.nih.gov/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 0 Z9 0 U1 2 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD JUL PY 2016 VL 12 IS 7 AR e1006150 DI 10.1371/journal.pgen.1006150 PG 19 WC Genetics & Heredity SC Genetics & Heredity GA DS8RI UT WOS:000381050100019 PM 27414798 ER PT J AU Zhao, XN Lokanga, R Allette, K Gazy, I Wu, D Usdin, K AF Zhao, Xiao-Nan Lokanga, Rachel Allette, Kimaada Gazy, Inbal Wu, Di Usdin, Karen TI A MutS beta-Dependent Contribution of MutS alpha to Repeat Expansions in Fragile X Premutation Mice? SO PLOS GENETICS LA English DT Article ID MISMATCH-REPAIR PROTEINS; KNOCK-IN MICE; MOUSE MODEL; TRINUCLEOTIDE REPEATS; SOMATIC EXPANSION; TRIPLET-REPEAT; DNA-REPAIR; CANCER SUSCEPTIBILITY; HAIRPIN STRUCTURES; TRANSGENIC MICE AB The fragile X-related disorders result from expansion of a CGG/CCG microsatellite in the 5' UTR of the FMR1 gene. We have previously demonstrated that the MSH2/MSH3 complex, MutS beta, that is important for mismatch repair, is essential for almost all expansions in a mouse model of these disorders. Here we show that the MSH2/MSH6 complex, MutS alpha also contributes to the production of both germ line and somatic expansions as evidenced by the reduction in the number of expansions observed in Msh6(-/-) mice. This effect is not mediated via an indirect effect of the loss of MSH6 on the level of MSH3. However, since MutS beta is required for 98% of germ line expansions and almost all somatic ones, MutS alpha is apparently not able to efficiently substitute for MutS beta in the expansion process. Using purified human proteins we demonstrate that MutS alpha, like MutS beta, binds to substrates with loop-outs of the repeats and increases the thermal stability of the structures that they form. We also show that MutS alpha facilitates binding of MutS beta to these loop-outs. These data suggest possible models for the contribution of MutS alpha to repeat expansion. In addition, we show that unlike MutS beta, MutS alpha may also act to protect against repeat contractions in the Fmr1 gene. C1 [Zhao, Xiao-Nan; Lokanga, Rachel; Allette, Kimaada; Gazy, Inbal; Usdin, Karen] NIDDKD, Sect Gene Struct & Dis, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. [Lokanga, Rachel] Univ Cape Town, Sch Med, Div Med Biochem, Cape Town, South Africa. [Wu, Di] NIDDKD, Sect Phys Biochem, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. [Allette, Kimaada] Icahn Sch Med Mt Sinai, Icahn Inst, New York, NY 10029 USA. [Allette, Kimaada] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Wu, Di] Florida State Univ, Inst Mol Biophys, Tallahassee, FL 32306 USA. RP Usdin, K (reprint author), NIDDKD, Sect Gene Struct & Dis, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. EM ku@helix.nih.gov RI Zhao, Xiaonan/S-3139-2016 FU National Institute of Diabetes, Digestive and Kidney Diseases [DK057808-07] FX The work described in this manuscript was funded by a grant from the Intramural Program of the National Institute of Diabetes, Digestive and Kidney Diseases to KU (Grant number DK057808-07). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 2 Z9 2 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD JUL PY 2016 VL 12 IS 7 AR e1006190 DI 10.1371/journal.pgen.1006190 PG 19 WC Genetics & Heredity SC Genetics & Heredity GA DS8RI UT WOS:000381050100049 PM 27427765 ER PT J AU Liu, H Ning, J Qin, J Shen, Y AF Liu, Hao Ning, Jing Qin, Jing Shen, Yu TI SEMIPARAMETRIC MAXIMUM LIKELIHOOD INFERENCE FOR TRUNCATED OR BIASED-SAMPLING DATA SO STATISTICA SINICA LA English DT Article DE Biased sampling; length bias data; truncated and right censored survival data ID PREVALENT COHORT DATA; SELECTION BIAS; SURVIVAL-DATA; NONPARAMETRIC-ESTIMATION; REGRESSION-ANALYSIS; HAZARDS REGRESSION; STATISTICAL-MODELS; ASYMPTOTIC THEORY; FRAILTY MODEL; CENSORED-DATA AB Sample selection bias has long been recognized in many fields including clinical trials, epidemiology studies, genome-wide association studies, and wildlife management. This paper investigates the maximum likelihood estimation for censored survival data with selection bias under the Cox regression models where the selection process is modeled parametrically. A novel expectation-maximization algorithm is proposed and shown to have considerable computational advantages. Rigorous asymptotic properties of the estimator are established. Extensive simulation studies and a data analysis are conducted to investigate the performance of the proposed estimation procedure. C1 [Liu, Hao] Baylor Coll Med, Div Biostat, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Ning, Jing; Shen, Yu] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. [Qin, Jing] NIAID, Biostat Res Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Liu, H (reprint author), Baylor Coll Med, Div Biostat, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. EM haol@bcm.edu; jning@mdanderson.org; jingqin@niaid.nih.gov; yshen@mdanderson.org FU Seniors' Independence Research Program, through the National Health Research and Development Program of Health Canada [6606-3954-MC(S)]; Pfizer Canada Incorporated through the Medical Research Council/Pharmaceutical Manufacturers Association of Canada Health Activity Program, NHRDP [6603-1417-302(R)]; Bayer Incorporated; British Columbia Health Research Foundation Projects [38 (93-2), 34 (96-1)]; National Institutes of Health FX We thank Professor Masoud Asgharian and the investigators of the Canadian Study of Health and Aging (CHSA) for providing us with the dementia data, which were collected as part of the CHSA, funded by the Seniors' Independence Research Program, through the National Health Research and Development Program of Health Canada (Project no.6606-3954-MC(S)). Additional funding was provided by Pfizer Canada Incorporated through the Medical Research Council/Pharmaceutical Manufacturers Association of Canada Health Activity Program, NHRDP Project 6603-1417-302(R), Bayer Incorporated, and the British Columbia Health Research Foundation Projects 38 (93-2) and 34 (96-1). The study was coordinated through the University of Ottawa and the Division of Aging and Seniors, Health Canada. This work in this paper was supported in part by the National Institutes of Health. NR 47 TC 1 Z9 1 U1 0 U2 0 PU STATISTICA SINICA PI TAIPEI PA C/O DR H C HO, INST STATISTICAL SCIENCE, ACADEMIA SINICA, TAIPEI 115, TAIWAN SN 1017-0405 EI 1996-8507 J9 STAT SINICA JI Stat. Sin. PD JUL PY 2016 VL 26 IS 3 BP 1087 EP 1115 DI 10.5705/ss.2014.094 PG 29 WC Statistics & Probability SC Mathematics GA DT6JU UT WOS:000381591300010 ER PT J AU Jiang, SZ Eiden, LE AF Jiang, Sunny Zhihong Eiden, Lee E. TI Activation of the HPA axis and depression of feeding behavior induced by restraint stress are separately regulated by PACAPergic neurotransmission in the mouse SO STRESS-THE INTERNATIONAL JOURNAL ON THE BIOLOGY OF STRESS LA English DT Article; Proceedings Paper CT 11th International Symposium on Catecholamines and Other Neurotransmitters in Stress CY JUN, 2015 CL SLOVAKIA DE Acute psychogenic stress; chronic psychogenic stress; corticosterone; HPA axis; hypophagia; pituitary adenylate cyclase-activating polypeptide; prolonged psychogenic stress; restraint stress ID HYPOTHALAMIC PARAVENTRICULAR NUCLEUS; STRIA TERMINALIS BNST; PITUITARY-ADRENOCORTICAL AXIS; CENTRAL-NERVOUS-SYSTEM; HORMONE CRH GENE; POLYPEPTIDE PACAP; BED NUCLEUS; EMOTIONAL-STRESS; PEPTIDE PACAP; BRAIN-STEM AB We measured serum CORT elevation in wild-type and PACAP-deficient C57BL/6N male mice after acute (1h) or prolonged (2-3h) daily restraint stress for 7 d. The PACAP dependence of CORT elevation was compared to that of stress-induced hypophagia. Daily restraint induced unhabituated peak CORT elevation, and hypophagia/weight loss, of similar magnitude for 1, 2, and 3h of daily restraint, in wild-type mice. Peak CORT elevation, and hypophagia, were both attenuated in PACAP-deficient mice for 2 and 3h daily restraint. Hypophagia induced by 1-h daily restraint was also greatly reduced in PACAP-deficient mice, however CORT elevation, both peak and during recovery from stress, was unaffected. Thus, hypothalamic PACAPergic neurotransmission appears to affect CRH gene transcription and peptide production, but not CRH release, in response to psychogenic stress. A single exposure to restraint sufficed to trigger hypophagia over the following 24h. PACAP deficiency attenuated HPA axis response (CORT elevation) to prolonged (3h) but not acute (1h) single-exposure restraint stress, while hypophagia induced by either a single 1h or a single 3h restraint were both abolished in PACAP-deficient mice. These results suggest that PACAP's actions to promote suppression of food intake following an episode of psychogenic stress is unrelated to the release of CRH into the portal circulation to activate the pituitary-adrenal axis. Furthermore, demonstration of suppressed food intake after a single 1-h restraint stress provides a convenient assay for investigating the location of the synapses and circuits mediating the effects of PACAP on the behavioral sequelae of psychogenic stress. C1 [Jiang, Sunny Zhihong; Eiden, Lee E.] NIMH, Sect Mol Neurosci, Bldg 49,Room 5A-38,9000 Rockville Pike, Bethesda, MD 20892 USA. RP Eiden, LE (reprint author), NIMH, Sect Mol Neurosci, Bldg 49,Room 5A-38,9000 Rockville Pike, Bethesda, MD 20892 USA. EM eidenl@mail.nih.gov FU NIMH NIH HHS [Z01 MH002386] NR 42 TC 1 Z9 1 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1025-3890 EI 1607-8888 J9 STRESS JI Stress PD JUL PY 2016 VL 19 IS 4 BP 374 EP 382 DI 10.1080/10253890.2016.1174851 PG 9 WC Behavioral Sciences; Endocrinology & Metabolism; Neurosciences SC Behavioral Sciences; Endocrinology & Metabolism; Neurosciences & Neurology GA DU9EF UT WOS:000382518400005 PM 27228140 ER PT J AU Krizanova, O Babula, P Pacak, K AF Krizanova, O. Babula, P. Pacak, K. TI Stress, catecholaminergic system and cancer SO STRESS-THE INTERNATIONAL JOURNAL ON THE BIOLOGY OF STRESS LA English DT Article; Proceedings Paper CT 11th International Symposium on Catecholamines and Other Neurotransmitters in Stress CY JUN, 2015 CL SLOVAKIA DE Adrenergic receptors; -blockers; catecholamines; dopamine; epinephrine; norepinephrine; stress; tumor ID SQUAMOUS-CELL CARCINOMA; REPEATED IMMOBILIZATION STRESS; ENDOTHELIAL GROWTH-FACTOR; POPULATION-BASED COHORT; OVARIAN-CARCINOMA; BREAST-CANCER; COLORECTAL-CANCER; GASTRIC-CANCER; BETA-BLOCKERS; TUMOR-GROWTH AB Stress as a modern civilization factor significantly affects our lives. While acute stress might have a positive effect on the organism, chronic stress is usually detrimental and might lead to serious health complications. It is known that stress induced by the physical environment (temperature-induced cold stress) can significantly impair the efficacy of cytotoxic chemotherapies and the anti-tumor immune response. On the other hand, epidemiological evidence has shown that patients taking drugs known as -adrenergic antagonists (-blockers), which are commonly prescribed to treat arrhythmia, hypertension, and anxiety, have significantly lower rates of several cancers. In this review, we summarize the current knowledge about catecholamines as important stress hormones in tumorigenesis and discuss the use of -blockers as the potential therapeutic agents. C1 [Krizanova, O.] Slovak Acad Sci, Inst Clin & Translat Res, Biomed Res Ctr, Dubravska Cesta 9, Bratislava 84505, Slovakia. [Krizanova, O.; Babula, P.] Masaryk Univ, Dept Physiol, Fac Med, Brno, Czech Republic. [Pacak, K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Dev Endocrinol & Tumor Genet Affin Grp, Sect Med Neuroendocrinol, NIH, Bethesda, MD USA. RP Krizanova, O (reprint author), Slovak Acad Sci, Inst Clin & Translat Res, Biomed Res Ctr, Dubravska Cesta 9, Bratislava 84505, Slovakia. EM olga.krizanova@savba.sk NR 112 TC 2 Z9 2 U1 11 U2 11 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1025-3890 EI 1607-8888 J9 STRESS JI Stress PD JUL PY 2016 VL 19 IS 4 BP 419 EP 428 DI 10.1080/10253890.2016.1203415 PG 10 WC Behavioral Sciences; Endocrinology & Metabolism; Neurosciences SC Behavioral Sciences; Endocrinology & Metabolism; Neurosciences & Neurology GA DU9EF UT WOS:000382518400010 PM 27398826 ER PT J AU Stephens, ML Betts, K Beck, NB Cogliano, V Dickersin, K Fitzpatrick, S Freeman, J Gray, G Hartung, T McPartland, J Rooney, AA Scherer, RW Verloo, D Hoffmann, S AF Stephens, Martin L. Betts, Kellyn Beck, Nancy B. Cogliano, Vincent Dickersin, Kay Fitzpatrick, Suzanne Freeman, James Gray, George Hartung, Thomas McPartland, Jennifer Rooney, Andrew A. Scherer, Roberta W. Verloo, Didier Hoffmann, Sebastian TI The Emergence of Systematic Review in Toxicology SO TOXICOLOGICAL SCIENCES LA English DT Review DE systematic review; risk of bias; data integration ID EVIDENCE-BASED MEDICINE; ENVIRONMENTAL-HEALTH SCIENCE; FETAL-GROWTH; EPIDEMIOLOGIC EVIDENCE; ARSENIC EXPOSURE; QUALITY; INTEGRATION; VALIDATION AB The Evidence-based Toxicology Collaboration hosted a workshop on "The Emergence of Systematic Review and Related Evidence-based Approaches in Toxicology," on November 21, 2014 in Baltimore, Maryland. The workshop featured speakers from agencies and organizations applying systematic review approaches to questions in toxicology, speakers with experience in conducting systematic reviews in medicine and healthcare, and stakeholders in industry, government, academia, and non-governmental organizations. Based on the workshop presentations and discussion, here we address the state of systematic review methods in toxicology, historical antecedents in both medicine and toxicology, challenges to the translation of systematic review from medicine to toxicology, and thoughts on the way forward. We conclude with a recommendation that as various agencies and organizations adapt systematic review methods, they continue to work together to ensure that there is a harmonized process for how the basic elements of systematic review methods are applied in toxicology. C1 [Stephens, Martin L.; Hartung, Thomas] Johns Hopkins Ctr Alternat Anim Testing, Baltimore, MD USA. [Beck, Nancy B.] Amer Chem Council, Washington, DC USA. [Cogliano, Vincent] US EPA, Arlington, VA USA. [Dickersin, Kay; Scherer, Roberta W.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Fitzpatrick, Suzanne] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Freeman, James] ExxonMobil Biomed Sci, Annandale, NJ USA. [Gray, George] George Washington Univ, Milken Inst Sch Publ Hlth, Washington, DC USA. [Hartung, Thomas] Univ Konstanz, CAAT Europe, Constance, Germany. [McPartland, Jennifer] Environm Def Fund, Washington, DC USA. [Rooney, Andrew A.] NIEHS, Off Hlth Assessment & Translat, Div Natl Toxicol Program, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Verloo, Didier] European Food Safety Author, I-43126 Parma, Italy. [Hoffmann, Sebastian] Seh Consulting Serv, D-33098 Paderborn, Germany. RP Stephens, ML (reprint author), Johns Hopkins Ctr Alternat Anim Testing, Baltimore, MD USA. EM msteph14@jhu.edu FU ExxonMobil Foundation FX This work was supported by funding from an anonymous private charitable foundation and the ExxonMobil Foundation to the Johns Hopkins Center for Alternatives to Animal Testing (CAAT). CAAT serves as the secretariat for the Evidence-based Toxicology Collaboration, which hosted the workshop on which this article is based. Only those authors working at or for CAAT (K.B., T.H., S.H., and M.L.S.) received compensation from these sources via CAAT for their participation in the workshop or their preparation of this article. NR 44 TC 4 Z9 4 U1 4 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD JUL PY 2016 VL 152 IS 1 BP 10 EP 16 DI 10.1093/toxsci/kfw059 PG 7 WC Toxicology SC Toxicology GA DT2AA UT WOS:000381282000002 PM 27208075 ER PT J AU El-Masri, H Kleinstreuer, N Hines, RN Adams, L Tal, T Isaacs, K Wetmore, BA Tan, YM AF El-Masri, Hisham Kleinstreuer, Nicole Hines, Ronald N. Adams, Linda Tal, Tamara Isaacs, Kristin Wetmore, Barbara A. Tan, Yu-Mei TI Integration of Life-Stage Physiologically Based Pharmacokinetic Models with Adverse Outcome Pathways and Environmental Exposure Models to Screen for Environmental Hazards SO TOXICOLOGICAL SCIENCES LA English DT Article DE PBPK; AOPs; life-stage; developmental toxicology; environmental toxicology ID BLOOD-FLOW; IN-VITRO; PBPK MODELS; HUMAN FETUS; DEVELOPMENTAL EXPRESSION; TOXCAST PROGRAM; CARDIAC-OUTPUT; DUCTUS VENOSUS; TOXICITY; DOSIMETRY AB A computational framework was developed to assist in screening and prioritizing chemicals based on their dosimetry, toxicity, and potential exposures. The overall strategy started with contextualizing chemical activity observed in high-throughput toxicity screening (HTS) by mapping these assays to biological events described in Adverse Outcome Pathways (AOPs). Next, in vitro to in vivo (IVIVE) extrapolation was used to convert an in vitro dose to an external exposure level, which was compared with potential exposure levels to derive an AOP-based margins of exposure (MOE). In this study, the framework was applied to estimate MOEs for chemicals that can potentially cause developmental toxicity following a putative AOP for fetal vasculogenesis/angiogenesis. A physiologically based pharmacokinetic (PBPK) model was developed to describe chemical disposition during pregnancy, fetal, neonatal, and infant to adulthood stages. Using this life-stage PBPK model, maternal exposures were estimated that would yield fetal blood levels equivalent to the chemical concentration that altered in vitro activity of selected HTS assays related to the most sensitive vasculogenesis/angiogenesis putative AOP. The resulting maternal exposure estimates were then compared with potential exposure levels using literature data or exposure models to derive AOP-based MOEs. C1 [El-Masri, Hisham; Hines, Ronald N.; Adams, Linda; Tal, Tamara] US EPA, Natl Human & Environm Effects Res Lab, Off Res & Dev, Res Triangle Pk, NC USA. [Kleinstreuer, Nicole] Natl Inst Environm Hlth Sci, Natl Toxicol Program, Interagency Ctr Evaluat Alternat Toxicol Methods, Res Triangle Pk, NC USA. [Isaacs, Kristin; Tan, Yu-Mei] US EPA, Natl Exposure Res Lab, Off Res & Dev, Res Triangle Pk, NC USA. [Wetmore, Barbara A.] ScitoVation, Res Triangle Pk, NC USA. RP El-Masri, H (reprint author), US EPA, Natl Human & Environm Effects Res Lab, Off Res & Dev, Res Triangle Pk, NC USA. EM el-masri.hisham@epa.gov OI Kleinstreuer, Nicole/0000-0002-7914-3682; Tal, Tamara/0000-0001-8365-9385 NR 46 TC 0 Z9 0 U1 6 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD JUL PY 2016 VL 152 IS 1 BP 230 EP 243 DI 10.1093/toxsci/kfw082 PG 14 WC Toxicology SC Toxicology GA DT2AA UT WOS:000381282000020 PM 27208077 ER PT J AU Balandaram, G Kramer, LR Kang, BH Murray, LA Perdew, GH Gonzalez, FJ Peters, JM AF Balandaram, Gayathri Kramer, Lance R. Kang, Boo-Hyon Murray, Lain A. Perdew, Gary H. Gonzalez, Frank J. Peters, Jeffrey M. TI Ligand activation of peroxisome proliferator-activated receptor-beta/delta suppresses liver tumorigenesis in hepatitis B transgenic mice SO TOXICOLOGY LA English DT Article DE Peroxisome proliferator-activated receptor-beta/delta; Liver cancer; Kupffer cell; Hepatitis B; Inflammation ID HUMAN HEPATOCELLULAR-CARCINOMA; NECROSIS-FACTOR-ALPHA; E-2 SIGNALING PATHWAYS; CHOLINE-DEFICIENT DIET; PPAR-DELTA AGONIST; C VIRUS-INFECTION; GENE-EXPRESSION; CYCLIN D1; MOLECULAR PATHOGENESIS; METHIONINE-DEFICIENT AB Peroxisome proliferator-activated receptor-beta/delta (PPAR beta/delta) inhibits steatosis and inflammation, known risk factors for liver cancer. In this study, the effect of ligand activation of PPAR beta/delta in modulating liver tumorigenesis in transgenic hepatitis B virus (HBV) mice was examined. Activation of PPAR beta/delta in HBV mice reduced steatosis, the average number of liver foci, and tumor multiplicity. Reduced expression of hepatic CYCLIN D1 and c-MYC, tumor necrosis factor alpha (Tnfa) mRNA, serum levels of alanine aminotransaminase, and an increase in apoptotic signaling was also observed following ligand activation of PPAR beta/delta in HBV mice compared to controls. Inhibition of Tnfa mRNA expression was not observed in wild-type hepatocytes. Ligand activation of PPAR beta/delta inhibited lipopolysaccharide (LPS)-induced mRNA expression of Tnfa in wild-type, but not in Ppar beta/delta-null Kupffer cells. Interestingly, LPS-induced expression of Tnfa mRNA was also inhibited in Kupffer cells from a transgenic mouse line that expressed a DNA binding mutant form of PPAR beta/delta compared to controls. Combined, these results suggest that ligand activation of PPAR beta/delta attenuates hepatic tumorigenesis in HBV transgenic mice by inhibiting steatosis and cell proliferation, enhancing hepatocyte apoptosis, and modulating anti-inflammatory activity in Kupffer cells. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Balandaram, Gayathri; Kramer, Lance R.; Murray, Lain A.; Perdew, Gary H.; Peters, Jeffrey M.] Penn State Univ, Dept Vet & Biomed Sci, 312 Life Sci Bldg, University Pk, PA 16802 USA. [Balandaram, Gayathri; Kramer, Lance R.; Murray, Lain A.; Perdew, Gary H.; Peters, Jeffrey M.] Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, 312 Life Sci Bldg, University Pk, PA 16802 USA. [Kang, Boo-Hyon] Chemon Nonclin Res Inst, 240 Nampyeong Ro, Yongin, Gyeonggi Do, South Korea. [Gonzalez, Frank J.] NCI, Lab Metab, Bethesda, MD 20892 USA. RP Peters, JM (reprint author), Penn State Univ, Dept Vet & Biomed Sci, 312 Life Sci Bldg, University Pk, PA 16802 USA.; Peters, JM (reprint author), Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, 312 Life Sci Bldg, University Pk, PA 16802 USA. EM jmp21@psu.edu FU National Cancer Institute of the National Institutes of Health [CA140369, CA124533] FX The authors gratefully acknowledge Cherie Anderson from the Penn State Transgenic Mouse Facility, University Park, PA. for generating the transgenic Ppar beta/delta DNA binding domain mutant mouse line. Research reported in this publication was supported in part by the National Cancer Institute of the National Institutes of Health under Award Numbers CA140369 and CA124533. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 78 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD JUL 1 PY 2016 VL 363 BP 1 EP 9 DI 10.1016/j.tox.2016.07.010 PG 9 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA DU7PX UT WOS:000382408200001 PM 27427494 ER PT J AU Remy, KE Sun, J Wang, D Welsh, J Solomon, SB Klein, HG Natanson, C Cortes-Puch, I AF Remy, K. E. Sun, J. Wang, D. Welsh, J. Solomon, S. B. Klein, H. G. Natanson, C. Cortes-Puch, I. TI Transfusion of recently donated (fresh) red blood cells (RBCs) does not improve survival in comparison with current practice, while safety of the oldest stored units is yet to be established: a meta-analysis SO VOX SANGUINIS LA English DT Article DE blood safety; clinical trial; quality control; red cell components; transfusion medicine (in general); transfusion therapy ID IN-HOSPITAL MORTALITY; CARDIAC-SURGERY; STORAGE DURATION; CRITICALLY-ILL; PROLONGED STORAGE; RANDOMIZED-TRIAL; AGE; OUTCOMES; TRAUMA; ASSOCIATION AB Background and Objectives Preclinical studies generated the hypothesis that older stored red blood cells (RBCs) can increase transfusion risks. To examine the most updated and complete clinical evidence and compare results between two trial designs, we assessed both observational studies and randomized controlled trials (RCTs) studying the effect of RBC storage age on mortality. Materials and Methods Five databases were searched through December 2014 for studies comparing mortality using transfused RBCs having longer and shorter storage times. Results Analysis of six RCTs found no significant differences in survival comparing current practice (average storage age of 2 to 3 weeks) to transfusion of 1- to 10-day-old RBCs (OR 0.91, 95% CI 0.77-1.07). RBC storage age was lower in RCTs vs. observational studies (P = 0.01). The 31 observational studies found an increased risk of death (OR 1.13, 95% CI 1.03-1.24) (P = 0.01) with increasing age of RBCs, a different mortality effect than RCTs (P = 0.02). Conclusion RCTs established that transfusion of 1- to 10-day-old stored RBCs is not superior to current practice. The apparent discrepancy in mortality between analyses of RCTs and observational studies may in part relate to differences in hypotheses tested and ages of stored RBCs studied. Further trials investigating 1- to 10-day-old stored RBC benefits would seem of lower priority than studies to determine whether 4- to 6-week stored units have safety and efficacy equivalent to the 2- to 3-week-old stored RBCs commonly transfused today. C1 [Remy, K. E.; Sun, J.; Wang, D.; Solomon, S. B.; Natanson, C.; Cortes-Puch, I.] NIH, Dept Crit Care Med, Ctr Clin, 10 Ctr Dr,Room 2C145, Bethesda, MD 20892 USA. [Welsh, J.] NIH, NIH Lib, Bldg 10, Bethesda, MD 20892 USA. [Klein, H. G.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Remy, KE (reprint author), NIH, Dept Crit Care Med, Ctr Clin, 10 Ctr Dr,Room 2C145, Bethesda, MD 20892 USA. EM Kenneth.remy@nih.gov; irene.cortespuch@nih.gov FU NIH FX Intramural sources at NIH. NR 58 TC 8 Z9 8 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0042-9007 EI 1423-0410 J9 VOX SANG JI Vox Sang. PD JUL PY 2016 VL 111 IS 1 BP 43 EP 54 DI 10.1111/vox.12380 PG 12 WC Hematology SC Hematology GA DV2SY UT WOS:000382772900006 PM 26848822 ER PT J AU Di Siena, S Gimmelli, R Nori, SL Barbagallo, F Campolo, F Dolci, S Rossi, P Venneri, MA Giannetta, E Gianfrilli, D Feigenbaum, L Lenzi, A Naro, F Cianflone, E Mancuso, T Torella, D Isidori, AM Pellegrini, M AF Di Siena, S. Gimmelli, R. Nori, S. L. Barbagallo, F. Campolo, F. Dolci, S. Rossi, P. Venneri, M. A. Giannetta, E. Gianfrilli, D. Feigenbaum, L. Lenzi, A. Naro, F. Cianflone, E. Mancuso, T. Torella, D. Isidori, A. M. Pellegrini, M. TI Activated c-Kit receptor in the heart promotes cardiac repair and regeneration after injury SO CELL DEATH & DISEASE LA English DT Article ID STEM-CELL FACTOR; RANDOMIZED PHASE-1 TRIAL; MYOCARDIAL-INFARCTION; C-KIT(+) CELLS; ISCHEMIC CARDIOMYOPATHY; IN-VIVO; W-LOCUS; MUTATIONS; EXPRESSION; KINASE AB The role of endogenous c-Kit receptor activation on cardiac cell homeostasis and repair remains largely unexplored. Transgenic mice carrying an activating point mutation (TgD814Y) in the kinase domain of the c-Kit gene were generated. c-Kit(TgD814Y) receptor was expressed in the heart during embryonic development and postnatal life, in a similar timing and expression pattern to that of the endogenous gene, but not in the hematopoietic compartment allowing the study of a cardiac-specific phenotype. c-Kit(TgD814Y) mutation produced a constitutive active c-Kit receptor in cardiac tissue and cells from transgenic mice as demonstrated by the increased phosphorylation of ERK1/2 and AKT, which are the main downstream molecular effectors of c-Kit receptor signaling. In adult transgenic hearts, cardiac morphology, size and total c-Kit(+) cardiac cell number was not different compared with wt mice. However, when c-Kit(TgD814Y) mice were subjected to transmural necrotic heart damage by cryoinjury (CI), all transgenic survived, compared with half of wt mice. In the sub-acute phase after CI, transgenic and wt mice showed similar heart damage. However, 9 days after CI, transgenic mice exhibited an increased number of c-Kit(+)CD31(+) endothelial progenitor cells surrounding the necrotic area. At later follow-up, a consistent reduction of fibrotic area, increased capillary density and increased cardiomyocyte replenishment rate (as established by BrdU incorporation) were observed in transgenic compared with wt mice. Consistently, CD45(-)c-Kit(+) cardiac stem cells isolated from transgenic c-Kit(TgD814Y) mice showed an enhanced endothelial and cardiomyocyte differentiation potential compared with cells isolated from the wt. Constitutive activation of c-Kit receptor in mice is associated with an increased cardiac myogenic and vasculogenic reparative potential after injury, with a significant improvement of survival. C1 [Di Siena, S.; Naro, F.] Sapienza Univ, Dept Anat Histol Forens & Orthoped Sci, Rome, Italy. [Gimmelli, R.; Barbagallo, F.; Campolo, F.; Venneri, M. A.; Giannetta, E.; Gianfrilli, D.; Lenzi, A.; Isidori, A. M.] Sapienza Univ, Dept Expt Med, Viale Policlin 155, I-00161 Rome, Italy. [Nori, S. L.] Univ Salerno, Dept Med & Surg, Baronissi, Italy. [Dolci, S.; Rossi, P.] Tor Vergata Univ, Dept Biomed & Prevent, Rome, Italy. [Feigenbaum, L.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD USA. [Cianflone, E.; Mancuso, T.; Torella, D.] Magna Graecia Univ Catanzaro, Dept Med & Surg Sci, Catanzaro, Italy. [Pellegrini, M.] CNR, Inst Cell Biol & Neurobiol, Via E Ramarini 32, I-00015 Rome, Italy. RP Isidori, AM (reprint author), Sapienza Univ, Dept Expt Med, Viale Policlin 155, I-00161 Rome, Italy.; Pellegrini, M (reprint author), CNR, Inst Cell Biol & Neurobiol, Via E Ramarini 32, I-00015 Rome, Italy. EM andrea.isidori@uniroma1.it; manuela.pellegrini@cnr.it FU PRIN; FIRB; MFG PRIN FX PRIN 2010 to FN; FIRB 2010 to FN, AMI, AL; PRIN 2008 to SD; MFG 2009 PRIN 2012 to MP. NR 52 TC 0 Z9 0 U1 6 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-4889 J9 CELL DEATH DIS JI Cell Death Dis. PD JUL PY 2016 VL 7 AR e2317 DI 10.1038/cddis.2016.205 PG 15 WC Cell Biology SC Cell Biology GA DS6VD UT WOS:000380920200003 PM 27468693 ER PT J AU Coleman, CN Higgins, GS Brown, JM Baumann, M Kirsch, DG Willers, H Prasanna, PGS Dewhirst, MW Bernhard, EJ Ahmed, MM AF Coleman, C. Norman Higgins, Geoff S. Brown, J. Martin Baumann, Michael Kirsch, David G. Willers, Henning Prasanna, Pataje G. S. Dewhirst, Mark W. Bernhard, Eric J. Ahmed, Mansoor M. TI Improving the Predictive Value of Preclinical Studies in Support of Radiotherapy Clinical Trials SO CLINICAL CANCER RESEARCH LA English DT Review ID CANCER STEM-CELLS; RADIATION ONCOLOGY; TUMOR XENOGRAFTS; ANTICANCER AGENTS; DRUG SCREEN; THERAPY; HETEROGENEITY; EXPRESSION; RADIOSENSITIZERS; COMBINATIONS AB There is an urgent need to improve reproducibility and translatability of preclinical data to fully exploit opportunities for molecular therapeutics involving radiation and radiochemotherapy. For in vitro research, the clonogenic assay remains the current state-of-the-art of preclinical assays, whereas newer moderate and high-throughput assays offer the potential for rapid initial screening. Studies of radiation response modification by molecularly targeted agents can be improved using more physiologic 3D culture models. Elucidating effects on the cancer stem cells (CSC, and CSC-like) and developing biomarkers for defining targets and measuring responses are also important. In vivo studies are necessary to confirm in vitro findings, further define mechanism of action, and address immunomodulation and treatment-induced modification of the microenvironment. Newer in vivo models include genetically engineered and patient-derived xenograft mouse models and spontaneously occurring cancers in domesticated animals. Selection of appropriate endpoints is important for in vivo studies; for example, regrowth delay measures bulk tumor killing, whereas local tumor control assesses effects on CSCs. The reliability of individual assays requires standardization of procedures and cross-laboratory validation. Radiation modifiers must be tested as part of clinical standard of care, which includes radiochemotherapy for most tumors. Radiation models are compatible with but also differ from those used for drug screening. Furthermore, the mechanism of a drug as a chemotherapeutic agent may be different from its interaction with radiation and/or radiochemotherapy. This provides an opportunity to expand the use of molecular-targeted agents. (C) 2016 AACR. C1 [Coleman, C. Norman; Prasanna, Pataje G. S.; Bernhard, Eric J.; Ahmed, Mansoor M.] NCI, Radiat Res Program, Div Canc Treatment & Diag, NIH, 9609 Med Ctr Dr,3W102, Bethesda, MD 20892 USA. [Higgins, Geoff S.] Univ Oxford, Oxford Inst Radiat Oncol, MRC, Canc Res UK, Oxford OX1 2JD, England. [Brown, J. Martin] Stanford Univ, Sch Med, Dept Radiat Oncol, Stanford, CA 94305 USA. [Baumann, Michael] Tech Univ Dresden, Helmholtz Zenrtum Dresden Rossendorf, OncoRay Natl Ctr Radiat Res, Dresden, Germany. [Baumann, Michael] Dresden German Canc Res Ctr DKFZ, German Canc Consortium, Dresden, Germany. [Kirsch, David G.; Dewhirst, Mark W.] Duke Univ, Dept Radiat Oncol, Durham, NC USA. [Kirsch, David G.] Duke Univ, Dept Pharmacol, Durham, NC USA. [Kirsch, David G.] Duke Univ, Dept Canc Biol, Durham, NC USA. [Willers, Henning] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA USA. [Dewhirst, Mark W.] Duke Univ, Dept Pathol, Durham, NC 27706 USA. [Dewhirst, Mark W.] Duke Univ, Dept Biomed Engn, Durham, NC 27706 USA. RP Coleman, CN (reprint author), NCI, Radiat Res Program, Div Canc Treatment & Diag, NIH, 9609 Med Ctr Dr,3W102, Bethesda, MD 20892 USA. EM ccoleman@mail.nih.gov FU American Cancer Society [123420RSG-12-224-01-DMC] FX H. Willers is supported by the American Cancer Society (123420RSG-12-224-01-DMC). NR 71 TC 4 Z9 4 U1 5 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 1 PY 2016 VL 22 IS 13 BP 3138 EP 3147 DI 10.1158/1078-0432.CCR-16-0069 PG 10 WC Oncology SC Oncology GA DS7AE UT WOS:000380933900005 PM 27154913 ER PT J AU Medvar, B Raghuram, V Pisitkun, T Sarkar, A Knepper, MA AF Medvar, Barbara Raghuram, Viswanathan Pisitkun, Trairak Sarkar, Abhijit Knepper, Mark A. TI Comprehensive database of human E3 ubiquitin ligases: application to aquaporin-2 regulation SO PHYSIOLOGICAL GENOMICS LA English DT Article DE aquaporin-2; E3 ubiquitin ligases; collecting duct; kidney ID MEDULLARY COLLECTING DUCT; LC-MS/MS; VASOPRESSIN; KIDNEY; RAT; CELLS; PERMEABILITY; TRAFFICKING; PROTEINS; CHANNEL AB Aquaporin-2 (AQP2) is regulated in part via vasopressin-mediated changes in protein half-life that are in turn dependent on AQP2 ubiquitination. Here we addressed the question, "What E3 ubiquitin ligase is most likely to be responsible for AQP2 ubiquitination?" using large-scale data integration based on Bayes' rule. The first step was to bioinformatically identify all E3 ligase genes coded by the human genome. The 377 E3 ubiquitin ligases identified in the human genome, consisting predominant of HECT, RING, and U-box proteins, have been used to create a publically accessible and downloadable online database (https://hpcwebapps.cit.nih.gov/ESBL/Database/E3-ligases/). We also curated a second database of E3 ligase accessory proteins that included BTB domain proteins, cullins, SOCS-box proteins, and F-box proteins. Using Bayes' theorem to integrate information from multiple large-scale proteomic and transcriptomic datasets, we ranked these 377 E3 ligases with respect to their probability of interaction with AQP2. Application of Bayes' rule identified the E3 ligases most likely to interact with AQP2 as (in order of probability): NEDD4 and NEDD4L (tied for first), AMFR, STUB1, ITCH, ZFPL1. Significantly, the two E3 ligases tied for top rank have also been studied extensively in the reductionist literature as regulatory proteins in renal tubule epithelia. The concordance of conclusions from reductionist and systems-level data provides strong motivation for further studies of the roles of NEDD4 and NEDD4L in the regulation of AQP2 protein turnover. C1 [Medvar, Barbara; Raghuram, Viswanathan; Pisitkun, Trairak; Knepper, Mark A.] NHLBI, Epithelial Syst Biol Lab, NIH, Bethesda, MD USA. [Medvar, Barbara; Sarkar, Abhijit] Catholic Univ Amer, Vitreous State Lab, Washington, DC USA. [Pisitkun, Trairak] Chulalongkorn Univ, Fac Med, Syst Biol Ctr, Bangkok, Thailand. RP Knepper, MA (reprint author), NIH, Bldg 10,Rm 6N307,10 Ctr Dr,MSC-1603, Bethesda, MD 20892 USA. EM knepperm@nhlbi.nih.gov FU Chulalongkorn Academic Advancement into Its 2nd Century (CUAASC) Project; [HL-001285]; [HL-006129] FX The study was carried out in the Division of Intramural Research of the National Heart, Lung, and Blood Institute (Projects HL-001285 and HL-006129, M. A. Knepper). T. Pisitkun is supported by the Chulalongkorn Academic Advancement into Its 2nd Century (CUAASC) Project. NR 32 TC 3 Z9 3 U1 1 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1094-8341 EI 1531-2267 J9 PHYSIOL GENOMICS JI Physiol. Genomics PD JUL 1 PY 2016 VL 48 IS 7 BP 502 EP 512 DI 10.1152/physiolgenomics.00031.2016 PG 11 WC Cell Biology; Genetics & Heredity; Physiology SC Cell Biology; Genetics & Heredity; Physiology GA DS7ZA UT WOS:000381000800007 PM 27199454 ER PT J AU Carlin, DJ Naujokas, MF Bradham, KD Cowden, J Heacock, M Henry, HF Lee, JS Thomas, DJ Thompson, C Tokar, EJ Waalkes, MP Birnbaum, LS Suk, WA AF Carlin, Danielle J. Naujokas, Marisa F. Bradham, Karen D. Cowden, John Heacock, Michelle Henry, Heather F. Lee, Janice S. Thomas, David J. Thompson, Claudia Tokar, Erik J. Waalkes, Michael P. Birnbaum, Linda S. Suk, William A. TI Arsenic and Environmental Health: State of the Science and Future Research Opportunities SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Review ID DIFFERENTIAL DNA METHYLATION; UMBILICAL-CORD BLOOD; FATTY LIVER-DISEASE; DRINKING-WATER; RISK-ASSESSMENT; IN-UTERO; GUT MICROBIOME; RELATIVE BIOAVAILABILITY; REMEDIATION TECHNIQUES; 21ST-CENTURY ROADMAP AB BACKGROUND: Exposure to inorganic and organic arsenic compounds is a major public health problem that affects hundreds of millions of people worldwide. Exposure to arsenic is associated with cancer and noncancer effects in nearly every organ in the body, and evidence is mounting for health effects at lower levels of arsenic exposure than previously thought. Building from a tremendous knowledge base with > 1,000 scientific papers published annually with "arsenic" in the title, the question becomes, what questions would best drive future research directions? OBJECTIVES: The objective is to discuss emerging issues in arsenic research and identify data gaps across disciplines. METHODS: The National Institutes of Health's National Institute of Environmental Health Sciences Superfund Research Program convened a workshop to identify emerging issues and research needs to address the multi-faceted challenges related to arsenic and environmental health. This review summarizes information captured during the workshop. DISCUSSION: More information about aggregate exposure to arsenic is needed, including the amount and forms of arsenic found in foods. New strategies for mitigating arsenic exposures and related health effects range from engineered filtering systems to phytogenetics and nutritional interventions. Furthermore, integration of omics data with mechanistic and epidemiological data is a key step toward the goal of linking biomarkers of exposure and susceptibility to disease mechanisms and outcomes. Conclusions: Promising research strategies and technologies for arsenic exposure and adverse health effect mitigation are being pursued, and future research is moving toward deeper collaborations and integration of information across disciplines to address data gaps. C1 [Carlin, Danielle J.; Heacock, Michelle; Henry, Heather F.; Suk, William A.] NIEHS, Superfund Res Program, NIH, US Dept HHS, Res Triangle Pk, NC 27560 USA. [Naujokas, Marisa F.] MDB Inc, Durham, NC USA. [Bradham, Karen D.] US EPA, Human Exposure & Atmospher Sci Div, Natl Exposure Res Lab, Res Triangle Pk, NC 27711 USA. [Cowden, John] US EPA, Natl Ctr Computat Toxicol, ORD, Res Triangle Pk, NC 27711 USA. [Lee, Janice S.] US EPA, Natl Ctr Environm Assessment, ORD, Res Triangle Pk, NC 27711 USA. [Thomas, David J.] US EPA, Integrated Syst Toxicol Div, Natl Human & Environm Hlth Effects Res Lab, ORD, Res Triangle Pk, NC 27711 USA. [Thompson, Claudia] NIEHS, Populat Hlth Branch, NIH, US Dept HHS, Res Triangle Pk, NC 27560 USA. [Tokar, Erik J.; Waalkes, Michael P.; Birnbaum, Linda S.] NIEHS, Natl Toxicol Program, NIH, US Dept HHS, Res Triangle Pk, NC 27560 USA. [Birnbaum, Linda S.] NIEHS, NIH, US Dept HHS, Res Triangle Pk, NC 27560 USA. RP Carlin, DJ (reprint author), NIEHS, Div Extramural Res & Training, Hazardous Subst Res Branch, Superfund Res Program, Keystone Bldg,530 Davis Dr,POB 12233, Res Triangle Pk, NC 27560 USA. EM danielle.carlin@nih.gov FU NIH, NIEHS [ES-102925] FX This work was supported in part by the NIH, NIEHS, including grant ES-102925. NR 130 TC 6 Z9 6 U1 30 U2 41 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUL PY 2016 VL 124 IS 7 BP 890 EP 899 DI 10.1289/ehp.1510209 PG 10 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DS4KF UT WOS:000380749300009 PM 26587579 ER PT J AU Mansouri, K Abdelaziz, A Rybacka, A Roncaglioni, A Tropsha, A Varnek, A Zakharov, A Worth, A Richard, AM Grulke, CM Trisciuzzi, D Fourches, D Horvath, D Benfenati, E Muratov, E Wedebye, EB Grisoni, F Mangiatordi, GF Incisivo, GM Hong, HX Ng, HW Tetko, IV Balabin, I Kancherla, J Shen, J Burton, J Nicklaus, M Cassotti, M Nikolov, NG Nicolotti, O Andersson, PL Zang, QD Politi, R Beger, RD Todeschini, R Huang, RL Farag, S Rosenberg, SA Slavov, S Hu, X Judson, RS AF Mansouri, Kamel Abdelaziz, Ahmed Rybacka, Aleksandra Roncaglioni, Alessandra Tropsha, Alexander Varnek, Alexandre Zakharov, Alexey Worth, Andrew Richard, Ann M. Grulke, Christopher M. Trisciuzzi, Daniela Fourches, Denis Horvath, Dragos Benfenati, Emilio Muratov, Eugene Wedebye, Eva Bay Grisoni, Francesca Mangiatordi, Giuseppe F. Incisivo, Giuseppina M. Hong, Huixiao Ng, Hui W. Tetko, Igor V. Balabin, Ilya Kancherla, Jayaram Shen, Jie Burton, Julien Nicklaus, Marc Cassotti, Matteo Nikolov, Nikolai G. Nicolotti, Orazio Andersson, Patrik L. Zang, Qingda Politi, Regina Beger, Richard D. Todeschini, Roberto Huang, Ruili Farag, Sherif Rosenberg, Sine A. Slavov, Svetoslav Hu, Xin Judson, Richard S. TI CERAPP: Collaborative Estrogen Receptor Activity Prediction Project SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID ENDOCRINE-DISRUPTING CHEMICALS; COMPUTATIONAL TOXICOLOGY RESOURCE; QUANTITATIVE STRUCTURE-ACTIVITY; THROUGHPUT SCREENING ASSAYS; RELATIONSHIP QSDAR MODELS; ENVIRONMENTAL CHEMICALS; DECISION FOREST; PARTITION-COEFFICIENTS; BINARY CLASSIFICATION; BIOLOGICAL-ACTIVITY AB BACKGROUND: Humans are exposed to thousands of man-made chemicals in the environment. Some chemicals mimic natural endocrine hormones and, thus, have the potential to be endocrine disruptors. Most of these chemicals have never been tested for their ability to interact with the estrogen receptor (ER). Risk assessors need tools to prioritize chemicals for evaluation in costly in vivo tests, for instance, within the U.S. EPA Endocrine Disruptor Screening Program. OBJECTIVES: We describe a large-scale modeling project called CERAPP (Collaborative Estrogen Receptor Activity Prediction Project) and demonstrate the efficacy of using predictive computational models trained on high-throughput screening data to evaluate thousands of chemicals for ER-related activity and prioritize them for further testing. METHODS: CERAPP combined multiple models developed in collaboration with 17 groups in the United States and Europe to predict ER activity of a common set of 32,464 chemical structures. Quantitative structure-activity relationship models and docking approaches were employed, mostly using a common training set of 1,677 chemical structures provided by the U.S. EPA, to build a total of 40 categorical and 8 continuous models for binding, agonist, and antagonist ER activity. All predictions were evaluated on a set of 7,522 chemicals curated from the literature. To overcome the limitations of single models, a consensus was built by weighting models on scores based on their evaluated accuracies. RESULTS: Individual model scores ranged from 0.69 to 0.85, showing high prediction reliabilities. Out of the 32,464 chemicals, the consensus model predicted 4,001 chemicals (12.3%) as high priority actives and 6,742 potential actives (20.8%) to be considered for further testing. CONCLUSION: This project demonstrated the possibility to screen large libraries of chemicals using a consensus of different in silico approaches. This concept will be applied in future projects related to other end points. C1 [Mansouri, Kamel; Richard, Ann M.; Grulke, Christopher M.; Kancherla, Jayaram; Judson, Richard S.] US EPA, Natl Ctr Computat Toxicol, 109 TW Alexander Dr, Res Triangle Pk, NC 27711 USA. [Mansouri, Kamel] Oak Ridge Inst Sci & Educ, Oak Ridge, TN USA. [Abdelaziz, Ahmed; Tetko, Igor V.] German Res Ctr Environm Hlth GmbH, Helmholtz Zentrum Muenchen, Inst Struct Biol, Neuherberg, Germany. [Rybacka, Aleksandra; Andersson, Patrik L.] Umea Univ, Dept Chem, Umea, Sweden. [Roncaglioni, Alessandra; Benfenati, Emilio; Incisivo, Giuseppina M.] Ist Ric Farmacol Mario Negri, IRCCS, Environm Chem & Toxicol Lab, Milan, Italy. [Tropsha, Alexander; Fourches, Denis; Muratov, Eugene; Politi, Regina; Farag, Sherif] Univ North Carolina Chapel Hill, Lab Mol Modeling, Chapel Hill, NC USA. [Varnek, Alexandre; Horvath, Dragos] Univ Strasbourg, Lab Chemoinformat, Strasbourg, France. [Zakharov, Alexey; Nicklaus, Marc] NCI, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Worth, Andrew; Burton, Julien] European Commiss Ispra, Joint Res Ctr, IHCP, Ispra, Italy. [Trisciuzzi, Daniela; Mangiatordi, Giuseppe F.; Nicolotti, Orazio] Univ Bari, Dept Pharmacy Drug Sci, Bari, Italy. [Wedebye, Eva Bay; Nikolov, Nikolai G.; Rosenberg, Sine A.] Tech Univ Denmark, Natl Food Inst, Div Toxicol & Risk Assessment, Copenhagen, Denmark. [Grisoni, Francesca; Cassotti, Matteo; Todeschini, Roberto] Univ Milano Bicocca, Milano Chemometr & QSAR Res Grp, Milan, Italy. [Hong, Huixiao; Ng, Hui W.] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, USDA, Jefferson, AZ USA. [Tetko, Igor V.] BigChem GmbH, Neuherberg, Germany. [Balabin, Ilya] Lockheed Martin, High Performance Comp, Res Triangle Pk, NC USA. [Shen, Jie] Res Inst Fragrance Mat Inc, Woodcliff Lake, NJ USA. [Zang, Qingda; Slavov, Svetoslav] Integrated Lab Syst Inc, Res Triangle Pk, NC USA. [Beger, Richard D.] USDA, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AZ USA. [Huang, Ruili; Hu, Xin] NIH, Natl Ctr Adv Translat Sci, DHHS, Bldg 10, Bethesda, MD 20892 USA. RP Judson, RS (reprint author), US EPA, Natl Ctr Computat Toxicol, 109 TW Alexander Dr, Res Triangle Pk, NC 27711 USA. EM judson.richard@epa.gov RI Tetko, Igor/B-1540-2010; Varnek, Alexandre/E-7076-2017; Kancherla, Jayaram/P-7756-2015; OI Tetko, Igor/0000-0002-6855-0012; Varnek, Alexandre/0000-0003-1886-925X; Kancherla, Jayaram/0000-0001-5855-5031; Mansouri, Kamel/0000-0002-6426-8036 FU NIGMS NIH HHS [T32 GM067553] NR 101 TC 17 Z9 17 U1 13 U2 15 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUL PY 2016 VL 124 IS 7 BP 1023 EP 1033 DI 10.1289/ehp.1510267 PG 11 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DS4KF UT WOS:000380749300025 PM 26908244 ER PT J AU Leung, MCK Phuong, J Baker, NC Sipes, NS Klinefelter, GR Martin, MT McLaurin, KW Setzer, RW Darney, SP Judson, RS Knudsen, TB AF Leung, Maxwell C. K. Phuong, Jimmy Baker, Nancy C. Sipes, Nisha S. Klinefelter, Gary R. Martin, Matthew T. McLaurin, Keith W. Setzer, R. Woodrow Darney, Sally Perreault Judson, Richard S. Knudsen, Thomas B. TI Systems Toxicology of Male Reproductive Development: Profiling 774 Chemicals for Molecular Targets and Adverse Outcomes SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID TESTICULAR DYSGENESIS SYNDROME; INTERLEUKIN-6 SIGNAL BLOCKADE; GERM-CELL DIFFERENTIATION; RECEPTOR TYROSINE KINASE; GENOME-WIDE ASSOCIATION; LARGE GENE LISTS; FETAL TESTIS; DI(N-BUTYL) PHTHALATE; NUCLEAR RECEPTORS; DIETHYLHEXYL PHTHALATE AB BACKGROUND: Trends in male reproductive health have been reported for increased rates of testicular germ cell tumors, low semen quality, cryptorchidism, and hypospadias, which have been associated with prenatal environmental chemical exposure based on human and animal studies. OBJECTIVE: In the present study we aimed to identify significant correlations between environmental chemicals, molecular targets, and adverse outcomes across a broad chemical landscape with emphasis on developmental toxicity of the male reproductive system. METHODS: We used U.S. EPA's animal study database (ToxRefDB) and a comprehensive literature analysis to identify 774 chemicals that have been evaluated for adverse effects on male reproductive parameters, and then used U.S. EPA's in vitro high-throughput screening (HTS) database (ToxCastDB) to profile their bioactivity across approximately 800 molecular and cellular features. RESULTS: A phenotypic hierarchy of testicular atrophy, sperm effects, tumors, and malformations, a composite resembling the human testicular dysgenesis syndrome (TDS) hypothesis, was observed in 281 chemicals. A subset of 54 chemicals with male developmental consequences had in vitro bioactivity on molecular targets that could be condensed into 156 gene annotations in a bipartite network. CONCLUSION: Computational modeling of available in vivo and in vitro data for chemicals that produce adverse effects on male reproductive end points revealed a phenotypic hierarchy across animal studies consistent with the human TDS hypothesis. We confirmed the known role of estrogen and androgen signaling pathways in rodent TDS, and importantly, broadened the list of molecular targets to include retinoic acid signaling, vascular remodeling proteins, G-protein coupled receptors (GPCRs), and cytochrome P450s. C1 [Leung, Maxwell C. K.; Sipes, Nisha S.; McLaurin, Keith W.] Oak Ridge Inst Sci & Educ, Oak Ridge, TN USA. [Leung, Maxwell C. K.; Phuong, Jimmy; Sipes, Nisha S.; Martin, Matthew T.; McLaurin, Keith W.; Setzer, R. Woodrow; Judson, Richard S.; Knudsen, Thomas B.] US EPA, Natl Ctr Computat Toxicol, Res Triangle Pk, NC 27711 USA. [Baker, Nancy C.] Lockheed Martin, Res Triangle Pk, NC USA. [Klinefelter, Gary R.; Darney, Sally Perreault] US EPA, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. [Darney, Sally Perreault] NIEHS, Environm Hlth Perspect, NIH, US Dept HHS, POB 12233, Res Triangle Pk, NC 27709 USA. RP Leung, MCK; Knudsen, TB (reprint author), US EPA, 109 TW Alexander Dr, Res Triangle Pk, NC 27711 USA. EM leung.max-well@epa.gov; knudsen.thomas@epa.gov OI Leung, Maxwell/0000-0003-1530-3306 NR 98 TC 2 Z9 2 U1 8 U2 12 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUL PY 2016 VL 124 IS 7 BP 1050 EP 1061 DI 10.1289/ehp.1510385 PG 12 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DS4KF UT WOS:000380749300028 PM 26662846 ER PT J AU Larson, CL Martinez, E Beare, PA Jeffrey, B Heinzen, RA Bonazzi, M AF Larson, Charles L. Martinez, Eric Beare, Paul A. Jeffrey, Brendan Heinzen, Robert A. Bonazzi, Matteo TI Right on Q: genetics begin to unravel Coxiella burnetii host cell interactions SO FUTURE MICROBIOLOGY LA English DT Review DE apoptosis; autophagy; Coxiella burnetii; effector protein; host cell invasion; macrophages; mutagenesis; phagolysosome; type 4B secretion; vacuole remodeling ID IV SECRETION SYSTEM; CLATHRIN-MEDIATED ENDOCYTOSIS; PNEUMOPHILA DOT/ICM SYSTEM; RESPONSE REGULATOR PMRA; Q-FEVER; LEGIONELLA-PNEUMOPHILA; PHASE-II; EFFECTOR PROTEIN; INTRACELLULAR REPLICATION; ANTIAPOPTOTIC ACTIVITY AB Invasion of macrophages and replication within an acidic and degradative phagolysosome-like vacuole are essential for disease pathogenesis by Coxiella burnetii, the bacterial agent of human Q fever. Previous experimental constraints imposed by the obligate intracellular nature of Coxiella limited knowledge of pathogen strategies that promote infection. Fortunately, new genetic tools facilitated by axenic culture now allow allelic exchange and transposon mutagenesis approaches for virulence gene discovery. Phenotypic screens have illuminated the critical importance of Coxiella's type 4B secretion system in host cell subversion and discovered genes encoding translocated effector proteins that manipulate critical infection events. Here, we highlight the cellular microbiology and genetics of Coxiella and how recent technical advances now make Coxiella a model organism to study macrophage parasitism. C1 [Larson, Charles L.; Beare, Paul A.; Heinzen, Robert A.] NIAID, Coxiella Pathogenesis Sect, Bacteriol Lab, Rocky Mt Labs,NIH, 903 South 4th St, Hamilton, MT 59840 USA. [Martinez, Eric; Bonazzi, Matteo] CNRS, FRE3698, CPBS, 1919 Route Mende, F-34293 Montpellier, France. [Martinez, Eric; Bonazzi, Matteo] Univ Montpellier, Montpellier, France. [Jeffrey, Brendan] NIAID, Bioinformat & Computat Biosci Branch, Rocky Mt Labs, NIH, 903 South 4th St, Hamilton, MT 59840 USA. RP Heinzen, RA (reprint author), NIAID, Coxiella Pathogenesis Sect, Bacteriol Lab, Rocky Mt Labs,NIH, 903 South 4th St, Hamilton, MT 59840 USA. EM rheinzen@niaid.nih.gov FU Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases; Agence Nationale de la Recherche (ANR) [ANR-14-CE14-0012-01]; ERA-NET Infect-ERA [ANR-13-IFEC-0003]; ATIP-AVENIR programme FX This work was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases (RA Heinzen) and by grants from the Agence Nationale de la Recherche (ANR) (ANR-14-CE14-0012-01; Project AttaQ), ERA-NET Infect-ERA (ANR-13-IFEC-0003; Project EUGENPATH) and the ATIP-AVENIR programme (M Bonazzi). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 155 TC 2 Z9 2 U1 1 U2 3 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1746-0913 EI 1746-0921 J9 FUTURE MICROBIOL JI Future Microbiol. PD JUL PY 2016 VL 11 IS 7 BP 919 EP 939 DI 10.2217/fmb-2016-0044 PG 21 WC Microbiology SC Microbiology GA DS8LB UT WOS:000381033700008 PM 27418426 ER PT J AU Alexander-Bloch, A Clasen, L Stockman, M Ronan, L Lalonde, F Giedd, J Raznahan, A AF Alexander-Bloch, Aaron Clasen, Liv Stockman, Michael Ronan, Lisa Lalonde, Francois Giedd, Jay Raznahan, Armin TI Subtle In-Scanner Motion Biases Automated Measurement of Brain Anatomy From In Vivo MRI SO HUMAN BRAIN MAPPING LA English DT Article DE functional neuroimaging; magnetic resonance imaging; motion; bias; cortical thickness; cortical surface area; cortical curvature ID FMRI TIME-SERIES; HUMAN CEREBRAL-CORTEX; FUNCTIONAL CONNECTIVITY MRI; MAGNETIC-RESONANCE IMAGES; SURFACE-BASED ANALYSIS; HEAD MOTION; NAVIGATOR ECHOES; GEOMETRICALLY ACCURATE; ADAPTIVE TECHNIQUE; MOVING STRUCTURES AB While the potential for small amounts of motion in functional magnetic resonance imaging (fMRI) scans to bias the results of functional neuroimaging studies is well appreciated, the impact of in-scanner motion on morphological analysis of structural MRI is relatively under-studied. Even among "good quality" structural scans, there may be systematic effects of motion on measures of brain morphometry. In the present study, the subjects' tendency to move during fMRI scans, acquired in the same scanning sessions as their structural scans, yielded a reliable, continuous estimate of in-scanner motion. Using this approach within a sample of 127 children, adolescents, and young adults, significant relationships were found between this measure and estimates of cortical gray matter volume and mean curvature, as well as trend-level relationships with cortical thickness. Specifically, cortical volume and thickness decreased with greater motion, and mean curvature increased. These effects of subtle motion were anatomically heterogeneous, were present across different automated imaging pipelines, showed convergent validity with effects of frank motion assessed in a separate sample of 274 scans, and could be demonstrated in both pediatric and adult populations. Thus, using different motion assays in two large non-overlapping sets of structural MRI scans, convergent evidence showed that in-scanner motion-even at levels which do not manifest in visible motion artifact-can lead to systematic and regionally specific biases in anatomical estimation. These findings have special relevance to structural neuroimaging in developmental and clinical datasets, and inform ongoing efforts to optimize neuroanatomical analysis of existing and future structural MRI datasets in non-sedated humans. (C) 2016 Wiley Periodicals, Inc. C1 [Alexander-Bloch, Aaron; Clasen, Liv; Stockman, Michael; Lalonde, Francois; Raznahan, Armin] NIMH, Dev Neurogen Unit, Child Psychiat Branch, 10 Ctr Dr,Bldg 10,Room 4D18, Bethesda, MD 20892 USA. [Alexander-Bloch, Aaron] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06508 USA. [Ronan, Lisa] Univ Cambridge, Brain Mapping Unit, Cambridge, England. [Giedd, Jay] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92093 USA. RP Raznahan, A (reprint author), NIMH, Dev Neurogen Unit, Child Psychiat Branch, 10 Ctr Dr,Bldg 10,Room 4D18, Bethesda, MD 20892 USA. EM raznahana@mail.nih.gov FU Intramural NIH HHS [Z99 MH999999] NR 62 TC 5 Z9 5 U1 0 U2 3 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 2016 VL 37 IS 7 BP 2385 EP 2397 DI 10.1002/hbm.23180 PG 13 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DU8TV UT WOS:000382488800002 PM 27004471 ER PT J AU Smith, E Thurm, A Greenstein, D Farmer, C Swedo, S Giedd, J Raznahan, A AF Smith, Elizabeth Thurm, Audrey Greenstein, Deanna Farmer, Cristan Swedo, Susan Giedd, Jay Raznahan, Armin TI Cortical Thickness Change in Autism During Early Childhood SO HUMAN BRAIN MAPPING LA English DT Article DE autism spectrum disorder; cortical thickness; surface based morphometry; expressive language; MRI ID LANGUAGE-ASSOCIATION CORTEX; SPECTRUM DISORDERS; WHITE-MATTER; GRAY-MATTER; LONGITUDINAL CHANGES; BRAIN MATURATION; YOUNG ADULTHOOD; CEREBRAL-CORTEX; MOTOR CORTEX; SURFACE-AREA AB Structural magnetic resonance imaging (MRI) scans at high spatial resolution can detect potential foci of early brain dysmaturation in children with autism spectrum disorders (ASD). In addition, comparison between MRI and behavior measures over time can identify patterns of brain change accompanying specific outcomes. We report structural MRI data from two time points for a total of 84 scans in children with ASD and 30 scans in typical controls (mean age time one = 4.1 years, mean age at time two - 6.6 years). Surface-based cortical morphometry and linear mixed effects models were used to link changes in cortical anatomy to both diagnostic status and individual differences in changes in language and autism severity. Compared with controls, children with ASD showed accelerated gray matter volume gain with age, which was driven by a lack of typical age-related cortical thickness (CT) decrease within 10 cortical regions involved in language, social cognition, and behavioral control. Greater expressive communication gains with age in children with ASD were associated with greater CT gains in a set of right hemisphere homologues to dominant language cortices, potentially identifying a compensatory system for closer translational study. (C) 2016 Wiley Periodicals, Inc. C1 [Smith, Elizabeth; Thurm, Audrey; Farmer, Cristan; Swedo, Susan] NIMH, Pediat & Dev Neurosci Branch, 10 Ctr Dr MSC 1255,Bldg 10,Room 1C250, Bethesda, MD 20892 USA. [Greenstein, Deanna; Raznahan, Armin] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. [Giedd, Jay] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. RP Smith, E (reprint author), NIMH, Pediat & Dev Neurosci Branch, 10 Ctr Dr MSC 1255,Bldg 10,Room 1C250, Bethesda, MD 20892 USA. EM elizabeth.smith3@nih.gov FU Intramural NIH HHS [ZIA MH002914-08]; NIMH NIH HHS [ZIA MH002914] NR 87 TC 2 Z9 2 U1 19 U2 21 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 2016 VL 37 IS 7 BP 2616 EP 2629 DI 10.1002/hbm.23195 PG 14 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DU8TV UT WOS:000382488800019 PM 27061356 ER PT J AU Merlino, G Herlyn, M Fisher, DE Bastian, BC Flaherty, KT Davies, MA Wargo, JA Curiel-Lewandrowski, C Weber, MJ Leachman, SA Soengas, MS McMahon, M Harbour, JW Swetter, SM Aplin, AE Atkins, MB Bosenberg, MW Dummer, R Gershenwald, JE Halpern, AC Herlyn, D Karakousis, GC Kirkwood, JM Krauthammer, M Lo, RS Long, GV McArthur, G Ribas, A Schuchter, L Sosman, JA Smalley, KS Steeg, P Thomas, NE Tsao, H Tueting, T Weeraratna, A Xu, G Lomax, R Martin, A Silverstein, S Turnham, T Ronai, ZA AF Merlino, Glenn Herlyn, Meenhard Fisher, David E. Bastian, Boris C. Flaherty, Keith T. Davies, Michael A. Wargo, Jennifer A. Curiel-Lewandrowski, Clara Weber, Michael J. Leachman, Sancy A. Soengas, Maria S. McMahon, Martin Harbour, J. William Swetter, Susan M. Aplin, Andrew E. Atkins, Michael B. Bosenberg, Marcus W. Dummer, Reinhard Gershenwald, Jeffrey E. Halpern, Allan C. Herlyn, Dorothee Karakousis, Giorgos C. Kirkwood, John M. Krauthammer, Michael Lo, Roger S. Long, Georgina V. McArthur, Grant Ribas, Antoni Schuchter, Lynn Sosman, Jeffrey A. Smalley, Keiran S. Steeg, Patricia Thomas, Nancy E. Tsao, Hensin Tueting, Thomas Weeraratna, Ashani Xu, George Lomax, Randy Martin, Alison Silverstein, Steve Turnham, Tim Ronai, Ze'ev A. TI The state of melanoma: challenges and opportunities SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Article DE melanoma; prevention; early diagnosis; metastasis; dormancy; therapy AB The Melanoma Research Foundation (MRF) has charted a comprehensive assessment of the current state of melanoma research and care. Intensive discussions among members of the MRF Scientific Advisory Council and Breakthrough Consortium, a group that included clinicians and scientists, focused on four thematic areas diagnosis/early detection, prevention, tumor cell dormancy (including metastasis), and therapy (response and resistance). These discussions extended over the course of 2015 and culminated at the Society of Melanoma Research 2015 International Congress in November. Each of the four groups has outlined their thoughts as per the current status, challenges, and opportunities in the four respective areas. The current state and immediate and longterm needs of the melanoma field, from basic research to clinical management, are presented in the following report. C1 [Merlino, Glenn] NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. [Herlyn, Meenhard; Herlyn, Dorothee; Weeraratna, Ashani] Wistar Inst Anat & Biol, Melanoma Res Ctr, 3601 Spruce St, Philadelphia, PA 19104 USA. [Fisher, David E.] Massachusetts Gen Hosp, Dept Dermatol, Cutaneous Biol Res Ctr, Charlestown, MA USA. [Bastian, Boris C.] Univ Calif San Francisco, Dept Dermatol, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Bastian, Boris C.] Univ Calif San Francisco, Dept Pathol, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94140 USA. [Flaherty, Keith T.] Massachusetts Gen Hosp, Dev Therapeut, Ctr Canc, Charlestown, MA USA. [Davies, Michael A.; Wargo, Jennifer A.; Gershenwald, Jeffrey E.] Univ Texas MD Anderson Canc Ctr, Dept Genom Med & Surg Oncol, Houston, TX 77030 USA. [Curiel-Lewandrowski, Clara] Univ Arizona, Ctr Canc, Dept Med, Tucson, AZ USA. [Curiel-Lewandrowski, Clara] Univ Arizona, Ctr Canc, Dept Dermatol, Tucson, AZ USA. [Weber, Michael J.] Univ Virginia, Sch Med, Dept Microbiol Immunol & Canc Biol, Charlottesville, VA 22908 USA. [Leachman, Sancy A.] Oregon Hlth & Sci Univ, Dept Dermatol, Knight Canc Inst, Melanoma & Skin Canc Program, Portland, OR USA. [Soengas, Maria S.] CNIO, Mol Oncol Program, Melanoma Lab, Madrid, Spain. [McMahon, Martin] Huntsman Canc Inst, Dept Dermatol, Salt Lake City, UT USA. [Harbour, J. William] Univ Miami, Bascom Palmer Eye Inst, Miami, FL USA. [Harbour, J. William] Univ Miami, Sylvester Comprehens Canc Ctr, Miami, FL USA. [Swetter, Susan M.] Stanford Univ, Med Ctr, Dept Dermatol, Palo Alto, CA 94304 USA. [Swetter, Susan M.] VA Palo Alto Hlth Care Syst, Inst Canc, Palo Alto, CA USA. [Aplin, Andrew E.] Thomas Jefferson Univ, Sidney Kimmel Canc Ctr, Philadelphia, PA 19107 USA. [Atkins, Michael B.] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. [Bosenberg, Marcus W.] Yale Univ, Ctr Canc, Dept Dermatol & Dermatopathol, New Haven, CT USA. [Dummer, Reinhard] Univ Zurich, Dept Dermatol, Zurich, Switzerland. [Halpern, Allan C.] Mem Sloan Kettering Canc Ctr, Dermatol, 1275 York Ave, New York, NY 10021 USA. [Karakousis, Giorgos C.; Schuchter, Lynn; Xu, George] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Kirkwood, John M.] Univ Pittsburgh, Melanoma & Skin Canc Program, Pittsburgh, PA USA. [Krauthammer, Michael] Yale Univ, Dept Pathol, Ctr Canc, New Haven, CT USA. [Lo, Roger S.; Ribas, Antoni] Univ Calif Los Angeles, Dept Med Oncol & Dermatol, Los Angeles, CA USA. [Long, Georgina V.] Univ Sydney, Melanoma Inst, Sydney, NSW, Australia. [McArthur, Grant] Peter MacCallum Canc Ctr, Dept Canc Med, East Melbourne, Vic, Australia. [Sosman, Jeffrey A.] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Dept Med, Nashville, TN 37212 USA. [Smalley, Keiran S.] H Lee Moffitt Canc Ctr & Res Inst, Dept Tumor Biol, Tampa, FL USA. [Steeg, Patricia] NCI, Women Malignancies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Thomas, Nancy E.] Univ N Carolina, Melanoma Program, Dept Dermatol, Lineberger Canc Ctr, Chapel Hill, NC USA. [Tsao, Hensin] Massachusetts Gen Hosp, Melanoma & Pigmented Lesion Ctr, Charlestown, MA USA. [Tueting, Thomas] Univ Bonn, Dept Dermatol, Bonn, Germany. [Lomax, Randy; Martin, Alison; Silverstein, Steve; Turnham, Tim] Melanoma Res Fdn, Washington, DC USA. [Ronai, Ze'ev A.] Sanford Burnham Prebys Med Discovery Inst, Tumor Initiat & Maintenance Program, La Jolla, CA 92037 USA. RP Ronai, ZA (reprint author), Sanford Burnham Prebys Med Discovery Inst, Tumor Initiat & Maintenance Program, La Jolla, CA 92037 USA. EM ronai@SBPdiscovery.org FU NCI NIH HHS [P30 CA016672, P30 CA010815, P50 CA121973]; NIAMS NIH HHS [R01 AR043369] NR 0 TC 6 Z9 6 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1755-1471 EI 1755-148X J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD JUL PY 2016 VL 29 IS 4 BP 404 EP 416 DI 10.1111/pcmr.12475 PG 13 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA DT2IC UT WOS:000381303000005 PM 27087480 ER PT J AU George, AL Boulanger, CA Smith, GH AF George, Andrea L. Boulanger, Corinne A. Smith, Gilbert H. TI Telomerase and estrogen-sensing activities are essential for continued mammary growth in vivo but dispensable for "reprogramming" neural stem cells SO AGING-US LA English DT Article DE telomeres; mammary; senescence; stem cells ID EPITHELIAL-CELLS; LIFE-SPAN; TRANSFORMING GROWTH-FACTOR-BETA-1; SERIAL TRANSPLANTATION; TGF-BETA-1 EXPRESSION; RECEPTOR-ALPHA; IMMORTAL CELLS; DEFICIENT MICE; MOUSE; GLAND AB It has been proposed that the erosion of telomere length is a limiting factor in replicative capacity and important in cell senescence. To determine if this activity was essential in the mouse mammary gland in vivo, we serially transplanted mammary fragments from wild type (TER+/+), heterozygous (TER+/-), and homozygous (TER-/-) mammary tissues into the cleared mammary fat pads of immune-compromised nude mice. Individual implants from both homozygous and heterozygous TER null outgrowths showed growth senescence beginning at transplant generation two, earlier than implants from TER+/+ mammary glands which continued to show growth. This result suggests that either mammary epithelial stem cells maintain their telomere length in order to self renew, or that the absence or reduction of telomerase template results in more frequent death/extinction of stem cells during symmetric divisions. A third possibility is the inability of signaling cells in the niche to replicate resulting in reduction of the maintenance signals necessary for stem cell renewal. Consistent with this, examination of senescent outgrowths revealed the absence of estrogen receptor alpha (ER alpha(+)) epithelium although progesterone receptor (PR+) cells were abundant. Despite their inability to establish mammary growth in vivo, TER+/- cells were able to direct neural stem cells to mammary cell fates. C1 [George, Andrea L.; Boulanger, Corinne A.; Smith, Gilbert H.] NCI, Basic Res Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Smith, GH (reprint author), NCI, Basic Res Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM gs4d@nih.gov FU intramural research program of the Center for Cancer Research NCI, NIH FX The intramural research program of the Center for Cancer Research NCI, NIH, supported this work. NR 45 TC 0 Z9 0 U1 3 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1945-4589 J9 AGING-US JI Aging-US PD JUL PY 2016 VL 8 IS 7 BP 1353 EP 1363 DI 10.18632/aging.100985 PG 11 WC Cell Biology SC Cell Biology GA DU1DV UT WOS:000381949300008 PM 27347776 ER PT J AU Arrigoni, F Peruzzo, D Gagliardi, C Maghini, C Colombo, P Iammarrone, FS Pierpaoli, C Triulzi, F Turconi, AC AF Arrigoni, F. Peruzzo, D. Gagliardi, C. Maghini, C. Colombo, P. Iammarrone, F. Servodio Pierpaoli, C. Triulzi, F. Turconi, A. C. TI Whole-Brain DTI Assessment of White Matter Damage in Children with Bilateral Cerebral Palsy: Evidence of Involvement beyond the Primary Target of the Anoxic Insult SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Article ID GROSS MOTOR FUNCTION; PERIVENTRICULAR LEUKOMALACIA; CLASSIFICATION-SYSTEM; FIBER-TRACKING; BORN PRETERM; TRACTOGRAPHY; INJURY; IMPAIRMENT; TRACTS; ANISOTROPY AB BACKGROUND AND PURPOSE: Cerebral palsy is frequently associated with both motor and nonmotor symptoms. DTI can characterize the damage at the level of motor tracts but provides less consistent results in nonmotor areas. We used a standardized pipeline of analysis to describe and quantify the pattern of DTI white matter abnormalities of the whole brain in a group of children with chronic bilateral cerebral palsy and periventricular leukomalacia. We also explored potential correlations between DTI and clinical scale metrics. MATERIALS AND METHODS: Twenty-five patients (mean age, 11.8 years) and 25 healthy children (mean age, 11.8 years) were studied at 3T with a 2-mm isotropic DTI sequence. Differences between patients and controls were assessed both voxelwise and in ROIs obtained from an existing DTI atlas. Clinical metrics included the Gross Motor Function Classification System, the Manual Ability Classification System, and intelligence quotient. RESULTS: The voxel-level and ROI-level analyses demonstrated highly significant (P < .001) modifications of DTI measurements in patients at several levels: cerebellar peduncles, corticospinal tracts and posterior thalamic radiations, posterior corpus callosum, external capsule, anterior thalamic radiation, superior longitudinal fasciculi and corona radiata, optic nerves, and chiasm. The reduction of fractional anisotropy values in significant tracts was between 8% and 30%. Statistically significant correlations were found between motor impairment and fractional anisotropy in corticospinal tracts and commissural and associative tracts of the supratentorial brain. CONCLUSIONS: We demonstrated the involvement of several motor and nonmotor areas in the chronic damage associated with periventricular leukomalacia and showed new correlations between motor skills and DTI metrics. C1 [Arrigoni, F.; Peruzzo, D.] Sci Inst IRCCS Eugenio Medea, Neuroimaging Lab, Bosisio Parini, Italy. [Gagliardi, C.; Maghini, C.; Iammarrone, F. Servodio; Turconi, A. C.] Sci Inst IRCCS Eugenio Medea, Funct Neurorehabil Unit, Bosisio Parini, Italy. [Colombo, P.] Sci Inst IRCCS Eugenio Medea, Child Psychopathol Unit, Bosisio Parini, Italy. [Pierpaoli, C.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Triulzi, F.] Osped Maggiore Policlin, Fdn IRCCS Ca Granda, Dept Neuroradiol, Milan, Italy. RP Arrigoni, F (reprint author), Sci Inst IRCCS Eugenio Medea, Via Don L Monza 20, I-23842 Bosisio Parini, Lecco, Italy. EM filippo.arrigoni@bp.lnf.it RI ARRIGONI, FILIPPO/G-5828-2011; OI ARRIGONI, FILIPPO/0000-0002-5508-1149; Gagliardi, Chiara/0000-0001-9931-9879 FU Italian Ministry of Health FX This work was supported by the Italian Ministry of Health (Ricerca Corrente 2012 to A.C. Turconi). NR 36 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC NEURORADIOLOGY PI DENVILLE PA PO BOX 3000, DENVILLE, NJ 07834-9349 USA SN 0195-6108 EI 1936-959X J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD JUL PY 2016 VL 37 IS 7 BP 1347 EP 1353 DI 10.3174/ajnr.A4717 PG 7 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DS1NL UT WOS:000380362600024 PM 26988814 ER PT J AU Sigurdson, AJ Brenner, AV Roach, JA Goudeva, L Muller, JA Nerlich, K Reiners, C Schwab, R Pfeiffer, L Waldenberger, M Braganza, M Xu, L Sturgis, EM Yeager, M Chanock, SJ Pfeiffer, RM Abend, M Port, M AF Sigurdson, Alice J. Brenner, Alina V. Roach, James A. Goudeva, Lilia Mueller, Joerg A. Nerlich, Kai Reiners, Christoph Schwab, Robert Pfeiffer, Liliane Waldenberger, Melanie Braganza, Melissa Xu, Li Sturgis, Erich M. Yeager, Meredith Chanock, Stephen J. Pfeiffer, Ruth M. Abend, Michael Port, Matthias TI Selected single-nucleotide polymorphisms in FOXE1, SERPINA5, FTO, EVPL, TICAM1 and SCARB1 are associated with papillary and follicular thyroid cancer risk: replication study in a German population SO CARCINOGENESIS LA English DT Article ID COMMON GENETIC-VARIANTS; CUMULATIVE RISK; POOLED ANALYSIS; OVARIAN-CANCER; UNITED-STATES; CARCINOMA; OBESITY; SUSCEPTIBILITY; DETERMINANT; RADIATION AB We confirmed associations with papillary thyroid cancer risk and several FOXE1/HEMGN polymorphisms, as well as polymorphisms in SERPINA5, FTO, EVPL, TICAM1 and SCARB1. Polymorphisms in FOXE1, SERPINA5, FTO, TICAM1 and HSPA6 were also associated with risk of follicular thyroid cancer.Several single-nucleotide polymorphisms (SNPs) have been associated with papillary and follicular thyroid cancer (PTC and FTC, respectively) risk, but few have replicated. After analyzing 17525 tag SNPs in 1129 candidate genes, we found associations with PTC risk in SERPINA5, FTO, HEMGN (near FOXE1) and other genes. Here, we report results from a replication effort in a large independent PTC/FTC case-control study conducted in Germany. We evaluated the best tagging SNPs from our previous PTC study and additionally included SNPs in or near FOXE1 and NKX2-1 genes, known susceptibility loci for thyroid cancer. We genotyped 422 PTC and 130 FTC cases and 752 controls recruited from three German clinical centers. We used polytomous logistic regression to simultaneously estimate PTC and FTC associations for 79 SNPs based on log-additive models. We assessed effect modification by body mass index (BMI), gender and age for all SNPs, and selected SNP by SNP interactions. We confirmed associations with PTC and SNPs in FOXE1/HEMGN, SERPINA5 (rs2069974), FTO (rs8047395), EVPL (rs2071194), TICAM1 (rs8120) and SCARB1 (rs11057820) genes. We found associations with SNPs in FOXE1, SERPINA5, FTO, TICAM1 and HSPA6 and FTC. We found two significant interactions between FTO (rs8047395) and BMI (P = 0.0321) and between TICAM1 (rs8120) and FOXE1 (rs10984377) (P = 0.0006). Besides the known associations with FOXE1 SNPs, we confirmed additional PTC SNP associations reported previously. We also found several new associations with FTC risk and noteworthy interactions. We conclude that multiple variants and host factors might interact in complex ways to increase risk of PTC and FTC. C1 [Sigurdson, Alice J.; Brenner, Alina V.; Roach, James A.; Braganza, Melissa] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Goudeva, Lilia] Hannover Med Sch, Dept Transfus Med, Hannover, Germany. [Mueller, Joerg A.] Hannover Med Sch, Dept Nucl Med, Hannover, Germany. [Nerlich, Kai; Reiners, Christoph] Univ Hosp Wurzburg, Dept Nucl Med, Wurzburg, Germany. [Schwab, Robert] Fed Armed Forces Hosp, Dept Surg, Koblenz, Germany. [Pfeiffer, Liliane; Waldenberger, Melanie] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany. [Pfeiffer, Liliane; Waldenberger, Melanie] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany. [Xu, Li; Sturgis, Erich M.] Univ Texas MD Anderson Canc Ctr, Dept Head & Neck Surg, Houston, TX 77030 USA. [Yeager, Meredith; Chanock, Stephen J.] NCI, Lab Translat Genet, Bethesda, MD 20892 USA. [Pfeiffer, Ruth M.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Abend, Michael] Univ Ulm, Bundeswehr Inst Radiobiol, Neuherbergstr 11, D-80937 Munich, Germany. [Port, Matthias] Hannover Med Sch, Dept Hematol Hemostasis Oncol & Stem Cell Transpl, Hannover, Germany. RP Abend, M (reprint author), Univ Ulm, Bundeswehr Inst Radiobiol, Neuherbergstr 11, D-80937 Munich, Germany. EM michaelabend@bundeswehr.org RI Waldenberger, Melanie/B-5355-2014 OI Waldenberger, Melanie/0000-0003-0583-5093 FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health; German Ministry of Defense FX Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health; German Ministry of Defense. NR 41 TC 2 Z9 2 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 EI 1460-2180 J9 CARCINOGENESIS JI Carcinogenesis PD JUL PY 2016 VL 37 IS 7 BP 677 EP 684 DI 10.1093/carcin/bgw047 PG 8 WC Oncology SC Oncology GA DT0XJ UT WOS:000381206000004 PM 27207655 ER PT J AU Bassig, BA Zhang, LP Vermeulen, R Tang, XJ Li, GL Hu, W Guo, WH Purdue, MP Yin, SN Rappaport, SM Shen, M Ji, ZY Qiu, CY Ge, YC Hosgood, HD Reiss, B Wu, BH Xie, YX Li, LY Yue, F Freeman, LEB Blair, A Hayes, RB Huang, HL Smith, MT Rothman, N Lan, Q AF Bassig, Bryan A. Zhang, Luoping Vermeulen, Roel Tang, Xiaojiang Li, Guilan Hu, Wei Guo, Weihong Purdue, Mark P. Yin, Songnian Rappaport, Stephen M. Shen, Min Ji, Zhiying Qiu, Chuangyi Ge, Yichen Hosgood, H. Dean Reiss, Boris Wu, Banghua Xie, Yuxuan Li, Laiyu Yue, Fei Freeman, Laura E. Beane Blair, Aaron Hayes, Richard B. Huang, Hanlin Smith, Martyn T. Rothman, Nathaniel Lan, Qing TI Comparison of hematological alterations and markers of B-cell activation in workers exposed to benzene, formaldehyde and trichloroethylene SO CARCINOGENESIS LA English DT Article ID MYELOID PROGENITOR CELLS; NON-HODGKIN-LYMPHOMA; OCCUPATIONAL-EXPOSURE; CHINESE WORKERS; RISK; CANCER; METAANALYSIS; HEMATOTOXICITY; LEUKEMIA; COHORT AB The current study demonstrates differences in how cells derived from the myeloid versus the lymphoid lineage are affected by exposures to benzene, formaldeyde and TCE, all of which have been associated with specific hematologic cancers in epidemiologic studies.Benzene, formaldehyde (FA) and trichloroethylene (TCE) are ubiquitous chemicals in workplaces and the general environment. Benzene is an established myeloid leukemogen and probable lymphomagen. FA is classified as a myeloid leukemogen but has not been associated with non-Hodgkin lymphoma (NHL), whereas TCE has been associated with NHL but not myeloid leukemia. Epidemiologic associations between FA and myeloid leukemia, and between benzene, TCE and NHL are, however, still debated. Previously, we showed that these chemicals are associated with hematotoxicity in cross-sectional studies of factory workers in China, which included extensive personal monitoring and biological sample collection. Here, we compare and contrast patterns of hematotoxicity, monosomy 7 in myeloid progenitor cells (MPCs), and B-cell activation biomarkers across these studies to further evaluate possible mechanisms of action and consistency of effects with observed hematologic cancer risks. Workers exposed to benzene or FA, but not TCE, showed declines in cell types derived from MPCs, including granulocytes and platelets. Alterations in lymphoid cell types, including B cells and CD4+ T cells, and B-cell activation markers were apparent in workers exposed to benzene or TCE. Given that alterations in myeloid and lymphoid cell types are associated with hematological malignancies, our data provide biologic insight into the epidemiological evidence linking benzene and FA exposure with myeloid leukemia risk, and TCE and benzene exposure with NHL risk. C1 [Bassig, Bryan A.; Hu, Wei; Purdue, Mark P.; Shen, Min; Freeman, Laura E. Beane; Blair, Aaron; Rothman, Nathaniel; Lan, Qing] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Rockville, MD USA. [Zhang, Luoping; Guo, Weihong; Rappaport, Stephen M.; Ji, Zhiying; Smith, Martyn T.] Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA. [Vermeulen, Roel] Univ Utrecht, Inst Risk Assessment Sci, Utrecht, Netherlands. [Tang, Xiaojiang; Qiu, Chuangyi; Ge, Yichen; Wu, Banghua; Xie, Yuxuan; Li, Laiyu; Yue, Fei; Huang, Hanlin] Guangdong Poison Control Ctr, Guangzhou, Guangdong, Peoples R China. [Li, Guilan; Yin, Songnian] Chinese Ctr Dis Control & Prevent, Inst Occupat Hlth & Poison Control, Beijing, Peoples R China. [Hosgood, H. Dean] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Reiss, Boris] Univ Washington, Dept Environm & Occupat Hlth Sci, Seattle, WA 98195 USA. [Hayes, Richard B.] NYU, Dept Environm Med, Sch Med, Div Epidemiol, 550 1St Ave, New York, NY 10016 USA. RP Bassig, BA; Lan, Q (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Rockville, MD USA.; Zhang, LP (reprint author), Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA. EM bryan.bassig@nih.gov; luoping@berkeley.edu; qingl@mail.nih.gov RI Vermeulen, Roel/F-8037-2011; OI Vermeulen, Roel/0000-0003-4082-8163; Hayes, Richard/0000-0002-0918-661X FU National Cancer Institute; National Institute of Environmental Health Sciences [P42ES04705, P30ES01896, R01ES017452]; Northern California Center for Occupational and Environmental Health; Department of Science and Technology of Guangdong Province, China [2007A050100004]; National Institutes of Health [P42ES04705, P30ES01896, RO1ES06721, P42ES05948, P30ES10126, N01-CO-12400]; SAIC-Frederick, Inc. FX TCE study: National Institutes of Health and National Cancer Institute; National Institute of Environmental Health Sciences (P42ES04705, P30ES01896); Northern California Center for Occupational and Environmental Health; Department of Science and Technology of Guangdong Province, China (2007A050100004). FA study: National Cancer Institute; National Institute of Environmental Health Sciences (P42ES04705, R01ES017452); the Northern California Center for Occupational and Environmental Health; Department of Science and Technology of Guangdong Province, China (2007A050100004). Benzene study: National Institutes of Health (RO1ES06721, P42ES04705, P30ES01896, P42ES05948, P30ES10126) and National Institutes of Health contract N01-CO-12400 with SAIC-Frederick, Inc. NR 46 TC 1 Z9 1 U1 3 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 EI 1460-2180 J9 CARCINOGENESIS JI Carcinogenesis PD JUL PY 2016 VL 37 IS 7 BP 692 EP 700 DI 10.1093/carcin/bgw053 PG 9 WC Oncology SC Oncology GA DT0XJ UT WOS:000381206000006 PM 27207665 ER PT J AU Williams, R White, P Nieto, J Vieira, D Francois, F Hamilton, F AF Williams, Renee White, Pascale Nieto, Jose Vieira, Dorice Francois, Fritz Hamilton, Frank TI Colorectal Cancer in African Americans: An Update SO CLINICAL AND TRANSLATIONAL GASTROENTEROLOGY LA English DT Review ID BLACK-WHITE DIFFERENCES; RANDOMIZED-CLINICAL-TRIAL; PRIMARY-CARE; RACIAL-DIFFERENCES; UNITED-STATES; SCREENING COLONOSCOPY; SOCIOECONOMIC-STATUS; ETHNIC DISPARITIES; HEALTH DISPARITIES; RECTAL-CANCER AB This review is an update to the American College of Gastroenterology (ACG) Committee on Minority Affairs and Cultural Diversity's paper on colorectal cancer (CRC) in African Americans published in 2005. Over the past 10 years, the incidence and mortality rates of CRC in the United States has steadily declined. However, reductions have been strikingly much slower among African Americans who continue to have the highest rate of mortality and lowest survival when compared with all other racial groups. The reasons for the health disparities are multifactorial and encompass physician and patient barriers. Patient factors that contribute to disparities include poor knowledge of benefits of CRC screening, limited access to health care, insurance status along with fear and anxiety. Physician factors include lack of knowledge of screening guidelines along with disparate recommendations for screening. Earlier screening has been recommended as an effective strategy to decrease observed disparities; currently the ACG and American Society of Gastrointestinal Endoscopists recommend CRC screening in African Americans to begin at age 45. Despite the decline in CRC deaths in all racial and ethnic groups, there still exists a significant burden of CRC in African Americans, thus other strategies including educational outreach for health care providers and patients and the utilization of patient navigation systems emphasizing the importance of screening are necessary. These strategies have been piloted in both local communities and Statewide resulting in notable significant decreases in observed disparities. C1 [Williams, Renee; Vieira, Dorice; Francois, Fritz] NYU, Sch Med, Bellevue Hosp Ctr, 462 First Ave,Room CD 697, New York, NY 10016 USA. [White, Pascale] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Nieto, Jose] Borland Groover Clin, Jacksonville, FL USA. [Hamilton, Frank] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Williams, R (reprint author), NYU, Sch Med, Bellevue Hosp Ctr, 462 First Ave,Room CD 697, New York, NY 10016 USA. EM Renee.Williams@nyumc.org OI Francois, Fritz/0000-0003-4491-2637; Williams, Renee/0000-0001-5530-2207; Vieira, Dorice/0000-0003-4232-9413 NR 95 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2155-384X J9 CLIN TRANSL GASTROEN JI Clin. Transl. Gastroenterol. PD JUL PY 2016 VL 7 AR e185 DI 10.1038/ctg.2016.36 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DU3CD UT WOS:000382087500008 PM 27467183 ER PT J AU Catanzaro, D Shackney, SE Schaffer, AA Schwartz, R AF Catanzaro, Daniele Shackney, Stanley E. Schaffer, Alejandro A. Schwartz, Russell TI Classifying the Progression of Ductal Carcinoma from Single-Cell Sampled Data via Integer Linear Programming: A Case Study SO IEEE-ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS LA English DT Article DE Tumor profiling; single-cell sequencing; ductal carcinoma of the breast; phylogeny estimation; parsimony criterion; computational biology; distance methods; network design; combinatorial optimization; mixed integer linear programming ID HETEROGENEOUS BREAST-TUMORS; IN-SITU; CANCER; EVOLUTION; GENOME; PATHWAYS; AMPLIFICATION; GLIOBLASTOMA; HALLMARKS; INFERENCE AB Ductal Carcinoma In Situ (DCIS) is a precursor lesion of Invasive Ductal Carcinoma (IDC) of the breast. Investigating its temporal progression could provide fundamental new insights for the development of better diagnostic tools to predict which cases of DCIS will progress to IDC. We investigate the problem of reconstructing a plausible progression from single-cell sampled data of an individual with synchronous DCIS and IDC. Specifically, by using a number of assumptions derived from the observation of cellular atypia occurring in IDC, we design a possible predictive model using integer linear programming (ILP). Computational experiments carried out on a preexisting data set of 13 patients with simultaneous DCIS and IDC show that the corresponding predicted progression models are classifiable into categories having specific evolutionary characteristics. The approach provides new insights into mechanisms of clonal progression in breast cancers and helps illustrate the power of the ILP approach for similar problems in reconstructing tumor evolution scenarios under complex sets of constraints. C1 [Catanzaro, Daniele] Catholic Univ Louvain, Louvain Sch Management, B-1517000 Mons, Belgium. [Catanzaro, Daniele] Catholic Univ Louvain, Ctr Operat Res & Econometr, B-1517000 Mons, Belgium. [Shackney, Stanley E.] Drexel Univ, Sch Med, Dept Human Oncol, Pittsburgh, PA 15243 USA. [Shackney, Stanley E.] Drexel Univ, Sch Med, Dept Human Genet, Pittsburgh, PA 15243 USA. [Schaffer, Alejandro A.] NCBI, Computat Biol Branch, NIH, Bethesda, MD 20894 USA. [Schwartz, Russell] Carnegie Mellon Univ, Dept Biol Sci, Pittsburgh, PA USA. [Schwartz, Russell] Carnegie Mellon Univ, Computat Biol Dept, Pittsburgh, PA USA. RP Catanzaro, D (reprint author), Catholic Univ Louvain, Louvain Sch Management, B-1517000 Mons, Belgium.; Catanzaro, D (reprint author), Catholic Univ Louvain, Ctr Operat Res & Econometr, B-1517000 Mons, Belgium. EM daniele.catanzaro@uclouvain.be; aschaffe@helix.nih.gov; russells@andrew.cmu.edu RI Schwartz, Russell/A-1998-2016; OI Schwartz, Russell/0000-0002-4970-2252; Catanzaro, Daniele/0000-0001-9427-1562 FU Belgian National Fund for Scientific Research (FRS-FNRS); US National Institutes of Health [1R01CA140214, 1R01AI076318]; Intramural Research Program of the NIH, NLM FX This research was supported in part by the Belgian National Fund for Scientific Research (FRS-FNRS) (D.C), US National Institutes of Health grants 1R01CA140214 (R.S.) and 1R01AI076318 (R.S.), and the Intramural Research Program of the NIH, NLM (A.A.S.). The authors thank the anonymous reviewers whose insightful suggestions helped them improve the manuscript. NR 50 TC 1 Z9 1 U1 2 U2 3 PU IEEE COMPUTER SOC PI LOS ALAMITOS PA 10662 LOS VAQUEROS CIRCLE, PO BOX 3014, LOS ALAMITOS, CA 90720-1314 USA SN 1545-5963 EI 1557-9964 J9 IEEE ACM T COMPUT BI JI IEEE-ACM Trans. Comput. Biol. Bioinform. PD JUL-AUG PY 2016 VL 13 IS 4 BP 643 EP 655 DI 10.1109/TCBB.2015.2476808 PG 13 WC Biochemical Research Methods; Computer Science, Interdisciplinary Applications; Mathematics, Interdisciplinary Applications; Statistics & Probability SC Biochemistry & Molecular Biology; Computer Science; Mathematics GA DT5FI UT WOS:000381506500005 PM 26353381 ER PT J AU Miller, A Yeskey, K Garantziotis, S Arnesen, S Bennett, A O'Fallon, L Thompson, C Reinlib, L Masten, S Remington, J Love, C Ramsey, S Rosselli, R Galluzzo, B Lee, J Kwok, R Hughes, J AF Miller, Aubrey Yeskey, Kevin Garantziotis, Stavros Arnesen, Stacey Bennett, April O'Fallon, Liam Thompson, Claudia Reinlib, Les Masten, Scott Remington, James Love, Cindy Ramsey, Steve Rosselli, Richard Galluzzo, Betsy Lee, Joy Kwok, Richard Hughes, Joseph TI Integrating Health Research into Disaster Response: The New NIH Disaster Research Response Program SO INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH LA English DT Editorial Material DE disasters; disaster research; disaster epidemiology; environmental health; science preparedness; disaster risk reduction; strategic science ID COMMUNITY; EPIDEMIOLOGY; TOOL AB The need for high quality and timely disaster research has been a topic of great discussion over the past several years. Recent high profile incidents have exposed gaps in knowledge about the health impacts of disasters or the benefits of specific interventions-such was the case with the 2010 Gulf Oil Spill and recent events associated with lead-contaminated drinking water in Flint, Michigan, and the evolving health crisis related to Zika virus disease. Our inability to perform timely research to inform the community about health and safety risks or address specific concerns further heightens anxiety and distrust. Since nearly all disasters, whether natural or man-made, have an environmental health component, it is critical that specialized research tools and trained researchers be readily available to evaluate complex exposures and health effects, especially for vulnerable sub-populations such as the elderly, children, pregnant women, and those with socioeconomic and environmental disparities. In response, the National Institute of Environmental Health Science has initiated a Disaster Research Response Program to create new tools, protocols, networks of researchers, training exercises, and outreach involving diverse groups of stakeholders to help overcome the challenges of disaster research and to improve our ability to collect vital information to reduce the adverse health impacts and improve future preparedness. C1 [Miller, Aubrey; Bennett, April] NIEHS, Bethesda, MD 20892 USA. [Yeskey, Kevin; Galluzzo, Betsy; Lee, Joy] MDB Inc, Washington, DC 20036 USA. [Garantziotis, Stavros; O'Fallon, Liam; Thompson, Claudia; Reinlib, Les; Masten, Scott; Remington, James; Kwok, Richard; Hughes, Joseph] NIEHS, Res Triangle Pk, NC 27709 USA. [Arnesen, Stacey; Love, Cindy] Natl Lib Med, Bethesda, MD 20892 USA. [Ramsey, Steve; Rosselli, Richard] Social & Sci Syst Inc, Durham, NC 27703 USA. RP Miller, A (reprint author), NIEHS, Bethesda, MD 20892 USA. EM miller.aubrey@nih.gov; kyeskey@michaeldbaker.com; garantziotis@niehs.nih.gov; arneses@mail.nlm.nih.gov; april.bennett@nih.gov; ofallon@niehs.nih.gov; thompso1@niehs.nih.gov; reinlib@niehs.nih.gov; masten@niehs.nih.gov; remingtonj@niehs.nih.gov; lovec@mail.nlm.nih.gov; SRamsey@s-3.com; RRosselli@s-3.com; beagin@michaeldbaker.com; jlee@michaeldbaker.com; Richard.Kwok@nih.gov; hughes3@niehs.nih.gov RI masten, scott/R-1403-2016; Garantziotis, Stavros/A-6903-2009; Kwok, Richard/B-6907-2017 OI masten, scott/0000-0002-7847-181X; Garantziotis, Stavros/0000-0003-4007-375X; Kwok, Richard/0000-0002-6794-8360 NR 14 TC 0 Z9 0 U1 57 U2 65 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 1660-4601 J9 INT J ENV RES PUB HE JI Int. J. Environ. Res. Public Health PD JUL PY 2016 VL 13 IS 7 AR 676 DI 10.3390/ijerph13070676 PG 12 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA DS4OG UT WOS:000380759800052 ER PT J AU Zaleski, RT Egeghy, PP Hakkinen, PJ AF Zaleski, Rosemary T. Egeghy, Peter P. Hakkinen, Pertti J. TI Exploring Global Exposure Factors Resources for Use in Consumer Exposure Assessments SO INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH LA English DT Review DE consumer products; exposure factors; databases; exposure assessments; online; time-activity patterns; consumer behavior; household products ID PERSONAL CARE PRODUCTS; NONDIETARY INGESTION EXPOSURE; MOUTH FREQUENCY DATA; FACTORS HANDBOOK; COSMETIC PRODUCTS; RISK-ASSESSMENT; 21ST-CENTURY ROADMAP; YOUNG-CHILDREN; INDOOR AIR; CHEMICALS AB This publication serves as a global comprehensive resource for readers seeking exposure factor data and information relevant to consumer exposure assessment. It describes the types of information that may be found in various official surveys and online and published resources. The relevant exposure factors cover a broad range, including general exposure factor data found in published compendia and databases and resources about specific exposure factors, such as human activity patterns and housing information. Also included are resources on exposure factors related to specific types of consumer products and the associated patterns of use, such as for a type of personal care product or a type of children's toy. Further, a section on using exposure factors for designing representative exposure scenarios is included, along with a look into the future for databases and other exposure science developments relevant for consumer exposure assessment. C1 [Zaleski, Rosemary T.] ExxonMobil Biomed Sci Inc, 1545 Route 22 East, Annandale, NJ 08801 USA. [Egeghy, Peter P.] US EPA, Off Res & Dev, Natl Exposure Res Lab, Res Triangle Pk, NC 27711 USA. [Hakkinen, Pertti J.] Natl Lib Med, NIH, 6707 Democracy Blvd,Suite 510, Bethesda, MD 20894 USA. RP Zaleski, RT (reprint author), ExxonMobil Biomed Sci Inc, 1545 Route 22 East, Annandale, NJ 08801 USA. EM rosemary.t.zaleski@exxonmobil.com; egeghy.peter@epa.gov; pertti.hakkinen@nih.gov FU ExxonMobil Biomedical Sciences, Inc. FX The International Society of Exposure Science Symposium on Exploring Global Data Resources for Consumer Exposure Assessment served both as the inspiration for developing this publication, as well as the basis for much of the information provided in the document (costs of open access were paid for by ExxonMobil Biomedical Sciences, Inc.). The authors (symposium co-organizers) would like to thank all of the conference presenters for the information shared both at the symposium and for inclusion in this paper, as well as help in manuscript review, by recognizing them as contributors below. NR 139 TC 0 Z9 0 U1 3 U2 3 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 1660-4601 J9 INT J ENV RES PUB HE JI Int. J. Environ. Res. Public Health PD JUL PY 2016 VL 13 IS 7 AR 744 DI 10.3390/ijerph13070744 PG 26 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA DS4OG UT WOS:000380759800120 ER PT J AU Dong, BX Somani, AK Love, PE Zheng, X Chen, XQ Zhang, JY AF Dong, Baoxia Somani, Ally-Khan Love, Paul E. Zheng, Xuan Chen, Xiequn Zhang, Jinyi TI CD5-mediated inhibition of TCR signaling proceeds normally in the absence of SHP-1 SO INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE LA English DT Article DE T-cell antigen receptor signaling; tyrosine phosphatase; thymic selection; CD5; SHP-1 ID CELL ANTIGEN RECEPTOR; CYTOPLASMIC FREE CALCIUM; PROTEIN-KINASE-C; TYROSINE-PHOSPHATASE; NEGATIVE REGULATION; T-CELLS; B-CELLS; PHOSPHATIDYLINOSITOL 3-KINASE; CD5 EXPRESSION; ACTIVATION AB The CD5 transmembrane glycoprotein functions as a co-receptor in the signaling pathway linking T-cell antigen receptor (TCR) engagement to activation and differentiation. Although CD5 effects on TCR signaling have been shown to be primarily inhibitory, the underlying mechanisms remain unclear. In view of recent data revealing the ability of CD5 to associate with the SHP-1 tyrosine phosphatase, a protein that also downregulates TCR signaling, we examined the role of SHP-1 in modulating CD5 function using thymocytes from SHP-1-deficient viable motheaten (me(v)) mice. The results revealed the association of SHP-1 with CD5 to be markedly increased following TCR stimulation and indicated that this interaction was enhanced by and was dependent on CD5 tyrosine phosphorylation. However, there was no difference of the tyrosine phosphorylation status of CD5 between resting and TCR-stimulated cells in SHP-1-deficient compared to wildtype thymocytes. Lack of SHP-1 activity did not affect the levels of CD5 surface expression, CD5 co-immunoprecipitable tyrosine phosphatase activity and intracellular calcium increase following co-crosslinking of the TCR and CD5. Similarly, an analysis of T-cell thymocyte populations in me(v) mice expressing an H-Y transgene as well as a construct mediating T-cell restricted CD5 overexpression, revealed that the reduction in the positive selection conferred by CD5 overexpression was unaffected by SHP-1 deficiency. CD5 is not a SHP-1 substrate and SHP-1 is not required for and possibly not involved in the CD5-mediated modulation of TCR signaling. C1 [Dong, Baoxia; Zheng, Xuan; Chen, Xiequn] Fourth Mil Med Univ, Xijing Hosp, Dept Haematol, Xian 710032, Shaanxi, Peoples R China. [Somani, Ally-Khan; Zhang, Jinyi] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. [Love, Paul E.] NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. [Somani, Ally-Khan] Indiana Univ Sch Med, Dept Dermatol, Indianapolis, IN 46202 USA. RP Dong, BX (reprint author), Fourth Mil Med Univ, Xijing Hosp, Dept Haematol, Xian 710032, Shaanxi, Peoples R China.; Zhang, JY (reprint author), Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. EM dongbaoxia18@163.com; jinyi@mshri.on.ca NR 55 TC 0 Z9 0 U1 2 U2 2 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1107-3756 EI 1791-244X J9 INT J MOL MED JI Int. J. Mol. Med. PD JUL PY 2016 VL 38 IS 1 BP 45 EP 56 DI 10.3892/ijmm.2016.2592 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DT2CZ UT WOS:000381289700006 PM 27221212 ER PT J AU Campbell, CMP Viscidi, RP Torres, BN Lin, HY Fulp, W Abrahamsen, M Lazcano-Ponce, E Villa, LL Kreimer, AR Giuliano, AR AF Campbell, Christine M. Pierce Viscidi, Raphael P. Torres, B. Nelson Lin, Hui-Yi Fulp, William Abrahamsen, Martha Lazcano-Ponce, Eduardo Villa, Luisa L. Kreimer, Aimee R. Giuliano, Anna R. TI Human Papillomavirus (HPV) L1 Serum Antibodies and the Risk of Subsequent Oral HPV Acquisition in Men: The HIM Study SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE oral HPV; HPV16; antibodies; serology; men ID CANCER INCIDENCE; NATURAL-HISTORY; INFECTION; VACCINATION; RESPONSES; COHORT AB The role of antibody-mediated immunity in preventing newly acquired oral human papillomavirus (HPV) is not well understood. Among 1618 men participating in the HPV Infection in Men (HIM) Study, we evaluated oral rinses for HPV DNA and baseline sera for HPV-6, -11, -16, and -18 L1 antibodies. Thirty percent of men (486) were seropositive for >= 1 HPV type, and 25 men developed incident oral HPV infection (HPV-6 was detected in 7, HPV-11 in 0, HPV-16 in 17, and HPV-18 in 1). Cox models revealed that men with circulating antibodies to HPV-6, -11, -16, or -18 were not less likely to acquire type-specific oral HPV than men without antibodies (hazard ratio for the risk of acquiring HPV-6, -11, -16, or -18, 1.63; 95% confidence interval,.56-4.76). C1 [Campbell, Christine M. Pierce; Torres, B. Nelson; Abrahamsen, Martha; Giuliano, Anna R.] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL USA. [Lin, Hui-Yi; Fulp, William] H Lee Moffitt Canc Ctr & Res Inst, Dept Biostat & Bioinformat, Tampa, FL USA. [Viscidi, Raphael P.] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. [Kreimer, Aimee R.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Lazcano-Ponce, Eduardo] Inst Nacl Salud Publ, Ctr Invest Salud Poblac, Cuernavaca, Morelos, Mexico. [Villa, Luisa L.] Univ Sao Paulo, Sch Med, Dept Radiol & Oncol, BR-05508 Sao Paulo, Brazil. [Villa, Luisa L.] Canc Inst State Sao Paulo, Sao Paulo, Brazil. [Lin, Hui-Yi] Louisiana State Univ, Sch Publ Hlth, Hlth Sci Ctr, Dept Biostat, New Orleans, LA USA. [Fulp, William] Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent, 1124 Columbia St, Seattle, WA 98104 USA. RP Giuliano, AR (reprint author), MRC CANCONT, Ctr Infect Res Canc, 12902 Magnolia Dr, Tampa, FL 33612 USA. EM anna.giuliano@moffitt.org FU NCI, NIH [R01 CA098803]; National Cancer Institute Intramural Program; Investigator-Initiated Studies Program, Merck Sharp and Dohme; American Cancer Society [PF-13-222-01-MPC] FX This work was supported by the NCI, NIH (grant R01 CA098803 to A. R. G.); the National Cancer Institute Intramural Program (to A. R. K.); the Investigator-Initiated Studies Program, Merck Sharp and Dohme (to A. R. G.); and the American Cancer Society (postdoctoral fellowship PF-13-222-01-MPC to C. M. P. C.). NR 15 TC 0 Z9 0 U1 2 U2 2 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 JUL 1 PY 2016 VL 214 IS 1 BP 45 EP 48 DI 10.1093/infdis/jiw083 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DR3SF UT WOS:000379822200008 ER PT J AU Beigi, RH Noguchi, L Brown, G Piper, J Watts, DH AF Beigi, Richard H. Noguchi, Lisa Brown, Gina Piper, Jeanna Watts, D. Heather TI Performing Drug Safety Research During Pregnancy and Lactation: Biomedical HIV Prevention Research as a Template SO JOURNAL OF WOMENS HEALTH LA English DT Article ID TO-CHILD TRANSMISSION; PREEXPOSURE PROPHYLAXIS; PRETERM DELIVERY; WOMEN; RISK; INFECTION; MEDICATIONS; UGANDA; TERM; PHARMACOKINETICS AB Evidence-based guidance regarding use of nearly all pharmaceuticals by pregnant and lactating women is limited. Models for performing research may assist in filling these knowledge gaps. Internationally, reproductive age women are at high risk of human immunodeficiency virus (HIV) acquisition. Susceptibility to HIV infection may be increased during pregnancy, and risk of maternal-child transmission is increased with incident HIV infection during pregnancy and lactation. A multidisciplinary meeting of experts was convened at the United States National Institutes of Health to consider paradigms for drug research in pregnancy and lactation applicable to HIV prevention. This report summarizes the meeting proceedings and describes a framework for research on candidate HIV prevention agent use during pregnancy and lactation that may also have broader applications to other pharmaceutical products. C1 [Beigi, Richard H.] Univ Pittsburgh, Med Ctr, Div Reprod Infect Dis, Dept Obstet Gynecol & Reprod Sci,Magee Womens, 300 Halket St, Pittsburgh, PA 15213 USA. [Beigi, Richard H.; Noguchi, Lisa] Magee Womens Res Inst, Microbicide Trials Network, Pittsburgh, PA USA. [Noguchi, Lisa] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Brown, Gina] NIH, Off AIDS Res, Bldg 10, Bethesda, MD 20892 USA. [Piper, Jeanna] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Watts, D. Heather] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Beigi, RH (reprint author), Univ Pittsburgh, Med Ctr, Div Reprod Infect Dis, Dept Obstet Gynecol & Reprod Sci,Magee Womens, 300 Halket St, Pittsburgh, PA 15213 USA. EM rbeigi@mail.magee.edu FU National Institute of Allergy and Infectious Diseases, Division of AIDS, National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland FX Funding for the meeting was provided by National Institute of Allergy and Infectious Diseases, Division of AIDS, National Institutes of Health, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. All authors planned and attended the meeting, reviewed all of the relevant literature, and reviewed all drafts of the manuscript. NR 48 TC 1 Z9 1 U1 2 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 EI 1931-843X J9 J WOMENS HEALTH JI J. Womens Health PD JUL PY 2016 VL 25 IS 7 BP 761 EP 766 DI 10.1089/jwh.2013.4398 PG 6 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA DS5GB UT WOS:000380808300016 PM 23808668 ER PT J AU Awuah, P Bera, TK Folivi, M Chertov, O Pastan, I AF Awuah, Prince Bera, Tapan K. Folivi, Messan Chertov, Oleg Pastan, Ira TI Reduced Shedding of Surface Mesothelin Improves Efficacy of Mesothelin-Targeting Recombinant Immunotoxins SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID EXPRESSING TUMOR XENOGRAFTS; PANCREATIC-CANCER; MONOCLONAL-ANTIBODY; POTENTIATING FACTOR; ANTITUMOR-ACTIVITY; SOLID TUMORS; IN-VITRO; THERAPY; OVARIAN; SS1P AB Mesothelin (MSLN) is a differentiation antigen that is highly expressed in many epithelial cancers. MSLN is an important therapeutic target due to its high expression in cancers and limited expression in normal human tissues. Although it has been assumed that shed antigen is a barrier to immunotoxin action, a modeling study predicted that shed MSLN may enhance the action of MSLN-targeting recombinant immunotoxins such as SS1P and similar therapeutics by facilitating their redistribution within tumors. We aimed to determine whether shed MSLN enhances or reduces the antitumor effect of MSLN-targeting immunotoxins SS1P and RG7787. We engineered a cell line, A431/G9 (TACE mutant) that expresses a mutant form of MSLN in which the TNF-converting enzyme protease site is replaced with GGGS. We compared the response of the TACE-mutant cells with immunotoxins SS1P and RG7787 with that of the parental A431/H9 cell line. We show that TACE-mutant cells shed 80% less MSLN than A431/H9 cells, that TACE-mutant cells show a 2- to 3-fold increase in MSLN-targeted immunotoxin uptake, and that they are about 5-fold more sensitive to SS1P killing in cell culture. Tumors with reduced shedding respond significantly better to treatment with SS1P and RG7787. Our data show that MSLN shedding is an impediment to the antitumor activity of SS1P and RG7787. Approaches that decrease MSLN shedding could enhance the efficacy of immunotoxins and immunoconjugates targeting MSLN-expressing tumors. (C) 2016 AACR. C1 [Awuah, Prince; Bera, Tapan K.; Folivi, Messan; Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. [Chertov, Oleg] Leidos Biomed Inc, Canc Res Technol Program, Frederick, MD USA. RP Pastan, I (reprint author), NCI, NIH, 37 Convent Dr,Room 5106, Bethesda, MD 20892 USA. EM pastani@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; National Cancer Institute, NIH [HHSN261200800001E] FX This work was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and by the National Cancer Institute, NIH, Contract HHSN261200800001E (to O. Chertov). NR 40 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 EI 1538-8514 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JUL PY 2016 VL 15 IS 7 BP 1648 EP 1655 DI 10.1158/1535-7163.MCT-15-0863 PG 8 WC Oncology SC Oncology GA DS9FC UT WOS:000381087200021 PM 27196771 ER PT J AU Gurard-Levin, ZA Wilson, LOW Pancaldi, V Postel-Vinay, S Sousa, FG Reyes, C Marangoni, E Gentien, D Valencia, A Pommier, Y Cottu, P Almouzni, G AF Gurard-Levin, Zachary A. Wilson, Laurence O. W. Pancaldi, Vera Postel-Vinay, Sophie Sousa, Fabricio G. Reyes, Cecile Marangoni, Elisabetta Gentien, David Valencia, Alfonso Pommier, Yves Cottu, Paul Almouzni, Genevieve TI Chromatin Regulators as a Guide for Cancer Treatment Choice SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID NEGATIVE BREAST-CANCER; GENE-EXPRESSION; INDUCTION CHEMOTHERAPY; RANDOM FORESTS; CLASSIFICATION; CENTROMERES; RESISTANCE; CHAPERONES; CELLS; EPIGENETICS AB The limited capacity to predict a patient's response to distinct chemotherapeutic agents is a major hurdle in cancer management. The efficiency of a large fraction of current cancer therapeutics (radio-and chemotherapies) is influenced by chromatin structure. Reciprocally, alterations in chromatin organization may affect resistance mechanisms. Here, we explore how the misexpression of chromatin regulators-factors involved in the establishment and maintenance of functional chromatin domains-can inform about the extent of docetaxel response. We exploit Affymetrix and NanoString gene expression data for a set of chromatin regulators generated from breast cancer patient-derived xenograft models and patient samples treated with doc-etaxel. Random Forest classification reveals specific panels of chromatin regulators, including key components of the SWI/SNF chromatin remodeler, which readily distinguish docetaxel highresponders and poor-responders. Further exploration of SWI/SNF components in the comprehensive NCI-60 dataset reveals that the expression inversely correlates with docetaxel sensitivity. Finally, we show that loss of the SWI/SNF subunit BRG1 (SMARCA4) in a model cell line leads to enhanced docetaxel sensitivity. Altogether, our findings point toward chromatin regulators as biomarkers for drug response as well as therapeutic targets to sensitize patients toward docetaxel and combat drug resistance. (C) 2016 AACR. C1 [Gurard-Levin, Zachary A.; Wilson, Laurence O. W.; Almouzni, Genevieve] PSL Res Univ, CNRS, Inst Curie, UMR3664,Equipe Labellisee Ligue Canc, Paris, France. [Gurard-Levin, Zachary A.; Wilson, Laurence O. W.; Almouzni, Genevieve] Univ Paris 06, Sorbonne Univ, CNRS, UMR3664, Paris, France. [Pancaldi, Vera; Valencia, Alfonso] Care of Fernandez M, Spanish Natl Canc Res Ctr CNIO, Madrid, Spain. [Postel-Vinay, Sophie] Gustave Roussy, DITEP Dept Innovat Therapeut & Essais Precoces, Villejuif, France. [Postel-Vinay, Sophie] Gustave Roussy, Inserm Unit U981, Villejuif, France. [Postel-Vinay, Sophie] Univ Paris 11, Univ Paris Saclay, Fac Med, Le Kremlin Bicetre, France. [Sousa, Fabricio G.; Pommier, Yves] NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Sousa, Fabricio G.; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Reyes, Cecile; Marangoni, Elisabetta; Gentien, David] PSL Res Univ, Inst Curie, Translat Res Dept, Genom Platform, Paris, France. [Cottu, Paul] Inst Curie, Med Oncol, Paris, France. RP Almouzni, G (reprint author), PSL Res Univ, CNRS, Inst Curie, UMR3664,Equipe Labellisee Ligue Canc, Paris, France.; Almouzni, G (reprint author), Univ Paris 06, Sorbonne Univ, CNRS, UMR3664, Paris, France.; Gurard-Levin, ZA (reprint author), Inst Curie, 26 Rue Ulm, F-75005 Paris, France. EM zachary.gurard-levin@curie.fr; genevieve.almouzni@curie.fr RI Sousa, Fabricio/O-8878-2015; Pancaldi, Vera/I-2555-2015 OI Sousa, Fabricio/0000-0003-0444-754X; valencia, alfonso/0000-0002-8937-6789; Pancaldi, Vera/0000-0002-7433-624X FU la Ligue Nationale contre le Cancer (Equipe labellisee Ligue); European Commission Network of Excellence EpiGeneSys [HEALTH-F4-2010-257082]; ERC [2009AdG_20090506, 678563]; European Commission [FP7_HEALTH-2010-259743, ANR-11-LABX-0044_DEEP, ANR-10-IDEX-0001-02 PSL, ANR-12-BSV5-0022-02, ANR-14-CE16-0009, ANR-14-CE100013]; Aviesan ITMO cancer project "Epigenomics of breast cancer; Grant "INCa-DGOS-4654" [SIRIC11-002]; FEBS fellowship; NIH Intramural Program, Center for Cancer Research [Z01 BC 006150]; [ANR10-IDEX-0001-02 PSL]; [ANR-11-LBX-0044] FX G. Almouzni's team is supported by la Ligue Nationale contre le Cancer (Equipe labellisee Ligue), the European Commission Network of Excellence EpiGeneSys [HEALTH-F4-2010-257082; an EpiGeneSys small call award to Z.A. Gurard-Levin and V. Pancaldi (2014)] ERC Advanced Grant 2009AdG_20090506 "Eccentric," ERC Proof of Concept No 678563 "EPOCH28" to G. Almouzni, the European Commission large-scale integrating project FP7_HEALTH-2010-259743 "MODHEP," ANR-11-LABX-0044_DEEP and ANR-10-IDEX-0001-02 PSL, ANR "CHAPINHIB" ANR-12-BSV5-0022-02, ANR "Epicure" ANR-14-CE16-0009, ANR "CELLECTCHIP" ANR-14-CE100013, and Aviesan ITMO cancer project "Epigenomics of breast cancer." Acquisition of the Nanostring platform was initiated and supported by ANR10-IDEX-0001-02 PSL, ANR-11-LBX-0044, and Grant "INCa-DGOS-4654" SIRIC11-002. V. Pancaldi is supported by a FEBS fellowship. Y. Pommier and F.G. Sousa were supported by the NIH Intramural Program, Center for Cancer Research (Z01 BC 006150). NR 58 TC 1 Z9 1 U1 1 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 EI 1538-8514 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JUL PY 2016 VL 15 IS 7 BP 1768 EP 1777 DI 10.1158/1535-7163.MCT-15-1008 PG 10 WC Oncology SC Oncology GA DS9FC UT WOS:000381087200032 PM 27196757 ER PT J AU Hammel, M Amlanjyoti, D Reyes, FE Chen, JH Parpana, R Tang, HYH Larabell, CA Tainer, JA Adhya, S AF Hammel, Michal Amlanjyoti, Dhar Reyes, Francis E. Chen, Jian-Hua Parpana, Rochelle Tang, Henry Y. H. Larabell, Carolyn A. Tainer, John A. Adhya, Sankar TI HU multimerization shift controls nucleoid compaction SO SCIENCE ADVANCES LA English DT Article ID X-RAY-SCATTERING; BINDING PROTEIN HU; ESCHERICHIA-COLI; DNA-BINDING; BIOLOGICAL MACROMOLECULES; CRYSTAL-STRUCTURE; GENE-EXPRESSION; BENT DNA; SAXS; TRANSCRIPTION AB Molecular mechanisms controlling functional bacterial chromosome (nucleoid) compaction and organization are surprisingly enigmatic but partly depend on conserved, histone-like proteins HU alpha alpha and HU alpha beta and their interactions that span the nanoscale and mesoscale from protein-DNA complexes to the bacterial chromosome and nucleoid structure. We determined the crystal structures of these chromosome-associated proteins in complex with native duplex DNA. Distinct DNA binding modes of HU alpha alpha and HU alpha beta elucidate fundamental features of bacterial chromosome packing that regulate gene transcription. By combining crystal structures with solution x-ray scattering results, we determined architectures of HU-DNA nucleoproteins in solution under near-physiological conditions. These macromolecular conformations and interactions result in contraction at the cellular level based on in vivo imaging of native unlabeled nucleoid by soft x-ray tomography upon HU beta and ectopic HU alpha 38 expression. Structural characterization of charge-altered HU alpha alpha-DNA complexes reveals an HU molecular switch that is suitable for condensing nucleoid and reprogramming noninvasive Escherichia coli into an invasive form. Collective findings suggest that shifts between networking and cooperative and noncooperative DNA-dependent HU multimerization control DNA compaction and supercoiling independently of cellular topoisomerase activity. By integrating x-ray crystal structures, x-ray scattering, mutational tests, and x-ray imaging that span from protein-DNA complexes to the bacterial chromosome and nucleoid structure, we show that defined dynamic HU interaction networks can promote nucleoid reorganization and transcriptional regulation as efficient general microbial mechanisms to help synchronize genetic responses to cell cycle, changing environments, and pathogenesis. C1 [Hammel, Michal; Reyes, Francis E.; Parpana, Rochelle; Tang, Henry Y. H.; Larabell, Carolyn A.; Tainer, John A.] Lawrence Berkeley Natl Lab, Mol Biophys & Integrated Bioimaging, Berkeley, CA 94720 USA. [Amlanjyoti, Dhar; Adhya, Sankar] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. [Chen, Jian-Hua; Larabell, Carolyn A.] Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA. [Tainer, John A.] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, 1515 Holcombe Blvd, Houston, TX 77030 USA. RP Hammel, M; Tainer, JA (reprint author), Lawrence Berkeley Natl Lab, Mol Biophys & Integrated Bioimaging, Berkeley, CA 94720 USA.; Tainer, JA (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM mhammel@lbl.gov; jatainer@lbl.gov FU NCI NIH HHS [P01 CA092584]; NIGMS NIH HHS [P41 GM103445, R01 GM105404] NR 57 TC 1 Z9 1 U1 6 U2 7 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 2375-2548 J9 SCI ADV JI Sci. Adv. PD JUL PY 2016 VL 2 IS 7 AR e1600650 DI 10.1126/sciadv.1600650 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT9GQ UT WOS:000381805300035 PM 27482541 ER PT J AU Tian, PF Jones, RW Yu, F AF Tian, Pengfei Jones, Richard W. Yu, Fei TI Elliptical modelling of hysteresis operating characteristics in a dielectric elastomer tubular actuator SO SMART MATERIALS AND STRUCTURES LA English DT Article DE high voltage power supply; slew-rate; hysteresis; ellipse; dielectric elastomer; tubular actuator; linearization ID COMPENSATION; FABRICATION; DAMPERS AB A dielectric elastomer (DE) tubular actuator, based on compliant metal electrode technology, exhibits hysteresis-like characteristics when driven with a low power rated high voltage power supply (HVPS). This behavior occurs mainly because the DE actuator acts as a capacitive load compromising the 'slew rate' of the HVPS during the actuator's operation. The motivation of this contribution is to investigate the use of elliptical modelling approaches for capturing the hysteresis characteristics exhibited by the DE tubular actuator when it is driven by a low cost low power rated HVPS. The DE tubular actuator considered in this work demonstrates asymmetric hysteresis behaviour due to the nonlinear voltage-strain behaviour of the actuator. A linearization filter placed in series with the actuator (during its operation) ensures a symmetric hysteresis characteristic that can then be modelled using an ellipse-based approach. Elliptical models come in many forms with the two most popular being the constrained general conic form and the general parametric form. Elliptical-based hysteresis model fits are carried out on experimental data obtained from the application of periodic input voltages, at a number of different low-frequencies, to the tubular actuator. The range of frequencies used is related to the possible use of the tubular actuator for attenuating low frequency vibration during DE actuator-based load positioning applications. Constrained conic and general parametric forms of elliptical model are used for modelling the hysteresis characteristics of the DE actuator and rate dependent models developed based on both approaches. The sensitivity of both of these rate dependent models to small inaccuracies in model parameters was then investigated. The general parametric form was found to be more robust in this respect. C1 [Tian, Pengfei; Yu, Fei] Univ Southern Denmark, Mads Clausen Inst, Alsion 2, DK-6400 Sonderborg, Denmark. [Jones, Richard W.] Univ York, Dept Comp Sci, York YO10 5DD, N Yorkshire, England. [Tian, Pengfei] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Yu, F (reprint author), Univ Southern Denmark, Mads Clausen Inst, Alsion 2, DK-6400 Sonderborg, Denmark. EM pengfei.tian@nih.gov; richardwjones1014@hotmail.com; fei@mci.sdu.dk NR 37 TC 0 Z9 0 U1 2 U2 5 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0964-1726 EI 1361-665X J9 SMART MATER STRUCT JI Smart Mater. Struct. PD JUL PY 2016 VL 25 IS 7 AR 075038 DI 10.1088/0964-1726/25/7/075038 PG 11 WC Instruments & Instrumentation; Materials Science, Multidisciplinary SC Instruments & Instrumentation; Materials Science GA DT5IY UT WOS:000381517900041 ER PT J AU Bachran, C Leppla, SH AF Bachran, Christopher Leppla, Stephen H. TI Tumor Targeting and Drug Delivery by Anthrax Toxin SO TOXINS LA English DT Review DE drug delivery; immunotoxin; targeted toxin; cancer; tumor therapies ID CAPILLARY MORPHOGENESIS PROTEIN-2; THERAPY PRODUCES REGRESSIONS; PROTECTIVE ANTIGEN PORE; LETHAL FACTOR CLEAVES; CANCER-CELL-LINES; ATHYMIC NUDE-MICE; BACILLUS-ANTHRACIS; MAMMALIAN-CELLS; EDEMA TOXIN; IN-VIVO AB Anthrax toxin is a potent tripartite protein toxin from Bacillus anthracis. It is one of the two virulence factors and causes the disease anthrax. The receptor-binding component of the toxin, protective antigen, needs to be cleaved by furin-like proteases to be activated and to deliver the enzymatic moieties lethal factor and edema factor to the cytosol of cells. Alteration of the protease cleavage site allows the activation of the toxin selectively in response to the presence of tumor-associated proteases. This initial idea of re-targeting anthrax toxin to tumor cells was further elaborated in recent years and resulted in the design of many modifications of anthrax toxin, which resulted in successful tumor therapy in animal models. These modifications include the combination of different toxin variants that require activation by two different tumor-associated proteases for increased specificity of toxin activation. The anthrax toxin system has proved to be a versatile system for drug delivery of several enzymatic moieties into cells. This highly efficient delivery system has recently been further modified by introducing ubiquitin as a cytosolic cleavage site into lethal factor fusion proteins. This review article describes the latest developments in this field of tumor targeting and drug delivery. C1 [Bachran, Christopher] BioMed X Innovat Ctr, D-69120 Heidelberg, Germany. [Leppla, Stephen H.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Bachran, C (reprint author), BioMed X Innovat Ctr, D-69120 Heidelberg, Germany. EM bachran@bio.mx; sleppla@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD, USA FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD, USA. NR 99 TC 1 Z9 1 U1 11 U2 11 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 2072-6651 J9 TOXINS JI Toxins PD JUL PY 2016 VL 8 IS 7 AR 197 DI 10.3390/toxins8070197 PG 16 WC Toxicology SC Toxicology GA DS4PU UT WOS:000380763800007 ER PT J AU Forman-Hoffman, VL Hedden, SL Glasheen, C Davies, C Colpe, LJ AF Forman-Hoffman, Valerie L. Hedden, Sarra L. Glasheen, Cristie Davies, Christine Colpe, Lisa J. TI The role of mental illness on cigarette dependence and successful quitting in a nationally representative, household-based sample of US adults SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Cigarette smoking; Tobacco use disorder; Smoking cessation; Mental disorders ID NONSPECIFIC PSYCHOLOGICAL DISTRESS; HEALTH INTERVIEW SURVEY; SMOKING-CESSATION; UNITED-STATES; NICOTINE DEPENDENCE; FAGERSTROM TEST; TOBACCO USE; PSYCHIATRIC-DISORDERS; ADDICTIVE DISORDERS; DRUG-USE AB Purpose: To begin to explore whether the association between mental illness (MI), cigarette dependence, and unsuccessful quit attempts differs across particular demographic subgroups. Methods: This study examines data from adults aged 18 years or older participating in the 2008-2012 National Surveys on Drug Use and Health. Analyses explored the moderating effects of age, gender, and race and/or ethnicity on associations between three levels of MI: (serious mental illness [SMI], any mental illness but no SMI, and no MI) and two smoking-related outcomes (cigarette dependence among current smokers and successful quitting among ever daily smokers). Results: After confirming that adults with MI were more likely to be dependent on cigarettes and less likely to successfully quit smoking, particularly among those with SMI, adjusted analyses indicated that age (but not gender or race/ethnicity) moderated the associations between MI and cigarette dependence and between MI. Conclusions: The magnitude of the association between MI and cigarette dependence and between MI and successful quitting appears to be stronger among older adults than among younger adults. Identifying subgroups at particular high risk of cigarette dependence is paramount to targeting smoking prevention, cessation, and treatment services appropriately. Published by Elsevier Inc. C1 [Forman-Hoffman, Valerie L.; Glasheen, Cristie; Davies, Christine] RTI Int, Res Triangle Pk, NC USA. [Hedden, Sarra L.] SAMHSA, Subst Abuse & Mental Hlth Serv Adm, Ctr Behav Hlth Stat & Qual, Rockville, MD USA. [Colpe, Lisa J.] NIMH, Div Serv & Intervent Res, 6001 Execut Blvd, Bethesda, MD 20892 USA. RP Colpe, LJ (reprint author), NIMH, Div Serv & Intervent Res, 6001 Execut Blvd, Bethesda, MD 20892 USA. EM lcolpe@mail.nih.gov OI Glasheen, Cristie/0000-0003-4419-9659 FU NIMH; SAMHSA; [HHSS283201300001 C] FX This work was supported by NIMH and SAMHSA and funded through contract HHSS283201300001 C. NR 43 TC 1 Z9 1 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 EI 1873-2585 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD JUL PY 2016 VL 26 IS 7 BP 447 EP 454 DI 10.1016/j.annepidem.2016.05.004 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DS6BL UT WOS:000380866600001 PM 27247163 ER PT J AU Dahle, O Kuehn, MR AF Dahle, Oyvind Kuehn, Michael R. TI Inhibiting Smad2/3 Signaling in Pluripotent Mouse Embryonic Stem Cells Enhances Endoderm Formation by Increasing Transcriptional Priming of Lineage-Specifying Target Genes SO DEVELOPMENTAL DYNAMICS LA English DT Article DE Smad2/3; nodal signaling; embryonic stem cells; pluripotency; transcriptional priming; Prdm14; Jarid2; polycomb repressive complex 2 ID HISTONE DEMETHYLASE JMJD3; RNA-POLYMERASE-II; NAIVE PLURIPOTENCY; DIFFERENTIATION; PRDM14; JARID2; STATE AB Background: Pluripotent embryonic stem cells (ESCs) offer great potential for regenerative medicine. However, efficient in vitro generation of specific desired cell types is still a challenge. We previously established that Smad2/3 signaling, essential for endoderm formation, regulates target gene expression by counteracting epigenetic repression mediated by Polycomb Repressive Complex 2 (PRC2). Although this mechanism has been demonstrated during differentiation and reprogramming, little is known of its role in pluripotent cells. Results: Chromatin immunoprecipitation-deep sequencing of undifferentiated mouse ESCs inhibited for Smad2/3 signaling identified Prdm14, important for protecting pluripotency, as a target gene. Although Prdm14 accumulates the normally repressive PRC2 deposited histone modification H3K27me3 under these conditions, surprisingly, expression increases. Analysis indicates that increased H3K27me3 leads to increased binding of PRC2 accessory component Jarid2 and recruitment of RNA polymerase II. Similar increases were found at the Nodal endoderm target gene Eomes but it remained unexpressed in pluripotent cells as normal. Upon differentiation, however, Eomes expression was significantly higher than in cells that had not been inhibited for signaling before differentiation. In addition, endoderm formation was markedly increased. Conclusions: Blocking Smad2/3 signaling in pluripotent stem cells results in epigenetic changes that enhance the capacity for endoderm differentiation. (C) 2016 Wiley Periodicals, Inc. C1 [Dahle, Oyvind; Kuehn, Michael R.] NCI, Basic Res Lab, NIH, Frederick, MD 21701 USA. RP Kuehn, MR (reprint author), NCI, Frederick, MD 21702 USA. EM mkuehn@mail.nih.gov FU National Cancer Institute, National Institutes of Health FX Grant sponsor: the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 21 TC 0 Z9 0 U1 3 U2 3 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 2016 VL 245 IS 7 SI SI BP 807 EP 815 DI 10.1002/DVDY.24407 PG 9 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA DT8AJ UT WOS:000381709600011 PM 27012147 ER PT J AU Arbore, G Kemper, C AF Arbore, Giuseppina Kemper, Claudia TI A novel "complement-metabolism-inflammasome axis" as a key regulator of immune cell effector function SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Review DE Complement; Metabolism; NLRP3 inflammasome ID CD4(+) T-CELLS; NLRP3 INFLAMMASOME; MEDIATED INFLAMMATION; DIABETIC-NEPHROPATHY; IL-1-BETA SECRETION; PATTERN-RECOGNITION; INNATE IMMUNITY; HUMAN-MONOCYTES; CUTTING EDGE; IFN-GAMMA AB The inflammasomes are intracellular multiprotein complexes that induce and regulate the generation of the key pro-inflammatory cytokines IL-1 beta and IL-18 in response to infectious microbes and cellular stress. The activation of inflammasomes involves several upstream signals including classic pattern or danger recognition systems such as the TLRs. Recently, however, the activation of complement receptors, such as the anaphylatoxin C3a and C5a receptors and the complement regulator CD46, in conjunction with the sensing of cell metabolic changes, for instance increased amino acid influx and glycolysis (via mTORC1), have emerged as additional critical activators of the inflammasome. This review summarizes recent advances in our knowledge about complement-mediated inflammasome activation, with a specific focus on a novel " complement - metabolism - NLRP3 inflammasome axis." C1 [Arbore, Giuseppina; Kemper, Claudia] Kings Coll London, Div Transplant Immunol & Mucosal Biol, MRC Ctr Transplantat, London SE1 9RT, England. [Kemper, Claudia] NHLBI, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. [Kemper, Claudia] NHLBI, Ctr Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Kemper, C (reprint author), Kings Coll London, Div Transplant Immunol & Mucosal Biol, MRC Ctr Transplantat, London SE1 9RT, England. EM Claudia.kemper@kcl.ac.uk FU MRC Centre [MR/J006742/1]; EU; Wellcome Trust Investigator Award; King's Bioscience Institute at King's College London; National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St. Thomas' NHS Foundation Trust and King's College London; Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH; intramural research program of NIAID, NIH FX Work in the Kemper laboratory is supported by the MRC Centre. Grant MR/J006742/1, an EU-funded Innovative Medicines Initiative BTCURE (C.K.), a Wellcome Trust Investigator Award (C.K.), and the King's Bioscience Institute at King's College London (G.A.), the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St. Thomas' NHS Foundation Trust and King's College London, and by the Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH and the intramural research program of NIAID, NIH. NR 92 TC 5 Z9 5 U1 5 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD JUL PY 2016 VL 46 IS 7 BP 1563 EP 1573 DI 10.1002/eji.201546131 PG 11 WC Immunology SC Immunology GA DS4LM UT WOS:000380752600004 PM 27184294 ER PT J AU Bode, C Fox, M Tewary, P Steinhagen, A Ellerkmann, RK Klinman, D Baumgarten, G Hornung, V Steinhagen, F AF Bode, Christian Fox, Mario Tewary, Poonam Steinhagen, Almut Ellerkmann, Richard K. Klinman, Dennis Baumgarten, Georg Hornung, Veit Steinhagen, Folkert TI Human plasmacytoid dentritic cells elicit a Type I Interferon response by sensing DNA via the cGAS-STING signaling pathway SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Cytosolic sensor; Dentritic cells; DNA; Innate immunity; Interferon; Toll-like-receptors ID CYCLIC GMP-AMP; DENDRITIC CELLS; CYTOSOLIC DNA; ANTIVIRAL DEFENSE; IMMUNE-SYSTEM; IFN-BETA; RECOGNITION; 2ND-MESSENGER; ACTIVATION; SYNTHASE AB Plasmacytoid dendritic cells (pDCs) are a major source of type I interferon (IFN) and are important for host defense by sensing microbial DNA via TLR9. pDCs also play a critical role in the pathogenesis of IFN-driven autoimmune diseases. Yet, this autoimmune reaction is caused by the recognition of self-DNA and has been linked to TLR9-independent pathways. Increasing evidence suggests that the cytosolic DNA receptor cyclic GMP-AMP (cGAMP) synthase (cGAS) is a critical component in the detection of pathogens and contributes to autoimmune diseases. It has been shown that binding of DNA to cGAS results in the synthesis of cGAMP and the subsequent activation of the stimulator of interferon genes (STING) adaptor to induce IFNs. Our results show that the cGAS-STING pathway is expressed and activated in human pDCs by cytosolic DNA leading to a robust type I IFN response. Direct activation of STING by cyclic dinucleotides including cGAMP also activated pDCs and knockdown of STING abolished this IFN response. These results suggest that pDCs sense cytosolic DNA and cyclic dinucleotides via the cGAS-STING pathway and that targeting this pathway could be of therapeutic interest. C1 [Bode, Christian; Fox, Mario; Ellerkmann, Richard K.; Baumgarten, Georg; Steinhagen, Folkert] Univ Bonn, Dept Anesthesiol & Crit Care Med, D-53127 Bonn, Germany. [Tewary, Poonam] FNLCR, Expt Immunol Lab, Canc Inflammat Program, Leidos Biomed Res Inc, Frederick, MD USA. [Klinman, Dennis] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. [Steinhagen, Almut] Univ Bonn, Inst Clin Chem & Clin Pharmacol, Bonn, Germany. [Hornung, Veit] Univ Bonn, Inst Mol Med, Bonn, Germany. RP Bode, C; Steinhagen, F (reprint author), Univ Bonn, Dept Anesthesiol & Crit Care Med, D-53127 Bonn, Germany. EM christian.bode@ukb.uni-bonn.de; folkert.steinhagen@ukb.uni-bonn.de FU University of Bonn (BONFOR); National Cancer Institute, National Institutes of Health [HHSN26120080001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This study was supported by grants from the University of Bonn (BONFOR). The authors would like to thank Dr. T. Maeda and Dr. S. Kamihira (Department of Island Medicine, Nagasaki University, Japan) for providing CAL-1 cells. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This Research was supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 36 TC 2 Z9 2 U1 4 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD JUL PY 2016 VL 46 IS 7 BP 1615 EP 1621 DI 10.1002/eji.201546113 PG 7 WC Immunology SC Immunology GA DS4LM UT WOS:000380752600010 PM 27125983 ER PT J AU Kim, HK Waickman, AT Castro, E Flomerfelt, FA Hawk, NV Kapoor, V Telford, WG Gress, RE AF Kim, Hye Kyung Waickman, Adam T. Castro, Ehydel Flomerfelt, Francis A. Hawk, Nga V. Kapoor, Veena Telford, William G. Gress, Ronald E. TI Distinct IL-7 signaling in recent thymic emigrants versus mature naive T cells controls T-cell homeostasis SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Apoptosis; Bcl-2; Cytokine; Proliferation; STAT5 ID IN-VIVO; CYCLE PROGRESSION; RECEPTOR-ALPHA; PROLIFERATION; EXPRESSION; SURVIVAL; INTERLEUKIN-7; PHENOTYPE; DEATH; MICE AB IL-7 is essential for T-cell survival but its availability is limited in vivo. Consequently, all peripheral T cells, including recent thymic emigrants (RTEs) are constantly competing for IL-7 to survive. RTEs are required to replenish TCR diversity and rejuvenate the peripheral T-cell pool. However, it remains unknown how RTEs successfully compete with resident mature T cells for IL-7. Moreover, RTEs express low levels of IL-7 receptors, presumably rendering them even less competitive. Here, we show that, surprisingly, RTEs are more responsive to IL-7 than mature naive T cells as demonstrated by markedly increased STAT5 phosphorylation upon IL-7 stimulation. Nonetheless, adoptive transfer of RTE cells into lymphopenic host mice resulted in slower IL-7-induced homeostatic proliferation and diminished expansion compared to naive donor T cells. Mechanistically, we found that IL-7 signaling in RTEs preferentially upregulated expression of Bcl-2, which is antiapoptotic but also anti-proliferative. In contrast, naive T cells showed diminished Bcl-2 induction but greater proliferative response to IL-7. Collectively, these data indicate that IL-7 responsiveness in RTE is designed to maximize survival at the expense of reduced proliferation, consistent with RTE serving as a subpopulation of T cells rich in diversity but not in frequency. C1 [Kim, Hye Kyung; Castro, Ehydel; Flomerfelt, Francis A.; Hawk, Nga V.; Kapoor, Veena; Telford, William G.; Gress, Ronald E.] Expt Transplantat & Immunol Branch, Bethesda, MD USA. [Waickman, Adam T.] NCI, Expt Immunol Branch, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Waickman, AT (reprint author), NCI, Expt Immunol Branch, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA.; Kim, HK (reprint author), NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bldg 10 CRC,Room 3E-3288,10 Ctr, Bethesda, MD 20892 USA. EM kihye@mail.nih.gov; adam.waickman@nih.gov FU Intramural Research Program of the US National Institutes of Health; National Cancer Institute; Center for Cancer Research FX We thank Dr. Hyun Park for critical review of this manuscript. This study was supported by the Intramural Research Program of the US National Institutes of Health, the National Cancer Institute, and the Center for Cancer Research. NR 54 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD JUL PY 2016 VL 46 IS 7 BP 1669 EP 1680 DI 10.1002/eji.201546214 PG 12 WC Immunology SC Immunology GA DS4LM UT WOS:000380752600015 PM 27129922 ER PT J AU Burotto, M Berkovits, A Dunleavy, K AF Burotto, Mauricio Berkovits, Alejandro Dunleavy, Kieron TI Double hit lymphoma: from biology to therapeutic implications SO EXPERT REVIEW OF HEMATOLOGY LA English DT Review DE Double-hit; MYC; BCL2; BCL6; triple-hit; BCL2 inhibitors; MYC inhibitors; double-expresser; DPE; DHL ID B-CELL LYMPHOMA; RITUXIMAB PLUS CYCLOPHOSPHAMIDE; NON-HODGKINS-LYMPHOMA; BURKITT-LYMPHOMA; C-MYC; MOLECULAR SUBTYPES; GENE-EXPRESSION; GERMINAL CENTER; PROGNOSTIC-SIGNIFICANCE; PROTEIN EXPRESSION AB Introduction: Diffuse large B-cell lymphoma (DLBCL) is a molecularly heterogeneous disease defined by different cellular origins and mechanisms of oncogenic activation. Approximately 10% of DLBCL cases harbor a MYC rearrangement and this has been associated with a more aggressive clinical course following standard therapy.Areas covered: So-called double-hit lymphomas' (DHL) or triple hit lymphomas' (THL) occur when MYC is concurrently rearranged with BCL2 and/or BCL6. These tumors are characterized by high proliferation rate and a very poor outcome following standard R-CHOP (rituximab, cyclophosphamide, doxorubicin vincristine and prednisone) therapy, in most (though not all) studies that have looked at this. Though there is a paucity of published experience with other chemotherapy regimens, there is emerging evidence that more intensive approaches may improve outcome. Recently, there has been a lot of focus in the literature on double-expresser lymphomas' (DEL) with high MYC, BCL2 and/or BCL6 expression but typically without rearrangements of these genes. These DEL cases, have a poor outcome with R-CHOP and there is little consensus on how they should be approached.Expert commentary: This review will focus on the biology and treatment of DHL and DEL, discuss the outcome of these diseases with current standard as well as promising new approaches and conclude with a section on novel agents that are in development for these diseases. C1 [Burotto, Mauricio; Berkovits, Alejandro] Univ Desarrollo, Sch Med, Hemato Oncol Serv, Clin Alemana Santiago, Santiago, Chile. [Dunleavy, Kieron] NCI, Lymphoid Malignancies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Dunleavy, K (reprint author), NCI, Lymphoid Malignancy Branch, Bldg 10,Room 4N 115,9000 Rockville Pike, Bethesda, MD 20892 USA. EM dunleavk@mail.nih.gov FU intramural program of the National Cancer Institute FX This work was partly supported by the intramural program of the National Cancer Institute. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 92 TC 1 Z9 1 U1 2 U2 4 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1747-4086 EI 1747-4094 J9 EXPERT REV HEMATOL JI Expert Rev. Hematol. PD JUL PY 2016 VL 9 IS 7 BP 669 EP 678 DI 10.1080/17474086.2016.1182858 PG 10 WC Hematology SC Hematology GA DR8LQ UT WOS:000380149800008 PM 27166590 ER PT J AU Chlanda, P Zimmerberg, J AF Chlanda, Petr Zimmerberg, Joshua TI Protein-lipid interactions critical to replication of the influenza A virus SO FEBS LETTERS LA English DT Review DE influenza virus; lipid microdomains; membrane fission; membrane fusion; virus budding; virus entry ID HEMAGGLUTININ FUSION PEPTIDE; MEMBRANE-FUSION; M2 PROTEIN; MATRIX PROTEIN; CHOLESTEROL-BINDING; CYTOPLASMIC TAIL; PLASMA-MEMBRANE; M1 PROTEIN; LOW PH; CRYOELECTRON TOMOGRAPHY AB Influenza A virus (IAV) assembles on the plasma membrane where viral proteins localize to form a bud encompassing the viral genome, which ultimately pinches off to give rise to newly formed infectious virions. Upon entry, the virus faces the opposite task-fusion with the endosomal membrane and disassembly to deliver the viral genome to the cytoplasm. There are at least four influenza proteins-hemagglutinin (HA), neuraminidase (NA), matrix 1 protein (M1), and the M2 ion channel-that are known to directly interact with the cellular membrane and modify membrane curvature in order to both assemble and disassemble membrane-enveloped virions. Here, we summarize and discuss current knowledge of the interactions of lipids and membrane proteins involved in the IAV replication cycle. C1 [Chlanda, Petr; Zimmerberg, Joshua] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Integrat Biophys, NIH, Bethesda, MD 20892 USA. RP Zimmerberg, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Integrat Biophys, NIH, Bethesda, MD 20892 USA. EM joshz@helix.nih.gov FU Division of Intramural Research of the NICHD; Intramural Research Program of the NIH FX We thank to Mary L. Kraft for kindly providing the nano-SIMS figure and Samuel T. Hess for useful suggestions. We are grateful to members of the Zimmerberg lab and to Fredric S. Cohen for critical reading of the manuscript. We sincerely apologize to all scientists whose important work could not be cited here due to space restrictions. This work was supported by the Division of Intramural Research of the NICHD, in the Intramural Research Program of the NIH. NR 103 TC 2 Z9 2 U1 10 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-5793 EI 1873-3468 J9 FEBS LETT JI FEBS Lett. PD JUL PY 2016 VL 590 IS 13 SU 3 SI SI BP 1940 EP 1954 DI 10.1002/1873-3468.12118 PG 15 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA DS4OQ UT WOS:000380760800007 PM 26921878 ER PT J AU Mooney, LJ Hillhouse, MP Thomas, C Ang, A Sharma, G Terry, G Chang, L Walker, R Trivedi, M Croteau, D Sparenborg, S Ling, W AF Mooney, Larissa J. Hillhouse, Maureen P. Thomas, Christie Ang, Alfonso Sharma, Gaurav Terry, Garth Chang, Linda Walker, Robrina Trivedi, Madhukar Croteau, David Sparenborg, Steven Ling, Walter TI Utilizing a Two-stage Design to Investigate the Safety and Potential Efficacy of Monthly Naltrexone Plus Once-daily Bupropion as a Treatment for Methamphetamine Use Disorder SO JOURNAL OF ADDICTION MEDICINE LA English DT Article DE bupropion; extended-release naltrexone; medication treatment; methamphetamine dependence; pharmacotherapy; Vivitrol ID PLACEBO-CONTROLLED TRIAL; DEPENDENCE; INTERVENTIONS; AMPHETAMINE; ANTAGONIST; MANAGEMENT; BEHAVIOR; OUTCOMES AB Objectives: This 2-stage open-label pilot study evaluated the safety and potential efficacy of naltrexone + bupropion as a pharmacotherapy for methamphetamine (MA) use disorder. Methods: The study was conducted in 2 stages of recruitment across 3 sites; 20 participants were enrolled in stage 1 and 29 participants were enrolled in stage 2. Eight weeks of open-label pharmacotherapy with a combination of extended-release injectable naltrexone (XR-NTX; Vivitrol) plus extended-release oral bupropion (BRP; Wellbutrin XL) were provided with a smartphone-assisted medication adherence platform. Participants met Diagnostic and Statistical Manual of Mental Disorders, 5th Edition criteria for severe MA use disorder, self-reported >= 20 days of MA use in the 30 days prior to consent, and submitted 3 MA-positive urine drug screens (UDS) out of 4 collected during screening. Participants attended clinic twice weekly for observed BRP dosing, UDS testing, assessments, and medical management; XR-NTX was administered at weeks 1 and 5. A BRP taper and follow-up visit occurred in week 9. Results: Analyses evaluated effects of XR-NTX+BRP to determine the number of "responders" according to a statistically pre-defined response criterion (6 of 8 MA-negative UDS during the last 4 weeks of medication). The 2-stage design required that stage 1 yield >= 3 responders to continue to stage 2; 11 of the 49 participants met responder criteria across both stages (5 in stage 1, 6 in stage 2). Conclusions: Under the statistical analysis plan, study "success" required >= 9 responders. With 11 responders, the study demonstrated sufficient potential of naltrexone plus bupropion as a combination pharmacotherapy for MA use disorder to warrant further study. C1 [Mooney, Larissa J.; Hillhouse, Maureen P.; Thomas, Christie; Ang, Alfonso; Terry, Garth; Ling, Walter] Univ Calif Los Angeles, Los Angeles, CA USA. [Sharma, Gaurav; Croteau, David] Emmes, Rockville, MD USA. [Chang, Linda] Univ Hawaii, Honolulu, HI 96822 USA. [Chang, Linda] Queens Med Ctr, Honolulu, HI USA. [Walker, Robrina; Trivedi, Madhukar] Univ Texas Southwestern Med Ctr, Dallas, TX USA. [Sparenborg, Steven] NIDA, Bethesda, MD 20892 USA. RP Mooney, LJ (reprint author), UCLA Integrated Subst Abuse Programs, 11075 Santa Monica Blvd,Suite 200, Los Angeles, CA 90025 USA. EM lmooney@mednet.ucla.edu RI Emchi, Karma/Q-1952-2016 FU National Institute on Drug Abuse [DA13045] FX Alkermes Inc. (Waltham, MA) provided monthly naltrexone (Vivitrol). Support for this research was provided through the National Institute on Drug Abuse (DA13045). NR 37 TC 0 Z9 0 U1 6 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1932-0620 EI 1935-3227 J9 J ADDICT MED JI J. Addict. Med. PD JUL-AUG PY 2016 VL 10 IS 4 BP 236 EP 243 DI 10.1097/ADM.0000000000000218 PG 8 WC Substance Abuse SC Substance Abuse GA DS5SL UT WOS:000380842500004 PM 27379819 ER PT J AU Trigo, JM Soliman, A Staios, G Quilty, L Fischer, B George, TP Rehm, J Selby, P Barnes, AJ Huestis, MA Le Foll, B AF Trigo, Jose M. Soliman, Alexandra Staios, Gregory Quilty, Lena Fischer, Benedikt George, Tony P. Rehm, Juergen Selby, Peter Barnes, Allan J. Huestis, Marilyn A. Le Foll, Bernard TI Sativex Associated With Behavioral-Relapse Prevention Strategy as Treatment for Cannabis Dependence: A Case Series SO JOURNAL OF ADDICTION MEDICINE LA English DT Article DE Abstinence; cannabidiol; cannabis; marijuana; THC; withdrawal ID MASS-SPECTROMETRY; DELTA-9-TETRAHYDROCANNABINOL; WITHDRAWAL; QUANTIFICATION; CHROMATOGRAPHY; INDIVIDUALS; PSYCHOSIS; SEEKING; ADULTS; THC AB Objectives: Cannabis is the most commonly used illicit drug; a substantial minority of users develop dependence. The current lack of pharmacological treatments for cannabis dependence warrants the use of novel approaches and further investigation of promising pharmacotherapy. In this case series, we assessed the use of self-titrated dosages of Sativex (1: 1, Delta(9)-tetrahydrocannabinol [THC]/cannabidiol [CBD] combination) and motivational enhancement therapy and cognitive behavioral therapy (MET/CBT) for the treatment of cannabis dependence among 5 treatment-seeking community-recruited cannabis-dependent subjects. Methods: Participants underwent a 3-month open-label self-titration phase with Sativex (up to 113.4 of THC/105 mg of CBD) and weekly MET/CBT, with a 3-month follow-up. Results: Sativex was well-tolerated by all participants (average dosage 77.5 THC/71.7mg CBD). The combination of Sativex and MET/CBT reduced the amount of cannabis use and progressively reduced craving and withdrawal scores. THC/CBD metabolite concentration indicated reduced cannabis use and compliance with medication. Conclusions: In summary, this pilot study found that with Sativex in combination with MET/CBT reduced cannabis use while preventing increases in craving and withdrawal in the 4 participants completing the study. Further systematic exploration of Sativex as a pharmacological treatment option for cannabis dependence should be performed. C1 [Trigo, Jose M.; Soliman, Alexandra; Staios, Gregory; Le Foll, Bernard] Campbell Family Mental Hlth, Res Inst, Translat Addict Res Lab, Toronto, ON, Canada. [Quilty, Lena] CAMH, Clin Res, Toronto, ON, Canada. [Fischer, Benedikt; Rehm, Juergen] CAMH, Social & Epidemiol Res Dept, Toronto, ON, Canada. [George, Tony P.] CAMH, Schizophrenia Div, Toronto, ON, Canada. [George, Tony P.] CAMH, Complex Mental Illness Program, Toronto, ON, Canada. [Rehm, Juergen] Univ Toronto, Addict Policy, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Fischer, Benedikt; Rehm, Juergen] Univ Toronto, Inst Med Sci, Fac Med, Toronto, ON, Canada. [Fischer, Benedikt; George, Tony P.; Rehm, Juergen; Selby, Peter] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. [Rehm, Juergen] Tech Univ Dresden, Inst Clin Psychol & Psychotherapy, Dresden, Germany. [Rehm, Juergen] Tech Univ Dresden, Ctr Clin Epidemiol & Longitudinal Studies CELOS, Dresden, Germany. [Selby, Peter; Le Foll, Bernard] CAMH, Addict Div, Toronto, ON, Canada. [Selby, Peter] Univ Toronto, Dept Family & Community Med, Toronto, ON, Canada. [Fischer, Benedikt] Simon Fraser Univ, Ctr Appl Res Mental Hlth & Addict, Fac Hlth Sci, Vancouver, BC, Canada. [Barnes, Allan J.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab, NIH, Baltimore, MD USA. RP Le Foll, B (reprint author), CAMH, Toronto, ON, Canada. EM bernard.lefoll@camh.ca FU National Institute On Drug Abuse of the National Institutes of Health [R21DA031906]; National Institute on Drug Abuse, NIH, DHHS FX Research reported in this publication was supported by the National Institute On Drug Abuse of the National Institutes of Health under Award Number R21DA031906 (to Dr Le Foll) and in part by Intramural Research Program of National Institute on Drug Abuse, NIH, DHHS. NR 28 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1932-0620 EI 1935-3227 J9 J ADDICT MED JI J. Addict. Med. PD JUL-AUG PY 2016 VL 10 IS 4 BP 274 EP 279 DI 10.1097/ADM.0000000000000229 PG 6 WC Substance Abuse SC Substance Abuse GA DS5SL UT WOS:000380842500010 PM 27261670 ER PT J AU Flannery, M Mohile, SG Dale, W Arora, NK Azar, L Breslau, ES Cohen, HJ Dotan, E Eldadah, BA Leach, CR Mitchell, SA Rowland, JH Hurria, A AF Flannery, Marie Mohile, Supriya Gupta Dale, William Arora, Neeraj K. Azar, Lauren Breslau, Erica S. Cohen, Harvey Jay Dotan, Efrat Eldadah, Basil A. Leach, Corinne R. Mitchell, Sandra A. Rowland, Julia H. Hurria, Arti TI Interventions to improve the quality of life and survivorship of older adults with cancer: The funding landscape at NIH, ACS and PCORI SO JOURNAL OF GERIATRIC ONCOLOGY LA English DT Article DE Aging; Cancer; Older adults; Frail; Funding; NIH; ACS; PCORI; Survivorship; Quality of life ID TRIALS AB Identifying knowledge gaps and research opportunities in cancer and aging research was the focus of a three-part conference series led by the Cancer and Aging Research Group from 2010 to 2015. The third meeting, featured representatives from the NIA, NCI, ACS and PCORI each of whom discussed research priorities and funding opportunities in cancer and aging at their respective agencies. This manuscript reports on the proceedings of that conference with a specific focus on funding priorities for interventions to improve the quality of life and survivorship of older adults with cancer. Helpful tips from each funder regarding writing a scientifically strong research proposal are presented. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Flannery, Marie] Univ Rochester, Med Ctr, Box SON 601,Elmwood Ave, Rochester, NY 14642 USA. [Mohile, Supriya Gupta] Univ Rochester, 601 Elmwood Ave,Box 704, Rochester, NY 14642 USA. [Dale, William] Univ Chicago, Dept Med, Sect Geriatr & Palliat Med, MC 6098,5841 S Maryland Ave, Chicago, IL 60637 USA. [Arora, Neeraj K.] PCORI, 1919 M St,NW,Suite 250, Washington, DC 20036 USA. [Azar, Lauren] PCORI, 1919 M St,NW,4th Floor, Washington, DC 20036 USA. [Breslau, Erica S.] NCI, 9609 Med Ctr Dr,3E520, Rockville, MD 20850 USA. [Cohen, Harvey Jay] Duke Univ, Med Ctr, Room 3502 Blue Zone,Box 3003, Durham, NC 27710 USA. [Dotan, Efrat] Fox Chase Canc Ctr, 333 Cottman Ave, Philadelphia, PA USA. [Eldadah, Basil A.] NIA, 7201 Wisconsin Ave,3C307, Bethesda, MD 20892 USA. [Leach, Corinne R.] ACS, 250 Williams St, Atlanta, GA 30303 USA. [Mitchell, Sandra A.] NCI, 9609 Med Ctr Dr,3E448, Rockville, MD 20850 USA. [Rowland, Julia H.] NCI, 9609 Med Ctr Dr,4E450, Rockville, MD 20850 USA. [Hurria, Arti] City Hope Comprehens Canc Ctr, 1500 E Duarte Rd, Duarte, CA USA. RP Flannery, M (reprint author), Univ Rochester, Med Ctr, Box SON 601,Elmwood Ave, Rochester, NY 14642 USA. EM marie_flannery@urmc.rochester.edu; supriya_mohile@urmc.rochester.edu; wdale@medicine.bsd.uchicago.edu; narora@pcori.org; lholuj@pcori.org; breslaue@mail.nih.gov; efrat.dotan@fccc.edu; eldadahb@nia.nih.gov; corinne.leach@cancer.org; mitchlls@mail.nih.gov; rowlandj@mail.nih.gov; ahurria@coh.org FU NCI NIH HHS [R25 CA102618, UG1 CA189961, R01 CA177592, UG1 CA189823]; NIA NIH HHS [U13 AG038151, R03 AG042342] NR 11 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1879-4068 EI 1879-4076 J9 J GERIATR ONCOL JI J. Geriatr. Oncol. PD JUL PY 2016 VL 7 IS 4 SI SI BP 225 EP 233 DI 10.1016/j.jgo.2016.02.001 PG 9 WC Oncology; Geriatrics & Gerontology SC Oncology; Geriatrics & Gerontology GA DS7NP UT WOS:000380970500002 PM 27197917 ER PT J AU Berger, A AF Berger, Ann TI "Mother MD Intense": The Need for Intentional Healing SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Editorial Material C1 [Berger, Ann] NIH, Ctr Clin, 10 Ctr Dr,Bldg 10,Room 21733, Bethesda, MD 20892 USA. RP Berger, A (reprint author), NIH, Ctr Clin, 10 Ctr Dr,Bldg 10,Room 21733, Bethesda, MD 20892 USA. EM aberger@cc.nih.gov NR 2 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 EI 1873-6513 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD JUL PY 2016 VL 52 IS 1 BP 151 EP 153 DI 10.1016/j.jpainsymman.2016.05.006 PG 3 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA DT7QS UT WOS:000381681900020 PM 27256617 ER PT J AU Nath, A Griffin, DE AF Nath, Avindra Griffin, Diane E. TI Dedication to Dr. Richard T. Johnson SO NEUROTHERAPEUTICS LA English DT Biographical-Item C1 [Nath, Avindra] NINDS, Sect Infect Nervous Syst, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Griffin, Diane E.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA. RP Nath, A (reprint author), NINDS, Sect Infect Nervous Syst, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM avindra.nath@nih.gov; dgriffi6@jhmi.edu NR 1 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1933-7213 EI 1878-7479 J9 NEUROTHERAPEUTICS JI Neurotherapeutics PD JUL PY 2016 VL 13 IS 3 BP 451 EP 452 DI 10.1007/s13311-016-0456-0 PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA DS3JP UT WOS:000380679400001 PM 27365084 ER PT J AU Nath, A Jacobson, S AF Nath, Avindra Jacobson, Steven TI Current Status, Future Directions and Challenges in Management of CNS Viral Infections SO NEUROTHERAPEUTICS LA English DT Editorial Material C1 [Jacobson, Steven] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Jacobson, S (reprint author), NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM avi1258@gmail.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1933-7213 EI 1878-7479 J9 NEUROTHERAPEUTICS JI Neurotherapeutics PD JUL PY 2016 VL 13 IS 3 BP 453 EP 454 DI 10.1007/s13311-016-0459-x PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA DS3JP UT WOS:000380679400002 PM 27388287 ER PT J AU Billioux, BJ Smith, B Nath, A AF Billioux, Bridgette Jeanne Smith, Bryan Nath, Avindra TI Neurological Complications of Ebola Virus Infection SO NEUROTHERAPEUTICS LA English DT Review DE Ebola; meningitis; encephalitis; microvascular disease; deafness; vertigo; insomnia; cognition; magnetic resonance imaging ID HEMORRHAGIC-FEVER; WEST-AFRICA; NONHUMAN-PRIMATES; SIERRA-LEONE; DISEASE; TRANSMISSION; CONGO; MARBURG; KIKWIT; MANAGEMENT AB Ebola virus disease is one of the deadliest pathogens known to man, with a mortality rate between 25-90% depending on the species and outbreak of Ebola. Typically, it presents with fever, headache, voluminous vomiting and diarrhea, and can progress to a hemorrhagic illness; neurologic symptoms, including meningoencephalitis, seizures, and coma, can also occur. Recently, an outbreak occurred in West Africa, affecting > 28,000 people, and killing > 11,000. Owing to the magnitude of this outbreak, and the large number (> 17,000) of Ebola survivors, the medical and scientific communities are learning much more about the acute manifestations and sequelae of Ebola. A number of neurologic complications can occur after Ebola, such as seizures, memory loss, headaches, cranial nerve abnormalities, and tremor. Ebola may also persist in some immunologically privileged sites, including the central nervous system, and can rarely lead to relapse in disease. Owing to these findings, it is important that survivors are evaluated and monitored for neurologic symptoms. Much is unknown about this disease, and treatment remains largely supportive; however, with ongoing clinical and basic science, the mechanisms of how Ebola affects the central nervous system and how it persists after acute disease will hopefully become more clear, and better treatments and clinical practices for Ebola patients will be developed. C1 [Billioux, Bridgette Jeanne; Smith, Bryan; Nath, Avindra] NINDS, Sect Infect Nervous Syst, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Nath, A (reprint author), NINDS, Sect Infect Nervous Syst, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM natha@ninds.nih.gov OI Billioux, Bridgette Jeanne/0000-0003-4208-7100 NR 55 TC 0 Z9 0 U1 7 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1933-7213 EI 1878-7479 J9 NEUROTHERAPEUTICS JI Neurotherapeutics PD JUL PY 2016 VL 13 IS 3 BP 461 EP 470 DI 10.1007/s13311-016-0457-z PG 10 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA DS3JP UT WOS:000380679400004 PM 27412684 ER PT J AU Anderson, MR Kashanchi, F Jacobson, S AF Anderson, Monique R. Kashanchi, Fatah Jacobson, Steven TI Exosomes in Viral Disease SO NEUROTHERAPEUTICS LA English DT Review DE Exosomes; microvesicles; multivesicular bodies; "back fusion"; ESCRT ID CELL-DERIVED EXOSOMES; MATURE DENDRITIC CELLS; STRUCTURES L-PARTICLES; HEPATITIS-C VIRUS; EXTRACELLULAR VESICLES; T-CELLS; SECRETE EXOSOMES; EBOLA-VIRUS; DC-SIGN; PHOSPHATIDYLSERINE RECEPTOR AB Viruses have evolved many mechanisms by which to evade and subvert the immune system to ensure survival and persistence. However, for each method undertaken by the immune system for pathogen removal, there is a counteracting mechanism utilized by pathogens. The new and emerging role of microvesicles in immune intercellular communication and function is no different. Viruses across many different families have evolved to insert viral components in exosomes, a subtype of microvesicle, with many varying downstream effects. When assessed cumulatively, viral antigens in exosomes increase persistence through cloaking viral genomes, decoying the immune system, and even by increasing viral infection in uninfected cells. Exosomes therefore represent a source of viral antigen that can be used as a biomarker for disease and targeted for therapy in the control and eradication of these disorders. With the rise in the persistence of new and reemerging viruses like Ebola and Zika, exploring the role of exosomes become more important than ever. C1 [Anderson, Monique R.; Jacobson, Steven] NINDS, NIH, Neuroimmunol Branch, Viral Immunol Sect, Bethesda, MD 20892 USA. [Anderson, Monique R.] Univ Virginia, Sch Med, Dept Pathol, Mol & Cellular Basis Dis Grad Program, Charlottesville, VA 22903 USA. [Kashanchi, Fatah] George Mason Univ, Natl Ctr Biodef & Infect Dis, Mol Virol Lab, Manassas, VA 20110 USA. RP Anderson, MR (reprint author), NINDS, NIH, Neuroimmunol Branch, Viral Immunol Sect, Bethesda, MD 20892 USA.; Anderson, MR (reprint author), Univ Virginia, Sch Med, Dept Pathol, Mol & Cellular Basis Dis Grad Program, Charlottesville, VA 22903 USA. EM andersonmr2@mail.nih.gov NR 149 TC 1 Z9 1 U1 7 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1933-7213 EI 1878-7479 J9 NEUROTHERAPEUTICS JI Neurotherapeutics PD JUL PY 2016 VL 13 IS 3 BP 535 EP 546 DI 10.1007/s13311-016-0450-6 PG 12 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA DS3JP UT WOS:000380679400010 PM 27324390 ER PT J AU Azodi, S Jacobson, S AF Azodi, Shila Jacobson, Steven TI Cytokine Therapies in Neurological Disease SO NEUROTHERAPEUTICS LA English DT Review DE Cytokine; anticytokine; neurology; drug development ID AMYOTROPHIC-LATERAL-SCLEROSIS; MYELOPATHY/TROPICAL SPASTIC PARAPARESIS; REMITTING MULTIPLE-SCLEROSIS; COLONY-STIMULATING FACTOR; MESSENGER-RNA EXPRESSION; DOUBLE-BLIND; NEUROMYELITIS-OPTICA; ALZHEIMERS-DISEASE; CEREBROSPINAL-FLUID; INFLAMMATORY MYOPATHIES AB Cytokines are a heterogeneous group of glycoproteins that coordinate physiological functions. Cytokine deregulation is observed in many neurological diseases. This article reviews current research focused on human clinical trials of cytokine and anticytokine therapies in the treatment of several neurological disease including stroke, neuromuscular diseases, neuroinfectious diseases, demyelinating diseases, and neurobehavioral diseases. This research suggests that cytokine therapy applications may play an important role in offering new strategies for disease modulation and treatment. Further, this research provides insights into the causal link between cytokine deregulation and neurological diseases. C1 [Azodi, Shila; Jacobson, Steven] NINDS, Viral Immunol Sect, NIH, Bethesda, MD 20892 USA. RP Jacobson, S (reprint author), NINDS, Viral Immunol Sect, NIH, Bethesda, MD 20892 USA. EM jacobsons@ninds.nih.gov NR 57 TC 1 Z9 1 U1 3 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1933-7213 EI 1878-7479 J9 NEUROTHERAPEUTICS JI Neurotherapeutics PD JUL PY 2016 VL 13 IS 3 BP 555 EP 561 DI 10.1007/s13311-016-0455-1 PG 7 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA DS3JP UT WOS:000380679400012 PM 27388288 ER PT J AU Leibovitch, EC Jacobson, S AF Leibovitch, Emily C. Jacobson, Steven TI Vaccinations for Neuroinfectious Disease: A Global Health Priority SO NEUROTHERAPEUTICS LA English DT Review DE Vaccines; Neuroinfectious; Neuroinvasive; Meningitis; Encephalitis; CNS infections ID CENTRAL-NERVOUS-SYSTEM; TICK-BORNE ENCEPHALITIS; VENEZUELAN EQUINE ENCEPHALITIS; JAPANESE ENCEPHALITIS; VIRUS-INFECTION; VACCINE STRAIN; DENGUE VACCINE; ZIKA VIRUS; COMPLICATIONS; MICE AB Vaccines for neuroinfectious diseases are becoming an ever-increasing global health priority, as neurologic manifestations and sequelae from existing and emerging central nervous system infections account for significant worldwide morbidity and mortality. The prevention of neurotropic infections can be achieved through globally coordinated vaccination campaigns, which have successfully eradicated nonzoonotic agents such as the variola viruses and, hopefully soon, poliovirus. This review discusses vaccines that are currently available or under development for zoonotic flaviviruses and alphaviruses, including Japanese and tick-borne encephalitis, yellow fever, West Nile, dengue, Zika, encephalitic equine viruses, and chikungunya. Also discussed are nonzoonotic agents, including measles and human herpesviruses, as well as select bacterial, fungal, and protozoal pathogens. While therapeutic vaccines will be required to treat a multitude of ongoing infections of the nervous system, the ideal vaccination strategy is pre-exposure vaccination, with the ultimate goals of minimizing disease associated with zoonotic viruses and the total eradication of nonzoonotic agents. C1 [Leibovitch, Emily C.; Jacobson, Steven] NINDS, Viral Immunol Sect, NIH, Bethesda, MD 20892 USA. [Leibovitch, Emily C.] George Washington Univ, Sch Med, Inst Biomed Sci, Washington, DC 20037 USA. RP Jacobson, S (reprint author), NINDS, Viral Immunol Sect, NIH, Bethesda, MD 20892 USA. EM jacobsons@ninds.nih.gov NR 74 TC 1 Z9 1 U1 55 U2 55 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1933-7213 EI 1878-7479 J9 NEUROTHERAPEUTICS JI Neurotherapeutics PD JUL PY 2016 VL 13 IS 3 BP 562 EP 570 DI 10.1007/s13311-016-0453-3 PG 9 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA DS3JP UT WOS:000380679400013 PM 27365085 ER PT J AU Haubenberger, D Clifford, DB AF Haubenberger, Dietrich Clifford, David B. TI Clinical Trials in Neurovirology: Successes, Challenges, and Pitfalls SO NEUROTHERAPEUTICS LA English DT Review DE Clinical trials; randomization; methodology; statistics; ethics ID PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; HERPES-SIMPLEX ENCEPHALITIS; AIDS DEMENTIA COMPLEX; ACQUIRED-IMMUNODEFICIENCY-SYNDROME; HIV-INFECTED INDIVIDUALS; PLACEBO-CONTROLLED TRIAL; CENTRAL-NERVOUS-SYSTEM; COMBINATION ANTIRETROVIRAL THERAPY; POLYMERASE-CHAIN-REACTION; CEREBROSPINAL-FLUID AB Clinical trials in neurovirology illustrate the special challenges confronting investigators planning to study these conditions, as well as the contributions of successful trials in establishing appropriate management for these devastating diseases. This article reviews key examples of progress in neurovirology that have been spurred by clinical trials, emphasizing human herpes virus encephalitis, HIV, and JC virus. Clinical trials in the setting of neurovirological diseases are characterized by specific challenges, which may include small sample sizes, clinical presentations from life-threatening conditions to chronic courses of disease, regional and temporally restricted outbreaks scenarios, and the unavailability of validated diagnostic tests that can be rapidly deployed at the bedside. This review aims to highlight these methodological challenges and pitfalls in designing and executing clinical neurovirology trials, as well as to outline innovative trial designs, which could be useful in addressing common challenges. C1 [Haubenberger, Dietrich] NINDS, Clin Trials Unit, Off Clin Director, Intramural Res Program,NIH, 9000 Rockville Pike,Rm 6-5700, Bethesda, MD 20892 USA. [Clifford, David B.] Washington Univ, Dept Neurol, Box 8111,660 S Euclid Ave, St Louis, MO 63110 USA. [Clifford, David B.] Washington Univ, Dept Med, Box 8111,660 S Euclid Ave, St Louis, MO 63110 USA. RP Haubenberger, D (reprint author), NINDS, Clin Trials Unit, Off Clin Director, Intramural Res Program,NIH, 9000 Rockville Pike,Rm 6-5700, Bethesda, MD 20892 USA. EM dietrich.haubenberger@nih.gov NR 82 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1933-7213 EI 1878-7479 J9 NEUROTHERAPEUTICS JI Neurotherapeutics PD JUL PY 2016 VL 13 IS 3 BP 571 EP 581 DI 10.1007/s13311-016-0440-8 PG 11 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA DS3JP UT WOS:000380679400014 PM 27194073 ER PT J AU Sibley, DR Free, RB Xiao, JB Ferrer, M Southall, N Stanwood, G Mach, R Bertz, J Woods, JH Shi, L Marugan, JJ AF Sibley, David R. Free, R. Benjamin Xiao, Jingbo Ferrer, Marc Southall, Noel Stanwood, Gregg Mach, Robert Bertz, Jeremiah Woods, James H. Shi, Lei Marugan, Juan J. TI Identification and Characterization of a Novel and Highly Selective D-2 Dopamine Receptor Antagonist SO NEUROTHERAPEUTICS LA English DT Meeting Abstract C1 [Sibley, David R.; Free, R. Benjamin] NINDS, Mol Neuropharmacol Sect, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Xiao, Jingbo; Ferrer, Marc; Southall, Noel; Marugan, Juan J.] NIH, Natl Ctr Adv Translat Sci, Rockville, MD USA. [Stanwood, Gregg] Florida State Univ, Coll Med, Tallahassee, FL 32306 USA. [Mach, Robert] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Bertz, Jeremiah; Woods, James H.] Univ Michigan, Sch Med, Ann Arbor, MI USA. [Shi, Lei] NIDA, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1933-7213 EI 1878-7479 J9 NEUROTHERAPEUTICS JI Neurotherapeutics PD JUL PY 2016 VL 13 IS 3 BP 657 EP 657 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA DS3JP UT WOS:000380679400044 ER PT J AU Nalbantoglu, S Abu-Asab, M Tan, M Zhang, XM Cai, L Amri, H AF Nalbantoglu, Sinem Abu-Asab, Mones Tan, Ming Zhang, Xuemin Cai, Ling Amri, Hakima TI Study of Clinical Survival and Gene Expression in a Sample of Pancreatic Ductal Adenocarcinoma by Parsimony Phylogenetic Analysis SO OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY LA English DT Article ID GROWTH-FACTOR RECEPTOR; PHASE-III TRIAL; NATIONAL-CANCER-INSTITUTE; POOR-PROGNOSIS; K-RAS; KRAS MUTATIONS; GEMCITABINE; ERLOTINIB; PATHWAY; EVOLUTIONARY AB Pancreatic ductal adenocarcinoma (PDAC) is one of the rapidly growing forms of pancreatic cancer with a poor prognosis and less than 5% 5-year survival rate. In this study, we characterized the genetic signatures and signaling pathways related to survival from PDAC, using a parsimony phylogenetic algorithm. We applied the parsimony phylogenetic algorithm to analyze the publicly available whole-genome in silico array analysis of a gene expression data set in 25 early-stage human PDAC specimens. We explain here that the parsimony phylogenetics is an evolutionary analytical method that offers important promise to uncover clonal (driver) and nonclonal (passenger) aberrations in complex diseases. In our analysis, parsimony and statistical analyses did not identify significant correlations between survival times and gene expression values. Thus, the survival rankings did not appear to be significantly different between patients for any specific gene (p > 0.05). Also, we did not find correlation between gene expression data and tumor stage in the present data set. While the present analysis was unable to identify in this relatively small sample of patients a molecular signature associated with pancreatic cancer prognosis, we suggest that future research and analyses with the parsimony phylogenetic algorithm in larger patient samples are worthwhile, given the devastating nature of pancreatic cancer and its early diagnosis, and the need for novel data analytic approaches. The future research practices might want to place greater emphasis on phylogenetics as one of the analytical paradigms, as our findings presented here are on the cusp of this shift, especially in the current era of Big Data and innovation policies advocating for greater data sharing and reanalysis. C1 [Nalbantoglu, Sinem; Amri, Hakima] Georgetown Univ, Sch Med, Dept Biochem Cellular & Mol Biol, Washington, DC 20007 USA. [Abu-Asab, Mones] NEI, Immunol Lab, Immunopathol Sect, Bldg 10, Bethesda, MD 20892 USA. [Tan, Ming; Zhang, Xuemin; Cai, Ling] Georgetown Univ, Dept Biostat Bioinformat & Biomath, Washington, DC USA. RP Amri, H (reprint author), Georgetown Univ, Sch Med, Dept Biochem Cellular & Mol Biol, Washington, DC 20007 USA. EM amrih@georgetown.edu FU Scientific and Technological Research Council of Turkey FX S.N. was funded by a grant from the Scientific and Technological Research Council of Turkey. NR 52 TC 0 Z9 0 U1 5 U2 5 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1536-2310 EI 1557-8100 J9 OMICS JI OMICS PD JUL PY 2016 VL 20 IS 7 BP 442 EP 447 DI 10.1089/omi.2016.0059 PG 6 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA DS2NF UT WOS:000380615000006 PM 27428255 ER PT J AU O'Hayre, M Inoue, A Kufareva, I Wang, Z Mikelis, CM Drummond, RA Avino, S Finkel, K Kalim, KW DiPasquale, G Guo, F Aoki, J Zheng, Y Lionakis, MS Molinolo, AA Gutkind, JS AF O'Hayre, M. Inoue, A. Kufareva, I. Wang, Z. Mikelis, C. M. Drummond, R. A. Avino, S. Finkel, K. Kalim, K. W. DiPasquale, G. Guo, F. Aoki, J. Zheng, Y. Lionakis, M. S. Molinolo, A. A. Gutkind, J. S. TI Inactivating mutations in GNA13 and RHOA in Burkitt's lymphoma and diffuse large B-cell lymphoma: a tumor suppressor function for the G alpha(13)/RhoA axis in B cells SO ONCOGENE LA English DT Article ID PROTEIN-COUPLED RECEPTORS; HETEROTRIMERIC G-PROTEINS; UVEAL MELANOMA; CANCER-CELLS; SOMATIC MUTATIONS; ALPHA-SUBUNIT; P115 RHOGEF; G12 FAMILY; ACTIVATION; METASTASIS AB G proteins and their cognate G protein-coupled receptors (GPCRs) function as critical signal transduction molecules that regulate cell survival, proliferation, motility and differentiation. The aberrant expression and/or function of these molecules have been linked to the growth, progression and metastasis of various cancers. As such, the analysis of mutations in the genes encoding GPCRs, G proteins and their downstream targets provides important clues regarding how these signaling cascades contribute to malignancy. Recent genome-wide sequencing efforts have unveiled the presence of frequent mutations in GNA13, the gene encoding the G protein G alpha(13), in Burkitt's lymphoma and diffuse large B-cell lymphoma (DLBCL). We found that mutations in the downstream target of G alpha(13), RhoA, are also present in Burkitt's lymphoma and DLBCL. By multiple complementary approaches, we now show that that these cancer-specific GNA13 and RHOA mutations are inhibitory in nature, and that the expression of wild-type G alpha(13) in B-cell lymphoma cells with mutant GNA13 has limited impact in vitro but results in a remarkable growth inhibition in vivo. Thus, although G alpha(13) and RhoA activity has previously been linked to cellular transformation and metastatic potential of epithelial cancers, our findings support a tumor suppressive role for G alpha(13) and RhoA in Burkitt's lymphoma and DLBCL. C1 [O'Hayre, M.; Wang, Z.; Avino, S.; Finkel, K.; Molinolo, A. A.; Gutkind, J. S.] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. [Inoue, A.; Aoki, J.] Tohoku Univ, Grad Sch Pharmaceut Sci, Sendai, Miyagi, Japan. [Inoue, A.] Japan Sci & Technol Agcy JST, PRESTO, Kawaguchi, Saitama, Japan. [Kufareva, I.] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA. [Mikelis, C. M.] Texas Tech Univ, Hlth Sci Ctr, Sch Pharm, Dept Biomed Sci, Amarillo, TX USA. [Drummond, R. A.; Lionakis, M. S.] NIAID, Fungal Pathogenesis Unit, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Avino, S.] Univ Calabria, Dept Pharm Hlth & Nutr Sci, Arcavacata Di Rende, Cs, Italy. [Kalim, K. W.; Guo, F.; Zheng, Y.] Cincinnati Childrens Hosp Med Ctr, Div Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA. [DiPasquale, G.] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. [Aoki, J.] Japan Agcy Med Res & Dev, Core Res Evolut Sci & Technol AMED CREST, AMED, Chiyoda Ku, Tokyo, Japan. [Gutkind, J. S.] UC San Diego Moores Canc Ctr, Dept Pharmacol, 3855 Hlth Sci Dr,0803, La Jolla, CA 92093 USA. RP Gutkind, JS (reprint author), UC San Diego Moores Canc Ctr, Dept Pharmacol, 3855 Hlth Sci Dr,0803, La Jolla, CA 92093 USA. EM sgutkind@ucsd.edu FU National Institute of Dental and Craniofacial Research intramural program at NIH; PRESTO from JST; AMED-CREST from AMED; Division of Intramural Research, NIAID, NIH; NIH [R01 GM071872, R01 AI118985] FX This study was supported by the National Institute of Dental and Craniofacial Research intramural program at NIH. We thank Maria S Degese for her help with immunohistochemistry. AI was funded by PRESTO from JST. JA was funded by AMED-CREST from AMED. We thank Miho Morikawa for technical assistance with the TGF alpha shedding assay. RAD and MSL are supported by the Division of Intramural Research, NIAID, NIH. IK is supported by NIH grants R01 GM071872 and R01 AI118985. NR 47 TC 1 Z9 1 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD JUL PY 2016 VL 35 IS 29 BP 3771 EP 3780 DI 10.1038/onc.2015.442 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA DS4LS UT WOS:000380753200003 PM 26616858 ER PT J AU Ringeisen, H Miller, S Munoz, B Rohloff, H Hedden, SL Colpe, LJ AF Ringeisen, Heather Miller, Shari Munoz, Breda Rohloff, Harley Hedden, Sarra L. Colpe, Lisa J. TI Mental Health Service Use in Adolescence: Findings From the National Survey on Drug Use and Health SO PSYCHIATRIC SERVICES LA English DT Article ID TRANSITION-AGE YOUTH; COMORBIDITY SURVEY-ADOLESCENT; YOUNG-ADULTS; DISORDERS; PREVALENCE; CHILDREN AB Objective: This study examined mental health service use, by service type, of adolescents ages 12-17. Methods: Data were from approximately 113,000 adolescents who participated in the 2008-2012 National Survey on Drug Use and Health, an annual nationally representative survey of the civilian, noninstitutionalized U.S. population. Polynomial contrasts tested for linear and quadratic changes across age in the use of three types of past-year mental health services: school-based services, outpatient therapist or clinic, and overnight hospital stay. Results: Although mental health service use increased from age 12 to age 14 across all service types, it decreased or stabilized from age 15 to 17. School-based services were the most commonly used servi